[Federal Register Volume 80, Number 152 (Friday, August 7, 2015)][Proposed Rules]
[Pages 47565-47828]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-17596]

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DEPARTMENT OF LABOR

Occupational Safety and Health Administration


[Docket No. OSHA-H005C-2006-0870]
RIN 1218-AB76

Occupational Exposure to Beryllium and Beryllium Compounds

AGENCY: Occupational Safety and Health Administration (OSHA),
Department of Labor.

ACTION: Proposed rule; request for comments.

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SUMMARY: The Occupational Safety and Health Administration (OSHA)
proposes to amend its existing exposure limits for occupational
exposure in general industry to beryllium and beryllium compounds and
promulgate a substance-specific standard for general industry
regulating occupational exposure to beryllium and beryllium compounds.
This document proposes a new permissible exposure limit (PEL), as well
as ancillary provisions for employee protection such as methods for
controlling exposure, respiratory protection, medical surveillance,
hazard communication, and recordkeeping. In addition, OSHA seeks
comment on a number of alternatives, including a lower PEL, that could
affect construction and maritime, as well as general industry.

DATES: Written comments. Written comments, including comments on the
information collection determination described in Section IX of the
preamble (OMB Review under the Paperwork Reduction Act of 1995), must
be submitted (postmarked, sent, or received) by November 5, 2015.
    Informal public hearings. The Agency will schedule an informal
public hearing on the proposed rule if requested during the comment
period. The location and date of the hearing, procedures for interested
parties to notify the Agency of their intention to participate, and
procedures for participants to submit their testimony and documentary
evidence will be announced in the Federal Register if a hearing is
requested.

ADDRESSES: Written comments. You may submit comments, identified by
Docket No. OSHA-H005C-2006-0870, by any of the following methods:
    Electronically: You may submit comments and attachments
electronically at http://www.regulations.gov, which is the Federal e-
Rulemaking Portal. Follow the instructions on-line for making
electronic submissions. When uploading multiple attachments into
Regulations.gov, please number all of your attachments because
http://www.regulations.gov will not automatically number the attachments. This
will be very useful in identifying all attachments in the beryllium
rule. For example, Attachment 1_title of your document, Attachment 2_
title of your document, Attachment 3_title of your document, etc.
Specific instructions on uploading all documents are found in the
Facts, Answer, Questions portion and the commenter check list on
Regulations.gov Web page.
    Fax: If your submissions, including attachments, are not longer
than 10 pages, you may fax them to the OSHA Docket Office at (202) 693-
1648.
    Mail, hand delivery, express mail, messenger, or courier service:
You may submit your comments to the OSHA Docket Office, Docket No.
OSHA-H005C-2006-0870, U.S. Department of Labor, Room N-2625, 200
Constitution Avenue NW., Washington, DC 20210, telephone (202) 693-2350
(OSHA's TTY number is (877) 889-5627). Deliveries (hand, express mail,
messenger, or courier service) are accepted during the Docket Office's
normal business hours, 8:15 a.m.-4:45 p.m., E.S.T.
    Instructions: All submissions must include the Agency name and the
docket number for this rulemaking (Docket No. OSHA-H005C-2006-0870).
All comments, including any personal information you provide, are
placed in the public docket without change and may be made available
online at http://www.regulations.gov. Therefore, OSHA cautions you
about submitting personal information such as Social Security numbers
and birthdates.
    If you submit scientific or technical studies or other results of
scientific research, OSHA requests (but is not requiring) that you also
provide the following information where it is available: (1)
Identification of the funding source(s) and sponsoring organization(s)
of the research; (2) the extent to which the research findings were
reviewed by a potentially affected party prior to publication or
submission to the docket, and identification of any such parties; and
(3) the nature of any financial relationships (e.g., consulting
agreements, expert witness support, or research funding) between
investigators who conducted the research and any organization(s) or
entities having an interest in the rulemaking. If you are submitting
comments or testimony on the Agency's scientific or technical analyses,
OSHA requests that you disclose: (1) The nature of any financial
relationships you may have with any organization(s) or entities having
an interest in the rulemaking; and (2) the extent to which your
comments or testimony were reviewed by an interested party before you
submitted them. Disclosure of such information is intended to promote
transparency and scientific integrity of data and technical information
submitted to the record. This request is consistent with Executive
Order 13563, issued on January 18, 2011, which instructs agencies to
ensure the objectivity of any scientific and technological information
used to support their regulatory actions. OSHA emphasizes that all
material submitted to the rulemaking record will be considered by the
Agency to develop the final rule and supporting analyses.
    Docket: To read or download comments and materials submitted in
response to this Federal Register notice, go to Docket No. OSHA-H005C-
2006-0870 at http://www.regulations.gov, or to the OSHA Docket Office
at the address above. All comments and submissions are listed in the
http://www.regulations.gov index; however, some information (e.g.,
copyrighted material) is not publicly available to read or download
through that Web site. All comments and submissions are available for
inspection at the OSHA Docket Office.
    Electronic copies of this Federal Register document are available
at http://www.regulations.gov. Copies also are available from the OSHA
Office of Publications, Room N-3101, U.S. Department of Labor, 200
Constitution Avenue NW., Washington, DC 20210; telephone (202) 693-
1888. This document, as well as news releases and other relevant
information, is also available at OSHA's Web site at http://www.osha.gov.
    OSHA has not provided the document ID numbers for all submissions
in the record for this beryllium proposal. The proposal only contains a
reference list for all submissions relied upon. The public can find all
document ID numbers in an Excel spreadsheet that is posted on OSHA's
rulemaking Web page (see www.osha.gov/berylliumrulemaking). The public
will be able to locate submissions in the record in the public docked
Web page: http://www.regulations.gov. To locate a particular submission
contained in http://www.regulations.gov, the public should enter the
full document ID number in the search bar.

FOR FURTHER INFORMATION CONTACT: For general information and press
inquiries, contact Frank Meilinger, Director, Office of Communications,
Room N-3647, OSHA, U.S. Department of Labor, 200 Constitution Avenue NW.,
Washington, DC 20210; telephone: (202) 693-1999; email:
meilinger.francis2@dol.gov. For technical inquiries, contact: William
Perry or Maureen Ruskin, Directorate of Standards and Guidance, Room N-
3718, OSHA, U.S. Department of Labor, 200 Constitution Avenue NW.,
Washington, DC 20210; telephone (202) 693-1955 or fax (202) 693-1678;
email: perry.bill@dol.gov.

SUPPLEMENTARY INFORMATION:
    The preamble to the proposed standard on occupational exposure to
beryllium and beryllium compounds follows this outline:

Executive Summary

I. Issues and Alternatives
II. Pertinent Legal Authority
III. Events Leading to the Proposed Standards
IV. Chemical Properties and Industrial Uses
V. Health Effects
VI. Preliminary Risk Assessment
VII. Response to Peer Review
VIII. Significance of Risk
IX. Summary of the Preliminary Economic Analysis and Initial
Regulatory Flexibility Analysis
X. OMB Review under the Paperwork Reduction Act of 1995
XI. Federalism
XII. State-Plan States
XIII. Unfunded Mandates Reform Act
XIV. Protecting Children from Environmental Health and Safety Risks
XV. Environmental Impacts
XVI. Consultation and Coordination with Indian Tribal Governments
XVII. Public Participation
XVIII. Summary and Explanation of the Proposed Standard
    (a) Scope and Application
    (b) Definitions
    (c) Permissible Exposure Limits (PELs)
    (d) Exposure Assessment
    (e) Beryllium Work Areas and Regulated Areas
    (f) Methods of Compliance
    (g) Respiratory Protection
    (h) Personal Protective Clothing and Equipment
    (i) Hygiene Areas and Practices
    (j) Housekeeping
    (k) Medical Surveillance
    (l) Medical Removal
    (m) Communication of Hazards to Employees
    (n) Recordkeeping
    (o) Dates
XIX. References

Executive Summary

    OSHA currently enforces permissible exposure limits (PELs) for
beryllium in general industry, construction, and shipyards. These PELs
were adopted in 1971, shortly after the Agency was created, and have
not been updated since then. The time-weighted average (TWA) PEL for
beryllium is 2 micrograms per cubic meter of air ([mu]g/m\3\) as an 8-
hour time-weighted average. OSHA is proposing a new TWA PEL of 0.2
[mu]g/m\3\ in general industry. OSHA is also proposing other elements
of a comprehensive health standard, including requirements for exposure
assessment, preferred methods for controlling exposure, respiratory
protection, personal protective clothing and equipment (PPE), medical
surveillance, medical removal, hazard communication, and recordkeeping.
    OSHA's proposal is based on the requirements of the Occupational
Safety and Health Act (OSH Act) and court interpretations of the Act.
For health standards issued under section 6(b)(5) of the OSH Act, OSHA
is required to promulgate a standard that reduces significant risk to
the extent that it is technologically and economically feasible to do
so. See Section II of this preamble, Pertinent Legal Authority, for a
full discussion of OSHA legal requirements.
    OSHA has conducted an extensive review of the literature on adverse
health effects associated with exposure to beryllium. The Agency has
also assessed the risk of beryllium-related diseases at the current TWA
PEL, the proposed TWA PEL and the alternative TWA PELs. These analyses
are presented in this preamble at Section V, Health Effects, Section
VI, Preliminary Risk Assessment, and Section VIII, Significance of
Risk. As discussed in Section VIII of this preamble, Significance of
Risk, the available evidence indicates that worker exposure to
beryllium at the current PEL poses a significant risk of chronic
beryllium disease (CBD) and lung cancer, and that the proposed standard
will substantially reduce this risk.
    Section 6(b) of the OSH Act requires OSHA to determine that its
standards are technologically and economically feasible. OSHA's
examination of the technological and economic feasibility of the
proposed rule is presented in the Preliminary Economic Analysis and
Initial Regulatory Flexibility Analysis (PEA) (OSHA, 2014), and is
summarized in Section IX of this preamble, Summary of the Preliminary
Economic Analysis and Initial Regulatory Flexibility Analysis. OSHA has
preliminarily concluded that the proposed PEL of 0.2 [mu]g/m\3\ is
technologically feasible for all affected industries and application
groups. Thus, OSHA preliminarily concludes that engineering and work
practices will be sufficient to reduce and maintain beryllium exposures
to the proposed PEL of 0.2 [mu]g/m\3\ or below in most operations most
of the time in the affected industries. For those few operations within
an industry or application group where compliance with the proposed PEL
cannot be achieved even when employers implement all feasible
engineering and work practice controls, the proposed standard would
require employers to supplement controls with respirators.
    OSHA developed quantitative estimates of the compliance costs of
the proposed rule for each of the affected industry sectors. The
estimated compliance costs were compared with industry revenues and
profits to provide a screening analysis of the economic feasibility of
complying with the revised standard and an evaluation of the potential
economic impacts. Industries with unusually high costs as a percentage
of revenues or profits were further analyzed for possible economic
feasibility issues. After performing these analyses, OSHA has
preliminarily concluded that compliance with the requirements of the
proposed rule would be economically feasible in every affected industry
sector.
    The Regulatory Flexibility Act, as amended by the Small Business
Regulatory Enforcement Fairness Act (SBREFA), requires that OSHA either
certify that a rule would not have a significant economic impact on a
substantial number of small entities or prepare a regulatory
flexibility analysis and hold a Small Business Advocacy Review (SBAR)
Panel prior to proposing the rule. OSHA has determined that a
regulatory flexibility analysis is needed and has provided this
analysis in Chapter IX of the PEA (OSHA, 2014). A summary is provided
in Section IX of this preamble, Summary of the Preliminary Economic
Analysis and Initial Regulatory Flexibility Analysis. OSHA also
previously held a SBAR Panel for this rule. The recommendations of the
Panel and OSHA's response to them are summarized in Section IX of this
preamble.
    Executive Orders 13563 and 12866 direct agencies to assess all
costs and benefits of available regulatory alternatives. Executive
Order 13563 emphasizes the importance of quantifying both costs and
benefits, of reducing costs, of harmonizing rules, and of promoting
flexibility. This rule has been designated an economically significant
regulatory action under section 3(f)(1) of Executive Order 12866.
Accordingly, this proposed rule has been reviewed by the Office of
Management and Budget. The remainder of this section summarizes the key
findings of the analysis with respect to costs and benefits of the
proposed standard, presents alternatives to the proposed standard,
and requests comments on a number of issues.
    Table I-1, which is derived from material presented in the PEA,
provides a summary of OSHA's best estimate of the costs and benefits of
this proposed rule. As shown, this proposed rule is estimated to
prevent 96 fatalities and 50 non-fatal beryllium-related illnesses
annually once it is fully effective, and the monetized annualized
benefits of the proposed rule are estimated to be $576 million using a
3-percent discount rate and $255 million using a 7-percent discount
rate. Also as shown in Table I-1, the estimated annualized cost of the
rule is $37.6 million using a 3-percent discount rate and $39.1 million
using a 7-percent discount rate. This proposed rule is estimated to
generate net benefits of $538 million annually using a 3-percent
discount rate and $216 million annually using a 7-percent discount
rate. These estimates are for informational purposes only and have not
been used by OSHA as the basis for its decision concerning the choice
of a PEL or of other ancillary requirements for this proposed beryllium
rule. The courts have ruled that OSHA may not use benefit-cost analysis
or a criterion of maximizing net benefits as a basis for setting OSHA
health standards.\1\
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    \1\ Am. Textile Mfrs. Inst., Inc. v. Nat'l Cotton Council of
Am., 452 U.S. 490, 513 (1981); Pub. Citizen Health Research Group v.
U.S. Dep't of Labor, 557 F.3d 165, 177 (3d Cir. 2009).

 Table I-1--Annualized Costs, Benefits and Net Benefits of OSHA's Proposed Beryllium Standard of 0.2 [mu]g/m\3\
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                  Discount rate                                            3%                       7%
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Annualized Costs
    Engineering Controls.........................                            $9,540,189              $10,334,036
    Respirators..................................                               249,684                  252,281
    Exposure Assessment..........................                             2,208,950                2,411,851
    Regulated Areas and Beryllium Work Areas.....                               629,031                  652,823
    Medical Surveillance.........................                             2,882,076                2,959,448
    Medical Removal..............................                               148,826                  166,054
    Exposure Control Plan........................                             1,769,506                1,828,766
    Protective Clothing and Equipment............                             1,407,365                1,407,365
    Hygiene Areas and Practices..................                               389,241                  389,891
    Housekeeping.................................                            12,574,921               12,917,944
    Training.....................................                             5,797,535                5,826,975
Total Annualized Costs (Point Estimate)..........                            37,597,325               39,147,434
Annual Benefits: Number of Cases Prevented
    Fatal Lung Cancer............................          4.0
    CBD-Related Mortality........................         92.0
    Total Beryllium Related Mortality............         96.0              572,981,864              253,743,368
Morbidity........................................         49.5                2,844,770                1,590,927
Monetized Annual Benefits (midpoint estimate)....                           575,826,633              255,334,295
        Net Benefits.............................                           538,229,308              216,186,861
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Source: OSHA, Directorate of Standards and Guidance, Office of Regulatory Analysis.

    Both the costs and benefits of Table I-1 reflect the incremental
costs and benefits associated with achieving full compliance with the
proposed standard. They do not include costs and benefits associated
with employers' current exposure control measures or other aspects of
the proposed standard they have already implemented. For example, for
employers whose exposures are already below the proposed PEL, OSHA's
estimated costs and benefits for the proposed standard do not include
the costs of their exposure control measures or the benefits of these
employers' compliance with the proposed PEL. The costs and benefits of
Table I-1 also do not include costs and benefits associated with
achieving compliance with existing requirements, to the extent that
some employers may currently not be fully complying with applicable
regulatory requirements.

I. Issues and Alternatives

    In addition to the proposed standard itself, this preamble
discusses more than two dozen regulatory alternatives, including
various sub-alternatives, to the proposed standard and requests
comments and information on a variety of topics pertinent to the
proposed standard. The regulatory alternatives OSHA is considering
include alternatives to the proposed scope of the standard, regulatory
alternatives to the proposed TWA PEL of 0.2 [mu]g/m\3\ and proposed
STEL of 2 [mu]g/m\3\, a regulatory alternative that would modify the
proposed methods of compliance, and regulatory alternatives that affect
proposed ancillary provisions. The Agency solicits comment on the
proposed phase-in schedule for the various provisions of the standard.
Additional requests for comments and information follow the summaries
of regulatory alternatives, under the "Issues" heading.

Regulatory Alternatives

    OSHA believes that inclusion of regulatory alternatives serves two
important functions. The first is to explore the possibility of less
costly ways (than the proposed standard) to provide an adequate level
of worker protection from exposure to beryllium. The second is tied to
the Agency's statutory requirement, which underlies the proposed
standard, to reduce significant risk to the extent feasible. Each
regulatory alternative presented here is described and analyzed more
fully elsewhere in this preamble or in the PEA. Where appropriate, the
alternative is included in this preamble at the end of the relevant
section of Section XVIII, Summary and Explanation of the Proposed
Standard, to facilitate comparison of the alternative to the proposed
standard. For example, alternative PELs under consideration by the
Agency are presented in the discussion of paragraph (c) in Section
XVIII. In addition, all alternatives are discussed in the PEA,
Chapter VIII: Regulatory Alternatives (OSHA, 2014). The costs and
benefits of each regulatory alternative are presented both in
Section IX of this preamble and in Chapter VIII of the PEA.
    The more than two dozen regulatory alternatives, including various
sub-alternatives regulatory alternatives under consideration are
summarized below, and are organized into the following categories:
alternatives to the proposed scope of the standard; alternatives to the
proposed PELs; alternatives to the proposed methods of compliance;
alternatives to the proposed ancillary provisions; and the timing of
the standard.
Scope
    OSHA has examined three alternatives that would alter the groups of
employers and employees covered by this rulemaking. Regulatory
Alternative #1a would expand the scope of the proposed standard to
include all operations in general industry where beryllium exists only
as a trace contaminant; that is, where the materials used contain no
more than 0.1% beryllium by weight. Regulatory Alternative #1b is
similar to Regulatory Alternative #1a, but exempts operations where the
employer can show that employees' exposures will not meet or exceed the
action level or exceed the STEL. Where the employer has objective data
demonstrating that a material containing beryllium or a specific
process, operation, or activity involving beryllium cannot release
beryllium in concentrations at or above the proposed action level or
above the proposed STEL under any expected conditions of use, that
employer would be exempt from the proposed standard except for
recordkeeping requirements pertaining to the objective data.
Alternative #1a and Alternative #1b, like the proposed rule, would not
cover employers or employees in construction or shipyards.
    Regulatory Alternative #2a would expand the scope of the proposed
standard to also include employers in construction and maritime. For
example, this alternative would cover abrasive blasters, pot tenders,
and cleanup staff working in construction and shipyards who have the
potential for airborne beryllium exposure during blasting operations
and during cleanup of spent media. Regulatory Alternative #2b would
update Sec. Sec.  1910.1000 Tables Z-1 and Z-2, 1915.1000 Table Z, and
1926.55 Appendix A so that the proposed TWA PEL and STEL would apply to
all employers and employees in general industry, shipyards, and
construction, including occupations where beryllium exists only as a
trace contaminant. However, all other provisions of the standard would
be in effect only for employers and employees that fall within the
scope of the proposed rule. More detailed discussion of Regulatory
Alternatives #1a, #1b, #2a, and #2b appears in Section IX of this
preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition,
Section XVIII of this preamble, Summary and Explanation, includes a
discussion of paragraph (a) that describes the scope of the proposed
rule, issues with the proposed scope, and Regulatory Alternatives #1a,
#1b, #2a, and #2b.
    Another regulatory alternative that would impact the scope of
affected industries, extending eligibility for medical surveillance to
employees in shipyards, construction, and parts of general industry
excluded from the scope of the proposed standard, is discussed along
with other medical surveillance alternatives later in this section
(Regulatory Alternative #21) and in the discussion of paragraph (k) in
this preamble at Section XVIII, Summary and Explanation of the Proposed
Standard.
Permissible Exposure Limits
    OSHA has examined several regulatory alternatives that would modify
the TWA PEL or STEL for the proposed rule. Under Regulatory Alternative
#3, OSHA would adopt a STEL of 5 times the proposed PEL. Thus, this
alternative STEL would be 1.0 [mu]g/m\3\ if OSHA adopts a PEL of 0.2
[mu]g/m\3\; it would be 0.5 [mu]g/m\3\ if OSHA adopts a PEL of 0.1
[mu]g/m\3\; and it would be 2.5 [micro]g/m\3\ if OSHA adopts a PEL of
0.5 [micro]g/m\3\ (see Regulatory Alternatives #4 and #5). Under
Regulatory Alternative #4, the proposed PEL would be lowered from 0.2
[mu]g/m\3\ to 0.1 [mu]g/m\3\. Under Regulatory Alternative #5, the
proposed PEL would be raised from 0.2 [mu]g/m\3\ to 0.5 [mu]g/m\3\. In
addition, for informational purposes, OSHA examined a regulatory
alternative that would maintain the TWA PEL at 2.0 [mu]g/m\3\, but all
of the other proposed provisions would be required with their triggers
remaining the same as in the proposed rule. This alternative is not one
OSHA could legally adopt because the absence of a more protective
requirement for engineering controls would not be consistent with
section 6(b)(5) of the OSH Act. More detailed discussion of these
alternatives to the proposed PEL appears in Section IX of this preamble
and in Chapter VIII of the PEA (OSHA, 2014). In addition, in Section
XVIII of this preamble, Summary and Explanation of the Proposed
Standard, the discussion of proposed paragraph (c) describes the
proposed TWA PEL and STEL, issues with the proposed exposure limits,
and Regulatory Alternatives #3, #4, and #5.
Methods of Compliance
    The proposed standard would require employers to implement
engineering and work practice controls to reduce employees' exposures
to or below the TWA PEL and STEL. Where engineering and work practice
controls are insufficient to reduce exposures to or below the TWA PEL
and STEL, employers would still be required to implement them to reduce
exposure as much as possible, and to supplement them with a respiratory
protection program. In addition, for each operation where there is
airborne beryllium exposure, the employer must ensure that one or more
of the engineering and work practice controls listed in paragraph
(f)(2) are in place, unless all of the listed controls are infeasible,
or the employer can demonstrate that exposures are below the action
level based on two samples taken seven days apart. Regulatory
Alternative #6 would eliminate the engineering and work practice
controls provision currently specified in paragraph (f)(2). This
regulatory alternative does not eliminate the need for engineering
controls to lower exposure levels to or below the TWA PEL and STEL;
rather, it dispenses with the mandatory use of certain engineering
controls that must be installed above the action level but at or below
the TWA PEL.
    More detailed discussion of Regulatory Alternative #6 appears in
Section IX of this preamble and in Chapter VIII of the PEA (OSHA,
2014). In addition, the discussion of paragraph (f) in Section XVIII of
this preamble, Summary and Explanation, provides a more detailed
explanation of the proposed methods of compliance, issues with the
proposed methods of com pli ance, and Regulatory Alternative #6.
Ancillary Provisions
    The proposed rule contains several ancillary provisions, including
requirements for exposure assessment, personal protective clothing and
equipment (PPE), medical surveillance, medical removal, training, and
regulated areas or access control. OSHA has examined a variety of
regulatory alternatives involving changes to one or more of these
ancillary provisions. OSHA has preliminarily determined that several of
these ancillary provisions will increase the benefits of the proposed
rule, for example, by helping to ensure the TWA PEL is not exceeded
or by lowering the risks to workers given the significant risk
remaining at the proposed TWA PEL. However, except for Regulatory
Alternative #7 (involving the elimination of all ancillary provisions),
OSHA did not estimate changes in monetized benefits for the regulatory
alternatives that affect ancillary provisions. Two regulatory
alternatives that involve all ancillary provisions are presented below
(#7 and #8), followed by regulatory alternatives for exposure
monitoring (#9, #10, and #11), for regulated areas (#12), for personal
protective clothing and equipment (#13), for medical surveillance (#14
through #21), and for medical removal (#22).
All Ancillary Provisions
    During the Small Business Regulatory Fairness Act (SBREFA) process
conducted in 2007, the SBAR Panel recommended that OSHA analyze a PEL-
only standard as a regulatory alternative. The Panel also recommended
that OSHA consider applying ancillary provisions of the standard so as
to minimize costs for small businesses where exposure levels are low
(OSHA, 2008b). In response to these recommendations, OSHA analyzed
Regulatory Alternative #7, a PEL-only standard, and Regulatory
Alternative #8, which would only apply ancillary provisions of the
beryllium standard at exposures above the proposed PEL of 0.2 [micro]g/
m\3\ or the proposed STEL of 2 [micro]g/m\3\. Regulatory Alternative #7
would update the Z tables for Sec.  1910.1000, so that the proposed TWA
PEL and STEL would apply to all workers in general industry. All other
provisions of the proposed standard would be dropped.
    As indicated previously, OSHA has preliminarily determined that
there is significant risk remaining at the proposed PEL of 0.2 [mu]g/
m\3\. However, the available evidence on feasibility suggests that 0.2
[mu]g/m\3\ may be the lowest feasible PEL (see Chapter IV of the PEA,
OSHA 2014). Therefore, the Agency believes that it is necessary to
include ancillary provisions in the proposed rule to further reduce the
remaining risk. In addition, the recommended standard provided to OSHA
by representatives of the primary beryllium manufacturing industry and
the Steelworkers Union further supports the importance of ancillary
provisions in protecting workers from the harmful effects of beryllium
exposure (Materion and USW, 2012).
    Under Regulatory Alternative #8, several ancillary provisions that
the current proposal would require under a variety of exposure
conditions (e.g., dermal contact; any airborne exposure; exposure at or
above the action level) would instead only apply where exposure levels
exceed the TWA PEL or STEL. Regulatory Alternative #8 affects the
following provisions of the proposed standard:

--Exposure monitoring. Whereas the proposed standard requires annual
monitoring where exposure levels are at or above the action level and
at or below the TWA PEL, Alternative #8 would require annual exposure
monitoring only where exposure levels exceed the TWA PEL or STEL;
-- Written exposure control plan. Whereas the proposed standard
requires written exposure control plans to be maintained in any
facility covered by the standard, Alternative #8 would require only
facilities with exposures above the TWA PEL or STEL to maintain a plan;
--PPE. Whereas the proposed standard requires PPE for employees under a
variety of conditions, such as exposure to soluble beryllium or visible
contamination with beryllium, Alternative #8 would require PPE only for
employees exposed above the TWA PEL or STEL;
--Housekeeping. Whereas the proposed standard's housekeeping
requirements apply across a wide variety of beryllium exposure
conditions, Alternative #8 would limit housekeeping requirements to
areas with exposures above the TWA PEL or STEL.
--Medical Surveillance. Whereas the proposed standard's medical
surveillance provisions require employers to offer medical surveillance
to employees with signs or symptoms of beryllium-related health effects
regardless of their exposure level, Alternative #8 would make
surveillance available to such employees only if they were exposed
above the TWA PEL or STEL.

More detailed discussions of Regulatory Alternatives #7 and #8,
including a description of the considerations pertinent to these
alternatives, appear in Section IX of this preamble and in Chapter VIII
of the PEA (OSHA, 2014).
Exposure Monitoring
    OSHA has examined three regulatory alternatives that would modify
the proposed standard's provisions on exposure monitoring, which
require periodic monitoring annually where exposures are at or above
the action level and at or below the TWA PEL. Under Regulatory
Alternative #9, employers would be required to perform periodic
exposure monitoring every 180 days where exposures are at or above the
action level or above the STEL, and at or below the TWA PEL. Under
Regulatory Alternative #10, employers would be required to perform
periodic exposure monitoring every 180 days where exposures are at or
above the action level or above the STEL, including where exposures
exceed the TWA PEL. Under Regulatory Alternative #11, employers would
be required to perform periodic exposure monitoring every 180 days
where exposures are at or above the action level or above the STEL, and
every 90 days where exposures exceed the TWA PEL. More detailed
discussions of Regulatory Alternatives #9, #10, and #11 appear in
Section IX of this preamble and in Chapter VIII of the PEA (OSHA,
2014). In addition, the discussion of proposed paragraph (d) in Section
XVIII of this preamble, Summary and Explanation of the Proposed
Standard, provides a more detailed explanation of the proposed
requirements for exposure monitoring, issues with exposure monitoring,
and the considerations pertinent to Regulatory Alternatives #9, #10,
and #11.
Regulated Areas
    The proposed standard would require employers to establish and
maintain two types of areas: beryllium work areas, wherever employees
are, or can reasonably be expected to be, exposed to any level of
airborne beryllium; and regulated areas, wherever employees are, or can
reasonably be expected to be, exposed to airborne beryllium at levels
above the TWA PEL or STEL. Employers are required to demarcate
beryllium work areas, but are not required to restrict access to
beryllium work areas or provide respiratory protection or other forms
of PPE within work areas that are not also regulated areas. Employers
must demarcate regulated areas, restrict access to them, post warning
signs and provide respiratory protection and other PPE within regulated
areas, as well as medical surveillance for employees who work in
regulated areas for more than 30 days in a 12-month period. During the
SBREFA process conducted in 2007, the SBAR Panel recommended that OSHA
consider dropping or limiting the provision for regulated areas (OSHA,
2008b). In response to this recommendation, OSHA analyzed Regulatory
Alternative #12, which would not require employers to establish
regulated areas. More detailed discussion of Regulatory Alternative #12
appears in Section IX of this preamble and in Chapter VIII of the PEA
(OSHA, 2014). In addition, the discussion of paragraph (e) in Section XVIII
of this preamble, Summary and Explanation, provides a more detailed
explanation of the proposed requirements for regulated areas, issues
with regulated areas, and considerations pertinent to Regulatory
Alternative #12. Personal Protective Clothing and Equipment (PPE)
    Regulatory Alternative #13 would modify the proposed requirements
for PPE, which require PPE where exposure exceeds the TWA PEL or STEL;
where employees' clothing or skin may become visibly contaminated with
beryllium; and where employees may have skin contact with soluble
beryllium compounds. The requirement to use PPE where work clothing or
skin may become "visibly contaminated" with beryllium differs from
prior standards that do not require contamination to be visible in
order for PPE to be required. In the case of beryllium, which OSHA has
preliminarily concluded can sensitize through dermal exposure, the
exposure levels capable of causing adverse health effects and the PELs
in effect are so low that beryllium surface contamination is unlikely
to be visible (see this preamble at section V, Health Effects). OSHA is
therefore considering Regulatory Alternative #13, which would require
appropriate PPE wherever there is potential for skin contact with
beryllium or beryllium-contaminated surfaces. More detailed discussion
of Regulatory Alternative #13 is provided in Section IX of this
preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, the
discussion of paragraph (h) in Section XVIII of this preamble, Summary
and Explanation, provides a more detailed explanation of the proposed
requirements for PPE, issues with PPE, and the considerations pertinent
to Regulatory Alternative #13.
Medical Surveillance
    The proposed requirements for medical surveillance include: (1)
Medical examinations, including a test for beryllium sensitization, for
employees who are exposed to beryllium above the proposed PEL for 30
days or more per year, who are exposed to beryllium in an emergency, or
who show signs or symptoms of CBD; and (2) low-dose helical tomography
(low-dose computed tomography, hereafter referred to as "CT scans"),
for employees who were exposed above the proposed PEL for more than 30
days in a 12-month period for 5 years or more. This type of CT scan is
a method of detecting tumors, and is commonly used to diagnose lung
cancer. The proposed standard would require periodic medical exams to
be provided for employees in the medical surveillance program annually,
while tests for beryllium sensitization and CT scans would be provided
to eligible employees biennially.
    OSHA has examined eight regulatory alternatives (#14 through #21)
that would modify the proposed rule's requirements for employee
eligibility, the types of exam that must be offered, and the frequency
of periodic exams. Medical surveillance was a subject of special
concern to SERs during the SBREFA process, and the SBREFA Panel offered
many comments and recommendations related to medical surveillance for
OSHA's consideration. Some of the Panel's concerns have been addressed
in this proposal, which was modified since the SBREFA Panel was
convened (see this preamble at Section XVIII, Summary and Explanation
of the Proposed Standard, for more detailed discussion). Several of the
alternatives presented here (#16, #18, and #20) also respond to
recommendations by the SBREFA Panel to reduce burdens on small
businesses by dropping or reducing the frequency of medical
surveillance requirements. OSHA also seeks to ensure that the
requirements of the final standard offer workers adequate medical
surveillance while limiting the costs to employers. Thus, OSHA requests
feedback on several additional alternatives and on a variety of issues
raised later in this section of the preamble.
    Regulatory Alternatives #14, #15, and #21 would expand eligibility
for medical surveillance to a broader group of employees than would be
eligible in the proposed standard. Under Regulatory Alternative #14,
medical surveillance would be available to employees who are exposed to
beryllium above the proposed PEL, including employees exposed for fewer
than 30 days per year. Regulatory Alternative #15 would expand
eligibility for medical surveillance to employees who are exposed to
beryllium above the proposed action level, including employees exposed
for fewer than 30 days per year. Regulatory Alternative #21 would
extend eligibility for medical surveillance as set forth in proposed
paragraph (k) to all employees in shipyards, construction, and general
industry who meet the criteria of proposed paragraph (k)(1) (or any of
the alternative criteria under consideration). However, all other
provisions of the standard would be in effect only for employers and
employees that fall within the scope of the proposed rule.
    Regulatory Alternatives #16 and #17 would modify the proposed
standard's requirements to offer beryllium sensitization testing to
eligible employees. Under Regulatory Alternative #16, employers would
not be required to offer employees testing for beryllium sensitization.
Regulatory Alternative #17 would increase the frequency of periodic
sensitization testing, from the proposed standard's biennial
requirement to annual testing. Regulatory Alternatives #18 and #19
would similarly modify the proposed standard's requirements to offer CT
scans to eligible employees. Regulatory Alternative #18 would drop the
CT scan requirement from the proposed rule, whereas Regulatory
Alternative #19 would increase the frequency of periodic CT scans from
biennial to annual scans. Finally, under Regulatory Alternative #20,
all periodic components of the medical surveillance exams would be
available biennially to eligible employees. Instead of requiring
employers to offer eligible employees a medical examination every year,
employers would be required to offer eligible employees a medical
examination every other year. The frequency of testing for beryllium
sensitization and CT scans would also be biennial for eligible
employees, as in the proposed standard.
    More detailed discussions of Regulatory Alternatives #14, #15, #16,
#17, #18, #19, #20, and #21 appear in Section IX of this preamble and
in Chapter VIII of the PEA (OSHA, 2014). In addition, Section XVIII of
this preamble, Summary and Explanation, paragraph (k) provides a more
detailed explanation of the proposed requirements for medical
surveillance, issues with medical surveillance, and the considerations
pertinent to Regulatory Alternatives #14 through #21.
Medical Removal Protection (MRP)
    The proposed requirements for medical removal protection provide an
option for medical removal to an employee who is working in a job with
exposure at or above the action level and is diagnosed with CBD or
confirmed positive for beryllium sensitization. If the employee chooses
removal, the employer must either remove the employee to comparable
work in a work environment where exposure is below the action level, or
if comparable work is not available, must place the employee on paid
leave for 6 months or until such time as comparable work becomes
available. In either case, the employer must maintain for 6 months the
employee's base earnings, seniority, and other rights and benefits that
existed at the time of removal. During the SBREFA process, the Panel
recommended that OSHA give careful consideration to the impacts that an MRP
requirement could have on small businesses (OSHA, 2008b). In response to
this recommendation, OSHA analyzed Regulatory Alternative #22, which would
not require employers to offer MRP. More detailed discussion of Regulatory
Alternative #22 appears in Section IX of this preamble and in Chapter
VIII of the PEA (OSHA, 2014). In addition, the discussion of paragraph
(l) in section XVIII of this preamble, Summary and Explanation,
provides a more detailed explanation of the proposed requirements for
MRP, issues with MRP, and considerations pertinent to Regulatory
Alternative #22.
Timing of the Standard
    The proposed standard would become effective 60 days following
publication of the final standard in the Federal Register. The
effective date is the date on which the standard imposes compliance
obligations on employers. However, the standard would not become
enforceable by OSHA until 90 days following the effective date for
exposure monitoring, work areas and regulated areas, written exposure
control plan, respiratory protection, other personal protective
clothing and equipment, hygiene areas and practices (except change
rooms), housekeeping, medical surveillance, and medical removal. The
proposed requirement for change rooms would not be enforceable until
one year after the effective date, and the requirements for engineering
controls would not be enforceable until two years after the effective
date. In summary, employers will have some period of time after the
standard becomes effective to come into compliance before OSHA will
begin enforcing it: 90 days for most provisions, one year for change
rooms, and two years for engineering controls. Beginning 90 days
following the effective date, during periods necessary to install or
implement feasible engineering controls where exposure exceed the TWA
PEL or STEL, employers must provide employees with respiratory
protection as described in the proposed standard under section (g),
Respiratory Protection.
    OSHA invites comment and suggestions for phasing in requirements
for engineering controls, medical surveillance, and other provisions of
the standard. A longer phase-in time would have several advantages,
such as reducing initial costs of the standard or allowing employers to
coordinate their environmental and occupational safety and health
control strategies to minimize potential costs. However, a longer
phase-in would also postpone and reduce the benefits of the standard.
Suggestions for alternatives may apply to specific industries (e.g.,
industries where first-year or annualized cost impacts are highest),
specific size-classes of employers (e.g., employers with fewer than 20
employees), combinations of these factors, or all firms covered by the
rule.
    OSHA requests comments on these regulatory alternatives, including
the Agency's choice of regulatory alternatives (and whether there are
other regulatory alternatives the Agency should consider) and the
Agency's analysis of them. In addition, OSHA requests comments and
information on a number of specific topics and issues pertinent to the
proposed standard. These are summarized below.

Regulatory Issues

    In this section, we solicit public feedback on issues associated
with the proposed standard and request information that would help the
Agency craft the final standard. In addition to the issues specified
here, OSHA also raises issues for comment on technical questions and
discussions of economic issues in the PEA (OSHA, 2014). OSHA requests
comment on all relevant issues, including health effects, risk
assessment, significance of risk, technological and economic
feasibility, and the provisions of the proposed regulatory text. In
addition, OSHA requests comments on all of the issues raised by the
Small Business Advocacy Review (SBAR) Panel, as summarized in the SBAR
report (OSHA, 2008b)
    We present these issues and requests for information in the first
chapter of the preamble to assist readers as they review the preamble
and consider any comments they may want to submit. The issues are
presented here in summary form. However, to fully understand the
questions in this section and provide substantive input in response to
them, the sections of the preamble relevant to these issues should be
reviewed. These include: Section V, Health Effects; Section VI, the
Preliminary Risk Assessment; Section VIII, Significance of Risk;
Section IX, Summary of the Preliminary Economic Analysis and Initial
Regulatory Flexibility Analysis; and Section XVIII, Summary and
Explanation of the Proposed Standard.
    OSHA requests that comments be organized, to the extent possible,
around the following issues and numbered questions. Comment on
particular provisions should contain a heading setting forth the
section and the paragraph in the proposed standard that the comment
addresses. Comments addressing more than one section or paragraph will
have correspondingly more headings.
    Submitting comments in an organized manner and with clear reference
to the issue raised will enable all participants to easily see what
issues the commenter addressed and how they were addressed. Many
commenters, especially small businesses, are likely to confine their
comments to the issues that affect them, and they will benefit from
being able to quickly identify comments on these issues in others'
submissions. The Agency welcomes comments concerning all aspects of
this proposal. However, OSHA is especially interested in responses,
supported by evidence and reasons, to the following questions:

Health Effects

    1. OSHA has described a variety of studies addressing the major
adverse health effects that have been associated with exposure to
beryllium. Using currently available epidemiologic and experimental
studies, OSHA has made a preliminary determination that beryllium
presents risks of lung cancer; sensitization; CBD at 0.1 [micro]g/m\3\;
and at higher exposures acute beryllium disease, and hepatic, renal,
cardiovascular and ocular diseases. Is this determination correct? Are
there additional studies or other data OSHA should consider in
evaluating any of these health outcomes?
    2. Has OSHA adequately identified and documented all critical
health impairments associated with occupational exposure to beryllium?
If not, what other adverse health effects should be added? Are there
additional studies or other data OSHA should consider in evaluating any
of these health outcomes?
    3. Are there any additional studies, other data, or information
that would affect the information discussed or significantly change the
determination of material health impairment?
    Please submit any relevant information, data, or additional studies
(or citations to studies), and explain your reasons for recommending
any studies you suggest.

Risk Assessment and Significance of Risk

    4. OSHA has developed an analysis of health risks associated with
occupational beryllium exposure, including an analysis of sensitization
and CBD based on a selection of recent studies in the epidemiological
literature, a data set on a population of beryllium machinists provided by
the National Jewish Medical Research Center (NJMRC), and an assessment of
lung cancer risk using an analysis provided by NIOSH. Did OSHA rely on the
best available evidence in its risk assessment? Are there additional studies
or other data OSHA should consider in evaluating risk for these health
outcomes? Please provide the studies, citations to studies, or data you suggest.
    5. OSHA preliminarily concluded that there is significant risk of
material health impairment (lung cancer or CBD) from a working lifetime
of occupational exposure to beryllium at the current TWA PEL of 2
[micro]g/m\3\, which would be substantially reduced by the proposed TWA
PEL of 0.2 [micro]g/m\3\ and the alternative TWA PEL of 0.1 [micro]g/
m\3\. OSHA's preliminary risk assessment also concludes that there is
still significant risk of CBD and lung cancer at the proposed PEL and
the alternative PELs, although substantially less than at the current
PEL. Are these preliminary conclusions reasonable, based on the best
available evidence? If not, please provide a detailed explanation of
your position, including data to support your position and a detailed
analysis of OSHA's risk assessment if appropriate.
    6. Please provide comment on OSHA's analysis of risk for beryllium
sensitization, CBD and lung cancer. Are there important gaps or
uncertainties in the analysis, such that the Agency's preliminary
conclusions regarding significance of risk at the current, proposed,
and alternative PELs may be in error? If so, please provide a detailed
explanation and suggestions for how OSHA's analysis should be corrected
or improved.
    7. OSHA has made a preliminary determination that the available
data are not sufficient or suitable for risk analysis of effects other
than beryllium sensitization, CBD and lung cancer. Do you have, or are
you aware of, studies or data that would be suitable for a risk
assessment for these adverse health effects? Please provide the
studies, citations to studies, or data you suggest.

(a) Scope

    8. Has OSHA defined the scope of the proposed standard
appropriately? Does it currently include employers who should not be
covered, or exclude employers who should be covered by a comprehensive
beryllium standard? Are you aware of employees in construction or
maritime, or in general industry who deal with beryllium only as a
trace contaminant, who may be at significant risk from occupational
beryllium exposure? Please provide the basis for your response and any
applicable supporting information.

(b) Definitions

    9. Has OSHA defined the Beryllium lymphocyte proliferation test
appropriately? If not, please provide the definition that you believe
is appropriate. Please provide rationale and citations supporting your
comments.
    10. Has OSHA defined CBD Diagnostic Center appropriately? In
particular, should a CBD diagnostic center be required to analyze
biological samples on-site, or should diagnostic centers be allowed to
send samples off-site for analysis? Is the list of tests and procedures
a CBD Diagnostic Center is required to be able to perform appropriate?
Should any of the tests or procedures be removed from the definition?
Should other tests or procedures be added to the definition? Please
provide rationale and information supporting your comments.

(d) Exposure Monitoring

    11. Do you currently monitor for beryllium exposures in your
workplace? If so, how often? Please provide the reasoning for the
frequency of your monitoring. If periodic monitoring is performed at
your workplace for exposures other than beryllium, with what frequency
is it repeated?
    12. Is it reasonable to allow discontinuation of monitoring based
on one sample below the action level? Should more than one result below
the action level be required to discontinue monitoring?

(e) Work Areas and Regulated Areas

    The proposed standard would require employers to establish and
maintain two types of areas: beryllium work areas, wherever employees
are, or can reasonably be expected to be, exposed to any level of
airborne beryllium; and regulated areas, wherever employees are, or can
reasonably be expected to be, exposed to airborne beryllium at levels
above the TWA PEL or STEL. Employers are required to demarcate
beryllium work areas, but are not required to restrict access to
beryllium work areas or provide respiratory protection or other forms
of PPE within work areas with exposures at or below the TWA PEL or
STEL. Employers must also demarcate regulated areas, including posting
warning signs; restrict access to regulated areas; and provide
respiratory protection and other PPE within regulated areas.
    13. Does your workplace currently have regulated areas? If so, how
are regulated areas demarcated?
    14. Please describe work settings where establishing regulated
areas could be problematic or infeasible. If establishing regulated
areas is problematic, what approaches might be used to warn employees
in such work settings of high risk areas?

(f) Methods of Compliance

    Paragraph (f)(2) of the proposed standard would require employers
to implement engineering and work practice controls to reduce
employees' exposures to or below the TWA PEL and STEL. Where
engineering and work practice controls are insufficient to reduce
exposures to or below the TWA PEL and STEL, employers would still be
required to implement them to reduce exposure as much as possible, and
to supplement them with a respiratory protection program. In addition,
for each operation where there is airborne beryllium exposure, the
employer must ensure that at least one of the engineering and work
practice controls listed in paragraph (f)(2) is in place, unless all of
the listed controls are infeasible, or the employer can demonstrate
that exposures are below the action level based on no fewer than two
samples taken seven days apart.
    15. Do you usually use engineering or work practices controls
(local exhaust ventilation, isolation, substitution) to reduce
beryllium exposures? If so, which controls do you use?
    16. Are the controls and processes listed in paragraph (f)(2)(i)(A)
appropriate for controlling beryllium exposures? Are there additional
controls or processes that should be added to paragraph (f)(2)(i)(A)?

(g) Respiratory Protection

    17. OSHA's asbestos standard (CFR 1910.1001) requires employers to
provide each employee with a tight-fitting, powered air-purifying
respirator (PAPR) instead of a negative pressure respirator when the
employee chooses to use a PAPR and it provides adequate protection to
the employee. Should the beryllium standard similarly require employers
to provide PAPRs (instead of allowing a negative pressure respirator)
when requested by the employee? Are there other circumstances where a
PAPR should be specified as the appropriate respiratory protection?
Please provide the basis for your response and any applicable
supporting information.

(h) Personal Protective Clothing and Equipment

    18. Do you currently require specific PPE or respirators when
employees are working with beryllium? If so, what type?
    19. The proposal requires PPE wherever work clothing or skin may
become visibly contaminated with beryllium; where employees' skin can
reasonably be expected to be exposed to soluble beryllium compounds; or
where employee exposure exceeds or can reasonably be expected to exceed
the TWA PEL or STEL. The requirement to use PPE where work clothing or
skin may become "visibly contaminated" with beryllium differs from
prior standards which do not require contamination to be visible in
order for PPE to be required. Is "visibly contaminated" an
appropriate trigger for PPE? Is there reason to require PPE where
employees' skin can be exposed to insoluble beryllium compounds? Please
provide the basis for your response and any applicable supporting
information.

(i) Hygiene Areas and Practices

    20. The proposal requires employers to provide showers in their
facilities if (A) Exposure exceeds or can reasonably be expected to
exceed the TWA PEL or STEL; and (B) Beryllium can reasonably be
expected to contaminate employees' hair or body parts other than hands,
face, and neck. Is this requirement reasonable and adequately
protective of beryllium-exposed workers? Should OSHA amend the
provision to require showers in facilities where exposures exceed the
PEL or STEL, without regard to areas of bodily contamination?

(j) Housekeeping

    21. The proposed rule prohibits dry sweeping or brushing for
cleaning surfaces in beryllium work areas unless HEPA-filtered
vacuuming or other methods that minimize the likelihood and level of
exposure have been tried and were not effective. Please comment on this
provision. What methods do you use to clean work surfaces at your
facility? Are HEPA-filtered vacuuming or other methods to minimize
beryllium exposure used to clean surfaces at your facility? Have they
been effective? Are there any circumstances under which dry sweeping or
brushing are necessary? Please explain your response.
    22. The proposed rule requires that materials designated for
recycling that are visibly contaminated with beryllium particulate
shall be cleaned to remove visible particulate, or placed in sealed,
impermeable enclosures. However, small particles (< 10 [mu]g) may not be
visible to the naked eye, and there are studies suggesting that small
particles may penetrate the skin, beyond which beryllium sensitization
can occur (Tinkle et al., 2003). OSHA requests feedback on this
provision. Should OSHA require that all material to be recycled be
decontaminated regardless of perceived surface cleanliness? Should OSHA
require that all material disposed or discarded be in enclosures
regardless of perceived surface cleanliness? Please provide explanation
or data to support your comments.

 (k) Medical Surveillance

    The proposed requirements for medical surveillance include: (1)
Medical examinations, including a test for beryllium sensitization, for
employees who are exposed to beryllium above the proposed PEL for 30
days or more per year, who are exposed to beryllium in an emergency, or
who show signs or symptoms of CBD; and (2) CT scans for employees who
were exposed above the proposed PEL for more than 30 days in a 12-month
period for 5 years or more. The proposed standard would require
periodic medical exams to be provided for employees in the medical
surveillance program annually, while tests for beryllium sensitization
and CT scans would be provided to eligible employees biennially.
    23. Is medical surveillance being provided for beryllium-exposed
employees at your worksite? If so:
    a. Do you provide medical surveillance to employees under another
OSHA standard or as a matter of company policy? What OSHA standard(s)
does the program address?
    b. How many employees are included, and how do you determine which
employees receive medical surveillance (e.g., by exposure level, other
factors)?
    c. Who administers and implements the medical surveillance (e.g.,
company doctor, nurse practitioner, physician assistant, or nurse; or
outside doctor, nurse practitioner, physician assistant, or nurse)?
    d. What examinations, tests, or evaluations are included in the
medical surveillance program, and with what frequency are they
administered? Does your program include a surveillance program
specifically for beryllium-related health effects (e.g., the BeLPT or
other tests for beryllium sensitization)?
    e. If your facility offers the BeLPT, please provide feedback and
data on your experience with the BeLPT, including the analytical or
interpretive procedure you use and its role in your facility's exposure
control program. Has identification of sensitized workers led to
interventions to reduce exposures to sensitized individuals, or in the
facility generally? If a worker is found to be sensitized, do you track
worker health and possible progression of disease beyond sensitization?
If so, how is this done?
    f. What difficulties and benefits (e.g., health, reduction in
absenteeism, or financial) have you experienced with your medical
surveillance program? If applicable, please discuss benefits and
difficulties you have experienced with the use of the BeLPT, providing
detailed information or examples if possible.
    g. What are the costs of your medical surveillance program? How do
your costs compare with OSHA's estimated unit costs for the physical
examination and employee time involved in the medical surveillance
program? Are OSHA's baseline assumptions and cost estimates for medical
surveillance consistent with your experiences providing medical
surveillance to your employees?
    24. Please review paragraph (k) of the proposed rule, Medical
Surveillance, and comment on the frequency and contents of medical
surveillance in the proposed rule. Is 30 days from initial assignment a
reasonable time at which to provide a medical exam? Should there be a
requirement for beryllium sensitization testing at time of employment?
Should there be a requirement for beryllium sensitization testing at an
employee's exit exam, regardless of when the employee's most recent
sensitization test was administered? Are the tests required and the
testing frequencies specified appropriate? Should sensitized employees
have the opportunity to be examined at a CBD Diagnostic Center more
than once following a confirmed positive BeLPT? Are there additional
tests or alternate testing schedules you would suggest? Should the skin
be examined for signs and symptoms of beryllium exposure or other
medical issues, as well as for breaks and wounds? Please explain the
basis for your position and provide data or studies if applicable.
    25. Please provide comments on the proposed requirements regarding
referral of a sensitized employee to a CBD diagnostic center, which
specify referral to a diagnostic center "mutually agreed upon" by the
employer and employee. Is this requirement for mutual agreement
necessary and appropriate? How should a diagnostic center be chosen if
the employee and employer cannot come to agreement? Should OSHA
consider alternate language, such as referral for CBD evaluation at a
diagnostic center in a reasonable location?
    26. In the proposed rule, OSHA specifies that all medical
examinations and procedures required by the standard must be performed
by or under the direction of a licensed physician. Are physicians
available in your geographic area to provide medical surveillance to
workers who are covered by the proposed rule? Are other licensed health
care professionals available to provide medical surveillance? Do you
have access to other qualified personnel such as qualified X-ray
technicians, and pulmonary specialists? Should the proposal be amended
to allow examination by, or under the direction of, a physician or
other licensed health care professional (PLHCP)? Please explain your
position. Please note what you consider your geographic area in
responding to this question.
    27. The proposed standard requires the employer to obtain the
Licensed Physician's Written Medical Opinion from the PLHCP within 30
days of the examination. Should OSHA revise the medical surveillance
provisions of the proposed standard to allow employees to choose what,
if any, medical information goes to the employer from the PLHCP? For
example, the employer could instead be required to obtain a
certification from the PLCHP within 30 days of the examination stating
(1) when the examination took place, (2) that the examination complied
with the standard, and (3) that the PLHCP provided the employee a copy
of the Licensed Physician's Written Medical Opinion required by the
standard. The PLHCP would need the employee's written consent to send
the employer the Licensed Physician's Written Medical Opinion or any
other medical information about the employee. This approach might lead
to corresponding changes in proposed paragraphs (f)(1) (written
exposure control program), (l) (medical removal) and (n)
(recordkeeping) to reflect that employers will not automatically be
receiving any medical information about employees as a result of the
medical surveillance required by the proposed standard, but would
instead only receive medical information the employee chooses to share
with the employer. Please comment on the relative merits of the
proposed standard's requirement that employers obtain the PLHCP's
written opinion or an alternative that would provide employees with
greater discretion over the information that goes to employers, and
explain the basis for your position and the potential impact on the
benefits of medical surveillance.
    28. Appendix A to the proposed standard reviews procedures for
conducting and interpreting the results of BeLPT testing for beryllium
sensitization. Is there now, or should there be, a standard method for
BeLPT laboratory procedure? If yes, please describe the existing or
proposed method. Is there now, or should there be, a standard algorithm
for interpreting BeLPT results to determine sensitization? Please
describe the existing or proposed laboratory method or interpretation
algorithm. Should OSHA require that BeLPTs performed to comply with the
medical surveillance provisions of this rule adhere to the Department
of Energy (DOE) analytical and interpretive specifications issued in
2001? Should interpretation of laboratory results be delegated to the
employee's occupational physician or PLHCP?
    29. Should OSHA require the clinical laboratories performing the
BeLPT to be accredited by the College of American Pathologists or
another accreditation organization approved under the Clinical
Laboratory Improvement Amendments (CLIA)? What other standards, if any,
should be required for clinical laboratories providing the BeLPT?
    30. Are there now, or are there being developed, alternative tests
to the BeLPT you would suggest? Please explain the reasons for your
suggestion. How should alternative tests for beryllium sensitization be
evaluated and validated? How should OSHA determine whether a test for
beryllium sensitization is more reliable and accurate than the BeLPT?
Please see Appendix A to the proposed standard for a discussion of the
accuracy of the BeLPT.
    31. The proposed rule requires employers to provide OSHA with the
results of BeLPTs performed to comply with the medical surveillance
provisions upon request, provided that the employer obtains a release
from the tested employee. Will this requirement be unduly burdensome
for employers? Are there alternative organizations that would be
appropriate to send test results to?

 (l) Medical Removal Protection

    The proposed requirements for medical removal protection provide an
option for medical removal to an employee who is working in a job with
exposure at or above the action level and is diagnosed with CBD or
confirmed positive for beryllium sensitization. If the employee chooses
removal, the employer must remove the employee to comparable work in a
work environment where exposure is below the action level, or if
comparable work is not available, must place the employee on paid leave
for 6 months or until such time as comparable work becomes available.
In either case, the employer must maintain for 6 months the employee's
base earnings, seniority, and other rights and benefits that existed at
the time of removal.
    32. Do you provide MRP at your facility? If so, please comment on
the program's benefits, difficulties, and costs, and the extent to
which eligible employees make use of MRP.
    33. OSHA has included requirements for medical removal protection
(MRP) in the proposed rule, which includes provisions for medical
removal for employees with beryllium sensitization or CBD, and an
extension of removed employees' rights and benefits for six months. Are
beryllium sensitization and CBD appropriate triggers for medical
removal? Are there other medical conditions or findings that should
trigger medical removal? For what amount of time should a removed
employee's benefits be extended?

(p) Appendices

    34. Some OSHA health standards include appendices that address
topics such as the hazards associated with the regulated substance,
health screening considerations, occupational disease questionnaires,
and PLHCP obligations. In this proposed rule, OSHA has included a non-
mandatory appendix to describe and discuss the BeLPT (Appendix A), and
a non-mandatory appendix presenting a non-exhaustive list of
engineering controls employers may use to comply with paragraph (f)
(Appendix B). What would be the advantages and disadvantages of
including each appendix in the final rule? What would be the advantages
and disadvantages of providing this information in guidance materials?
    35. What additional information, if any, should be included in the
appendices? What additional information, if any, should be provided in
guidance materials?

General

    36. The current beryllium proposal includes triggers that require
employers to initiate certain provisions, programs, and activities to
protect workers from beryllium exposure. All employers covered under an
OSHA health standard are required to initiate certain activities such
as initial monitoring to evaluate the potential hazard to employees.
OSHA health standards typically include ancillary provisions with
various triggers indicating when an employer covered under the standard
would need to comply with a provision. The most common triggers are ones
based an exposure level such as the PEL or action level. These exposure
level triggers are sometimes combined with a minimum duration of exposure
(e.g., >= 30 days per year). Other triggers may include reasonably
anticipated exposure, medical surveillance findings, certain work activities,
or simply the presence of the regulated substance in the workplace.
    For the current Proposal, exposures to beryllium above the TWA PEL
or STEL trigger the provisions for regulated areas, additional or
enhanced engineering or work practice controls to reduce airborne
exposures to or below the TWA PEL and STEL, personal protective
clothing and equipment, medical surveillance, showers, and respiratory
protection if feasible engineering and work practice controls cannot
reduce airborne exposures to or below the TWA PEL and STEL. Exposures
at or above the action level in turn trigger the provisions for
periodic exposure monitoring, and medical removal eligibility (along
with a diagnosis of CBD or confirmed positive for beryllium
sensitization). Finally, an employer covered under the scope of the
proposed standard must establish a beryllium work area where employees
are, or can reasonably be expected to be, exposed to airborne beryllium
regardless of the level of exposure. In beryllium work areas, employers
must implement a written exposure control plan, provide washing
facilities and change rooms (change rooms are only necessary if
employees are required to remove their personal clothing), and follow
housekeeping provisions. The employers must also implement at least one
of the engineering and work practice controls listed in paragraph
(f)(2) of the proposed standard. An employer is exempt from this
requirement if he or she can demonstrate that such controls are not
feasible or that exposures are below the action level.
    Certain provisions are triggered by one condition and other
provisions are triggered only if multiple conditions are present. For
example, medical removal is only triggered if an employee has CBD or is
confirmed positive AND the employee is exposed at or above the action
level.
    OSHA is requesting comment on the triggers in the proposed
beryllium standard. Are the triggers OSHA has proposed appropriate?
OSHA is also requesting comment on these triggers relative to the
regulatory alternatives affecting the scope and PELs as described in
this preamble in section I, Issues and Alternatives. For example, are
the triggers in the proposed standard appropriate for Alternative #1a,
which would expand the scope of the proposed standard to include all
operations in general industry where beryllium exists only as a trace
contaminant (less than 0.1% beryllium by weight)? Are the triggers
appropriate for the alternatives that change the TWA PEL, STEL, and
action level? Please specify the trigger and the alternative, if
applicable, and why you agree or disagree with the trigger.

Relevant Federal Rules Which May Duplicate, Overlap, or Conflict With
the Proposed Rule

    37. In Section IX--Preliminary Economic Analysis under the Initial
Regulatory Flexibility Analysis, OSHA identifies, to the extent
practicable, all relevant Federal rules which may duplicate, overlap,
or conflict with the proposed rule. One potential area of overlap is
with the U.S. Department of Energy (DOE) beryllium program. In 1999,
DOE established a chronic beryllium disease prevention program (CBDPP)
to reduce the number of workers (DOE employees and DOE contractors)
exposed to beryllium at DOE facilities (10 CFR part 850, published at
64 FR 68854-68914 (Dec. 8, 1999)). In establishing this program, DOE
has exercised its statutory authority to prescribe and enforce
occupational safety and health standards. Therefore pursuant to section
4(b)(1) of the OSH Act, 29 U.S.C. 653(b)(1), the DOE facilities are
exempt from OSHA jurisdiction.
    Nevertheless, under 10 CFR 850.22, DOE has included in its CBDPP
regulation a requirement for compliance with the current OSHA
permissible exposure limit (PEL), and any lower PEL that OSHA
establishes in the future. Thus, although DOE has preempted OSHA's
standard from applying at DOE facilities and OSHA cannot exercise any
authority at those facilities, DOE relies on OSHA's PEL in implementing
its own program. However, DOE's decision to tie its own standard to
OSHA's PEL has little consequence to this rulemaking because the
requirements in DOE's beryllium program (controls, medical
surveillance, etc.) are triggered by DOE's action level of 0.2
[micro]g/m\3\, which is much lower than DOE's existing PEL and the same
as OSHA's proposed PEL. DOE's action level is not tied to OSHA's
standard, so 10 CFR 850.22 would not require the CBDPP's action level
or any non-PEL requirements to be automatically adjusted as a result of
OSHA's rulemaking. For this reason, DOE has indicated to OSHA that
OSHA's proposed rule would not have any impact on DOE's CBDPP,
particularly since 10 CFR 850.25(b), Exposure reduction and
minimization, requires DOE contractors to reduce exposures to below the
DOE's action level of 0.2 [micro]g/m\3\, if practicable.
    DOE has expressed to OSHA that DOE facilities are already in
compliance with 10 CFR 850 and its action level of 0.2 [micro]g/
m\3\,\2\ so the only potential impact on DOE's CBDPP that could flow
from OSHA's rulemaking would be if OSHA ultimately adopted a PEL of 0.1
[micro]g/m\3\, as discussed in alternative #4, instead of the proposed
PEL of 0.2 [micro]g/m\3\, and DOE did not make any additional
adjustments to its standards. Even in that hypothetical scenario, the
impact would still be limited because of the odd result that DOE's PEL
would drop below its own action level, while the action level would
continue to serve as the trigger for most of DOE's program
requirements.
---------------------------------------------------------------------------

    \2\ This would mean the prevailing beryllium exposures at DOE
facilities are at or below 0.2 [micro]g/m\3\.
---------------------------------------------------------------------------

    DOE also has noted some potential overlap with a separate DOE
provision in 10 CFR part 851, which requires its contractors to comply
with DOE's CBDPP (10 CFR 851.23(a)(1)) and also with all OSHA standards
under 29 CFR part 1910 except "Ionizing Radiation" (Sec.  1910.1096)
(10 CFR 851.23(a)(3)). These requirements, which DOE established in
2006 (71 FR 6858 (February 9, 2006)), make sense in light of OSHA's
current regulation because OSHA's only beryllium protection is a PEL,
so compliance with 10 CFR 851.23(a)(1) and (3) merely make OSHA's
current PEL the relevant level for purposes of the CBDPP. However, its
function would be less clear if OSHA adopts a beryllium standard as
proposed. OSHA's proposed beryllium standard would establish additional
substantive protections beyond the PEL. Consequently, notwithstanding
the CBDPP's preemptive effect on the OSHA beryllium standard as a
result of 29 U.S.C. 653(b)(1), 10 CFR 851.23(a)(3) could be read to
require DOE contractors to comply with all provisions in OSHA's
proposal (if finalized), including the ancillary provisions, creating a
dual regulatory scheme for beryllium protection at DOE facilities.
    DOE officials have indicated that this is not their intent.
Instead, their intent is that DOE contractors comply solely with the
CBDPP provisions in 10 CFR part 850 for protection from beryllium.
Based on its discussions with DOE officials, OSHA anticipates that DOE
will clarify that its contractors do not need to comply with any
ancillary provisions in a beryllium standard that OSHA may promulgate.
    OSHA can envision several potential scenarios developing from its
rulemaking, ranging from OSHA retaining the proposed PEL of 0.2
[micro]g/m\3\ and action level of 0.1 [micro]g/m\3\ in the final rule
to adopting the PEL of 0.1 [micro]g/m\3\, as discussed in alternative
#4. Because OSHA's beryllium standard does not apply directly to DOE
facilities, and the only impact of its rules on those facilities is the
result of DOE's regulatory choices, there is also a range of actions
that DOE could take to minimize any potential impact of any change to
OSHA's rules, including (1) taking no action at all, (2) simply
clarifying the CBDPP, as described above, to mean that OSHA's beryllium
standard (other than its PEL) does not apply to contractors, or (3)
revising both parts 850 and 851 to completely disassociate DOE's
regulation of beryllium at DOE facilities from OSHA's regulation of
beryllium.
    OSHA is aware that, in the preamble to its 1999 CBDPP rule, DOE
analyzed the costs for implementing the CBDPP for action levels of 0.1
[micro]g/m\3\, 0.2 [micro]g/m\3\, and 0.5 [micro]g/m\3\ (64 FR 68875,
December 8, 1999). DOE estimated costs for periodic exposure
monitoring, notifying workers of the results of such monitoring,
exposure reduction and minimization, regulated areas, change rooms and
showers, respiratory protection, protective clothing, and disposal of
protective clothing. All of these provisions are triggered by DOE's
action level (64 FR 68874, December 8, 1999). Although DOE's rule is
not identical to OSHA's proposed standard, OSHA believes that DOE's
costs are sufficiently representative to form the basis of a
preliminary estimate of the costs that could flow from OSHA's standard,
if finalized.
    Based on the range of potential scenarios and the prior DOE cost
estimates, OSHA estimates that the annual cost impact on DOE facilities
could range from $0 to $4,065,768 (2010 dollars). The upper end of the
cost range would reflect the unlikely scenario in which OSHA
promulgates a final PEL of 0.1 [micro]g/m\3\, 10 CFR 851.23(a)(3) is
found to compel DOE contractors to comply with OSHA's comprehensive
beryllium standard in addition to DOE's CBDPP, and DOE takes no action
to clarify that OSHA's beryllium standard does not apply to DOE
contractors. The lower end of the cost range assumes OSHA promulgates
its rule as proposed with a PEL of 0.2 [micro]g/m\3\ and action level
of 0.1 [micro]g/m\3\, and DOE clarifies that it intends its contractors
to follow DOE's CBDPP and not OSHA's beryllium standard, so that the
ancillary provisions of OSHA's beryllium standard do not apply to DOE
facilities. Additionally, OSHA assumes that DOE contractors are in
compliance with DOE's current rule and therefore took the difference in
cost between implementation of an action level of 0.2 [micro]g/m\3\ and
an action level of 0.1 [micro]g/m\3\ for the above estimates. Finally,
OSHA used the GDP price deflator to present the cost estimate in 2010
dollars.
    OSHA requests comment on the potential overlap of DOE's rule with
OSHA's proposed rule.

II. Pertinent Legal Authority

    The purpose of the Occupational Safety and Health Act, 29 U.S.C.
651 et seq. ("the Act"), is to "...assure so far as possible
every working man and woman in the nation safe and healthful working
conditions and to preserve our human resources." 29 U.S.C. 651(b).
    To achieve this goal Congress authorized the Secretary of Labor
(the Secretary) to promulgate and enforce occupational safety and
health standards. 29 U.S.C. 654(b) (requiring employers to comply with
OSHA standards), 655(a) (authorizing summary adoption of existing
consensus and federal standards within two years of the Act's
enactment), and 655(b) (authorizing promulgation, modification or
revocation of standards pursuant to notice and comment).
    The Act provides that in promulgating health standards dealing with
toxic materials or harmful physical agents, such as this proposed
standard regulating occupational exposure to beryllium, the Secretary,
shall set the standard which most adequately assures, to the extent
feasible, on the basis of the best available evidence that no employee
will suffer material impairment of health or functional capacity even
if such employee has regular exposure to the hazard dealt with by such
standard for the period of his working life. See 29 U.S.C. 655(b)(5).
    The Supreme Court has held that before the Secretary can promulgate
any permanent health or safety standard, he must make a threshold
finding that significant risk is present and that such risk can be
eliminated or lessened by a change in practices. Industrial Union
Dept., AFL-CIO v. American Petroleum Institute, 448 U.S. 607, 641-42
(1980) (plurality opinion) ("The Benzene case"). Thus, section
6(b)(5) of the Act requires health standards to reduce significant risk
to the extent feasible. Id.
    The Court further observed that what constitutes "significant
risk" is "not a mathematical straitjacket" and must be "based
largely on policy considerations." The Benzene case, 448 U.S. at 655.
The Court gave the example that if,

    . . . the odds are one in a billion that a person will die from
cancer . . . the risk clearly could not be considered significant.
On the other hand, if the odds are one in one thousand that regular
inhalation of gasoline vapors that are 2% benzene will be fatal, a
reasonable person might well consider the risk significant. [Id.]

    OSHA standards must be both technologically and economically
feasible. United Steelworkers v. Marshall, 647 F.2d 1189, 1264 (D.C.
Cir. 1980) ("The Lead I case"). The Supreme Court has defined
feasibility as "capable of being done." Am. Textile Mfrs. Inst. v.
Donovan, 452 U.S. 490, 509-510 (1981) ("The Cotton Dust case"). The
courts have further clarified that a standard is technologically
feasible if OSHA proves a reasonable possibility,

    . . . within the limits of the best available evidence . . .
that the typical firm will be able to develop and install
engineering and work practice controls that can meet the PEL in most
of its operations. [See The Lead I case, 647 F.2d at 1272]

    With respect to economic feasibility, the courts have held that a
standard is feasible if it does not threaten massive dislocation to or
imperil the existence of the industry. Id. at 1265. A court must
examine the cost of compliance with an OSHA standard,

    . . . in relation to the financial health and profitability of
the industry and the likely effect of such costs on unit consumer
prices . . . [T]he practical question is whether the standard
threatens the competitive stability of an industry, . . . or whether
any intra-industry or inter-industry discrimination in the standard
might wreck such stability or lead to undue concentration. [Id.
(citing Indus. Union Dep't, AFL-CIO v. Hodgson, 499 F.2d 467 (D.C.
Cir. 1974))]

The courts have further observed that granting companies reasonable
time to comply with new PELs may enhance economic feasibility. The Lead
I case at 1265. While a standard must be economically feasible, the
Supreme Court has held that a cost-benefit analysis of health standards
is not required by the Act because a feasibility analysis is required.
The Cotton Dust case, 453 U.S. at 509.

    Finally, sections 6(b)(7) and 8(c) of the Act authorize OSHA to
include among a standard's requirements labeling, monitoring, medical
testing, and other information-gathering and -transmittal provisions.
29 U.S.C. 655(b)(7), 657(c).

III. Events Leading to the Proposed Standards

    The first occupational exposure limit for beryllium was set in 1949
by the Atomic Energy Commission (AEC), which required that beryllium
exposure in the workplaces under its jurisdiction be limited to 2
[micro]g/m\3\ as an 8-hour time-weighted average (TWA), and 25
[micro]g/m\3\ as a peak exposure never to be exceeded (Department of
Energy, 1999). These exposure limits were adopted by all AEC
installations handling beryllium, and were binding on all AEC
contractors involved in the handling of beryllium.
    In 1956, the American Industrial Hygiene Association (AIHA)
published a Hygienic Guide which supported the AEC exposure limits. In
1959, the American Conference of Governmental Industrial Hygienists
(ACGIH[supreg]) also adopted a Threshold Limit Value (TLV[supreg]) of 2
[micro]g/m\3\ as an 8-hour TWA (Borak, 2006).
    In 1971, OSHA adopted, under Section 6(a) of the Occupational
Safety and Health Act of 1970, and made applicable to general industry,
a national consensus standard (ANSI Z37.29-1970) for beryllium and
beryllium compounds. The standard set a permissible exposure limit
(PEL) for beryllium and beryllium compounds at 2 [micro]g/m\3\ as an 8-
hour TWA; 5 [micro]g/m\3\ as an acceptable ceiling concentration; and
25 [micro]g/m\3\ as an acceptable maximum peak above the acceptable
ceiling concentration for a maximum duration of 30 minutes in an 8-hour
shift (OSHA, 1971).
    Section 6(a) stipulated that in the first two years after the
effective date of the Act, OSHA was to promulgate "start-up"
standards, on an expedited basis and without public hearing or comment,
based on national consensus or established Federal standards that
improved employee safety or health. Pursuant to that authority, in
1971, OSHA promulgated approximately 425 PELs for air contaminants,
including beryllium, derived principally from Federal standards
applicable to government contractors under the Walsh-Healey Public
Contracts Act, 41 U.S.C. 35, and the Contract Work Hours and Safety
Standards Act (commonly known as the Construction Safety Act), 40
U.S.C. 333. The Walsh-Healey Act and Construction Safety Act standards,
in turn, had been adopted primarily from ACGIH[supreg]'s TLV[supreg]s.
    The National Institute for Occupational Safety and Health (NIOSH)
issued a document entitled Criteria for a Recommended Standard:
Occupational Exposure to Beryllium (Criteria Document) in June 1972.
OSHA reviewed the findings and recommendations contained in the
Criteria Document along with the AEC control requirements for beryllium
exposure. OSHA also considered existing data from animal and
epidemiological studies, and studies of industrial processes of
beryllium extraction, refinement, fabrication, and machining. In 1975,
OSHA asked NIOSH to update the evaluation of the existing data
pertaining to the carcinogenic potential of beryllium. In response to
OSHA's request, the Director of NIOSH stated that, based on animal data
and through all possible routes of exposure including inhalation,
"beryllium in all likelihood represents a carcinogenic risk to man."
    In October 1975, OSHA proposed a new beryllium standard for all
industries based on information that beryllium caused cancer in animal
experiments (40 FR 48814 (October 17, 1975)). Adoption of this proposal
would have lowered the 8-hour TWA exposure limit from 2 [micro]g/m\3\
to 1 [micro]g/m\3\. In addition, the proposal included ancillary
provisions for such topics as exposure monitoring, hygiene facilities,
medical surveillance, and training related to the health hazards from
beryllium exposure. The rulemaking was never completed.
    In 1977, NIOSH recommended an exposure limit of 0.5 [micro]g/m\3\
and identified beryllium as a potential occupational carcinogen. In
December 1998, ACGIH published a Notice of Intended Change for its
beryllium exposure limit. The notice proposed a lower TLV of 0.2
[micro]g/m\3\ over an 8-hour TWA based on evidence of CBD and
sensitization in exposed workers.
    In 1999, the Department of Energy (DOE) issued a Chronic Beryllium
Disease Prevention Program (CBDPP) Final Rule for employees exposed to
beryllium in its facilities (DOE, 1999). The DOE rule set an action
level of 0.2 [mu]g/m\3\, and adopted OSHA's PEL of 2 [mu]g/m\3\ or any
more stringent PEL OSHA might adopt in the future. The DOE action level
triggers workplace precautions and control measures such as periodic
monitoring, exposure reduction or minimization, regulated areas,
hygiene facilities and practices, respiratory protection, protective
clothing and equipment, and warning signs (DOE, 1999).
    Also in 1999, OSHA was petitioned by the Paper, Allied-Industrial,
Chemical and Energy Workers International Union (PACE) (OSHA, 2002) and
by Dr. Lee Newman and Ms. Margaret Mroz, from the National Jewish
Medical Research Center (NJMRC) (OSHA, 2002), to promulgate an
Emergency Temporary Standard (ETS) for beryllium in the workplace. In
2001, OSHA was petitioned for an ETS by Public Citizen Health Research
Group and again by PACE (OSHA, 2002). In order to promulgate an ETS,
the Secretary of Labor must prove (1) that employees are exposed to
grave danger from exposure to a hazard, and (2) that such an emergency
standard is necessary to protect employees from such danger (29 U.S.C.
655(c)). The burden of proof is on the Department and because of the
difficulty of meeting this burden, the Department usually proceeds when
appropriate with 6(b) rulemaking rather than a 6(c) ETS. Thus, instead
of granting the ETS requests, OSHA instructed staff to further collect
and analyze research regarding the harmful effects of beryllium.
    On November 26, 2002, OSHA published a Request for Information
(RFI) for "Occupational Exposure to Beryllium" (OSHA, 2002). The RFI
contained questions on employee exposure, health effects, risk
assessment, exposure assessment and monitoring methods, control
measures and technological feasibility, training, medical surveillance,
and impact on small business entities. In the RFI, OSHA expressed
concerns about health effects such as CBD, lung cancer, and beryllium
sensitization. OSHA pointed to studies indicating that even short-term
exposures below OSHA's PEL of 2 [micro]g/m\3\ could lead to CBD. The
RFI also cited studies describing the relationship between beryllium
sensitization and CBD (67 FR at 70708). In addition, OSHA stated that
beryllium had been identified as a carcinogen by organizations such as
NIOSH, the International Agency for Research on Cancer (IARC), and the
Environmental Protection Agency (EPA); and cancer had been evidenced in
animal studies (67 FR at 70709).
    On November 15, 2007, OSHA convened a Small Business Advocacy
Review Panel for a draft proposed standard for occupational exposure to
beryllium. OSHA convened this panel under Section 609(b) of the
Regulatory Flexibility Act (RFA), as amended by the Small Business
Regulatory Enforcement Fairness Act of 1996 (SBREFA) (5 U.S.C. 601 et
seq.).
    The Panel included representatives from OSHA, the Solicitor's
Office of the Department of Labor, the Office of Advocacy within the
Small Business Administration, and the Office of Information and
Regulatory Affairs of the Office of Management and Budget. Small Entity
Representatives (SERs) made oral and written comments on the draft rule
and submitted them to the panel.
    The SBREFA Panel issued a report which included the SERs' comments
on January 15, 2008. SERs expressed concerns about the impact of the
ancillary requirements such as exposure monitoring and medical
surveillance. Their comments addressed potential costs associated with
compliance with the draft standard, and possible impacts of the
standard on market conditions, among other issues. In addition, many
SERs sought clarification of some of the ancillary requirements such as
the meaning of "routine" contact or "contaminated surfaces."
    The SBREFA Panel issued a number of recommendations, which OSHA
carefully considered. In section XVIII of this preamble, Summary and
Explanation, OSHA has responded to the Panel's recommendations and
clarified the requirements about which SERs expressed confusion. OSHA
also examined the regulatory alternatives recommended by the SBREFA
Panel. The regulatory alternatives examined by OSHA are listed in
section I of this preamble, Issues and Alternatives. The alternatives
are discussed in greater detail in section XVIII of this preamble,
Summary and Explanation, and in the PEA (OSHA, 2014). In addition, the
Agency intends to develop interpretive guidance documents following the
publication of a final rule.
    In 2010, OSHA hired a contractor to oversee an independent
scientific peer review of a draft preliminary beryllium health effects
evaluation (OSHA, 2010a) and a draft preliminary beryllium risk
assessment (OSHA, 2010b). The contractor identified experts familiar
with beryllium health effects research and ensured that these experts
had no conflict of interest or apparent bias in performing the review.
The contractor selected five experts with expertise in such areas as
pulmonary and occupational medicine, CBD, beryllium sensitization, the
BeLPT, beryllium toxicity and carcinogenicity, and medical
surveillance. Other areas of expertise included animal modeling,
occupational epidemiology, biostatistics, risk and exposure assessment,
exposure-response modeling, beryllium exposure assessment, industrial
hygiene, and occupational/environmental health engineering.
    Regarding the health effects evaluation, the peer reviewers
concluded that the health effect studies were described accurately and
in sufficient detail, and OSHA's conclusions based on the studies were
reasonable. The reviewers agreed that the OSHA document covered the
significant health endpoints related to occupational beryllium
exposure. Peer reviewers considered the preliminary conclusions
regarding beryllium sensitization and CBD to be reasonable and well
presented in the draft health evaluation section. All reviewers agreed
that the scientific evidence supports sensitization as a necessary
condition in the development of CBD. In response to reviewers'
comments, OSHA made revisions to more clearly describe certain sections
of the health effects evaluation. In addition, OSHA expanded its
discussion regarding the BeLPT.
    Regarding the preliminary risk assessment, the peer reviewers were
highly supportive of the Agency's approach and major conclusions. The
peer reviewers stated that the key studies were appropriate and their
selection clearly explained in the document. They regarded the
preliminary analysis of these studies to be reasonable and
scientifically sound. The reviewers supported OSHA's conclusion that
substantial risk of sensitization and CBD were observed in facilities
where the highest exposure generating processes had median full-shift
exposures around 0.2 [micro]g/m\3\ or higher, and that the greatest
reduction in risk was achieved when exposures for all processes were
lowered to 0.1 [micro]g/m\3\ or below.
    In February 2012 the Agency received for consideration a draft
recommended standard for beryllium (Materion and USW, 2012). This draft
proposal was the product of a joint effort between two stakeholders:
Materion Corporation, a leading producer of beryllium and beryllium
products in the United States, and the United Steelworkers, an
international labor union representing workers who manufacture
beryllium alloys and beryllium-containing products in a number of
industries. The United Steelworkers and Materion sought to craft an
OSHA-like model beryllium standard that would have support from both
labor and industry. OSHA has considered this proposal along with other
information submitted during the development of the Notice of Proposed
Rulemaking for beryllium.

IV. Chemical Properties and Industrial Uses

Chemical and Physical Properties

    Beryllium (Be; CAS Number 7440-41-7) is a silver-grey to greyish-
white, strong, lightweight, and brittle metal. It is a Group IIA
element with an atomic weight of 9.01, atomic number of 4, melting
point of 1,287 [deg]C, boiling point of 2,970[deg]C, and a density of
1.85 at 20 [deg]C (NTP 2014). It occurs naturally in rocks, soil, coal,
and volcanic dust (ATSDR, 2002). Beryllium is insoluble in water and
soluble in acids and alkalis. It has two common oxidation states, Be(0)
and Be(+2). There are several beryllium compounds with unique CAS
numbers and chemical and physical properties. Table IV-1 describes the
most common beryllium compounds.

                                              Table IV--1, Properties of Beryllium and Beryllium Compounds
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                Synonyms and     Molecular     Melting point
         Chemical name            CAS No.       trade names        weight        ([deg]C)         Description    Density  (g/cm3)        Solubility
--------------------------------------------------------------------------------------------------------------------------------------------------------
Beryllium metal...............    7440-41-7  Beryllium;              9.0122  1287............  Grey, close-      1.85 (20 [deg]C)  Soluble in most
                                              beryllium-9,                                      packed,                             dilute acids and
                                              beryllium                                         hexagonal,                          alkali; decomposes
                                              element;                                          brittle metal.                      in hot water;
                                              beryllium                                                                             insoluble in mercury
                                              metallic.                                                                             and cold water.
Beryllium chloride............    7787-47-5  Beryllium              79.92    399.2...........  Colorless to      1.899 (25         Soluble in water,
                                              dichloride.                                       slightly          [deg]C).          ethanol, diethyl
                                                                                                yellow;                             ether and pyridine;
                                                                                                orthorhombic,                       slightly soluble in
                                                                                                deliquescent                        benzene, carbon
                                                                                                crystal.                            disulfide and
                                                                                                                                    chloroform;
                                                                                                                                    insoluble in
                                                                                                                                    acetone, ammonia,
                                                                                                                                    and toluene.


Beryllium fluoride............    7787-49-7  Beryllium              47.01    555.............  Colorless or      1.986...........  Soluble in water,
                                (12323-05-6   difluoride.                                       white,                              sulfuric acid,
                                          )                                                     amorphous,                          mixture of ethanol
                                                                                                hygroscopic                         and diethyl ether;
                                                                                                solid.                              slightly soluble in
                                                                                                                                    ethanol; insoluble
                                                                                                                                    in hydrofluoric
                                                                                                                                    acid.
Beryllium hydroxide...........   13327-32-7  Beryllium              43.3     138 (decomposes   White,            1.92............  Soluble in hot
                                (1304-49-0)   dihydroxide.                    to beryllium      amorphous,                          concentrated acids
                                                                              oxide).           amphoteric                          and alkali; slightly
                                                                                                powder.                             soluble in dilute
                                                                                                                                    alkali; insoluble in
                                                                                                                                    water.
Beryllium sulfate.............   13510-49-1  Sulfuric acid,        105.07    550-600 [deg]C    Colorless         2.443...........  Forms soluble
                                              beryllium salt                  (decomposes to    crystal.                            tetrahydrate in hot
                                              (1:1).                          beryllium                                             water; insoluble in
                                                                              oxide).                                               cold water.
Beryllium sulfate tetrhydrate.    7787-56-6  Sulfuric acid;        177.14    100 [deg]C......  Colorless,        1.713...........  Soluble in water;
                                              beryllium salt                                    tetragonal                          slightly soluble in
                                              (1:1),                                            crystal.                            concentrated
                                              tetrahydrate.                                                                         sulfuric acid;
                                                                                                                                    insoluble in
                                                                                                                                    ethanol.
Beryllium Oxide...............    1304-56-9  Beryllia;              25.01    2508-2547 [deg]C  Colorless to      3.01 (20 [deg]C)  Soluble in
                                              beryllium                                         white,                              concentrated acids
                                              monoxide                                          hexagonal                           and alkali;
                                              thermalox TM.                                     crystal or                          insoluble in water.
                                                                                                amorphous,
                                                                                                amphoteric
                                                                                                powder.
Beryllium carbonate...........    1319-43-3  Carbonic acid,        112.05    No data.........  White powder....  No data.........  Soluble in acids and
                                              beryllium salt,                                                                       alkali; insoluble in
                                              mixture with                                                                          cold water;
                                              beryllium                                                                             decomposes in hot
                                              hydroxide.                                                                            water.
Beryllium nitrate trihydrate..    7787-55-5  Nitric acid,          187.97    60..............  White to faintly  1.56............  Very soluble in water
                                              beryllium salt,                                   yellowish,                          and ethanol.
                                              trihydrate.                                       deliquescent
                                                                                                mass.
Beryllium phosphate...........   13598-15-7  Phosphoric acid,      104.99    No data.........  Not reported....  Not reported....  Slightly soluble in
                                              beryllium salt                                                                        water.
                                              (1:1).
--------------------------------------------------------------------------------------------------------------------------------------------------------
ATSDR, 2002.

    The physical and chemical properties of beryllium were realized
early in the 20th century, and it has since gained commercial
importance in a wide range of industries. Beryllium is lightweight,
hard, spark resistant, non-magnetic, and has a high melting point. It
lends strength, electrical and thermal conductivity, and fatigue
resistance to alloys (NTP, 2014). Beryllium also has a high affinity
for oxygen in air and water, which can cause a thin surface film of
beryllium oxide to form on the bare metal, making it extremely
resistant to corrosion. These properties make beryllium alloys highly
suitable for defense, nuclear, and aerospace applications (IARC, 1993).
    There are approximately 45 mineralized forms of beryllium. In the
United States, the predominant mineral form mined commercially and
refined into pure beryllium and beryllium alloys is bertrandite.
Bertrandite, while containing less than 1% beryllium compared to 4% in
beryl, is easily and efficiently processed into beryllium hydroxide
(IARC, 1993). Imported beryl is also converted into beryllium hydroxide
as the United States has very little beryl that can be economically
mined (USGS, 2013a).

Industrial Uses

    Materion Corporation, formerly called Brush Wellman, is the only
producer of primary beryllium in the United States. Beryllium is used
in a variety of industries, including aerospace, defense,
telecommunications, automotive, electronic, and medical specialty
industries. Pure beryllium metal is used in a range of products such as
X-ray transmission windows, nuclear reactor neutron reflectors, nuclear
weapons, precision instruments, rocket propellants, mirrors, and
computers (NTP, 2014). Beryllium oxide is used in components such as
ceramics, electrical insulators, microwave oven components, military
vehicle armor, laser structural components, and automotive ignition
systems (ATSDR, 2002). Beryllium oxide ceramics are used to produce
sensitive electronic items such as lasers and satellite heat sinks.
    Beryllium alloys, typically beryllium/copper or beryllium/aluminum,
are manufactured as high beryllium content or low beryllium content
alloys. High content alloys contain greater than 30% beryllium. Low
content alloys are typically less than 3% beryllium. Beryllium alloys
are used in automotive electronics (e.g., electrical connectors and
relays and audio components), computer components, home appliance
parts, dental appliances (e.g., crowns), bicycle frames, golf clubs,
and other articles (NTP, 2014; Ballance et al., 1978; Cunningham et
al., 1998; Mroz, et al., 2001). Electrical components and conductors
are stamped and formed from beryllium alloys. Beryllium-copper
alloys are used to make switches in automobiles (Ballance et al., 1978,
2002; Cunningham et al., 1998) and connectors, relays, and switches in
computers, radar, satellite, and telecommunications equipment (Mroz et
al., 2001). Beryllium-aluminum alloys are used in the construction of
aircraft, high resolution medical and industrial X-ray equipment, and
mirrors to measure weather patterns (Mroz et al., 2001). High content
and low content beryllium alloys are precision machined for military
and aerospace applications. Some welding consumables are also
manufactured using beryllium.
    Beryllium is also found as a trace metal in materials such as
aluminum ore, abrasive blasting grit, and coal fly ash. Abrasive
blasting grits such as coal slag and copper slag contain varying
concentrations of beryllium, usually less than 0.1% by weight. The
burning of bituminous and sub-bituminous coal for power generation
causes the naturally occurring beryllium in coal to accumulate in the
coal fly ash byproduct. Scrap and waste metal for smelting and refining
may also contain beryllium. A detailed discussion of the industries and
job tasks using beryllium is included in the Preliminary Economic
Analysis (OSHA, 2014).
    Occupational exposure to beryllium can occur from inhalation of
dusts, fume, and mist. Beryllium dusts are created during operations
where beryllium is cut, machined, crushed, ground, or otherwise
mechanically sheared. Mists can also form during operations that use
machining fluids. Beryllium fume can form while welding with or on
beryllium components, and from hot processes such as those found in
metal foundries.
    Occupational exposure to beryllium can also occur from skin, eye,
and mucous membrane contact with beryllium particulate or solutions.

V. Health Effects

    Beryllium-associated health effects, including acute beryllium
disease (ABD), beryllium sensitization (also referred to in this
preamble as "sensitization"), chronic beryllium disease (CBD), and
lung cancer, can lead to a number of highly debilitating and life-
altering conditions including pneumonitis, loss of lung capacity
(reduction in pulmonary function leading to pulmonary dysfunction),
loss of physical capacity associated with reduced lung capacity,
systemic effects related to pulmonary dysfunction, and decreased life
expectancy (NIOSH, 1972).
    This Health Effects section presents information on beryllium and
its compounds, the fate of beryllium in the body, research that relates
to its toxic mechanisms of action, and the scientific literature on the
adverse health effects associated with beryllium exposure, including
ABD, sensitization, CBD, and lung cancer. OSHA considers CBD to be a
progressive illness with a continuous spectrum of symptoms ranging from
no symptomatology at its earliest stage following sensitization to mild
symptoms such as a slight almost imperceptible shortness of breath, to
loss of pulmonary function, debilitating lung disease, and, in many
cases, death. This section also discusses the nature of these
illnesses, the scientific evidence that they are causally associated
with occupational exposure to beryllium, and the probable mechanisms of
action with a more thorough review of the supporting studies.

A. Beryllium and Beryllium Compounds

1. Particle Physical/Chemical Properties
    Beryllium (Be; CAS No. 7440-41-7) is a steel-grey, brittle metal
with an atomic number of 4 and an atomic weight of 9.01 (Group IIA of
the periodic table). Because of its high reactivity, beryllium is not
found as a free metal in nature; however, there are approximately 45
mineralized forms of beryllium. Beryllium compounds and alloys include
commercially valuable metals and gemstones.
    Beryllium has two oxidative states: Be(0) and Be(2\+\) Agency for
Toxic Substance and Disease Registry (ATSDR) 2002). It is likely that
the Be(2\+\) state is the most biologically reactive and able to form a
bond with peptides leading to it becoming antigenic (Snyder et al.,
2003). This will be discussed in more detail in the Beryllium
Sensitization section below. Beryllium has a high charge-to-radius
ratio and in addition to forming various types of ionic bonds,
beryllium has a strong tendency for covalent bond formation (e.g., it
can form organometallic compounds such as
Be(CH3)2 and many other complexes) (ATSDR, 2002;
Greene et al., 1998). However, it appears that few, if any, toxicity
studies exist for the organometallic compounds. Additional physical/
chemical properties for beryllium compounds that may be important in
their biological response are summarized in Table 1 below. This
information was obtained from their International Chemical Safety Cards
(ICSC) (beryllium metal (ICSC 0226), beryllium oxide (ICSC 1325),
beryllium sulfate (ICSC 1351), beryllium nitrate (ICSC 1352), beryllium
carbonate (ICSC 1353), beryllium chloride (ICSC 1354), beryllium
fluoride (ICSC 1355)) and from the hazardous substance data bank (HSDB)
for beryllium hydroxide (CASRN: 13327-32-7), and beryllium phosphate
(CASRN: 13598-15-7). Additional information on chemical and physical
properties as well as industrial uses for beryllium can be found in
this preamble at Section IV, Chemical Properties and Industrial Uses.

                                            Table 1--Physical/Chemical Properties of Beryllium and Compounds
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                  Solubility in water at
           Compound name              Physical  appearance      Chemical formula     Molecular mass     Acute physical hazards           20 [deg]C
--------------------------------------------------------------------------------------------------------------------------------------------------------
Beryllium Metal....................  Grey to White Powder..  Be....................             9.0  Combustible; Finely          None.
                                                                                                      dispersed particles--
                                                                                                      Explosive.
Beryllium Oxide....................  White Crystals or       BeO...................            25.0  Not combustible or           Very sparingly
                                      Powder.                                                         explosive.                   soluble.
Beryllium Carbonate................  White Powder..........  Be2CO3(OH)/Be2CO5H2...          181.07  Not combustible or           None.
                                                                                                      explosive.
Beryllium Sulfate..................  Colorless Crystals....  BeSO4.................           105.1  Not combustible or           Slightly soluble.
                                                                                                      explosive.
Beryllium Nitrate..................  White to Yellow Solid.  BeN2O6/Be(NO3)2.......           133.0  Enhances combustion of       Very soluble (1.66 x
                                                                                                      other substances.            10\6\ mg/L).
Beryllium Hydroxide................  White amorphous powder  Be(OH)2...............            43.0  Not reported...............  Slightly soluble 0.8 x
                                      or crystalline solid.                                                                        10-4 mol/L
                                                                                                                                  (3.44 mg/L).
Beryllium Chloride.................  Colorless to Yellow     BeCl2.................            79.9  Not combustible or           Soluble.
                                      Crystals.                                                       explosive.
Beryllium Fluoride.................  Colorless Lumps.......  BeF2..................            47.0  Not combustible or           Very soluble.
                                                                                                      explosive.

Beryllium Phosphate................  White solid...........  Be3(PO4)2.............           271.0  Not reported...............  Soluble.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: International Chemical Safety Cards (except beryllium phosphate and hydroxide--HSDB).

    Beryllium shows a high affinity for oxygen in air and water,
resulting in a thin surface film of beryllium oxide on the bare metal.
If the surface film is disturbed, it may become airborne or dermal
exposure may occur. The solubility, particle surface area, and particle
size of some beryllium compounds are examined in more detail below.
These properties have been evaluated in many toxicological studies. In
particular, the properties related to the calcination (firing
temperatures) and differences in crystal size and solubility are
important aspects in their toxicological profile.
2. Factors Affecting Potency and Effect of Beryllium Exposure
    The effect and potency of beryllium and its compounds, as for any
toxicant, immunogen, or immunotoxicant, may be dependent upon the
physical state in which they are presented to a host. For occupational
airborne materials and surface contaminants, it is especially critical
to understand those physical parameters in order to determine the
extent of exposure to the respiratory tract and skin since these are
generally the initial target organs for either route of exposure.
    For example, large particles may have less of an effect in the lung
than smaller particles due to reduced potential to stay airborne to be
inhaled or be deposited along the respiratory tract. In addition, once
inhalation occurs particle size is critical in determining where the
particle will deposit along the respiratory tract. Solubility also has
an important part in determining the toxicity and bioavailability of
airborne materials as well. Respiratory tract retention and skin
penetration are directly influenced by the solubility and reactivity of
airborne material.
    These factors may be responsible, at least in part, for the process
by which beryllium sensitization progresses to CBD in exposed workers.
Other factors influencing beryllium-induced toxicity include the
surface area of beryllium particles and their persistence in the lung.
With respect to dermal exposure, the physical characteristics of the
particle are important as well since they can influence skin absorption
and bioavailability. This section addresses certain physical
characteristics (i.e., solubility, particle size, particle surface
area) that are important in influencing the toxicity of beryllium
materials in occupational settings.
a. Solubility
    Solubility may be an important determinant of the toxicity of
airborne materials, influencing the deposition and persistence of
inhaled particles in the respiratory tract, their bioavailability, and
the likelihood of presentation to the immune system. A number of
chemical agents, including metals that contact and penetrate the skin,
are able to induce an immune response, such as sensitization (Boeniger,
2003; Mandervelt et al., 1997). Similar to inhaled agents, the ability
of materials to penetrate the skin is also influenced by solubility
since dermal absorption may occur at a greater rate for soluble
materials than insoluble materials (Kimber et al., 2011).
    This section reviews the relevant information regarding solubility,
its importance in a biological matrix and its relevance to
sensitization and beryllium lung disease. The weight of evidence
presented below suggests that both soluble and non-soluble forms of
beryllium can induce a sensitization response and result in progression
of lung disease.
    Beryllium salts, including the chloride (BeCl2),
fluoride (BeF2), nitrate (Be(NO3)2),
phosphate (Be3(PO4)2), and sulfate
(tetrahydrate) (BeSO4 [middot] 4H2O) salts, are
all water soluble. However, soluble beryllium salts can be converted to
less soluble forms in the lung (Reeves and Vorwald, 1967). Aqueous
solutions of the soluble beryllium salts are acidic as a result of the
formation of Be(OH2)4 2\+\, the tetrahydrate,
which will react to form insoluble hydroxides or hydrated complexes
within the general physiological range of pH values (between 5 and 8)
(EPA, 1998). This may be an important factor in the development of CBD
since lower-solubility forms of beryllium have been shown to persist in
the lung for longer periods of time and persistence in the lung may be
needed in order for this disease to occur (NAS, 2008).
    Beryllium oxide (BeO), hydroxide (Be(OH)2), carbonate
(Be2CO3(OH)2), and sulfate (anhydrous)
(BeSO4) are either insoluble, slightly soluble, or
considered to be sparingly soluble (almost insoluble or having an
extremely slow rate of dissolution). The solubility of beryllium oxide,
which is prepared from beryllium hydroxide by calcining (heating to a
high temperature without fusing in order to drive off volatile
chemicals) at temperatures between 500 and 1,750 [deg]C, has an inverse
relationship with calcination temperature. Although the solubility of
the low-fired crystals can be as much as 10 times that of the high-
fired crystals, low-fired beryllium oxide is still only sparingly
soluble (Delic, 1992). In a study that measured the dissolution
kinetics (rate to dissolve) of beryllium compounds calcined at
different temperatures, Hoover et al., compared beryllium metal to
beryllium oxide particles and found them to have similar solubilities.
This was attributed to a fine layer of beryllium oxide that coats the
metal particles (Hoover et al., 1989). A study conducted by Deubner et
al., (2011) determined ore materials to be more soluble than beryllium
oxide at pH 7.2 but similar in solubility at pH 4.5. Beryllium
hydroxide was more soluble than beryllium oxide at both pHs (Deubner et
al., 2011).
    Investigators have also attempted to determine how biological
fluids can dissolve beryllium materials. In two studies, insoluble
beryllium, taken up by activated phagocytes, was shown to be ionized by
myeloperoxidases (Leonard and Lauwerys, 1987; Lansdown, 1995). The
positive charge resulting from ionization enabled the beryllium to bind
to receptors on the surface of cells such as lymphocytes or antigen-
presenting cells which could make it more biologically active (NAS,
2008). In a study utilizing phagolysosomal-simulating fluid (PSF) with
a pH of 4.5, both beryllium metal and beryllium oxide dissolved at a
greater rate than that previously reported in water or SUF (simulant
fluid) (Stefaniak et al., 2006), and the rate of dissolution of the
multi-constituent (mixed) particles was greater than that of the
single-constituent beryllium oxide powder. The authors speculated that
copper in the particles rapidly dissolves, exposing the small
inclusions of beryllium oxide, which have higher specific surface areas
(SSA) and therefore dissolve at a higher rate. A follow-up study by the same
investigational team (Duling et al., 2012) confirmed dissolution of
beryllium oxide by PSF and determined the release rate was biphasic
(initial rapid diffusion followed by a latter slower surface reaction-
driven release). During the latter phase, dissolution half-times were
1,400 to 2,000 days. The authors speculated this indicated bertrandite
was persistent in the lung (Duling et al., 2012).
    In a recent study investigating the dissolution and release of
beryllium ions for 17 beryllium-containing materials (ore, hydroxide,
metal, oxide, alloys, and processing intermediates) using artificial
human airway epithelial lining fluid, Stefaniak et al., (2011) found
release of beryllium ions within 7 days (beryl ore melter dust). The
authors calculated dissolution half-times ranging from 30 days
(reduction furnace material) to 74,000 days (hydroxide). Stefaniak et
al., (2011) speculated that despite the rapid mechanical clearance,
billions of beryllium ions could be released in the respiratory tract
via dissolution in airway lining fluid (ALF). Under this scenario
beryllium-containing particles depositing in the respiratory tract
dissolving in ALF could provide beryllium ions for absorption in the
lung and interact with immune cells in the respiratory tract (Stefaniak
et al., 2011).
    Huang et al., (2011) investigated the effect of simulated lung
fluid (SLF) on dissolution and nanoparticle generation and beryllium-
containing materials. Bertrandite-containing ore, beryl-containing ore,
frit (a processing intermediate), beryllium hydroxide (a processing
intermediate) and silica (used as a control), were equilibrated in SLF
at two pH values (4.5 and 7.2) to reflect inter- and intra-cellular
environments in the lung tissue. Concentrations of beryllium, aluminum,
and silica ions increased linearly during the first 20 days in SLF,
rose slowly thereafter, reaching equilibrium over time. The study also
found nanoparticle formation (in the size range of 10-100 nm) for all
materials (Huang et al., 2011).
    In an in vitro skin model, Sutton et al., (2003) demonstrated the
dissolution of beryllium compounds (insoluble beryllium hydroxide,
soluble beryllium phosphate) in a simulated sweat fluid. This model
showed beryllium can be dissolved in biological fluids and be available
for cellular uptake in the skin. Duling et al., (2012) confirmed
dissolution and release of ions from bertrandite ore in an artificial
sweat model (pH 5.3 and pH 6.5).
b. Particle Size
    The toxicity of beryllium as exemplified by beryllium oxide also is
dependent, in part, on the particle size, with smaller particles (< 10
[mu]m) able to penetrate beyond the larynx (Stefaniak et al., 2008).
Most inhalation studies and occupational exposures involve quite small
(< 1-2 [mu]m) beryllium oxide particles that can penetrate to the
pulmonary regions of the lung (Stefaniak et al., 2008). In inhalation
studies with beryllium ores, particle sizes are generally much larger,
with deposition occurring in several areas throughout the respiratory
tract for particles < 10 [mu]m.
    The temperature at which beryllium oxide is calcined influences its
particle size, surface area, solubility, and ultimately its toxicity
(Delic, 1992). Low-fired (500 [deg]C) beryllium oxide is predominantly
made up of poorly crystallized small particles, while higher firing
temperatures (1000--1750 [deg]C) result in larger particle sizes
(Delic, 1992).
    In order to determine the extent to which particle size plays a
role in the toxicity of beryllium in occupational settings, several key
studies are reviewed and detailed below. The findings on particle size
have been related, where possible, to work process and biologically
relevant toxicity endpoints of either sensitization or CBD.
    Numerous studies have been conducted evaluating the particle size
generated during basic industrial and machining operations. In a study
by Cohen et al., (1983), a multi-cyclone sampler was utilized to
measure the size mass distribution of the beryllium aerosol at a
beryllium-copper alloy casting operation. Briefly, Cohen et al., (1983)
found variable particle size generation based on the operations being
sampled with particle size ranging from 3 to 16 [mu]m. Hoover et al.,
(1990) also found variable particle sizes being generated based on
operations. In general, Hoover et al., (1990) found that milling
operations generated smaller particle sizes than sawing operations.
Hoover et al., (1990) also found that beryllium metal generated higher
concentrations than metal alloys. Martyny et al., (2000) characterized
generation of particle size during precision beryllium machining
processes. The study found that more than 50 percent of the beryllium
machining particles collected in the breathing zone of machinists were
less than 10 [mu]m in aerodynamic diameter with 30 percent of that
fraction being particles of less than 0.6 [mu]m. A study by Thorat et
al., (2003) found similar results with ore mixing, crushing, powder
production and machining ranging from 5.0 to 9.5 [mu]m. Kent et al.,
(2001) measured airborne beryllium using size-selective samplers in
five furnace areas at a beryllium processing facility. A statistically
significant linear trend was reported between the above alveolar-
deposited particle mass concentration and prevalence of CBD and
sensitization in the furnace production areas. The study authors
suggested that the concentration of alveolar-deposited particles (e.g.,
< 3.5 [mu]m) may be a better predictor of sensitization and CBD than the
total mass concentration of airborne beryllium.
    A recent study by Virji et al. (2011) evaluated particle size
distribution, chemistry and solubility in areas with historically
elevated risk of sensitization and CBD at a beryllium metal powder,
beryllium oxide, and alloy production facility. The investigators
observed that historically, exposure-response relationships have been
inconsistent when using mass concentration to identify process-related
risk, possibly due to incomplete particle characterization. Two
separate exposure surveys were conducted in March 1999 and June-August
1999 using multi-stage personal impactor samplers (to determine
particle size distribution) and personal 37 mm closed face cassette
(CFC) samplers, both located in workers' breathing zones. One hundred
and ninety eight time-weighted-average (TWA) personal impactor samples
were analyzed for representative jobs and processes. A total of 4,026
CFC samples were collected over the 5-month collection period and
analyzed for mass concentration, particle size, chemical content and
solubility and compared to process areas with high risk of
sensitization and CBD. The investigators found that total beryllium
concentration varied greatly between workers and among process areas.
Analysis of chemical form and solubility also revealed wide variability
among process areas, but high risk process areas had exposures to both
soluble and insoluble forms of beryllium. Analysis of particle size
revealed most process areas had particles ranging from 5-14 [micro]m
mass median aerodynamic diameter (MMAD). Rank order correlating jobs to
particle size showed high overall consistency (Spearman r=0.84) but
moderate correlation (Pearson r=0.43). The investigators concluded that
consideration of relevant aspects of exposure such as particle size
distribution, chemical form, and solubility will likely improve
exposure assessments (Virji et al., 2011)
c. Particle Surface Area.
    Particle surface area has been postulated as an important metric
for beryllium exposure. Several studies have demonstrated a
relationship between the inflammatory and tumorigenic potential of
ultrafine particles and their increased surface area (Driscoll, 1996;
Miller, 1995; Oberdorster et al., 1996). While the exact mechanism
explaining how particle surface area influences its biological activity
is not known, a greater particle surface area has been shown to
increase inflammation, cytokine production, anti-oxidant defenses and
apoptosis (Elder et al., 2005; Carter et al., 2006; Refsne et al.,
2006).
    Finch et al., (1988) found that beryllium oxide calcined at 500
[deg]C had 3.3 times greater specific surface area (SSA) than beryllium
oxide calcined at 1000 [deg]C, although there was no difference in size
or structure of the particles as a function of calcining temperature.
The beryllium-metal aerosol (airborne beryllium particles), although
similar to the beryllium oxide aerosols in aerodynamic size, had an SSA
about 30 percent that of the beryllium oxide calcined at 1000 [deg]C.
As discussed above, a later study by Delic (1992) found calcining
temperatures had an effect on SSA as well as particle size.
    Several studies have investigated the lung toxicity of beryllium
oxide calcined at different temperatures and generally had found that
those calcined at lower temperatures have greater toxicity and effect
than materials calcined at higher temperatures. This may be because
beryllium oxide fired at the lower temperature has a loosely formed
crystalline structure with greater specific surface area than the fused
crystal structure of beryllium oxide fired at the higher temperature.
For example, beryllium oxide calcined at 500 [deg]C has been found to
have stronger pathogenic effects than material calcined at 1,000
[deg]C, as shown in several of the beagle dog, rat, mouse and guinea
pig studies discussed in the section on CBD pathogenesis that follows
(Finch et al., 1988; Polak et al., 1968; Haley et al., 1989; Haley et
al., 1992; Hall et al., 1950). Finch et al. have also observed higher
toxicity of beryllium oxide calcined at 500 [deg]C, an observation they
attribute to the greater surface area of beryllium particles calcined
at the lower temperature (Finch et al., 1988). These authors found that
the in vitro cytotoxicity to Chinese hamster ovary (CHO) cells and
cultured lung epithelial cells of 500 [deg]C beryllium oxide was
greater than that of 1,000 [deg]C beryllium oxide, which in turn was
greater than that of beryllium metal. However, when toxicity was
expressed in terms of particle surface area, the cytotoxicity of all
three forms was similar. Similar results were observed in a study
comparing the cytotoxicity of beryllium metal particles of various
sizes to cultured rat alveolar macrophages, although specific surface
area did not entirely predict cytotoxicity (Finch et al., 1991).
    Stefaniak et al., (2003b) investigated the particle structure and
surface area of particles (powder and process-sampled) of beryllium
metal, beryllium oxide, and copper-beryllium alloy. Each of these
samples was separated by aerodynamic size, and their chemical
compositions and structures were determined with x-ray diffraction and
transmission electron microscopy, respectively. In summary, beryllium-
metal powder varied remarkably from beryllium oxide powder and alloy
particles. The metal powder consisted of compact particles, in which
SSA decreases with increasing surface diameter. In contrast, the alloys
and oxides consisted of small primary particles in clusters, in which
the SSA remains fairly constant with particle size. SSA for the metal
powders varied based on production and manufacturing process with
variations among samples as high as a factor of 37. Stefaniak et al.
(2003b) found lesser variation in SSA for the alloys or oxides. This is
consistent with data from other studies summarized above showing that
process may affect particle size and surface area. Particle size and/or
surface area may explain differences in the rate of BeS and CBD
observed in some epidemiological studies. However, these properties
have not been consistently characterized in most studies.

B. Kinetics and Metabolism of Beryllium

    Beryllium enters the body by inhalation, ingestion, or absorption
through the skin. For occupational exposure, the airways and the skin
are the primary routes of uptake.
 1. Exposure via the Respiratory System
    The respiratory tract, especially the lung, is the primary target
of inhalation exposure in workers. Inhaled beryllium particles are
deposited along the respiratory tract in a size dependent manner. In
general, particles larger than 10 [mu]m tend to deposit in the upper
respiratory tract or nasal region and do not appreciably penetrate
lower in the tracheobronchial or pulmonary regions (Figure 1).
Particles less than 10 [mu]m increasingly penetrate and deposit in the
tracheobronchial and pulmonary regions with peak deposition in the
pulmonary region occurring below 5 [mu]m in particle diameter. The CBD
pathology of concern is found in the pulmonary region. For particles
below 1 [mu]m, regional deposition changes dramatically. Ultrafine
particles (generally considered to be 100 nm or lower) have a higher
rate of deposition along the entire respiratory system (ICRP model,
1994). Those particles depositing in the lung and along the entire
respiratory tract may encounter immunologic cells or may move into the
vascular system where they are free to leave the lung and can
contribute to systemic beryllium concentrations.
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    Beryllium is removed from the respiratory tract by various
clearance mechanisms. Soluble beryllium is removed from the respiratory
tract via absorption. Sparingly soluble or insoluble beryllium may
remain in the lungs for many years after exposure, as has been observed
in workers (Schepers, 1962). Clearance mechanisms for sparingly soluble
or insoluble beryllium particles include: In the nasal passage,
sneezing, mucociliary transport to the throat, or dissolution; in the
tracheobronchial region, mucociliary transport, coughing, phagocytosis,
or dissolution; in the pulmonary or alveolar region, phagocytosis,
movement through the interstitium (translocation), or dissolution
(Schlesinger, 1997).
    Clearance mechanisms may occur slowly in humans, which is
consistent with some animal studies. For example, subjects in the
Beryllium Case Registry (BCR), which identifies and tracks cases of
acute and chronic beryllium diseases, had elevated concentrations of
beryllium in lung tissue (e.g., 3.1 [mu]g/g of dried lung tissue and
8.5 [mu]g/g in a mediastinal node) more than 20 years after termination
of short-term (generally between 2 and 5 years) occupational exposure
to beryllium (Sprince et al., 1976).
    Clearance rates may depend on the solubility, dose, and size of the
beryllium particles inhaled as well as the sex and species of the
animal tested. As reviewed in a WHO Report (2001), more soluble
beryllium compounds generally tend to be cleared from the respiratory
system and absorbed into the bloodstream more rapidly than less soluble
compounds (Van Cleave and Kaylor, 1955; Hart et al., 1980; Finch et
al., 1990). Animal inhalation or intratracheal instillation studies
administering soluble beryllium salts demonstrated significant
absorption of approximately 20 percent of the initial lung burden,
while sparingly soluble compounds such as beryllium oxide demonstrated
that absorption was slower and less significant (Delic, 1992).
Additional animal studies have demonstrated that clearance of soluble
and sparingly soluble beryllium compounds was biphasic: A more rapid
initial mucociliary transport phase of particles from the
tracheobronchial tree to the gastrointestinal tract, followed by a
slower phase via translocation to tracheobronchial lymph nodes,
alveolar macrophages uptake, and beryllium particles dissolution
(Camner et al., 1977; Sanders et al., 1978; Delic, 1992; WHO, 2001).
Confirmatory studies in rats have shown the half-time for the rapid
phase between 1-60 days, while the slow phase ranged from 0.6-2.3
years. It was also shown that this process was influenced by the
solubility of the beryllium compounds: Weeks/months for soluble
compounds, months/years for sparingly soluble compounds (Reeves and
Vorwald, 1967; Reeves et al., 1967; Zorn et al., 1977; Rhoads and
Sanders, 1985). Studies in guinea-pigs and rats indicate that 40-50
percent of the inhaled soluble beryllium salts are retained in the
respiratory tract. Similar data could not be found for the sparingly or
less soluble beryllium compounds or metal administered by this exposure
route. (WHO, 2001; ATSDR, 2002).
    Evidence from animal studies suggests that greater amounts of
beryllium deposited in the lung may result in slower clearance times. A
comparative study of rats and mice using a single dose of inhaled
aerosolized beryllium metal demonstrated that an acute inhalation
exposure to beryllium metal can slow particle clearance and induce lung
damage in rats (Haley et al., 1990) and mice (Finch et al., 1998a). In
another study Finch et al. (1994) exposed male F344/N rats to beryllium
metal at concentrations resulting in beryllium lung burdens of 1.8, 10,
and 100 [micro]g. These exposure levels resulted in an estimated
clearance half-life ranging from 250-380 days for the three concentrations.
For mice (Finch et al., 1998a), lung clearance half-lives were 91-150 days
(for 1.7- and 2.6-[mu]g lung burden groups) or 360-400 days
(for 12- and 34-[mu]g lung burden groups). While the lower exposure groups
were quite different for rats and mice, the highest groups were similar in
clearance half-lives for both species.
    Beryllium absorbed from the respiratory system is mainly
distributed to the tracheobronchial lymph nodes via the lymph system,
bloodstream, and skeleton, which is the ultimate site of beryllium
storage (Stokinger et al., 1953; Clary et al., 1975; Sanders et al.,
1975; Finch et al., 1990). Trace amounts are distributed throughout the
body (Zorn et al., 1977; WHO, 2001). Studies in rats have demonstrated
accumulation of beryllium chloride in the skeletal system following
intraperitoneal injection (Crowley et al., 1949; Scott et al., 1950)
and accumulation of beryllium phosphate and beryllium sulfate in both
nonparenchymal and parenchymal cells of the liver after intravenous
administration in rats (Skilleter and Price, 1978). Studies have also
demonstrated intracellular accumulation of beryllium oxide in bone
marrow throughout the skeletal system after intravenous administration
to rabbits (Fodor, 1977; WHO, 2001).
    Systemic distribution of the more soluble compounds appears to be
greater than that of the insoluble compounds (Stokinger et al., 1953).
Distribution has also been shown to be dose dependent in research using
intravenous administration of beryllium in rats; small doses were
preferentially taken up in the skeleton, while higher doses were
initially distributed preferentially to the liver. Beryllium was later
mobilized from the liver and transferred to the skeleton (IARC, 1993).
A half-life of 450 days has been estimated for beryllium in the human
skeleton (ICRP, 1960). This indicates the skeleton may serve as a
repository for beryllium that may later be reabsorbed by the
circulatory system, making beryllium available to the immunological
system.
2. Dermal Exposure
    Beryllium compounds have been shown to cause skin irritation and
sensitization in humans and certain animal models (Van Orstrand et al.,
1945; de Nardi et al., 1953; Nishimura 1966; Epstein 1990; Belman,
1969; Tinkle et al., 2003; Delic, 1992). The Agency for Toxic
Substances and Disease Registry (ATSDR) estimated that less than 0.1
percent of beryllium compounds are absorbed through the skin (ATSDR,
2002). However, even minute contact and absorption across the skin may
directly elicit an immunological sensitization response (Deubner et
al., 2001; Toledo et al., 2011). Recent studies by Tinkle et al. (2003)
showed that penetration of beryllium oxide particles was possible ex
vivo for human intact skin at particle sizes of <= 1[mu]m, as confirmed
by scanning electron microscopy. Using confocal microscopy, Tinkle et
al. demonstrated that surrogate fluorescent particles up to 1 [mu]m in
size could penetrate the mouse epidermis and dermis layers in a model
designed to mimic the flexing and stretching of human skin in motion.
Other poorly soluble particles, such as titanium dioxide, have been
shown to penetrate normal human skin (Tan et al., 1996) suggesting the
flexing and stretching motion as a plausible mechanism for dermal
penetration of beryllium as well. As earlier summarized, insoluble
forms of beryllium can be solubilized in biological fluids (e.g.,
sweat) making them available for absorption through intact skin (Sutton
et al., 2003; Stefaniak et al., 2011; Duling et al., 2012).
    Although its precise role remains to be elucidated, there is
evidence to indicate that dermal exposure can contribute to beryllium
sensitization. As early as the 1940s it was recognized that dermatitis
experienced by workers in primary beryllium production facilities was
linked to exposures to the soluble beryllium salts. Except in cases of
wound contamination, dermatitis was rare in workers whose exposures
were restricted to exposure to poorly soluble beryllium-containing
particles (Van Ordstrand et al., 1945). Further investigation by McCord
in 1951 indicated that direct skin contact with soluble beryllium
compounds, but not beryllium hydroxide or beryllium metal, caused
dermal lesions (reddened, elevated, or fluid-filled lesions on exposed
body surfaces) in susceptible persons. Curtis, in 1951, demonstrated
skin sensitization to beryllium with patch testing using soluble and
insoluble forms of beryllium in beryllium-na[iuml]ve subjects. These
subjects later developed granulomatous skin lesions with the classical
delayed-type contact dermatitis following repeat challenge (Curtis,
1951). These lesions appeared after a latent period of 1-2 weeks,
suggesting a delayed allergic reaction. The dermal reaction occurred
more rapidly and in response to smaller amounts of beryllium in those
individuals previously sensitized (Van Ordstrand et al., 1945).
Contamination of cuts and scrapes with beryllium can result in the
beryllium becoming embedded within the skin causing a granuloma to
develop in the skin (Epstein, 1991). Introduction of soluble or
insoluble beryllium compounds into or under the skin as a result of
abrasions or cuts at work has been shown to result in chronic
ulcerations with granuloma formation (Van Orstrand et al., 1945;
Lederer and Savage, 1954). Beryllium absorption through bruises and
cuts has been demonstrated as well (Rossman et al., 1991). In a study
by Invannikov et al., (1982), beryllium chloride was applied directly
to the skin of live animals with three types of wounds: abrasions
(superficial skin trauma), cuts (skin and superficial muscle trauma),
and penetration wounds (deep muscle trauma). The percentage of the
applied dose absorbed into the systemic circulation during a 24-hour
exposure was significant, ranging from 7.8 percent to 11.4 percent for
abrasions, from 18.3 percent to 22.9 percent for cuts, and from 34
percent to 38.8 percent for penetration wounds (WHO, 2001).
    A study by Deubner et al., (2001) concluded that exposure across
damaged skin can contribute as much systemic loading of beryllium as
inhalation (Deubner et al., 2001). Deubner et al., (2001) estimated
dermal loading (amount of particles penetrating into the skin) in
workers as compared to inhalation exposure. Deubner's calculations
assumed a dermal loading rate for beryllium on skin of 0.43 [mu]g/
cm\2\, based on the studies of loading on skin after workers cleaned up
(Sanderson et al., 1999), multiplied by a factor of 10 to approximate
the workplace concentrations and the very low absorption rate of 0.001
percent (taken from EPA estimates). It should be noted that these
calculations did not take into account absorption of soluble beryllium
salts that might occur across nasal mucus membranes, which may result
from contact between contaminated skin and the nose (EPA, 1998).
    A study conducted by Day et al. (2007) evaluated the effectiveness
of a dermal protection program implemented in a beryllium alloy
facility in 2002. The investigators evaluated levels of beryllium in
air, on workplace surfaces, on cotton gloves worn over nitrile gloves,
and on the necks and faces of workers over a six day period. The
investigators found a good correlation between air samples and work
surface contamination at this facility. The investigators also found
measurable levels of beryllium on the skin of workers as a result of
work processes even from workplace areas promoted as "visually clean"
by the company housekeeping policy. Importantly, the investigators found
that the beryllium contamination could be transferred from body region
to body region (e.g., hand to face, neck to face). The investigators
demonstrated multiple pathways of exposure which could lead to sensitization,
increasing risk for developing CBD (Day, et al., 2007).
    The same group of investigators (Armstrong et al., 2014) extended
their work on investigating multiple exposure pathways contributing to
sensitization and CBD. The investigators evaluated four different
beryllium manufacturing and processing facilities to assess the
contribution of various exposure pathways on worker exposure. Airborne,
work surface and cotton glove beryllium concentrations were evaluated.
The investigators found strong correlations between air-surface
concentrations, glove-surface concentrations, and air-glove
concentrations at this facility. This work confirms findings from Day
et al. (2007) demonstrating the importance of airborne beryllium
concentrations to surface contamination and dermal exposure even at
exposures below the current OSHA PEL (Armstrong et al., 2014).
3. Oral and Gastrointestinal Exposure
    According to the WHO Report (2001), gastrointestinal absorption of
beryllium can occur by both the inhalation and oral routes of exposure.
Through inhalation exposure, a fraction of the inhaled material is
transported to the gastrointestinal tract by the mucociliary escalator
or by the swallowing of the insoluble material deposited in the upper
respiratory tract (WHO, 2001). Gastrointestinal absorption of beryllium
can occur by both the inhalation and oral routes of exposure. In the
case of inhalation, a portion of the inhaled material is transported to
the gastrointestinal tract by the mucociliary escalator or by the
swallowing of the insoluble material deposited in the upper respiratory
tract (Schlesinger, 1997). Animal studies have shown oral
administration of beryllium compounds to result in very limited
absorption and storage (as reviewed by U.S. EPA, 1998). In animal
ingestion studies using radio-labeled beryllium chloride in rats, mice,
dogs, and monkeys, the vast majority of the ingested dose passed
through the gastrointestinal tract unabsorbed and was excreted in the
feces. In most studies, < 1 percent of the administered radioactivity
was absorbed into the bloodstream and subsequently excreted in the
urine (Crowley et al., 1949; Furchner et al., 1973; LeFevre and Joel,
1986). Research using soluble beryllium sulfate has shown that as the
compound passes into the intestine, which has a higher pH than the
stomach (approximate pH of 6 to 8 for the intestine, pH of 1 or 2 for
the stomach), the beryllium is precipitated as the insoluble phosphate
and thus is no longer available for absorption (Reeves, 1965; WHO,
2001).
    Urinary excretion of beryllium has been shown to correlate with the
amount of occupational exposure (Klemperer et al., 1951). Beryllium
that is absorbed into the bloodstream is excreted primarily in the
urine (Crowley et al., 1949; Scott et al., 1950; Furchner et al., 1973;
Stiefel et al., 1980), whereas excretion of unabsorbed beryllium is
primarily via the fecal route (Hart et al., 1980; Finch et al., 1990).
A far higher percentage of the beryllium administered parenterally in
various animal species was eliminated in the urine than in the feces
(Crowley et al., 1949; Scott et al., 1950; Furchner et al., 1973),
confirming that beryllium found in the feces following oral exposure is
primarily unabsorbed material. A study using percutaneous incorporation
of soluble beryllium nitrate in rats similarly demonstrated that more
than 90 percent of the beryllium in the bloodstream was eliminated via
urine (Zorn et al., 1977; WHO, 2001). More than 99 percent of ingested
beryllium chloride was excreted in the feces (Mullen et al., 1972).
Elimination half-times of 890-1,770 days (2.4-4.8 years) were
calculated for mice, rats, monkeys, and dogs injected intravenously
with beryllium chloride (Furchner et al., 1973). Mean daily excretion
of beryllium metal was 4.6 x 10-5 percent of the dose
administered by intratracheal instillation in baboons and 3.1 x
10-5 percent in rats (Andre et al., 1987).
4. Metabolism
    Beryllium and its compounds are not metabolized or biotransformed,
but soluble beryllium salts may be converted to less soluble forms in
the lung (Reeves and Vorwald, 1967). As stated earlier, solubility is
an important factor for persistence of beryllium in the lung. Insoluble
beryllium, engulfed by activated phagocytes, can be ionized by an
acidic environment and by myeloperoxidases (Leonard and Lauwerys, 1987;
Lansdown, 1995; WHO, 2001), and this positive charge could potentially
make it more biologically reactive because it may allow the beryllium
to bind to a peptide or protein and be presented to the T cell receptor
or antigen-presenting cell (Fontenot, 2000).
5. Preliminary Conclusion for Particle Characterization and Kinetics of
Beryllium
    The forms and concentrations of beryllium across the workplace vary
substantially based upon location, process, production and work task.
Many factors influence the potency of beryllium including
concentration, composition, structure, size and surface area of the
particle.
    Studies have demonstrated that beryllium sensitization can occur
via the skin or inhalation from soluble or poorly soluble beryllium
particles. Beryllium must be presented to a cell in a soluble form for
activation of the immune system (NAS, 2008), and this will be discussed
in more detail in the section to follow. Poorly soluble beryllium can
be solubilized via intracellular fluid, lung fluid and sweat (Sutton et
al., 2003; Stefaniak et al., 2011). For beryllium to persist in the
lung it needs to be insoluble. However, soluble beryllium has been
shown to precipitate in the lung to form insoluble beryllium (Reeves
and Vorwald, 1967).
    Some animal and epidemiological studies suggest that the form of
beryllium may affect the rate of development of BeS and CBD. Beryllium
in an inhalable form (either as soluble or insoluble particles or mist)
can deposit in the respiratory tract and interact with immune cells
located along the entire respiratory tract (Scheslinger, 1997).
However, more study is needed to precisely determine the physiochemical
characteristics of beryllium that influence toxicity and
immunogenicity.

C. Acute Beryllium Diseases

    Acute beryllium disease (ABD) is a relatively rapid onset
inflammatory reaction resulting from breathing high airborne
concentrations of beryllium. It was first reported in workers
extracting beryllium oxide (Van Ordstrand et al., 1943). Since the
Atomic Energy Commission's adoption of occupational exposure limits for
beryllium beginning in 1949, cases of ABD have been rare. According to
the World Health Organization (2001), ABD is generally associated with
exposure to beryllium levels at or above 100 [mu]g/m\3\ and may be
fatal in 10 percent of cases. However, cases have been reported with
beryllium exposures below 100 [micro]g/m\3\ (Cummings et al., 2009).
The disease involves an inflammatory reaction that may include the
entire respiratory tract, involving the nasal passages, pharynx,
bronchial airways and alveoli. Other tissues including skin and
conjunctivae may be affected as well. The clinical features of
ABD include a nonproductive cough, chest pain, cyanosis, shortness of
breath, low-grade fever and a sharp drop in functional parameters of
the lungs. Pathological features of ABD include edematous distension,
round cell infiltration of the septa, proteinaceous materials, and
desquamated alveolar cells in the lung. Monocytes, lymphocytes and
plasma cells within the alveoli are also characteristic of the acute
disease process (Freiman and Hardy, 1970).
    Two types of acute beryllium disease have been characterized in the
literature: a rapid and severe course of acute fulminating pneumonitis
generally developing within 48 to 72 hours of a massive exposure, and a
second form that takes several days to develop from exposure to lower
concentrations of beryllium (still above the levels set by regulatory
and guidance agencies) (Hall, 1950; DeNardi et al., 1953; Newman and
Kreiss, 1992). Evidence of a dose-response relationship to the
concentration of beryllium is limited (Eisenbud et al., 1948;
Stokinger, 1950; Sterner and Eisenbud, 1951). Recovery from either type
of ABD is generally complete after a period of several weeks or months
(DeNardi et al., 1953). However, deaths have been reported in more
severe cases (Freiman and Hardy, 1970). There have been documented
cases of progression to CBD (ACCP, 1965; Hall, 1950) suggesting the
possibility of an immune component to this disease (Cummings et al.,
2009) as well. According to the BCR, in the United States,
approximately 17 percent of ABD patients developed CBD (BCR, 2010). The
majority of ABD cases occurred between 1932 and 1970 (Eisenbud, 1983;
Middleton, 1998). ABD is extremely rare in the workplace today due to
more stringent exposure controls implemented following occupational and
environmental standards set in 1970-1972 (OSHA, 1971; ACGIH, 1971;
ANSI, 1970) and 1974 (EPA, 1974).

D. Chronic Beryllium Disease

    This section provides an overview of the immunology and
pathogenesis of BeS and CBD, with particular attention to the role of
skin sensitization, particle size, beryllium compound solubility, and
genetic variability in individuals' susceptibility to beryllium
sensitization and CBD.
    Chronic beryllium disease (CBD), formerly known as "berylliosis"
or "chronic berylliosis," is a granulomatous disorder primarily
affecting the lungs. CBD was first described in the literature by Hardy
and Tabershaw (1946) as a chronic granulomatous pneumonitis. It was
proposed as early as 1951 that CBD could be a chronic disease resulting
from an immune sensitization to beryllium (Sterner and Eisenbud, 1951;
Curtis, 1959; Nishimura, 1966). However, for a time, there remained
some controversy as to whether CBD was a delayed-onset hypersensitivity
disease or a toxicant-induced disease (NAS, 2008). Wide acceptance of
CBD as a hypersensitivity lung disease did not occur until bronchoscopy
studies and bronchoalveolar lavage (BAL) studies were performed
demonstrating that BAL cells from CBD patients responded to beryllium
challenge (Epstein et al., 1982; Rossman et al., 1988; Saltini et al.,
1989).
    CBD shares many clinical and histopathological features with
pulmonary sarcoidosis, a granulomatous lung disease of unknown
etiology. This includes such debilitating effects as airway
obstruction, diminishment of physical capacity associated with reduced
lung function, possible depression associated with decreased physical
capacity, and decreased life expectancy. Without appropriate
information, CBD may be difficult to distinguish from sarcoidosis. It
is estimated that up to 6 percent of all patients diagnosed with
sarcoidosis may actually have CBD (Fireman et al., 2003; Rossman and
Kreiber, 2003). Among patients diagnosed with sarcoidosis in which
beryllium exposure can be confirmed, as many as 40 percent may actually
have CBD (Muller-Quernheim et al., 2006; Cherry et al., 2015).
    Clinical signs and symptoms of CBD may include, but are not limited
to, a simple cough, shortness of breath or dypsnea, fever, weight loss
or anorexia, skin lesions, clubbing of fingers, cyanosis, night sweats,
cor pulmonale, tachycardia, edema, chest pain and arthralgia. Changes
or loss of pulmonary function also occur with CBD such as decrease in
vital capacity, reduced diffusing capacity, and restrictive breathing
patterns. The signs and symptoms of CBD constitute a continuum of
symptoms that are progressive in nature with no clear demarcation
between any stages in the disease (Rossman, 1996; NAS, 2008). Besides
these listed symptoms from CBD patients, there have been reported cases
of CBD that remained asymptomatic (Muller-Querheim, 2005; NAS, 2008).
    Unlike ABD, CBD can result from inhalation exposure to beryllium at
levels below the current OSHA PEL, can take months to years after
initial beryllium exposure before signs and symptoms of CBD occur
(Newman 1996, 2005 and 2007; Henneberger, 2001; Seidler et al., 2012;
Schuler et al., 2012), and may continue to progress following removal
from beryllium exposure (Newman, 2005; Sawyer et al., 2005; Seidler et
al., 2012). Patients with CBD can progress to a chronic obstructive
lung disorder resulting in loss of quality of life and the potential
for decreased life expectancy (Rossman, et al., 1996; Newman et al.,
2005). The NAS report (2008) noted the general lack of published
studies on progression of CBD from an early asymptomatic stage to
functionally significant lung disease (NAS, 2008). The report
emphasized that risk factors and time course for clinical disease have
not been fully delineated. However, for people now under surveillance,
clinical progression from immunological sensitization and early
pathological lesions (i.e., granulomatous inflammation) prior to onset
of symptoms to symptomatic disease appears to be slow, although more
follow-up is needed (NAS, 2008). A study by Newman (1996) emphasized
the need for prospective studies to determine the natural history and
time course from BeS and asymptomatic CBD to full-blown disease
(Newman, 1996). Drawing from his own clinical experience, Newman was
able to identify the sequence of events for those with symptomatic
disease as follows: Initial determination of beryllium sensitization;
gradual emergence of chronic inflammation of the lung; pathologic
alterations with measurable physiologic changes (e.g., pulmonary
function and gas exchange); progression to a more severe lung disease
(with extrapulmonary effects such as clubbing and cor pulmonale in some
cases); and finally death in some cases (reported between 5.8 to 38
percent) (NAS, 2008; Newman, 1996).
    In contrast to some occupationally related lung diseases, the early
detection of chronic beryllium disease may be useful since treatment of
this condition can lead not only to regression of the signs and
symptoms, but also may prevent further progression of the disease in
certain individuals (Marchand-Adam, 2008; NAS, 2008). The management of
CBD is based on the hypothesis that suppression of the hypersensitivity
reaction (i.e., granulomatous process) will prevent the development of
fibrosis. However, once fibrosis has developed, therapy cannot reverse
the damage.
    To date, there have been no controlled studies to determine the
optimal treatment for CBD (Rossman, 1996; NAS 2008; Sood, 2009).
Management of CBD is generally modeled after sarcoidosis treatment.
Oral corticosteroid treatment can be initiated in patients with
evidence of disease (either by bronchoscopy or other diagnostic
measures before progression of disease or after clinical signs of
pulmonary deterioration occur). This includes treatment with other
anti-inflammatory agents (NAS, 2008; Maier et al., 2012; Salvator et
al., 2013) as well. It should be noted, however, that treatment with
corticosteroids has side-effects of their own that need to be measured
against the possibility of progression of disease (Gibson et al., 1996;
Zaki et al., 1987). Alternative treatments such as azathiopurine and
infliximab, while successful at treating symptoms of CBD, have been
demonstrated to have side-effects as well (Pallavicino et al., 2013;
Freeman, 2012).
1. Development of Beryllium Sensitization
    Sensitization to beryllium is an essential step for worker
development of CBD. Sensitization to beryllium can result from
inhalation exposure to beryllium (Newman et al., 2005; NAS, 2008), as
well as from skin exposure to beryllium (Curtis, 1951; Newman et al.,
1996; Tinkle et al., 2003). Sensitization is currently detected using a
laboratory blood test described in Appendix A. Although there may be no
clinical symptoms associated with BeS, a sensitized worker's immune
system has been activated to react to beryllium exposures such that
subsequent exposure to beryllium can progress to serious lung disease
(Kreiss et al., 1996; Kreiss et al., 1997; Kelleher et al., 2001; and
Rossman, 2001). Since the pathogenesis of CBD involves a beryllium-
specific, cell-mediated immune response, CBD cannot occur in the
absence of sensitization (NAS, 2008). Various factors, including
genetic susceptibility, have been shown to influence risk of developing
sensitization and CBD (NAS 2008) and will be discussed later in this
section.
    While various mechanisms or pathways may exist for beryllium
sensitization, the most plausible mechanisms supported by the best
available and most current science are discussed below. Sensitization
occurs via the formation of a beryllium-protein complex (an antigen)
that causes an immunological response. In some instances, onset of
sensitization has been observed in individuals exposed to beryllium for
only a few months (Kelleher et al., 2001; Henneberger et al., 2001).
This suggests the possibility that relatively brief, short-term
beryllium exposures may be sufficient to trigger the immune
hypersensitivity reaction. Several studies (Newman et al., 2001;
Henneberger et al., 2001; Rossman, 2001; Schuler et al., 2005; Donovan
et al., 2007, Schuler et al., 2012) have detected a higher prevalence
of sensitization among workers with less than one year of employment
compared to some cross-sectional studies which, due to lack of
information regarding initial exposure, cannot determine time of
sensitization (Kreiss et al., 1996; Kreiss et al., 1997). While only
very limited evidence has described humoral changes in certain patients
with CBD (Cianciara et al., 1980), clear evidence exists for an immune
cell-mediated response, specifically the T-cell (NAS, 2008). Figure 2
delineates the major steps required for progression from beryllium
contact to sensitization to CBD.
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    Beryllium presentation to the immune system is believed to occur
either by direct presentation or by antigen processing. It has been
postulated that beryllium must be presented to the immune system in an
ionic form for cell-mediated immune activation to occur (Kreiss et al.,
2007). Some soluble forms of beryllium are readily presented, since the
soluble beryllium form disassociates into its ionic components.
However, for insoluble forms, dissolution may need to occur. A study by
Harmsen et al. (1986) suggested that a sufficient rate of dissolution
of small amounts of poorly soluble beryllium compounds might occur in
the lungs to allow persistent low-level beryllium presentation to the
immune system. Stefaniak et al. (2005 and 2012) reported that insoluble
beryllium particles phagocytized by macrophages were dissolved in
phagolysomal fluid (Stefaniak et al., 2005; Stefaniak et al., 2012) and
that the dissolution rate stimulated by phagolysomal fluid was
different for various forms of beryllium (Stefaniak et al., 2006;
Duling et al., 2012). Several studies have demonstrated that macrophage
uptake of beryllium can induce aberrant apoptotic processes leading to
the continued release of beryllium ions which will continually
stimulate T-cell activation (Sawyer et al., 2000; Sawyer et al., 2004;
Kittle et al., 2002). Antigen processing can be mediated by antigen-
presenting cells (APC). These may include macrophages, dendritic cells,
or other antigen-presenting cells, although this has not been well
defined in most studies (NAS, 2008).
    Because of their strong positive charge, beryllium ions have the
ability to haptenate and alter the structure of peptides occupying the
antigen-binding cleft of major histocompatibility complex (MHC) class
II on antigen-presenting cells (APC). The MHC class II antigen-binding
molecule for beryllium is the human leukocyte antigen (HLA) with
specific alleles (e.g., HLA-DP, HLA-DR, HLA-DQ) associated with the
progression to CBD (NAS, 2008; Yucesoy and Johnson, 2011). Several studies
have also demonstrated that the electrostatic charge of HLA may be a
factor in binding beryllium (Snyder et al., 2003; Bill et al., 2005;
Dai et al., 2010). The strong positive ionic charge of the beryllium ion
would have a strong attraction for the negatively charged patches of certain
HLA alleles (Snyder et al., 2008; Dai et al., 2010). Alternatively,
beryllium oxide has been demonstrated to bind to the MHC class II
receptor in a neutral pH. The six carboxylates in the amino acid
sequence of the binding pocket provide a stable bond with the Be-O-Be
molecule when the pH of the substrate is neutral (Keizer et al., 2005).
The direct binding of BeO may eliminate the biological requirement for
antigen processing or dissolution of beryllium oxide to activate an
immune response.
    Next in sequence is the beryllium-MHC-APC complex binding to a T-
cell receptor (TCR) on a na[iuml]ve T-cell which stimulates the
proliferation and accumulation of beryllium-specific CD4\+\ (cluster of
differentiation 4\+\) T-cells (Saltini et al., 1989 and 1990; Martin et
al., 2011) as depicted in Figure 3. Fontenot et al. (1999) demonstrated
that diversely different variants of TCR were expressed by CD4\+\ T-
cells in peripheral blood cells of CBD patients. However, the CD4\+\ T-
cells from the lung were more homologous in expression of TCR variants
in CBD patients, suggesting clonal expansion of a subset of T-cells in
the lung (Fontenot et al., 1999). This may also indicate a pathogenic
potential for subsets of T-cell clones expressing this homologous TCR
(NAS, 2008). Fontenot et al. (2006) reported beryllium self-
presentation by HLA-DP expressing BAL CD4\+\ T-cells. Self-presentation
by BAL T-cells in the lung granuloma may result in activation-induced
cell death, which may then lead to oligoclonality of the T-cell
population characteristic of CBD (NAS, 2008).
[GRAPHIC] [TIFF OMITTED] TP07AU15.002

    As CD4\+\ T-cells proliferate, clonal expansion of various subsets
of the CD4\+\ beryllium specific T-cells occurs (Figure 3). In the
peripheral blood, the beryllium-specific CD4\+\ T cells require co-
stimulation with a co-stimulant CD28 (cluster of differentiation 28).
During the proliferation and differentiation process CD4\+\ T-cells
secrete pro-inflammatory cytokines that may influence this process
(Sawyer et al., 2004; Kimber et al., 2011).
2. Development of CBD
    The continued persistence of residual beryllium in the lung leads
to a T-cell maturation process. A large portion of beryllium-specific
CD4\+\ T cells were shown to cease expression of CD28 mRNA and protein,
indicating these cells no longer required co-stimulation with the CD28
ligand (Fontenot et al., 2003). This change in phenotype correlated
with lung inflammation (Fontenot et al., 2003). The CD4\+\ independent
cells continued to secrete cytokines necessary for additional
recruitment of inflammatory and immunological cells; however, they were
less proliferative and less susceptible to cell death compared to the
CD28 dependent cells (Fontenot et al., 2005; Mack et al., 2008). These
beryllium-specific CD4\+\ independent cells are considered to be mature
memory effector cells (Ndejembi et al., 2006; Bian et al., 2005).
Repeat exposure to beryllium in the lung resulting in a mature
population of T cell development independent of co-stimulation by CD28
and development of a population of T effector memory cells
(Tem cells) may be one of the mechanisms that lead to the
more severe reactions observed specifically in the lung (Fontenot et
al., 2005).
    CD4\+\ T cells created in the sensitization process recognize the
beryllium antigen, and respond by proliferating and secreting cytokines
and inflammatory mediators, including IL-2, IFN-[gamma], and TNF-
[alpha] (Tinkle et al., 1997a and b; Fontenot et al., 2002) and MIP-
1[alpha] and GRO-1 (Hong-Geller, 2006). This also results in the
accumulation of various types of inflammatory cells including
mononuclear cells (mostly CD4\+\ T cells) in the bronchoalveolar lavage
fluid (BAL fluid) (Saltini et al., 1989, 1990).
    The development of granulomatous inflammation in the lung of CBD
patients has been associated with the accumulation of beryllium
responsive CD4\+\ Tem cells in BAL fluid (NAS, 2008). The
subsequent release of pro-inflammatory cytokines, chemokines and
reactive oxygen species by these cells may lead to migration of
additional inflammatory/immune cells and the development of a
microenvironment that contributes to the development of CBD (Sawyer et
al., 2005; Tinkle et al., 1996; Hong-Geller et al., 2006; NAS, 2008).
    The cascade of events described above results in the formation of a
noncaseating granulomatous lesion. Release of cytokines by the accumulating
T cells leads to the formation of granulomatous lesions that are characterized
by an outer ring of histiocytes surrounding non-necrotic tissue with embedded
multi-nucleated giant cells (Saltini et al., 1989, 1990).
    Over time, the granulomas spread and can lead to lung fibrosis and
abnormal pulmonary function, with symptoms including a persistent dry
cough and shortness of breath (Saber and Dweik, 2000). Fatigue, night
sweats, chest and joint pain, clubbing of fingers (due to impaired
oxygen exchange), loss of appetite or unexplained weight loss, and cor
pulmonale have been experienced in certain patients as the disease
progresses (Conradi et al., 1971; ACCP, 1965; Kriebel et al., 1988a and
b). While CBD primarily affects the lungs, it can also involve other
organs such as the liver, skin, spleen, and kidneys (ATSDR, 2002).
    As previously mentioned, the uptake of beryllium may lead to an
aberrant apoptotic process with rerelease of beryllium ions and
continual stimulation of beryllium-responsive CD4+ cells in
the lung (Sawyer et al., 2000; Kittle et al., 2002; Sawyer et al.,
2004). Several research studies suggest apoptosis may be one mechanism
that enhances inflammatory cell recruitment, cytokine production and
inflammation, thus creating a scenario for progressive granulomatous
inflammation (Palmer et al., 2008; Rana, 2008). Macrophages and
neutrophils can phagocytize beryllium particles in an attempt to remove
the beryllium from the lung (Ding, et al., 2009). Multiple studies
(Sawyer et al., 2004; Kittle et al., 2002) using BAL cells (mostly
macrophages and neutrophils) from patients with CBD found that in vitro
stimulation with beryllium sulfate induced the production of TNF-
[alpha] (one of many cytokines produced in response to beryllium), and
that production of TNF-[alpha] might induce apoptosis in CBD and
sarcoidosis patients (Bost et al., 1994; Dai et al., 1999). The
stimulation of CBD-derived macrophages by beryllium sulphate resulted
in cells becoming apoptotic, as measured by propidium iodide. These
results were confirmed in a mouse macrophage cell-line (p388D1) (Sawyer
et al., 2000). However, other factors may influence the development of
CBD and are outlined in the following section.
3. Genetic and Other Susceptibility Factors
    Evidence from a variety of sources indicates genetic susceptibility
may play an important role in the development of CBD in certain
individuals, especially at levels low enough not to invoke a response
in other individuals. Early occupational studies proposed that CBD was
an immune reaction based on the high susceptibility of some individuals
to become sensitized and progress to CBD and the lack of CBD in others
who were exposed to levels several orders of magnitude higher (Sterner
and Eisenbud, 1951). Additional in vitro human research has identified
genes coding for specific protein molecules on the surface of their
immune cells that place carriers at greater risk of becoming sensitized
to beryllium and developing CBD (McCanlies et al., 2004). Recent
studies have confirmed genetic susceptibility to CBD involves either
HLA variants, T-cell receptor clonality, tumor necrosis factor (TNF-
[alpha]) polymorphisms and/or transforming growth factor-beta (TGF-
[beta]) polymorphisms (Fontenot et al., 2000; Amicosante et al., 2005;
Tinkle et al., 1996; Gaede et al., 2005; Van Dyke et al., 2011;
Silveira et al., 2012).
    Single Nucleotide Polymorphisms (SNPs) have been studied with
regard to genetic variations associated with increased risk of
developing CBD. SNPs are the most abundant type of human genetic
variation. Polymorphisms in MHC class II and pro-inflammatory genes
have been shown to contribute to variations in immune responses
contributing to the susceptibility and resistance in many diseases
including auto-immunity, and beryllium sensitization and CBD (McClesky
et al., 2009). Specific SNPs have been evaluated as a factor in Glu69
variant from the HLA-DPB1 locus (Richeldi et al., 1993; Cai et al.,
2000; Saltini et al., 2001; Silviera et al., 2012; Dai et al., 2013),
HLA-DRPhe[beta]47 (Amicosante et al., 2005).
    HLA-DPB1 with a glutamic acid at amino position 69 (Glu 69) has
been shown to confer increased risk of beryllium sensitization and CBD
(Richeldi et al., 1993; Saltini et al., 2001; Amicosante et al., 2005;
Van Dyke et al., 2011; Silveira et al., 2012). Fontenot et al. (2000)
demonstrated that beryllium presentation by certain alleles of the
class II human leukocyte antigen-DP (HLA-DP) to CD4+ T cells is the
mechanism underlying the development of CBD. Richeldi et al. (1993)
reported a strong association between the MHC class II allele HLA-DP 1
and the development of CBD in beryllium-exposed workers from a Tucson,
AZ facility. This marker was found in 32 of the 33 workers who
developed CBD, but in only 14 of 44 similarly exposed workers without
CBD. The more common allele of the HLA-DP 1 variant is negatively
charged at this site and could directly interact with the positively
charged beryllium ion. The high percentage (~30 percent) of beryllium-
exposed workers without CBD who had this allele indicates that other
factors also contribute to the development of CBD (EPA, 1998).
Additional studies by Amicosante et al. (2005) using blood lymphocytes
derived from beryllium-exposed workers found a high frequency of this
gene in those sensitized to beryllium. In a study of 82 CBD patients
(beryllium-exposed workers), Stubbs et al. (1996) also found a
relationship between the HLA-DP 1 allele and BeS. The glutamate-69
allele was present in 86 percent of sensitized subjects, but in only 48
percent of beryllium-exposed, non-sensitized subjects. Some variants of
the HLA-DPB1 allele convey higher risk of BeS and CBD than others. For
example, HLA-DPB1*0201 yielded an approximately 3-fold increase in
disease outcome relative to controls; HLA-DPB1*1901 yielded an
approximately 5-fold increase, and HLA-DPB1*1701 an approximately 10-
fold increase (Weston et al., 2005; Snyder et al., 2008). By assigning
odds ratios for specific alleles on the basis of previous studies
discussed above, the researchers found a strong correlation (88
percent) between the reported risk of CBD and the predicted surface
electrostatic potential and charge of the isotypes of the genes. They
were able to conclude that the alleles associated with the most
negatively charged proteins carry the greatest risk of developing
beryllium sensitization and CBD. This confirms the importance of
beryllium charge as a key factor in haptogenic potential.
    In contrast, the HLA-DRB1 allele, which lacks Glu 69, has also been
shown to increase the risk of developing sensitization and CBD
(Amicosante et al., 2005; Maier et al., 2003). Bill et al. (2005) found
that HLA-DR has a glutamic acid at position 71 of the [beta] chain,
functionally equivalent to the Glu 69 of HLA-DP (Bill et al., 2005).
Associations with BeS and CBD have also been reported with the HLA-DQ
markers (Amicosante et al., 2005; Maier et al., 2003). Stubbs et al.
also found a biased distribution of the MHC class II HLA-DR gene
between sensitized and non-sensitized subjects. Neither of these
markers was completely specific for CBD, as each study found beryllium
sensitization or CBD among individuals without the genetic risk factor.
While there remains uncertainty as to which of the MHC class II genes
interact directly with the beryllium ion, antibody inhibition data
suggest that the HLA-DR gene product may be involved in the
presentation of beryllium to T lymphocytes (Amicosante et al., 2002).
In addition, antibody blocking experiments revealed that anti-HLA-DP
strongly reduced proliferation responses and cytokine secretion by BAL
CD4 T cells (Chou et al., 2005). In the study by Chou (2005), anti-HLA-
DR ligand antibodies mainly affected beryllium-induced proliferation
responses with little impact on cytokines other than IL-2, thus
implying that nonproliferating BAL CD4 T cells may still contribute to
inflammation leading to the progression of CBD (Chou et al., 2005).
    TNF alpha (TNF-[alpha]) polymorphisms and TGF beta (TGF-[beta])
polymorphisms have also been shown to confer a genetic susceptibility
for developing CBD in certain individuals. TNF-[alpha] is a pro-
inflammatory cytokine associated with a more severe pulmonary disease
in CBD (NAS, 2008). Beryllium exposure has been shown to upregulate
transcription factors AP-1 and NF-[kappa]B (Sawyer et al., 2007)
inducing an inflammatory response by stimulating production of pro-
inflammatory cytokines such as TNF-[alpha] by inflammatory cells.
Polymorphisms in the 308 position of the TNF-[alpha] gene have been
demonstrated to increase production of the cytokine and increase
severity of disease (Maier et al., 2001; Saltini et al., 2001; Dotti et
al., 2004). While a study by McCanlies et al. (2007) found no
relationship between TNF-[alpha] polymorphism and BeS or CBD, the
inconsistency may be due to misclassification, exposure differences or
statistical power (NAS, 2008).
    Other genetic variations have been shown to be associated with
increased risk of beryllium sensitization and CBD (NAS, 2008). These
include TGF-[beta] (Gaede et al., 2005), angiotensin-1 converting
enzyme (ACE) (Newman et al., 1992; Maier et al., 1999) and an enzyme
involved in glutathione synthesis (glutamate cysteine ligase) (Bekris
et al., 2006). McCanlies et al. (2010) evaluated the association
between polymorphisms in a select group of interleukin genes (IL-1A;
IL-1B, IL-1RN, IL-2, IL-9, IL-9R) due to their role in immune and
inflammatory processes. The study evaluated SNPs in three groups of
workers from large beryllium manufacturing facilities in OH and AZ. The
investigators found a significant association between variants IL-1A-
1142, IL-1A-3769 and IL-1A-4697 and CBD but not with beryllium
sensitization. However, these still require confirmation in larger
studies (NAS, 2008).
    In addition to the genetic factors which may contribute to the
susceptibility and severity of disease, other factors such as smoking
and gender may play a role in the development of CBD (NAS, 2008). A
recent longitudinal cohort study by Mroz et al. (2009) of 229
individuals identified with beryllium sensitization or CBD through
workplace medical surveillance found that the prevalence of CBD among
ever smokers was significantly lower than among never smokers (38.1
percent versus 49.4 percent, p=0.025). BeS subjects that never smoked
were found to be more likely to develop CBD over the course of the
study compared to current smokers (12.6 percent versus 6.4 percent,
p=0.10). The authors suggested smoking may confer a protective effect
against development of lung granulomas as has been demonstrated with
hypersensitivity pneumonitis (Mroz et al., 2009).
4. Beryllium Sensitization and CBD in the Workforce
    Sensitization to beryllium is currently detected in the workforce
with the beryllium lymphocyte proliferation test (BeLPT), a laboratory
blood test developed in the 1980s, also referred to as the LTT
(Lymphocyte Transformation Test) or BeLT (Beryllium Lymphocyte
Transformation Test). In this test, lymphocytes obtained from either
bronchoalveolar lavage fluid (the BAL BeLPT) or from peripheral blood
(the blood BeLPT) are cultured in vitro and exposed to beryllium
sulfate to stimulate lymphocyte proliferation. The observation of
beryllium-specific proliferation indicates beryllium sensitization.
Hereafter, "BeLPT" generally refers to the blood BeLPT, which is
typically used in screening for beryllium sensitization. This test is
described in more detail in subsection D.5.b.
    CBD can be detected at an asymptomatic stage by a number of
techniques including bronchoalveolar lavage and biopsy (Cordeiro et
al., 2007; Maier, 2001). Bronchoalveolar lavage is a method of
"washing" the lungs with fluid inserted via a flexible fiberoptic
instrument known as a bronchoscope, removing the fluid and analyzing
the content for the inclusion of immune cells reactive to beryllium
exposure, as described earlier in this section. Fiberoptic bronchoscopy
can be used to detect granulomatous lung inflammation prior to the
onset of CBD symptoms as well, and has been used in combination with
the BeLPT to diagnose pre-symptomatic CBD in a number of recent
screening studies of beryllium-exposed workers, which are discussed in
the following section detailing diagnostic procedures. Of workers who
were found to be sensitized and underwent clinical evaluation, 31-49
percent of them were diagnosed with CBD (Kreiss et al., 1993; Newman et
al., 1996, 2005, 2007; Mroz, 2009), however some estimate that with
increased surveillance the percent could be much higher (Newman, 2005;
Mroz, 2009). It has been estimated from ongoing surveillance studies of
sensitized individuals with an average follow-up time of 4.5 years that
31 percent of beryllium-sensitized employees were estimated to progress
to CBD (Newman et al., 2005). A study of nuclear weapons facility
employees enrolled in an ongoing medical surveillance program found
that only 20 percent of sensitized workers employed less than 5 years
eventually were diagnosed with CBD, while 40 percent of sensitized
workers employed 10 years or more developed CBD (Stange et al., 2001).
One limitation for all these studies is lack of long-term follow-up. It
may be necessary to continue to monitor these workers in order to
determine whether all BeS workers will develop CBD (Newman et al.,
2005).
    CBD has a clinical spectrum ranging from evidence of beryllium
sensitization and granulomas in the lung with little symptomatology to
loss of lung function and end stage disease which may result in the
need for lung transplantation and decreased life expectancy.
Unfortunately, there are very few published clinical studies describing
the full range and progression of CBD from the beginning to the end
stages and very few of the risk factors for progression of disease have
been delineated (NAS, 2008). Clinical management of CBD is modeled
after sarcoidosis where oral corticosteroid treatment is initiated in
patients who have evidence of progressive lung disease, although
progressive lung disease has not been well defined (NAS, 2008). In
advanced cases of CBD, corticosteroids are the standard treatment (NAS,
2008). No comprehensive studies have been published measuring the
overall effect of removal of workers from beryllium exposure on
sensitization and CBD (NAS, 2008) although this has been suggested as
part of an overall treatment regime for CBD (Mapel et al., 2002; Sood
et al., 2004; Maier et al., 2006; Sood, 2009; Maier et al., 2012). Sood
et al. reported that cessation of exposure can sometimes have
beneficial effects on lung function (Sood et al., 2004). However, this
was based on anecdotal evidence from six patients with CBD, so more
research is needed to better determine the relationship between exposure
duration and disease progression
5. Human Epidemiological Studies
    This section describes the human epidemiological data supporting
the mechanistic overview of beryllium-induced disease in workers. It
has been divided into reviews of epidemiological studies performed
prior to development and implementation of the BeLPT in the late 1980s
and after wide use of the BeLPT for screening purposes. Use of the
BeLPT has allowed investigators to screen for beryllium sensitization
and CBD prior to the onset of clinical symptoms, providing a more
sensitive and thorough analysis of the worker population. The
discussion of the studies has been further divided by manufacturing
processes that may have similar exposure profiles. Table A.1 in the
Appendix summarizes the prevalence of beryllium sensitization and CBD,
range of exposure measurements, and other salient information from the
key epidemiological studies.
    It has been well-established that beryllium exposure, either via
inhalation or skin, may lead to beryllium sensitization, or, with
inhalation exposure, may lead to the onset and progression of CBD. The
available published epidemiological literature discussed below provides
strong evidence of beryllium sensitization and CBD in workers exposed
to airborne beryllium well below the current OSHA PEL of 2 [mu]g/m\3\.
Several studies demonstrate the prevalence of sensitization and CBD is
related to the level of airborne exposure, including a cross-sectional
survey of employees at a beryllium ceramics plant in Tucson, AZ
(Henneberger et al., 2001), case-control studies of workers at the
Rocky Flats nuclear weapons facility (Viet et al., 2000), and workers
from a beryllium machining plant in Cullman, AL (Kelleher et al.,
2001). The prevalence of beryllium sensitization also may be related to
dermal exposure. An increased risk of CBD has been reported in workers
with skin lesions, potentially increasing the uptake of beryllium
(Curtis, 1951; Johnson et al., 2001; Schuler et al., 2005). Three
studies describe comprehensive preventive programs, which included
expanded respiratory protection, dermal protection, and improved
control of beryllium dust migration, that substantially reduced the
rate of beryllium sensitization among new hires (Cummings et al., 2007;
Thomas et al., 2009; Bailey et al., 2010; Schuler et al., 2012).
    Some of the epidemiological studies presented in this review suffer
from challenges common to many published epidemiological studies:
Limitations in study design (particularly cross-sectional); small
sample size; lack of personal and/or short-term exposure data,
particularly those published before the late 1990s; and incomplete
information regarding specific chemical form and/or particle
characterization. Challenges that are specific to beryllium
epidemiological studies include: uncertainty regarding the contribution
of dermal exposure; use of various BeLPT protocols; a variety of case
definitions for determining CBD; and use of various exposure sampling/
assessment methods (e.g., daily weighted average (DWA), lapel
sampling). Even with these limitations, the epidemiological evidence
presented in this section clearly demonstrates that beryllium
sensitization and CBD are continuing to occur from present-day
exposures below OSHA's PEL. The available literature also indicates
that the rate of BeS can be substantially lowered by reducing
inhalation exposure and minimizing dermal contact.
a. Studies Conducted Prior to the BeLPT
    First reports of CBD came from studies performed by Hardy and
Tabershaw (1946). Cases were observed in industrial plants that were
refining and manufacturing beryllium metal and beryllium alloys and in
plants manufacturing fluorescent light bulbs (NAS, 2008). From the late
1940s through the 1960s, clusters of non-occupational CBD cases were
identified around beryllium refineries in Ohio and Pennsylvania, and
outbreaks in family members of beryllium factory workers were assumed
to be from exposure to contaminated clothes (Hardy, 1980). It had been
established that the risk of disease among beryllium workers was
variable and generally rose with the levels of airborne concentrations
(Machle et al., 1948). And while there was a relationship between air
concentrations of beryllium and risk of developing disease both in and
surrounding these plants, the disease rates outside the plants were
higher than expected and not very different from the rate of CBD within
the plants (Eisenbud et al., 1949; Lieben and Metzner, 1959). There
remained considerable uncertainty regarding diagnosis due to lack of
well-defined cohorts, modern diagnostic methods, or inadequate follow-
up. In fact, many patients with CBD may have been misdiagnosed with
sarcoidosis (NAS, 2008).
    The difficulties in distinguishing lung disease caused by beryllium
from other lung diseases led to the establishment of the BCR in 1952 to
identify and track cases of ABD and CBD. A uniform diagnostic criterion
was introduced in 1959 as a way to delineate CBD from sarcoidosis.
Patient entry into the BCR required either: documented past exposure to
beryllium or the presence of beryllium in lung tissue as well as
clinical evidence of beryllium disease (Hardy et al., 1967); or any
three of the six criteria listed below (Hasan and Kazemi, 1974).
Patients identified using the above criteria were registered and added
to the BCR from 1952 through 1983 (Eisenbud and Lisson, 1983).
    The BCR listed the following criteria for diagnosing CBD (Eisenbud
and Lisson, 1983):
    (1) Establishment of significant beryllium exposure based on sound
epidemiologic history;
    (2) Objective evidence of lower respiratory tract disease and
clinical course consistent with beryllium disease;
    (3) Chest X-ray films with radiologic evidence of interstitial
fibronodular disease;
    (4) Evidence of restrictive or obstructive defect with diminished
carbon monoxide diffusing capacity (DLCO) by physiologic
studies of lung function;
    (5) Pathologic changes consistent with beryllium disease on
examination of lung tissue; and
    (6) Presence of beryllium in lung tissue or thoracic lymph nodes.
    Prevalence of CBD in workers during the time period between the
1940s and 1950s was estimated to be between 1-10% (Eisenbud and Lisson,
1983). In a 1969 study, Stoeckle et al. presented 60 case histories
with a selective literature review utilizing the above criteria except
that urinary beryllium was substituted for lung beryllium to
demonstrate beryllium exposure. Stoeckle et al. (1969) were able to
demonstrate corticosteroids as a successful treatment option in one
case of confirmed CBD. This study also presented a 28 percent mortality
rate from complications of CBD at the time of publication. However,
even with the improved methodology for determining CBD based on the BCR
criteria, these studies suffered from lack of well-defined cohorts,
modern diagnostic techniques or adequate follow-up.
b. Criteria for Beryllium Sensitization and CBD Case Definition
Following the Development of the BeLPT
    The criteria for diagnosis of CBD have evolved over time as more
advanced diagnostic technology, such as the (blood) BeLPT and BAL BeLPT, has
become available. More recent diagnostic criteria have both higher
specificity than earlier methods and higher sensitivity, identifying
subclinical effects. Recent studies typically use the following
criteria (Newman et al., 1989; Pappas and Newman, 1993; Maier et al.,
1999):
    (1) History of beryllium exposure;
    (2) Histopathological evidence of noncaseating granulomas or
mononuclear cell infiltrates in the absence of infection; and
    (3) Positive blood or BAL BeLPT (Newman et al., 1989).
    The availability of transbronchial lung biopsy facilitates the
evaluation of the second criterion, by making histopathological
confirmation possible in almost all cases.
    A significant component for the identification of CBD is the
demonstration of a confirmed abnormal BeLPT result in a blood or BAL
sample (Newman, 1996). Since the development of the BeLPT in the 1980s,
it has been used to screen beryllium-exposed workers for sensitization
in a number of studies to be discussed below. The BeLPT is a non-
invasive in vitro blood test which measures the beryllium antigen-
specific T-cell mediated immune response and is the most commonly
available diagnostic tool for identifying beryllium sensitization. The
BeLPT measures the degree to which beryllium stimulates lymphocyte
proliferation under a specific set of conditions, and is interpreted
based upon the number of stimulation indices that exceed the normal
value. The `cut-off' is based on the mean value of the peak stimulation
index among controls plus 2 or 3 standard deviations. This methodology
was modeled into a statistical method known as the "least absolute
values" or "statistical-biological positive" method and relies on
natural log modeling of the median stimulation index values (DOE, 2001;
Frome, 2003). In most applications, two or more stimulation indices
that exceed the cut-off constitute an abnormal test.
    Early versions of the BeLPT test had high variability, but the use
of tritiated thymidine to identify proliferating cells has led to a
more reliable test (Mroz et al., 1991; Rossman et al., 2001). In recent
years, the peripheral blood test has been found to be as sensitive as
the BAL assay, although larger abnormal responses have been observed
with the BAL assay (Kreiss et al., 1993; Pappas and Newman, 1993).
False negative results have also been observed with the BAL BeLPT in
cigarette smokers who have marked excess of alveolar macrophages in
lavage fluid (Kreiss et al., 1993). The BeLPT has also been a useful
tool in animal studies to identify those species with a beryllium-
specific immune response (Haley et al., 1994).
    Screenings for beryllium sensitization have been conducted using
the BeLPT in several occupational surveys and surveillance programs,
including nuclear weapons facilities operated by the Department of
Energy (Viet et al., 2000; Strange et al., 2001; DOE/HSS Report, 2006),
a beryllium ceramics plant in Arizona (Kreiss et al., 1996; Henneberger
et al., 2001; Cummings et al., 2007), a beryllium production plant in
Ohio (Kreiss et al., 1997; Kent et al., 2001), a beryllium machining
facility in Alabama (Kelleher et al., 2001; Madl et al., 2007), a
beryllium alloy plant (Schuler et al., 2005, Thomas et al., 2009), and
another beryllium processing plant (Rosenman et al., 2005) in
Pennsylvania. In most of these studies, individuals with an abnormal
BeLPT result were retested and were identified as sensitized (i.e.,
confirmed positive) if the abnormal result was repeated.
    There has been criticism regarding the reliability and specificity
of the BeLPT as a screening tool (Borak et al., 2006). Stange et al.
(2004) studied the reliability and laboratory variability of the BeLPT
by splitting blood samples and sending samples to two laboratories
simultaneously for BeLPT analysis. Stange et al. found the range of
agreement on abnormal (positive BeLPT) results was 26.2--61.8 percent
depending upon the labs tested (Stange et al., 2004). Borak et al.
(2006) contended that the positive predictive value (PPV) (PPV is the
portion of patients with positive test result correctly diagnosed) is
not high enough to meet the criteria of a good screening tool.
Middleton et al. (2008) used the data from the Stange et al. (2004)
study to estimate the PPV and determined that the PPV of the BeLPT
could be improved from 0.383 to 0.968 when an abnormal BeLPT result is
confirmed with a second abnormal result (Middleton et al., 2008).
However, an apparent false positive can occur in people not
occupationally exposed to beryllium (NAS, 2008). An analysis of survey
data from the general workforce and new employees at a beryllium
manufacturer was performed to assess the reliability of the BeLPT
(Donovan et al. 2007). Donovan et al. analyzed more than 10,000 test
results from nearly 2400 participants over a 12-year period. Donovan et
al. found that approximately 2 percent of new employees had at least
one positive BeLPT at the time of hire and 1 percent of new hires with
no known occupational exposure were confirmed positive at the time of
hire with two BeLPTs. Since there are currently no alternatives to the
BeLPT in a screening program many programs rely on a second test to
confirm a positive result (NAS, 2008).
    The epidemiological studies presented in this section utilized the
BeLPT as either a surveillance tool or a screening tool for determining
sensitization status and/or sensitization/CBD prevalence in workers for
inclusion in the published studies. Most epidemiological studies have
reported rates of sensitization and disease based on a single screening
of a working population (`cross-sectional' or 'population prevalence'
rates). Studies of workers in a beryllium machining plant and a nuclear
weapons facility have included follow-up of the population originally
screened, resulting in the detection of additional cases of
sensitization over several years (Newman et al., 2001, Stange et al.,
2001). OSHA regards the BeLPT as a reliable medical surveillance tool.
The BeLPT is discussed in more detail in Non-Mandatory Appendix A to
the proposed standard, Immunological Testing for the Determination of
Beryllium Sensitization.
c. Beryllium Mining and Extraction
    Mining and extraction of beryllium usually involves the two major
beryllium minerals, beryl (an aluminosilicate containing up to 4
percent beryllium) and bertrandite (a beryllium silicate hydrate
containing generally less than 1 percent beryllium) (WHO, 2001). The
United States is the world leader in beryllium extraction and also
leads the world in production and use of beryllium and its alloys (WHO,
2001). Most exposures from mining and extraction come in the form of
beryllium ore, beryllium salts, beryllium hydroxide (NAS 2008) or
beryllium oxide (Stefaniak et al., 2008).
    Deubner et al. published a study of 75 workers employed at a
beryllium mining and extraction facility in Delta, UT (Deubner et al.,
2001b). Of the 75 workers surveyed for sensitization with the BeLPT,
three were identified as sensitized by an abnormal BeLPT result. One of
those found to be sensitized was diagnosed with CBD. Exposures at the
facility included primarily beryllium ore and salts. General area (GA),
breathing zone (BZ), and personal lapel (LP) exposure samples were
collected from 1970 to 1999. Jobs involving beryllium hydrolysis and
wet-grinding activities had the highest air concentrations, with an
annual median GA concentration ranging from 0.1 to 0.4 [mu]g/m\3\.
Median BZ concentrations were higher than either LP or GA. The average
duration of exposure for beryllium sensitized workers was 21.3 years
(27.7 years for the worker with CBD), compared to an average duration
for all workers of 14.9 years. However, these exposures were less than
either the Elmore, OH, or Tucson, AZ, facilities described below, which
also had higher reported rates of BeS and CBD. A study by Stefaniak
et al. (2008) demonstrated that beryllium was present at the mill in
three forms: mineral, poorly crystalline oxide, and hydroxide.
    There was no sensitization or CBD among those who worked only at
the mine where exposure to beryllium resulted solely from working with
bertrandite ore. The authors concluded that the results of this study
indicated that beryllium ore and salts may pose less of a hazard than
beryllium metal and beryllium hydroxide. These results are consistent
with the previously discussed animal studies examining solubility and
particle size.
d. Beryllium Metal Processing and Alloy Production
    Kreiss et al. (1997) conducted a study of workers at a beryllium
production facility in Elmore, OH. The plant, which opened in 1953 and
initially specialized in production of beryllium-copper alloy, later
expanded its operations to include beryllium metal, beryllium oxide,
and beryllium-aluminum alloy production; beryllium and beryllium alloy
machining; and beryllium ceramics production, which was moved to a
different factory in the early 1980s. Production operations included a
wide variety of jobs and processes, such as work in arc furnaces and
furnace rebuilding, alloy melting and casting, beryllium powder
processing, and work in the pebble plant. Non-production work included
jobs in the analytical laboratory, engineering research and
development, maintenance, laundry, production-area management, and
office-area administration. While the publication refers to the use of
respiratory protection in some areas, such as the pebble plant, the
extent of its use across all jobs or time periods was not reported. Use
of dermal PPE was not reported.
    The authors characterized exposures at the plant using industrial
hygiene (IH) samples collected between 1980 and 1993. The exposure
samples and the plant's formulas for estimating workers' DWA exposures
were used, together with study participants' work histories, to
estimate their cumulative and average beryllium exposure levels.
Exposure concentrations reflected the high exposures found historically
in beryllium production and processing. Short-term BZ measurements had
a median of 1.4, with 18.5 percent of samples exceeding OSHA's STEL of
5.0 [mu]g/m\3\. Particularly high beryllium concentrations were
reported in the areas of beryllium powder production, laundry, alloy
arc furnace (approximately 40 percent of DWA estimates over 2.0 [mu]g/
m\3\) and furnace rebuild (28.6 percent of short-term BZ samples over
the OSHA STEL of 5 [mu]g/m\3\). LP samples (n = 179), which were
available from 1990 to 1992, had a median value of 1 [mu]g/m\3\.
    Of 655 workers employed at the time of the study, 627 underwent
BeLPT screening. Blood samples were divided and split between two labs
for analysis, with repeat testing for results that were abnormal or
indeterminate. Thirty-one workers had an abnormal blood test upon
initial testing and at least one of two subsequent tests was classified
as sensitized. These workers, together with 19 workers who had an
initial abnormal result and one subsequent indeterminate result, were
offered clinical evaluation for CBD including the BAL-BeLPT and
transbronchial lung biopsy. Nine with an initial abnormal test followed
by two subsequent normal tests were not clinically evaluated, although
four were found to be sensitized upon retesting in 1995. Of 47 workers
who proceeded with evaluation for CBD (3 of the 50 initial workers with
abnormal results declined to participate), 24 workers were diagnosed
with CBD based on evidence of granulomas on lung biopsy (20 workers) or
on other findings consistent with CBD (4 workers) (Kreiss et al.,
1997). After including five workers who had been diagnosed prior to the
study, a total of 29 (4.6 percent) current workers were found to have
CBD. In addition, the plant medical department identified 24 former
workers diagnosed with CBD before the study.
    Kreiss et al. reported that the highest prevalence of sensitization
and CBD occurred among workers employed in beryllium metal production,
even though the highest airborne total mass concentrations of beryllium
were generally among employees operating the beryllium alloy furnaces
in a different area of the plant (Kreiss et al., 1997). Preliminary
follow-up investigations of particle size-specific sampling at five
furnace sites within the plant determined that the highest respirable
(e.g., particles < 10 [mu]m in diameter as defined by the authors) and
alveolar-deposited (e.g., particles < 1 [mu]m in diameter as defined by
the authors) beryllium mass and particle number concentrations, as
collected by a general area impactor device, were measured at the
beryllium metal production furnaces rather than the beryllium alloy
furnaces (Kent et al., 2001; McCawley et al., 2001). A statistically
significant linear trend was reported between the above alveolar-
deposited particle mass concentration and prevalence of CBD and
sensitization in the furnace production areas. The authors concluded
that alveolar-deposited particles may be a more relevant exposure
metric for predicting the incidence of CBD or sensitization than the
total mass concentration of airborne beryllium.
    Bailey et al. (2010) evaluated the effectiveness of a workplace
preventive program in lowering BeS at the beryllium metal, oxide, and
alloy production plant studied by Kreiss et al. (1997). The preventive
program included use of administrative and PPE controls (e.g., improved
training, skin protection and other PPE, half-mask or air-purified
respirators, medical surveillance, improved housekeeping standards,
clean uniforms) as well as engineering controls (e.g., migration
controls, physical separation of administrative offices from production
facilities) implemented over the course of five years.
    In a cross-sectional/longitudinal hybrid study, Bailey et al.
compared rates of sensitization in pre-program workers to those hired
after the preventive program began. Pre-program workers were surveyed
cross-sectionally in 1993-1994, and again in 1999 using the BeLPT to
determine sensitization and CBD prevalence rates. The 1999 cross-
sectional survey was conducted to determine if improvements in
engineering and administrative controls were successful, however,
results indicated no improvement in reducing rates of sensitization or
CBD.
    An enhanced preventive program including particle migration
control, respiratory and dermal protection, and process enclosure was
implemented in 2000, with continuing improvements made to the program
in 2001, 2002-2004, and 2005. Workers hired during this period were
longitudinally surveyed for sensitization using the BeLPT. Both the
pre-program and program survey of worker sensitization status utilized
split-sample testing to verify positive test results using the BeLPT.
Of the total 660 workers employed at the production plant, 258 workers
participated from the pre-program group while 290 participated from the
program group (206 partial program, 84 full program). Prevalence
comparisons of the pre-program and program groups (partial and full)
were performed by calculating prevalence ratios. A 95 percent confidence
interval (95 percent CI) was derived using a cohort study method that
accounted for the variance in survey techniques (cross-sectional
versus longitudinal) (Bailey et al., 2010). The sensitization prevalence
of the pre-program group was 3.8 times higher (95 percent CI, 1.5-9.3)
than the program group, 4.0 times higher (95 percent CI, 1.4-11.6) than
the partial program subgroup, and 3.3 times higher (95 percent CI, 0.8-13.7)
than the full program subgroup indicating that a comprehensive preventive
program can reduce, but not eliminate, occurrence of sensitization
among non-sensitized workers (Bailey et al., 2010).
    Rosenman et al. (2005) studied a group of several hundred workers
who had been employed at a beryllium production and processing facility
that operated in eastern Pennsylvania between 1957 and 1978. Of 715
former workers located, 577 were screened for BeS with the BLPT and 544
underwent chest radiography to identify cases of BeS and CBD. Workers
were reported to have exposure to beryllium dust and fume in a variety
of chemical forms including beryl ore, beryllium metal, beryllium
fluoride, beryllium hydroxide, and beryllium oxide.
    Rosenman et al. used the plant's DWA formulas to assess workers'
full-shift exposure levels, based on IH data collected between 1957-
1962 and 1971-1976, to calculate exposure metrics including cumulative,
average, and peak for each worker in the study. The DWA was calculated
based on air monitoring that consisted of GA and short-term task-based
BZ samples. Workers' exposures to specific chemical and physical forms
of beryllium were assessed, including insoluble beryllium (metal and
oxide), soluble beryllium (fluoride and hydroxide), mixed soluble and
insoluble beryllium, beryllium dust (metal, hydroxide, or oxide), fume
(fluoride), and mixed dust and fume. Use of respiratory or dermal
protection by workers was not reported. Exposures in the plant were
high overall. Representative task-based IH samples ranged from 0.9 [mu]
g/m\3\ to 84 [mu] g/m\3\ in the 1960s, falling to a range of 0.5-16.7
[mu] g/m\3\ in the 1970s. A large number of workers' mean DWA estimates
(25 percent) were above the OSHA PEL of 2.0 [mu] g/m\3\, while most
workers had mean DWA exposures between 0.2 and 2.0 [mu] g/m\3\ (74
percent) or below 0.02 [mu] g/m\3\ (1 percent) (Rosenman et al., Table
11; revised erratum April, 2006).
    Blood samples for the BeLPT were collected from the former workers
between 1996 and 2001 and were evaluated at a single laboratory.
Individuals with an abnormal test result were offered repeat testing,
and were classified as sensitized if the second test was also abnormal.
Sixty workers with two positive BeLPTs and 50 additional workers with
chest radiography suggestive of disease were offered clinical
evaluation, including bronchoscopy with bronchial biopsy and BAL-BeLPT.
Seven workers met both criteria. Only 56 (51 percent) of these workers
proceeded with clinical evaluation, including 57 percent of those
referred on the basis of confirmed abnormal BeLPT and 47 percent of
those with abnormal radiographs.
    Of those workers who underwent bronchoscopy, 32 (5.5 percent) with
evidence of granulomas were classified as "definite" CBD cases.
Twelve (2.1 percent) additional workers with positive BAL-BeLPT or
confirmed positive BeLPT and radiographic evidence of upper lobe
fibrosis were classified as "probable" CBD cases. Forty workers (6.9
percent) without upper lobe fibrosis who had confirmed abnormal BeLPT,
but who were not biopsied or who underwent biopsy with no evidence of
granuloma, were classified as sensitized without disease. It is not
clear how many of the 40 workers underwent biopsy. Another 12 (2.1
percent) workers with upper lobe fibrosis and negative or unconfirmed
positive BeLPT were classified as "possible" CBD cases. Nine
additional workers who were diagnosed with CBD before the screening
were included in some parts of the authors' analysis.
    The authors reported a total prevalence of 14.5 percent for CBD
(definite and probable) and sensitization. This rate, considerably
higher than the overall prevalence of sensitization and disease in
several other worker cohorts as described earlier in this section,
reflects in part the very high exposures experienced by many workers
during the plant's operation in the 1950s, 1960s and 1970s. A total of
115 workers had mean DWAs above the OSHA PEL of 2 [mu] g/m\3\. Of
those, 7 (6.0 percent) had definite or probable CBD and another 13 (11
percent) were classified as sensitized without disease. The true
prevalence of CBD in the group may be higher than reported, due to the
low rate of clinical evaluation among sensitized workers.
    Although most of the workers in this study had high exposures,
sensitization and CBD also were observed within the small subgroup of
participants believed to have relatively low beryllium exposures.
Thirty-three cases of CBD and 24 additional cases of sensitization
occurred among 339 workers with mean DWA exposures below OSHA's PEL of
2.0 [mu] g/m\3\ (Rosenman et al., Table 11, erratum 2006). Ten cases of
sensitization and five cases of CBD were found among office and
clerical workers, who were believed to have low exposures (levels not
reported).
    Follow-up time for sensitization screening of workers in this study
who became sensitized during their employment had a minimum of 20 years
to develop CBD prior to screening. In this sense the cohort is
especially well suited to compare the exposure patterns of workers with
CBD and those sensitized without disease, in contrast to several other
studies of workers with only recent beryllium exposures. Rosenman et
al. characterized and compared the exposures of workers with definite
and probable CBD, sensitization only, and no disease or sensitization
using chi-squared tests for discrete outcomes and analysis of variance
(ANOVA) for continuous variables (cumulative, mean, and peak exposure
levels). Exposure-response relationships were further examined with
logistic regression analysis, adjusting for potential confounders
including smoking, age, and beryllium exposure from outside of the
plant. The authors found that cumulative, peak, and duration of
exposure were significantly higher for workers with CBD than for
sensitized workers without disease (p < 0.05), suggesting that the risk
of progressing from sensitization to CBD is related to the level or
extent of exposure a worker experiences. The risk of developing CBD
following sensitization appeared strongly related to exposure to
insoluble forms of beryllium, which are cleared slowly from the lung
and increase beryllium lung burden more rapidly than quickly mobilized
soluble forms. Individuals with CBD had higher exposures to insoluble
beryllium than those classified as sensitized without disease, while
exposure to soluble beryllium was higher among sensitized individuals
than those with CBD.
    Cumulative, mean, peak, and duration of exposure were found to be
comparable for workers with CBD and workers without sensitization or
CBD ("normal" workers). Cumulative, peak, and duration of exposure
were significantly lower for sensitized workers without disease than
for normal workers. Rosenman et al. suggested that genetic
predisposition to sensitization and CBD may have obscured an exposure-
response relationship in this study, and plan to control for genetic
risk factors in future studies. Exposure misclassification from the
1950s and 1960s may have been another limitation in this study,
introducing bias that could have influenced the lack of exposure response.
It is also unknown if the 25 percent who died from CBD-related conditions
may have had higher exposures.
    A follow-up was conducted of the cross-sectional study of a
population of workers first evaluated by Kreiss et al. (1997) and
Rosenman et al. (2005) at a beryllium production and processing
facility in eastern Pennsylvania by Schuler et al. (2012), and in a
companion study by Virji et al. (2012). Schuler et al. evaluated the
worker population employed in 1999 with six years or less work tenure
in a cross-sectional study. The investigators evaluated the worker
population by administering a work history questionnaire with a follow-
up examination for sensitization and CBD. A job-exposure matrix (JEM)
was combined with work histories to create individual estimates of
average, cumulative, and highest-job-related exposure for total,
respirable, and sub-micron beryllium mass concentration. Of the 291
eligible workers, 90.7 percent (264) participated in the study.
Sensitization prevalence was 9.8 percent (26/264) with CBD prevalence
of 2.3 percent (6/264). The investigators found a general pattern of
increasing sensitization prevalence as the exposure quartile increased
indicating an exposure-response relationship. The investigators found
positive associations with both total and respirable mass concentration
with sensitization (average and highest job) and CBD (cumulative).
Increased sensitization prevalence was observed with metal oxide
production alloy melting and casting, and maintenance. CBD was
associated with melting and casting. The investigators summarized that
both total and respirable mass concentration were relevant predictors
of risk (Schuler et al., 2012).
    In the companion study by Virji et al. (2012), the investigators
reconstructed historical exposure from 1994 to 1999 utilizing the
personal sampling data collected in 1999 as baseline exposure estimates
(BEE). The study evaluated techniques for reconstructing historical
data to evaluate exposure-response relationships for epidemiological
studies. The investigators constructed JEMs using the BEE and estimates
of annual changes in exposure for 25 different process areas. The
investigators concluded these reconstructed JEMs could be used to
evaluate a range of exposure parameters from total, respirable and
submicron mass concentration including cumulative, average, and highest
exposure. These two studies demonstrate that high-quality exposure
estimates can be developed both for total mass and respirable mass
concentrations.
e. Beryllium Machining Operations
    Newman et al. (2001) and Kelleher et al. (2001) studied a group of
235 workers at a beryllium metal machining plant. Since the plant
opened in 1969, its primary operations have been machining and
polishing beryllium metal and high-beryllium content composite
materials, with occasional machining of beryllium oxide/metal matrix
(`E-metal'), and beryllium alloys. Other functions include machining of
metals other than beryllium; receipt and inspection of materials; acid
etching; final inspection, quality control, and shipping of finished
materials; tool making; and engineering, maintenance, administrative
and supervisory functions (Newman et al., 2001; Madl et al., 2007).
Machining operations, including milling, grinding, lapping, deburring,
lathing, and electrical discharge machining (EDM), were performed in an
open-floor plan production area. Most non-machining jobs were located
in a separate, adjacent area; however, non-production employees had
access to the machining area.
    Engineering and administrative measures, rather than PPE, were
primarily used to control beryllium exposures at the plant (Madl et
al., 2007). Based on interviews with long-standing employees of the
plant, Kelleher et al. reported that work practices were relatively
stable until 1994, when a worker was diagnosed with CBD and a new
exposure control program was initiated. Between 1995 and 1999 new
engineering and work practice controls were implemented, including
removal of pressurized air hoses and discouragement of dry sweeping
(1995), enclosure of deburring processes (1996), mandatory uniforms
(1997), and installation or updating of local exhaust ventilation (LEV)
in EDM, lapping, deburring, and grinding processes (1998) (Madl et al.,
2007). Throughout the plant's history, respiratory protection was used
mainly for "unusually large, anticipated exposures" to beryllium
(Kelleher et al., 2001), and was not routinely used otherwise (Newman
et al., 2001).
    All workers at the plant participated in a beryllium disease
surveillance program initiated in 1994, and were screened for beryllium
sensitization with the BeLPT beginning in 1995. A BeLPT result was
considered abnormal if two or more of six stimulation indices exceeded
the normal range (see section on BeLPT testing above), and was
considered borderline if one of the indices exceeded the normal range.
A repeat BeLPT was conducted for workers with abnormal or borderline
initial results. Workers were identified as beryllium sensitized and
referred for a clinical evaluation, including bronchoalveolar lavage
(BAL) and transbronchial lung biopsy, if the repeat test was abnormal.
CBD was diagnosed upon evidence of sensititization with granulomas or
mononuclear cell infiltrates in the lung tissue (Newman et al., 2001).
Following the initial plant-wide screening, plant employees were
offered BeLPT testing at two-year intervals. Workers hired after the
initial screening were offered a BeLPT within 3 months of their hire
date, and at 2-year intervals thereafter (Madl et al., 2007).
    Kelleher et al. performed a nested case-control study of the 235
workers evaluated in Newman et al. (2001) to evaluate the relationship
between beryllium exposure levels and risk of sensitization and CBD
(Kelleher et al., 2001). The authors evaluated exposures at the plant
using IH samples they had collected between 1996 and 1999, using
personal cascade impactors designed to measure the mass of beryllium
particles less than 6 [mu] m, particles less than 1 [mu]m in diameter,
and total mass. The great majority of workers' exposures were below the
OSHA PEL of 2 [mu] g/m\3\. However, a few higher levels were observed
in machining jobs including deburring, lathing, lapping, and grinding.
Based on a statistical comparison between their samples and historical
data provided by the plant, the authors concluded that worker beryllium
exposures across all time periods could be approximated using the 1996-
1999 data. They estimated workers' cumulative and 'lifetime weighted'
(LTW) beryllium exposure based on the exposure samples they collected
for each job in 1996-1999 and company records of each worker's job
history.
    Twenty workers with beryllium sensitization or CBD (cases) were
compared to 206 workers (controls) for the case-control analysis from
the study evaluating workers originally conducted by Newman et al.
Thirteen workers were diagnosed with CBD based on lung biopsy evidence
of granulomas and/or mononuclear cell infiltrates (11) or positive BAL
results with evidence of lymphocytosis (2). Seven were evaluated for
CBD and found to be sensitized only, thus twenty composing the case
group. Nine of the remaining 215 workers first identified in original
study (Newman et al., 2001) were excluded due to incomplete job history
information, leaving 206 workers in the control group.
    Kelleher et al.'s analysis included comparisons of the case and
control groups' median exposure levels; calculation of odds ratios for
workers in high, medium, and low exposure groups; and logistic
regression testing of the association of sensitization or CBD with
exposure level and other variables. Median cumulative exposures for
total mass, particles < 6 [mu] m, and particles < 1 [mu]m were
approximately three times higher among the cases than controls,
although the relationships observed were not statistically significant
(p values ~ 0.2). No clear difference between cases and controls was
observed for the median LTW exposures. Odds ratios with sensitization
and CBD as outcomes were elevated in high (upper third) and
intermediate exposure groups relative to low (lowest third) exposure
groups for both cumulative and LTW exposure, though the results were
not statistically significant (p > 0.1). In the logistic regression
analysis, only machinist work history was a significant predictor of
case status in the final model. Quantitative exposure measures were not
significant predictors of sensitization or disease risk.
    Citing an 11.5 percent prevalence of beryllium sensitization or CBD
among machinists as compared with 2.9 percent prevalence among workers
with no machinist work history, the authors concluded that the risk of
sensitization and CBD is increased among workers who machine beryllium.
Although differences between cases and controls in median cumulative
exposure did not achieve conventional thresholds for statistical
significance, the authors noted that cumulative exposures were
consistently higher among cases than controls for all categories of
exposure estimates and for all particle sizes, suggesting an effect of
cumulative exposure on risk. The levels at which workers developed CBD
and sensitization were predominantly below OSHA's current PEL of 2 [mu]
g/m\3\, and no cases of sensitization or CBD were observed among
workers with LTW exposure < 0.02 [mu]g/m\3\. Twelve (60 percent) of the
20 sensitized workers had LTW exposures > 0.20 [mu] g/m\3\.
    In 2007, Madl et al. published an additional study of 27 workers at
the machining plant who were found to be sensitized or diagnosed with
CBD between the start of medical surveillance in 1995 and 2005. As
previously described, workers were offered a BeLPT in the initial 1995
screening (or within 3 months of their hire date if hired after 1995)
and at 2-year intervals after their first screening. Workers with two
positive BeLPTs were identified as sensitized and offered clinical
evaluation for CBD, including bronchoscopy with BAL and transbronchial
lung biopsy. The criteria for CBD in this study were somewhat stricter
than those used in the Newman et al. study, requiring evidence of
granulomas on lung biopsy or detection of X-ray or pulmonary function
changes associated with CBD, in combination with two positive BeLPTs or
one positive BAL-BeLPT.
    Based on the history of the plant's control efforts and their
analysis of historical IH data, Madl et al. identified three "exposure
control eras": A relatively uncontrolled period from 1980-1995; a
transitional period from 1996 to 1999; and a relatively well-controlled
"modern" period from 2000-2005. They found that the engineering and
work practice controls instituted in the mid-1990s reduced workers'
exposures substantially, with nearly a 15-fold difference in reported
exposure levels between the pre-control and the modern period (Madl et
al., 2007). Madl et al. estimated workers' exposures using LP samples
collected between 1980 and 2005, including those collected by Kelleher
et al., and work histories provided by the plant. As described more
fully in the study, they used a variety of approaches to describe
individual workers' exposures, including approaches designed to
characterize the highest exposures workers were likely to have
experienced. Their exposure-response analysis was based primarily on an
exposure metric they derived by identifying the year and job of each
worker's pre-diagnosis work history with the highest reported
exposures. They used the upper 95th percentile of the LP samples
collected in that job and year (in some cases supplemented with data
from other years) to characterize the worker's upper-level exposures.
    Based on their estimates of workers' upper level exposures, Madl et
al. concluded that workers with sensitization or CBD were likely to
have been exposed to airborne beryllium levels greater than 0.2 [mu]g/
m\3\ as an 8-hour TWA at some point in their history of employment in
the plant. They also concluded that most sensitization and CBD cases
were likely to have been exposed to levels greater than 0.4 [mu]g/m\3\
at some point in their work at the plant. Madl et al. did not
reconstruct exposures for workers at the plant who did not have
sensitization or CBD and therefore could not determine whether non-
cases had upper-bound exposures lower than these levels. They found
that upper-bound exposure estimates were generally higher for workers
with CBD than for those who were sensitized but not diagnosed with CBD
at the conclusion of the study (Madl et al., 2007). Because CBD is an
immunological disease and beryllium sensitization has been shown to
occur within a year of exposure for some workers, Madl et al. argued
that their estimates of workers' short-term upper-bound exposures may
better capture the exposure levels that led to sensitization and
disease than estimates of long-term cumulative or average exposures
such as the LTW exposure measure constructed by Kelleher et al. (Madl
et al., 2007).
f. Beryllium Oxide Ceramics
    Kreiss et al. (1993) conducted a screening of current and former
workers at a plant that manufactured beryllium ceramics from beryllium
oxide between 1958 and 1975, and then transitioned to metalizing
circuitry onto beryllium ceramics produced elsewhere. Of the plant's
1,316 current and 350 retired workers, 505 participated who had not
previously been diagnosed with CBD or sarcoidosis, including 377
current and 128 former workers. Although beryllium exposure was not
estimated quantitatively in this survey, the authors conducted a
questionnaire to assess study participants' exposures qualitatively.
Results showed that 55 percent of participants reported working in jobs
with exposure to beryllium dust. Close to 25 percent of participants
did not know if they had exposure to beryllium, and just over 20
percent believed they had not been exposed.
    BeLPT tests were administered to all 505 participants in the 1989-
1990 screening period and evaluated at a single lab. Seven workers had
confirmed abnormal BeLPT results and were identified as sensitized;
these workers were also diagnosed with CBD based on findings of
granulomas upon clinical evaluation. Radiograph screening led to
clinical evaluation and diagnosis of two additional CBD cases, who were
among three participants with initially abnormal BeLPT results that
could not be confirmed on repeat testing. In addition, nine workers had
been previously diagnosed with CBD, and another five were diagnosed
shortly after the screening period, in 1991-1992.
    Eight (3.7 percent of the screening population) of the nine CBD
cases identified in the screening population were hired before the
plant stopped producing beryllium ceramics in 1975, and were among the
216 participants who had reported having been near or exposed to
beryllium dust. Particularly high CBD rates of 11.1-15.8 percent were
found among screening participants who had worked in process
development/engineering, dry pressing, and ventilation maintenance
jobs believed to have high or uncontrolled dust exposure. One case
(0.6 percent) of CBD was diagnosed among the 171 study participants
who had been hired after the plant stopped producing beryllium ceramics.
Although this worker was hired eight years after the end of
ceramics production, he had worked in an area later found to be
contaminated with beryllium dust. The authors concluded that the
study results suggested an exposure-response relationship between
beryllium exposure and CBD, and recommended beryllium exposure control
to reduce workers' risk of CBD.
    Kreiss et al. later published a study of workers at a second
ceramics plant located in Tucson, AZ (Kreiss et al., 1996), which since
1980 had produced beryllium ceramics from beryllium oxide powder
manufactured elsewhere. IH measurements collected between 1981 and
1992, primarily GA or short-term BZ samples and a few (< 100) LP
samples, were available from the plant. Airborne beryllium exposures
were generally low. The majority of area samples were below the
analytical detection limit of 0.1 [mu]g/m\3\, while LP and short-term
BZ samples had medians of 0.3 [mu]g/m\3\. However, 3.6 percent of
short-term BZ samples and 0.7 percent of GA samples exceeded 5.0 [mu]g/
mg\3\, while LP samples ranged from 0.1 to 1.8 [mu]g/m\3\. Machining
jobs had the highest beryllium exposure levels among job tasks, with
short-term BZ samples significantly higher for machining jobs than for
non-machining jobs (median 0.6 [mu]g/m\3\ vs. 0.3 [mu]g/mg\3\, p =
0.0001). The authors used DWA formulas provided by the plant to
estimate workers' full-shift exposure levels, and to calculate
cumulative and average beryllium exposures for each worker in the
study. The median cumulative exposure was 591.7 mg-days/m\3\ and the
median average exposure was 0.35 [mu]g/m\3\.
    One hundred thirty-six of the 139 workers employed at the plant at
the time of the Kreiss et al. (1996) study underwent BeLPT screening
and chest radiographs in 1992. Blood samples were split between two
laboratories. If one or both test results were abnormal, an additional
sample was collected and split between the labs. Seven workers with an
abnormal result on two draws were initially identified as sensitized.
Those with confirmed abnormal BeLPTs or abnormal chest X-rays were
offered clinical evaluation for CBD, including transbronchial lung
biopsy and BAL BeLPT. CBD was diagnosed based on observation of
granulomas on lung biopsy, in five of the six sensitized workers who
accepted evaluation. An eighth case of sensitization and sixth case of
CBD were diagnosed in one worker hired in October 1991 whose initial
BeLPT was normal, but who was confirmed as sensitized and found to have
lung granulomas less than two years later, after sustaining a
beryllium-contaminated skin wound. The plant medical department
reported 11 additional cases of CBD among former workers (Kreiss et
al., 1996). The overall prevalence of sensitization in the plant was
5.9 percent, with a 4.4 percent prevalence of CBD.
    Kreiss et al. reported that six (75 percent) of the eight
sensitized workers were exposed as machinists during or before the
period October 1985-March 1988, when measurements were first available
for machining jobs. The authors reported that 14.3 percent of
machinists were sensitized, compared to 1.2 percent of workers who had
never been machinists (p < 0.01). Workers' estimated cumulative and
average beryllium exposures did not differ significantly for machinists
and non-machinists, or for cases and non-cases. As in the previous
study of the same ceramics plant published by Kreiss et al. in 1993,
one case of CBD was diagnosed in a worker who had never been employed
in a production job. This worker was employed in administration, a job
with a median DWA of 0.1 [mu]g/m\3\ (range 0.1-0.3).
    In 1998, Henneberger et al. conducted a follow-up cross-sectional
survey of 151 employees employed at the beryllium ceramics plant
studied by Kreiss et al. (1996) (Henneberger et al., 2001). Employees
were eligible who either had not participated in the Kreiss et al.
survey ("short-term workers"--74 of those studied by Henneberger et
al.), or who had participated and were not found to have sensitization
or disease ("long-term workers"--77 of those studied by Henneberger
et al.).
    The authors estimated workers' cumulative, average, and peak
beryllium exposures based on the plant's formulas for estimating job-
specific DWA exposures, participants' work histories, and area and
short-term task-specific BZ samples collected from the start of full
production at the plant in 1981 to 1998. The long-term workers, who
were hired before the 1992 study was conducted, had generally higher
estimated exposures (median of average exposures--0.39 [mu]g/m\3\;
mean--14.9 [mu]g/m\3\) than the short-term workers, who were hired
after 1992 (median 0.28 [mu]g/m\3\, mean 6.1 [mu]g/m\3\).
    Fifteen cases of sensitization were found, including eight among
short-term and seven among long-term workers. Eight of the 15 workers
were found to have CBD. Of the workers diagnosed with CBD, seven (88
percent) were long-term workers. One non-sensitized long-term worker
and one sensitized long-term worker declined clinical examination.
    Henneberger et al. reported a higher prevalence of sensitization
among long-term workers with "high" (greater than median) peak
exposures compared to long-term workers with "low" exposures;
however, this relationship was not statistically significant. No
association was observed for average or cumulative exposures. The
authors reported higher prevalence of sensitization (but not
statistically significant) among short-term workers with "high"
(greater than median) average, cumulative, and peak exposures compared
to short-term workers with "low" exposures of each type.
    The cumulative incidence of sensitization and CBD was investigated
in a cohort of 136 workers at the beryllium ceramics plant previously
studied by the Kreiss and Henneberger groups (Schuler et al., 2008).
The study cohort consisted of those who participated in the plant-wide
BeLPT screening in 1992. Both current and former workers from this
group were invited to participate in follow-up BeLPT screenings in
1998, 2000, and 2002-03. A total of 106 of the 128 non-sensitized
individuals in 1992 participated in the 11-year follow-up.
Sensitization was defined as a confirmed abnormal BeLPT based on the
split blood sample-dual laboratory protocol described earlier. CBD was
diagnosed in sensitized individuals based on pathological findings from
transbronchial biopsy and BAL fluid analysis. The 11-year crude
cumulative incidence of sensitization and CBD was 13 percent (14 of
106) and 8 percent (9 of 106) respectively. The cumulative prevalence
was about triple the point prevalences determined in the initial 1992
cross-sectional survey. The corrected cumulative prevalences for those
that ever worked in machining were nearly twice that for non-
machinists. The data illustrate the value of longitudinal medical
screening over time to obtain a more accurate estimate of the
occurrence of sensitization and CBD among an exposed working
population.
    Following the 1998 survey, the company continued efforts to reduce
exposures and risk of sensitization and CBD by implementing additional
engineering, administrative, and PPE measures (Cummings et al., 2007).
Respirator use was required in production areas beginning in 1999, and
latex gloves were required beginning in 2000. The lapping area was
enclosed in 2000, and enclosures were installed for all mechanical
presses in 2001. Between 2000 and 2003, water-resistant or water-proof
garments, shoe covers, and taped gloves were incorporated to keep
beryllium-containing fluids from wet machining processes off the skin.
The new engineering measures did not appear to substantially reduce
airborne beryllium levels in the plant. LP samples collected between
2000 and 2003 had a median of 0.18 [mu]g/m\3\, similar to the 1994-1999
samples. However, respiratory protection requirements to control
workers' airborne beryllium exposures were instituted prior to the 2000
sample collections.
    To test the efficacy of the new measures instituted after 1998, in
January 2000 the company began screening new workers for sensitization
at the time of hire and at 3, 6, 12, 24, and 48 months of employment.
These more stringent measures appear to have substantially reduced the
risk of sensitization among new employees. Of 126 workers hired between
2000 and 2004, 93 completed BeLPT testing at hire and at least one
additional test at 3 months of employment. One case of sensitization
was identified at 24 months of employment (1 percent). This worker had
experienced a rash after an incident of dermal exposure to lapping
fluid through a gap between his glove and uniform sleeve, indicating
that he may have become sensitized via the skin. He was tested again at
48 months of employment, with an abnormal result.
    A second worker in the 2000-2004 group had two abnormal BeLPT tests
at the time of hire, and a third had one abnormal test at hire and a
second abnormal test at 3 months. Both had normal BeLPTs at 6 months,
and were not tested thereafter. A fourth worker had one abnormal BeLPT
result at the time of hire, a normal result at 3 months, an abnormal
result at 6 months, and a normal result at 12 months. Four additional
workers had one abnormal result during surveillance, which could not be
confirmed upon repeat testing.
    Cummings et al. calculated two sensitization rates based on these
screening results: (1) a rate using only the sensitized worker
identified at 24 months, and (2) a rate including all four workers who
had repeated abnormal results. They reported a sensitization incidence
rate (IR) of 0.7 per 1,000 person-months to 2.7 per 1,000 person-months
for the workers hired between 2000 and 2004, using the sum of
sensitization-free months of employment among all 93 workers as the
denominator.
    The authors also estimated an incidence rate (IR) of 5.6 per 1,000
person-months for workers hired between 1993 and the 1998 survey. This
estimated IR was based on one BeLPT screening, rather than BeLPTs
conducted throughout the workers' employment. The denominator in this
case was the total months of employment until the 1998 screening.
Because sensitized workers may have been sensitized prior to the
screening, the denominator may overestimate sensitization-free time in
the legacy group, and the actual sensitization IR for legacy workers
may be somewhat higher than 5.6 per 1,000 person-months. Based on
comparison of the IRs, the authors concluded that the addition of
respirator use, dermal protection, and housekeeping improvements
appeared to have reduced the risk of sensitization among workers at the
plant, even though airborne beryllium levels in some areas of the plant
had not changed significantly since the 1998 survey.
g. Copper-Beryllium Alloy Processing and Distribution
    Schuler et al. (2005) studied a group of 152 workers at a facility
processing copper-beryllium alloys and small quantities of nickel-
beryllium alloys, and converting semi-finished alloy strip and wire
into finished strip, wire and rod. Production activities included
annealing, drawing, straightening, point and chamfer, rod and wire
packing, die grinding, pickling, slitting, and degreasing. Periodically
in the plant's history, they also did salt baths, cadmium plating,
welding and deburring. Since the late 1980s, rod and wire production
processes were physically segregated from strip metal production.
Production support jobs included mechanical maintenance, quality
assurance, shipping and receiving, inspection, and wastewater
treatment. Administration was divided into staff primarily working
within the plant and personnel who mostly worked in office areas
(Schuler, et al., 2005). Workers' respirator use was limited, mostly to
occasional tasks where high exposures were anticipated.
    Following the 1999 diagnosis of a worker with CBD, the company
surveyed the workforce, offering all current employees BeLPT testing in
2000 and offering sensitized workers clinical evaluation for CBD,
including BAL and transbronchial biopsy. Of the facility's 185
employees, 152 participated in the BeLPT screening. Samples were split
between two laboratories, with additional draws and testing for
confirmation if conflicting tests resulted in the initial draw. Ten
participants (7 percent) had at least two abnormal BeLPT results. The
results of nine workers who had abnormal BeLPT results from only one
laboratory were not included because the authors believed it was
experiencing technical problems with the test (Schuler et al., 2005).
CBD was diagnosed in six workers (4 percent) on evidence of pathogenic
abnormalities (e.g., granulomas) or evidence of clinical abnormalities
consistent with CBD based on pulmonary function testing, pulmonary
exercise testing, and/or chest radiography. One worker diagnosed with
CBD had been exposed to beryllium during previous work at another
copper-beryllium processing facility.
    Schuler et al. evaluated airborne beryllium levels at the plant
using IH samples collected between 1969 and 2000, including 4,524 GA
samples, 650 LP samples and 815 short-duration (3-5 min) high volume
(SD-HV) BZ task-specific samples. Occupational exposures to airborne
beryllium were generally low. Ninety-nine percent of all LP
measurements were below the current OSHA PEL of 2.0 [mu]g/m\3\ (8-hr
TWA); 93 percent were below the DOE action level of 0.2 [mu]g/m\3\; and
the median value was 0.02 [mu]g/m\3\. The SD-HV BZ samples had a median
value of 0.44 [mu]g/m\3\, with 90 percent below the OSHA Short-Term
Exposure Limit (STEL) of 5.0 [mu]g/m\3\. The highest levels of
beryllium were found in rod and wire production, particularly in wire
annealing and pickling, the only production job with a median personal
sample measurement greater than 0.1 [mu]g/m\3\ (median 0.12 [mu]g/m\3\;
range 0.01-7.8 [mu]g/m\3\) (Schuler et al., Table 4). These
concentrations were significantly higher than the exposure levels in
the strip metal area (median 0.02, range 0.01-0.72 [mu]g/m\3\), in
production support jobs (median 0.02, range < 0.01-0.33 [mu]g/m\3\),
plant administration (median 0.02, range < 0.01-0.11 [mu]g/m\3\), and
office administration jobs (median 0.01, range < 0.01-0.06 [mu]g/m\3\).
    The authors reported that eight of the ten sensitized employees,
including all six CBD cases, had worked in both major production areas
during their tenure with the plant. The 7 percent prevalence (6 of 81
workers) of CBD among employees who had ever worked in rod and wire was
statistically significantly elevated compared with employees who had
never worked in rod and wire (p < 0.05), while the 6 percent prevalence
(6 of 94 workers) among those who had worked in strip metal was not
significantly elevated compared to non-strip metal workers (p > 0.1).
Based on these results, together with the higher exposure levels
reported for the rod and wire production area, Schuler et al. concluded
that work in rod and wire was a key risk factor for CBD in this
population. Schuler et al. also found a high prevalence (13 percent) of
sensitization among workers who had been exposed to beryllium for less
than a year at the time of the screening, a rate similar to that found
by Henneberger et al. among beryllium ceramics workers exposed for one
year or less (16 percent, Henneberger et al., 2001). All four workers
who were sensitized without disease had been exposed 5 years or less;
conversely, all six of the workers with CBD had first been exposed to
beryllium at least five years prior to the screening (Schuler et al.,
Table 2).
    As has been seen in other studies, beryllium sensitization and CBD
were found among workers who were typically exposed to low time-
weighted average airborne concentrations of beryllium. While jobs in
the rod and wire area had the highest exposure levels in the plant, the
median personal sample value was only 0.12 [mu]g/m\3\. However, workers
may have occasionally been exposed to higher beryllium levels for short
periods during specific tasks. A small fraction of personal samples
recorded in rod and wire were above the OSHA PEL of 2.0 [mu]g/m\3\, and
half of workers with sensitization or CBD reported that they had
experienced a "high-exposure incident" at some point in their work
history (Schuler et al., 2005). The only group of workers with no cases
of sensitization or CBD, a group of 26 office administration workers,
was the group with the lowest recorded exposures (median personal
sample 0.01 [mu]g/m\3\, range < 0.01-0.06 [mu]g/m\3\).
    After the BeLPT screening was conducted in 2000, the company began
implementing new measures to further reduce workers' exposure to
beryllium (Thomas et al., 2009). Requirements designed to minimize
dermal contact with beryllium, including long-sleeve facility uniforms
and polymer gloves, were instituted in production areas in 2000. In
2001 the company installed LEV in die grinding and polishing. LP
samples collected between June 2000 and December 2001 show reduced
exposures plant-wide. Of 2,211 exposure samples collected, 98 percent
were below 0.2 [mu]g/m\3\, and 59 percent below the limit of detection
(LOD), which was either 0.02 [micro]g/m\3\ or 0.2 [micro]g/m\3\
depending on the method of sample analysis (Thomas et al., 2009).
Median values below 0.03 [mu]g/m\3\ were reported for all processes
except the wire annealing and pickling process. Samples for this
process remained somewhat elevated, with a median of 0.1 [mu]g/m\3\. In
January 2002, the plant enclosed the wire annealing and pickling
process in a restricted access zone (RAZ), requiring respiratory PPE in
the RAZ and implementing stringent measures to minimize the potential
for skin contact and beryllium transfer out of the zone. While exposure
samples collected by the facility were sparse following the enclosure,
they suggest exposure levels comparable to the 2000-01 samples in areas
other than the RAZ. Within the RAZ, required use of powered air-
purifying respirators indicates that respiratory exposure was
negligible.
    To test the efficacy of the new measures in preventing
sensitization and CBD, in June 2000 the facility began an intensive
BeLPT screening program for all new workers. The company screened
workers at the time of hire; at intervals of 3, 6, 12, 24, and 48
months; and at 3-year intervals thereafter. Among 82 workers hired
after 1999, three (3.7 percent) cases of sensitization were found. Two
(5.4 percent) of 37 workers hired prior to enclosure of the wire
annealing and pickling process were found to be sensitized within 3 and
6 months of beginning work at the plant. One (2.2 percent) of 45
workers hired after the enclosure was confirmed as sensitized.
    Thomas et al. calculated a sensitization IR of 1.9 per 1,000
person-months for the workers hired after the exposure control program
was initiated in 2000 ("program workers"), using the sum of
sensitization-free months of employment among all 82 workers as the
denominator (Thomas et al., 2009). They calculated an estimated IR of
3.8 per 1,000 person-months for 43 workers hired between 1993 and 2000
who had participated in the 2000 BeLPT screening ("legacy workers").
This estimated IR was based on one BeLPT screening, rather than BeLPTs
conducted throughout the legacy workers' employment. The denominator in
this case is the total months of employment until the 2000 screening.
Because sensitized workers may have been sensitized prior to the
screening, the denominator may overestimate sensitization-free time in
the legacy group, and the actual sensitization IR for legacy workers
may be somewhat higher than 3.8 per 1,000 person-months. Based on
comparison of the IRs and the prevalence rates discussed previously,
the authors concluded that the combination of dermal protection,
respiratory protection, housekeeping improvements and engineering
controls implemented beginning in 2000 appeared to have reduced the
risk of sensitization among workers at the plant. However, they noted
that the small size of the study population and the short follow-up
time for the program workers suggested that further research is needed
to confirm the program's efficacy (Thomas et al., 2009).
    Stanton et al. (2006) conducted a study of workers in three
different copper-beryllium alloy distribution centers in the United
States. The distribution centers, including one bulk products center
established in 1963 and strip metal centers established in 1968 and
1972, sell products received from beryllium production and finishing
facilities and small quantities of copper-beryllium, aluminum-
beryllium, and nickel-beryllium alloy materials. Work at distribution
centers does not require large-scale heat treatment or manipulation of
material typical of beryllium processing and machining plants, but
involves final processing steps that can generate airborne beryllium.
Slitting, the main production activity at the two strip product
distribution centers, generates low levels of airborne beryllium
particles, while operations such as tensioning and welding used more
frequently at the bulk products center can generate somewhat higher
levels. Non-production jobs at all three centers included shipping and
receiving, palletizing and wrapping, production-area administrative
work, and office-area administrative work.
    The authors estimated workers' beryllium exposures using IH data
from company records and job history information collected through
interviews conducted by a company occupational health nurse. Stanton et
al. evaluated airborne beryllium levels in various jobs based on 393
full-shift LP samples collected from 1996 to 2004. Airborne beryllium
levels at the plant were generally very low, with 54 percent of all
samples at or below the LOD, which ranged from 0.02 to 0.1 [mu]g/m\3\.
The authors reported a median of 0.03 [mu]g/m\3\ and an arithmetic mean
of 0.05 [mu]g/m\3\ for the 393 full-shift LP samples, where samples
below the LOD were assigned a value of half the applicable LOD. Median
and geometric mean values for specific jobs ranged from 0.01-0.07 and
0.02-0.07 [micro]g/m\3\, respectively. All measurements were
below the OSHA PEL of 2.0 [mu]g/m\3\ and 97 percent were below the DOE
action level of 0.2 [mu]g/m\3\. The paper does not report use of
respiratory or skin protection. Exposure conditions may have changed
somewhat over the history of the plant due to changes in exposure
control measures, including improvements to product and container
cleaning practices instituted during the 1990s.
    Eighty-eight of the 100 workers (88 percent) employed at the three
centers at the time of the study participated in screening for
beryllium sensitization. Blood samples were collected between November
2000 and March 2001 by the company's medical staff. Samples collected
from employees of the strip metal centers were split and evaluated at
two laboratories, while samples from the bulk product center workers
were evaluated at a single laboratory. Participants were considered to
be "sensitized" to beryllium if two or more BeLPT results, from two
laboratories or from repeat testing at the same laboratory, were found
to be abnormal. One individual was found to be sensitized and was
offered clinical evaluation, including BAL and fiberoptic bronchoscopy.
He was found to have lung granulomas and was diagnosed with CBD.
    The worker diagnosed with CBD had been employed at a strip metal
distribution center from 1978 to 2000 as a shipper and receiver,
loading and unloading trucks delivering materials from a beryllium
production facility and to the distribution center's customers.
Although the LP samples collected for his job between 1996 and 2000
were generally low (n = 35, median 0.01, range < 0.02-0.13 [micro]g/
m\3\), it is not clear whether these samples adequately characterize
his exposure conditions over the course of his work history. He
reported that early in his work history, containers of beryllium oxide
powder were transported on the trucks he entered. While he did not
recall seeing any breaks or leaks in the beryllium oxide containers,
some containers were known to have been punctured by forklifts on
trailers used by the company during the period of his employment, and
could have contaminated trucks he entered. With 22 years of employment
at the facility, this worker had begun beryllium-related work earlier
and performed it longer than about 90 percent of the study population
(Stanton et al., 2006).
h. Nuclear Weapons Production Facilities & Cleanup of Former Facilities
    Primary exposure from nuclear weapons production facilities comes
from beryllium metal and beryllium alloys. A study conducted by Kreiss
et al. (1989) documented sensitization and CBD among beryllium-exposed
workers in the nuclear industry. A company medical department
identified 58 workers with beryllium exposure among a work force of
500, of whom 51 (88 percent) participated in the study. Twenty-four
workers were involved in research and development (R&D), while the
remaining 27 were production workers. The R&D workers had a longer
tenure with a mean time from first exposure of 21.2 years, compared to
a mean time since first exposure of 5 years among the production
workers. The number of workers with abnormal BeLPT readings was 6, with
4 being diagnosed with CBD. This resulted in an estimated 11.8 percent
prevalence of sensitization.
    Kreiss et al. (1993) expanded the work of Kreiss et al. (1989) by
performing a cross-sectional study of 895 (current and former)
beryllium workers in the same nuclear weapons plant. Participants were
placed in qualitative exposure groups ("no exposure," "minimal
exposure," "intermittent exposure," and "consistent exposure")
based on questionnaire responses. The number of workers with abnormal
BeLPT totaled 18 with 12 being diagnosed with CBD. Three additional
workers with sensitization developed CBD over the next 2 years.
Sensitization occurred in all of the qualitatively defined exposure
groups. Individuals who had worked as machinists were statistically
overrepresented among beryllium-sensitized cases, compared with non-
cases. Cases were more likely than non-cases to report having had a
measured overexposure to beryllium (p = 0.009), a factor which proved
to be a significant predictor of sensitization in logistic regression
analyses, as was exposure to beryllium prior to 1970. Beryllium
sensitized cases were also significantly more likely to report having
had cuts that were delayed in healing (p = 0.02). The authors concluded
that individual variability and susceptibility along with exposure
circumstances are important factors in developing beryllium
sensitization and CBD.
    In 1991, the Beryllium Health Surveillance Program (BHSP) was
established at the Rocky Flats Nuclear Weapons Facility to offer BLPT
screening to current and former employees who may have been exposed to
beryllium (Stange et al., 1996). Participants received an initial BeLPT
and follow-ups at one and three years. Based on histologic evidence of
pulmonary granulomas and a positive BAL-BeLPT, Stange et al. published
a study of 4,397 BHSP participants tested from June 1991 to March 1995,
including current employees (42.8 percent) and former employees (57.2
percent). Twenty-nine cases of CBD and 76 cases of sensitization were
identified. The sensitization rate for the population was 2.43 percent.
Available exposure data included fixed airhead (FAH) exposure samples
collected between 1970 and 1988 (mean concentration 0.016 [micro]g/
m\3\) and personal samples collected between 1984 and 1987 (mean
concentration 1.04 [micro]g/m\3\). Cases of CBD and sensitization were
noted in individuals in all jobs classifications, including those
believed to involve minimal exposure to beryllium. The authors
recommended ongoing surveillance for workers in all jobs with potential
for beryllium exposure.
    Stange et al. (2001) extended the previous study, evaluating 5,173
participants in the Rocky Flats BHSP who were tested between June 1991
and December 1997. Three-year serial testing was offered to employees
who had not been tested for three years or more and did not show
beryllium sensitization during the previous study. This resulted in
2,891 employees being tested. Of the 5,173 workers participating in the
study, 172 were found to have abnormal BeLPT. Ninety-eight (3.33
percent) of the workers were found to be sensitized (confirmed abnormal
BeLPT results) in the initial screening, conducted in 1991. Of these
workers 74 were diagnosed with CBD (history of beryllium exposure,
evidence of non-caseating granulomas or mononuclear cell infiltrates on
lung biopsy, and a positive BeLPT or BAL-BeLPT). A follow-up survey of
2,891 workers three years later identified an additional 56 sensitized
workers and an additional seven cases of CBD. Sensitization and CBD
rates were analyzed with respect to gender, building work locations,
and length of employment. Historical employee data included hire date,
termination date, leave of absences, and job title changes. Exposure to
beryllium was determined by job categories and building or work area
codes. Personal beryllium air monitoring results were used, when
available, from employees with the same job title or similar job.
However, no quantitative information was presented in the study. The
authors conclude that for some individuals, exposure to beryllium at
levels less that the OSHA PEL could cause sensitization and CBD.
    Viet et al. (2001) conducted a case-control study of the Rocky
Flats worker population studied by Stange et al. (1996 and 2001) to
examine the relationship between estimated beryllium exposure level
and risk of sensitization or CBD. The worker population included
74 beryllium-sensitized workers and 50 workers diagnosed with CBD.
Beryllium exposure levels were estimated based on FAH airhead samples
from one building, the beryllium machine shop. These were collected
 away from the BZ of the machine operator and likely underestimated exposure.
To estimate levels in other locations, these air sample concentrations were
used to construct a job exposure matrix that included the determination of
the Building 444 exposure estimates for a 30-year period; each subject's
work history by job location, task, and time period; and assignment of
exposure estimates to each combination of job location, task, and time period
as compared to Building 444 machinists. The authors adjusted the levels
observed in the machine shop by factors based on interviews with former
workers. Workers' estimated mean exposure concentrations ranged from 0.083
[micro]g/m\3\ to 0.622 [micro]g/m\3\. Estimated maximum air
concentrations ranged from 0.54 [micro]g/m\3\ to 36.8 [micro]g/m\3\.
Cases were matched to controls of the same age, race, gender, and
smoking status (Viet et al., 2001).
    Estimated mean and cumulative exposure levels and duration of
employment were found to be significantly higher for CBD cases than for
controls. Estimated mean exposure levels were significantly higher for
sensitization cases than for controls. No significant difference was
observed for estimated cumulative exposure or duration of exposure.
Similar results were found using logistic regression analysis, which
identified statistically significant relationships between CBD and both
cumulative and mean estimated exposure, but did not find significant
relationships between estimated exposure levels and sensitization
without CBD. Comparing CBD with sensitization cases, Viet et al. found
that workers with CBD had significantly higher estimated cumulative and
mean beryllium exposure levels than workers who were sensitized, but
did not have CBD.
    Johnson et al. (2001) conducted a review of personal sampling
records and medical surveillance reports at an atomic weapons
establishment in Cardiff, United Kingdom. The study evaluated airborne
samples collected over the 36-year period of operation for the plant.
Data included 367,757 area samples and 217,681 personal lapel samples
from 194 workers over the time period from 1981-1997. Data was
available prior to this time period but was not analyzed since this
data was not available electronically. The authors estimated that over
the 17 years of measurement data analyzed, airborne beryllium
concentrations did exceed 2.0 [micro]g/m\3\, however, due to the
limitations with regard to collection times it is difficult to assess
the full reliability of this estimate. The authors noted that in the
entire plant's history, only one case of CBD had been diagnosed. It was
also noted that BeLPT has not been routinely conducted among any of the
workers at this facility.
    Armojandi et al. (2010) conducted a cross-sectional study of
workers at a nuclear weapons research and development (R&D) facility to
determine the risk of developing CBD in sensitized workers at
facilities with exposures much lower than production plants. Of the
1875 current or former workers at the R&D facility, 59 were determined
to be sensitized based on at least two positive BeLPTs (i.e., samples
drawn on two separate occasions or on split samples tested in two
separate DOE-approved laboratories) for a sensitization rate of 3.1
percent. Workers found to have positive BeLPTs were further evaluated
in an Occupational Medicine Clinic between 1999 through 2005. Armojandi
et al. (2010) evaluated 50 of the sensitized workers who also had
medical and occupational histories, physical examination, chest imaging
with high-resolution computed tomography (HRCT) (N = 49), and pulmonary
function testing (nine of the 59 workers refused physical examinations
so were not included in this study). Forty of the 50 workers chosen for
this study underwent bronchoscopy for bronchoalveolar lavage and
transbronchial biopsies in additional to the other testing. Five of the
49 workers had CBD at the time of evaluation (based on histology or
high-resolution computed tomography); three others had evidence of
probable CBD; however, none of these cases were classified as severe at
the time of evaluation. The rate of CBD at the time of study among
sensitized individuals was 12.5 percent (5/40) for those using
pathologic review of lung tissue, and 10.2 percent (5/49) for those
using HRCT as a criteria for diagnosis. The rate of CBD among the
entire population (5/1875) was 0.3 percent.
    The mean duration of employment at the facility was 18 years, and
the mean latency period (from first possible exposure) to time of
evaluation and diagnosis was 32 years. There was no available exposure
monitoring in the breathing zone of workers at the facility but the
beryllium levels were believed to be relatively low (possibly less than
0.1 [mu]g/m\3\ for most jobs). There was not an apparent exposure-
response relationship for sensitization or CBD. The sensitization
prevalence was similar and the CBD prevalence higher among workers with
the lower-exposure jobs. The authors concluded that these sensitized
workers, who were subjected to an extended duration of low potential
beryllium exposures over a long latency period, had a low prevalence of
CBD (Armojandi et al., 2010).
i. Aluminum Smelting
    Bauxite ore, the primary source of aluminum, contains naturally
occurring beryllium. Worker exposure to beryllium can occur at aluminum
smelting facilities where aluminum extraction occurs via electrolytic
reduction of aluminum oxide into aluminum metal. Characterization of
beryllium exposures and sensitization prevalence rates were examined by
Taiwo et al. (2010) in a study of nine aluminum smelting facilities
from four different companies in the U.S., Canada, Italy and Norway.
    Of the 3,185 workers determined to be potentially exposed to
beryllium, 1,932 agreed to participate in a medical surveillance
program between 2000 and 2006 (60 percent participation rate). The
medical surveillance program included serum BeLPT analysis,
confirmation of an abnormal BeLPT with a second BeLPT, and follow-up of
all confirmed positive responses by a pulmonary physician to evaluate
for progression to CBD.
    Eight-hour TWAs were assessed utilizing 1,345 personal samples
collected from the 9 smelters. The personal beryllium samples obtained
showed a range of 0.01-13.00 [mu]g/m\3\ time-weighted average with an
arithmetic mean of 0.25 [mu]g/m\3\ and geometric mean of 0.06 [mu]g/
m\3\. Exposure levels to beryllium observed in aluminum smelters are
similar to those seen in other industries that utilize beryllium. Of
the 1,932 workers surveyed by BeLPT, nine workers were diagnosed with
sensitization (prevalence rate of 0.47 percent, 95% confidence interval
= 0.21-0.88 percent) with 2 of these workers diagnosed with probable
CBD after additional medical evaluations.
    The authors concluded that compared with beryllium-exposed workers
in other industries, the rate of sensitization among aluminum smelter
workers appears lower. The authors speculated that this lower observed
rate could be related to a more soluble form of beryllium found in the
aluminum smelting work environment as well as the consistent use of
respiratory protection. However, the authors also speculated that the
60 percent participation rate may have underestimated the sensitization
rate in this worker population.
    A study by Nilsen et al. (2010) also found a low rate of
sensitization among aluminum workers in Norway. Three-hundred sixty-two
workers and thirty-one control individuals were tested for beryllium
sensitization based on the BeLPT. The results found that one (0.28%) of
the smelter workers had been sensitized. No borderline results were
reported. The exposure estimated in this plant was 0.1 [micro]g/m\3\ to
0.31 [micro]g/m\3\ (Nilsen et al., 2010).
6. Animal Models of CBD
    This section reviews the relevant animal studies supporting the
mechanisms outlined above. Researchers have attempted to identify
animal models with which to further investigate the mechanisms
underlying the development of CBD. A suitable animal model should
exhibit major characteristics of CBD, including the demonstration of a
beryllium-specific immune response, the formation of immune granulomas
following inhalation exposure to beryllium, and mimicking the
progressive nature of the human disease. While exposure to beryllium
has been shown to cause chronic granulomatous inflammation of the lung
in animal studies using a variety of species, most of the granulomatous
lesions were formed by foreign-body reactions, which result from
persistent irritation and consist predominantly of macrophages and
monocytes, and small numbers of lymphocytes. Foreign-body granulomas
are distinct from the immune granulomas of CBD, which are caused by
antigenic stimulation of the immune system and contain large numbers of
lymphocytes. Animal studies have been useful in providing biological
plausibility for the role of immunological alterations and lung
inflammation and in clarifying certain specific mechanistic aspects of
beryllium disease. However, the lack of a dependable animal model that
mimics all facets of the human response combined with study limitations
in terms of single dose experiments, few animals, or abbreviated
observation periods have limited the utility of the data. Currently, no
single model has completely mimicked the disease process as it
progresses in humans. The following is a discussion of the most
relevant animal studies regarding the mechanisms of sensitization and
CBD development in humans. Table A.2 in the Appendix summarizes
species, route, chemical form of beryllium, dose levels, and
pathological findings of the key studies.
    Harmsen et al. performed a study to assess whether the beagle dog
could provide an adequate model for the study of beryllium-induced lung
diseases (Harmsen et al., 1986). One group of dogs served as a control
group (air inhalation only) and four other groups received high
(approximately 50 [mu]g/kg) and low (approximately 20 [mu]g/kg) doses
of beryllium oxide calcined at 500 [deg]C or 1,000[deg] C, administered
as aerosols in a single exposure. As discussed above, calcining
temperature controls the solubility and SSA of beryllium particles.
Those particles calcined at higher temperatures (e.g., 1,000[deg] C)
are less soluble and have lower SSA than particles calcined at lower
temperatures (e.g., 500 [deg]C). Solubility and SSA are factors in
determining the toxic potential of beryllium compounds or materials.
    Cells were collected from the dogs by BAL at 30, 60, 90, 180, and
210 days after exposure, and the percentages of neutrophils and
lymphocytes were determined. In addition, the mitogenic responses of
blood lymphocytes and lavage cells collected at 210 days were
determined with either phytohemagglutinin or beryllium sulfate as
mitogen. The percentage of neutrophils in the lavage fluid was
significantly elevated only at 30 days with exposure to either dose of
500 [deg]C beryllium oxide. The percentage of lymphocytes in the fluid
was significantly elevated in samples across all times with exposure to
the high dose of this beryllium oxide form. Beryllium oxide calcined at
1,000[deg] C elevated lavage lymphocytes only in high dose at 30 days.
No significant effect of 1,000[deg] C beryllium oxide exposure on
mitogenic response of any lymphocytes was seen. In contrast, peripheral
blood lymphocytes from the 500 [deg]C beryllium oxide exposed groups
were significantly stimulated by beryllium sulfate compared with the
phytohemagglutinin exposed cells. The investigators in this study were
able to replicate some of the same findings as those observed in human
studies--specifically, that beryllium in soluble and insoluble forms
can be mitogenic to immune cells, an important finding for progression
of sensitization and proliferation of immune cells to developing full-
blown CBD.
    In another beagle study Haley et al. also found that the beagle dog
appears to model some aspects of human CBD (Haley et al., 1989). The
authors monitored lung pathologic effects, particle clearance, and
immune sensitization of peripheral blood leukocytes following a single
exposure to beryllium oxide aerosol generated from beryllium oxide
calcined at 500 [deg]C or 1,000[deg] C. The aerosol was administered to
the dogs perinasally to attain initial lung burdens of 6 or 18 [mu]g
beryllium/kg body weight. Granulomatous lesions and lung lymphocyte
responses consistent with those observed in humans with CBD were
observed, including perivascular and peribronchiolar infiltrates of
lymphocytes and macrophages, progressing to microgranulomas with areas
of granulomatous pneumonia and interstitial fibrosis. Beryllium
specificity of the immune response was demonstrated by positive results
in the BeLPT, although there was considerable inter-animal variation.
The lesions declined in severity after 64 days post-exposure. Thus,
while this model was able to mimic the formation of Be-specific immune
granulomas, it was not able to mimic the progressive nature of disease.
    This study also provided an opportunity to compare the effects of
beryllium oxide calcination temperature on granulomatous disease in the
beagle respiratory system. Haley et al. found an increase in the
percentage and numbers of lymphocytes in BAL fluid at 3 months post-
exposure in dogs exposed to either dose of beryllium oxide calcined at
500 [deg]C, but not in dogs exposed to the material calcined at the
higher temperature. Although there was considerable inter-animal
variation, lesions were generally more severe in the dogs exposed to
material calcined at 500 [deg]C. Positive BeLPT results were observed
with BAL lymphocytes only in the group with a high initial lung burden
of the material calcined at 500 [deg]C, but positive results with
peripheral blood lymphocytes were observed at both doses with material
calcined at both temperatures.
    The histologic and immunologic responses of canine lungs to
aerosolized beryllium oxide were investigated in another Haley et al.
(1989) study. Beagle-dogs were exposed in a single exposure to high
dose (50 [micro]g/kg of body weight) or low dose (l7 [micro]g/kg)
levels of beryllium oxide calcined at either 500[deg] or 1000[deg] C.
One group of dogs was examined up to 365 days after exposure for lung
histology and biochemical assay to determine the fate of inhaled
beryllium oxide. A second group underwent BAL for lung lymphocyte
analysis for up to 22 months after exposure. Histopathologic
examination revealed peribronchiolar and perivascular lymphocytic
histiocytic inflammation, peaking at 64 days after beryllium oxide exposure.
Lymphocytes were initially well differentiated, but progressed to
lymphoblastic cells and aggregated in lymphofollicular nodules or
microgranulomas over time. Alveolar macrophages were large, and filled
with intracytoplasmic material. Cortical and paracortical lymphoid
hyperplasia of the tracheobronchial nodes was found. Lung lymphocyte
concentrations were increased at 3 months and returned to normal in
both dose groups given 500 [deg]C treated beryllium chloride. No
significant elevations in lymphocyte concentrations were found in dogs
given 1,000[deg] C treated beryllium oxide. Lung retention was higher
in the 500 [deg]C treated beryllium oxide group. The lesions found in
dog lungs closely resembled those found in humans with CBD: severe
granulomas, lymphoblast transformation, increased pulmonary lymphocyte
concentrations and variation in beryllium sensitivity. It was concluded
that the canine model for berylliosis may provide insight into this
disease.
    In a follow-up experiment, control dogs and those exposed to
beryllium oxide calcined at 500 [deg]C were allowed to rest for 2.5
years, and then re-exposed to filtered air (controls) or beryllium
oxide calcined at 500 [deg]C for an initial lung burden (ILB) target of
50 [mu]g beryllium oxide/kg body weight (Haley et al., 1992). Immune
responses of blood and BAL lymphocytes, and lung lesions in dogs
sacrificed 210 days post-exposure, were compared with results following
the initial exposure. The severity of lung lesions was comparable under
both conditions, suggesting that a 2.5-year interval was sufficient to
prevent cumulative pathologic effects. Conradi et al. (1971) found no
exposure-related histological alterations in the lungs of six beagle
dogs exposed to a range of 3,300-4,380 [mu]g Be/m\3\ as beryllium oxide
calcined at 1,400[deg] C for 30 min, once per month for 3 months.
Because the dogs were sacrificed 2 years post-exposure, the long time
period between exposure and response may have allowed for the reversal
of any beryllium-induced changes (EPA, 1998).
    A 1994 study by Haley et al. showed that intra-bronchiolar
instillation of beryllium induced immune granulomas and sensitization
in monkeys. Haley et al. (1994) exposed male cynomolgus monkeys to
either beryllium metal or beryllium oxide calcined at 500 [deg]C by
intrabronchiolar instillation as a saline suspension. Lymphocyte counts
in BAL fluid were observed, and were found to be significantly
increased in monkeys exposed to beryllium metal on post-exposure days
14 to 90, and on post-exposure day 60 in monkeys exposed to beryllium
oxide. The lungs of monkeys exposed to beryllium metal had lesions
characterized by interstitial fibrosis, Type II cell hyperplasia, and
lymphocyte infiltration. Some monkeys also exhibited immune granulomas.
Similar lesions were observed in monkeys exposed to beryllium oxide,
but the incidence and severity were much less. BAL lymphocytes from
monkeys exposed to beryllium metal, but not from monkeys exposed to
beryllium oxide, proliferated in response to beryllium sulfate in the
BeLPT (EPA, 1998).
    In an experiment similar to the one conducted with dogs, Conradi et
al. (1971) found no effect in monkeys (Macaca irus) exposed via whole-
body inhalation for three 30-minute monthly exposures to a range of
3,300-4,380 [mu]g Be/m\3\ as beryllium oxide calcined at 1,400[deg] C.
The lack of effect may have been related to the long period (2 years)
between exposure and sacrifice, or to low toxicity of beryllium oxide
calcined at such a high temperature.
    As discussed earlier in this Health Effects section, at the
cellular level, beryllium dissolution must occur for either a dendritic
cell or a macrophage to present beryllium as an antigen to induce the
cell-mediated CBD immune reactions (Stefaniak et al., 2006). Several
studies have shown that low-fired beryllium oxide, which is
predominantly made up of poorly crystallized small particles, is more
immunologically reactive than beryllium oxide calcined at higher firing
temperatures that result in less reactivity due to increasing crystal
size. As discussed previously, Haley et al. (1989a) found more severe
lung lesions and a stronger immune response in beagle dogs receiving a
single inhalation exposure to beryllium oxide calcined at 500 [deg]C
than in dogs receiving an equivalent initial lung burden of beryllium
oxide calcined at 1,000[deg] C. Haley et al. found that beryllium oxide
calcined at 1,000[deg] C elicited little local pulmonary immune
response, whereas the much more soluble beryllium oxide calcined at 500
[deg]C produced a beryllium-specific, cell-mediated immune response in
dogs (Haley et al., 1991).
    In a later study, beryllium metal appeared to induce a greater
toxic response than beryllium oxide following intrabronchiolar
instillation in cynomolgus monkeys, as evidenced by more severe lung
lesions, a larger effect on BAL lymphocyte counts, and a positive
response in the BeLPT with BAL lymphocytes only after exposure to
beryllium metal (Haley et al., 1994). Because an oxide layer may form
on beryllium-metal surfaces after exposure to air (Mueller and
Adolphson, 1979; Harmsen et al., 1986) dissolution of small amounts of
poorly soluble beryllium compounds in the lungs might be sufficient to
allow persistent low-level beryllium presentation to the immune system
(NAS, 2008).
    Genetic studies in humans led to the creation of an animal model
containing different human HLA-DP alleles inserted into FVB/N mice for
mechanistic studies of CBD. Three strains of genetically engineered
mice (transgenic mice) were created that conferred different risks for
developing CBD based on human studies (Weston et al., 2005; Snyder et
al., 2008): (1) the HLDPB1*401 transgenic strain, where the transgene
codes for lysine residue at the 69th position of the B-chain conferred
low risk of CBD; (2) the HLA-DPB1*201 mice, where the transgene codes
for glutamic acid residue at the 69th position of the B-chain and
glycine residues at positions 84 and 85 conferred medium risk of CBD;
and (3) the HLA-DPB1*1701 mice, where the transgene codes for glutamic
acid at the 69th position of the B-chain and aspartic acid and glutamic
acid residues at positions 84 and 85, respectively, conferred high risk
of CBD (Tarantino-Hutchinson et al., 2009).
    In order to validate the transgenic model, Tarantino-Hutchison et
al. challenged the transgenic mice along with seven different inbred
mouse strains to determine the susceptibility and sensitivity to
beryllium exposure. Mice were dermally exposed with either saline or
beryllium, then challenged with either saline or beryllium (as
beryllium sulfate) using the MEST protocol (mouse ear-swelling test).
The authors determined that the high risk HLA-DPB1*1701 transgenic
strain responded 4 times greater (as measured via ear swelling) than
control mice and at least 2 times greater than other strains of mice.
The findings correspond to epidemiological study results reporting an
enhanced CBD odds ratio for the HLA-DPB1*1701 in humans (Weston et al.,
2005; Snyder et al., 2008). Transgenic mice with the genes
corresponding to the low and medium odds ratio study did not respond
significantly over the control group. The authors concluded that while
HLA-DPB1*1701 is important to beryllium sensitization and progression
to CBD, other genetic and environmental factors contribute to the
disease process as well.

7. Preliminary Beryllium Sensitization and CBD Conclusions
    It is well-established that skin and inhalation exposure to
beryllium may lead to sensitization and that inhalation exposure, or
skin exposure coupled with inhalation exposure, may lead to the onset
and progression of CBD. This is supported by extensive human studies.
While all facets of the biological mechanism for this complex disease
have yet to be fully elucidated, many of the key events in the disease
sequence have been identified and described in the previous sections.
Sensitization is a necessary first step to the onset of CBD (NAS,
2008). Sensitization is the process by which the immune system
recognizes beryllium as a foreign substance and responds in a manner
that may lead to development of CBD. It has been documented that a
substantial proportion of sensitized workers exposed to airborne
beryllium progress to CBD (Rosenman et al., 2005; NAS, 2008; Mroz et
al., 2009). Animal studies, particularly in dogs and monkeys, have
provided supporting evidence for T-cell lymphocyte proliferation in the
development of granulomatous lung lesions after exposure to beryllium
(Harmsen et al., 1986; Haley et al., 1989, 1992, 1994). The animal
studies have also provided important insights into the roles of
chemical form, genetic susceptibility, and residual lung burden in the
development of beryllium lung disease (Harmsen et al., 1986; Haley et
al., 1992; Tarantino-Hutchison et al., 2009). OSHA has made a
preliminary determination to consider sensitization and CBD to be
adverse events along the pathological continuum in the disease process,
with sensitization being the necessary first step in the progression to
CBD.
    The epidemiological evidence presented in this section demonstrates
that sensitization and CBD are continuing to occur from present-day
exposures below OSHA's PEL (Rosenman, 2005 with erratum published
2006). The available literature discussed above shows that disease
prevalence can be reduced by reducing inhalation exposure (Thomas et
al., 2009). However, the available epidemiological studies also
indicate that it may be necessary to minimize skin exposure to further
reduce the incidence of sensitization (Bailey et al., 2010). The
preliminary risk assessment further discusses the effectiveness of
interventions to reduce beryllium exposures and the risk of
sensitization and CBD (see section VI, Preliminary Risk Assessment).
    Studies have demonstrated there remains a prevalence of
sensitization and CBD in facilities with exposure levels below the
current OSHA PEL (Rosenman et al., 2005; Thomas et al., 2009), that
risk of sensitization and CBD appears to vary across industries and
processes (Deubner et al., 2001; Kreiss et al., 1997; Newman et al.,
2001; Henneberger et al., 2001; Schuler et al., 2005; Stange et al.,
2001; Taiwo et al., 2010), and that efforts to reduce exposure have
succeeded in reducing the frequency of beryllium sensitization and CBD
(Bailey et al., 2010) (See Table A-1 in the Appendix).
    Of workers who were found to be sensitized and underwent clinical
evaluation, 20-49 percent were diagnosed with CBD (Kreiss et al., 1993;
Newman, 1996, 2005 and 2007; Stange et al., 2001). Overall prevalence
of CBD in cross-sectional screenings ranges from 0.6 to 8 percent
(Kreiss et al., 2007). A study by Newman (2005) estimated from ongoing
surveillance of sensitized individuals, with an average follow-up time
of 6 years, that 31 percent of beryllium-exposed employees progressed
to CBD (Newman, 2005). However, Newman (2005) went on to suggest that
if follow-up times were increased the rate of progression from
sensitization to CBD could be much higher. A study of nuclear weapons
facility employees enrolled in an ongoing medical surveillance program
found that only about 20 percent of sensitized individuals employed
less than five years eventually were diagnosed with CBD, while 40
percent of sensitized employees employed ten years or more developed
CBD (Stange et al., 2001) indicating length of exposure may play a role
in further development of the disease. In addition, Mroz et al. (2009)
conducted a longitudinal study of individuals clinically evaluated at
National Jewish Health (between 1982 and 2002) who were identified as
having sensitization and CBD through workforce medical surveillance.
The authors identified 171 cases of CBD and 229 cases of sensitization;
all individuals were identified through workplace screening using the
BeLPT (Mroz et al., 2009). Over the 20-year study period, 8.8 percent
(i.e., 22 cases out 251 sensitized) of individuals with sensitization
went on to develop CBD. The findings from this study indicated that on
the average span of time from initial beryllium exposure to CBD
diagnosis was 24 years (Mroz et al., 2009).

E. Beryllium Lung Cancer Section

    Beryllium exposure has been associated with a variety of adverse
health effects including lung cancer. The potential for beryllium and
its compounds to cause cancer has been previously assessed by various
other agencies (EPA, ATSDR, NAS, NIEHS, and NIOSH) with each agency
identifying beryllium as a potential carcinogen. In addition, the
International Agency for Research on Cancer (IARC) did an extensive
evaluation in 1993 and reevaluation in April 2009 (IARC, 2012). In
brief, IARC determined beryllium and its compounds to be carcinogenic
to humans (Group 1 category), while EPA considers beryllium to be a
probable human carcinogen (EPA, 1998), and the National Toxicology
Program (NTP) has determined beryllium and its compounds to be known
carcinogens (NTP, 2014). OSHA has conducted an independent evaluation
of the carcinogenic potential of beryllium and these compounds as well.
The following is a summary of the studies used to support the Agency
findings that beryllium and its compounds are human carcinogens.
1. Genotoxicity Studies
    Genotoxicity can be an important indicator for screening the
potential of a material to induce cancer and an important mechanism
leading to tumor formation and carcinogenesis. In a review conducted by
the National Academy of Science, beryllium and its compounds have
tested positively in nearly 50 percent of the genotoxicity studies
conducted without exogenous metabolic activity. However, they were
found to be non-genotoxic in most bacterial assays (NAS, 2008).
    Gene mutations have been observed in mammalian cells cultured with
beryllium chloride in a limited number of studies (EPA, 1998; ATSDR,
2002; Gordon and Bowser, 2003). Culturing mammalian cells with
beryllium chloride, beryllium sulfate, or beryllium nitrate has
resulted in clastogenic alterations. However, most studies have found
that beryllium chloride, beryllium nitrate, beryllium sulfate, and
beryllium oxide did not induce gene mutations in bacterial assays with
or without metabolic activation. In the case of beryllium sulfate, all
mutagenicity studies (Ames (Simmon, 1979; Dunkel et al., 1984;
Arlauskas et al., 1985; Ashby et al., 1990); E. coli pol A (Rosenkranz
and Poirer, 1979); E. coli WP2 uvr A (Dunkel et al., 1984) and
Saccharomyces cerevisiae (Simmon, 1979)) were negative with the
exception of results reported for Bacillus subtilis rec assay (Kada et
al., 1980; Kanematsu et al., 1980; EPA, 1998). Beryllium sulfate did
not induce unscheduled DNA synthesis in primary rat hepatocytes and was not
mutagenic when injected intraperitoneally in adult mice in a host-mediated
assay using Salmonella typhimurium (Williams et al., 1982).
    Beryllium nitrate was negative in the Ames assay (Tso and Fung,
1981; Kuroda et al., 1991) but positive in a Bacillus subtilis rec
assay (Kuroda et al., 1991). Beryllium chloride was negative in a
variety of studies (Ames (Ogawa et al., 1987; Kuroda et al., 1991); E.
coli WP2 uvr A (Rossman and Molina, 1984); and Bacillus subtilis rec
assay (Nishioka, 1975)). In addition, beryllium chloride failed to
induce SOS DNA repair in E. coli (Rossman et al., 1984). However,
positive results were reported for Bacillus subtilis rec assay using
spores (Kuroda et al., 1991), E. coli KMBL 3835; lacI gene (Zakour and
Glickman, 1984), and hprt locus in Chinese hamster lung V79 cells
(Miyaki et al., 1979). Beryllium oxide was negative in the Ames assay
and Bacillus subtilis rec assays (Kuroda et al., 1991; EPA, 1998).
    Gene mutations have been observed in mammalian cells (V79 and CHO)
cultured with beryllium chloride (Miyaki et al., 1979; Hsie et al.,
1979a, b), and culturing of mammalian cells with beryllium chloride
(Vegni-Talluri and Guiggiani, 1967), and beryllium sulfate (Brooks et
al., 1989; Larramendy et al., 1981) has resulted in clastogenic
alterations--producing breakage or disrupting chromosomes (EPA, 1998).
Beryllium chloride evaluated in a mouse model indicated increased DNA
strand breaks and the formation of micronuclei in bone marrow (Attia et
al., 2013).
    Data on the in vivo genotoxicity of beryllium are limited to a
single study that found beryllium sulfate (1.4 and 2.3 g/kg, 50 percent
and 80 percent of median lethal dose) administered by gavage did not
induce micronuclei in the bone marrow of CBA mice. However, a marked
depression of erythropoiesis (red blood cell production) was suggestive
of bone marrow toxicity which was evident 24 hours after dosing. No
mutations were seen in p53 or c-raf-1 and only weak mutations were
detected in K-ras in lung carcinomas from F344/N rats given a single
nose-only exposure to beryllium metal (Nickell-Brady et al., 1994). The
authors concluded that the mechanisms for the development of lung
carcinomas from inhaled beryllium in the rat do not involve gene
dysfunctions commonly associated with human non-small-cell lung cancer
(EPA, 1998).
2. Human Epidemiological Studies
    This section reviews in greater detail the studies used to support
the mechanistic findings for beryllium-induced cancer. Table A.3 in the
Appendix summarizes the important features and characteristics of each
study.
    a. Beryllium Case Registry (BCR).
    Two studies evaluated participants in the BCR (Infante et al.,
1980; Steenland and Ward, 1991). Infante et al. (1980) evaluated the
mortality patterns of white male participants in the BCR diagnosed with
non-neoplastic respiratory symptoms of beryllium disease. Of the 421
cases evaluated, 7 of the participants had died of lung cancer. Six of
the deaths occurred more than 15 years after initial beryllium
exposure. The duration of exposure for 5 of the 7 participants with
lung cancer was less than 1 year, with the time since initial exposure
ranging from 12 to 29 years. One of the participants was exposed for 4
years with a 26-year interval since the initial exposure. Exposure
duration for one participant diagnosed with pulmonary fibrosis could
not be determined; however, it had been 32 years since the initial
exposure. Based on BCR records, the participants were classified as
being in the acute respiratory group (i.e., those diagnosed with acute
respiratory illness at the time of entry in the registry) or the
chronic respiratory group (i.e., those diagnosed with pulmonary
fibrosis or some other chronic lung condition at the time of entry into
the BCR). The 7 participants with lung cancer were in the BCR because
of diagnoses of acute respiratory illness. For only one of those
individuals was initial beryllium exposure less than 15 years prior.
Only 1 of the 6 (with greater than 15 years since initial exposure to
beryllium) had been diagnosed with chronic respiratory disease. The
study did not report exposure concentrations or smoking habits. The
authors concluded that the results of this cohort agreed with previous
animal studies and with epidemiological studies demonstrating an
increased risk of lung cancer in workers exposed to beryllium.
    Steenland and Ward (1991) extended the work of Infante et al.
(1980) to include females and to include 13 additional years of follow-
up. At the time of entry in the BCR, 93 percent of the women in the
study, but only 50 percent of the men, had been diagnosed with CBD. In
addition, 61 percent of the women had worked in the fluorescent tube
industry and 50 percent of the men had worked in the basic
manufacturing industry. A total of 22 males and 6 females died of lung
cancer. Of the 28 total deaths from lung cancer, 17 had been exposed to
beryllium for less than 4 years and 11 had been exposed for greater
than 4 years. The study did not report exposure concentrations. Survey
data collected in 1965 provided information on smoking habits for 223
cohort members (32 percent), on the basis of which the authors
suggested that the rate of smoking among workers in the cohort may have
been lower than U.S. rates. The authors concluded that there was
evidence of increased risk of lung cancer in workers exposed to
beryllium and diagnosed with beryllium disease.
b. Beryllium Manufacturing and/or Processing Plants (Extraction,
Fabrication, and Processing)
    Several epidemiological cohort studies have reported excess lung
cancer mortality among workers employed in U.S. beryllium production
and processing plants during the 1930s to 1960s. The largest and most
comprehensive study investigated the mortality experience of 9,225
workers employed in seven different beryllium processing plants over a
30-year period (Ward et al., 1992). The workers at the two oldest
facilities (i.e., Lorain, OH, and Reading, PA) were found to have
significant excess lung cancer mortality relative to the U.S.
population. Of the seven plants in the study, these two plants were
believed to have the highest exposure levels to beryllium. A different
analysis of the lung cancer mortality in this cohort using various
local reference populations and alternate adjustments for smoking
generally found smaller, non-significant rates of excess mortality
among the beryllium employees (Levy et al., 2002). Both cohort studies
are limited by a lack of job history and air monitoring data that would
allow investigation of mortality trends with beryllium exposure. The
majority of employees at the Lorain, OH, and Reading, PA, facilities
were employed for a relatively short period of less than one year.
    Bayliss et al. (1971) performed a nested cohort study of more than
7,000 former workers from the beryllium processing industry employed
from 1942-1967. Information for the workers was collected from the
personnel files of participating companies. Of the more than 7,000
employees, a cause of death was known for 753 male workers. The number
of observed lung cancer deaths was 36 compared to 34.06 expected for a
standardized mortality ratio (SMR) of 1.06. When evaluated by the
number of years of employment, 24 of the 36 men were employed for less
than 1 year in the industry (SMR = 1.24), 8 were employed for 1 to 5 years
(SMR 1.40), and 4 were employed for more than 5 years (SMR = 0.54). Half of
the workers who died from lung cancer began employment in the beryllium
production industry prior to 1947. When grouped by job classification,
over two thirds of the workers with lung cancer were in production-
related jobs while the rest were classified as office workers. The
authors concluded that while the lung cancer mortality rates were the
highest of all other mortality rates, the SMR for lung cancer was still
within range of the expected based on death rates in the United States.
The limitations of this study included the lack of information
regarding exposure concentrations, smoking habits, and the age and race
of the participants.
    Mancuso (1970, 1979, 1980) and Mancuso and El-Attar (1969)
performed a series of occupational cohort studies on a group of over
3,685 workers (primarily white males) employed in the beryllium
manufacturing industry during 1937-1948.\3\ The beryllium production
facilities were located in Ohio and Pennsylvania and the records for
the employees, including periods of employment, were obtained from the
Social Security Administration. These studies did not include analyses
of mortality by job title or exposure category. In addition, there were
no exposure concentrations estimated or adjustments for smoking. The
estimated duration of employment ranged from less than 1 year to
greater than 5 years. In the most recent study (Mancuso, 1980),
employees from the viscose rayon industry served as a comparison
population. There was a significant excess of lung cancer deaths based
on the total number of 80 observed lung cancer mortalities at the end
of 1976 compared to an expected number of 57.06 based on the comparison
population resulting in an SMR of 1.40 (p < 0.01) (Mancuso, 1980).
There was a statistically significant excess in lung cancer deaths for
the shortest duration of employment (< 12 months, p < 0.05) and the
longest duration of employment (> 49 months, p < 0.01). Based on the
results of this study, the author concluded that the ability of
beryllium to induce cancer in workers does not require continuous
exposure and that it is reasonable to assume that the amount of
exposure required to produce lung cancer can occur within a few months
of exposure regardless of the length of employment.
---------------------------------------------------------------------------

    \3\ The third study (Mancuso et al., 1979) restricted the cohort
to workers employed between 1942 and 1948.
---------------------------------------------------------------------------

    Wagoner et al. (1980) expanded the work of Mancuso (1970; 1979;
1980) using a cohort of 3,055 white males from the beryllium
extraction, processing, and fabrication facility located in Reading,
Pennsylvania. The men included in the study worked at the facility
sometime between 1942 and 1968, and were followed through 1976. The
study accounted for length of employment. Other factors accounted for
included age, smoking history, and regional lung cancer mortality.
Forty-seven members of the cohort died of lung cancer compared to an
expected 34.29 based on U.S. white male lung cancer mortality rates (p
< .05). The results of this cohort showed an excess risk of lung cancer
in beryllium-exposed workers at each duration of employment (< 5 years
and >= 5 years), with a statistically significant excess noted at < 5
years durations of employment and a >= 25-year interval since the
beginning of employment (p < 0.05). The study was criticized by several
epidemiologists (MacMahon, 1978, 1979; Roth, 1983), by a CDC Review
Committee appointed to evaluate the study, and by one of the study's
coauthors (Bayliss, 1980) for inadequate discussion of possible
alternative explanations of excess lung cancer in the cohort. The
specific issues identified include the use of 1965-1967 U.S. white male
lung cancer mortality rates to generate expected numbers of lung
cancers in the period 1968-1975 and inadequate adjustment for smoking.
    Ward et al. (1992) performed a retrospective mortality cohort study
of 9,225 male workers employed at seven beryllium processing
facilities, including the Ohio and Pennsylvania facilities studied by
Mancuso and El-Attar (1969), Mancuso (1970; 1979; 1980), and Wagoner et
al. (1980). The men were employed for no less than 2 days between
January 1940 and December 1988. At the end of the study 61.1 percent of
the cohort was known to be living and 35.1 percent was known to be
deceased. The duration of employment ranged from 1 year or less to
greater than 10 years with the largest percentage of the cohort (49.7
percent) employed for less than one year, followed by 1 to 5 years of
employment (23.4 percent), greater than 10 years (19.1 percent), and 5
to 10 years (7.9 percent). Of the 3,240 deaths, 280 observed deaths
were caused by lung cancer compared to 221.5 expected deaths, yielding
a statistically significant SMR of 1.26 (p < 0.01). Information on the
smoking habits of 15.9 percent of the cohort members, obtained from a
1968 Public Health Service survey conducted at four of the plants, was
used to calculate a smoking-adjusted SMR of 1.12, which was not
statistically significant. The number of deaths from lung cancer was
also examined by decade of hire. The authors reported a relationship
between earlier decades of hire and increased lung cancer risk.
    The EPA Integrated Risk Information System (IRIS), IARC, and
California EPA Office of Environmental Health Hazard Assessment (OEHHA)
have all based their cancer assessment on the Ward et al. 1992 study,
with supporting data concerning exposure concentrations from Eisenbud
and Lisson (1983) and NIOSH (1972), who estimated that the lower-bound
estimate of the median exposure concentration exceeded 100 [micro]g/
m\3\ and found that concentrations in excess of 1,000 [micro]g/m\3\
were common. The IRIS cancer risk assessment recalculated expected lung
cancers based on U.S. white male lung cancer rates (including the
period 1968-1975) and used an alternative adjustment for smoking. In
addition, one individual with lung cancer, who had not worked at the
plant, was removed from the cohort. After these adjustments were made,
an elevated rate of lung cancer was still observed in the overall
cohort (46 cases vs. 41.9 expected cases). However, based on duration
of employment or interval since beginning of employment, neither the
total cohort nor any of the subgroups had a statistically significant
excess in lung cancer (EPA, 1987). Based on their evaluation of this
and other epidemiological studies, the EPA characterized the human
carcinogenicity data then available as "limited" but "suggestive of
a causal relationship between beryllium exposure and an increased risk
of lung cancer" (IRIS database). This report includes quantitative
estimates of risk that were derived using the information presented in
Wagoner et al. (1980), the expected lung cancers recalculated by the
EPA, and bounds on presumed exposure levels.
    Levy et al. (2002) questioned the results of Ward et al. (1992) and
performed a reanalysis of the Ward et al. data. The Levy et al.
reanalysis differed from the Ward et al. analysis in the following
significant ways. First, Levy et al. (2002) examined two alternative
adjustments for smoking, which were based on (1) a different analysis
of the American Cancer Society (ACS) data used by Ward et al. (1992)
for their smoking adjustment, or (2) results from a smoking/lung cancer
study of veterans (Levy and Marimont, 1998). Second, Levy et al. (2002)
also examined the impact of computing different reference rates derived
from information about the lung cancer rates in the cities in which most of
the workers at two of the plants lived. Finally, Levy et al. (2002) considered
a meta-analytical approach to combining the results across beryllium
facilities. For all of the alternatives Levy et al. (2002) considered,
except the meta-analysis, the facility-specific and combined SMRs
derived were lower than those reported by Ward et al. (1992). Only the
SMR for the Lorain, OH, facility remained statistically significantly
elevated in some reanalyses. The SMR obtained when combining over the
plants was not statistically significant in eight of the nine
approaches they examined, leading Levy et al. (2002) to conclude that
there was little evidence of statistically significant elevated SMRs in
those plants.
    One occupational nested case-control study evaluated lung cancer
mortality in a cohort of 3,569 male workers employed at a beryllium
alloy production plant in Reading, PA, from 1940 to 1969 and followed
through 1992 (Sanderson et al., 2001). There were a total of 142 known
lung cancer cases and 710 controls. For each lung cancer death, 5 age-
and race-matched controls were selected by incidence density sampling.
Confounding effects of smoking were evaluated. Job history and
historical air measurements at the plant were used to estimate job-
specific beryllium exposures from the 1930s to 1990s. Calendar-time-
specific beryllium exposure estimates were made for every job and used
to estimate workers' cumulative, average, and maximum exposure. Because
of the long period of time required for the onset of lung cancer, an
"exposure lag" was employed to discount recent exposures less likely
to contribute to the disease.
    The cumulative, average, and maximum beryllium exposure
concentration estimates for the 142 known lung cancer cases were 46.06
 9.3[micro]g/m\3\-days, 22.8  3.4 [micro]g/
m\3\, and 32.4  13.8 [micro]g/m\3\, respectively. The lung
cancer mortality rate was 1.22 (95 percent CI = 1.03 - 1.43). Exposure
estimates were lagged by 10 and 20 years in order to account for
exposures that did not contribute to lung cancer because they occurred
after the induction of cancer. In the 10- and 20-year lagged exposures
the geometric mean tenures and cumulative exposures of the lung cancer
mortality cases were higher than the controls. In addition, the
geometric mean and maximum exposures of the workers were significantly
higher than controls when the exposure estimates were lagged 10 and 20
years (p < 0.01).
    Results of a conditional logistic regression analysis indicated
that there was an increased risk of lung cancer in workers with higher
exposures when dose estimates were lagged by 10 and 20 years. There was
also a lack of evidence that confounding factors such as smoking
affected the results of the regression analysis. The authors noted that
there was considerable uncertainty in the estimation of exposure in the
1940's and 1950's and the shape of the dose-response curve for lung
cancer. Another analysis of the study data using a different
statistical method did not find a significantly greater relative risk
of lung cancer with increasing beryllium exposures (Levy et al., 2007).
The average beryllium air levels for the lung cancer cases were
estimated to be an order of magnitude above the current 8-hour OSHA TWA
PEL (2 [mu]g/m\3\) and roughly two orders of magnitude higher than the
typical air levels in workplaces where beryllium sensitization and
pathological evidence of CBD have been observed. IARC evaluated this
reanalysis in 2012 and found the study introduced a downward bias into
risk estimates (IARC, 2012).
    Schubauer-Berigan et al. reanalyzed data from the nested case-
control study of 142 lung cancer cases in the Reading, PA, beryllium
processing plant (Schubauer-Berigan et al., 2008). This dataset was
reanalyzed using conditional (stratified by case age) logistic
regression. Independent adjustments were made for potential confounders
of birth year and hire age. Average and cumulative exposures were
analyzed using the values reported in the original study. The objective
of the reanalysis was to correct for the known differences in smoking
rates by birth year. In addition, the authors evaluated the effects of
age at hire to determine differences observed by Sanderson et al. in
2001. The effect of birth cohort adjustment on lung cancer rates in
beryllium-exposed workers was evaluated by adjusting in a multivariable
model for indicator variables for the birth cohort quartiles.
    Unadjusted analyses showed little evidence of lung cancer risk
associated with beryllium occupational exposure using cumulative
exposure until a 20-year lag was used. Adjusting for either birth
cohort or hire age attenuated the risk for lung cancer associated with
cumulative exposure. Using a 10- or 20-year lag in workers born after
1900 also showed little evidence of lung cancer risk, while those born
prior to 1900 did show a slight elevation in risk. Unlagged and lagged
analysis for average exposure showed an increase in lung cancer risk
associated with occupational exposure to beryllium. The finding was
consistent for either workers adjusted or unadjusted for birth cohort
or hire age. Using a 10-year lag for average exposure showed a
significant effect by birth cohort.
    The authors stated that the reanalysis indicated that differences
in the hire ages among cases and controls, first noted by Deubner et
al. (2001) and Levy et al. (2007), were primarily due to the fact that
birth years were earlier among controls than among cases, resulting
from much lower baseline risk of lung cancer for men born prior to 1900
(Schubauer-Berigan et al., 2008). The authors went on to state that the
reanalysis of the previous NIOSH case-control study suggested the
relationship observed previously between cumulative beryllium exposure
and lung cancer was greatly attenuated by birth cohort adjustment.
    Hollins et al. (2009) re-examined the weight of evidence of
beryllium as a lung carcinogen in a recent publication (Hollins et al.,
2009). Citing more than 50 relevant papers, the authors noted the
methodological shortcomings examined above, including lack of well-
characterized historical occupational exposures and inadequacy of the
availability of smoking history for workers. They concluded that the
increase in potential risk of lung cancer was observed among those
exposed to very high levels of beryllium and that beryllium's
carcinogenic potential in humans at these very high exposure levels
were not relevant to today's industrial settings. IARC performed a
similar re-evaluation in 2009 (IARC, 2012) and found that the weight of
evidence for beryllium lung carcinogenicity, including the animal
studies described below, still warranted a Group I classification, and
that beryllium should be considered carcinogenic to humans.
    Schubauer-Berigan et al. (2010) extended their analysis from a
previous study estimating associations between mortality risk and
beryllium exposure to include workers at 7 beryllium processing plants.
The study (Schubauer-Berigan et al., 2010) followed the mortality
incidences of 9,199 workers from 1940 through 2005 at the 7 beryllium
plants. JEMs were developed for three plants in the cohort: The Reading
plant, the Hazleton plant, and the Elmore plant. The last is described
in Couch et al. 2010. Including these JEMs substantially improved the
evidence base for evaluating the carcinogenicity of beryllium and, and
this change represents more than an update of the beryllium cohort.
Standardized mortality ratios (SMRs) were estimated based on US population
comparisons for lung, nervous system and urinary tract cancers, chronic
obstructive pulmonary disease (COPD), chronic kidney disease, and
categories containing chronic beryllium disease (CBD) and cor
pulmonale. Associations with maximum and cumulative exposure were
calculated for a subset of the workers.
    Overall mortality in the cohort compared with the US population was
elevated for lung cancer (SMR 1.17; 95% CI 1.08 to 1.28), COPD (SMR
1.23; 95% CI 1.13 to 1.32), and the categories containing CBD (SMR
7.80; 95% CI 6.26 to 9.60) and cor pulmonale (SMR 1.17; 95% CI 1.08 to
1.26). Mortality rates for most diseases of interest increased with
time-since-hire. For the category including CBD, rates were
substantially elevated compared to the US population across all
exposure groups. Workers whose maximum beryllium exposure was >= 10
[mu]g/m\3\ had higher rates of lung cancer, urinary tract cancer, COPD
and the category containing cor pulmonale than workers with lower
exposure. These studies showed strong associations for cumulative
exposure (when short-term workers were excluded), maximum exposure or
both. Significant positive trends with cumulative exposure were
observed for nervous system cancers (p = 0.0006) and, when short-term
workers were excluded, lung cancer (p = 0.01), urinary tract cancer (p
= 0.003) and COPD (p < 0.0001).
    The authors concluded the findings from this reanalysis reaffirmed
that lung cancer and CBD are related to beryllium exposure. The authors
went on to suggest that beryllium exposures may be associated with
nervous system and urinary tract cancers and that cigarette smoking and
other lung carcinogens were unlikely to explain the increased
incidences in these cancers. The study corrected an error that was
discovered in the indirect smoking adjustment initially conducted by
Ward et al., concluding that cigarette smoking rates did not differ
between the cohort and the general U.S. population. No association was
found between cigarette smoking and either cumulative or maximum
beryllium exposure, making it very unlikely that smoking was a
substantial confounder in this study (Schubauer-Berigan et al., 2010).
3. Animal Cancer Studies
    This section reviews the animal literature used to support the
findings for beryllium-induced lung cancer. Lung tumors have been
induced via inhalation and intratracheal administration of beryllium to
rats and monkeys, and osteosarcomas have been induced via intravenous
and intramedullary (inside the bone) injection of beryllium in rabbits
and possibly in mice. The chronic oral studies did not report increased
incidences of tumors in rodents, but these were conducted at doses
below the maximum tolerated dose (MTD) (EPA, 1998).
    Early animal studies revealed that some beryllium compounds are
carcinogenic when inhaled (ATSDR, 2002). Animal experiments have shown
consistent increases in lung cancers in rats, mice and rabbits
chronically exposed to beryllium and beryllium compounds by inhalation
or intratracheal instillation. In addition to lung cancer,
osteosarcomas have been produced in mice and rabbits exposed to various
beryllium salts by intravenous injection or implantation into the bone
(NTP, 1999).
    In an inhalation study assessing the potential tumorigenicity of
beryllium, Schepers et al. (1957) exposed 115 albino Sherman and Wistar
rats (male and female) via inhalation to 0.0357 mg beryllium/m\3\ (1
[gamma] beryllium/ft\3\) \4\ as an aqueous aerosol of beryllium sulfate
for 44 hours/week for 6 months, and observed the rats for 18 months
after exposure. Three to four control rats were killed every two months
for comparison purposes. Seventy-six lung neoplasms, \5\ including
adenomas, squamous-cell carcinomas, acinous adenocarcinomas, papillary
adenocarcinomas, and alveolar-cell adenocarcinomas, were observed in 52
rats exposed to beryllium sulfate aerosol. Adenocarcinomata were the
most numerous. Pulmonary metastases tended to localize in areas with
foam cell clustering and granulomatosis. No neoplasia was observed in
any of the control rats. The incidence of lung tumors in exposed rats
is presented in the following Table 2:
---------------------------------------------------------------------------

    \4\ Schepers et al. (1957) reported concentrations in [gamma]
Be/ft\3\; however, [gamma]/ft\3\ is no longer a common unit.
Therefore, the concentration was converted to mg/m\3\.
    \5\ While a total of 89 tumors were observed or palpated at the
time of autopsy in the BeSO4-exposed animals, only 76
tumors are listed as histologically neoplastic. Only the new growths
identified in single midcoronal sections of both lungs were
recorded.

                       Table 2--Neoplasm Analysis
------------------------------------------------------------------------
                     Neoplasm                       Number    Metastases
------------------------------------------------------------------------
Adenoma..........................................        18
Squamous carcinoma...............................         5            1
Acinous adenocarcinoma...........................        24            2
Papillary adenocarcinoma.........................        11            1
Alveolar-cell adenocarcinoma.....................         7
Mucigenous tumor.................................         7            1
Endothelioma.....................................         1
Retesarcoma......................................         3            3
                                                  ----------------------
  Total..........................................        76            8
------------------------------------------------------------------------

    Schepers (1962) reviewed 38 existing beryllium studies that
evaluated seven beryllium compounds and seven mammalian species.
Beryllium sulfate, beryllium fluoride, beryllium phosphate, beryllium
alloy (BeZnMnSiO4), and beryllium oxide were proven to be
carcinogenic and have remarkable pleomorphic neoplasiogenic
proclivities. Ten varieties of tumors were observed, with
adenocarcinoma being the most common variety.
    In another study, Vorwald and Reeves (1959) exposed Sherman albino
rats via the inhalation route to aerosols of 0.006 mg beryllium/m\3\ as
beryllium oxide and 0.0547 mg beryllium/m\3\ as beryllium sulfate for 6
hours/day, 5 days/week for an unspecified duration. Lung tumors (single
or multifocal) were observed in the animals sacrificed following 9
months of daily inhalation exposure. The histologic pattern of the
cancer was primarily adenomatous; however, epidermoid and squamous cell
cancers were also observed. Infiltrative, vascular, and lymphogenous
extensions often developed with secondary metastatic growth in the
tracheobronchial lymph nodes, the mediastinal connective tissue, the
parietal pleura, and the diaphragm.
    In the first of two articles, Reeves et al. (1967a) investigated
the carcinogenic process in lungs resulting from chronic (up to 72
weeks) beryllium sulfate inhalation. One hundred fifty male and female
Sprague Dawley C.D. strain rats were exposed to beryllium sulfate
aerosol at a mean atmospheric concentration of 34.25 [mu]g beryllium/
m\3\ (with an average particle diameter of 0.12 [micro]m). Prior to
initial exposure and again during the 67-68 and 75-76 weeks of life,
the animals received prophylactic treatments of tetracycline-HCl to
combat recurrent pulmonary infections.
    The animals entered the exposure chamber at 6 weeks of age and were
exposed 7 hours per day/5 days per week for up to 2,400 hours of total
exposure time. An equal number of unexposed controls were held in a
separate chamber. Three male and three female rats were sacrificed
monthly during the 72-week exposure period. Mortality due to
respiratory or other infections did not appear until 55 weeks of age,
and 87 percent of all animals survived until their scheduled
sacrifices.
    Average lung weight towards the end of exposure was 4.25 times
normal with progressively increasing differences between control and
exposed animals. The increase in lung weight was accompanied by notable
changes in tissue texture with two distinct pathological processes--
inflammatory and proliferative. The inflammatory response was
characterized by marked accumulation of histiocytic elements forming
clusters of macrophages in the alveolar spaces. The proliferative
response progressed from early epithelial hyperplasia of the alveolar
surfaces, through metaplasia (after 20-22 weeks of exposure), anaplasia
(cellular dedifferentiation) (after 32-40 weeks of exposure), and
finally to lung tumors.
    Although the initial proliferative response occurred early in the
exposure period, tumor development required considerable time. Tumors
were first identified after nine months of beryllium sulfate exposure,
with rapidly increasing rates of incidence until tumors were observed
in 100 percent of exposed animals by 13 months. The 9-to-13-month
interval is consistent with earlier studies. The tumors showed a high
degree of local invasiveness. No tumors were observed in control rats.
All 56 tumors studied appeared to be alveolar adenocarcinomas and 3
"fast-growing" tumors that reached a very large size comparatively
early. About one-third of the tumors showed small foci where the
histologic pattern differed. Most of the early tumor foci appeared to
be alveolar rather than bronchiolar, which is consistent with the
expected pathogenesis, since permanent deposition of beryllium was more
likely on the alveolar epithelium rather than on the bronchiolar
epithelium. Female rats appeared to have an increased susceptibility to
beryllium exposure. Not only did they have a higher mortality (control
males [n = 8], exposed males [n = 9] versus control females [n = 4],
exposed females [n = 17]) and body weight loss than male rats, but the
three "fast-growing" tumors only occurred in females.
    In the second article, Reeves et al. (1967b) described the rate of
accumulation and clearance of beryllium sulfate aerosol from the same
experiment (Reeves et al., 1967a). At the time of the monthly
sacrifice, beryllium assays were performed on the lungs,
tracheobronchial lymph nodes, and blood of the exposed rats. The
pulmonary beryllium levels of rats showed a rate of accumulation which
decreased during continuing exposure and reached a plateau (defined as
equilibrium between deposition and clearance) of about 13.5 [mu]g
beryllium for males and 9 [mu]g beryllium for females in whole lungs
after approximately 36 weeks. Females were notably less efficient than
males in utilizing the lymphatic route as a method of clearance,
resulting in slower removal of pulmonary beryllium deposits, lower
accumulation of the inhaled material in the tracheobronchial lymph
nodes, and higher morbidity and mortality.
    There was no apparent correlation between the extent and severity
of pulmonary pathology and total lung load. However, when the beryllium
content of the excised tumors was compared with that of surrounding
nonmalignant pulmonary tissues, the former showed a notable decrease
(0.50  0.35 [mu]g beryllium/gram versus 1.50
0.55 [mu]g beryllium/gram). This was believed to be largely a result of
the dilution factor operating in the rapidly growing tumor tissue.
However, other factors, such as lack of continued local deposition due
to impaired respiratory function and enhanced clearance due to high
vascularity of the tumor, may also have played a role. The portion of
inhaled beryllium retained in the lungs for a longer duration, which is
in the range of one-half of the original pulmonary load, may have
significance for pulmonary carcinogenesis. This pulmonary beryllium
burden becomes localized in the cell nuclei and may be an important
factor in eliciting the carcinogenic response associated with beryllium
inhalation.
    Groth et al. (1980) conducted a series of experiments to assess the
carcinogenic effects of beryllium, beryllium hydroxide, and various
beryllium alloys. For the beryllium metal/alloys experiment, 12 groups
of 3-month-old female Wistar rats (35 rats/group) were used. All rats
in each group received a single intratracheal injection of either 2.5
or 0.5 mg of one of the beryllium metals or beryllium alloys as
described in Table 3 below. These materials were suspended in 0.4 cc of
isotonic saline followed by 0.2 cc of saline. Forty control rats were
injected with 0.6 cc of saline. The geometric mean particle sizes
varied from 1 to 2 [micro]m. Rats were sacrificed and autopsied at
various intervals ranging from 1 to 18 months post-injection.

                           Table 3--Summary of Beryllium Dose From Groth et al. (1980)
----------------------------------------------------------------------------------------------------------------
                                                  Percent other   Total No. rats   Compound dose
          Form of Be              Percent Be        compounds        autopsied         (mg)        Be dose  (mg)
----------------------------------------------------------------------------------------------------------------
Be metal.....................  100.............  None...........              16             2.5             2.5
                                                                              21             0.5             0.5
Passivated Be metal..........  99..............  0.26% Chromium.              26             2.5             2.5
                                                                              20             0.5             0.5
BeAl alloy...................  62..............  38% Aluminum...              24             2.5            1.55
                                                                              21             0.5             0.3
BeCu alloy...................  4...............  96% Copper.....              28             2.5             0.1
                                                                              24             0.5            0.02
BeCuCo alloy.................  2.4.............  0.4% Cobalt....              33             2.5            0.06
                                                 96% Copper.....              30             0.5           0.012
BeNi alloy...................  2.2.............  97.8% Nickel...              28             2.5           0.056
                                                                              27             0.5           0.011
----------------------------------------------------------------------------------------------------------------

    Lung tumors were observed only in rats exposed to beryllium metal,
passivated beryllium metal, and beryllium-aluminum alloy. Passivation
refers to the process of removing iron contamination from the surface
of beryllium metal. As discussed, metal alloys may have a different
toxicity than beryllium alone. Rats exposed to 100 percent beryllium
exhibited relatively high mortality rates, especially in the groups
where lung tumors were observed. Nodules varying from 1 to 10 mm in
diameter were also observed in the lungs of rats exposed to beryllium
metal, passivated beryllium metal, and beryllium-aluminum alloy. These
nodules were suspected of being malignant.
    To test this hypothesis, transplantation experiments involving the
suspicious nodules were conducted in nine rats. Seven of the nine
suspected tumors grew upon transplantation. All transplanted tumor
types metastasized to the lungs of their hosts. Lung tumors were
observed in rats injected with both the high and low doses of beryllium
metal, passivated beryllium metal, and beryllium-aluminum alloy. No
lung tumors were observed in rats injected with the other compounds.
From a total of 32 lung tumors detected, most were adenocarcinomas and
adenomas; however, two epidermoid carcinomas and at least one poorly
differentiated carcinoma were observed. Bronchiolar alveolar cell
tumors were frequently observed in rats injected with beryllium metal,
passivated beryllium metal, and beryllium-aluminum alloy. All stages of
cuboidal, columnar, and squamous cell metaplasia were observed on the
alveolar walls in the lungs of rats injected with beryllium metal,
passivated beryllium metal, and beryllium-aluminum alloy. These lesions
were generally reduced in size and number or absent from the lungs of
animals injected with the other alloys (BeCu, BeCuCo, BeNi).
    The extent of alveolar metaplasia could be correlated with the
incidence of lung cancer. The incidences of lung tumors in the rats
that received 2.5 mg of beryllium metal, and 2.5 and 0.5 mg of
passivated beryllium metal, were significantly different (p <= 0.008)
from controls. When autopsies were performed at the 16-to-19-month
interval, the incidence (2/6) of lung tumors in rats exposed to 2.5 mg
of beryllium-aluminum alloy was statistically significant (p = 0.004)
when compared to the lung tumor incidence (0/84) in rats exposed to
BeCu, BeNi, and BeCuCo alloys, which contained much lower
concentrations of Be (Groth et al., 1980).
    Finch et al. (1998b) investigated the carcinogenic effects of
inhaled beryllium on heterozygous TSG-p53 knockout mice
(p53+/-) and wild-type (p53+/+) mice. Knockout mice can be
valuable tools in determining the role of specific genes on the
toxicity of a material of interest, in this case, beryllium. Equal
numbers of approximately 10-week-old male and female mice were used for
this study. Two exposure groups were used to provide dose-response
information on lung carcinogenicity. The maximum initial lung burden
(ILB) target of 60 [mu]g beryllium was based on previous acute
inhalation exposure studies in mice. The lower exposure target level of
15 [mu]g was selected to provide a lung burden significantly less than
the high-level group, but high enough to yield carcinogenic responses.
Mice were exposed in groups to beryllium metal or to filtered air
(controls) via nose-only inhalation. The specific exposure parameters
are presented in Table 4 below. Mice were sacrificed 7 days post
exposure for ILB analysis, and either at 6 months post exposure (n = 4-
5 mice per group per gender) or when 10 percent or less of the original
population remained (19 months post exposure for p53+/-
knockout and 22.5 months post exposure for p53+/+ wild-type mice). The
sacrifice time was extended in the study because a significant number
of lung tumors were not observed at 6 months post exposure.

                                                Table 4--Summary of Animal Data From Finch Et Al., 1998 b
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                        Number of mice
                                  Mean  exposure      Target be lung                        Mean daily  exposure                        with 1 or more
         Mouse strain              concentration      burden  ([mu]g)     Number of mice     duration  (minutes)   Mean ILB  ([mu]g)   lung tumors/total
                                   ([mu]g Be/L)                                                                                        number  examined
--------------------------------------------------------------------------------------------------------------------------------------------------------
Knockout (p53+/-).............  34                  15                  30                  112 (single)          NA                  0/29
                                36                  60                  30                  139[Dagger]           NA                  4/28
Wild-type (p53\+/+\)            34                  15                  6*                  112 (single)          12  4   NA
                                36                  60                  36[dagger]          139[Dagger]           54  6   0/28
Knockout (p53+/-).............  NA (air)            Control             30                  60-180 (single)       NA                  0/30
--------------------------------------------------------------------------------------------------------------------------------------------------------
ILB = initial lung burden; NA = not applicable
Median aerodynamic diameter of Be aerosol = 1.4 [mu]m ([sigma]g = 1.8)
* Wild-type mice in the low exposure group were not evaluated for carcinogenic effects; however ILB was analyzed in six wild-type mice.
[dagger] Thirty wild-type mice were analyzed for carcinogenic effects; six wild-type mice were analyzed for ILB.
[Dagger] Mice were exposed for 2.3 hours/day for three consecutive days.

    Lung burdens of beryllium measured in wild-type mice at 7 days post
exposure were approximately 70-90 percent of target levels. No
exposure-related effects on body weight were observed in mice; however,
lung weights and lung-to-body-weight ratios were somewhat elevated in
60 [mu]g target ILB p53+/- knockout mice compared to
controls (0.05 < p < 0.10). In general, p53+/+ wild-type mice survived
longer than p53+/- knockout mice and beryllium exposure
tended to decrease survival time in both groups. The incidence of
beryllium-induced lung tumors was marginally higher in the 60 [mu]g
target ILB p53+/- knockout mice compared to 60 [mu]g target
ILB p53+/+ wild-type mice (p = 0.056). The incidence of lung tumors in
the 60 [mu]g target ILB p53+/- knockout mice was also
significantly higher than controls (p = 0.048). No tumors developed in
the control mice, 15 [mu]g target ILB p53+/- knockout mice,
or 60 [mu]g target ILB p53+/+ wild-type mice throughout the length of
the study. Most lung tumors in beryllium-exposed mice were squamous
cell carcinomas, three of four of which were poorly circumscribed and
all were associated with at least some degree of granulomatous
pneumonia. The study results suggest that having an inactivated p53
allele is associated with lung tumor progression in p53+/-
knockout mice. This is based on the significant difference seen in the
incidence of beryllium-induced lung neoplasms for the
p53+/-knockout mice compared with the p53\+/+\ wild-type
mice. The authors conclude that since there was a relatively late onset
of tumors in the beryllium-exposed p53+/- knockout mice, a
6-month bioassay in this mouse strain might not be an appropriate model
for lung carcinogenesis (Finch et al., 1998b).
    Nickell-Brady et al. (1994) investigated the development of lung
tumors in 12-week-old F344/N rats after a single nose-only inhalation
exposure to beryllium aerosol, and evaluated whether beryllium lung
tumor induction involves alterations in the K-ras, p53, and c-raf-1
genes. Four groups of rats (30 males and 30 females per group) were
exposed to different mass concentrations of beryllium (Group 1: 500 mg/
m\3\ for 8 min; Group 2: 410 mg/m\3\ for 30 min; Group 3: 830 mg/m\3\
for 48 min; Group 4: 980 mg/m\3\ for 39 min). The beryllium mass median
aerodynamic diameter was 1.4 [mu]m ([sigma]g = 1.9). The
mean beryllium lung burdens for each exposure group were 40, 110, 360,
and 430 [mu]g, respectively.
    To examine genetic alterations, DNA isolation and sequencing
techniques (PCR amplification and direct DNA sequence analysis) were
performed on wild-type rat lung tissue (i.e., control samples) along
with two mouse lung tumor cell lines containing known K-ras mutations,
12 carcinomas induced by beryllium (i.e., experimental samples), and 12
other formalin-fixed specimens. Tumors appeared in beryllium-exposed
rats by 14 months, and 64 percent of exposed rats developed lung tumors
during their lifetime. Lungs frequently contained multiple tumor sites,
with some of the tumors greater than 1 cm. A total of 24 tumors were
observed. Most of the tumors (n = 22) were adenocarcinomas exhibiting a
papillary pattern characterized by cuboidal or columnar cells, although
a few had a tubular or solid pattern. Fewer than 10 percent of the
tumors were adenosquamous (n = 1) or squamous cell (n = 1) carcinomas.
    No transforming mutations of the K-ras gene (codons 12, 13, or 61)
were detected by direct sequence analysis in any of the lung tumors
induced by beryllium. However, using a more sensitive sequencing
technique (PCR enrichment restriction fragment length polymorphism
(RFLP) analysis) resulted in the detection of K-ras codon 12 GGT to GTT
transversions in 2 of 12 beryllium-induced adenocarcinomas. No p53 and
c-raf-1 alterations were observed in any of the tumors induced by
beryllium exposure (i.e., no differences observed between beryllium-
exposed and control rat tissues). The authors note that the results
suggest that activation of the K-ras proto-oncogene is both a rare and
late event, possibly caused by genomic instability during the
progression of beryllium-induced rat pulmonary adenocarcinomas. It is
unlikely that the K-ras gene plays a role in the carcinogenicity of
beryllium. The results also indicate that p53 mutation is unlikely to
play a role in tumor development in rats exposed to beryllium.
    Belinsky et al. (1997) reviewed the findings by Nickell-Brady et
al. (1994) to further examine the role of the K-ras and p53 genes in
lung tumors induced in the F344 rat by non-mutagenic (non-genotoxic)
exposures to beryllium. Their findings are discussed along with the
results of other genomic studies that look at carcinogenic agents that
are either similarly non-mutagenic or, in other cases, mutagenic. The
authors conclude that the identification of non-ras transforming genes
in rat lung tumors induced by non-mutagenic exposures, such as
beryllium, as well as mutagenic exposures will help define some of the
mechanisms underlying cancer induction by different types of DNA
damage.
    The inactivation of the p16INK4a (p16) gene is a contributing
factor in disrupting control of the normal cell cycle and may be an
important mechanism of action in beryllium-induced lung tumors.
Swafford et al. (1997) investigated the aberrant methylation and
subsequent inactivation of the p16 gene in primary lung tumors induced
in F344/N rats exposed to known carcinogens via inhalation. The
research involved a total of 18 primary lung tumors that developed
after exposing rats to five agents, one of which was beryllium. In this
study, only one of the 18 lung tumors was induced by beryllium
exposure; the majority of the other tumors were induced by radiation
(x-rays or plutonium-239 oxide). The authors hypothesized that if p16
inactivation plays a central role in development of non-small-cell lung
cancer, then the frequency of gene inactivation in primary tumors
should parallel that observed in the corresponding cell lines. To test
the hypothesis, a rat model for lung cancer was used to determine the
frequency and mechanism for inactivation of p16 in matched primary lung
tumors and derived cell lines. The methylation-specific PCR (MSP)
method was used to detect methylation of p16 alleles. The results
showed that the presence of aberrant p16 methylation in cell lines was
strongly correlated with absent or low expression of the gene. The
findings also demonstrated that aberrant p16 CpG island methylation, an
important mechanism in gene silencing leading to the loss of p16
expression, originates in primary tumors.
    Building on the rat model for lung cancer and associated findings
from Swafford et al. (1997), Belinsky et al. (2002) conducted
experiments in 12-week-old F344/N rats (male and female) to determine
whether beryllium-induced lung tumors involve inactivation of the p16
gene and estrogen receptor [alpha] (ER) gene. Rats received a single
nose-only inhalation exposure to beryllium aerosol at four different
exposure levels. The mean lung burdens measured in each exposure group
were 40, 110, 360, and 430 [mu]g. The methylation status of the p16 and
ER genes was determined by MSP. A total of 20 tumors detected in
beryllium-exposed rats were available for analysis of gene-specific
promoter methylation. Three tumors were classified as squamous cell
carcinomas and the others were determined to be adenocarcinomas.
Methylated p16 was present in 80 percent (16/20), and methylated ER was
present in one-half (10/20), of the lung tumors induced by exposure to
beryllium. Additionally, both genes were methylated in 40 percent of
the tumors. The authors noted that four tumors from beryllium-exposed
rats appeared to be partially methylated at the p16 locus. Bisulfite
sequencing of exon 1 of the ER gene was conducted on normal lung DNA
and DNA from three methylated, beryllium-induced tumors to determine
the density of methylation within amplified regions of exon 1 (referred
to as CpG sites). Two of the three methylated, beryllium-induced lung
tumors showed extensive methylation, with more than 80 percent of all
CpG sites methylated.
    The overall findings of this study suggest that inactivation of the
p16 and ER genes by promoter hypermethylation are likely to contribute
to the development of lung tumors in beryllium-exposed rats. The
results showed a correlation between changes in p16 methylation and
loss of gene transcription. The authors hypothesize that the mechanism
of action for beryllium-induced p16 gene inactivation in lung tumors
may be inflammatory mediators that result in oxidative stress. The
oxidative stress damages DNA directly through free radicals or
indirectly through the formation of 8-hydroxyguanosine DNA adducts,
resulting primarily in a single-strand DNA break.
    Wagner et al. (1969) studied the development of pulmonary tumors
after intermittent daily chronic inhalation exposure to beryllium ores
in three groups of male squirrel monkeys. One group was exposed to
bertrandite ore, a second to beryl ore, and the third served as
unexposed controls. Each of these three exposure groups contained 12
monkeys. Monkeys from each group were sacrificed after 6, 12, or 23
months of exposure. The 12-month sacrificed monkeys
(n = 4 for bertrandite and control groups; n = 2 for beryl group)
were replaced by a separate replacement group to maintain a total
animal population approximating the original numbers and to provide
a source of confirming data for biologic responses that might arise
following the ore exposures. Animals were exposed to bertrandite
and beryl ore concentrations of 15 mg/m\3\, corresponding to 210 [mu]g
beryllium/m\3\ and 620 [mu]g beryllium/m\3\ in each exposure chamber,
respectively. The parent ores were reduced to particles with geometric
mean diameters of 0.27 [mu]m ( 2.4) for bertrandite and
0.64 [mu]m ( 2.5) for beryl. Animals were exposed for
approximately 6 hours/day, 5 days/week. The histological changes in the
lungs of monkeys exposed to bertrandite and beryl ore exhibited a
similar pattern. The changes generally consisted of aggregates of dust-
laden macrophages, lymphocytes, and plasma cells near respiratory
bronchioles and small blood vessels. There were, however, no consistent
or significant pulmonary lesions or tumors observed in monkeys exposed
to either of the beryllium ores. This is in contrast to the findings in
rats exposed to beryl ore and to a lesser extent bertrandite, where
atypical cell proliferation and tumors were frequently observed in the
lungs. The authors hypothesized that the rats' greater susceptibility
may be attributed to the spontaneous lung disease characteristic of
rats, which might have interfered with lung clearance.
    As previously described, Conradi et al. (1971) investigated changes
in the lungs of monkeys and dogs two years after intermittent
inhalation exposure to beryllium oxide calcined at 1,400 [deg]C. Five
adult male and female monkeys (Macaca irus) weighing between 3 and 5.75
kg were used in the study. The study included two control monkeys.
Beryllium concentrations in the atmosphere of whole-body exposed
monkeys varied between 3.30 and 4.38 mg/m\3\. Thirty-minute exposures
occurred once a month for three months, with beryllium oxide
concentrations increasing at each exposure interval. Lung tissue was
investigated using electron microscopy and morphometric methods.
Beryllium content in portions of the lungs of five monkeys was measured
two years following exposure by emission spectrography. The reported
concentrations in monkeys (82.5, 143.0, and 112.7 [mu]g beryllium per
100 gm of wet tissue in the upper lobe, lower lobe, and combined lobes,
respectively) were higher than those in dogs. No neoplastic or
granulomatous lesions were observed in the lungs of any exposed animals
and there was no evidence of chronic proliferative lung changes after
two years.
4. In vitro Studies
    The exact mechanism by which beryllium induces pulmonary neoplasms
in animals remains unknown (NAS 2008). Keshava et al. (2001) performed
studies to determine the carcinogenic potential of beryllium sulfate in
cultured mammalian cells. Joseph et al. (2001) investigated
differential gene expression to understand the possible mechanisms of
beryllium-induced cell transformation and tumorigenesis. Both
investigations used cell transformation assays to study the cellular/
molecular mechanisms of beryllium carcinogenesis and assess
carcinogenicity. Cell lines were derived from tumors developed in nude
mice injected subcutaneously with non-transformed BALB/c-3T3 cells that
were morphologically transformed in vitro with 50-200 [mu]g beryllium
sulfate/ml for 72 hours. The non-transformed cells were used as
controls.
    Keshava et al. (2001) found that beryllium sulfate is capable of
inducing morphological cell transformation in mammalian cells and that
transformed cells are potentially tumorigenic. A dose-dependent
increase (9-41 fold) in transformation frequency was noted. Using
differential polymerase chain reaction (PCR), gene amplification was
investigated in six proto-oncogenes (K-ras, c-myc, c-fos, c-jun, c-sis,
erb-B2) and one tumor suppressor gene (p53). Gene amplification was
found in c-jun and K-ras. None of the other genes tested showed
amplification. Additionally, Western blot analysis showed no change in
gene expression or protein level in any of the genes examined. Genomic
instability in both the non-transformed and transformed cell lines was
evaluated using random amplified polymorphic DNA fingerprinting (RAPD
analysis). Using different primers, 5 of the 10 transformed cell lines
showed genomic instability when compared to the non-transformed BALB/c-
3T3 cells. The results indicate that beryllium sulfate-induced cell
transformation might, in part, involve gene amplification of K-ras and
c-jun and that some transformed cells possess neoplastic potential
resulting from genomic instability.
    Using the Atlas mouse 1.2 cDNA expression microarrays, Joseph et
al. (2001) studied the expression profiles of 1,176 genes belonging to
several different functional categories. Compared to the control cells,
expression of 18 genes belonging to two functional groups (nine cancer-
related genes and nine DNA synthesis, repair, and recombination genes)
was found to be consistently and reproducibly different (at least 2-
fold) in the tumor cells. Differential gene expression profile was
confirmed using reverse transcription-PCR with primers specific to the
differentially expressed genes. Two of the differentially expressed
genes (c-fos and c-jun) were used as model genes to demonstrate that
the beryllium-induced transcriptional activation of these genes was
dependent on pathways of protein kinase C and mitogen-activated protein
kinase and independent of reactive oxygen species in the control cells.
These results indicate that beryllium-induced cell transformation and
tumorigenesis are associated with up-regulated expression of the
cancer-related genes (such as c-fos, c-jun, c-myc, and R-ras) and down-
regulated expression of genes involved in DNA synthesis, repair, and
recombination (such as MCM4, MCM5, PMS2, Rad23, and DNA ligase I).
5. Preliminary Lung Cancer Conclusions
    OSHA has preliminarily determined that the weight of evidence
indicates that beryllium compounds should be regarded as potential
occupational lung carcinogens. Other scientific organizations,
including the International Agency for Research on Cancer (IARC), the
National Toxicology Program (NTP), the U.S. Environmental Protection
Agency (EPA), the National Institute for Occupational Safety and Health
(NIOSH), and the American Conference of Governmental Industrial
Hygienists (ACGIH) have reached similar conclusions with respect to the
carcinogenicity of beryllium.
    While some evidence exists for direct-acting genotoxicity as a
possible mechanism for beryllium carcinogenesis, the weight of evidence
suggests a possible indirect mechanism may be responsible for most
tumorigenic activity of beryllium in animal models and possibly humans
(EPA, 1998). Inflammation has been postulated to be a key contributor
to many different forms of cancer (Jackson et al., 2006; Pikarsky et
al., 2004; Greten et al., 2004; Leek, 2002). In fact, chronic
inflammation may be a primary factor in the development of up to one-
third of all cancers (Ames et al., 1990; NCI, 2010).
    In addition to a T-cell mediated response beryllium has been
demonstrated to produce an inflammatory response in animal models
similar to other particles (Reeves et al., 1967; Swafford et al., 1997;
Wagner et al., 1969) possibly contributing to its carcinogenic potential.
Animal studies, as summarized above, have demonstrated a consistent scenario
of beryllium exposure resulting in chronic pulmonary inflammation. Studies
conducted in rats have demonstrated that chronic inhalation of materials
similar in solubility to beryllium result in increased pulmonary inflammation,
fibrosis, epithelial hyperplasia, and, in some cases, pulmonary
adenomas and carcinomas (Heinrich et al., 1995; Nikula et al., 1995;
NTP, 1993; Lee et al., 1985; Warheit et al., 1996). This response is
generally referred to as an "overload" response or threshold effect.
Substantial data indicate that tumor formation in the rat after
exposure to some sparingly soluble particles at doses causing marked,
chronic inflammation is due to a secondary mechanism unrelated to the
genotoxicity (or lack thereof) of the particle itself.
    It has been hypothesized that the recruitment of neutrophils during
the inflammatory response and subsequent release of oxidants from these
cells have been demonstrated to play an important role in the
pathogenesis of rat lung tumors (Borm et al., 2004; Carter and
Driscoll, 2001; Carter et al., 2006; Johnston et al., 2000; Knaapen et
al., 2004; Mossman, 2000). Inflammatory mediators, as characterized in
many of the studies summarized above, have been shown to play a
significant role in the recruitment of cells responsible for the
release of reactive oxygen and hydrogen species. These species have
been determined to be highly mutagenic themselves as well as mitogenic,
inducing a proliferative response (Feriola and Nettesheim, 1994; Jetten
et al., 1990; Moss et al., 1994; Coussens and Werb, 2002). The
resultant effect is an environment rich for neoplastic transformations
and the progression of fibrosis and tumor formation. This finding does
not imply no risk at levels below an inflammatory response; rather, the
overall weight of evidence is suggestive of a mechanism of an indirect
carcinogen at levels where inflammation is seen. While tumorigenesis
secondary to inflammation is one reasonable mode of action, other
plausible modes of action independent of inflammation (e.g.,
epigenetic, mitogenic, reactive oxygen mediated, indirect genotoxicity,
etc.) may also contribute to the lung cancer associated with beryllium
exposure.
    Epidemiological studies indicate excess risk of lung cancer
mortality from occupational beryllium exposure levels at or below the
current OSHA PEL (Schubauer-Berigan et al., 2010; Table 4).

F. Other Health Effects

    Past studies on other health effects have been thoroughly reviewed
by several scientific organizations (NTP, 1999; EPA, 1998; ATSDR, 2002;
WHO, 2001; HSDB, 2010). These studies include summaries of animal
studies, in vitro studies, and human epidemiological studies associated
with cardiovascular, hematological, hepatic, renal, endocrine,
reproductive, ocular and mucosal, and developmental effects. High-dose
exposures to beryllium have been shown to have an adverse effect upon a
variety of organs and tissues in the body, particularly the liver. The
adverse systemic effects from human exposures mostly occurred prior to
the introduction of occupational and environmental standards set in
1970-1972 (OSHA, 1971; ACGIH, 1971; ANSI, 1970) and 1974 (EPA, 1974)
and therefore are less relevant today than in the past. The available
data is fairly limited. The hepatic, cardiovascular, renal, and ocular
and mucosal effects are briefly summarized below. Health effects in
other organ systems listed above were only observed in animal studies
at very high exposure levels and are, therefore, not discussed here.
 1. Hepatic Effects
    Beryllium has been shown to accumulate in the liver and a
correlation has been demonstrated between beryllium content and hepatic
damage. Different compounds have been shown to distribute differently
within the hepatic tissues. For example, beryllium phosphate had
accumulated almost exclusively within sinusoidal (Kupffer) cells of the
liver, while the beryllium derived from beryllium sulfate was found
mainly in parenchymal cells. Conversely, beryllium sulphosalicylic acid
complexes were rapidly excreted (Skillteter and Paine, 1979).
    According to a few autopsies, beryllium-laden liver had central
necrosis, mild focal necrosis as well as congestion, and occasionally
beryllium granuloma.
    Residents near a beryllium plant may have been exposed by inhaling
trace amounts of beryllium powder, and different beryllium compounds
may have induced different toxicant reactions (Yian and Yin, 1982).
2. Cardiovascular Effects
    There is very limited evidence of cardiovascular effects of
beryllium and its compounds in humans. Severe cases of chronic
beryllium disease can result in cor pulmonale, which is hypertrophy of
the right heart ventricle. In a case history study of 17 individuals
exposed to beryllium in a plant that manufactured fluorescent lamps,
autopsies revealed right atrial and ventricular hypertrophy (Hardy and
Tabershaw, 1946). It is not likely that these cardiac effects were due
to direct toxicity to the heart, but rather were a response to impaired
lung function. However, an increase in deaths due to heart disease or
ischemic heart disease was found in workers at a beryllium
manufacturing facility (Ward et al., 1992).
    Animal studies performed in monkeys indicate heart enlargement
after acute inhalation exposure to 13 mg beryllium/m\3\ as beryllium
hydrogen phosphate, 0.184 mg beryllium/m\3\ as beryllium fluoride, or
0.198 mg beryllium/m\3\ as beryllium sulfate (Schepers 1964). Decreased
arterial oxygen tension was observed in dogs exposed to 30 mg
beryllium/m\3\ as beryllium oxide for 15 days (HSDB, 2010), 3.6 mg
beryllium/m\3\ as beryllium oxide for 40 days (Hall et al., 1950), or
0.04 mg beryllium/m\3\ as beryllium sulfate for 100 days (Stokinger et
al., 1950). These are expected to be indirect effects on the heart due
to pulmonary fibrosis and toxicity which can increase arterial pressure
and restrict blood flow.
3. Renal Effects
    Renal calculi (stones) were unusually prevalent in severe cases
that resulted from high levels of beryllium exposure. Renal stones
containing beryllium occurred in about 10 percent of patients affected
by high exposures (Barnett, et al., 1961). Kidney stones were observed
in 10 percent of the CBD cases collected by the BCR up to 1959 (Hall et
al., 1959). In addition, an excess of calcium in the blood and urine
has been seen frequently in patients with chronic beryllium disease
(ATSDR, 2002).
4. Ocular and Mucosal Effects
    Both the soluble, sparingly soluble, and insoluble beryllium
compounds have been shown to cause ocular irritation in humans (Van
Orstrand et al., 1945; De Nardi et al., 1953; Nishimura, 1966; Epstein,
1990; NIOSH, 1994). In addition, beryllium compounds (soluble,
sparingly soluble, or insoluble) have been demonstrated to induce acute
conjunctivitis with corneal maculae and diffuse erythema (HSDB, 2010).
    The mucosa (mucosal membrane) is the moist lining of certain
tissues/organs including the eyes, nose, mouth, lungs, and the urinary
and digestive tracts. Soluble beryllium salts have been shown to be
directly irritating to mucous membranes (HSDB, 2010).

G. Summary of Preliminary Conclusions Regarding Health Effects

    Through careful analysis of the current best available scientific
information outlined in this Health Effects Section V, OSHA has
preliminarily determined that beryllium and beryllium-containing
compounds are able to cause sensitization, chronic beryllium disease
(CBD) and lung cancer below the current OSHA PEL of 2 [mu]g/m\3\. The
Agency has preliminarily determined through the studies outlined in
section V.A.2 of this health effects section that skin and inhalation
exposure to beryllium can lead to sensitization; and inhalation
exposure, or skin exposure coupled with inhalation, can cause onset and
progression of CBD. In addition, the Agency has preliminarily
determined through studies outlined in section V.E. of this health
effects section that inhalation exposure to beryllium and beryllium
containing materials causes lung cancer.
1. Beryllium Causes Sensitization Below the Current PEL and
Sensitization is a Precursor to CBD
    Through the biological and immunological processes outlined in
section V.B. of the Health Effects, the Agency believes that the
scientific evidence supports the following mechanism for the
development of sensitization and CBD.
     Inhaled beryllium and beryllium-containing materials able
to be retained and solubilized in the lungs initiate sensitization and
facilitate CBD development (Section V.B.5).
     Beryllium compounds that dissolve in biological fluids,
such as sweat, can penetrate intact skin and initiate sensitization
(section V.A.2; V.B). Phagosomal fluid and lung fluid have been
demonstrated to dissolve beryllium compounds in the lung (section
V.A.2a).
     Sensitization occurs through a CD4+ T-cell mediated
process with both soluble and insoluble beryllium and beryllium-
containing compounds through direct antigen presentation or through
further antigen processing (section V.D.1) in the skin or lung. T-cell
mediated responses, such as sensitization, are generally regarded as
long-lasting (e.g., not transient or readily reversible) immune
conditions.
     Beryllium sensitization and CBD are adverse events along a
pathological continuum in the disease process with sensitization being
the necessary first step in the progression to CBD (section V.D).
    [cir] Animal studies have provided supporting evidence for T-cell
proliferation in the development of granulomatous lung lesions after
beryllium exposure (section V.D.2; V.D.6).
    [cir] Since the pathogenesis of CBD involves a beryllium-specific,
cell-mediated immune response, CBD cannot occur in the absence of
beryllium sensitization (V.D.1). While no clinical symptoms are
associated with sensitization, a sensitized worker is at risk of
developing CBD upon subsequent inhalation exposure to beryllium.
    [cir] Epidemiological evidence that covers a wide variety of
different beryllium compounds and industrial processes demonstrates
that sensitization and CBD are continuing to occur at present-day
exposures below OSHA's PEL (section V.D.4; V.D.5).
     OSHA considers CBD to be a progressive illness with a
continuous spectrum of symptoms ranging from its earliest asymptomatic
stage following sensitization through to full-blown CBD and death
(section V.D.7).
     Genetic variabilities may enhance risk for developing
sensitization and CBD in some groups (section V.D.3).
    In addition, epidemiological studies outlined in section V.D.5 have
demonstrated that efforts to reduce exposures have succeeded in
reducing the frequency of sensitization and CBD.
2. Evidence Indicates Beryllium is a Human Carcinogen
    OSHA has conducted an evaluation of the current available
scientific information of the carcinogenic potential of beryllium and
beryllium-containing compounds (section V.E). Based on weight of
evidence and plausible mechanistic information obtained from in vitro
and in vivo animal studies as well as clinical and epidemiological
investigations, the Agency has preliminarily determined that beryllium
and beryllium-containing materials should be regarded as human
carcinogens. This information is in accordance with findings from IARC,
NTP, EPA, NIOSH, and ACGIH (section V.E).
     Lung cancer is an irreversible and frequently fatal
disease with an extremely poor 5-year survival rate (NCI, 2009).
     Epidemiological cohort studies have reported statistically
significant excess lung cancer mortality among workers employed in U.S.
beryllium production and processing plants during the 1930s to 1970s
(Section V.E.2).
     Significant positive associations were found between lung
cancer mortality and both average and cumulative beryllium exposures
when appropriately adjusted for birth cohort and short-term work status
(Section V.E.2).
     Studies in which large amounts of different beryllium
compounds were inhaled or instilled in the respiratory tracts of
experimental animals resulted in an increased incidence of lung tumors
(Section V.E.3).
     Authoritative scientific organizations, such as the IARC,
NTP, and EPA, have classified beryllium as a known or probable human
carcinogen.
    While OSHA has preliminarily determined there is sufficient
evidence of beryllium carcinogenicity, the exact tumorigenic mechanism
for beryllium is unclear and a number of mechanisms are plausibly
involved, including chronic inflammation, genotoxicity, mitogenicity
oxidative stress, and epigenetic changes (section V.E.3).
     Studies of beryllium exposed animals have consistently
demonstrated chronic pulmonary inflammation after exposure (section
V.E.3).
    [cir] Substantial data indicate that tumor formation in certain
animal models after inhalation exposure to sparingly soluble particles
at doses causing marked, chronic inflammation is due to a secondary
mechanism unrelated to the genotoxicty of the particle (section V.E.5).
     A review conducted by the NAS (2008) found that beryllium
and beryllium-containing compounds tested positive for genotoxicity in
nearly 50 percent of studies without exogenous metabolic activity,
suggesting a possible direct-acting mechanism may exist (section V.E.1)
as well as the potential for epigenetic changes (section V.E.4).
    Other health effects have been summarized in sections F of the
Health Effects Section and include hepatic, cardiovascular, renal,
ocular, and mucosal effects. The adverse systemic effects from human
exposures mostly occurred prior to the introduction of occupational and
environmental standards set in 1970-1972 (OSHA, 1971; ACGIH, 1971;
ANSI, 1970) and 1974 (EPA, 1974) and therefore are less relevant today
than in the past.


APPENDIX

                           Table A.1--Summary of Beryllium Sensitization and Chronic Beryllium Disease Epidemiological Studies
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           (%) Prevalence                Range of         Exposure-
          Reference               Study type    ------------------------------------     exposure          response          Study          Additional
                                                   Sensitization          CBD          measurements      relationship     limitations        comments
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Studies Conducted Prior to BeLPT
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hardy and Tabershaw, 1946....  Case-series.....  N/A.............  N/A.............  N/A.............  N/A............  Selection bias.  Small sample
                                                                                                                                          size.
Hardy, 1980..................  Case-series.....  N/A.............  N/A.............  N/A.............  N/A............  Selection bias.  Small sample
                                                                                                                                          size.
Machle et al., 1948..........  Case-series.....  N/A.............  N/A.............  Semi-             Yes............  Selection bias.  Small sample
                                                                                      quantitative.                                       size;
                                                                                                                                          unreliable
                                                                                                                                          exposure data.
Eisenbud et al., 1949........  Case-series.....  N/A.............  N/A.............  Average           ...............  ...............  Non-
                                                                                      concentration:                                      occupational;
                                                                                      350-750 ft from                                     ambient air
                                                                                      plant--0.05-0.1                                     sampling.
                                                                                      5 [mu]g/m\3\;.
                                                                                     < 350 ft from
                                                                                      plant--2.1
                                                                                      [mu]g/m\3\.
Lieben and Metzner, 1959.....  ................  N/A.............  ................  N/A.............  ...............  No quantitative  Family member
                                                                                                                         exposure data.   contact with
                                                                                                                                          contaminated
                                                                                                                                          clothes.
Hardy et al., 1967...........  Case Registry     N/A.............  N/A.............  N/A.............  N/A............  Incomplete       ...............
                                Review.                                                                                  exposure
                                                                                                                         concentration
                                                                                                                         data.
Hasan and Kazemi, 1974.......  ................  N/A.............  ................  ................  ...............  ...............  ...............
Eisenbud and Lisson, 1983....  ................  N/A.............  1-10............  ................  ...............  ...............  ...............
Stoeckle et al., 1969........  Case-series (60   N/A.............  ................  ................  No.............  Selection bias.  Provided
                                cases).                                                                                                   information
                                                                                                                                          regarding
                                                                                                                                          progression
                                                                                                                                          and
                                                                                                                                          identifying
                                                                                                                                          sarcoidosis
                                                                                                                                          from CBD.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                Studies Conducted Following the Development of the BeLPT
--------------------------------------------------------------------------------------------------------------------------------------------------------

                                                             Beryllium Mining and Extraction
--------------------------------------------------------------------------------------------------------------------------------------------------------
Deubner et al., 2001b........  Cross-sectional   4.0 (3 cases)...  1.3 (1 case)....  Mining, milling-- No.............  Small sample     Personal
                                (75 workers).                                         range 0.05-0.8                     size.            sampling.
                                                                                      [mu]g/m\3\;
                                                                                     Annual maximum
                                                                                      0.04-165.7
                                                                                      [mu]g/m\3\.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                     Beryllium Metal Processing and Alloy Production
--------------------------------------------------------------------------------------------------------------------------------------------------------
Kreiss et al., 1997..........  Cross-sectional   6.9 (43 cases)..  4.6 (29 cases)..  Median--1.4       No.............  Inconsistent     Short-term
                                study of 627                                          [mu]g/m\3\.                        BeLPT results    Breathing Zone
                                workers.                                                                                 between labs.    sampling.
Rosenman et al., 2005........  Cross-sectional   14.5 (83 cases).  5.5 (32 cases)..  Mean average      No.............  ...............  Daily weighted
                                study of 577                                          range--7.1-8.7                                      average:
                                workers.                                              [mu]g/m\3\;.                                       High exposures
                                                                                     Mean peak range--                                    compared to
                                                                                      53-87 [mu]g/                                        other studies.
                                                                                      m\3\;.
                                                                                     Mean cumulative
                                                                                      range--100-209
                                                                                      [mu]g/m\3\.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                             Beryllium Machining Operations
--------------------------------------------------------------------------------------------------------------------------------------------------------
Newman et al., 2001..........  Longitudinal      9.4 (22 cases)..  8.5 (20 cases)..  ................  No.............  ...............  Engineering and
                                study of 235                                                                                              administrative
                                workers.                                                                                                  controls
                                                                                                                                          primarily used
                                                                                                                                          to control
                                                                                                                                          exposures.


Kelleher et al., 2001........  Case-control      11.5              11.5              0.08-0.6 [mu]g/   Yes............  ...............  Identified 20
                                study of 20       (machinists).     (machinists).     m\3\--lifetime                                      workers with
                                cases and 206    2.9 (non-         2.9 (non-          weighted                                            Sensitization
                                controls.         machinists).      machinists).      exposures.                                          or CBD.
Madl et al., 2007............  Longitudinal      ................  ................  Machining.......  Yes............  ...............  Personal
                                study of 27                                          1980-1995 median                                     sampling:
                                cases.                                                -0.33 [mu]g/                                       Required
                                                                                      m\3\; 1996-1999                                     evidence of
                                                                                      median--0.16                                        granulomas for
                                                                                      [mu]g/m\3\;                                         CBD diagnosis.
                                                                                      2000-2005
                                                                                      median--0.09
                                                                                      [mu]g/m\3\;.
                                                                                     Non-machining
                                                                                      1980-1995
                                                                                      median--0.12
                                                                                      [mu]g/m\3\;
                                                                                      1996-1999
                                                                                      median--0.08
                                                                                      [mu]g/m\3\;
                                                                                      2000-2005
                                                                                      median--0.06
                                                                                      [mu]g/m\3\.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                Beryllium Oxide Ceramics
--------------------------------------------------------------------------------------------------------------------------------------------------------
Kreiss et al., 1993b.........  Cross-sectional   3.6 (18 cases)..  1.8 (9 cases)...  ................  No                                ...............
                                survey of 505
                                workers.
Kreiss et al., 1996..........  Cross-sectional   5.9 (8 cases)...  4.4 (6 cases)...  Machining         No.............  Small study      Breathing Zone
                                survey of 136                                         median--0.6                        population.      Sampling.
                                workers.                                              [mu]g/m\3\;.
                                                                                     Other Areas
                                                                                      median--< 0.3
                                                                                      [mu]g/m\3\;.
Henneberger et al., 2001.....  Cross-sectional   9.9 (15 cases)..  5.3 (8 cases)...  6.4% samples >2   Yes............  Small study      Breathing zone
                                survey of 151                                         [mu]g/m\3\;                        population.      sampling.
                                workers.                                              2.4% samples >5
                                                                                      [mu]g/m\3\;.
                                                                                     0.3% samples >25
                                                                                      [mu]g/m\3\.
Cummings et al., 2007........  Longitudinal      0.7-5.6 (4        0.1--7.9 (3       Production......  Yes............  Small sample     Personal
                                study of 93       cases).           cases).          1994-1999                           size.            sampling was
                                workers.                                              median--0.1[mu]                                     effective in
                                                                                      g/m\3\; 2000-                                       reducing rates
                                                                                      2003 median--                                       of new cases
                                                                                      0.04[mu]g/m\3\;.                                    of
                                                                                     Administrative                                       sensitization.
                                                                                      1994-1999
                                                                                      median < 0.2
                                                                                      [mu]g/m\3\;
                                                                                      2000-2003
                                                                                      median--0.02
                                                                                      [mu]g/m\3\.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                   Copper-Beryllium Alloy Processing and Distribution
--------------------------------------------------------------------------------------------------------------------------------------------------------
Schuler et al., 2005.........  Cross-sectional   7.0 (10 cases)..  4.0 (6 cases)...  Rod and Wire      ...............  Small study      Personal
                                survey of 153                                         Production                         population.      sampling.
                                workers.                                              median--0.12
                                                                                      [mu]g/m\3\;
                                                                                     Strip Metal
                                                                                      Production
                                                                                      median--0.02
                                                                                      [mu]g/m\3\;.
                                                                                     Production
                                                                                      Support median--
                                                                                      0.02 [mu]g/
                                                                                      m\3\;.
                                                                                     Administration
                                                                                      median--0.02
                                                                                      [mu]g/m\3\.


Thomas et al., 2009..........  Cross-sectional   3.8 (3 cases)...  1.9 (1 case)....  Used exposure     ...............  Authors noted    Instituted PPE
                                study of 82                                           profile from                       workers may      to reduce
                                workers.                                              Schuler study.                     have been        dermal
                                                                                                                         sensitized       exposures.
                                                                                                                         prior to
                                                                                                                         available
                                                                                                                         screening,
                                                                                                                         underestimatin
                                                                                                                         g
                                                                                                                         sensitization
                                                                                                                         rate in legacy
                                                                                                                         workers.
Stanton et al., 2006.........  Cross-sectional   1.1 (1 case)....  1.1 (1 case)....  Bulk Products     ...............  Study did not    Personal
                                study of 88                                           Production                         report use of    sampling.
                                workers.                                              median 0.04                        PPE or
                                                                                      [mu]g/m\3\;                        respirators.
                                                                                      Strip Metal
                                                                                      Production
                                                                                      median--0.03
                                                                                      [mu]g/m\3\;
                                                                                      Production
                                                                                      support.
                                                                                     median--0.01
                                                                                      [mu]g/m\3\;
                                                                                      Administration
                                                                                      median 0.01
                                                                                      [mu]g/m\3\.
Bailey et al., 2010..........  Cross-sectional   11.0............  14.5 total......  ................  ...............  Study reported   ...............
                                study of 660                                                                             prevalence
                                total workers                                                                            rates for pre
                                (258 partial                                                                             enhanced
                                program, 290                                                                             control-
                                full program).                                                                           program,
                                                                                                                         partial
                                                                                                                         enhanced
                                                                                                                         control
                                                                                                                         program, and
                                                                                                                         full enhanced
                                                                                                                         control
                                                                                                                         program.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                         Nuclear Weapons Production Facilities and Cleanup of Former Facilities
--------------------------------------------------------------------------------------------------------------------------------------------------------
Kreiss et al., 1989..........  Cross-sectional   11.8 (6 cases)..  7.8 (4 cases)...  ................  No.............  Small study      ...............
                                survey of 51                                                                             population
                                workers.
Kreiss et al., 1993a.........  Cross-sectional   1.9 (18 cases)..  1.7 (15 cases)..  ................  No.............  Study            ...............
                                survey of 895                                                                            population
                                workers.                                                                                 includes some
                                                                                                                         workers with
                                                                                                                         no reported Be
                                                                                                                         exposure.
Stange et al., 1996..........  Longitudinal      2.4 (76 cases)..  0.7 (29 cases)..  Annual mean       No.............  ...............  Personal
                                Study of 4,397                                        concentration.                                      sampling.
                                BHSP                                                 1970-1988 0.016
                                participants.                                         [mu]g/m\3\;
                                                                                      1984-1987 1.04
                                                                                      [mu]g/m\3\.
Stange et al., 2001..........  Longitudinal      4.5 (154 cases).  1.6 (81 cases)..  No quantitative   No.............  ...............  Personal
                                study of 5,173                                        information                                         sampling.
                                workers.                                              presented in
                                                                                      study.
Viet et al., 2000............  Case-control....  74 workers        50 workers CBD..  Mean exposure     Yes............  Likely           Fixed airhead
                                                  sensitized.                         range: 0.083-                      underestimated   sampling away
                                                                                      0.622 [mu]g/                       exposures.       from breathing
                                                                                      m\3\.                                               zone:
                                                                                     Maximum                                             Matched
                                                                                      exposures: 0.54-                                    controls for
                                                                                      36.8 [mu]g/                                         age, sex,
                                                                                      m.\3\.                                              smoking.
--------------------------------------------------------------------------------------------------------------------------------------------------------
N/A = Information not available from study reports.



                                       Table A.2--Summary of Mechanistic Animal Studies for Sensitization and CBD
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                  Dose or exposure       Type of                              Other
           Reference                 Species               Study length            concentration        beryllium       Study results      information
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                  Intratracheal (intrabroncheal) or Nasal Instillation
--------------------------------------------------------------------------------------------------------------------------------------------------------
Barna et al., 1981............  Guinea pig.......                       3 month  10 mg-5[mu]m       beryllium oxide.  Granulomas,
                                                                                  particle size.                       interstitial
                                                                                                                       infiltrate with
                                                                                                                       fibrosis with
                                                                                                                       thickening of
                                                                                                                       alveolar septae.
Barna et al., 1984............  Guinea pig.......                       3 month  5 mg.............  beryllium oxide.  Granulomatous
                                                                                                                       lesions in
                                                                                                                       strain 2 but
                                                                                                                       not strain 13
                                                                                                                       indicating a
                                                                                                                       genetic
                                                                                                                       component.
Benson et al., 2000...........  Mouse............  ............................  0, 12.5, 25,       beryllium copper  Acute pulmonary
                                                                                  100[mu]g; 0, 2,    alloy;            toxicity
                                                                                  8 [mu]g.           beryllium metal.  associated with
                                                                                                                       beryllium/
                                                                                                                       copper alloy
                                                                                                                       but not
                                                                                                                       beryllium metal.
Haley et al., 1994............  Cynomolgus monkey               14, 60, 90 days  0, 1, 50, 150      Beryllium metal,  Beryllium oxide
                                                                                  [mu]g.             beryllium oxide.  particles were
                                                                                 0, 2.5, 12.5,                         less toxic than
                                                                                  37.5 [mu]g.                          the beryllium
                                                                                                                       metal.
Huang et al., 1992............  Mouse............  ............................  5 [mu]g..........  Beryllium         Granulomas        ................
                                                                                 1-5 [mu]g........   sulfate           produced in A/J
                                                                                                     immunization;     strain but not
                                                                                                     beryllium metal   BALB/c or C57BL/
                                                                                                     challenge.        6.
Votto et al., 1987............  Rat..............                       3 month  2.4 mg...........  Beryllium         Granulomas,
                                                                                 8 mg/ml..........   sulfate           however, no
                                                                                                     immunization;     correlation
                                                                                                     beryllium         between T-cell
                                                                                                     sulfate           subsets in lung
                                                                                                     challenge.        and BAL fluid.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                               Inhalation--Single Exposure
--------------------------------------------------------------------------------------------------------------------------------------------------------
Haley et al., 1989a...........  Beagle dog.......             Chronic--one dose  0, 6 [mu]g/kg, 18  500 [deg]C; 1000  Positive BeLPT    Granulomas
                                                                                  [mu]g/kg.          [deg]C            results--develo   resolved with
                                                                                                     beryllium oxide.  ped granulomas;   time, no full-
                                                                                                                       low-calcined      blown CBD.
                                                                                                                       beryllium oxide
                                                                                                                       more toxic than
                                                                                                                       high-calcined.
Haley et al., 1989b...........  Beagle dog.......      Chronic--one dose/2 year  0, 17 [mu]g/kg,    500 [deg]C; 1000  Granulomas,       Granulomas
                                                                       recovery   50 [mu]g/kg.       [deg]C            sensitization,    resolved over
                                                                                                     beryllium oxide.  low-fired more    time.
                                                                                                                       toxic than high
                                                                                                                       fired.
Robinson et al., 1968.........  Dog..............                       Chronic  0. 115mg/m\3\....  Beryllium oxide,  Foreign body
                                                                                                     beryllium         reaction in
                                                                                                     fluoride,         lung.
                                                                                                     beryllium
                                                                                                     chloride.
Sendelbach et al., 1989.......  Rat..............                        2 week  0, 4.05 [mu]g/L..  Beryllium as      Interstial
                                                                                                     beryllium         pneumonitis.
                                                                                                     sulfate.
Sendelbach and Witschi, 1987..  Rat..............                        2 week  0, 3.3, 7 [mu]g/L  Beryllium as      Enzyme changes
                                                                                                     beryllium         in BAL fluid.
                                                                                                     sulfate.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                               Inhalation--Repeat Exposure
--------------------------------------------------------------------------------------------------------------------------------------------------------
Conradi et al., 1971..........  Beagle dog.......               Chronic--2 year  0. 3300 [mu]g/     1400 [deg]C       No changes        May have been
                                                                                  m\3\, 4380 [mu]g/  beryllium oxide.  detected.         due to short
                                                                                  m\3\ once/month                                        exposure time
                                                                                  for 3 months.                                          followed by
                                                                                                                                         long recovery.


                                Macaca irus                     Chronic--2 year  0. 3300 [mu]g/     1400 [deg]C       No changes        May have been
                                 Monkey.                                          m\3\, 4380 [mu]g/  beryllium oxide.  detected.         due to short
                                                                                  m\3\ once/month                                        exposure time
                                                                                  for 3 months.                                          followed by
                                                                                                                                         long recovery.
Haley et al., 1992............  Beagle dog.......     Chronic--repeat dose (2.5  17, 50 [mu]g/kg..  500 [deg]C; 1000  Granulomatous
                                                                year intervals)                      [deg]C            pneumonitis.
                                                                                                     beryllium oxide.
Harmsen et al., 1985..........  Beagle dog.......                       Chronic  0, 20 [mu]g/kg,    500[deg]C; 1000
                                5 dogs per group.                                 50 [mu]g/kg.       [deg]C
                                                                                                     beryllium oxide.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                  Dermal or Intradermal
--------------------------------------------------------------------------------------------------------------------------------------------------------
Kang et al., 1977.............  Rabbit...........  ............................  10mg.............  Beryllium         Skin
                                                                                                     sulfate.          sensitization
                                                                                                                       and skin
                                                                                                                       granulomas.
Tinkle et al., 2003...........  Mouse............                       3 month  25 [mu]L.........  Beryllium         Microgranulomas
                                                                                 70 [mu]g.........   sulfate.          with some
                                                                                                    Beryllium oxide.   resolution over
                                                                                                                       time of study.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                      Intramuscular
--------------------------------------------------------------------------------------------------------------------------------------------------------
Eskenasy, 1979................  Rabbit...........  35 days (injections at 7 day  10mg.ml..........  Beryllium         Sensitization,
                                                                     intervals)                      sulfate.          evidence of CBD.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                Intraperitoneal Injection
--------------------------------------------------------------------------------------------------------------------------------------------------------
Marx and Burrell, 1973........  Guinea pig.......            24 weeks (biweekly  2.6 mg + 10 [mu]g  Beryllium         Sensitization...
                                                                    injections)   dermal             sulfate.
                                                                                  injections.
--------------------------------------------------------------------------------------------------------------------------------------------------------


                                           Table A-3--Summary of Beryllium Lung Cancer Epidemiological Studies
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                         Confounding         Study          Additional
          Reference               Study type      Exposure range     Study number     Mortality ratio      factors        limitations        comments
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 Beryllium Case Registry
--------------------------------------------------------------------------------------------------------------------------------------------------------
Infante et al., 1980.........  Cohort..........  N/D.............  421 cases from    SMR 2.12........  Not reported...  Exposure         ...............
                                                                    the BCR.         7 lung cancer                       concentration
                                                                                      deaths.                            data or
                                                                                                                         smoking habits
                                                                                                                         not reported.
Steenland and Ward, 1991.....  Cohort..........  N/D.............  689 cases from    SMR 2.00 (95% CI  ...............  ...............  Included women:
                                                                    the BCR.          1.33-2.89).                                         93% women
                                                                                     28 lung cancer                                       diagnosed with
                                                                                      deaths.                                             CBD; 50% men
                                                                                                                                          diagnosed with
                                                                                                                                          CBD;
                                                                                                                                         SMR 157 for
                                                                                                                                          those with CBD
                                                                                                                                          and SMR 232
                                                                                                                                          for those with
                                                                                                                                          ABD.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                               Beryllium Manufacturing and/or Processing Plants (Extraction, Fabrication, and Processing)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ward et al., 1992............  Retrospective     N/D.............  9,225 males.....  SMR 1.26........  ...............  Lack of job      Employment
                                Mortality                                            (95% CI 1.12-                       history and      period 1940-
                                Cohort.                                               1.42).                             air monitoring   1969.
                                                                                     280 lung cancer                     data.
                                                                                      deaths.


Levy et al., 2002............  Cohort..........  N/D.............  9225 males......  Statistically     Adjusted for     Lack of job      Majority of
                                                                                      non-significant   smoking.         history and      workers
                                                                                      elevation in                       air monitoring   studied
                                                                                      lung cancer                        data.            employed for
                                                                                      deaths.                                             less than one
                                                                                                                                          year
Bayliss et al., 1971.........  Nested cohort...  ................  8,000 workers...  SMR 1.06........  ...............  ...............  Employed prior
                                                                                     36 lung cancer                                       to 1947 for
                                                                                      deaths.                                             almost half
                                                                                                                                          lung cancer
                                                                                                                                          deaths.
Mancuso, 1970................  Cohort..........  411-43,300 [mu]g/ 1,222 workers at  SMR 1.42........  Only partial     Partial smoking  Employment
                                                  m\3\ annual       OH plant; 2,044  (95% CI 1.1-1.8)   smoking          history; No      period from
                                                  exposure          workers at PA    80 lung cancer     history.         job analysis     1937-1948.
                                                  (reported from    plant.            deaths.                            by title or
                                                  Zielinsky,                                                             exposure
                                                  1961).                                                                 category.
Mancuso, 1980................  Cohort..........  N/D.............  Same OH and PA    SMR 1.40........  No smoking       No adjustment    Employment
                                                                    plant analysis.                     adjustment.      by job title     period from
                                                                                                                         or exposure.     1942-1948;
                                                                                                                                          Used workers
                                                                                                                                          at rayon plant
                                                                                                                                          for
                                                                                                                                          comparison.
Mancuso and El Attar, 1969...  Cohort..........  N/D.............  3,685 white       SMR 1.49........  Adjusted for     No job exposure  Employment
                                                                    males.                              age and local.   data or          history from
                                                                                                                         smoking          1937-1944.
                                                                                                                         adjustment.
Wagner et al., 1980..........  Cohort..........  N/D.............  3,055 white       SMR 1.25........  ...............  Inadequately     Reanalysis
                                                                    males PA plant.  (95% CI 0.9-1.7)                    adjusted for     using PA lung-
                                                                                     47 lung cancer                      smoking; Used    cancer rate
                                                                                      deaths.                            national lung-   revealed 19%
                                                                                                                         cancer risk      underestimatio
                                                                                                                         for cancer not   n of beryllium
                                                                                                                         PA.              lung cancer
                                                                                                                                          deaths.
Sanderson et al., 2001.......  Nested case-      -- Average        3,569 males PA    SMR 1.22........  Smoking was      May not have     Found
                                control.          exposure          plant.           (95% CI 1.03-      found not to     adjusted         association
                                                  22.8[mu]g/m\3\.                     1.43).            be a             properly for     with 20 year
                                                 -- Maximum                          142 lung cancer    confounding      birth-year or    latency.
                                                  exposure                            deaths.           factor.          age at hire.
                                                  32.4[mu]g/m\3\.
Levy et al., 2007............  Nested case-      Used log          Reanalysis of     SMR 1.04........  Different        ...............  Found no
                                control.          transformed       Sanderson et     (95% CI 0.92-      methodology                       association
                                                  exposure data.    al., 2001.        1.17).            for smoking                       between
                                                                                                        adjustment.                       beryllium
                                                                                                                                          exposure and
                                                                                                                                          increased risk
                                                                                                                                          of lung
                                                                                                                                          cancer.
Schubauer-Berigan et al.,      Nested case-      Used exposure     Reanalysis of     Used Odds ratio:  Adjusted for     ...............  -- Controlled
 2008.                          control.          data from         Sanderson et      1.91 (95% CI      smoking, birth                    for birth-year
                                                  Sanderson et      al., 2001.        1.06-3.44)        cohort, age.                      and age at
                                                  al., 2001, Chen                     unadjusted;.                                        hire;
                                                  2001, and Couch                    1.29 (95% CI                                        -- Found
                                                  et al., 2010.                       0.61-2.71)                                          similar
                                                                                      birth-year                                          results to
                                                                                      adjusted;.                                          Sanderson et
                                                                                     1.24 (95% CI                                         al., 2001;
                                                                                      0.58-2.65) age-                                    -- Found
                                                                                      hire adjusted.                                      association
                                                                                                                                          with 10 year
                                                                                                                                          latency
                                                                                                                                         -- "0" = used
                                                                                                                                          minuscule
                                                                                                                                          value at start
                                                                                                                                          to eliminate
                                                                                                                                          the use of 0
                                                                                                                                          in a
                                                                                                                                          logarithmic
                                                                                                                                          analysis
Schubauer-Berigan et al.,      Cohort..........  N/D.............  9199 workers      SMR 1.17 (95%CI   Adjusted for     ...............  Male workers
 2010a.                                                             from 7            1.08-1.28).       smoking.                          employed at
                                                                    processing       545 deaths......                                     least 2 days
                                                                    plants.                                                               between 1940
                                                                                                                                          and 1970.
Schubauer-Berigan et al.,      Cohort..........  Used exposure     5436 workers OH   Evaluated using   Adjusted for     ...............  -- Exposure
 2010b.                                           data from         and PA plants.    hazard ratios     age, birth                        response was
                                                  Sanderson et                        and excess        cohort,                           found between
                                                  al., 2001.                          absolute risk.    asbestos                          0-10[mu]g/m\3\
                                                                                     293 deaths......   exposure,                         mean DWA;
                                                                                                        short-term                       -- Increased
                                                                                                        work status.                      with
                                                                                                                                          statistical
                                                                                                                                          significance
                                                                                                                                          at 4[mu]g/
                                                                                                                                          m\3\;
                                                                                                                                         -- 1 in 1000
                                                                                                                                          risk at
                                                                                                                                          0.033[mu]g/
                                                                                                                                          m\3\ mean DWA.
--------------------------------------------------------------------------------------------------------------------------------------------------------


                                                           Re-evaluation of Published Studies
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hollins et al., 2009.........  Review..........  Re-examination    ................  ................  ...............  ...............  Found lung
                                                  of weight-of-                                                                           cancer excess
                                                  evidence from                                                                           risk was
                                                  more than 50                                                                            associated
                                                  publications.                                                                           with higher
                                                                                                                                          levels of
                                                                                                                                          exposure not
                                                                                                                                          relevant in
                                                                                                                                          today's
                                                                                                                                          industrial
                                                                                                                                          settings.
IARC, 2012...................  Multiple........  Insufficient      ................  Sufficient        IARC concluded   ...............  -- Greater lung
                                                  exposure                            evidence for      beryllium lung                    cancer risk in
                                                  concentration.                      carcinogenicity   cancer risk                       the BCR cohort
                                                 Data............                     of beryllium.     was not                          -- Correlation
                                                                                                        associated                        between
                                                                                                        with smoking.                     highest lung
                                                                                                                                          cancer rates
                                                                                                                                          and highest
                                                                                                                                          amounts of ABD
                                                                                                                                          or other non-
                                                                                                                                          malignant lung
                                                                                                                                          diseases
                                                                                                                                         -- Increased
                                                                                                                                          risk with
                                                                                                                                          longer latency
                                                                                                                                         -- Greater
                                                                                                                                          excess lung
                                                                                                                                          cancers among
                                                                                                                                          those hired
                                                                                                                                          prior to 1950.
--------------------------------------------------------------------------------------------------------------------------------------------------------
N/D = information not determined for most studies
DWA--daily weighted average

VI. Preliminary Beryllium Risk Assessment

    The Occupational Safety and Health (OSH) Act and court cases
arising under it have led OSHA to rely on risk assessment to support
the risk determinations required to set a permissible exposure limit
(PEL) for a toxic substance in standards under the OSH Act. Section
6(b)(5) of the OSH Act states that "The Secretary [of Labor], in
promulgating standards dealing with toxic materials or harmful physical
agents under this subsection, shall set the standard which most
adequately assures, to the extent feasible, on the basis of the best
available evidence, that no employee will suffer material impairment of
health or functional capacity even if such employee has regular
exposure to the hazard dealt with by such standard for the period of
his working life" (29 U.S.C. 655(b)(5)).
    In Industrial Union Department, AFL-CIO v. American Petroleum
Institute, 448 U.S. 607 (1980) (Benzene), the United States Supreme
Court ruled that the OSH Act requires that, prior to the issuance of a
new standard, a determination must be made that there is a significant
risk of material impairment of health at the existing PEL and that
issuance of a new standard will significantly reduce or eliminate that
risk. The Court stated that "before [the Secretary] can promulgate any
permanent health or safety standard, the Secretary is required to make
a threshold finding that a place of employment is unsafe--in the sense
that significant risks are present and can be eliminated or lessened by
a change in practices" (Id. at 642). The Court also stated "that the
Act does limit the Secretary's power to requiring the elimination of
significant risks" (488 U.S. at 644 n.49), and that "OSHA is not
required to support its finding that a significant risk exists with
anything approaching scientific certainty" (Id. at 656).
    OSHA's approach for the risk assessment incorporates both a review
of the recent literature on populations of workers exposed to beryllium
below the current Permissible Exposure Limit (PEL) of 2 [mu]g/m\3\ and
a statistical exposure-response analysis. OSHA evaluated risk at
several alternate PELs under consideration by the Agency: 2 [mu]g/m\3\,
1 [mu]g/m\3\, 0.5 [mu]g/m\3\, 0.2 [mu]g/m\3\, and 0.1 [mu]g/m\3\. A
number of recently published epidemiological studies evaluate the risk
of sensitization and CBD for workers exposed at and below the current
PEL and the effectiveness of exposure control programs in reducing
risk. OSHA also conducted a statistical analysis of the exposure-
response relationship for sensitization and CBD at the current PEL and
alternate PELs the Agency is considering. For this analysis, OSHA used
data provided by National Jewish Medical and Research Center (NJMRC) on
a population of workers employed at a beryllium machining plant in
Cullman, AL. The review of the epidemiological studies and OSHA's own
analysis show substantial risk of sensitization and CBD among workers
exposed at and below the current PEL of 2 [mu]g/m\3\. They also show
substantial reduction in risk where employers have implemented a
combination of controls, including stringent control of airborne
beryllium levels and additional measures such as respirators, dermal
personal protective equipment (PPE), and strict housekeeping to protect
workers against dermal and respiratory beryllium exposure. To evaluate
lung cancer risk, OSHA relied primarily on a quantitative risk
assessment published in 2011 by NIOSH. This risk assessment was based
on an update of the Reading cohort analyzed by Sanderson et al., as
well as workers from two smaller plants (Schubauer-Berigan et al.,
2011) where workers were exposed to lower levels of beryllium and
worked for longer periods than at the Reading plant. The authors found
that lung cancer risk was strongly and significantly related to mean,
cumulative, and maximum measures of workers' exposure; they predicted
substantial risk of lung cancer at the current PEL, and substantial
reductions in risk at the alternate PELs OSHA considered for the
proposed rule (Schubauer-Berigan et al., 2011).

A. Review of Epidemiological Literature on Sensitization and Chronic
Beryllium Disease From Occupational Exposure

    As discussed in the Health Effects section, studies of beryllium-
exposed workers conducted using the beryllium lymphocyte proliferation
test (BeLPT) have found high rates of beryllium sensitization and CBD
among workers in many industries, including at some facilities where
exposures were primarily below OSHA's PEL of 2 [mu]g/m\3\ (Kreiss et
al., 1993; Henneberger et al., 2001; Schuler et al., 2005; Schuler et
al., 2012). In the mid-1990s, some facilities using beryllium began to
aggressively monitor and reduce workplace exposures. Four plants where
several rounds of BeLPT screening were conducted before and after
implementation of new exposure control methods provide the best
currently available evidence on the effectiveness of various exposure
control measures in reducing the risk of sensitization and CBD. The
experiences of these plants--a copper-beryllium processing facility in
Reading, PA, a beryllia ceramics facility in Tucson, AZ; a beryllium
processing facility in Elmore, OH; and a machining facility in Cullman,
AL--show that efforts to prevent sensitization and CBD by using
engineering controls to reduce workers' beryllium exposures to median
levels at or around 0.2 [mu]g/m\3\ and did not emphasize PPE and
stringent housekeeping methods, had only limited impact on risk.
However, exposure control programs implemented more recently, which
drastically reduced respiratory exposure to beryllium via a combination
of engineering controls and respiratory protection, controlled dermal
contact with beryllium using PPE, and employed stringent housekeeping
methods to keep work areas clean and prevent transfer of beryllium
between work areas, sharply curtailed new cases of sensitization among
newly-hired workers. There is additional, but more limited, information
available on the occurrence of sensitization and CBD among aluminum
smelter workers with low-level beryllium exposures (Taiwo et al., 2008;
Taiwo et al., 2010; Nilsen et al., 2010). A discussion of the
experiences at these plants follows.
    The Health Effects section also discussed the role of particle
characteristics and beryllium compound solubility in the development of
sensitization and CBD among beryllium-exposed workers. Respirable
particles small enough to reach the deep lung are responsible for CBD.
However, larger inhalable particles that deposit in the upper
respiratory tract may lead to sensitization. The weight of evidence
indicates that both soluble and insoluble forms of beryllium are able
to induce sensitization and CBD. Insoluble forms of beryllium that
persist in the lung for longer periods may pose greater risk of CBD
while soluble forms may more easily trigger immune sensitization.
Although these factors potentially influence the toxicity of beryllium,
the available data are too limited to reliably account for solubility
and particle size in the Agency estimates of risk. The qualitative
impact on conclusions and uncertainties with regard to risk are
discussed in a later section.
1. Reading, PA, Plant
    Schuler et al. conducted a study of workers at a copper-beryllium
processing facility in Reading, PA, screening 152 workers with the
BeLPT (Schuler et al., 2005). Exposures at this plant were believed to
be low throughout its history due to the low percentage of beryllium in
the metal alloys used, and the relatively low exposures found in
general area samples collected starting in 1969 (sample median <= 0.1
[mu]g/m\3\, 97% < 0.5 [mu]g/m\3\). The reported prevalences of
sensitization (6.5 percent) and CBD (3.9 percent) showed substantial
risk at this facility, even though airborne exposures were primarily
below OSHA's current PEL of 2 [mu]g/m\3\.
    Personal lapel samples were collected in production and production
support jobs between 1995 and May 2000. These samples showed primarily
very low airborne beryllium levels, with a median of 0.073 [mu]g/
m\3\.\6\ The wire annealing and pickling process had the highest
personal lapel sample values, with a median of 0.149 [mu]g/m\3\.
Despite these low exposure levels, cases of sensitization continued to
occur among workers whose first exposures to beryllium occurred in the
1990s. Five (11.5 percent) workers of 43 hired after 1992 who had no
prior beryllium exposure became sensitized, including four in
production work and one in production support (Thomas et al., 2009;
evaluation for CBD not reported). Two (13 percent) of these sensitized
workers were among 15 workers in this group who had been hired less
than a year before the screening.
---------------------------------------------------------------------------

    \6\ In their publication, Schuler et al. presented median values
for plant-wide and work-category-specific exposure levels; they did
not present arithmetic or geometric mean values for personal
samples.
---------------------------------------------------------------------------

    After the BeLPT screening was conducted in 2000, the company began
implementing new measures to further reduce workers' exposure to
beryllium. Requirements designed to minimize dermal contact with
beryllium, including long-sleeve facility uniforms and polymer gloves,
were instituted in production areas in 2000. In 2001 the company
installed local exhaust ventilation (LEV) in die grinding and
polishing. Personal lapel samples collected between June 2000 and
December 2001 show reduced exposures plant-wide. Of 2,211 exposure
samples collected during this "pre-enclosure program" period, 98
percent were below 0.2 [mu]g/m\3\ (Thomas et al., 2009, p. 124).
Median, arithmetic mean, and geometric mean values <= 0.03 [mu]g/m\3\
were reported in this period for all processes except the wire
annealing and pickling process. Samples for this process remained
elevated, with a median of 0.1 [mu]g/m\3\ (arithmetic mean of 0.127
[mu]g/m\3\, geometric mean of 0.083 [mu]g/m\3\). In January 2002, the
plant enclosed the wire annealing and pickling process in a restricted
access zone (RAZ), required respiratory PPE in the RAZ, and implemented
stringent measures to minimize the potential for skin contact and
beryllium transfer out of the zone. While exposure samples collected by
the facility were sparse following the enclosure, they suggest exposure
levels comparable to the 2000-01 samples in areas other than the RAZ.
Within the RAZ, required use of powered air-purifying respirators
(PAPRs) indicates that respiratory exposure was negligible. A 2009
publication on the facility reported that outside the RAZ, "the vast
majority of employees do not wear any form of respiratory protection
due to very low airborne beryllium concentrations" (Thomas et al.,
2009, p. 122).
    To test the efficacy of the new measures in preventing
sensitization and CBD, in June 2000 the facility began an intensive
BeLPT screening program for all new workers. The company screened
workers at the time of hire; at intervals of 3, 6, 12, 24, and 48
months; and at 3-year intervals thereafter. Among 82 workers hired
after 1999, three cases of sensitization were found (3.7 percent). Two
(5.4 percent) of 37 workers hired prior to enclosure of the wire
annealing and pickling process were found to be sensitized within 3 and
6 months of beginning work at the plant. One (2.2 percent) of 45
workers hired after the enclosure was confirmed as sensitized. Among
these early results, it appears that the greatest reduction in
sensitization risk was achieved after median exposures in all areas of
the plant were reduced to below 0.1 [mu]g/m\3\ and PPE to prevent dermal
contact was instituted.
2. Tucson, AZ, Plant
    Kreiss et al. conducted a study of workers at a beryllia ceramics
plant, screening 136 workers with the BeLPT in 1992 (Kreiss et al.,
1996). Full-shift area samples collected between 1983 and 1992 showed
primarily low airborne beryllium levels at this facility. Of 774 area
samples, 76 percent were at or below 0.1 [mu]g/m\3\ and less than 1
percent exceeded 2 [mu]g/m\3\. A small set (75) of personal lapel
samples collected at the plant beginning in 1991 had a median of 0.2
[mu]g/m\3\ and ranged from 0.1 to 1.8 [mu]g/m\3\ (arithmetic and
geometric mean values not reported) (Kreiss et al., 1996, p. 19).
However, area samples and short-term breathing zone samples also showed
occasional instances of very high beryllium exposure levels, with
extreme values of several hundred [mu]g/m\3\ and 3.6 percent of short-
term breathing zone samples in excess of 5 [mu]g/m\3\.
    Kreiss et al. reported that eight (5.9 percent) of 136 workers
tested were sensitized, six (4.4 percent) of whom were diagnosed with
CBD. Seven of the eight sensitized employees had worked in machining,
where general area samples collected between October 1985 and March
1988 had a median of 0.3 [mu]g/m\3\, in contrast to a median value of
less than 0.1 [mu]g/m\3\ in other areas of the plant (Kreiss et al.,
1996, p. 20; mean values not reported). Short-term breathing zone
measurements associated with machining had a median of 0.6 [mu]g/m\3\,
double the median of 0.3 [mu]g/m\3\ for breathing zone measurements
associated with other processes (id., p. 20; mean values not reported).
One sensitized worker was one of 13 administrative workers screened,
and was among those diagnosed with CBD. Exposures of administrative
workers were not well-characterized, but were believed to be among the
lowest in the plant. Of three personal lapel samples reported for
administrative staff during the 1990s, all were below the then
detection limit of 0.2 [mu]g/m\3\ (Cummings et al., 2007, p.138).
    Following the 1992 screening, the facility reduced exposures in
machining areas by enclosing machines and installing HEPA filter
exhaust systems. Personal samples collected between 1994 and 1999 had a
median of 0.2 [mu]g/m\3\ in production jobs and 0.1 [mu]g/m\3\ in
production support (geometric means 0.21 [mu]g/m\3\ and 0.11 [mu]g/
m\3\, respectively; arithmetic means not reported. Cummings et al.,
2007, p. 138). In 1998, a second screening found that 9 percent of
tested workers hired after the 1992 screening were sensitized, of whom
one was diagnosed with CBD. All of the sensitized workers had been
employed at the plant for less than two years (Henneberger et al.,
2001).
    Following the 1998 screening, the company continued efforts to
reduce exposures and risk of sensitization and CBD by implementing
additional engineering and administrative controls and PPE. Respirator
use was required in production areas beginning in 1999, and latex
gloves were required beginning in 2000. The lapping area was enclosed
in 2000, and enclosures were installed for all mechanical presses in
2001. Between 2000 and 2003, water-resistant or water-proof garments,
shoe covers, and taped gloves were incorporated to keep beryllium-
containing fluids from wet machining processes off the skin. The new
engineering measures did not appear to substantially reduce airborne
beryllium levels in the plant. Personal lapel samples collected in
production processes between 2000 and 2003 had a median and geometric
mean of 0.18 [mu]g/m\3\, similar to the 1994-1999 samples (Cummings et
al., 2007, p. 138). However, respiratory protection requirements were
instituted in 2000 to control workers' airborne beryllium exposures.
    To test the efficacy of the new measures instituted after 1998, in
January 2000 the company began screening new workers for sensitization
at the time of hire and at 3, 6, 12, 24, and 48 months of employment
(Cummings et al., 2007). These more stringent measures appear to have
substantially reduced the risk of sensitization among new employees. Of
97 workers hired between 2000 and 2004, one case of sensitization was
identified (1 percent). This worker had experienced a rash after an
incident of dermal exposure to lapping fluid through a gap between the
glove and uniform sleeve, indicating that sensitization may have
occurred via skin exposure.
3. Elmore, OH, Plant
    Kreiss et al., Schuler et al., and Bailey et al. conducted studies
of workers at a beryllium metal, alloy, and oxide production plant.
Workers participated in BeLPT surveys in 1992 (Kreiss et al., 1997) and
in 1997 and 1999 (Schuler et al., 2012). Exposure levels at the plant
between 1984 and 1993 were characterized by a mixture of general area,
short-term breathing zone, and personal lapel samples. Kreiss et al.
reported that the median area samples for various work areas ranged
from 0.1 to 0.7 [mu]g/m\3\, with the highest values in the alloy arc
furnace and alloy melting-casting areas (other measures of central
tendency not reported). Personal lapel samples were available from
1990-1992, and showed high exposures overall (median value of 1.0
[mu]g/m\3\) with very high exposures for some processes. The authors
reported median sample values of 3.8 [mu]g/m\3\ for beryllium oxide
production, 1.75 [mu]g/m\3\ for alloy melting and casting, and 1.75
[mu]g/m\3\ for the arc furnace.
    Kreiss et al. reported that 43 (6.9 percent) of 627 workers tested
in 1992 were sensitized, six of whom were diagnosed with CBD (4.4
percent). Workers with less than one year tenure at the plant were not
tested in this survey (Bailey et al., 2010, p. 511). The work processes
that appeared to carry the highest risk for sensitization and CBD
(e.g., ceramics) were not those with the highest reported exposure
levels (e.g., arc furnace and melting-casting). The authors noted
several possible reasons for this, including factors such as
solubility, particle size/number, and particle surface area that could
not be accounted for in their analysis (Kreiss et al., 1997).
    In 1996-1999, the company took steps to reduce workers' beryllium
exposures: some high-exposure processes were enclosed, special
restricted-access zones were set up, HEPA filters were installed in air
handlers, and some ventilation systems were updated. In 1997 workers in
the pebble plant restricted access zone were required to wear half-face
air-purifying respirators, and beginning in 1999 all new employees were
required to wear loose-fitting powered air-purifying respirators (PAPR)
in manufacturing buildings (Bailey et al., 2010, p. 506). Skin
protection became part of the protection program for new employees in
2000, and glove use was required in production areas and for handling
work boots beginning in 2001. Also beginning in 2001, either half-mask
respirators or PAPRs were required in the production facility (type
determined by airborne beryllium levels), and respiratory protection
was required for roof work and during removal of work boots (Bailey et
al., 2010, p. 506). Respirator use was reported to be used on about
half or less of industrial hygiene sample records for most processes in
1990-1992 (Kreiss et al., 1996).
    Beginning in 2000, workers were offered periodic BeLPT testing to
evaluate the effectiveness of a new exposure control program
implemented by the company. Bailey et al. (2010) reported on the
results of this surveillance for 290 workers hired between February 21,
2000 and December 18, 2006. They compared the occurrence of beryllium
sensitization and disease among 258 employees who began work at the Elmore
plant between January 15, 1993 and August 9, 1999 (the 'pre-program group')
and among 290 employees who were hired between February 21, 2000 and
December 18, 2006 and were tested at least once after hire
(the 'program group'). They found that, as of 1999, 23 (8.9 percent) of the
pre-program group were sensitized to beryllium. Six (2.1 percent) of the
program group had confirmed abnormal results on their final round of BeLPTs,
which occurred in different years for different employees. In addition,
another five employees had confirmed abnormal BeLPT results at some point
during the testing period, followed by at least one instance of a normal test
result. One of these employees had a confirmed abnormal baseline BeLPT
at hire, and had two subsequent normal BeLPT results at 6 and 12 months
after hire. Four others had confirmed abnormal BeLPT results at 3 or 6
months after hire, later followed by a normal test. Including these
four in the count of sensitized workers, there were a total of ten (3.5
percent) workers sensitized after hire in the program group. It is not
clear whether the occurrence of a normal result following an abnormal
result reflects an error in one of the test results, a change in the
presence or level of memory T-cells circulating in the worker's blood,
or other possibilities. Because most of the workers in the study had
been employed at the facility for less than two years, Bailey et al.
did not report the incidence of CBD among the sensitized workers
(Bailey et al., 2010, p. 511).
    In addition, Bailey et al. divided the program group into the
'partial program subgroup' (206 employees hired between February 21,
2000 and December 31, 2003) and the `full program subgroup' (84
employees hired between January 1, 2004 and December 18, 2006) to
account for the greater effectiveness of the exposure control program
after the first three years of implementation (Bailey et al., pp 506-
507). Four (1.9 percent) of the partial program group were found to be
sensitized on their final BeLPT (excluding one with a confirmed
abnormal BeLPT from their baseline test at hire). Two (2.4 percent) of
the full program group were found to be sensitized on their final BeLPT
(Bailey et al., 2010, p. 509). An additional three employees in the
partial program group and one in the full program group were confirmed
sensitized at 3 or 6 months after hire, then later had a single normal
BeLPT (Bailey et al., 2010, p. 509).
    Schuler et al. (2012) published a study examining beryllium
sensitization and CBD among short-term workers at the Elmore, OH plant,
using exposure estimates created by Virji et al. (2012). The study
population included 264 workers employed in 1999 with up to six years
tenure at the plant (91 percent of the 291 eligible workers). By
including only short-term workers, Virji et al. were able to construct
participants' exposures with more precision than was possible in
studies involving workers exposed for longer durations and in time
periods with less exposure sampling. Each participant completed a work
history questionnaire and was tested for beryllium sensitization. The
overall prevalence of sensitization was 9.8 percent (26/264).
Sensitized workers were offered further evaluation for CBD. Twenty-two
sensitized workers consented to clinical testing for CBD via
transbronchial biopsy. Six of those sensitized were diagnosed with CBD
(2.3 percent, 6/264).
    Exposure estimates were constructed using two exposure surveys
conducted in 1999: a survey of total mass exposures (4022 full-shift
personal samples) and a survey of size-separated impactor samples (198
samples). The 1999 exposure surveys and work histories were used to
estimate long-term lifetime weighted (LTW) average, cumulative, and
highest-job-worked exposure for total, respirable, and submicron
beryllium mass concentrations. Schuler et al. (2012) found no cases of
sensitization among workers with total mass LTW average exposures below
0.09 [mu]g/m\3\, among workers with total mass cumulative exposures
below 0.08 [mu]g/m\3\-yr, or among workers with total mass highest job
worked exposures below 0.12 [mu]g/m\3\. Twenty-four percent, 16
percent, and 25 percent of the study population were exposed below
those levels, respectively. Both total and respirable beryllium mass
concentration estimates were positively associated with sensitization
(average and highest job), and CBD (cumulative) in logistic regression
models.
4. Cullman, AL, Plant
    Newman et al. conducted a series of BeLPT screenings of workers at
a precision machining facility between 1995 and 1999 (Newman et al.,
2001). A small set of personal lapel samples collected in the early
1980s and in 1995 suggests that exposures in the plant varied widely
during this time period. In some processes, such as engineering,
lapping, and electrical discharge machining (EDM), exposures were
apparently low (<= 0.1 [mu]g/m\3\). Madl et al. reported that personal
lapel samples from all machining processes combined had a median of
0.33 [mu]g/m\3\, with a much higher arithmetic mean of 1.63 [mu]g/m\3\
(Madl et al., 2007, Table IV, p. 457). The majority of these samples
were collected in the high-exposure processes of grinding (median of
1.05 [mu]g/m\3\, mean of 8.48 [mu]g/m\3\), milling (median of 0.3
[mu]g/m\3\, mean of 0.82 [mu]g/m\3\), and lathing (median of 0.35
[mu]g/m\3\, mean of 0.88 [mu]g/m\3\) (Madl et al., 2007, Table IV, p.
457). As discussed in greater detail in the background document,\7\ the
data set of machining exposure measurements included a few extremely
high values (41-73 [mu]g/m\3\) that a NIOSH researcher identified as
probable errors, and that appear to be included in Madl et al.'s
arithmetic mean calculations. Because high single-data point exposure
errors influence the arithmetic mean far more than the median value of
a data range, OSHA believes the median values reported by Madl et al.
are more reliable than the arithmetic means they reported.
---------------------------------------------------------------------------

    \7\ When used throughout this section, "background document"
refers to a more comprehensive, companion risk-assessment document
that can be found at www.regulations.gov in OSHA Docket No. ___.
---------------------------------------------------------------------------

    After a sentinel case of CBD was diagnosed at the plant in 1995,
the company began BeLPT screenings to identify workers at increased
risk of CBD and implemented engineering and administrative controls and
PPE designed to reduce workers' beryllium exposures in machining
operations. Newman et al. reported 22 (9.4 percent) sensitized workers
among 235 tested, 13 of whom were diagnosed with CBD within the study
period. Between 1995 and 1997, the company built enclosures and
installed or updated local exhaust ventilation (LEV) for several
machining departments, removed pressurized air hoses, and required the
use of company uniforms. Madl et al. reported that historically,
engineering and work process controls, rather than personal protective
equipment, were used to limit workers' exposure to beryllium;
respirators were used only in cases of high exposure, such as during
sandblasting (Madl et al., 2007, p. 450). In contrast to the Reading
and Tucson plants, gloves were not required at this plant.
    Personal lapel samples collected extensively between 1996 and 1999
in machining jobs have an overall median of 0.16 [mu]g/m\3\, showing
that the new controls achieved a marked reduction in machinists'
exposures during this period. Nearly half of the samples were collected in
milling (median = 0.18 [mu]g/m\3\). Exposures in other machining processes
were also reduced, including grinding (median of 0.18 [mu]g/m\3\) and lathing
(median of 0.13 [mu]g/m\3\). However, cases of sensitization and CBD
continued to occur.
    At the time that Newman et al. reviewed the results of BeLPT
screenings conducted in 1995-1999, a subset of 60 workers had been
employed at the plant for less than a year. Four (6.7 percent) of these
workers were found to be sensitized, of whom two were diagnosed with
CBD and one with probable CBD (Newman et al., 2001). All four had been
hired in 1996. Two (one CBD case, one sensitized only) had worked only
in milling, and had worked for approximately 3-4 months (0.3-0.4 yrs)
at the time of diagnosis. One of those diagnosed with CBD worked only
in EDM, where lapel samples collected between 1996 and 1999 had a
median of 0.03 [mu]g/m\3\. This worker was diagnosed with CBD in the
same year that he began work at the plant. The last CBD case worked as
a shipper, where exposures in 1996-1999 were similarly low, with a
median of 0.09 [mu]g/m\3\.
    Beginning in 2000, exposures in all jobs at the machining facility
were reduced to extremely low levels. Personal lapel samples collected
in machining processes between 2000 and 2005 had a median of 0.09
[mu]g/m\3\, where more than a third of samples came from the milling
process (n = 765, median of 0.09 [mu]g/m\3\). A later publication on
this plant by Madl et al. reported that only one worker hired after
1999 became sensitized. This worker had been employed for 2.7 years in
chemical finishing, where exposures were roughly similar to other
machining processes (n = 153, median of 0.12 [mu]g/m\3\). Madl et al.
did not report whether this worker was evaluated for CBD.
5. Aluminum Smelting Plants
    Taiwo et al. (2008) studied a population of 734 employees at four
aluminum smelters located in Canada (2), Italy (1), and the United
States (1). In 2000, a beryllium exposure limit of 0.2 [mu]g/m\3\ 8-
hour TWA (action level 0.1 [mu]g/m\3\) and a short-term exposure limit
(STEL) of 1.0 [mu]g/m\3\ (15-minute sample) were instituted at these
plants. Sampling to determine compliance with the exposure limit began
at all smelters in 2000. Table VI-1 below, adapted from Taiwo et al.
(2008), shows summary information on samples collected from the start
of sampling through 2005.

                             Table VI-1--Exposure Sampling Data by Plant--2000-2005
----------------------------------------------------------------------------------------------------------------
                                                                                    Arithmetic
                     Smelter                         Number of    Median  ([mu]g/  mean  ([mu]g/  Geometric mean
                                                      samples          m\3\)           m\3\)        ([mu]g/m\3\)
----------------------------------------------------------------------------------------------------------------
Canadian smelter 1..............................             246            0.03            0.09            0.03
Canadian smelter 2..............................             329            0.11            0.29            0.08
Italian smelter.................................              44            0.12            0.14            0.10
U.S. smelter....................................             346            0.03            0.26            0.04
----------------------------------------------------------------------------------------------------------------
Adapted from Taiwo et al., 2008, Table 1.

    All employees potentially exposed to beryllium levels at or above
the action level for at least 12 days per year, or exposed at or above
the STEL 12 or more times per year, were offered medical surveillance
including the BeLPT (Taiwo et al., 2008, p. 158). Table VI-2 below,
adapted from Taiwo et al. (2008), shows test results for each facility
between 2001 and 2005.

                                  Table VI-2--BeLPT Results by Plant--2001-2005
----------------------------------------------------------------------------------------------------------------
                                                     Employees                    Abnormal BeLPT     Confirmed
                     Smelter                          tested          Normal       (unconfirmed)    Sensitized
----------------------------------------------------------------------------------------------------------------
Canadian smelter 1..............................             109             107               1               1
Canadian smelter 2..............................             291             290               1               0
Italian smelter.................................              64              63               0               1
U.S. smelter....................................             270             268               2               0
----------------------------------------------------------------------------------------------------------------
Adapted from Taiwo et al., 2008, Table 2.

    The two workers with confirmed beryllium sensitization were offered
further evaluation for CBD. Both were diagnosed with CBD, based on
broncho-alveolar lavage (BAL) results in one case and pulmony function
tests, respiratory symptoms, and radiographic evidence in the other.
    In 2010, Taiwo et al. published a study of beryllium-exposed
workers from smelters at four companies, including some of the workers
from the 2008 publication. 3,185 workers were determined to be
"significantly exposed" to beryllium and invited to participate in
BeLPT screening. Each company used different criteria to determine
"significant" exposure, which appeared to vary considerably (p. 570).
About 60 percent of invited workers participated in the program between
2000 and 2006, of whom nine were determined to be sensitized (see Table
VI-3 below). The authors state that all nine workers were referred to a
respiratory physician for further evaluation for CBD. Two were
diagnosed with CBD, as described above (Taiwo et al., 2008). The
authors do not report the details of other sensitized workers'
evaluation for CBD.


                          Table VI-3--Medical Surveillance for BeS in ALUMINUM Smelters
----------------------------------------------------------------------------------------------------------------
                                                     Number of        At-risk        Employees
                     Company                         smelters        employees        tested            BeS
----------------------------------------------------------------------------------------------------------------
A...............................................               4            1278             734               4
B...............................................               3             423             328               0
C...............................................               1            1100             508               4
D...............................................               1             384             362               1
                                                 ---------------------------------------------------------------
    Total.......................................               9            3185            1932               9
----------------------------------------------------------------------------------------------------------------
Adapted from Taiwo et al., 2011, Table 1.

    In general, there appeared to be a low level of sensitization and
CBD among employees at the aluminum smelters studied by Taiwo et al.
This is striking in light of the fact that many of the employees tested
had worked at the smelters long before the institution of exposure
limits for beryllium at some smelters in 2000. However, the authors
note that respiratory protection had long been used at these plants to
protect workers from other hazards. The results are roughly consistent
with the observed prevalence of sensitization following the institution
of respiratory protection at the Tucson beryllium ceramics plant
discussed previously. A study by Nilsen et al. (2010) also found a low
rate of sensitization among aluminum workers in Norway. Three-hundred
sixty-two workers and thirty-one control individuals received BeLPT
testing for beryllium sensitization. The authors found one sensitized
worker (0.28 percent). No borderline results were reported. The authors
reported that current exposures in this plant ranged from 0.1 [micro]g/
m\3\ to 0.31 [micro]g/m\3\ (Nilsen et al., 2010) and that respiratory
protection was in use, as is the case in the smelters studied by Taiwo
et al. (2008, 2010).

B. Preliminary Conclusions

    The published literature on beryllium sensitization and CBD shows
that risk of both can be substantial in workplaces in compliance with
OSHA's current PEL (Kreiss et al., 1993; Schuler et al., 2005). The
experiences of several facilities in developing effective industrial
hygiene programs have shown that minimizing both airborne and dermal
exposure, using a combination of engineering and administrative
controls, respiratory protection, and dermal PPE, has substantially
lowered workers' risk of beryllium sensitization. In contrast, risk-
reduction programs that relied primarily on engineering controls to
reduce workers' exposures to median levels in the range of 0.1-0.2
[micro]g/m\3\, such as those implemented in Tucson following the 1992
survey and in Cullman during 1996-1999, had only limited impact on
reducing workers' risk of sensitization. The prevalence of
sensitization among workers hired after such controls were installed at
the Cullman plant remained high (Newman et al. (6.7 percent) and
Henneberger et al. (9 percent)). A similar prevalence of sensitization
was found in the screening conducted in 2000 at the Reading plant,
where the available sampling data show median exposure levels of less
than 0.2 [micro]g/m\3\ (6.5 percent). The risk of sensitization was
found to be particularly high among newly-hired workers (<=1 year of
beryllium exposure) in the Reading 2000 screening (13 percent) and the
Tucson 1998 screening (16 percent).
    Cases of CBD have also continued to develop among workers in
facilities and jobs where exposures were below 0.2 [micro]g/m\3\. One
case of CBD was found in the Tucson 1998 screening among nine
sensitized workers hired less than two years previously (Henneberger et
al., 2001). At the Cullman plant, at least two cases of CBD were found
among four sensitized workers screened in 1995-1999 and hired less than
a year previously (Newman et al., 2001). These results suggest a
substantial risk of progression from sensitization to CBD among workers
exposed at levels well below the current PEL, especially considering
the extremely short time of exposure and follow-up for these workers.
Six of 10 sensitized workers identified at Reading in the 2000
screening were diagnosed with CBD. The four sensitized workers who did
not have CBD at their last clinical evaluation had been hired between
one and five years previously; therefore, the time may have been too
short for CBD to develop.
    In contrast, more recent exposure control programs that have used a
combination of engineering controls, PPE, and stringent housekeeping
measures to reduce workers' airborne and dermal exposures have
substantially lowered risk of sensitization among newly-hired workers.
Of 97 workers hired between 2000 and 2004 in Tucson, where respiratory
and skin protection was instituted for all workers in production areas,
only one (1 percent) worker became sensitized, and in that case the
worker's dermal protection had failed during wet-machining work (Thomas
et al., 2009). In the aluminum smelters discussed by Taiwo et al.,
where available exposure samples indicated median beryllium levels of
about 0.1 [mu]g/m\3\ or below (measured as an 8-hour TWA) and workers
used respiratory and dermal protection, confirmed cases of
sensitization were rare (zero or one case per location). Sensitization
was also rare among workers at a Norwegian aluminum smelter (Nilsen et
al., 2010), where estimated exposures in the plant ranged from 0.1
[mu]g/m\3\ to 0.3 [mu]g/m\3\ and respiratory protection was regularly
used. In Reading, where in 2000-2001 airborne exposures in all jobs
were reduced to a median of 0.1 [mu]g/m\3\ or below (measured as an 8-
hour TWA) and dermal protection was required for production-area
workers, two (5.4 percent) of 37 newly hired workers became sensitized
(Thomas et al., 2009). After the process with the highest exposures
(median of 0.1 [mu]g/m\3\) was enclosed in 2002 and workers in that
process were required to use respiratory protection, the remaining jobs
had very low exposures (medians ~ 0.03 [mu]g/m\3\). Among 45 workers
hired after the enclosure, one was found to be sensitized (2.2
percent). In Elmore, where all workers were required to wear
respirators and skin PPE in production areas beginning in 2000-2001,
the estimated prevalence of sensitization among workers hired after
these measures were put in place was around 2-3 percent (Bailey et al.,
2010). In addition, Schuler et al. (2012) found no cases of
sensitization among short-term Elmore workers employed in 1999 who had
total mass LTW average exposures below 0.09 [mu]g/m\3\, among workers
with total mass cumulative exposures below 0.08 [mu]g/m\3\-yr, or among
workers with total mass highest job worked exposures below 0.12 [mu]g/
m\3\.
    Madl et al. reported one case of sensitization among workers at the
Cullman plant hired after 2000. The median personal exposures were
about 0.1 [mu]g/m\3\ or below for all jobs during this period. Several
changes in the facility's exposure control methods were instituted in
the late 1990s that were likely to have reduced dermal as well as
respiratory exposure to beryllium. For example, the plant installed
change/locker rooms for workers entering the production facility,
instituted requirements for work uniforms and dedicated work shoes for
production workers, implemented annual beryllium hazard awareness
training that encouraged glove use, and purchased high efficiency
particulate air (HEPA) filter vacuum cleaners for workplace cleanup and
decontamination.
    The results of the Reading, Tucson, and Elmore studies show that
reducing airborne exposures to below 0.1 [mu]g/m\3\ and protecting
workers from dermal exposure, in combination, have achieved a
substantial reduction in sensitization risk among newly-hired workers.
Because respirator use, dermal protection, and engineering changes were
often implemented concurrently at these plants, it is difficult to
attribute the reduced risk to any single control measure. The reduction
is particularly evident when comparing newly-hired workers in the most
recent Reading screenings (2.2-5.4 percent), and the rate of
sensitization found among workers hired within the year before the 2000
screening (13 percent). There is a similarly striking difference
between the rate of prevalence found among newly-hired workers in the
most recent Tucson study (1 percent) and the rate found among workers
hired within the year before the 1998 screening at that plant (16
percent). These results are echoed in the Cullman facility, which
combined engineering controls to reduce airborne exposures to below 0.1
[mu]g/m\3\ with measures such as housekeeping improvements and worker
training to reduce dermal exposure.
    The studies on recent programs to reduce workers' risk of
sensitization and CBD were conducted on populations with very short
exposure and follow-up time. Therefore, they could not address the
question of how frequently workers who become sensitized in
environments with extremely low airborne exposures (median < 0.1 [mu]g/
m\3\) develop CBD. Clinical evaluation for CBD was not reported for
sensitized workers identified in the most recent Tucson, Reading, and
Elmore studies. In Cullman, however, two of the workers with CBD had
been employed for less than a year and worked in jobs with very low
exposures (median 8-hour personal sample values of 0.03-0.09 [mu]g/
m\3\). The body of scientific literature on occupational beryllium
disease also includes case reports of workers with CBD who are known or
believed to have experienced minimal beryllium exposure, such as a
worker employed only in shipping at a copper-beryllium distribution
center (Stanton et al., 2006), and workers employed only in
administration at a beryllium ceramics facility (Kreiss et al., 1996).
    Arjomandi et al. published a study of 50 sensitized workers from a
nuclear weapons research and development facility (Arjomandi et al.,
2010). Occupational and medical histories including physical
examination and chest imaging were available for the great majority
(49) of these individuals. Forty underwent testing for CBD via
bronchoscopy and transbronchial biopsies. In contrast to the studies of
low-exposure populations discussed previously, this group had much
longer follow-up time (mean time since first exposure = 32 years) and
length of employment at the facility (mean of 18 years). Quantitative
exposure estimates for the workers were not presented; however, the
authors characterized their probable exposures as "low" (13 workers),
"moderate" (28 workers), or "high" (nine workers) based on the jobs
they performed at the facility.
    Five of the 50 sensitized workers (10 percent) were diagnosed with
CBD based on histology or high-resolution computed tomography. An
additional three (who had not undergone full clinical evaluation for
CBD) were identified as probable CBD cases, bringing the total
prevalence of CBD and probable CBD in this group to 16 percent. As
discussed in the epidemiology section of the Health Effects chapter,
the prevalence of CBD among worker populations regularly exposed at
higher levels (e.g., median > 0.1 [mu]g/m\3\) is typically much
greater, approaching 80-100% in several studies. The lower prevalence
of CBD in this group of sensitized workers, who were believed to have
primarily low exposure levels, suggests that controlling respiratory
exposure to beryllium may reduce risk of CBD among sensitized workers
as well as reducing risk of CBD via prevention of sensitization.
However, it also demonstrates that some workers in low-exposure
environments can become sensitized and go on to develop CBD. The next
section discusses an additional source of information on low-level
beryllium exposure and CBD: studies of community-acquired CBD in
residential areas surrounding beryllium production facilities.

C. Review of Community-Acquired CBD Literature

    The literature on community-acquired chronic beryllium disease (CA-
CBD) documents cases of CBD among individuals exposed to airborne
beryllium at concentrations below the proposed PEL. OSHA notes that
these case studies do not provide information on how frequently
individuals exposed to very low airborne levels develop CBD and that
reconstructed exposure estimates for CA-CBD cases are less reliable
than exposure estimates for working populations reviewed in the
previous sections. In addition, the cumulative exposure that an
occupationally exposed person would accrue at any given exposure
concentration is far less than would typically accrue from long-term
environmental exposure. The literature on CA-CBD thus has important
limitations and is not used as a basis for quantitative risk assessment
for CBD from low-level beryllium exposure. Nevertheless, these case
reports and the broader CA-CBD literature indicate that individuals
exposed to airborne beryllium below the proposed PEL can develop CBD.
    Cases of CA-CBD were first reported among residents of Lorain, OH,
and Reading, PA, who lived in the vicinity of beryllium plants. More
recently, BeLPT screening has been used to identify additional cases of
CA-CBD in Reading.
1. Lorain, OH
    In 1948, the State of Ohio Department of Public Health conducted an
X-ray program surveying more than 6,000 people who lived within 1.5
miles of a Lorain beryllium plant (Eisenbud, 1949; Eisenbud, 1982;
Eisenbud, 1998). This survey, together with a later review of all
reported cases of CBD in the area, found 13 cases of CBD. All of the
residents who developed CBD lived within 0.75 miles of the plant, and
none had occupational exposure or lived with beryllium-exposed workers.
Among the population of 500 people living within 0.25 miles of the
plant, seven residents (1.4 percent) were diagnosed with CBD. Five
cases were diagnosed among residents living between 0.25 and 0.5 miles
from the plant, one case was diagnosed among residents living between
0.5 and 0.75 miles from the plant, and no cases were found among those
living farther than 0.75 miles from the plant (total populations not
reported) (Eisenbud, 1998).
    Beginning in January 1948, air sampling was conducted using a
mobile sampling station to measure atmospheric beryllium downwind from the
plant. An approximate concentration of 0.2 [mu]g/m\3\ was measured at
0.25 miles from the plant's exhaust stack, and concentrations decreased
with greater distance from the plant, to 0.003 [mu]g/m\3\ at a distance of
5 miles (Eisenbud, 1982). A 10-week sampling program was conducted using
three fixed monitoring stations within 700 feet of the plant and one station
7,000 feet from the plant. Interpolating the measurements collected at
these locations, Eisenbud and colleagues estimated an average airborne
beryllium concentration of between 0.004 and 0.02 [mu]g/m\3\ at a
distance of 0.75 miles from the plant. Accounting for the possibility
that previous exposures may have been higher due to production level
fluctuations and greater use of rooftop emissions, they concluded that
the lowest airborne beryllium level associated with CA-CBD in this
community was somewhere between 0.01 [mu]g/m\3\ and 0.1 [mu]g/m\3\
(Eisenbud, 1982).
2. Reading, PA
    Thirty-two cases of CA-CBD were reported in a series of papers
published in 1959-1969 concerning a beryllium refinery in Reading
(Lieben and Metzner, 1959; Metzner and Lieben, 1961; Dattoli et al.,
1964; Lieben and Williams, 1969). The plant, which opened in 1935,
manufactured beryllium oxide, alloys and metal, and beryllium tools and
metal products (Maier et al., 2008; Sanderson et al., 2001b). In a
follow-up study, Maier et al. presented eight additional cases of CA-
CBD who had lived within 1.5 miles of the plant (Maier et al., 2008).
Individuals with a history of occupational beryllium exposure and those
who had resided with occupationally exposed workers were not classified
as having CA-CBD.
    The Pennsylvania Department of Health conducted extensive
environmental sampling in the area of the plant beginning in 1958.
Based on samples collected in 1958, Maier et al. stated that most cases
identified in their study would typically have been exposed to airborne
beryllium at levels between 0.0155 and 0.028 [mu]g/m\3\ on average,
with the potential for some excursions over 0.35 [mu]g/m\3\ (Maier et
al 2008, p. 1015). To characterize exposures to cases identified in the
earlier publications, Lieben and Williams cited a sampling program
conducted by the Department of Health between January and July 1962,
using nine sampling stations located between 0.2 and 4.8 miles from the
plant. They reported that 72 percent of 24-hour samples collected were
below 0.01 [mu]g/m\3\. Of samples that exceeded 0.01 [mu]g/m\3\, most
were collected at close proximity to the plant (e.g., 0.2 miles from
the plant).
    In the early series of publications, cases of CA-CBD were reported
among people living both close to the plant (Maier et al., 2008; Dutra,
1948) and up to several miles away. Of new cases identified in the 1968
update, all lived between 3 and 7.5 miles from the plant. Lieben and
Williams suggested that some cases of CA-CBD found among more distant
residents might have resulted from working or visiting a graveyard
closer to the plant (Lieben and Williams, 1969). For example, a milkman
who developed CA-CBD had a route in the neighborhood of the plant.
Another resident with CA-CBD had worked as a cleaning woman in the area
of the plant, and a third worked within a half-mile of the plant.
    At the time of the final follow-up study (1968), 11 residents
diagnosed with CA-CBD were alive and 21 were deceased. Among those who
had died, berylliosis was listed as the cause of death for three,
including a 10-year-old girl and two women in their sixties. Fibrosis,
granuloma or granulomatosis, and chronic or fibrous pneumonitis were
listed as the cause of death for eight more of those deceased.
Histologic evidence of CBD was reported for nine of 12 deceased
individuals who had been evaluated for it. In addition to showing
radiologic abnormalities associated with CBD, all living cases were
dyspneic.
    Following the 1969 publication by Liebman and Williams, no
additional CA-CBD cases were reported in the Reading area until 1999,
when a new case was diagnosed. The individual was a 72-year-old woman
who had had abnormal chest x-rays for the previous six years (Maier et
al., 2008). After the diagnosis of this case, Maier et al. reviewed
medical records and/or performed medical evaluations, including BeLPT
results for 16 community residents who were referred by family members
or an attorney.
    Among those referred, eight cases of definite or probable CBD were
identified between 1999 and 2002. All eight were women who lived
between 0.1 and 1.05 miles from the plant, beginning between 1943-1953
and ending between 1956-2001. Five of the women were considered
definite cases of CA-CBD, based on an abnormal blood or lavage cell
BeLPT and granulomatous inflammation on lung biopsy. Three probable
cases of CA-CBD were identified. One had an abnormal BeLPT and
radiography consistent with CBD, but granulomatous disease was not
pathologically proven. Two met Beryllium Case Registry epidemiologic
criteria for CBD based on radiography, pathology and a clinical course
consistent with CBD, but both died before they could be tested for
beryllium sensitization. One of the probable cases, who could not be
definitively diagnosed with CBD because she died before she could be
tested, was the mother of both a definite case and the probable case
who had an abnormal BeLPT but did not show granulomatous disease.
    The individuals with CA-CBD identified in this study suffered
significant health impacts from the disease, including obstructive,
restrictive, and gas exchange pulmonary defects in the majority of
cases. All but two had abnormal pulmonary physiology. Those two were
evaluated at early stages of disease following their mother's
diagnosis. Six of the eight women required treatment with prednisone, a
step typically reserved for severe cases due to the adverse side
effects of steroid treatment. Despite treatment, three had died of
respiratory impairment from CBD as of 2002 (Maier et al., 2008). The
authors concluded that "low levels of exposures with significant
disease latency can result in significant morbidity and mortality"
(id., p. 1017).
    OSHA notes that compared with the occupational studies discussed in
the previous section, there is comparatively sparse information on
exposure levels of Lorain and Reading residents. There remains the
possibility that some individuals with CA-CBD may have had higher
exposures than were known and reported in these studies, or have had
unreported exposure to beryllium dust via contact with beryllium-
exposed workers. Nevertheless, the studies conducted in Lorain and
Reading demonstrate that long-term exposure to the apparent low levels
of airborne beryllium, with sufficient disease latency, can lead to
serious or fatal CBD. Genetic susceptibility may play a role in cases
of CBD among individuals with very low or infrequent exposures to
beryllium. The role of genetic susceptibility in the CBD disease
process is discussed in detail in section V.D.3.

D. Exposure-Response Literature on Beryllium Sensitization and CBD

    To further examine the relationship between exposure level and risk
of both sensitization and disease, we next review exposure-response
studies in the CBD literature. Many publications have reported that
exposure levels correlate with risk, including a small number of
exposure-response analyses. Most of these studies examined the
association between job-specific beryllium air measurements and
prevalence of sensitization and CBD. This section focuses on studies at
three facilities that included a more rigorous historical
reconstruction of individual worker exposures in their exposure-
response analyses.
1. Rocky Flats, CO, Facility
    In 2000, Viet et al. published a case-control study of participants
in the Rocky Flats Beryllium Health Surveillance Program (BHSP), which
was established in 1991 to screen workers at the Department of Energy's
Rocky Flats, CO, nuclear weapons facility for beryllium sensitization
and evaluate sensitized workers for CBD (Viet et al., 2000). The
program, which at the time of publication had tested over 5,000 current
and former Rocky Flats employees, had identified a total of 127
sensitized individuals as of 1994 when Viet et al. initiated their
study.
    Workers were considered sensitized if two BeLPT results were
positive, either from two blood draws or from a single blood draw
analyzed by two different laboratories. All sensitized individuals were
offered clinical evaluation, and 51 were diagnosed with CBD based on
positive lung LPT and evidence of noncaseating granulomas upon lung
biopsy. The number of sensitized individuals who declined clinical
evaluation was not reported. Two cases, one with CBD and one who was
sensitized but not diagnosed with CBD, were excluded from the case-
control analysis due to reported or potential prior beryllium exposure
at a ceramics plant. Another sensitized individual who had not been
diagnosed with CBD was excluded because she could not be matched by the
study's criteria to a non-sensitized control within the BHSP database.
Viet et al. matched a total of 50 CBD cases to 50 controls who were
negative on the BeLPT and had the same age ( 3 years),
gender, race and smoking status, and were otherwise randomly selected
from the database. Using the same matching criteria, 74 sensitized
workers who were not diagnosed with CBD were age-, gender-, race-, and
smoking status-matched to 74 control individuals who tested negative by
the BeLPT from the BHSP database.
    Viet et al. developed exposure estimates for the cases and controls
based on daily beryllium air samples collected in one of 36 buildings
where beryllium was used at Rocky Flats, the Building 444 Beryllium
Machine Shop. Over half of the approximately 500,000 industrial hygiene
samples collected at Rocky Flats were taken from this building. Air
monitoring in other buildings was reported to be limited and
inconsistent and, thus, not utilized in the exposure assessment. The
sampling data used to develop worker exposure estimates were
exclusively Building 444 fixed airhead (FAH) area samples collected at
permanent fixtures placed around beryllium work areas and machinery.
    Exposure estimates for jobs in Building 444 were constructed for
the years 1960-1988 from this database. Viet et al. worked with Rocky
Flats industrial hygienists and staff to assign a "building area
factor" (BAF) to each of the other buildings, indicating the likely
level of exposure in a building relative to exposures in Building 444.
Industrial hygienists and staff similarly assigned a job factor (JF) to
all jobs, representing the likely level of beryllium exposure relative
to the levels experienced by beryllium machinists. A JF of 1 indicated
the lowest exposures, and a JF of 10 indicated the highest exposures.
For example, administrative work and vehicle operation were assigned a
JF of 1, while machining, mill operation, and metallurgical operation
were each assigned a JF of 10. Estimated FAH values for each
combination of job, building and year in the study subjects' work
histories were generated by multiplying together the job and building
factors and the mean annual FAH exposure level. Using data collected by
questionnaire from each BHSP participant, Viet et al. reconstructed
work histories for each case and control, including job title and
building location in each year of their employment at Rocky Flats.
These work histories and the estimated FAH values were used to generate
a cumulative exposure estimate (CEE) for each case and control in the
study. A long-term mean exposure estimate (MEE) was generated by
dividing each CEE by the individual's number of years employed at Rocky
Flats.
    Viet et al.'s statistical analysis of the resulting data set
included conditional logistic regression analysis, modeling the
relationship between risk of each health outcome and log-transformed
CEE and MEE. They found highly statistically significant relationships
between log-CEE and risk of CBD (coef = 0.837, p = 0.0006) and between
log-MEE (coef = 0.855, p = 0.0012) and risk of CBD, indicating that
risk of CBD increases with exposure level. These coefficients
correspond to odds ratios of 6.9 and 7.2 per 10-fold increase in
exposure, respectively. Risk of sensitization without CBD did not show
a statistically significant relationship with log-CEE (coef = 0.111, p
= 0.32), but showed a nearly-significant relationship with log-MEE
(coef = 0.230, p = 0.097).
2. Cullman, AL, Facility
    The Cullman, AL, precision machining facility discussed previously
was the subject of a case-control study published by Kelleher et al. in
2001. After the diagnosis of an index case of CBD at the plant in 1995,
NJMRC researchers worked with the plant to conduct a medical
surveillance program using the BeLPT to screen workers biennially for
beryllium sensitization and CBD. Of 235 employees screened between 1995
and 1999, 22 (9.4 percent) were found to be sensitized, including 13
diagnosed with CBD (Newman et al., 2001). Concurrently, research was
underway by Martyny et al. to characterize the particle size
distribution of beryllium exposures generated by processes at this
plant (Martyny et al., 2000). The exposure research showed that the
machining operations during this time period generated respirable
particles (10 [mu]m or less) at the worker breathing zone that made up
greater than 50 percent of the beryllium mass. Kelleher et al. used the
dataset of 100 personal lapel samples collected by Martyny et al. and
other NJMRC researchers in 1996, 1997, and 1999 to characterize
exposures for each job in the plant. Following a statistical analysis
comparing the samples collected by NJMRC with earlier samples collected
at the plant, Kelleher et al. concluded that the 1996-1999 data could
be used to represent job-specific exposures from earlier periods.
    Detailed work history information gathered from plant data and
worker interviews was used in combination with job exposure estimates
to characterize cumulative and LTW average beryllium exposures for
workers in the surveillance program. In addition to cumulative and LTW
exposure estimates based the total mass of beryllium reported in their
exposure samples, Kelleher et al. calculated cumulative and LTW
estimates based specifically on exposure to particles < 6 [mu]m and
particles < 1 [mu]m in diameter.
    To analyze the relationship between exposure level and risk of
sensitization and CBD, Kelleher et al. performed a case-control
analysis using measures of both total beryllium exposure and particle
size-fractionated exposure. The analysis included sensitization cases
identified in the 1995-1999 surveillance and 206 controls from the
group of 215 non-sensitized workers. For nine workers, the researchers
could not reconstruct complete job histories. Logistic regression models
using categorical exposure variables showed positive associations between
risk of sensitization and the six exposure measures tested: Total CEE,
total MEE, and variations of CEE and MEE constructed based on particles
< 6 [mu]m and < 1 [mu]m in diameter. None of the associations were
statistically significant (p < 0.05); however, the authors noted that
the dataset was relatively small, with limited power to detect a
statistically significant exposure-response relationship.
    Although the Viet et al. and Kelleher et al. exposure-response
analyses provide valuable insight into exposure-response for beryllium
sensitization and CBD, both studies have limitations that affect their
suitability as a basis for quantitative risk assessment. Their
limitations primarily involve the exposure data used to estimate
workers' exposures. Viet et al.'s exposure reconstruction was based on
area samples from a single building within a large, multi-building
facility. Where possible, OSHA prefers to base risk estimates on
exposure data collected in the breathing zone of workers rather than
area samples, because data collected in the breathing zone more
accurately represent workers' exposures. Kelleher's analysis, on the
other hand, was based on personal lapel samples. However, the samples
Kelleher et al. used were collected between 1996 and 1999, after the
facility had initiated new exposure control measures in response to the
diagnosis of a case of CBD in 1995. OSHA believes that industrial
hygiene samples collected at the Cullman plant prior to 1996 better
characterize exposures prior to the new exposure controls. In addition,
since the publication of the Kelleher study, the population has
continued to be screened for sensitization and CBD. Data collected on
workers hired in 2000 and later, after most exposure controls had been
completed, can be used to characterize risk at lower levels of exposure
than have been examined in many previous studies.
    To better characterize the relationship between exposure level and
risk of sensitization and CBD, OSHA developed an independent exposure-
response analysis based on a dataset maintained by NJMRC on workers at
the Cullman, AL, machining plant. The dataset includes exposure samples
collected between 1980 and 2005, and has updated work history and
screening information for several hundred workers through 2003. OSHA's
analysis of the NJMRC data set is presented in the next section, E.
OSHA's Exposure-Response Analysis.
3. Elmore, OH, Facility
    After OSHA completed its analysis of the NJMRC data set, Schuler et
al. (2012) published a study examining beryllium sensitization and CBD
among 264 short-term workers employed at the previously described
Elmore, OH plant in 1999. The analysis used a high-quality exposure
reconstruction by Virji et al. (2012) and presented a regression
analysis of the relationship between beryllium exposure levels and
beryllium sensitization and CBD in the short-term worker population. By
including only short-term workers, Virji et al. were able to construct
participants' exposures with more precision than was possible in
studies involving workers exposed for longer durations and in time
periods with less exposure sampling. In addition, the focus on short-
term workers allowed more precise knowledge of when sensitization and
CBD occurred than had been the case for previously published cross-
sectional studies of long-term workers. Each participant completed a
work history questionnaire and was tested for beryllium sensitization,
and sensitized workers were offered further evaluation for CBD. The
overall prevalence of sensitization was 9.8 percent (26/264). Twenty-
two sensitized workers consented to clinical testing for CBD via
transbronchial biopsy. Six of those sensitized were diagnosed with CBD
(2.3 percent, 6/264).
    Schuler et al. (2012) used logistic regression to explore the
relationship between estimated beryllium exposure and sensitization and
CBD, using estimates of total, respirable, and submicron mass
concentrations. Exposure estimates were constructed using two exposure
surveys conducted in 1999: a survey of total mass exposures (4,022
full-shift personal samples) and a survey of size-separated impactor
samples (198 samples). The 1999 exposure surveys and work histories
were used to estimate long-term lifetime weighted (LTW) average,
cumulative, and highest-job-worked exposure for total, respirable, and
submicron beryllium mass concentrations.
    For beryllium sensitization, logistic models showed elevated odds
ratios for average (OR 1.48) and highest job (OR 1.37) exposure for
total mass exposure; the OR for cumulative exposure was smaller (OR
1.23) and borderline statistically significant (95 percent CI barely
included unity). Relationships between sensitization and respirable
exposure estimates were similarly elevated for average (OR 1.37) and
highest job (OR 1.32). Among the submicron exposure estimates, only
highest job (OR 1.24) had a 95 percent CI that just included unity for
sensitization. For CBD, elevated odds ratios were observed only for the
cumulative exposure estimates and were similar for total mass and
respirable exposure (total mass OR 1.66, respirable (OR 1.68).
Cumulative submicron exposure showed an elevated, borderline
significant odds ratio (OR 1.58). The odds ratios for average exposure
and highest-exposed job were not statistically significantly elevated.
Schuler et al. concluded that both total and respirable mass
concentrations of beryllium exposure were relevant predictors of risk
for beryllium sensitization and CBD.

 E. OSHA's Exposure-Response Analysis

    OSHA evaluated exposure and health outcome data on a population of
workers employed at the Cullman machining facility. NJMRC researchers,
with consent and information provided by the facility, compiled a
dataset containing employee work histories, medical diagnoses, and air
sampling results and provided it to OSHA for analysis. OSHA's
contractors from Eastern Research Group (ERG) gathered additional
information from (1) two surveys of the Cullman plant conducted by
OSHA's contractor (ERG, 2003 and ERG, 2004a), (2) published articles of
investigations conducted at the plant by researchers from NJMRC
(Kelleher et al., 2001; Madl et al., 2007; Martyny et al., 2000; and
Newman et al., 2001), (3) a case file from a 1980 OSHA complaint
inspection at the plant, (4) comments submitted to the OSHA docket
office in 1976 and 1977 by representatives of the metal machining plant
regarding their beryllium control program, and (5) personal
communications with the plant's current industrial hygienist (ERG,
2009b) and an industrial hygiene researcher at NJMRC (ERG, 2009a).
1. Plant Operations
    The Cullman plant is a leading fabricator of precision-machined and
processed materials including beryllium and its alloys, titanium,
aluminum, quartz, and glass (ERG, 2009b). The plant has approximately
210 machines, primarily mills and lathes, and processes large
quantities of beryllium on an annual basis. The plant provides complete
fabrication services including ultra-precision machining; ancillary
processing (brazing, ion milling, photo etching, precision cleaning,
heat treating, stress relief, thermal cycling, mechanical assembly, and
chemical milling/etching); and coatings (plasma spray, anodizing, chromate
conversion coating, nickel sulfamate plate, nickel plate, gold plate,
black nickel plate, copper plate/strike, passivation, and painting).
Most of the plant's beryllium operations involve machining beryllium
metal and high beryllium content composite materials (beryllium metal/
beryllium oxide metal composites called E-Metal or E-Material), with
occasional machining of beryllium oxide/metal matrix (such as AlBeMet,
aluminum beryllium matrix) and beryllium-containing alloys. E-Materials
such as E-20 and E-60 are currently processed in the E-Cell department.
    The 120,000 square-foot plant has two main work areas: a front
office area and a large, open production shop. Operations in the
production shop include inspection of materials, machining, polishing,
and quality assurance. The front office is physically separated from
the production shop. Office workers enter through the front of the
facility and have access to the production shop through a change room
where they must don laboratory coats and shoe covers to enter the
production area. Production workers enter the shop area at the rear of
the facility where a change/locker room is available to change into
company uniforms and work shoes. Support operations are located in
separate areas adjacent to the production shop and include management
and administration, sales, engineering, shipping and receiving, and
maintenance. Management and administrative personnel include two
groups: those primarily working in the front offices (front office
management) and those primarily working on the shop floor (shop
management).
    In 1974, the company moved its precision machining operations to
the plant's current location in Cullman. Workplace exposure controls
reportedly did not change much until the diagnosis of an index case of
CBD in 1995. Prior to 1995, exposure controls for machining operations
primarily included a low volume/high velocity (LVHV) central exhaust
system with operator-adjusted exhaust pickups and wet machining
methods. Protective clothing, gloves, and respiratory protection were
not required. After the diagnosis, the facility established an in-house
target exposure level of 0.2 [mu]g/m\3\, installed change/locker rooms
for workers entering the production facility, eliminated pressurized
air hoses, discouraged the use of dry sweeping, initiated biennial
medical surveillance using the BeLPT, and implemented annual beryllium
hazard awareness training.
    In 1996, the company instituted requirements for work uniforms and
dedicated work shoes for production workers, eliminated dry sweeping in
all departments, and purchased high-efficiency particulate air (HEPA)
filter vacuum cleaners for workplace cleanup and decontamination. Major
engineering changes were also initiated in 1996, including the purchase
of a new local exhaust ventilation (LEV) system to exhaust machining
operations producing finer aerosols (e.g., dust and fume versus metal
chips). The facility also began installing mist eliminators for each
machine. Departments affected by these changes included cutter grind
(tool and die), E-cell, electrical discharge machining (EDM), flow
lines, grind, lapping, and optics. Dry machining operations producing
chips were exhausted using the existing LVHV exhaust system (ERG,
2004a). In the course of making the ventilation system changes, old
ductwork and baghouses were dismantled and new ductwork and air
cleaning devices were installed. The company also installed Plexiglas
enclosures on machining operations in 1996-1997, including the lapping,
deburring, grinding, EDM, and tool and die operations. In 1998, LEV was
installed in EDM and modified in the lap, deburr, and grind
departments.
    Most exposure controls were reportedly in place by 2000 (ERG,
2009a). In 2004, the plant industrial hygienist reported that all
machines had LEV and about 65 percent were also enclosed with either
partial or full enclosures to control the escape of machining coolant
(ERG, 2004b). Over time, the facility has built enclosures for
operations that consistently produce exposures greater than 0.2 [mu]g/
m\3\. The company has never required workers to use gloves or other
PPE.
2. Air Sampling Database and Job Exposure Matrix (JEM)
    The NJMRC dataset includes industrial hygiene sampling results
collected by the plant (1980-1984 and 1995-2005) and NJMRC researchers
(June 1996 to February 1997 and September 1999), including 4,370
breathing zone (personal lapel) samples and 712 area samples (ERG,
2004b). Limited air sampling data is available before 1980 and no
exposure data appears to be available for the 10-year time period 1985
through 1994. A review of the NJMRC air sampling database from 1995
through 2005 shows a significant increase in the number of air samples
collected beginning in 2000, which the plant industrial hygienist
attributes to an increase in the number of air sampling pumps (from 5
to 23) and the purchase of an automated atomic absorption
spectrophotometer.
    ERG used the personal breathing zone sampling results contained in
the sample database to quantify exposure levels for each year and for
several-year periods. Separate exposure statistics were calculated for
each job included in the job history database. For each job included in
the job history database, ERG estimated the arithmetic mean, geometric
mean, median, minimum, maximum, and 95th percentile value for the
available exposure samples. Prior to generating these statistics ERG
made several adjustments. After consultation with researchers at NJMRC,
four particularly high exposures were identified as probably erroneous
and excluded from calculations. In addition, a 1996 sample for the HS
(Health and Safety) process was removed from the sample calculations
after ERG determined it was for a non-employee researcher visiting the
facility.
    Most samples in the sample database for which sampling times were
recorded were long-term samples: 2,503 of the 2,557 (97.9 percent)
breathing zone samples with sampling time recorded had times greater
than or equal to 400 minutes. No adjustments were made for sampling
time, except in the case of four samples for the "maintenance"
process for 1995. These results show relatively high values and
exceptionally short sampling times consistent with the nature of much
maintenance work, marked by short-term exposures and periods of no
exposure. The four 1995 maintenance samples were adjusted for an eight-
hour sampling time assuming that the maintenance workers received no
further beryllium exposure over the rest of their work shift.
    OSHA examined the database for trends in exposure by reviewing
sample statistics for individual years and grouping years into four
time periods that correspond to stages in the plant's approach to
beryllium exposure control. These were: 1980-1995, a period of
relatively minimal control prior to the 1995 discovery of a case of CBD
among the plant's workers; 1996-1997, a period during which some major
engineering controls were in the process of being installed on
machining equipment; 1998-1999, a period during which most engineering
controls on the machining equipment had been installed; and 2000-2003,
a period when installation of all exposure controls on machining
equipment was complete and exposures very low throughout the plant.
Table VI-4 below summarized the available data for each time period. As
the four probable sampling errors identified in the original data set are
excluded here, arithmetic mean values are presented.

                 Table VI-4--Exposure Values for Machining Job Titles, Excluding Probable Sampling Errors ([mu]g/m\3\) in NJMRC Data Set
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        1980-1995             1996-1997             1998-1999             2000-2003
                            Job title                            ---------------------------------------------------------------------------------------
                                                                   Samples      Mean     Samples      Mean     Samples      Mean     Samples      Mean
--------------------------------------------------------------------------------------------------------------------------------------------------------
Deburring.......................................................         27       1.17         19       1.29          0         NA         67        0.1
Electrical Discharge Machining..................................          2       0.06          2       1.32         16       0.08         63        0.1
Grinding........................................................         12       3.07          6       0.49         15       0.24         68        0.1
Lapping.........................................................          9       0.15         16       0.24         42       0.21        103        0.1
Lathe...........................................................         18       0.88          8       1.13         40       0.17        200        0.1
Milling.........................................................         43       0.64         15       0.23         95       0.17        434        0.1
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Reviewing the revised statistics for individual years for different
groupings, OSHA noted that exposures in the 1996-1997 period were for
some machining jobs equivalent to, or even higher than, exposure levels
recording during the 1980-1995 period. During 1996-1997, major
engineering controls were being installed, but exposure levels were not
yet consistently reduced.
    Table VI-5 below summarizes exposures for the four time periods in
jobs other than beryllium machining. These include jobs such as
administrative work, health and safety, inspection, toolmaking (`Tool'
and `Cgrind'), and others. A description of jobs by title is available
in the risk assessment background document.

                                 Table VI-5--Exposure Values for Non-Machining Job Titles ([mu]g/m\3\) in NJMRC Data Set
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                         1980-1995                      1996-1997                      1998-1999                      2000-2003
          Job title           --------------------------------------------------------------------------------------------------------------------------
                                 Samples          mean          Samples          mean          Samples          mean          Samples          mean
--------------------------------------------------------------------------------------------------------------------------------------------------------
Administration...............            0  NA..............            0  NA..............           39  0.052...........           74  0.061
Assembly.....................            0  NA..............            0  NA..............            8  0.136...........            2  0.051
Cathode......................            0  NA..............            0  NA..............            0  NA..............            9  0.156
Cgrind.......................            1  0.120...........            0  NA..............           14  0.105...........           76  0.112
Chem.........................            0  NA..............            1  0.529...........           21  0.277...........           91  0.152
Ecell........................            0  NA..............           13  1.873...........            0  NA..............           26  0.239
Engineering..................            1  0.065...........            0  NA..............           49  0.069...........          125  0.062
Flow Lines...................            0  NA..............            0  NA..............            0  NA..............          113  0.083
Gas..........................            0  NA..............            0  NA..............            0  NA..............          121  0.058
Glass........................            0  NA..............            0  NA..............            0  NA..............           38  0.068
Health and Safety \8\........            0  NA..............            0  NA..............            0  NA..............            5  0.076
Inspection...................            0  NA..............            0  NA..............           32  0.101...........          150  0.066
Maintenance..................            4  1.257...........            1  0.160...........           16  0.200...........           70  0.126
Msupp........................            0  NA..............            0  NA..............           47  0.094...........           68  0.081
Optics.......................            0  NA..............            0  NA..............            0  NA..............           41  0.090
PCIC.........................            1  0.040...........            0  NA..............           13  0.071...........           42  0.083
Qroom........................            1  0.280...........            0  NA..............            0  NA..............            2  0.130
Shop.........................            0  NA..............            0  NA..............            4  0.060...........            0  NA
Spec.........................            3  0.247...........            0  NA..............           24  0.083...........           19  0.087
Tool.........................            0  NA..............            0  NA..............            0  NA..............            1  0.070
--------------------------------------------------------------------------------------------------------------------------------------------------------

    From Table VI-5, it is evident that exposure samples are not
available for many non-machining jobs prior to 2000. Where samples are
available before 2000, sample numbers are small, particularly prior to
1998. In jobs for which exposure values are available in 1998-1999 and
2000-2003, exposures appear either to decline from 1998-1999 to 2000-
2003 (Assembly, Chem, Inspection, Maintenance) or to be roughly
equivalent (Administration, Cgrind, Engineering, Msupp, PCIC, and
Spec). Among the jobs with exposure samples prior to 1998, most had
very few (1-5) samples, with the exception of Ecell (13 samples in
1996-1997). Based on this limited information, it appears that
exposures declined from the period before the first dentification of a
CBD case to the period in which exposure controls were introduced.
---------------------------------------------------------------------------

    \8\ An exceptionally high result (0.845 [mu]g/m\3\, not shown in
Table 5) for a 1996 sample for the HS (Health and Safety) process
was removed from the sample calculations. OSHA's contractor
determined this sample to be associated with a non-employee
researcher visiting the facility.
---------------------------------------------------------------------------

    Because exposure results from 1996-1997 were not found to be
consistently reduced in comparison to the 1985-1995 period in primary
machining jobs, these two periods were grouped together in the JEM.
Exposure monitoring for jobs other than the primary machining
operations were represented by a single mean exposure value for 1980-
2003. As respiratory protection was not routinely used at the plant,
there was no adjustment for respiratory protection in workers' exposure
estimates. The job exposure matrix is presented in full in the
background document for the quantitative risk assessment.
3. Worker Exposure Reconstruction
    The work history database contains job history records for 348
workers, including start years, duration of employment, and percentage
of worktime spent in each job. One hundred ninety-eight of the workers
had been employed at some point in primary machining jobs, including
deburring, EDM, grinding, lapping, lathing, and milling. The remainder
worked only in non-primary machining jobs, such as administration,
engineering, quality control, and shop management. The total number of years
worked at each job are presented as integers, leaving some uncertainty
regarding the worker's exact start and end date at the job.
    Based on these records and the JEM described previously, ERG
calculated cumulative and average exposure estimates for each worker in
the database. Cumulative exposure was calculated as, [Sigma]i ei t i,
where e(i) is the exposure level for job (i), and t(i) is the time
spent in job (i). Cumulative exposure was divided by total exposure
time to estimate each worker's long-term average exposure. These
exposures were computed in a time-dependent manner for the statistical
modeling. For workers with beryllium sensitization or CBD, exposure
estimates excluded exposures following diagnosis.
    Workers who were employed for long time periods in jobs with low-
level exposures tend to have low average and cumulative exposures due
to the way these measures are constructed, incorporating the worker's
entire work history. As discussed in the Health Effects chapter,
higher-level exposures or short-term peak exposures such as those
encountered in machining jobs may be highly relevant to risk of
sensitization. Unfortunately, because it is not possible to
continuously monitor individuals' beryllium exposure levels and
sensitization status, it is not known exactly when workers became
sensitized or what their "true" peak exposures leading up to
sensitization were. Only a rough approximation of the upper levels of
exposure a worker experienced is possible. ERG constructed a third type
of exposure estimate reflecting the exposure level associated with the
highest-exposure job (HEJ) and time period experienced by each worker.
This exposure estimate (HEJ), the cumulative exposure estimate, and the
average exposure were used in the quartile analysis and statistical
analyses.
4. Prevalence of Sensitization and CBD
    In the database provided to OSHA, seven workers were reported as
sensitized only. Sixteen workers were listed as sensitized and
diagnosed with CBD upon initial clinical evaluation. Three workers,
first shown to be sensitized only, were later diagnosed with CBD.
Tables VI-6, VI-7, and VI-8 below present the prevalence of
sensitization and CBD cases across several categories of lifetime-
weighted (LTW) average, cumulative, and highest-exposed job (HEJ)
exposure. Exposure values were grouped by quartile. Note that all
workers with CBD are also sensitized. Thus, the columns "Total
Sensitized" and "Total %" refer to all sensitized workers in the
dataset, including workers with and without a diagnosis of CBD.

                           Table VI-6--Prevalence of Sensitization and CBD by LTW Average Exposure Quartile in NJMRC Data Set
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                            Sensitized                         Total
              Average exposure ([mu]g/m\3\)                 Group size         only             CBD         sensitized        Total %          CBD %
--------------------------------------------------------------------------------------------------------------------------------------------------------
0.0-0.080...............................................              91               1               1               2             2.2             1.0
0.081-0.18..............................................              73               2               4               6             8.2             5.5
0.19-0.51...............................................              77               0               6               6             7.8             7.8
0.51-2.15...............................................              78               4               8              12            15.4            10.3
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................             319               7              19              26             8.2             6.0
--------------------------------------------------------------------------------------------------------------------------------------------------------


                            Table VI-7--Prevalence of Sensitization and CBD by Cumulative Exposure Quartile in NJMRC Data Set
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                            Sensitized                         Total
          Cumulative exposure ([mu]g/m\3\-yrs)              Group size         only             CBD         sensitized        Total %          CBD %
--------------------------------------------------------------------------------------------------------------------------------------------------------
0.0-0.147...............................................              81               2               2               4             4.9             2.5
0.148-1.467.............................................              79               0               2               2             2.5             2.5
1.468-7.008.............................................              79               3               8              11            13.9             8.0
7.009-61.86.............................................              80               2               7               9            11.3             8.8
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................             319               7              19              26             8.2             6.0
--------------------------------------------------------------------------------------------------------------------------------------------------------


                       Table VI-8--Prevalence of Sensitization and CBD by Highest-Exposed Job Exposure Quartile in NJMRC Data Set
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                            Sensitized                         Total
                HEJ exposure ([mu]g/m\3\)                   Group size         only             CBD         sensitized        Total %          CBD %
--------------------------------------------------------------------------------------------------------------------------------------------------------
0.0-0.086...............................................              86               1               0               1             1.2             0.0
0.091-0.214.............................................              81               1               6               7             8.6             7.4
0.387-0.691.............................................              76               2               9              11            14.5            11.8
0.954-2.213.............................................              76               3               4               7             9.2             5.3
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................             319               7              19              26             8.2             6.0
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Table VI-6 shows increasing prevalence of total sensitization and
CBD with increasing LTW average exposure, measured both as average and
cumulative exposure. The lowest prevalence of sensitization and CBD was
observed among workers with average exposure levels less than or equal
to 0.08 [mu]g/m\3\, where two sensitized workers (2.2 percent)
including one case of CBD (1.0 percent) were found. The sensitized
worker in this category without CBD had worked at the facility as an
inspector since 1972, one of the lowest-exposed jobs at the plant.
Because the job was believed to have very low exposures, it was not
sampled prior to 1998. Thus, estimates of exposures in this job are
based on data from 1998-2003 only. It is possible that exposures
earlier in this worker's employment history were somewhat higher than
reflected in his estimated average exposure. The worker diagnosed with
CBD in this group had been hired in 1996 in production control, and had
an estimated average exposure of 0.08 [mu]g/m\3\. He was diagnosed with
CBD in 1997.
    The second quartile of LTW average exposure (0.081--0.18 [mu]g/
m\3\) shows a marked rise in overall prevalence of beryllium-related
health effects, with six workers sensitized (8.2 percent), of whom four
(5.5 percent) were diagnosed with CBD. Among six sensitized workers in
the third quartile (0.19--0.50 [mu]g/m\3\), all were diagnosed with CBD
(7.8 percent). Another increase in prevalence is seen from the third to
the fourth quartile, with 12 cases of sensitization (15.4 percent),
including eight (10.3 percent) diagnosed with CBD.
    The quartile analysis of cumulative exposure also shows generally
increasing prevalence of sensitization and CBD with increasing
exposure. As shown in Table VI-7, the lowest prevalences of CBD and
sensitization are in the first two quartiles of cumulative exposure
(0.0-0.147 [mu]g/m\3\-yrs, 0.148-1.467 [mu]g/m\3\-yrs). The upper bound
on this cumulative exposure range, 1.467 [mu]g/m\3\-yrs, is the
cumulative exposure that a worker would have if exposed to beryllium at
a level of 0.03 [mu]g/m\3\ for a working lifetime of 45 years; 0.15
[mu]g/m\3\ for ten years; or 0.3 [mu]g/m\3\ for five years.
    A sharp increase in prevalence of sensitization and CBD and total
sensitization occurs in the third quartile (1.468-7.008 [mu]g/m\3\-
yrs), with roughly similar levels of both in the highest group (7.009-
61.86 [mu]g/m\3\-yrs). Cumulative exposures in the third quartile would
be experienced by a worker exposed for 45 years to levels between 0.03
and 0.16 [mu]g/m\3\, for 10 years to levels between 0.15 and 0.7 [mu]g/
m\3\, or for five years to levels between 0.3 and 1.4 [mu]g/m\3\.
    When workers' exposures from their highest-exposed job are
considered, the exposure-response pattern is similar to that for LTW
average exposure in the lower quartiles (Table VI-8). The lowest
prevalence is observed in the first quartile (0.0-0.86 [mu]g/m\3\),
with sharply rising prevalence from first to second and second to third
exposure quartiles. The prevalence of sensitization and CBD in the top
quartile (0.954-2.213 [mu]g/m\3\) decreases relative to the third, with
levels similar to the overall prevalence in the dataset. Many workers
in the highest exposure quartiles are long-time employees, who were
hired during the early years of the shop when exposures were highest.
One possible explanation for the drop in prevalence in the highest
exposure quartiles is that highly-exposed workers from early periods
may have developed CBD and left the plant before sensitization testing
began in 1995.
    It is of some value to compare the prevalence analysis of the
Cullman (NJMRC) data set with the results of the Reading and Tucson
studies discussed previously. An exact comparison is not possible, in
part because the Reading and Tucson exposure values are associated with
jobs and the NJMRC values are estimates of lifetime weighted average,
cumulative, and highest-exposed job (HEJ) exposures for individuals in
the data set. Nevertheless, OSHA believes it is possible to very
roughly compare the results of the Reading and Tucson studies and the
results of the NJMRC prevalence analysis presented above. As discussed
in detail below, OSHA found a general consistency between the
prevalence of sensitization and CBD in the quartiles of average
exposure in the NJMRC data set and the prevalence of sensitization and
CBD at the Reading and Tucson plants for similar exposure values.
    Personal lapel samples collected at the Reading plant between 1995
and 2000 were relatively low overall (median of 0.073 [mu]g/m\3\), with
higher exposures (median of 0.149 [mu]g/m\3\) concentrated in the wire
annealing and pickling process (Schuler et al., 2005). Exposures in the
Reading plant in this time period were similar to the second-quartile
average (Table VI-6-0.081-0.18 [mu]g/m\3\). The prevalence of
sensitization observed in the NJMRC second quartile was 8.2 percent and
appears roughly consistent with the prevalence of sensitization among
Reading workers in the mid-1990s (11.5 percent). The reported
prevalence of CBD (3.9 percent) among the Reading workforce was also
consistent with that observed in the second NJMRC quartile (5.5
percent), After 2000, exposure controls reduced exposures in most
Reading jobs to median levels below 0.03 [mu]g/m\3\, with a median
value of 0.1 [mu]g/m\3\ for the wire annealing and pickling process.
The wire annealing and pickling process was enclosed and stringent
respirator and skin protection requirements were applied for workers in
that area after 2002, essentially eliminating airborne and dermal
exposures for those workers. Thomas et al. (2009) reported that one of
45 workers (2.2 percent) hired after the enclosure in 2002 was
confirmed as sensitized, a value in line with the sensitization
prevalence observed in the lowest quartiles of average exposure (2.2
percent, 0.0-0.08 [mu]g/m\3\).
    As with Reading, the prevalence of sensitization observed at Tucson
and in the NJMRC data set are not exactly comparable due to the
different natures of the exposure estimates. Nevertheless, in a rough
sense the results of the Tucson study and the NJMRC prevalence analysis
appear similar. In Tucson, a 1998 BeLPT screening showed that 9.5
percent of workers hired after 1992 were sensitized (Henneberger et
al., 2001). Personal full-shift exposure samples collected in
production jobs between 1994 and 1999 had a median of 0.2 [mu]g/m\3\
(0.1 [mu]g/m\3\ for non-production jobs). In the NJMRC data set, a
sensitization prevalence of 8.2 percent was seen among workers with
average exposures between 0.081 and 0.18 [mu]g/m\3\. At the time of the
1998 screening, workers hired after 1992 had a median one year since
first beryllium exposure and, therefore, CBD prevalence was only 1.4
percent. This prevalence is likely an underestimate since CBD often
requires more than a year to develop. Longer-term workers at the Tucson
plant with a median 14 years since first beryllium exposure had a 9.1
percent prevalence of CBD. There was a 5.5 percent prevalence of CBD
among the entire workforce (Henneberger et al., 2001). As with the
Reading plant employees, this reported prevalence is reasonably
consistent with the 5.5 percent CBD prevalence observed in the second
NJMRC quartile.
    Beginning in 1999, the Tucson facility instituted strict
requirements for respiratory protection and other PPE, essentially
eliminating airborne and dermal exposure for most workers. After these
requirements were put in place, Cummings et al. (2007) reported only
one case of sensitization (1 percent; associated with a PPE failure)
among 97 workers hired between 2000 and 2004. This appears roughly in
line with the sensitization prevalence of 2.2 percent observed in the
lowest quartiles of average exposure (0.0-0.08 [mu]g/m\3\) in the NJMRC
data set.
    While the literature analysis presented here shows a clear
reduction in risk with well-controlled airborne exposures (<= 0.1
[mu]g/m\3\ on average) and protection from dermal exposure, the level
of detail presented in the published studies limits the Agency's
ability to characterize risk at all the alternate PELs OSHA is
considering. To better understand these risks, OSHA used the NJMRC dataset
to characterize risk of sensitization and CBD among workers exposed to
each of the alternate PELs under consideration in the proposed beryllium rule.

F. OSHA's Statistical Modeling

    OSHA's contractor performed a complementary log-log proportional
hazards model using the NJMRC data set. The proportional hazards model
is a generalization of logistic regression that allows for time-
dependent exposures and differential time at risk. The proportional
hazards model accounts for the fact that individuals in the dataset are
followed for different amounts of time, and that their exposures change
over time. The proportional hazards model provides hazards ratios,
which estimate the relative risk of disease at a specified time for
someone with exposure level 1 compared to exposure level 2. To perform
this analysis, OSHA's contractor constructed exposure files with time-
dependent cumulative and average exposures for each worker in the data
set in each year that a case of sensitization or CBD was identified.
Workers were included in only those years after they started working at
the plant and continued to be followed. Sensitized cases were not
included in analysis of sensitization after the year in which they were
identified as being sensitized, and CBD cases were not included in
analyses of CBD after the year in which they were diagnosed with CBD.
Follow-up is censored after 2002 because work histories were deemed to
be less reliable after that date.
    The results of the discrete proportional hazards analyses are
summarized in Tables VI-9-12 below. All coefficients used in the models
are displayed, including the exposure coefficient, the model constant
for diagnosis in 1995, and additional exposure-independent coefficients
for each succeeding year (1996-1999 for sensitization and 1996-2002 for
CBD) of diagnosis that are fit in the discrete time proportional
hazards modeling procedure. Model equations and variables are explained
more fully in the companion risk assessment background document.
    Relative risk of sensitization increased with cumulative exposure
(p = 0.05). A positive, but not statistically significant, association
was observed with LTW average exposure (p = 0.09). The association was
much weaker for exposure duration (p = 0.31), consistent with the
expected biological action of an immune hypersensitivity response where
onset is believed to be more dependent on the concentration of the
sensitizing agent at the target site rather than the number of years of
occupational exposure. The association was also much weaker for
highest-exposed job (HEJ) exposure (p = 0.3).

                  Table VI-9--Proportional Hazards Model--Cumulative Exposure and Sensitization
----------------------------------------------------------------------------------------------------------------
                   Variable                       Coefficient        95% Confidence interval          P-value
----------------------------------------------------------------------------------------------------------------
Cumulative Exposure ([mu]g/m\3\-yrs)..........           0.031  0.00 to 0.063...................            0.05
constant......................................           -3.48  -4.27 to -2.69..................          < 0.001
1996..........................................           -1.49  -3.04 to 0.06...................            0.06
1997..........................................           -0.29  -1.31 to 0.72...................            0.57
1998..........................................           -1.56  -3.11 to -0.01..................            0.05
1999..........................................           -1.57  -3.12 to -0.02..................            0.05
----------------------------------------------------------------------------------------------------------------


                 Table VI-10--Proportional Hazards Model--LTW Average Exposure and Sensitization
----------------------------------------------------------------------------------------------------------------
                   Variable                       Coefficient        95% Confidence interval          P-value
----------------------------------------------------------------------------------------------------------------
Average Exposure ([mu]g/m\3\).................            0.54  -0.09 to 1.17...................            0.09
constant......................................           -3.55  -4.42 to -2.69..................          < 0.001
1996..........................................           -1.48  -3.03 to 0.07...................            0.06
1997..........................................           -0.29  -1.31 to 0.72...................            0.57
1998..........................................           -1.54  -3.09 to 0.01...................            0.05
1999..........................................           -1.53  -3.08 to 0.03...................            0.05
----------------------------------------------------------------------------------------------------------------


                  Table VI-11--Proportional Hazards Model--Exposure Duration and Sensitization
----------------------------------------------------------------------------------------------------------------
                   Variable                       Coefficient        95% Confidence interval          P-value
----------------------------------------------------------------------------------------------------------------
Exposure Duration (years).....................            0.03  -0.03 to 0.08...................            0.31
constant......................................           -3.55  -4.57 to -2.53..................          < 0.001
1996..........................................           -1.48  -3.03 to 0.70...................            0.06
1997..........................................           -0.30  -1.31 to 0.72...................            0.57
1998..........................................           -1.59  -3.14 to -0.04..................            0.05
1999..........................................           -1.62  -3.17 to -0.72..................            0.04
----------------------------------------------------------------------------------------------------------------


                     Table VI-12--Proportional Hazards Model--HEJ Exposure and Sensitization
----------------------------------------------------------------------------------------------------------------
                   Variable                       Coefficient        95% Confidence interval          P-value
----------------------------------------------------------------------------------------------------------------
HEJ Exposure ([mu]g/m\3\).....................            0.31  -0.27 to 0.88...................            0.30
constant......................................           -3.42  -4.27 to -2.56..................          < 0.001
1996..........................................           -1.49  -3.04 to 0.06...................            0.06
1997..........................................           -0.31  -1.33 to 0.70...................            0.55
1998..........................................           -1.59  -3.14 to -0.04..................            0.05
1999..........................................           -1.60  -3.15 to -0.05..................            0.04
----------------------------------------------------------------------------------------------------------------


    The proportional hazards models for the CBD endpoint (Tables VI-13
through 16 below) showed positive relationships with cumulative
exposure (p = 0.09) and duration of exposure (p = 0.10). However, the
association with the cumulative exposure metric was not as strong as
that for sensitization, probably due to the smaller number of CBD
cases. LTW average exposure and HEJ exposure were not closely related
to relative risk of CBD (p-values > 0.5).

                      Table VI-13--Proportional Hazards Model--Cumulative Exposure and CBD
----------------------------------------------------------------------------------------------------------------
                   Variable                       Coefficient        95% Confidence interval          P-value
----------------------------------------------------------------------------------------------------------------
Cumulative Exposure ([mu]g/m\3\-yrs)..........            0.03  .00 to 0.07.....................            0.09
constant......................................           -3.77  -4.67 to -2.86..................          < 0.001
1997..........................................           -0.59  -1.86 to 0.68...................            0.36
1998..........................................           -2.01  -4.13 to 0.11...................            0.06
1999..........................................           -0.63  -1.90 to 0.64...................            0.33
2002..........................................           -2.13  -4.25 to -0.01..................            0.05
----------------------------------------------------------------------------------------------------------------


                      Table VI-14--Proportional Hazards Model--LTW Average Exposure and CBD
----------------------------------------------------------------------------------------------------------------
                   Variable                       Coefficient        95% Confidence interval          P-value
----------------------------------------------------------------------------------------------------------------
Average Exposure ([mu]g/m\3\).................            0.24  -0.59 to 1.06...................            0.58
constant......................................           -3.62  -4.60 to -2.64..................          < 0.001
1997..........................................           -0.61  -1.87 to 0.66...................            0.35
1998..........................................           -2.02  -4.14 to 0.10...................            0.06
1999..........................................           -0.64  -1.92 to 0.63...................            0.32
2002..........................................           -2.15  -4.28 to -0.02..................            0.05
----------------------------------------------------------------------------------------------------------------


                       Table VI-15--Proportional Hazards Model--Exposure Duration and CBD
----------------------------------------------------------------------------------------------------------------
                   Variable                       Coefficient        95% Confidence interval          P-value
----------------------------------------------------------------------------------------------------------------
Exposure Duration (yrs).......................            0.05  -0.01 to 0.11...................            0.10
constant......................................           -4.18  -5.40 to -2.96..................          < 0.001
1997..........................................           -0.53  1.84 to 0.69....................            0.38
1998..........................................           -2.01  -4.13 to 0.11...................            0.06
1999..........................................           -0.67  -1.94 to 0.60...................            0.30
2002..........................................           -2.22  -4.34 to -0.10..................            0.04
----------------------------------------------------------------------------------------------------------------


                          Table VI-16--Proportional Hazards Model--HEJ Exposure and CBD
----------------------------------------------------------------------------------------------------------------
                   Variable                       Coefficient        95% Confidence interval          P-value
----------------------------------------------------------------------------------------------------------------
HEJ Exposure ([mu]g/m\3\).....................            0.03  -0.70 to 0.77...................            0.93
constant......................................           -3.49  -4.45 to -2.53..................          < 0.001
1997..........................................           -0.62  -1.88 to 0.65...................            0.34
1998..........................................           -2.05  -4.16 to 0.07...................            0.06
1999..........................................           -0.68  -1.94 to 0.59...................            0.30
2002..........................................           -2.21  -4.33 to -0.09..................            0.04
----------------------------------------------------------------------------------------------------------------

    In addition to the models reported above, comparable models were
fit to the upper 95 percent confidence interval of the HEJ exposure;
log-transformed cumulative exposure; log-transformed LTW average
exposure; and log-transformed HEJ exposure. Each of these measures was
positively but not significantly associated with sensitization.
    OSHA used the proportional hazards models based on cumulative
exposure, shown in Tables VI-9 and VI-13, to derive quantitative risk
estimates. Of the metrics related to exposure level, the cumulative
exposure metric showed the most consistent association with
sensitization and CBD in these models. Table VI-17 summarizes these
risk estimates for sensitization and the corresponding 95 percent
confidence intervals separately for 1995 and 1999, the years with the
highest and lowest baseline rates, respectively. The estimated risks
for CBD are presented in VI-18. The expected number of cases is based
on the estimated conditional probability of being a case in the given
year. The models provide time-specific point estimates of risk for a
worker with any given exposure level, and the corresponding interval is
based on the uncertainty in the exposure coefficient (i.e., the
predicted values based on the 95 percent confidence limits for the
exposure coefficient).
    Each estimate represents the number of sensitized workers the model
predicts in a group of 1000 workers at risk during the given year with
an exposure history at the specified level and duration. For example,
in the exposure scenario where 1000 workers are occupationally exposed
to 2 [mu]g/m\3\ for 10 years in 1995, the model predicts that about 56
(55.7) workers would be sensitized that year. The model for CBD
predicts that about 42 (41.9) workers would be diagnosed with CBD that
year.


  Table VI-17a--Predicted Cases of Sensitization per 1000 Workers Exposed at Current and Alternate PELs Based on Proportional Hazards Model, Cumulative
                            Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient
                                                                     [1995 Baseline]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                             Exposure duration
                                                 -------------------------------------------------------------------------------------------------------
                                                           5 years                  10 years                  20 years                  45 years
        1995 Exposure level  ([mu]g/m\3\)        -------------------------------------------------------------------------------------------------------
                                                   Cumulative
                                                  ([mu]g/m\3\- cases/ 1000  [mu]g/m\3\-  cases/ 1000  [mu]g/m\3\-  cases/ 1000  [mu]g/m\3\-  cases/ 1000
                                                      yrs)                      yrs                       yrs                       yrs
--------------------------------------------------------------------------------------------------------------------------------------------------------
2.0.............................................         10.0         41.1         20.0         55.7         40.0        101.0         90.0        394.4
                                                                 30.3-56.2                30.3-102.9                30.3-318.1                30.3-999.9
1.0.............................................          5.0         35.3         10.0         41.1         20.0         55.7         45.0        116.9
                                                                 30.3-41.3                 30.3-56.2                30.3-102.9                30.3-408.2
0.5.............................................          2.5         32.7          5.0         35.3         10.0         41.1         22.5         60.0
                                                                 30.3-35.4                 30.3-41.3                 30.3-56.2                30.3-119.4
0.2.............................................          1.0         31.3          2.0         32.2          4.0         34.3          9.0         39.9
                                                                 30.3-32.3                 30.3-34.3                 30.3-38.9                 30.3-52.9
0.1.............................................          0.5         30.8          1.0         31.3          2.0         32.2          4.5         34.8
                                                                 30.3-31.3                 30.3-32.3                 30.3-34.3                 30.3-40.1
--------------------------------------------------------------------------------------------------------------------------------------------------------


  Table VI-17b--Predicted Cases of Sensitization per 1000 Workers Exposed at Current and Alternate PELs Based on Proportional Hazards Model, Cumulative
                            Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient
                                                                     [1999 Baseline]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                             Exposure duration
                                                 -------------------------------------------------------------------------------------------------------
                                                           5 years                  10 years                  20 years                  45 years
        1999 Exposure level  ([mu]g/m\3\)        -------------------------------------------------------------------------------------------------------
                                                   Cumulative
                                                  ([mu]g/m\3\- cases/ 1000  [mu]g/m\3\-  cases/ 1000  [mu]g/m\3\-  cases/ 1000  [mu]g/m\3\-  cases/ 1000
                                                      yrs)                      yrs                       yrs                       yrs
--------------------------------------------------------------------------------------------------------------------------------------------------------
2.0.............................................         10.0          8.4         20.0         11.5         40.0         21.3         90.0         96.3
                                                                  6.2-11.6                  6.2-21.7                  6.2-74.4                 6.2-835.4
1.0.............................................          5.0          7.2         10.0          8.4         20.0         11.5         45.0         24.8
                                                                   6.2-8.5                  6.2-11.6                  6.2-21.7                 6.2-100.5
0.5.............................................          2.5          6.7          5.0          7.2         10.0          8.4         22.5         12.4
                                                                   6.2-7.3                   6.2-8.5                  6.2-11.6                  6.2-25.3
0.2.............................................          1.0          6.4          2.0          6.6          4.0          7.0          9.0          8.2
                                                                   6.2-6.6                   6.2-7.0                   6.2-8.0                  6.2-10.9
0.1.............................................          0.5          6.3          1.0          6.4          2.0          6.6          4.5          7.1
                                                                   6.2-6.4                   6.2-6.6                   6.2-7.0                   6.2-8.2
--------------------------------------------------------------------------------------------------------------------------------------------------------


 Table VI-18a--Predicted Number of Cases of CBD per 1000 Workers Exposed at Current and Alternative PELs Based on Proportional Hazards Model, Cumulative
                            Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient
                                                                     [1995 baseline]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                             Exposure duration
                                                 -------------------------------------------------------------------------------------------------------
                                                           5 years                  10 years                  20 years                  45 years
        1995 Exposure level  ([mu]g/m\3\)        -------------------------------------------------------------------------------------------------------
                                                   Cumulative   Estimated                 Estimated                 Estimated                 Estimated
                                                  ([mu]g/m\3\-  cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000
                                                      yrs)       95% c.i.       yrs        95% c.i.       yrs        95% c.i.       yrs        95% c.i.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                  ...........         30.9  ...........         41.9  ...........         76.6  ...........        312.9
2.0.............................................         10.0    22.8-44.0         20.0    22.8-84.3         40.0   22.8-285.5         90.0   22.8-999.9
                                                  ...........         26.6  ...........         30.9  ...........         41.9  ...........         88.8
1.0.............................................          5.0    22.8-31.7         10.0    22.8-44.0         20.0    22.8-84.3         45.0   22.8-375.0
                                                  ...........         24.6  ...........         26.6  ...........         30.9  ...........         45.2
0.5.............................................          2.5    22.8-26.9          5.0    22.8-31.7         10.0    22.8-44.0         22.5    22.8-98.9
                                                  ...........         23.5  ...........         24.2  ...........         25.8  ...........         30.0
0.2.............................................          1.0    22.8-24.3          2.0    22.8-26.0          4.0    22.8-29.7          9.0    22.8-41.3
                                                  ...........         23.1  ...........         23.5  ...........         24.2  ...........         26.2
0.1.............................................          0.5    22.8-23.6          1.0    22.8-24.3          2.0    22.8-26.0          4.5    22.8-30.7
--------------------------------------------------------------------------------------------------------------------------------------------------------



 Table VI-18b--Predicted Number of Cases of CBD per 1000 Workers Exposed at Current and Alternative PELs Based on Proportional Hazards Model, Cumulative
                            Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient
                                                                     [2002 baseline]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                             Exposure duration
                                                 -------------------------------------------------------------------------------------------------------
                                                           5 years                  10 years                  20 years                  45 years
        2002 Exposure level  ([mu]g/m\3\)        -------------------------------------------------------------------------------------------------------
                                                   Cumulative   Estimated                 Estimated                 Estimated                 Estimated
                                                  ([mu]g/m\3\-  cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000
                                                      yrs)       95% c.i.       yrs        95% c.i.       yrs        95% c.i.       yrs        95% c.i.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                  ...........          3.7  ...........          5.1  ...........          9.4  ...........         43.6
2.0.............................................         10.0      2.7-5.3         20.0     2.7-10.4         40.0     2.7-39.2         90.0    2.7-679.8
                                                  ...........          3.2  ...........          3.7  ...........          5.1  ...........         11.0
1.0.............................................          5.0      2.7-3.8         10.0      2.7-5.3         20.0     2.7-10.4         45.0     2.7-54.3
                                                  ...........          3.0  ...........          3.2  ...........          3.7  ...........          5.5
0.5.............................................          2.5      2.7-3.2          5.0      2.7-3.8         10.0      2.7-5.3         22.5     2.7-12.3
                                                  ...........          2.8  ...........          2.9  ...........          3.1  ...........          3.6
0.2.............................................          1.0      2.7-2.9          2.0      2.7-3.1          4.0      2.7-3.6          9.0      2.7-5.0
                                                  ...........          2.8  ...........          2.8  ...........          2.9  ...........          3.1
0.1.............................................          0.5      2.7-2.8          1.0      2.7-2.9          2.0      2.7-3.1          4.5      2.7-3.7
--------------------------------------------------------------------------------------------------------------------------------------------------------

    The statistical modeling analysis predicts high risk of both
sensitization (96-394 cases per 1000, or 9.6-39.4 percent) and CBD (44-
313 cases per 1000, or 4.4-31.3 percent) at the current PEL of 2 [mu]g/
m\3\ for an exposure duration of 45 years (90 [mu]g/m\3\-yr). The
predicted risks of < 8.2-39.9 per 1000 (0.8-3.9 percent) cases of
sensitization or 3.6 to 30.0 per 1000 (0.4-3 percent) cases of CBD are
substantially less for a 45-year exposure at the proposed PEL, 0.2
[mu]g/m\3\ (9 [mu]g/m\3\-yr).
    The model estimates are not directly comparable to prevalence
values discussed in previous sections. They assume a group without
turnover and are based on a comparison of unexposed and hypothetically
exposed workers at specific points in time, whereas the prevalence
analysis simply reports the percentage of workers at the Cullman plant
with sensitization or CBD in each exposure category. Despite the
difficulty of direct comparison, the level of risk seen in the
prevalence analysis and predicted in the modeling analysis appear
roughly similar at low exposures. In the second quartile of cumulative
exposure (0.148-1.467 [mu]g/m\3\-yr), prevalence of sensitization and
CBD was 2.5 percent. This is roughly congruent with the model
predictions for workers with cumulative exposures between 0.5 and 1
[mu]g/m\3\-yr: 6.3-31.3 cases of sensitization per 1000 workers (0.6-
3.1 percent) and 2.8 to 23.5 cases of CBD per 1000 workers (0.28-2.4
percent). As discussed in the background document for this analysis,
most workers in the data set had low cumulative exposures (roughly half
below 1.5 [mu]g/m\3\-years). It is difficult to make any statement
about the results at higher levels, because there were few workers with
high exposure levels and the higher quartiles of cumulative exposure
include an extremely wide range of exposures. For example, the highest
quartile of cumulative exposure was 7.009-61.86 [mu]g/m\3\-yr. This
quartile, which showed an 11.3 percent prevalence of sensitization and
8.8 percent prevalence of CBD, includes the cumulative exposure that a
worker exposed for 45 years at the proposed PEL would experience (9
[mu]g/m\3\-yr) near its lower bound. Its upper bound approaches the
cumulative exposure that a worker exposed for 45 years at the current
PEL would experience (90 [mu]g/m\3\-yr).
    Due to limitations including the size of the dataset, relatively
limited exposure data from the plant's early years, study size-related
constraints on the statistical analysis of the dataset, and limited
follow-up time on many workers, OSHA must interpret the model-based
risk estimates presented in Tables VI-17 and VI-18 with caution. The
Cullman study population is a relatively small group and can support
only limited statistical analysis. For example, its size precludes
inclusion of multiple covariates in the exposure-response models or a
two-stage exposure-response analysis to model both sensitization and
the subsequent development of CBD within the subpopulation of
sensitized workers. The limited size of the Cullman dataset is
characteristic of studies on beryllium-exposed workers in modern, low-
exposure environments, which are typically small-scale processing
plants (up to several hundred workers, up to 20-30 cases). However,
these recent studies also have important strengths: They include
workers hired after the institution of stringent exposure controls, and
have extensive exposure sampling using full-shift personal lapel
samples. In contrast, older studies of larger populations tend to have
higher exposures, less exposure data, and exposure data collected in
short-term samples or outside of workers' breathing zones.
    Another limitation of the Cullman dataset, which is common to
recent low-exposure studies, is the short follow-up time available for
many of the workers. While in some cases CBD has been known to develop
in short periods (< 2 years), it more typically develops over a longer
time period. Sensitization occurs in a typically shorter time frame,
but new cases of sensitization have been observed in workers exposed to
beryllium for many years. Because the data set is limited to
individuals then working at the plant, the Cullman data set cannot
capture CBD occurring among workers who retire or leave the plant. OSHA
expects that the dataset does not fully represent the risk of
sensitization, and is likely to particularly under-represent CBD among
workers exposed to beryllium at this facility. The Agency believes the
short follow-up time to be a significant source of uncertainty in the
statistical analysis, a factor likely to lead to underestimation of
risk in this population.
    A common source of uncertainty in quantitative risk assessment is
the series of choices made in the course of statistical analysis, such
as model type, inclusion or exclusion of additional explanatory
variables, and the assumption of linearity in exposure-response.
Sensitivity analyses and statistical checks were conducted to test the
validity of the choices and assumptions in the exposure-response analysis
and the impact of alternative choices on the end results. These analyses did
not yield substantially different results, adding to OSHA's confidence in the
conclusions of its preliminary risk assessment.
    OSHA's contractor examined whether smoking and age were confounders
in the exposure-response analysis by adding them as variables in the
discrete proportional hazards model. Neither smoking status nor age was
a statistically significant predictor of sensitization or CBD. The
model coefficients, 95 percent confidence intervals, and p values can
be found in the background document. A sensitivity analysis was done
using the standard Cox model that treats survival time as continuous
rather than discrete. The model coefficients with the standard Cox
using cumulative exposure were 0.025 and very similar to the 0.03
reported in Tables VI-9 and VI-13 above. The interaction between
exposure and follow-up time was not significant in these models,
suggesting that the proportional hazard assumption should not be
rejected. The proportional hazards model assumes a linear relationship
between exposure level and relative risk. The linearity assumption was
assessed using a fractional polynomial approach. For both sensitization
and CBD, the best-fitting fractional polynomial model did not fit
significantly better than the linear model. This result supports OSHA's
use of the linear model to estimate risk. The details of these
statistical analyses can be found in the background document.
    The possibility that the number of times a worker has been tested
for sensitization might influence the probability of a positive test
was examined (surveillance bias). Surveillance bias could occur if
workers were tested because they showed some sign of disease, and not
tested otherwise. It is also possible that the original analysis
included erroneous assumptions about the dates of testing for
sensitization and CBD. OSHA's contractor performed a sensitivity
analysis, modifying the original analysis to gauge the effect of
different assumptions about testing dates. In the sensitivity analysis,
the exposure coefficients increased for all four indices of exposure
when the sensitization analysis was restricted to times when cohort
members were assumed to be tested. The exposure coefficient was
statistically significant for duration of exposure but not for
cumulative, LTW average, or HEJ exposure. The increase in exposure
coefficients suggests that the original models may have underestimated
the exposure-response relationship for sensitization and CBD.
    Errors in exposure measurement are a common source of uncertainty
in quantitative risk assessments. Because errors in high exposures can
heavily influence modeling results, OSHA's contractor performed
sensitivity analyses excluding the highest 5 percent of cumulative
exposures (those above 25.265 [mu]g/m\3\-yrs) and the highest 10
percent of cumulative exposures (those above 18.723 [mu]g/m\3\-yrs). As
discussed in more detail in the background document, exposure
coefficients were not statistically significant when these exposures
were dropped. This is not surprising, given that the exclusion of high
exposure values reduced the size of the data set. Prior to excluding
high exposure values, the data set was already relatively small and
many of the exposure coefficients were non-significant or weakly
significant in the original analyses. As a result, the sensitivity
analyses did not provide much information about uncertainty due to
exposure measurement error and its effects on the modeling analysis.
    Particle size, particle surface area, and beryllium compound
solubility are believed to be important factors influencing the risk of
sensitization and CBD among beryllium-exposed workers. The workers at
the Cullman machining plant were primarily handling insoluble beryllium
compounds, such as beryllium metal and beryllium metal/beryllium oxide
composites. Particle size distributions from a limited number of
airborne beryllium samples collected just after the 1996 installation
of engineering controls indicate worker exposure to a substantial
proportion of respirable particulates. There was no available particle
size data for the 1980 to 1995 period prior to installation of
engineering controls when total beryllium mass exposure levels were
greatest. Particle size data was also lacking from 1998 to 2003 when
additional control measures were in place and total beryllium mass
exposures were lowest. For these reasons, OSHA was not able to
quantitatively account for the influence of particle size and
solubility in developing the risk estimates based on the Cullman data
set. However, it is not unreasonable to expect the CBD experienced by
this cohort to generally reflect the risk from exposure to beryllium
that is relatively insoluble and enriched with respirable particles. As
explained previously, the role of particle size and surface area on
risk of sensitization is more difficult to predict.
    Additional uncertainty is introduced when extrapolating the
quantitative estimates presented above to operations that process
beryllium compounds that have different solubility and particle
characteristics than those encountered at the Cullman machining plant.
OSHA does not have sufficient information to quantitatively assess the
degree to which risks of beryllium sensitization and CBD based on the
NJMRC data may be impacted in workplaces where such beryllium forms and
processes are used. However, OSHA does not expect this uncertainty to
alter its qualitative conclusions with regard to the risk at the
current PEL and at alternate PELs as low as 0.1 [mu]g/m\3\. The
existing studies provide clear evidence of sensitization and CBD risk
among workers exposed to a number of beryllium forms as a result of
different processes such as beryllium machining, beryllium-copper alloy
production, and beryllium ceramics production. The Agency believes all
of these forms of beryllium exposure contribute to the overall risk of
sensitization and CBD among beryllium-exposed workers.

G. Lung Cancer

    OSHA considers lung cancer to be an important health endpoint for
beryllium-exposed workers. The International Agency for Research on
Cancer (IARC), National Toxicology Program (NTP), and American
Conference of Governmental Industrial Hygienists (ACGIH) have all
classified beryllium as a known human carcinogen. The National Academy
of Sciences (NAS), Environmental Protection Agency, the Agency for
Toxic Substances and Disease Registry (ATSDR), the National Institute
of Occupational Safety and Health (NIOSH), and other reputable
scientific organizations have reviewed the scientific evidence
demonstrating that beryllium is associated with an increased incidence
of cancer. OSHA also has performed an extensive review of the
scientific literature regarding beryllium and cancer. This includes an
evaluation of human epidemiological, animal cancer, and mechanistic
studies described in the Health Effects section of this preamble. Based
on the weight of evidence, the Agency has preliminarily determined
beryllium to be an occupational carcinogen.
    Although epidemiological and animal evidence supports a conclusion
of beryllium carcinogenicity, there is considerable uncertainty
surrounding the mechanism of carcinogenesis for beryllium. The evidence
for direct genotoxicity of beryllium and its compounds has been limited
and inconsistent (NAS, 2008; IARC, 1993; EPA, 1998; NTP, 2002; ATSDR,
2002). One plausible pathway for beryllium carcinogenicity described in
the Health Effects section of this preamble includes a chronic,
sustained neutrophilic inflammatory response that induces epigenetic
alterations leading to the neoplastic changes necessary for
carcinogenesis. The National Cancer Institute estimates that nearly
one-third of all cancers are caused by chronic inflammation (NCI,
2009). This mechanism of action has also been hypothesized for
crystalline silica and other agents that are known to be human
carcinogens but have limited evidence of genotoxicity.
    OSHA's review of epidemiological studies of lung cancer mortality
among beryllium workers found that most did not characterize exposure
levels sufficiently for exposure-response analysis. However, one NIOSH
study evaluated the association between beryllium exposure and lung
cancer mortality based on data from a beryllium processing plant in
Reading, PA (Sanderson et al., 2001a). As discussed in the Health
Effects section of this preamble, this case-control study evaluated
lung cancer incidence in a cohort of workers employed at the plant from
1940 to 1969 and followed through 1992. For each lung cancer victim, 5
age- and race-matched controls were selected by incidence density
sampling, for a total of 142 lung cancer cases and 710 controls.
    Between 1971 and 1992, the plant collected close to 7,000 high
volume filter samples consisting of both general area and short-term,
task-based breathing zone measurements for production jobs and
exclusively area measurements for office, lunch, and laboratory areas
(Sanderson et al., 2001b). In addition, a few (< 200) impinger and
high-volume filter samples were collected by other organizations
between 1947 and 1961, and about 200 6-to-8-hour personal samples were
collected in 1972 and 1975. Daily-weighted-average (DWA) exposure
calculations based on the impinger and high-volume samples collected
prior to the 1960s showed that exposures in this period were extremely
high. For example, about half of production jobs had estimated DWAs
ranging between 49 and 131 [mu]g/m\3\ in the period 1935-1960, and many
of the "lower-exposed" jobs had DWAs of approximately 20-30 [mu]g/
m\3\ (Table II, Sanderson et al., 2001b). Exposures were reported to
have decreased between 1959 and 1962 with the installation of
ventilation controls and improved housekeeping and following the
passage of the OSH Act in 1970. While no exposure measurements were
available from the period 1961-1970, measurements from the period 1971-
1980 showed a dramatic reduction in exposures plant-wide. Estimated
DWAs for all jobs in this period ranged from 0.1 [mu]g/m\3\ to 1.9
[mu]g/m\3\. Calendar-time-specific beryllium exposure estimates were
made for every job based on the DWA calculations and were used to
estimate workers' cumulative, average, and maximum exposures. Exposure
estimates were lagged by 10 and 20 years in order to account for
exposures that did not contribute to lung cancer because they occurred
after the induction of cancer.
    Results of a conditional logistic regression analysis showed an
increased risk of lung cancer in workers with higher exposures when
dose estimates were lagged by 10 and 20 years (Sanderson et al.,
2001a). The authors noted that there was considerable uncertainty in
the estimation of exposure in the 1940s and 1950s and the shape of the
dose-response curve for lung cancer. NIOSH later reanalyzed the data,
adjusting for potential confounders of hire age and birth year
(Schubauer-Berigan et al., 2008). The study reported a significant
increasing trend (p< 0.05) in the odds ratio when increasing quartiles
of average (log transformed) exposure were lagged by 10 years. However,
it did not find a significant trend when quartiles of cumulative (log
transformed) exposure were lagged by 0, 10, or 20 years.
    OSHA is interested in lung cancer risk estimates from a 45-year
(i.e., working lifetime) exposure to beryllium levels between 0.1
[mu]g/m\3\ and 2 [mu]g/m\3\. The majority of case and control workers
in the Sanderson et al. case-control analysis were first hired during
the 1940s when exposures were extremely high (estimated DWAs > 20
[mu]g/m\3\ for most jobs). The cumulative, average, and maximum
beryllium exposure concentration estimates for the 142 known lung
cancer cases were: 46.06  9.3[mu]g/m\3\-days, 22.8  3.4 [mu]g/m\3\, and
32.4  13.8 [mu]g/m\3\, respectively. About two-thirds of cases and half of
controls worked at the plant for less than a year. Thus, a risk assessment
based on this exposure-response analysis would need to extrapolate from very
high to very low exposures, based on a working population with extremely short
tenure. While OSHA risk assessments must often make extrapolations to
estimate risk within the range of exposures of interest, the Agency
acknowledges that these issues of short tenure and extremely high
exposures would create substantial uncertainty in a risk assessment
based on this study population.
    In addition, the relatively high exposures of even the least-
exposed workers in the NIOSH study may create methodological issues for
the lung cancer case-control study design. Mortality risk is expressed
as an odds ratio that compares higher exposure quartiles to the lowest
quartile. It is preferable that excess risks attributable to
occupational beryllium be determined relative to an unexposed or
minimally exposed reference population. However, in the NIOSH study
workers in the lowest quartile were exposed well above the OSHA PEL
(average exposure < 11.2 [mu]g/m\3\) and may have had a significant lung
cancer risk. This issue would introduce further uncertainty in lung
cancer risks estimated from this epidemiological study.
    In 2010, researchers at NIOSH published a quantitative risk
assessment based on an update of the Reading cohort analyzed by
Sanderson et al., as well as workers from two smaller plants
(Schubauer-Berigan et al., 2010b). This new risk assessment addresses
several of OSHA's concerns regarding the Sanderson et al. analysis. The
new cohort was exposed, on average, to lower levels of beryllium and
had fewer short-term workers. Finally, the updated cohorts followed the
populations through 2005, increasing the length of follow-up time
overall by an additional 17 years of observation. For these reasons,
OSHA considers the Schubauer-Berigan risk analysis more appropriate
than the Sanderson et al. analysis for its preliminary risk assessment.
    The cohort studied by Schubauer-Berigan et al. included 5,436 male
workers who had worked for at least two days at the Reading facility
and beryllium processing plants at Hazleton PA and Elmore OH prior to
1970. The authors developed job-exposure matrices (JEMs) for the three
plants based on extensive historical exposure data, primarily short-
term general area and personal breathing zone samples, collected on a
quarterly basis from a wide variety of operations. These samples were
used to create daily weighted average (DWA) estimates of workers' full-
shift exposures, using records of the nature and duration of tasks
performed by workers during a shift. Details on the JEM and DWA
construction can be found in Sanderson et al. (2001a), Chen et al.
(2001), and Couch et al. (2010).
    Workers' cumulative exposures ([mu]g/m\3\-days) were estimated by
summing daily average exposures (assuming five workdays per week).
To estimate mean exposure ([mu]g/m\3\), cumulative
exposure was divided by exposure time (in days). Maximum exposure
([mu]g/m\3\) was estimated as the highest annual DWA on record for a
worker prior to the study cutoff date of December 31, 2005 and
accounting where appropriate for lag time. Exposure estimates were
lagged by 5, 10, 15, and 20 years in order to account for exposures
that may not have contributed to lung cancer because of the long
latency required for manifestation of the disease. The authors also fit
models with no lag time. As shown in Table VI-19 below, estimated
exposure levels for workers from the Hazleton and Elmore plants were on
average far lower than those for workers from the Reading plant. The
median worker from Hazleton had a mean exposure across his tenure of
less than 2 [micro]g/m\3\, while the median worker from Elmore had a
mean exposure of less than 1 [micro]g/m\3\. The Elmore and Hazleton
worker populations also had fewer short-term workers than the Reading
population. This was particularly evident at Hazleton where the median
value for cumulative exposure among cases was higher than at Reading
despite the much lower mean and maximum exposure levels.

                   Table VI-19--Cohort Description and Distribution of Cases by Exposure Level
----------------------------------------------------------------------------------------------------------------
                                                    All plants     Reading plant  Hazleton plant   Elmore plant
----------------------------------------------------------------------------------------------------------------
Number of cases...............  ................             293             218              30              45
Number of non-cases...........  ................            5143            3337             583            1223
Median value for mean exposure  No lag..........           15.42              25           1.443           0.885
([micro]g/m\3\) among cases...  10-year lag.....           15.15              25           1.443           0.972
Median value for cumulative     No lag..........            2843            2895            3968            1654
 exposure.
([micro]g/m\3\-days) among      10-year lag.....            2583            2832            3648            1449
 cases.
Median value for maximum        No lag..........              25            25.1            3.15            2.17
 exposure.
([micro]g/m\3\) among cases...  10-year lag.....              25              25            3.15            2.17
Number of cases with potential  ................       100 (34%)        68 (31%)        16 (53%)        16 (36%)
 asbestos exposure.
Number of cases who were        ................         26 (9%)        21 (10%)         3 (10%)          2 (4%)
 professional workers.
----------------------------------------------------------------------------------------------------------------
Table adapted from Schubauer-Berigan et al. 2011, Table 1.

    Schubauer-Berigan et al. analyzed the data set using a variety of
exposure-response modeling approaches, including categorical analyses
and continuous-variable piecewise log-linear and power models,
described in Schubauer-Berigan et al. (2011). All models adjusted for
birth cohort and plant. As exposure values were log-transformed for the
power model analyses, the authors added small values to exposures of 0
in lagged analyses (0.05 [micro]g/m\3\ for mean and maximum exposure,
0.05 [micro]g/m\3\-days for cumulative exposure). The authors used
restricted cubic spline models to assess the shape of the exposure-
response curve and suggest appropriate parametric model forms. The
Akaike Information Criterion (AIC) value was used to evaluate the fit
of different model forms and lag times.
    Because smoking information was available for only about 25 percent
of the cohort, smoking could not be controlled for directly in the
models. The authors reported that within the subset with smoking
information, there was little difference in smoking by cumulative or
maximum exposure category (p. 6), suggesting that smoking was unlikely
to act as a confounder in the cohort. In addition to models based on
the full cohort, Schubauer-Berigan et al. also prepared risk estimates
based on models excluding professional workers and workers believed to
have asbestos exposure. These models were intended to mitigate the
potential impact of smoking and asbestos as confounders. If
professional workers had both lower beryllium exposures and lower
smoking rates than production workers, smoking could be a confounder in
the cohort comprising both production and professional workers.
However, the authors reasoned that smoking was unlikely to be
correlated with beryllium exposure among production workers, and would
therefore probably not act as a confounder in a cohort excluding
professional workers.
    The authors found that lung cancer risk was strongly and
significantly related to mean, cumulative, and maximum measures of
workers' exposure (all models reported in Schubauer-Berigan et al.,
2011). They selected the best-fitting categorical, power, and monotonic
piecewise log-linear (PWL) models with a 10-year lag to generate hazard
ratios for male workers with a mean exposure of 0.5 [micro]g/m\3\ (the
current NIOSH Recommended Exposure Limit for beryllium).\9\ To estimate
excess lifetime risk of cancer, they multiplied this hazard ratio by
the 2004-2006 background lifetime lung cancer rate among U.S. males who
had survived, cancer-free, to age 30. In addition, they estimated the
mean exposure that would be associated with an excess lifetime risk of
one in 1000, a value often used as a benchmark for significant risk in
OSHA regulations. At OSHA's request, they also estimated excess
lifetime risks for workers with mean exposures at the current PEL of 2
[mu]g/m\3\ each of the other alternate PELs under consideration: 1
[mu]g/m\3\, 0.2 [mu]g/m\3\, and 0.1 [mu]g/m\3\ (Schubauer-Berigan, 4/
22/11). The resulting risk estimates are presented in Table VI-20
below.
---------------------------------------------------------------------------

    \9\ Here, "monotonic PWL model" means a model producing a
monotonic exposure-response curve in the 0-2 ug/m\3\ region.


                         Table VI-20--Excess Lifetime Risk per 1000 [95% Confidence Interval] for Male Workers at Alternate PELs
                                                                     [NIOSH models]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                   Mean exposure
                 Exposure-response model                  ----------------------------------------------------------------------------------------------
                                                           0.1 [micro]g/m\3\  0.2 [micro]g/m\3\  0.5 [micro]g/m\3\   1 [micro]g/m\3\    2 [micro]g/m\3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Best monotonic PWL--all workers..........................        7.3[2.0-13]         15[3.3-29]           45[9-98]        120[20-340]        200[29-370]
Best monotonic PWL--excluding professional and asbestos           3.1[< 0-11]         6.4[< 0-23]          17[< 0-74]         39[39-230]         61[< 0-280]
 workers.................................................
Best categorical--all workers............................         4.4[1.3-8]          9[2.7-17]           25[6-48]         59[13-130]        170[29-530]
Best categorical--excluding professional and asbestos            1.4[< 0-6.0]         2.7[< 0-12]         7.1[< 0-35]          15[< 0-87]         33[< 0-290]
 workers.................................................
Power model--all workers.................................           12[6-19]         19[9.3-29]          30[15-48]          40[19-66]          52[23-88]
Power model--excluding professional and asbestos workers.         19[8.6-31]          30[13-50]          49[21-87]         68[27-130]         90[34-180]
--------------------------------------------------------------------------------------------------------------------------------------------------------

    Schubauer-Berigan et al. discuss several strengths, weaknesses, and
uncertainties of their analysis. Strengths include long (> 30 years)
follow-up time for members of the cohort and the extensive exposure and
work history data available for the development of exposure estimates
for workers in the cohort. Among the weaknesses and uncertainties of
the study are the limited information available on workers' smoking
habits: smoking information was available only for workers employed in
1968, about 25 percent of the cohort. In addition, the JEMs used did
not account for possible respirator use among workers in the cohort.
The authors note that workers' exposures may therefore have been
overestimated, and that overestimation may have been especially severe
for workers with high estimated exposures. They suggest that
overestimation of exposures for workers in highly exposed positions may
have caused attenuation of the exposure-response curve in some models
at higher exposures.
    The NIOSH publication did not discuss the reasons for basing risk
estimates on mean exposure rather than cumulative exposure that is more
commonly used for lung cancer risk analysis. OSHA believes the decision
may involve the nonmonotonic relationship NIOSH observed between cancer
risk and cumulative exposure level. As discussed previously, workers
from the Reading plant frequently had very short tenures and high
exposures yielding lower cumulative exposures compared to cohort
workers from other plants with longer employment. Despite the low
estimated cumulative exposures among the short-term Reading workers,
they may be at high risk of lung cancer due to the tendency of
beryllium to persist in the lung for long periods. This exposure
misclassification could lead to the appearance of a nonmonotonic
relationship between cumulative exposure and lung cancer risk. It is
possible that a dose-rate effect may exist for beryllium, such that the
risk from a cumulative exposure gained by long-term, low-level exposure
is not equivalent to the risk from a cumulative exposure gained by very
short-term, high-level exposure. In this case, mean exposure level may
better correlate with the risk of lung cancer than cumulative exposure
level. For these reasons OSHA considers the NIOSH choice of mean
exposure metric to be appropriate and scientifically defensible for
this particular dataset.

H. Preliminary Conclusions

    As described above, OSHA's risk assessment for beryllium
sensitization and CBD relied on two approaches: (1) review of the
literature and (2) analysis of a dataset provided by NJRMC. First, the
Agency reviewed the scientific literature to ascertain whether there is
substantial risk to workers exposed at and below the current PEL and to
characterize the expected impact of more stringent controls on workers'
risk of sensitization and CBD. This review focused on facilities where
exposures were primarily below the current PEL, and where several
rounds of BeLPT and CBD screening had been conducted to evaluate the
effectiveness of various exposure control measures. Second, OSHA
investigated the exposure-response relationship for beryllium
sensitization and CBD by analyzing a dataset that NJMRC provided on
workers at a prominent, long-established beryllium machining facility.
Although exposure-response studies have been published on sensitization
and CBD, OSHA believes the nature and quality of their exposure data
significantly limits their value for the Agency's risk assessment.
Therefore, OSHA developed an independent exposure-response analysis
using the NJMRC dataset, which was recently updated, includes workers
exposed at low levels, and includes extensive exposure data collected
in workers' breathing zones, as is preferred by OSHA.
    OSHA's review of the scientific literature found substantial risk
of both sensitization and CBD in workplaces in compliance with OSHA's
current PEL (e.g., Kreiss et al., 1992; Schuler et al., 2000; Madl et
al., 2007). At these plants, including a copper-beryllium processing
facility, a beryllia ceramics facility, and a beryllium machining
facility, exposure reduction programs that primarily used engineering
controls to reduce airborne exposures to median levels at or around 0.2
[mu]g/m\3\ had only limited impact on workers' risk. Cases of
sensitization continued to occur frequently among newly hired workers,
and some of these workers developed CBD within the short follow-up
time.
    In contrast, industrial hygiene programs that minimized both
airborne and dermal exposure substantially lowered workers' risk of
sensitization in the first years of employment. Programs that
drastically reduced respiratory exposure via a combination of
engineering controls and respiratory protection, minimized the
potential for skin exposure via dermal PPE, and employed stringent
housekeeping methods to keep work areas clean and prevent transfer of
beryllium between areas sharply curtailed new cases of sensitization
among newly-hired workers. For example, studies conducted at copper-
beryllium processing, beryllium production, and beryllia ceramics
facilities show that reduction of exposures to below 0.1 [mu]g/m\3\ and
protection from dermal exposure, in combination, achieved a substantial
reduction in sensitization risk among newly-hired workers. However,
even these stringent measures did not protect all workers from
sensitization.
    The most recent epidemiological literature on programs that have
been successful in reducing workers' risk of sensitization have had
very short follow-up time; therefore, they cannot address the question
of how frequently workers sensitized in very low-exposure environments
develop CBD. Clinical evaluation for CBD was not reported for workers
at the copper-beryllium processing, beryllium production, and ceramics
facilities. However, cases of CBD among workers exposed at low levels
at a machining plant and cases of CA-CBD demonstrate that individuals
exposed to low levels of airborne beryllium can develop CBD, and over
time, can progress to severe disease. This conclusion is also supported
by case reports within the literature of workers with CBD who may have
been minimally exposed to beryllium, such as a worker employed only in
administration at a beryllium ceramics facility (Kreiss et al., 1996).
    The Agency's analysis of the Cullman dataset provided by NJMRC
showed strong exposure-response trends using multiple analytical
approaches, including examination of sensitization and disease
prevalence by exposure categories and a proportional hazards modeling
approach. In the prevalence analysis, cases of sensitization and
disease were evident at all levels of exposure. The lowest prevalence
of sensitization (2.0 percent) and CBD (1.0 percent) was observed among
workers with LTW average exposure levels below 0.1 [mu]g/m\3\, while
those with LTW average exposure between 0.1-0.2 [mu]g/m\3\ showed a
marked increase in overall prevalence of sensitization (9.8 percent)
and CBD (7.3 percent). Prevalence of sensitization and CBD also
increased with cumulative exposure.
    OSHA's proportional hazards analysis of the Cullman dataset found
increasing risk of sensitization with both cumulative exposure and
average exposure. OSHA also found a positive relationship between risk
of CBD and cumulative exposure, but not between CBD and average
exposure. The Agency used the cumulative exposure model results to
estimate hazards ratios and risk of sensitization and CBD at the
current PEL of 2 [mu]g/m\3\ and each of the alternate PELs under
consideration: 1 [mu]g/m\3\, 0.5 [mu]g/m\3\, 0.2 [mu]g/m\3\, and 0.1
[mu]g/m\3\. To estimate risk of CBD from a working lifetime of
exposure, the Agency calculated the cumulative exposure associated with
45 years of exposure at each level, for total cumulative exposures of
90, 45, 22.5, 9, and 4.5 [mu]g/m\3\-years. The risk estimates for
sensitization and CBD ranged from 100-403 and 40-290 cases,
respectively, per 1000 workers exposed at the current PEL of 2 [mu]g/
m\3\. The risks are projected to be substantially lower for both
sensitization and CBD at 0.1 [mu]g/m\3\ and range from 7.2-35 cases per
1000 and 3.1-26 cases per 1000, respectively. In these ways, the
modeling results are similar to results observed from published studies
of the Reading, Tucson, and Cullman plants and the OSHA analysis of
sensitization and CBD prevalence within the Cullman plant.
    OSHA has a high level of confidence in the finding of substantial
risk of sensitization and CBD at the current PEL, and the Agency
believes that a standard requiring a combination of more stringent
controls on beryllium exposure will reduce workers' risk of both
sensitization and CBD. Programs that have reduced median levels to
below 0.1 [mu]g/m\3\, tightly controlled both respiratory and dermal
exposure, and incorporated stringent housekeeping measures have
substantially reduced risk of sensitization within the first years of
exposure. These conclusions are supported by the results of several
studies conducted in state-of-the-art facilities dealing with a variety
of production activities and physical forms of beryllium. In addition,
these conclusions are supported by OSHA's statistical analysis of a
dataset with highly detailed exposure and work history information on
several hundred beryllium workers. While there is uncertainty regarding
the precision of model-derived risk estimates, they provide further
evidence that there is substantial risk of sensitization and CBD
associated with exposure at the current PEL, and that this risk can be
substantially lessened by stringent measures to reduce workers'
beryllium exposure levels.
    Furthermore, OSHA believes that beryllium-exposed workers' risk of
lung cancer will be reduced by more stringent control of airborne
beryllium exposures. The risk estimates from NIOSH's recent lung cancer
study, described above, range from 33 to 140 excess lung cancers per
1000 workers exposed at the current PEL of 2 [mu]g/m\3\. The NIOSH risk
assessment's six best-fitting models each predict substantial
reductions in risk with reduced exposure, ranging from 3 to 19 excess
lung cancers per 1000 workers exposed at the proposed PEL of 0.1 [mu]g/
m\3\. The evidence of lung cancer risk from NIOSH's risk assessment
provides additional support for OSHA's preliminary conclusions
regarding the significance of risk to workers exposed to beryllium
levels at and below the current PEL. However, the lung cancer risks
require a sizable low dose extrapolation below beryllium exposure
levels experienced by workers in the NIOSH study. As a result, there is
a greater uncertainty in the lung cancer risk estimates and lesser
confidence in their significance of risk below the current PEL than
with beryllium sensitization and CBD. The preliminary conclusions with
regard to significance of risk are presented and further discussed in
section VIII of the preamble.

VII. Expert Peer Review of Health Effects and Preliminary Risk
Assessment

    In 2010, Eastern Research Group, Inc. (ERG), under contract to the
Occupational Safety and Health Administration (OSHA) ,\10\ conducted an
independent, scientific peer review of (1) a draft Preliminary
Beryllium Health Effects Evaluation (OSHA, 2010a), (2) a draft
Preliminary Beryllium Risk Assessment (OSHA, 2010b), and (3) two NIOSH
study manuscripts (Schubauer-Berigan et al., 2011 and 2011a). This
section of the preamble describes the review process and summarizes
peer reviewers' comments and OSHA's responses.
---------------------------------------------------------------------------

    \10\ Task Order No. DOLQ59622303, Contract No. GS10F0125P, with
a period of performance from May, 2010 through December, 2010.
---------------------------------------------------------------------------

    ERG conducted a search for nationally recognized experts in the
areas of occupational epidemiology, occupational medicine, toxicology,
immunology, industrial hygiene/exposure assessment, and risk
assessment/biostatistics as requested by OSHA. ERG sought experts
familiar with beryllium health effects research and who had no conflict
of interest (COI) or apparent bias in performing the review. Interested
candidates submitted evidence of their qualifications and responded to
detailed COI questions. ERG also searched the Internet to determine
whether qualified candidates had made public statements or declared a
particular bias regarding beryllium regulation.
    From the pool of qualified candidates, ERG selected five experts to
conduct the review, based on:
    [cir] Their qualifications, including their degrees, years of
relevant experience, number of related peer-reviewed publications,
experience serving as a peer reviewer for OSHA or other government
organizations, and committee and association memberships related to the
review topic;
    [cir] Lack of any actual, potential, or perceived conflict of
interest; and
    [cir] The need to ensure that the panel collectively was
sufficiently broad and diverse to fairly represent the relevant
scientific and technical perspectives and fields of knowledge appropriate
to the review.
    OSHA reviewed the qualifications of the candidates proposed by ERG
to verify that they collectively represented the technical areas of
interest. ERG then contracted the following experts to perform the
review.

    (1) John Balmes, MD, Professor of Medicine, University of
California-San Francisco
    Expertise: pulmonary and occupational medicine, CBD,
occupational lung disease, epidemiology, occupational exposures,
medical surveillance.
    (2) Patrick Breysse, Ph.D., Professor, Johns Hopkins University
Bloomberg School of Public Health
    Expertise: industrial hygiene, occupational/environmental health
engineering, exposure monitoring/analysis, biomarkers, beryllium
exposure assessment
    (3) Terry Gordon, Ph.D., Professor, New York University School
of Medicine.
    Expertise: inhalation toxicology, pulmonary disease, beryllium
toxicity and carcinogenicity, CBD genetic susceptibility, mode of
action, animal models.
    (4) Milton Rossman, MD, Professor of Medicine, Hospital of the
University of Pennsylvania School of Medicine.
    Expertise: pulmonary and clinical medicine, immunology,
beryllium sensitization, BeLPT, clinical diagnosis for CBD.
    (5) Kyle Steenland, Ph.D., Professor, Emory University, Rollins
School of Public Health.
    Expertise: occupational epidemiology, biostatistics, risk and
exposure assessment, lung cancer, CBD, exposure-response models.

    Reviewers were provided with the Technical Charge and Instructions
(see ERG, 2010), a Request for Peer Review of NIOSH Manuscripts (see
ERG, 2010), the draft Preliminary OSHA Health Effects Evaluation (OSHA,
2010a), the draft Preliminary Beryllium Risk Assessment (OSHA, 2010b),
and access to relevant references. Each reviewer independently provided
comments on the Health Effects, Risk Assessment, and NIOSH documents. A
briefing call was held early in the review to ensure that reviewers
understood the peer review process. ERG organized the call and OSHA
representatives were available to respond to technical questions of
clarification. Reviewers were invited to submit any subsequent
questions of clarification.
    The written comments from each reviewer were received and organized
by ERG by charge questions. The unedited individual and reorganized
comments were submitted to OSHA and the reviewers in preparation for a
follow-up conference call. The conference call, organized and
facilitated by ERG, provided an opportunity for OSHA to clarify
individual reviewer's comments. After the call, reviewers were given
the opportunity to revise their written comments to include the
clarifications or additional information provided on the call. ERG
submitted the revised comments to OSHA organized by both individual
reviewer and by charge question. A final peer review report is
available in the docket (ERG, 2010). Section VII.A of this preamble
summarizes the comments received on the draft health effects document
and OSHA's responses to those comments. Section VII.B summarizes
comments received on the draft Preliminary Risk Assessment and the OSHA
response.

A. Peer Review of Draft Health Effects Evaluation

    The Technical Charge to peer reviewers posed general questions on
the draft health effects document as well as specific questions
pertaining to particle/chemical properties, kinetics and metabolism,
acute beryllium disease, development of beryllium sensitization and
CBD, genetic susceptibility, epidemiological studies of sensitization
and CBD, animal models of chronic beryllium disease, genotoxicity, lung
cancer epidemiological studies, animal cancer studies, other health
effects, and preliminary conclusions drawn by OSHA.
    OSHA asked the peer reviewers to generally comment on whether the
draft health effects evaluation included the important studies,
appropriately addressed their strengths and limitations, accurately
described the results, and drew scientifically sound conclusions.
Overall, the reviewers felt that the studies were described in
sufficient detail, the interpretations accurate, and the conclusions
reasonable. They agreed that the OSHA document covered the significant
health endpoints related to occupational beryllium exposure. However,
several reviewers requested that additional studies and other specific
information be included in various sections of the document and these
are discussed further below.
    The reviewers had similar suggestions to improve the section V.A of
this preamble on physical/chemical properties and section V.B on
kinetics/metabolism. Dr. Balmes requested that physical and chemical
characteristics of beryllium more clearly relate to development of
sensitization and progression to CBD. Dr. Gordon requested greater
consistency in the terminology used to describe particle
characteristics, sampling methodologies, and the particle deposition in
the respiratory tract. Dr. Breysse agreed and requested that the
respiratory deposition discussion be better related to the onset of
sensitization and CBD. Dr. Rossman suggested that the discussion of
particle/chemical characteristics might be better placed after section
V.D on the immunobiology of sensitization and CBD.
    OSHA made a number of revisions to sections V.A and V.B to address
the peer review comments above. Terminology used to describe particle
characteristics in various studies was modified to be more consistent
and better reflect the authors' intent in the published research
articles. Section V.B.1 on respiratory kinetics of inhaled beryllium
was modified to more clearly describe particle deposition in the
different regions of the respiratory tract and their influence on CBD.
At the recommendation of Dr. Gordon, a confusing figure was removed
since it did not portray particle deposition in a clear manner. Rather
than relocate the entire discussion of particle/chemical
characteristics, a new section V.B.5 was added to specifically address
the influence of beryllium particle characteristics and chemical form
on the development of sensitization and CBD. Other section areas were
shortened to remove information that was not necessarily relevant to
the overall disease process. Statements were added on the effect of
pre-existing diseases and smoking on beryllium clearance from the lung.
It was made clear that the precise role of dermal exposure in beryllium
sensitization is not completely understood. These smaller changes were
made at the request of individual reviewers.
    There were a couple of comments from reviewers pertaining to acute
beryllium disease (ABD). Dr. Rossman commented that ABD did not make
the development of CBD more likely. He requested that the document
include a reference to the Van Ordstrand et al. (1943) article that
first reported ABD in the U.S. Dr. Balmes pointed out that
pathologists, rather than clinicians, interpret ABD pathology from lung
tissue biopsy. Dr. Gordon commented that ABD is of lesser importance
than CBD to the risk assessment and suggested that discussion of ABD be
moved later in the document.
    The Van Ordstrand reference was included in section V.C on acute
beryllium diseases and statements were modified to address the peer
review comments above. While OSHA agrees that ABD does not have a great
impact on the Agency risk findings, the Agency believes the current
organization does not create confusion on this point and decided not
to move the ABD section later in the document. A statement that ABD
is only relevant at exposures higher than the current PEL has been
added to section V.C. Other reviewers did not feel the ABD discussion
needed to be moved to a later section.
    Most reviewers found the description of the development and
pathogenesis of CBD in section V.D to be accurate and understandable.
Dr. Breysse felt the section could better delineate the steps in
disease development (e.g., development of beryllium sensitization, CBD
progression) and recommended the 2008 National Academy of Sciences
report as a model. He and Dr. Gordon felt the section overemphasized
the role of apoptosis in CBD development. Dr. Breysse and Dr. Balmes
recommended avoiding the phrase `subclinical' to describe sensitization
and asymptomatic CBD, preferring the term `early stage' as a more
appropriate description. Dr. Balmes requested clarification regarding
accumulation of inflammatory cells in the bronchoalveolar lavage (BAL)
fluid during CBD development. Dr. Rossman suggested some additional
description of beryllium binding with the HLA-class II receptor and
subsequent interaction with the na[iuml]ve CD4\+\ T cells in the
development of sensitization.
    OSHA extensively reorganized section V.D to clearly delineate the
disease process in a more linear fashion starting with the formation of
beryllium antigen complex, its interaction with na[iuml]ve T-cells to
trigger CD4\+\ T-cell proliferation, and development of beryllium
sensitization. This is presented in section V.D.1. A figure has been
added that schematically presents this process in its entirety and the
steps at which dermal exposure and genetic factors are believed to
influence disease development (Figure 2 in section V.D). Section V.D.2
describes how subsequent inhalation and the persistent residual
presence of beryllium in the lung leads to CD4\+\ T cell
differentiation, cytokine production, accumulation of inflammatory
cells in the alveolar region, granuloma formation, and progression of
CBD. The section was modified to present apoptosis as only one of the
plausible mechanisms for development/progression of CBD. The `early
stage' terminology was adopted and the role of inflammatory cells in
BAL was clarified.
    While peer reviewers felt genetic susceptibility was adequately
characterized, Dr. Rossman, Dr. Gordon, and Dr. Breysse suggested that
additional study data be discussed to provide more depth on the
subject, particularly the role genetic polymorphisms in providing a
negatively charged HLA protein binding site for the positively charged
beryllium ion. Section V.D.3 on genetic susceptibility now includes
more information on the importance of gene-environment interaction in
the development of CBD in low-exposed workers. The section expands on
HLA-DPB1 alleles that influence beryllium-hapten binding and its impact
on CBD risk.
    All reviewers found the definition of CBD to be clear and
understandable. However, several reviewers commented on the document
discussion of the BeLPT which operationally defines beryllium
sensitization. Drs. Balmes and Rossman requested a more clear statement
that two abnormal blood BeLPT results were generally necessary to
confirm sensitization. Dr. Balmes and Dr. Breysse requested more
discussion of historical changes in the BeLPT method that have led to
improvement in test performance and reductions in interlaboratory
variability. These comments were addressed in an expanded document
section V.D.5.b on criteria for sensitization and CBD case definition
following development of the BeLPT.
    Reviewers made suggestions to improve presentation of the many
epidemiological studies of sensitization and CBD in the draft health
effects document. Dr. Breysse and Dr. Gordon recommended that common
weaknesses that apply to multiple studies be more rigorously discussed.
Dr. Gordon requested that the discussion of the Beryllium Case Registry
be modified to clarify the case inclusion criteria. Most reviewers
called for the addition of tables to assist in summarizing the
epidemiological study information.
    A paragraph has been added near the beginning of section V.D.5 that
identifies the common challenges to interpreting the epidemiological
evidence that supports the occurrence of sensitization and CBD at
occupational beryllium exposures below the current PEL. These include
studies with small numbers of subjects and CBD cases, potential
exposure misclassification resulting from lack of personal and short-
term exposure data prior to the late 1990s, and uncertain dermal
contribution among other issues. Table A.1 summarizing the key
sensitization and CBD epidemiological studies was added to this
preamble in appendix A of section V. Subsection V.D.5.a on studies
conducted prior to the BeLPT has been reorganized to more clearly
present the need for the Registry prior to listing the inclusion
criteria.
    Several reviewers requested that the draft health effects document
discuss additional occupational studies on sensitization and CBD. Dr.
Balmes suggested including Bailey et al. (2010) on reduction in
sensitization at a beryllium production plant and Arjomandi et al.
(2010) on CBD among workers in a nuclear weapons facility. Dr. Breysse
recommended adding a brief discussion of Taiwo et al. (2008) on
sensitization in aluminum smelter workers. Dr. Gordon and Dr. Rossman
suggested mention of Curtis, (1951) on cutaneous hypersensitivity to
beryllium as important for the role of dermal exposure. Dr. Rossman
also provided a reference to a number of other sensitization and CBD
articles of historical significance.
    The above studies have been incorporated in several subsections of
V.D.5 on human epidemiological evidence. The 1951 Curtis study is
mentioned in the introduction to section V.D.5 as evidence of
sensitization from dermal exposure. The Bailey et al. (2010) study is
discussed in subsection V.D.5.d on beryllium metal processing and alloy
production. The Arjomandi et al. (2010) study is discussed subsection
V.D.5.h on nuclear weapons facilities and cleanup of former facilities.
The Taiwo et al. (2008) study is discussed in subsection V.D.5.i on
aluminum smelting. The other historical studies of historical
significance are referenced in subsection V.D.5.a on studies conducted
prior to the BeLPT.
    Dr. Gordon suggested that the draft health effects document make
clear that limitations in study design and lack of an appropriate model
limited extrapolation of animal findings to the human immune-based
respiratory disease. Dr. Rossman also remarked on the lack of a good
animal model that consistently demonstrates a specific cell-mediated
immune response to beryllium. Section V.D.6 was modified to include a
statement that lack of a dependable animal model combined with studies
that used single doses, few animals or abbreviated observation periods
have limited the utility of the data. Table A.2 was added that
summarizes important information on key animal studies of beryllium-
induced immune response and lung inflammation.
    In general, peer reviewers considered the preliminary conclusions
with regard to sensitization and CBD to be reasonable and well
presented in the draft health effects evaluation. All reviewers agreed
that the scientific evidence supports sensitization as a necessary
condition and an early endpoint in the development of CBD. The peer
reviewers did not consider the presented evidence to convincingly
show lung burden to be an important dose metric. Dr. Gordon explained
that some animal studies in dogs have indicated that lung dose does
influence granuloma formation but the importance of dose relative
to genetic susceptibility, and physical/chemical form is
unclear. He suggested the document indicate that many factors,
including lung burden, affect the pulmonary tissue response to
beryllium particles in the workplace.
    There were other suggested improvements to the preliminary
conclusion section of the draft document. Dr. Breysse felt that
presenting the range of observed prevalence from occupational studies
would help support the Agency findings. He also recommended that the
preliminary conclusions make clear that CBD is a very complex disease
and certain steps involved in the onset and progression are not yet
clearly understood. Dr. Rossman pointed out that a report from Mroz et
al. (2009) updated information on the rate at which beryllium
sensitized individuals progress to CBD.
    A statement has been added to section V.D.7 on the preliminary
sensitization and CBD conclusions to indicate that all facets of
development and progression of sensitization and CBD are not fully
understood. Study references and prevalence ranges were provided to
support the conclusion that epidemiological evidence demonstrates that
sensitization and CBD occur from present-day exposures below OSHA's
PEL. Statements were modified to indicate animal studies provide
important insights into the roles of chemical form, genetic
susceptibility, and residual lung burden in the development of
beryllium lung disease. Updated information on rate of progression from
sensitization to CBD was also included.
    Reviewers made suggestions to improve presentation of the
epidemiological studies of lung cancer that were similar to their
comments on the CBD studies. Dr. Steenland requested that a table
summarizing the lung cancer studies be added. He also recommended that
more emphasis be placed on the SMR results from the Ward et al. (1992)
study. Dr. Balmes felt that more detail was presented on the animal
cancer studies than necessary to convey the relevant message. All
reviewers thought that the Schubauer-Berigan et al. (2010) cohort
mortality study that addressed some of the shortcomings of earlier lung
cancer mortality studies should be discussed in the health effects
document.
    The recent Schubauer-Berigan et al. (2010) study conducted by the
NIOSH Division of Surveillance, Hazard Evaluations, and Field Studies
is now described and discussed in section V.E.2 on human epidemiology
studies. Table A.3 summarizing the range of exposure measurements,
study strengths and limitations, and other key lung cancer
epidemiological study information was added to the health effects
preamble. Section V.E.3 on the animal cancer studies already contained
several tables that present study data so OSHA decided a summary table
was not needed in this section.
    Reviewers were asked two questions regarding the OSHA preliminary
conclusions on beryllium-induced lung cancer: was the inflammation
mechanism presented in the lung cancer section reasonable; and were
there other mechanisms or modes of action to be considered? All
reviewers agreed that inflammation was a reasonable mechanistic
presentation as outlined in the document. Dr. Gordon requested OSHA
clarify that inflammation may not be the sole mechanism for
carcinogenicity. OSHA inserted statements in section V.E.5 on the
preliminary lung cancer conclusions clarifying that tumorigenesis
secondary to inflammation is a reasonable mechanism of action but other
plausible mechanisms independent of inflammation may also contribute to
the lung cancer associated with beryllium exposure.
    There were a few comments from reviewers on health effects other
than sensitization/CBD and lung cancer in the draft document. Dr.
Balmes requested that the term "beryllium poisoning" not be used when
referring to the hepatic effects of beryllium. He also offered language
to clarify that the cardiovascular mortality among beryllium production
workers in the Ward study cohort was probably due to ischemic heart
disease and not the result of impaired lung function. Dr. Gordon
requested removal of references to hepatic studies from in vitro and
intravenous administration done at very high dose levels of little
relevance to the occupational exposures of interest to OSHA. These
changes were made to section V.F on other health effects.

B. Peer Review of the Draft Preliminary Risk Assessment

    The Technical Charge to peer reviewers for review of the draft
preliminary risk assessment was to ensure OSHA selected appropriate
study data, assessed the data in a scientifically credible manner, and
clearly explained its analysis. Specific charge questions were posed
regarding choice of data sets, risk models, and exposure metrics; the
role of dermal exposure and dermal protection; construction of the job
exposure matrix; characterization of the risk estimates and their
uncertainties; and whether a quantitative assessment of lung cancer
risk, in addition to sensitization and CBD, was warranted.
    Overall, the peer reviewers were highly supportive of the Agency's
approach and major conclusions. They offered valuable suggestions for
revisions and additional analysis to improve the clarity and certain
technical aspects of the risk assessment. These suggestions and the
steps taken by OSHA to address them are summarized here. A final peer
review report (ERG, 2010c) and a risk assessment background document
(OSHA, 2014a) are available in the docket.
    OSHA asked peer reviewers a series of questions regarding its
selection of surveys from a beryllium ceramics facility, a beryllium
machining facility, and a beryllium alloy processing facility as the
critical studies that form the basis of the preliminary risk
assessment. Research showed that these workplaces had well
characterized and relatively low beryllium exposures and underwent
plant-wide screenings for sensitization and CBD before and after
implementation of exposure controls. The reviewers were requested to
comment on whether the study discussions were clearly presented,
whether the role of dermal exposure and dermal protection were
adequately addressed, and whether the preliminary conclusions regarding
the observed exposure-related prevalence and reduction in risk were
reasonable and scientifically credible. They were also asked to
identify other studies that should be reviewed as part of the
sensitization/CBD risk assessment.
    Every peer reviewer felt the key studies were appropriate and their
selection clearly explained in the document. Every peer reviewer
regarded the preliminary conclusions from the OSHA review of these
studies to be reasonable and scientifically sound. This conclusion
stated that substantial risk of sensitization and CBD were observed in
facilities where the highest exposed processes had median full-shift
beryllium exposures around 0.2 [mu]g/m\3\ or higher and that the
greatest reduction in risk was achieved when exposures for all
processes were lowered to 0.1 [mu]g/m\3\ or below.
    The reviewers suggested that three additional studies be added to
the risk assessment review of the epidemiological literature.
Dr. Balmes felt the document would be strengthened by
including the Bailey et al. (2010) investigation of sensitization
in a population of workers at the beryllium metal, alloy,
and oxide production plant in Elmore, OH and the Arjomandi et al.
(2010) publication on a group of 50 sensitized workers from a nuclear
plant. Dr. Breysse suggested the study by Taiwo et al. (2008) on
sensitization among workers in four aluminum smelters be considered.
    A new subsection VI.A.3 was added to the preliminary risk
assessment that describes the changes in beryllium exposure
measurements, prevalence of sensitization and CBD, and implementation
of exposure controls between 1992 and 2006 at the Elmore plant. This
subsection includes a discussion of the Bailey et al. study. A summary
of the Taiwo et al. (2008) study was added as subsection VI.A.5. A
discussion of the Arjomandi et al. (2010) study was added in subsection
VI.B as evidence that sensitized workers with primarily low beryllium
exposure go on to develop CBD. However, the low rates of CBD among this
group of sensitized workers also suggest that low beryllium exposure
may reduce CBD risk when compared to worker populations with higher
exposure levels.
    While the majority of reviewers stated that OSHA adequately
addressed the role of dermal exposure in sensitization and the
importance of dermal protection for workers, a few had additional
suggestions for OSHA's discussion. Dr. Breysse and Dr. Gordon pointed
out that because the beryllium exposure control programs featured steps
to reduce both skin contact and inhalation, it was difficult to
distinguish between the effects of reducing airborne and dermal
exposure. A statement was added to subsection VI.B that concurrent
implementation of respirator use, dermal protection and engineering
changes made it difficult to attribute reduced risk to any single
control measure. Since the Cullman plant did not require glove use,
OSHA believes it to be the best data set available for evaluating the
effects of airborne exposure control on risk of sensitization.
    Dr. Breysse requested additional discussion of the role of
respiratory protection in achieving reduction in risk. Dr. Gordon
suggested some additional clarification regarding mean and median
exposure measures. Additional information on respiratory programs and
exposure measures (e.g., median, arithmetic and geometric means), where
available, were presented for each of the studies discussed in
subsection VI.A.
    The peer reviewers generally agreed that it was reasonable to
conclude that community-acquired CBD (CA-CBD) resulted from low
beryllium exposures. Drs. Breysse, Balmes and others noted that higher
short-term excursions could not be ruled out. Dr. Gordon suggested that
genetic susceptibility may have a role in cases of CA-CBD. Dr. Rossman
raised the possibility that some CA-CBD cases could occur from contact
with beryllium workers. All these points were added to subsection VI.C.
    OSHA asked the peer reviewers to evaluate the choice of the
National Jewish Medical and Research Center (NJMRC) data set on the
Cullman, AL machinist population as a basis for exposure-response
analysis and the reliance on cumulative exposure as the basis for the
exposure-response analysis of sensitization and CBD. All peer reviewers
indicated that the choice of the NJMRC data set for exposure-response
analysis was clearly explained and reasonable and that they knew of no
better data set for the analysis. Dr. Rossman commented that the NJMRC
data set was an excellent source of exposures to different levels of
beryllium and testing and evaluation of the workers. Dr. Steenland and
Dr. Gordon suggested that the results from the OSHA analysis of the
NJMRC data be compared with the available data from the studies of
other beryllium facilities discussed in the epidemiological literature
analysis. While a rigorous quantitative comparison (e.g., meta
analysis) is difficult due to differences in the study designs and data
types available for each study, subsection VI.E.4 compares the results
of OSHA's prevalence analysis from the Cullman data with results from
studies of the Tucson and Reading facilities.
    OSHA asked the peer reviewers to evaluate methods used to construct
the job exposure matrix (JEM) and to estimate beryllium exposure for
each worker in the NJMRC data set. The JEM procedure was briefly
summarized in the review document and described in detail as part of a
risk assessment technical background document made available to the
reviewers (OSHA, 2014a). Dr. Balmes felt that a more thorough
discussion of the JEM would strengthen the preamble document. Dr.
Gordon requested information about values assigned exposures below the
limit of detection. Dr. Steenland requested that both the preamble and
technical background document contain additional information on aspects
of the JEM construction such as the job categories, job-specific
exposure values, how jobs were grouped, and how non-machining jobs were
handled in the JEM. He suggested the entire JEM be included in the
technical background document. OSHA greatly expanded subsection VI.E.2
on air sampling and JEM to include more detailed discussion of the JEM
construction. Exposure values for machining and non-machining job
titles were provided in Tables VI-4 and VI-5. The procedures and
rationale for grouping job-specific measurements into four time periods
was explained. Jobs were not grouped in the JEM; rather, individual
exposure estimates were created for each job in the work history data
set. The technical background document further clarifies the JEM
construction and the full JEM is included as an appendix to the revised
background document (OSHA, 2014a). Subsection VI.E.3 on worker exposure
reconstruction contains further detail about the work histories.
    Peer reviewers fully supported OSHA's choice of the cumulative
exposure metric to estimate risk of CBD from the NJMRC data set. As
explained by Dr. Steenland, "cumulative exposure is often the choice
for many chronic diseases as opposed to average or highest exposure."
He pointed out that the cumulative exposure metric also fit the CBD
data better than other metrics. The reviewers generally felt that
short-term peak exposure was probably the measure of airborne exposure
most relevant to risk of beryllium sensitization. However, peer
reviewers agreed that data required to capture workers' short-term peak
exposures and to relate the peak exposure levels to sensitization were
not available. Dr. Breysse explained that "short-term (hrs to minutes)
peak exposures may be important to sensitization risk, while long term
averages are more important for CBD risk. Unfortunately data for short-
term peak exposures may not exist." Dr. Steenland explained that of
the available metrics "cumulative exposure fits the sensitization data
better than the two alternatives, and hence is the best metric."
Statements were added to subsection VI.E.3 to indicate that while
short-term exposures may be highly relevant to risk of sensitization,
the individual peak exposures leading up to onset of sensitization was
not able to be determined in the NJRMC Cullman study.
    Peer reviewers found the methods used in the statistical exposure-
response analysis to be clearly described. With the exception of Dr.
Steenland, reviewers believed that a detailed critique of the
statistical approach was beyond their level of expertise.
Dr. Steenland supported OSHA's overall approach to the risk
modeling and recommended additional analyses to explore the sensitivity of
OSHA's results to alternate choices and to test the validity of aspects of
the analysis. Dr. Steenland recommended that the logistic
regression used by OSHA as a preliminary first analysis be
dropped as an inappropriate model for a situation where it
is important to account for changing exposures and case onset over
time. Instead, he suggested a sensitivity analysis in which exposure-
response coefficients generated using a traditional Cox proportionate
hazards model be compared to the discrete time Cox model analog (i.e.,
complementary log-log Cox model) used by OSHA. The sensitivity analysis
would facilitate examination of the proportional hazard assumption
implied by the use of these models. Dr. Steenland advocated that OSHA
include a table that displayed the mean number of BeLPT tests for the
study population in order to address whether the number of
sensitization tests introduced a potential bias. He inquired about the
possibility of determining a sensitization incidence rate using
cumulative or average exposure. Dr. Steenland suggested that the model
control for additional potential confounders, such as age, smoking
status, race and gender. He wanted a more complete explanation of the
model constant for the year of diagnosis in Tables VI-9 through VI-12
to be included in the preamble as it was in the technical background
document. Dr. Steenland recommended a sensitivity analysis that
excludes the highest 5 to 10 percent of cumulative exposures which
might address potential model uncertainty at the high end exposures. He
requested that the results of statistical tests for non-linearity be
included and confidence intervals for the risk estimates in Tables VI-
17 and VI-18 be determined.
    Many of Dr. Steenland's comments were addressed in subsection VI.F
on the statistical modeling. The logistic regression analysis was
removed from the section. A sensitivity analysis using the standard Cox
model that treats survival time as continuous rather than discrete was
added to the risk assessment background document and results were
described in subsection VI.F. The interaction between exposure and
follow-up time was not significant in the models suggesting that the
proportional hazard assumption should not be rejected. The model
coefficients using the standard Cox model were similar to model
coefficients for the discrete model. Given this, OSHA did not feel it
necessary to further estimate risks using the continuous Cox model at
specific exposure levels.
    A table of the mean number of BeLPT tests across the study
population was added to the risk assessment background document.
Subsection VI.F describes the table results and its impact on the
statistical modeling. Smoking status and age were included in the
discrete Cox proportional hazards model and not found to be significant
predictors of beryllium sensitization. However, the available study
population composition did not allow a confounder analysis of race and
gender. OSHA chose not to include a detailed explanation of the model
constant for the year of diagnosis in the preamble section. OSHA agrees
with Dr. Steenland that the risk assessment background document
adequately describes the model terms. For that reason, OSHA prefers
that the risk assessment preamble focus on the results and major points
of the analysis and refer the reader to the more technical background
document for an explanation of model parameters. The linearity
assumption was assessed using a fractional polynomial approach. The
best fitting polynomials did not fit significantly better than the
linear model. The details of the analysis were included in the risk
assessment background document. Tables VI-17 and VI-18 now include the
upper 95 percent confidence limits on the model-predicted cases of
sensitization and CBD for the current and alternative PELs.
    Most peer reviewers felt the major uncertainties of the risk
assessment were clearly and adequately discussed in the documents they
reviewed. Dr. Breysse requested that the risk assessment cover
potential underestimation of risk from exposure misclassification bias.
He requested further discussion of the degree to which the risk
estimates from the Cullman machining plant could be extrapolated to
workplaces that use other physical (e.g., particle size) and chemical
forms of beryllium. He went on to question the strength of evidence
that insoluble forms of beryllium cause CBD. Dr. Breysse also suggested
that the assumptions used in the risk modeling be consolidated and more
clearly presented. Dr. Steenland felt that there was potential
underestimation of CBD risk resulting from exclusion of former workers
and case status of current workers after employment.
    Discussion of these uncertainties was added in the final paragraphs
of section VI.F. The section was modified to more clearly identify
assumptions with regard to the risk modeling such as an assumed
linearity in exposure-response and cumulative dose equivalency when
extrapolating risks over a 45-year working lifetime. Section VI.F
recognizes the uncertainties in risk that can result from
reconstructing individual exposures with very limited sampling data
prior to 1994. The potential exposure misclassification can limit the
strength of exposure-response relationships and result in the
underestimation of risk. A more technical discussion of modeling
assumptions and exposure measurement error are provided in the risk
assessment background document. Section VI.F points out that the NJMRC
data set does not capture CBD that occurred among workers who retired
or left the Cullman plant. This and the short follow-up time is a
source of uncertainty that likely leads to underestimation of risk. The
section indicates that it is not unreasonable to expect the risk
estimates to generally reflect onset of sensitization and CBD from
exposure to beryllium forms that are relatively insoluble and enriched
with respirable particles as encountered at the Cullman machining
plant. Additional uncertainty is introduced when extrapolating the risk
estimates to beryllium compounds of vastly different solubility and
particle characteristics. OSHA does not agree with the comment
suggesting that the association between CBD and insoluble forms of
beryllium is weak. The principle sources of beryllium encountered at
the Cullman machining plant, the Reading copper beryllium processing
plant and the Tucson ceramics plant where excessive CBD was observed
are insoluble forms of beryllium, such as beryllium metal, beryllium
alloy, and beryllium oxide.
    Finally, OSHA asked the peer reviewers to evaluate its treatment of
lung cancer in the earlier draft preliminary risk assessment (OSHA,
2010b). When that document was prepared, OSHA had elected not to
conduct a lung cancer risk assessment. The Agency believed that the
exposure-response data available to conduct a lung cancer risk
assessment from a Sanderson et al. study of a Reading, PA beryllium
plant by was highly problematic. The Sanderson study primarily involved
workers with extremely high and short-term exposures above airborne
exposure levels of interest to OSHA (2 [mu]g/m\3\ and below).
    Just prior to arranging the peer review, a NIOSH study was
published by Schubauer-Berigan et al. updating the Reading, PA cohort
studied by Sanderson et al. and adding cohorts from two additional
plants in Elmore, OH and Hazleton, PA (Schubauer-Berigan, 2011).
At OSHA's request, the peer reviewers reviewed this study to
determine whether it could provide a better basis for lung
cancer risk analysis than the Sanderson et al. study. The reviewers
found that the NIOSH update addressed the major concerns OSHA had
expressed about the Sanderson study. In particular, they pointed out
that workers in the Elmore and Hazleton cohorts had longer tenure at
the plants and experienced lower exposures than those at the Reading,
PA plant. Dr. Steenland recommended that "OSHA consider the new NIOSH
data and develop risk estimates for lung cancer as well as
sensitization and CBD." Dr. Breysse believed that the NIOSH data
"suggest that a risk assessment for lung cancer should be conducted by
OSHA and the results be compared to the CBD/sensitization risk
assessment before recommending an appropriate exposure concentration."
While acknowledging the improvements in the quality of the data, other
reviewers were more restrained in their support for quantitative
estimates of lung cancer risk. Dr. Gordon stated that despite
improvements, there was "still uncertainty associated with the paucity
of data below the current PEL of 2 [mu]g/m\3\." Dr. Rossman noted that
the NIOSH study "did not address the problem of the uncertainty of the
mechanism of beryllium carcinogenicity." He felt that the updated
NIOSH lung cancer mortality data "should not change the Agency's
rationale for choosing to establish its risk findings for the proposed
rule on its analysis for beryllium sensitization and CBD." Dr. Balmes
agreed that "the agency will be on firmer ground by focusing on
sensitization and CBD."
    The preliminary risk assessment preamble subsection VI.G on lung
cancer includes a discussion of the quantitative lung cancer risk
assessment published by NIOSH researchers in 2010 (Schubauer-Berigan,
2011). The discussion describes the lower exposure levels, longer
tenure, fewer short-term workers and additional years of observation
that make the data more suitable for risk assessment. NIOSH relied on
several modeling approaches to show that lung cancer risk was
significantly related to both mean and cumulative beryllium exposure.
Subsection VI.G provides the excess lifetime lung cancer risks
predicted from several best-fitting NIOSH models at beryllium exposures
of interest to OSHA (Table VI-20). Using the piecewise log-linear
proportional hazards model favored by NIOSH, there is a projected drop
in excess lifetime lung cancer risks from approximately 61 cases per
1000 exposed workers at the current PEL of 2.0 [mu]g/m\3\ to
approximately 6 cases per 1000 at the proposed PEL of 0.2 [mu]g/m\3\.
Subsection VI.H on preliminary conclusions indicates that these
projections support a reduced risk of lung cancer from more stringent
control of beryllium exposures but that the lung cancer risk estimates
are more uncertain than those for sensitization and CBD.

VIII. Significance of Risk

    To promulgate a standard that regulates workplace exposure to toxic
materials or harmful physical agents, OSHA must first determine that
the standard reduces a "significant risk" of "material impairment."
The first part of this requirement, "significant risk," refers to the
likelihood of harm, whereas the second part, "material impairment,"
refers to the severity of the consequences of exposure.
    The Agency's burden to establish significant risk is based on the
requirements of the OSH Act (29 U.S.C. 651 et seq). Section 3(8) of the
Act requires that workplace safety and health standards be "reasonably
necessary or appropriate to provide safe or healthful employment" (29
U.S.C. 652(8)). The Supreme Court, in the Benzene decision, interpreted
section 3(8) to mean that "before promulgating any standard, the
Secretary must make a finding that the workplaces in question are not
safe" (Industrial Union Department, AFL-CIO v. American Petroleum
Institute, 448 U.S. 607, 642 (1980) (plurality opinion)). Examining
section 3(8) more closely, the Court described OSHA's obligation to
demonstrate significant risk:

    "Safe" is not the equivalent of "risk-free." A workplace
can hardly be considered "unsafe" unless it threatens the workers
with a significant risk of harm. Therefore, before the Secretary can
promulgate any permanent health or safety standard, he must make a
threshold finding that the place of employment is unsafe in the
sense that significant risks are present and can be eliminated or
lessened by a change in practices (Id).

    As the Court made clear, the Agency has considerable latitude in
defining significant risk and in determining the significance of any
particular risk. The Court did not specify a means to distinguish
significant from insignificant risks, but rather instructed OSHA to
develop a reasonable approach to making a significant risk
determination. The Court stated that "it is the Agency's
responsibility to determine in the first instance what it considers to
be a 'significant' risk," (448 U.S. at 655) and it did not express
"any opinion on the... difficult question of what factual
determinations would warrant a conclusion that significant risks are
present which make promulgation of a new standard reasonably necessary
or appropriate" (448 U.S. at 659). The Court also stated that, while
OSHA's significant risk determination must be supported by substantial
evidence, the Agency "is not required to support the finding that a
significant risk exists with anything approaching scientific
certainty" (448 U.S. at 656). Furthermore:

    A reviewing court [is] to give OSHA some leeway where its
findings must be made on the frontiers of scientific knowledge...
[T]he Agency is free to use conservative assumptions in
interpreting the data with respect to carcinogens, risking error on
the side of overprotection rather than underprotection [so long as
such assumptions are based on] a body of reputable scientific
thought (448 U.S. at 656).

Thus, to make the significance of risk determination for a new or
proposed standard, OSHA uses the best available scientific evidence to
identify material health impairments associated with potentially
hazardous occupational exposures and to evaluate exposed workers' risk
of these impairments.

    The OSH Act also requires that the Agency make a finding that the
toxic material or harmful physical agent at issue causes material
impairment to worker health. In that regard, the Act directs the
Secretary of Labor to set standards based on the available evidence
where no employee, over his/her working life time, will suffer from
material impairment of health or functional capacity, even if such
employee has regular exposure to the hazard, to the exent feasible (29
U.S.C. 655(b)(5)).
    As with significant risk, what constitutes material impairment in
any given case is a policy determination for which OSHA is given
substantial leeway. "OSHA is not required to state with scientific
certainty or precision the exact point at which each type of [harm]
becomes a material impairment" (AFL-CIO v. OSHA, 965 F.2d 962, 975
(11th Cir. 1992)). Courts have also noted that OSHA should consider all
forms and degrees of material impairment--not just death or serious
physical harm--and that OSHA may act with a "pronounced bias towards
worker safety" (Id; Bldg & Constr. Trades Dep't v. Brock, 838 F.2d
1258, 1266 (D.C. Cir. 1988)). OSHA's long-standing policy is to
consider 45 years as a "working life," over which it must evaluate
material impairment and risk.
    In formulating this proposed beryllium standard, OSHA has reviewed
the best available evidence pertaining to the adverse health effects of
occupational beryllium exposure, including lung cancer and chronic
beryllium disease (CBD), and has evaluated the risk of these effects
from exposures allowed under the current standard as well as the
expected impact of the proposed standard on risk. Based on its review
of extensive epidemiological and experimental research, OSHA has
preliminarily determined that long-term exposure at the current
Permissible Exposure Limit (PEL) would pose a significant risk of
material impairment to workers' health, and that adoption of the new
PEL and other provisions of the proposed rule will substantially reduce
this risk.

A. Material Impairment of Health

    In this preamble at section V, Health Effects, OSHA reviewed the
scientific evidence linking occupational beryllium exposure to a
variety of adverse health effects, including CBD and lung cancer. Based
on this review, OSHA preliminarily concludes that beryllium exposure
causes these effects. The Agency's preliminary conclusion was strongly
supported by a panel of independent peer reviewers, as discussed in
section VII.
    Here, OSHA discusses its preliminary conclusion that CBD and lung
cancer constitute material impairments of health, and briefly reviews
other adverse health effects that can result from beryllium exposure.
Based on this preliminary conclusion and on the scientific evidence
linking beryllium exposure to both CBD and lung cancer, OSHA concludes
that occupational exposure to beryllium causes "material impairment of
health or functional capacity" within the meaning of the OSH Act.
1. Chronic Beryllium Disease
    CBD is a respiratory disease in which the body's immune system
reacts to the presence of beryllium in the lung, causing a progression
of pathological changes including chronic inflammation and tissue
scarring. CBD can also impair other organs such as the liver, skin,
spleen, and kidneys and cause adverse health effects such as granulomas
of the skin and lymph nodes and cor pulmonale (i.e., enlargement of the
heart) (Conradi et al., 1971; ACCP, 1965; Kriebel et al., 1988a and b).
In early, asymptomatic stages of CBD, small granulomatous lesions and
mild inflammation occur in the lungs. Early stage CBD among some
workers has been observed to progress to more serious disease even
after the worker is removed from exposure (Mroz, 2009), probably
because common forms of beryllium have slow clearance rates and can
remain in the lung for years after exposure. Sood et al. has reported
that cessation of exposure can sometimes have beneficial effects on
lung function (Sood et al., 2004). However, this was based on a small
study of six patients with CBD, and more research is needed to better
determine the relationship between exposure duration and disease
progression. In general, progression of CBD from early to late stages
is understood to vary widely, responding differently to exposure
cessation and treatment for different individuals (Sood, 2009; Mroz,
2009).
    Over time, the granulomas can spread and lead to lung fibrosis
(scarring) and moderate to severe loss of pulmonary function, with
symptoms including a persistent dry cough and shortness of breath
(Saber and Dweik, 2000). Fatigue, night sweats, chest and joint pain,
clubbing of fingers (due to impaired oxygen exchange), loss of
appetite, and unexplained weight loss may occur as the disease
progresses. Corticosteroid therapy, in workers whose beryllium exposure
has ceased, has been shown to control inflammation, ease symptoms
(e.g., difficulty breathing, fever, cough, and weight loss) and in some
cases prevent the development of fibrosis (Marchand-Adam et al., 2008).
Thus early treatment can lead to CBD regression in some patients,
although there is no cure (Sood, 2004). Other patients have shown
short-term improvements from corticosteroid treatment, but then
developed serious fibrotic lesions (Marchand-Adam et al., 2008). Once
fibrosis has developed in the lungs, corticosteroid treatment cannot
reverse the damage (Sood, 2009). Persons with late-stage CBD experience
severe respiratory insufficiency and may require supplemental oxygen
(Rossman, 1991). Historically, late-stage CBD often ended in death
(NAS, 2008).
    While the use of steroid therapy has mitigated CBD mortality,
treatment with corticosteroids has side effects that need to be
measured against the possibility of progression of disease
(Trikudanathan and McMahon, 2008; Lipworth, 1999; Gibson et al., 1996;
Zaki et al., 1987). Adverse effects associated with long-term
corticosteroid use include, but are not limited to, increased risk of
opportunistic infections (Lionakis and Kontoyiannis, 2003;
Trikudanathan and McMahon, 2008); accelerated bone loss or osteoporosis
leading to increased risk of fractures or breaks (Hamida et al., 2011;
Lehouck et al., 2011; Silva et al., 2011; Sweiss et al., 2011;
Langhammer et al., 2009); psychiatric effects including depression,
sleep disturbances, and psychosis (Warrington and Bostwick, 2006;
Brown, 2009); adrenal suppression (Lipworth, 1999; Frauman, 1996);
ocular effects including cataracts, ocular hypertension, and glaucoma
(Ballonzolli and Bourchier, 2010; Trikudanathan and McMahon, 2008;
Lipworth, 1999); an increase in glucose intolerance (Trikudanathan and
McMahon, 2008); excessive weight gain (McDonough et al., 2008; Torres
and Nowson, 2007; Dallman et al., 2007; Wolf, 2002; Cheskin et al.,
1999); increased risk of atherosclerosis and other cardiovascular
syndromes (Franchimont et al., 2002); skin fragility (Lipworth, 1999);
and poor wound healing (de Silva and Fellows, 2010). Studies relating
the long-term effect of corticosteroid use for the treatment of CBD
need to be undertaken to evaluate the treatment's overall effectiveness
against the risk of adverse side effects from continued usage.
    OSHA considers late-stage CBD to be a material impairment of
health, as it involves permanent damage to the pulmonary system, causes
additional serious adverse health effects, can have adverse
occupational and social consequences, requires treatment associated
with severe and lasting side effects, and may in some cases be life-
threatening. Furthermore, OSHA believes that material impairment begins
prior to the development of symptoms of the disease.
    Although there are no symptoms associated with early-stage CBD,
during which small lesions and inflammation appear in the lungs, the
Agency has preliminarily concluded that the earliest stage of CBD is
material impairment of health. OSHA bases this conclusion on evidence
showing that early-stage CBD is a measurable change in the state of
health which, with and sometimes without continued exposure, can
progress to symptomatic disease. Thus, prevention of the earliest
stages of CBD will prevent development of more serious disease. The
OSHA Lead Standard established the Agency's position that a
'subclinical' health effect may be regarded as a material impairment of
health. In the preamble to that standard, the Agency said:

    OSHA believes that while incapacitating illness and death
represent one extreme of a spectrum of responses, other biological
effects such as metabolic or physiological changes are precursors or
sentinels of disease which should be prevented... Rather than
revealing beginnings of illness the standard must be selected to
prevent an earlier point of measurable change in the state of health
which is the first significant indicator of possibly more severe ill
health in the future. The basis for this decision is twofold--first,
pathophysiologic changes are early stages in the disease process
which would grow worse with continued exposure and which may include
early effects which even at early stages are irreversible, and
therefore represent material impairment themselves. Secondly,
prevention of pathophysiologic changes will prevent the onset of the
more serious, irreversible and debilitating manifestations of
disease.\11\ (43 FR 52952, 52954, November 14, 1978)

    \11\ Even if asymptomatic CBD were not itself a material
impairment of health, the D.C. Circuit upheld OSHA's authority to
regulate to prevent subclinical health effects as precursors to
disease in United Steelworkers of America, AFL-CIO v. Marshall, 647
F.2d 1189, 1252 (D.C. Cir. 1980), which reviewed the Lead standard.
Without deciding whether the early symptoms of disease were
themselves a material impairment, the court concluded that OSHA may
regulate subclinical effects if it can demonstrate on the basis of
substantial evidence that preventing subclinical effects would help
prevent the clinical phase of disease (Id.).

    Since the Lead rulemaking, OSHA has also found other non-
symptomatic health conditions to be material impairments of health. In
the Bloodborne Pathogens (BP) rulemaking, OSHA maintained that material
impairment includes not only workers with clinically "active"
hepatitis from the hepatitis B virus (HBV) but also includes
asymptomatic HBV "carriers" who remain infectious and are able to put
others at risk of serious disease through contact with body fluids
(e.g., blood, sexual contact) (56 FR 64004, December 6, 1991). OSHA
stated: "Becoming a carrier [of Hepatitis B] is a material impairment
of health even though the carrier may have no symptoms. This is because
the carrier will remain infectious, probably for the rest of his or her
life, and any person who is not immune to HBV who comes in contact with
the carrier's blood or certain other body fluids will be at risk of
becoming infected" (56 FR 64004, 64036).
    OSHA preliminarily finds that early-stage CBD is the type of
asymptomatic health effect the Agency determined to be a material
impairment of health in the lead standard. Early stage CBD involves
lung tissue inflammation without symptomatology that can worsen with--
or without--continued exposure. The lung pathology progresses over time
from a chronic inflammatory response to tissue scarring and fibrosis
accompanied by moderate to severe loss in pulmonary function. Early
stage CBD is clearly a precursor of advanced clinical disease,
prevention of which will prevent symptomatic disease. OSHA argued in
the Lead standard that such precursor effects should be considered
material health impairments in their own right, and that the Agency
should act to prevent them when it is feasible to do so. Therefore,
OSHA preliminarily finds all stages of CBD to be material impairments
of health.
2. Lung Cancer
    OSHA considers lung cancer, a frequently fatal disease, to be a
material impairment of health. OSHA's finding that inhaled beryllium
causes lung cancer is based on the best available epidemiological data,
reflects evidence from animal and mechanistic research, and is
consistent with the conclusions of other government and public health
organizations (see this preamble at section V, Health Effects). For
example, the International Agency for Research on Cancer (IARC),
National Toxicology Program (NTP), and American Conference of
Governmental Industrial Hygienists (ACGIH) have all classified
beryllium as a known human carcinogen (IARC, 2009).
    The Agency's epidemiological evidence comes from multiple studies
of U.S. beryllium workers (Sanderson et al., 2001a; Ward et al., 1992;
Wagoner et al., 1980; Mancuso et al., 1979). Most recently, a NIOSH
cohort study found significantly increased lung cancer mortality among
workers at seven beryllium processing facilities (Schubauer-Berigan et
al., 2011). The cohort was exposed, on average, to lower levels of
beryllium than those in most previous studies, had fewer short-term
workers, and had sufficient follow-up time to observe lung cancer in
the population. OSHA considers the Schubauer-Berigan study to be the
best available epidemiological evidence regarding the risk of lung
cancer from beryllium at exposure levels near the PEL.\12\
---------------------------------------------------------------------------

    \12\ The scientific peer review panel for OSHA's Preliminary
Risk Assessment agreed with the Agency that the Schubauer-Berigan
analysis improves upon the previously available data for lung cancer
risk assessment.
---------------------------------------------------------------------------

    Supporting evidence of beryllium carcinogenicity comes from various
animal studies as well as in vitro genotoxicity and other studies (EPA,
1998; ATSDR, 2002; Gordon and Bowser, 2003; NAS, 2008; Nickell-Brady et
al., 1994; NTP, 1999 and 2005; IARC, 1993 and 2009). Multiple
mechanisms may be involved in the carcinogenicity of beryllium, and
factors such as epigenetics, mitogenicity, reactive oxygen-mediated
indirect genotoxicity, and chronic inflammation may contribute to the
lung cancer associated with beryllium exposure, although the results of
studies testing the direct genotoxicity of beryllium are mixed (EPA
summary, 1998). While there is uncertainty regarding the exact
mechanism of carcinogenesis for beryllium, the overall weight of
evidence for the carcinogenicity of beryllium is strong. Therefore, the
Agency has preliminarily determined beryllium to be an occupational
carcinogen.
3. Other Impairments
    While OSHA has relied primarily on the relationship between
occupational beryllium exposure and CBD and lung cancer to demonstrate
the necessity of the standard, the Agency has also determined that
several other adverse health effects can result from exposure to
beryllium. Inhalation of high airborne concentrations of beryllium
(well above the 2 [mu]g/m\3\ OSHA PEL) can cause acute beryllium
disease, a severe (sometimes fatal), rapid-onset inflammation of the
lungs. Hepatic necrosis, damage to the heart and circulatory system,
chronic renal disease, mucosal irritation and ulceration, and urinary
tract cancer have also reportedly been associated with occupational
exposures well above the current PEL (see this preamble at section V,
Health Effects, subsection E, Epidemiological Studies, and subsection
F, Other Health Effects). These adverse systemic effects and acute
beryllium disease mostly occurred prior to the introduction of
occupational and environmental standards set in 1970-1972 (OSHA, 1971;
ACGIH, 1971; ANSI, 1970) and 1974 (EPA, 1974) and therefore are less
relevant today than in the past. Because they occur only rarely in
current-day occupational environments, they are not addressed in OSHA's
risk analysis or significance of risk determination.
    The Agency has also determined that beryllium sensitization, a
precursor which occurs before early stage CBD and is an essential step
for worker development of the disease, can result from exposure to
beryllium. The Agency takes no position at this time on whether
sensitization constitutes a material impairment of health, because it
was unnecessary to do so as part of this rulemaking. As discussed in
Section V, Health Effects, only sensitized individuals can develop CBD
(NAS, 2008). OSHA's risk assessment for sensitization informs the
Agency's understanding of what exposure control measures have been
successful in preventing sensitization, which in turn prevents
development of CBD. Therefore sensitization is considered in the next
section on significance of risk. In AFL-CIO v. Marshall, 617 F.2d 636,
654 n.83 (D.C. Cir. 1979) (Cotton Dust), the D.C. Circuit upheld OSHA's
authority to regulate to prevent precursors to a material impairment of
health without deciding whether the precursors themselves constituted
material impairment of health.

B. Significance of Risk and Risk Reduction

    To evaluate the significance of the health risks that result from
exposure to hazardous chemical agents, OSHA relies on the best
available epidemiological, toxicological, and experimental evidence.
The Agency uses both qualitative and quantitative methods to
characterize the risk of disease resulting from workers' exposure to a
given hazard over a working lifetime at levels of exposure reflecting
compliance with current standards and compliance with the new standards
being proposed.
    As discussed above, the Agency's characterization of risk is guided
in part by the Benzene decision. In Benzene, the Court broadly
describes the range of risks OSHA might determine to be significant:

    It is the Agency's responsibility to determine in the first
instance what it considers to be a "significant" risk. Some risks
are plainly acceptable and others are plainly unacceptable. If, for
example, the odds are one in a billion that a person will die from
cancer by taking a drink of chlorinated water, the risk clearly
could not be considered significant. On the other hand, if the odds
are one in a thousand that regular inhalation of gasoline vapors
that are 2 percent benzene will be fatal, a reasonable person might
well consider the risk significant and take the appropriate steps to
decrease or eliminate it (Benzene, 448 U.S. at 655).

The Court further stated, "The requirement that a 'significant' risk
be identified is not a mathematical straitjacket... Although the
Agency has no duty to calculate the exact probability of harm, it does
have an obligation to find that a significant risk is present before it
can characterize a place of employment as 'unsafe', "and proceed to
promulgate a regulation (Id.).

    In this preamble at section VI, Preliminary Risk Assessment, OSHA
finds that the available epidemiological data are sufficient to
evaluate risk for beryllium sensitization, CBD, and lung cancer among
beryllium-exposed workers. The preliminary findings from this
assessment are summarized below.
1. Risk of Beryllium Sensitization and CBD
    OSHA's preliminary risk assessment for CBD and beryllium
sensitization relies on studies conducted at a Tucson, AZ beryllium
ceramics plant (Kreiss et al., 1996; Henneberger et al., 2001; Cummings
et al., 2006); a Reading, PA alloy processing plant (Schuler et al.,
2005; Thomas et al., 2009); a Cullman, AL beryllium machining plant
(Kelleher et al., 2001; Madl et al., 2007); and an Elmore, OH metal,
alloy, and oxide production plant (Kreiss et al., 1997; Bailey et al.,
2010; Schuler et al., 2012). The Agency uses these studies to
demonstrate the significance of risk at the current PEL and the
significant reduction in risk expected with reduction of the PEL. In
addition to the effects OSHA anticipates from reduction of airborne
beryllium exposure, the Agency expects that dermal protection
provisions in the proposed rule will further reduce risk. Studies
conducted in the 1950s by Curtis et al. showed that soluble beryllium
particles could penetrate the skin and cause beryllium sensitization
(Curtis 1951, NAS 2008). Tinkle et al. established that 0.5- and 1.0-
[mu]m particles can penetrate intact human skin surface and reach the
epidermis, where beryllium particles would encounter antigen-presenting
cells and initiate sensitization (Tinkle et al., 2003). Tinkle et al.
further demonstrated that beryllium oxide and beryllium sulfate,
applied to the skin of mice, generate a beryllium-specific, cell-
mediated immune response similar to human beryllium sensitization
(Tinkle et al., 2003). In the epidemiological studies discussed below,
the exposure control programs that most effectively reduced the risk of
beryllium sensitization and CBD incorporated both respiratory and
dermal protection. OSHA has preliminarily determined that an effective
exposure control program should incorporate both airborne exposure
reduction and dermal protection provisions.
    In the Tucson ceramics plant, 4,133 short-term breathing zone
measurements collected between 1981 and 1992 had a median of 0.3 [mu]g/
m\3\. Kreiss et al. reported that eight (5.9 percent) of 136 workers
tested for beryllium sensitization in 1992 were sensitized, six (4.4
percent) of whom were diagnosed with CBD. Exposure control programs
were initiated in 1992 to reduce workers' airborne beryllium exposure,
but the programs did not address dermal exposure. Full-shift personal
samples collected between 1994 and 1999 showed a median beryllium
exposure of 0.2 [mu]g/m\3\ in production jobs and 0.1 [mu]g/m\3\ in
production support (Cummings et al., 2007). In 1998, a second screening
found that 6, (9 percent) of 69 tested workers hired after the 1992
screening, were sensitized, of whom 1 was diagnosed with CBD. All of
the sensitized workers had been employed at the plant for less than 2
years (Henneberger et al., 2001), too short a time period for most
people to develop CBD following sensitization. Of the 77 Tucson workers
hired prior to 1992 who were tested in 1998, 8 (10.4 percent) were
sensitized and all but 1 of these (9.7 percent) were diagnosed with CBD
(Henneberger et al., 2001).
    Kreiss et al., studied workers at a beryllium metal, alloy, and
oxide production plant in Elmore, OH. Workers participated in a BeLPT
survey in 1992 (Kreiss et al., 1997). Personal lapel samples collected
during 1990-1992 had a median value of 1.0 [mu]g/m\3\. Kreiss et al.
reported that 43 (6.9 percent) of 627 workers tested in 1992 were
sensitized, 6 of whom were diagnosed with CBD (4.4 percent).
    Newman et al. conducted a series of BeLPT screenings of workers at
a Cullman, AL precision machining facility between 1995 and 1999
(Newman et al., 2001). Personal lapel samples collected at this plant
in the early 1980s and in 1995 from all machining processes combined
had a median of 0.33 [mu]g/m\3\ (Madl et al., 2007). After a sentinel
case of CBD was diagnosed at the plant in 1995, the company implemented
engineering and administrative controls and PPE designed to reduce
workers' beryllium exposures in machining operations. Personal lapel
samples collected extensively between 1996 and 1999 in machining jobs
have an overall median of 0.16 [mu]g/m\3\, showing that the new
controls reduced machinists' exposures during this period. However, the
results of BeLPT screenings conducted in 1995-1999 showed that the
exposure control program initiated in 1995 did not sufficiently protect
workers from beryllium sensitization and CBD. In a group of 60 workers
who had been employed at the plant for less than a year, and thus would
not have been working there prior to 1995, 4 (6.7 percent) were found
to be sensitized. Two of these workers (3.35 percent) were diagnosed
with CBD. (Newman et al., 2001).
    Sensitization and CBD were studied in a population of workers at a
Reading, PA copper beryllium plant, where alloys containing a low level
of beryllium were processed (Schuler et al., 2005). Personal lapel
samples were collected in production and production support jobs
between 1995 and May 2000. These samples showed primarily very low
airborne beryllium levels, with a median of 0.073 [mu]g/m\3\. The wire
annealing and pickling process had the highest personal lapel sample
values, with a median of 0.149 [mu]g/m\3\. Despite these low exposure
levels, a BeLPT screening conducted in 2000 showed that 5, (11.5
percent) workers of 43 hired after 1992 were sensitized (evaluation for
CBD not reported). Two of the sensitized workers had been hired less
than a year before the screening (Thomas et al., 2009).
    In summary, the epidemiological literature on beryllium
sensitization and CBD that OSHA's risk assessment relied on show
sensitization prevalences ranging from 6.5 percent to 11.5 percent and
CBD prevalences ranging from 1.3 percent to 9.7 percent among workers
who had full-shift exposures well below the current PEL and median
full-shift exposures at or below the proposed PEL, and whose follow-up
time was less than 45 years. As referenced earlier, OSHA is interested
in the risk associated with a 45-year (i.e., working lifetime)
exposure. Because CBD often develops over the course of years following
sensitization, the risk of CBD that would result from 45 years'
occupational exposure to airborne beryllium is likely to be higher than
the prevalence of CBD observed among these workers.\13\ In either case,
based on these studies, the risks to workers appear to be significant.
---------------------------------------------------------------------------

    \13\ This point was emphasized by members of the scientific peer
review panel for OSHA's Preliminary Risk Assessment (see this
preamble at section VII).
---------------------------------------------------------------------------

    The available epidemiological evidence shows that reducing workers'
levels of airborne beryllium exposure can substantially reduce risk of
beryllium sensitization and CBD. The best available evidence on
effective exposure control programs comes partly from studies of
programs introduced around 2000 at Reading, Tucson, and Elmore that
used a combination of engineering controls, dermal and respiratory PPE,
and stringent housekeeping measures to reduce workers' dermal exposures
and airborne exposures to levels well below the proposed PEL of 0.2
[mu]g/m\3\. These programs have substantially lowered the risk of
sensitization among new workers. As discussed earlier, prevention of
beryllium sensitization prevents subsequent development of CBD.
    In the Reading, PA copper beryllium plant, full-shift airborne
exposures in all jobs were reduced to a median of 0.1 [mu]g/m\3\ or
below and dermal protection was required for production-area workers
beginning in 2000-2001 (Thomas et al., 2009). After these adjustments
were made, 2 (5.4 percent) of 37 newly hired workers became sensitized.
Thereafter, in 2002, the process with the highest exposures (median 0.1
[mu]g/m\3\) was enclosed and workers involved in that process were
required to use respiratory protection. As a result, the remaining jobs
had very low exposures (medians ~ 0.03 [mu]g/m\3\). Among 45 workers
hired after the enclosure was built and respiratory protection
instituted, 1 was found to be sensitized (2.2 percent). This is a sharp
reduction in sensitization from the 11.5 percent of 43 workers,
discussed above, who were hired after 1992 and had been sensitized by
the time of testing in 2000.
    In the Tucson beryllium ceramics plant, respiratory and skin
protection was instituted for all workers in production areas in 2000.
BeLPT testing done in 2000-2004 showed that only 1 (1 percent) worker
had been sensitized out of 97 workers hired during that time period
(Cummings et al., 2007; testing for CBD not reported). This contrasts
with the prevalence of sensitization in the 1998 Tucson BeLPT
screening, which found that 6 (9 percent) of 69 workers hired after
1992 were sensitized (Cummings et al., 2007).
    The modern Elmore facility provides further evidence that combined
reductions in respiratory exposure (via respirator use) and dermal
exposure are effective in reducing risk of beryllium sensitization. In
Elmore, historical beryllium exposures were higher than in Tucson,
Reading, and Cullman. Personal lapel samples collected at Elmore in
1990-1992 had a median of 1.0 [micro]g/m\3\. In 1996-1999, the company
took steps to reduce workers' beryllium exposures, including
engineering and process controls (Bailey et al., 2010; exposure levels
not reported). Skin protection was not included in the program until
after 1999. Beginning in 1999 all new employees were required to wear
loose-fitting powered air-purifying respirators (PAPR) in manufacturing
buildings (Bailey et al., 2010). Skin protection became part of the
protection program for new employees in 2000, and glove use was
required in production areas and for handling work boots beginning in
2001. Bailey et al., (2010) compared the occurrence of beryllium
sensitization and CBD in 2 groups of workers: 1) 258 employees who
began work at the Elmore plant between January 15, 1993 and August 9,
1999 (the "pre-program group") and were tested in 1997 and 1999, and
2) 290 employees who were hired between February 21, 2000 and December
18, 2006 and underwent BeLPT testing in at least one of frequent rounds
of testing conducted after 2000 (the "program group"). They found
that, as of 1999, 23 (8.9 percent) of the pre-program group were
sensitized to beryllium. The prevalence of sensitization among the
"program group" workers, who were hired after the respiratory
protection and PPE measures were put in place, was around 2-3 percent.
Respiratory protection and skin protection substantially reduced, but
did not eliminate, risk of sensitization. Evaluation of sensitized
workers for CBD was not reported.
    OSHA's preliminary risk assessment also includes analysis of a data
set provided to OSHA by the National Jewish Research and Medical Center
(NJMRC). The data set describes a population of 319 beryllium-exposed
workers at a Cullman, AL machining facility. It includes exposure
samples collected between 1980 and 2005, and has updated work history
and screening information for over three hundred workers through 2003.
Seven (2.2 percent) workers in the data set were reported as sensitized
only. Sixteen (5.0 percent) workers were listed as sensitized and
diagnosed with CBD upon initial clinical evaluation. Three (1.0
percent) workers, first shown to be sensitized only, were later
diagnosed with CBD. The data set includes workers exposed at airborne
beryllium levels near the proposed PEL, and extensive exposure data
collected in workers' breathing zones, as is preferred by OSHA. Unlike
the Tucson, Reading, and Elmore facilities, respirator use was not
generally required for workers at the Cullman facility. Thus, analysis
of this data set shows the risk associated with varying levels of
airborne exposure, rather than the virtual elimination of airborne
exposure via respiratory PPE. Also unlike the Tucson, Elmore, and
Reading facilities, glove use was not reported to be mandatory in the
Cullman facility. Thus, OSHA believes reductions in risk at the Cullman
facility to be the result of airborne exposure control, rather than the
combination of airborne and dermal exposure controls at the Tucson,
Elmore, and Reading facilities.
    OSHA analyzed the prevalence of beryllium sensitization and CBD
among workers at the Cullman facility who were exposed to airborne
beryllium levels at and below the current PEL of 2 [micro]g/m\3\. In
addition, a statistical modeling analysis of the NJMRC Cullman data set
was conducted under contract with Dr. Roslyn Stone of the University of
Pittsburgh Graduate School of Public Heath, Department of
Biostatistics. OSHA summarizes these analyses briefly below, and in
more detail in this preamble at section VI, Preliminary Risk
Assessment.
    Tables 1 and 2 below present the prevalence of sensitization and
CBD cases across several categories of lifetime-weighted (LTW) average
and highest-exposed job (HEJ) exposure at the Cullman facility. The HEJ
exposure is the exposure level associated with the highest-exposure job
and time period experienced by each worker. The columns "Total" and
"Total percent" refer to all sensitized workers in the dataset,
including workers with and without a diagnosis of CBD.

               Table 1--Prevalence of Sensitization and CBD by Lifetime Weighted Average Exposure Quartile, Cullman, AL Machining Facility
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                            Sensitized
            LTW Average exposure ([mu]g/m\3\)               Group size         only             CBD            Total          Total %          CBD %
--------------------------------------------------------------------------------------------------------------------------------------------------------
0.0-0.080...............................................              91               1               1               2             2.2             1.0
0.081-0.18..............................................              73               2               4               6             8.2             5.5
0.19-0.51...............................................              77               0               6               6             7.8             7.8
0.51-2.15...............................................              78               4               8              12            15.4            10.3
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................             319               7              19              26             8.2             6.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Section VI, Preliminary Risk Assessment.


                  Table 2--Prevalence of Sensitization and CBD by Highest-Exposed Job Exposure Quartile, Cullman, AL Machining Facility
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                            Sensitized
                HEJ Exposure ([mu]g/m\3\)                   Group size         only             CBD            Total          Total %          CBD %
--------------------------------------------------------------------------------------------------------------------------------------------------------
0.0-0.086...............................................              86               1               0               1             1.2             0.0
0.091-0.214.............................................              81               1               6               7             8.6             7.4
0.387-0.691.............................................              76               2               9              11            14.5            11.8
0.954-2.213.............................................              76               3               4               7             9.2             5.3
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................             319               7              19              26             8.2             6.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Section VI, Preliminary Risk Assessment.

    The current PEL of 2 [mu]g/m\3\ is close to the upper bound of the
highest quartile of LTW average (0.51-2.15 [mu]g/m\3\) and HEJ (0.954-
2.213) exposure levels. In the highest quartile of LTW average
exposure, there were 12 cases of sensitization (15.4 percent),
including 8 (10.3 percent) diagnosed with CBD. Notably, the Cullman
workers had been exposed to beryllium dust for considerably less than
45 years at the time of testing. A high prevalence of sensitization
(9.2 percent) and CBD (5.3 percent) is seen in the top quartile of HEJ
exposure as well, with even higher prevalences in the third quartile
(0.387-0.691 [mu]g/m\3\).\14\
---------------------------------------------------------------------------

    \14\ This exposure-response pattern is sometimes attributed to a
"healthy worker effect" or to exposure misclassification, as
discussed in this preamble at section VI, Preliminary Risk
Assessment.
---------------------------------------------------------------------------

    The proposed PEL of 0.2 [mu]g/m\3\ is close to the upper bound of
the second quartile of LTW average (0.81-0.18 [mu]g/m\3\) and HEJ
(0.091-0.214 [mu]g/m\3\) exposure levels and to the lower bound of the
third quartile of LTW average (0.19-0.50 [mu]g/m\3\) exposures. The
second quartile of LTW average exposure shows a high prevalence of
beryllium-related health effects, with six workers sensitized (8.2
percent), of whom four (5.5 percent) were diagnosed with CBD. The
second quartile of HEJ exposure also shows a high prevalence of
beryllium-related health effects, with seven workers sensitized (8.6
percent), of whom 6 (7.4 percent) were diagnosed with CBD. Among six
sensitized workers in the third quartile of LTW average exposures, all
were diagnosed with CBD (7.8 percent). The prevalence of CBD among
workers in these quartiles was approximately 5-8 percent, and overall
sensitization (including workers with and without CBD) was about 8
percent. OSHA considers these rates as evidence that the risk of
developing CBD is significant among workers exposed at and below the
current PEL, even down to the proposed PEL. Much lower prevalences of
sensitization and CBD were found among workers with exposure levels
less than or equal to about 0.08 [mu]g/m\3\. Two sensitized workers
(2.2 percent), including 1 case of CBD (1.0 percent), were found among
workers with LTW average exposure levels and HEJ exposure levels less
than or equal to 0.08 [mu]g/m\3\ and 0.086 [mu]g/m\3\, respectively.
Strict control of airborne exposure to levels below 0.1 [mu]g/m\3\ can,
therefore, significantly reduce risk of sensitization and CBD. Although
OSHA recognizes that maintaining exposure levels below 0.1 [mu]g/m\3\
may not be feasible in some operations (see this preamble at section
IX, Summary of the Preliminary Economic Analysis and Initial Regulatory
Flexibility Analysis), the Agency believes that workers in facilities
that meet the proposed action level of 0.1 [mu]g/m\3\ will be at less
risk of sensitization and CBD than workers in facilities that cannot
meet the action level.
    Table 3 below presents the prevalence of sensitization and CBD
cases across cumulative exposure quartiles, based on the same Cullman
data used to derive Tables 1 and 2. Cumulative exposure is the sum of a
worker's exposure across the duration of his employment.


                       Table 3--Prevalence of Sensitization and CBD by Cumulative Exposure Quartile Cullman, AL Machining Facility
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                            Sensitized
          Cumulative exposure ([mu]g/m\3\ yrs)              Group size         only             CBD            Total          Total %          CBD %
--------------------------------------------------------------------------------------------------------------------------------------------------------
0.0-0.147...............................................              81               2               2               4             4.9             2.5
0.148-1.467.............................................              79               0               2               2             2.5             2.5
1.468-7.008.............................................              79               3               8              11            13.9             8.0
7.009-61.86.............................................              80               2               7               9            11.3             8.8
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................             319               7              19              26             8.2             6.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Section VI, Preliminary Risk Assessment.

    A 45-year working lifetime of occupational exposure at the current
PEL would result in 90 [mu]g/m \3\-years, a value far higher than the
cumulative exposures of workers in this data set, who worked for
periods of time less than 45 years and whose exposure levels were
mostly well below the PEL. Workers with 45 years of exposure to the
proposed PEL would have a cumulative exposure (9 [mu]g/m \3\-years) in
the highest quartile for this worker population. As with the average
and HEJ exposures, the greatest risk of sensitization and CBD appears
at high exposure levels (> 1.468 [mu]g/m \3\-years). The third
cumulative quartile, at which a sharp increase in sensitization and CBD
appears, is bounded by 1.468 and 7.008 [mu]g/m \3\-years. This is
equivalent to 0.73-3.50 years of exposure at the current PEL of 2
[mu]g/m \3\, or 7.34-35.04 years of exposure at the proposed PEL of 0.2
[mu]g/m \3\. Prevalence of both sensitization and CBD is substantially
lower in the second cumulative quartile (0.148-1.467 [mu]g/m \3\-
years). This is equivalent to approximately 0.7 to 7 years at the
proposed PEL of 0.2 [mu]g/m \3\, or 1.5 to 15 years at the proposed
action level of 0.1 [mu]g/m \3\. This supports that maintaining
exposure levels below the proposed PEL, where feasible, will help to
protect long-term workers against risk of beryllium sensitization and
early stage CBD.
    As discussed in the Health Effects section (V.D), CBD often worsens
with increased time and level of exposure. In a longitudinal study,
workers initially identified as beryllium sensitized through workplace
surveillance developed early stage CBD defined by granulomatous
inflammation but no apparent physiological abnormalities (Newman et
al., 2005). A study of workers with this early stage CBD showed
significant declines in breathing capacity and gas exchange over the 30
years from first exposure (Mroz et al., 2009). Many of the workers went
on to develop more severe disease that required immunosuppressive
therapy despite being removed from exposure. While precise beryllium
exposure levels were not available on the individuals in these studies,
most started work in the 1980s and 1990s and were likely exposed to
average levels below the current 2 [mu]g/m \3\ PEL. The evidence for
time-dependent disease progression indicates that the CBD risk
estimates for a 45-year lifetime exposure at the current PEL will
include a higher proportion of individuals with advanced clinical CBD
than found among the workers in the NJMRC data set.
    Studies of community-acquired (CA) CBD support the occurrence of
advanced clinical CBD from long-term exposure to airborne beryllium
(Eisenbud, 1998; Maier et al., 2008). A discussion of the study
findings can be found in this preamble at section VI.C, Preliminary
Risk Assessment. For example, one study evaluated 16 potential cases of
CA-CBD in individuals that resided near a beryllium production facility
in the years between 1943 and 2001 (Maier et al., 2008). Five cases of
definite CBD and three cases of probable CBD were found. Two of the
subjects with probable cases died before they could be confirmed with
the BeLPT; the third had an abnormal BeLPT and radiography consistent
with CBD, but granulomatous disease was not pathologically proven. The
individuals with CA-CBD identified in this study suffered significant
health impacts from the disease, including obstructive, restrictive,
and gas exchange pulmonary defects. Six of the eight cases required
treatment with prednisone, a step typically reserved for severe cases
due to the adverse side effects of steroid treatment. Despite
treatment, three had died of respiratory impairment as of 2002. There
was insufficient information to estimate exposure to the individuals,
but the limited amount of ambient air sampling in the 1950s suggested
that average beryllium levels in the area where the cases resided were
below 2 [mu]g/m \3\. The authors concluded that "low levels of
exposures with significant disease latency can result in significant
morbidity and mortality" (Maier et al., 2008, p. 1017).
    OSHA believes that the literature review, prevalence analysis, and
the evidence for time-dependent progression of CBD described above
provide sufficient information to draw preliminary conclusions about
significance of risk, and that further quantitative analysis of the
NJMRC data set is not necessary to support the proposed rule. The
studies OSHA used to support its preliminary conclusions regarding risk
of beryllium sensitization and CBD were conducted at modern industrial
facilities with exposure levels in the range of interest for this
rulemaking, so a model is not needed to extrapolate risk estimates from
high to low exposures, as has often been the case in previous rules.
Nevertheless, the Agency felt further quantitative analysis might
provide additional insight into the exposure-response relationship for
sensitization and CBD.
    Using the NJMRC data set, Dr. Stone ran a complementary log-log
proportional hazards model, an extension of logistic regression that
allows for time-dependent exposures and differential time at risk.
Relative risk of sensitization increased with cumulative exposure (p =
0.05). A positive, but not statistically significant association was
observed with LTW average exposure (p = 0.09). There was little
association with highest-exposed job (HEJ) exposure (p = 0.3).
Similarly, the proportional hazards models for the CBD endpoint showed
positive relationships with cumulative exposure (p = 0.09), but LTW
average exposure and HEJ exposure were not closely related to relative
risk of CBD (p-values > 0.5). Dr. Stone used the cumulative exposure
models to generate risk estimates for sensitization and CBD.
    Tables 4 and 5 below present risk estimates from these models,
assuming 5, 10, 20, and 45 years of beryllium exposure. The tables
present sensitization and CBD risk estimates based on year-specific
intercepts, as explained in the section on Risk Assessment and the
accompanying background document. Each estimate represents the number of
sensitized workers the model predicts in a group of 1000 workers at risk
during the given year with an exposure history at the specified level and
duration. For example, in the exposure scenario for 1995, if 1000
workers were occupationally exposed to 2 [mu]g/m \3\ for 10 years, the
model predicts that about 56 (55.7) workers would be identified as
sensitized. The model for CBD predicts that about 42 (41.9) workers
would be diagnosed with CBD that year. The year 1995 shows the highest
risk estimates generated by the model for both sensitization and CBD,
while 1999 and 2002 show the lowest risk estimates generated by the
model for sensitization and CBD, respectively. The corresponding 95
percent confidence intervals are based on the uncertainty in the
exposure coefficient.

    Table 4a--Predicted Cases of Sensitization per 1000 Workers Exposed at Current and Alternate PELs Based on Proportional Hazards Model, Cumulative
                    Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient. 1995 Baseline.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                      1995                                                                   Exposure duration
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           5 years                  10 years                  20 years                  45 years
                                                 -------------------------------------------------------------------------------------------------------
          Exposure level  ([mu]g/m\3\)             Cumulative
                                                  ([mu]g/m\3\-  cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000
                                                      yrs)                      yrs                       yrs                       yrs
--------------------------------------------------------------------------------------------------------------------------------------------------------
2.0.............................................         10.0         41.1         20.0         55.7         40.0        101.0         90.0        394.4
                                                                 30.3-56.2                30.3-102.9                30.3-318.1                30.3-999.9
1.0.............................................          5.0         35.3         10.0         41.1         20.0         55.7         45.0        116.9
                                                                 30.3-41.3                 30.3-56.2                30.3-102.9                30.3-408.2
0.5.............................................          2.5         32.7          5.0         35.3         10.0         41.1         22.5         60.0
                                                                 30.3-35.4                 30.3-41.3                 30.3-56.2                30.3-119.4
0.2.............................................          1.0         31.3          2.0         32.2          4.0         34.3          9.0         39.9
                                                                 30.3-32.3                 30.3-34.3                 30.3-38.9                 30.3-52.9
0.1.............................................          0.5         30.8          1.0         31.3          2.0         32.2          4.5         34.8
                                                                 30.3-31.3                 30.3-32.3                 30.3-34.3                 30.3-40.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Section VI, Preliminary Risk Assessment.


    Table 4b--Predicted Cases of Sensitization per 1000 Workers Exposed at Current and Alternate PELs Based on Proportional Hazards Model, Cumulative
                    Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient. 1999 Baseline.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                      1999                                                                   Exposure duration
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           5 years                  10 years                  20 years                  45 years
                                                 -------------------------------------------------------------------------------------------------------
           Exposure level ([mu]g/m\3\)             Cumulative
                                                  ([mu]g/m\3\-  cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000
                                                      yrs)                      yrs                       yrs                       yrs
--------------------------------------------------------------------------------------------------------------------------------------------------------
2.0.............................................         10.0          8.4         20.0         11.5         40.0         21.3         90.0         96.3
                                                                  6.2-11.6                  6.2-21.7                  6.2-74.4                 6.2-835.4
1.0.............................................          5.0          7.2         10.0          8.4         20.0         11.5         45.0         24.8
                                                                   6.2-8.5                  6.2-11.6                  6.2-21.7                 6.2-100.5
0.5.............................................          2.5          6.7          5.0          7.2         10.0          8.4         22.5         12.4
                                                                   6.2-7.3                   6.2-8.5                  6.2-11.6                  6.2-25.3
0.2.............................................          1.0          6.4          2.0          6.6          4.0          7.0          9.0          8.2
                                                                   6.2-6.6                   6.2-7.0                   6.2-8.0                  6.2-10.9
0.1.............................................          0.5          6.3          1.0          6.4          2.0          6.6          4.5          7.1
                                                                   6.2-6.4                   6.2-6.6                   6.2-7.0                   6.2-8.2
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Section VI, Preliminary Risk Assessment.


   Table 5a--Predicted Number of Cases of CBD per 1000 Workers Exposed at Current and Alternative PELs Based on Proportional Hazards Model, Cumulative
                    Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient. 1995 Baseline.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                      1995                                                                   Exposure duration
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           5 years                  10 years                  20 years                  45 years
                                                 -------------------------------------------------------------------------------------------------------
           Exposure level ([mu]g/m\3\)             Cumulative    Estimated                Estimated                  Estimated                Estimated
                                                  ([mu]g/m\3\-  cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000
                                                      yrs)      (95% c.i.)      yrs       (95% c.i.)      yrs       (95% c.i.)      yrs       (95% c.i.)
--------------------------------------------------------------------------------------------------------------------------------------------------------
2.0.............................................         10.0         30.9         20.0         41.9         40.0         76.6         90.0        312.9
                                                                 22.8-44.0                 22.8-84.3                22.8-285.5                22.8-999.9
1.0.............................................          5.0         26.6         10.0         30.9         20.0         41.9         45.0         88.8
                                                                 22.8-31.7                 22.8-44.0                 22.8-84.3                22.8-375.0
0.5.............................................          2.5         24.6          5.0         26.6         10.0         30.9         22.5         45.2
                                                                 22.8-26.9                 22.8-31.7                 22.8-44.0                 22.8-98.9
0.2.............................................          1.0         23.5          2.0         24.2          4.0         25.8          9.0         30.0
                                                                 22.8-24.3                 22.8-26.0                 22.8-29.7                 22.8-41.3
0.1.............................................          0.5         23.1          1.0         23.5          2.0         24.2          4.5         26.2
                                                                 22.8-23.6                 22.8-24.3                 22.8-26.0                 22.8-30.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Section VI, Preliminary Risk Assessment.


   Table 5b--Predicted Number of Cases of CBD per 1000 Workers Exposed at Current and Alternative PELs Based on Proportional Hazards Model, Cumulative
                    Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient. 2002 Baseline.
--------------------------------------------------------------------------------------------------------------------------------------------------------
                      2002                                                                   Exposure duration
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           5 years                  10 years                  20 years                  45 years
                                                 -------------------------------------------------------------------------------------------------------
           Exposure level ([mu]g/m\3\)             Cumulative    Estimated                Estimated                  Estimated                Estimated
                                                  ([mu]g/m\3\-  cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000  [mu]g/m\3\-   cases/1000
                                                      yrs)      (95% c.i.)      yrs       (95% c.i.)      yrs       (95% c.i.)      yrs       (95% c.i.)
--------------------------------------------------------------------------------------------------------------------------------------------------------
2.0.............................................         10.0          3.7         20.0          5.1         40.0          9.4         90.0         43.6
                                                                   2.7-5.3                  2.7-10.4                  2.7-39.2                 2.7-679.8
1.0.............................................          5.0          3.2         10.0          3.7         20.0          5.1         45.0         11.0
                                                                   2.7-3.8                   2.7-5.3                  2.7-10.4                  2.7-54.3
0.5.............................................          2.5          3.0          5.0          3.2         10.0          3.7         22.5          5.5
                                                                   2.7-3.2                   2.7-3.8                   2.7-5.3                  2.7-12.3
0.2.............................................          1.0          2.8          2.0          2.9          4.0          3.1          9.0          3.6
                                                                   2.7-2.9                   2.7-3.1                   2.7-3.6                   2.7-5.0
0.1.............................................          0.5          2.8          1.0          2.8          2.0          2.9          4.5          3.1
                                                                   2.7-2.8                   2.7-2.9                   2.7-3.1                   2.7-3.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Section VI, Preliminary Risk Assessment.

    As shown in Tables 4 and 5, the exposure-response models Dr. Stone
developed based on the Cullman data set predict a high risk of both
sensitization (about 96-394 cases per 1000 exposed workers) and CBD
(about 44-313 cases per 1000) at the current PEL of 2 [mu]g/m\3\ for an
exposure duration of 45 years (90 [mu]g/m\3\-yr). For a 45-year
exposure at the proposed PEL of 0.2 [mu]g/m\3\, risk estimates for
sensitization (about 8-40 cases per 1000 exposed workers) and CBD
(about 4-30 per 1000 exposed workers) are substantially reduced. Thus,
the model predicts that the risk of sensitization and CBD at a PEL of
0.2 [mu]g/m\3\ will be about 10 percent of the risk at the current PEL
of 2 [mu]g/m\3\.
    OSHA does not believe the risk estimates generated by these
exposure-response models to be highly accurate. Limitations of the
analysis include the size of the dataset, relatively sparse exposure
data from the plant's early years, study size-related constraints on
the statistical analysis of the dataset, and limited follow-up time on
many workers. The Cullman study population is a relatively small group
and can support only limited statistical analysis. For example, its
size precludes inclusion of multiple covariates in the exposure-
response models or a two-stage exposure-response analysis to model both
sensitization and the subsequent development of CBD within the
subpopulation of sensitized workers. The limited size of the Cullman
dataset is characteristic of studies on beryllium-exposed workers in
modern, low-exposure environments, which are typically small-scale
processing plants (up to several hundred workers, up to 20-30 cases).
    Despite these issues with the statistical analysis, OSHA believes
its main policy determinations are well supported by the best available
evidence, including the literature review and careful examination of
the prevalence of sensitization and CBD among workers with exposure
levels comparable to the current and proposed PELs in the NJMRC data
set. The previously described literature analysis and prevalence
analysis demonstrate that workers with occupational exposure to
airborne beryllium at the current PEL face a risk of becoming
sensitized to beryllium and progressing to both early and advanced
stages of CBD that far exceeds the value of 1 in 1000 used by OSHA as a
benchmark of clearly significant risk. Furthermore, OSHA's preliminary
risk assessment indicates that risk of beryllium sensitization and CBD
can be significantly reduced by reduction of airborne exposure levels,
along with respiratory and dermal protection measures, as demonstrated
in facilities such as the Tucson ceramics plant, the Elmore beryllium
production facility, and the Reading copper beryllium facility
described in the literature review.
    OSHA's preliminary risk assessment also indicates that despite the
reduction in risk expected with the proposed PEL, the risk to workers
with average exposure levels of 0.2 [mu]g/m\3\ is still clearly
significant (see this preamble at section VI). In the prevalence
analysis, workers with LTW average or HEJ exposures close to 0.2 [mu]g/
m\3\ experienced high levels of sensitization and CBD. This finding is
corroborated by the literature analysis, which showed that workers
exposed to mean plant-wide airborne exposures between 0.1 and 0.5
[mu]g/m\3\ had a similarly high prevalence of sensitization and CBD.
Given the significant risk at these levels of exposure, the Agency
believes that the proposed action level of 0.1 [mu]g/m\3\, dermal
protection requirements, and other ancillary provisions of the proposed
rule are key to reducing the risk of beryllium sensitization and CBD
among exposed workers. OSHA preliminarily concludes that the proposed
standard, including the PEL of 0.2 [mu]g/m\3\, the action level of 0.1
[mu]g/m\3\, and provisions to limit dermal exposure to beryllium,
together will significantly reduce workers' risk of beryllium
sensitization and CBD from occupational beryllium exposure.
2. Risk of Lung Cancer
    OSHA's review of epidemiological studies of lung cancer mortality
among beryllium workers found that most did not characterize exposure
levels sufficiently to characterize risk of lung cancer at the current
and proposed PELs. However, as discussed in this preamble at section V,
Health Effects and section VI, Preliminary Risk Assessment, NIOSH
recently published a quantitative risk assessment based on beryllium
exposure and lung cancer mortality among 5436 male workers employed at
beryllium processing plants in Reading, PA; Elmore, OH; and Hazleton,
PA, prior to 1970 (Schubauer-Berigan et al., 2010b). This new risk
assessment addresses important sources of uncertainty for previous lung
cancer analyses, including the sole prior exposure-response analysis
for beryllium and lung cancer, conducted by Sanderson et al. (2001) on
workers from the Reading plant alone. Workers from the Elmore and
Hazleton plants who were added to the analysis by Schubauer-Berigan et
al. were, in general, exposed to lower levels of beryllium than those
at the Reading plant. The median worker from Hazleton had a mean
exposure across his tenure of less than 2 [mu]g/m\3\, while the median
worker from Elmore had a mean exposure of less than 1 [mu]g/m\3\. The
Elmore and Hazleton worker populations also had fewer short-term
workers than the Reading population. Finally, the updated cohorts
followed the worker populations through 2005, increasing the length of
follow-up time compared to the previous exposure-response analysis. For
these reasons, OSHA based its preliminary risk assessment for lung
cancer on the Schubauer-Berigan risk analysis.
    Schubauer-Berigan et al. (2011) analyzed the data set using a
variety of exposure-response modeling approaches, described in this
preamble at section VI, Preliminary Risk Assessment. The authors found
that lung cancer mortality risk was strongly and significantly related
to mean, cumulative, and maximum measures of workers' exposure to
beryllium (all models reported in Schubauer-Berigan et al., 2011). They
selected the best-fitting models to generate risk estimates for male
workers with a mean exposure of 0.5 [mu]g/m\3\ (the current NIOSH
Recommended Exposure Limit for beryllium). In addition, they estimated
the mean exposure that would be associated with an excess lung cancer
mortality risk of one in one thousand. At OSHA's request, the authors
also estimated excess risks for workers with mean exposures at each of
the other alternate PELs under consideration: 1 [mu]g/m\3\, 0.2 [mu]g/
m\3\, and 0.1 [mu]g/m\3\. Table 6 presents the estimated excess risk of
lung cancer mortality associated with various levels of beryllium
exposure allowed under the current rule, based on the final models
presented in Schubauer-Berigan et al's risk assessment.

      Table 6--Excess Risk of Lung Cancer Mortality per 1000 Male Workers at Alternate PELs (NIOSH Models)
----------------------------------------------------------------------------------------------------------------
                                                                   Mean exposure
                                 -------------------------------------------------------------------------------
     Exposure-response model       0.1 [micro]g/   0.2 [micro]g/   0.5 [micro]g/    1 [micro]g/     2 [micro]g/
                                       m\3\            m\3\            m\3\            m\3\            m\3\
----------------------------------------------------------------------------------------------------------------
Best monotonic PWL--all workers.             7.3              15              45             120             200
Best monotonic PWL--excluding                3.1             6.4              17              39              61
 professional and asbestos
 workers........................
Best categorical--all workers...             4.4               9              25              59             170
Best categorical--excluding                  1.4             2.7             7.1              15              33
 professional and asbestos
 workers........................
Power model--all workers........              12              19              30              40              52
Power model--excluding                        19              30              49              68              90
 professional and asbestos
 workers........................
----------------------------------------------------------------------------------------------------------------
Source: Section VI, Preliminary Risk Assessment.

    The lowest estimate of excess lung cancer deaths from the six final
models presented by Schubauer-Berigan et al. is 33 per 1000 workers
exposed at a mean level of 2 [mu]g/m\3\, the current PEL. Risk
estimates as high as 200 lung cancer deaths per 1000 result from the
other five models presented. Regardless of the model chosen, the excess
risk of about 33 to 200 per 1000 workers is clearly significant,
falling well above the level of risk the Supreme Court indicated a
reasonable person might consider acceptable (See Benzene, 448 U.S. at
655). The proposed PEL of 0.2 [mu]g/m\3\ is expected to reduce these
risks significantly, to somewhere between 2.7-30 excess lung cancer
deaths per 1000 workers. These risk estimates still fall above the
threshold of 1 in 1000 that OSHA considers clearly significant.
However, the Agency believes the lung cancer risks should be regarded
with a greater degree of uncertainty than the risk estimates for CBD
discussed previously. While the risk estimates for CBD at the proposed
PEL were determined from exposure levels observed in occupational
studies, the lung cancer risks are extrapolated from much higher
exposure levels.

C. Conclusions

    As discussed above, OSHA used the best available scientific
evidence to identify adverse health effects of occupational beryllium
exposure, and to evaluate exposed workers' risk of these impairments.
The Agency reviewed extensive epidemiological and experimental
research pertaining to adverse health effects of occupational
beryllium exposure, including lung cancer, immunological sensitization
to beryllium, and CBD, and has evaluated the risk of these effects
from exposures allowed under the current and proposed standards.
The Agency has, additionally, reviewed previous policy determinations
and case law regarding material impairment of health, and has
preliminarily determined that CBD, in all stages, and lung cancer
constitute material health impairments. Furthermore, OSHA has preliminarily
determined that long-term exposure to beryllium at the
current PEL would pose a risk of CBD and lung cancer greater than the
risk of 1 per 1000 exposed workers the Agency considers clearly
significant. OSHA's risk assessment for beryllium indicates that
adoption of the new PEL, action level, and dermal protection provisions
of the proposed rule will significantly reduce this risk. OSHA
therefore believes it has met the statutory requirements pertaining to
significance of risk, consistent with the OSH Act, Supreme Court
precedent, and the Agency's previous policy decisions.

IX. Summary of the Preliminary Economic Analysis and Initial Regulatory
Flexibility Analysis

A. Introduction and Summary

    OSHA's Preliminary Economic Analysis and Initial Regulatory
Flexibility Analysis (PEA) addresses issues related to the costs,
benefits, technological and economic feasibility, and the economic
impacts (including impacts on small entities) of this proposed
respirable beryllium rule and evaluates regulatory alternatives to the
proposed rule. Executive Orders 13563 and 12866 direct agencies to
assess all costs and benefits of available regulatory alternatives and,
if regulation is necessary, to select regulatory approaches that
maximize net benefits (including potential economic, environmental, and
public health and safety effects; distributive impacts; and equity),
unless a statute requires another regulatory approach. Executive Order
13563 emphasized the importance of quantifying both costs and benefits,
of reducing costs, of harmonizing rules, and of promoting flexibility.
The full PEA has been placed in OSHA rulemaking docket OSHA-H005C-2006-
0870. This rule is an economically significant regulatory action under
Sec. 3(f)(1) of Executive Order 12866 and has been reviewed by the
Office of Information and Regulatory Affairs in the Office of
Management and Budget, as required by executive order.
    The purpose of the PEA is to:
     Identify the establishments and industries potentially
affected by the proposed rule;
     Estimate current exposures and the technologically
feasible methods of controlling these exposures;
     Estimate the benefits resulting from employers coming into
compliance with the proposed rule in terms of reductions in cases of
lung cancer and chronic beryllium disease;
     Evaluate the costs and economic impacts that
establishments in the regulated community will incur to achieve
compliance with the proposed rule;
     Assess the economic feasibility of the proposed rule for
affected industries; and
     Assess the impact of the proposed rule on small entities
through an Initial Regulatory Flexibility Analysis (IRFA), to include
an evaluation of significant regulatory alternatives to the proposed
rule that OSHA has considered.
    The PEA contains the following chapters:

Chapter I. Introduction
Chapter II. Assessing the Need for Regulation
Chapter III. Profile of Affected Industries
Chapter IV. Technological Feasibility
Chapter V. Costs of Compliance
Chapter VI. Economic Feasibility Analysis and Regulatory Flexibility
Determination
Chapter VII. Benefits and Net Benefits
Chapter VIII. Regulatory Alternatives
Chapter IX. Initial Regulatory Flexibility Analysis

    The PEA includes all of the economic analyses OSHA is required to
perform, including the findings of technological and economic
feasibility and their supporting materials required by the OSH Act as
interpreted by the courts (in Chapters III, IV, V, and VI); those
required by EO 12866 and EO 13563 (primarily in Chapters III, V, and
VII, though these depend on material in other chapters); and those
required by the Regulatory Flexibility Act (in Chapters VI, VIII, and
IX, though these depend, in part, on materials presented in other
chapters).
    Key findings of these chapters are summarized below and in sections
IX.B through IX.I of this PEA summary.
Profile of Affected Industries
    This proposed rule would affect employers and employees in many
different industries across the economy. As described in Section IX.C
and reported in Table IX-2 of this preamble, OSHA estimates that a
total of 35,051 employees in 4,088 establishments are potentially at
risk from exposure to beryllium.
Technological Feasibility
    As described in more detail in Section IX.D of this preamble and in
Chapter IV of the PEA, OSHA assessed, for all affected sectors, the
current exposures and the technological feasibility of the proposed PEL
of 0.2 [mu]g/m\3\.
    Tables IX-5 in section IX.D of this preamble summarizes all nine
application groups (industry sectors and production processes) studied
in the technological feasibility analysis. The technological
feasibility analysis includes information on current exposures,
descriptions of engineering controls and other measures to reduce
exposures, and a preliminary assessment of the technological
feasibility of compliance with the proposed PELs.
    The preliminary technological feasibility analysis shows that for
the majority of the job groups evaluated, exposures are either already
at or below the proposed PEL, or can be adequately controlled with
additional engineering and work practice controls. Therefore, OSHA
preliminarily concludes that the proposed PEL of 0.2 [mu]g/m\3\ is
technologically feasible for most operations most of the time.
    Based on the currently available evidence, it is more difficult to
determine whether an alternative PEL of 0.1 [mu]g/m\3\ would also be
feasible in most operations. For some application groups, a PEL of 0.1
[mu]g/m\3\ would almost certainly be feasible. In other application
groups, a PEL of 0.1 [mu]g/m\3\ appears feasible, except for
establishments working with high beryllium content alloys. For
application groups with the highest exposure, the exposure monitoring
data necessary to more fully evaluate the effectiveness of exposure
controls adopted after 2000 are not currently available to OSHA, which
makes it difficult to determine the feasibility of achieving exposure
levels at or below 0.1 [mu]g/m\3\.
    OSHA also evaluated the feasibility of a STEL of 2.0 [mu]g/m\3\.
The majority of the available short-term measurements are below 2.0
[mu]g/m\3\; therefore OSHA preliminarily concludes that the proposed
STEL of 2.0 [mu]g/m\3\ can be achieved for most operations most of the
time. OSHA recognizes that for a small number of tasks, short-term
exposures may exceed the proposed STEL, even after feasible control
measures to reduce TWA exposure to below the proposed PEL have been
implemented, and therefore assumes that the use of respiratory
protection will continue to be required for some short-term tasks.
It is more difficult based on the currently available evidence
to determine whether the alternative STEL of 1.0 [mu]g/m\3\ would also
be feasible in most operations based on lack of detail in the
activities of the workers presented in the data. OSHA expects
additional use of respiratory protection would be required for tasks in
which peak exposures can be reduced to less than 2.0 [mu]g/m\3\ but not
less than 1.0 [mu]g/m\3\. Due to limitations in the available sampling
data and the higher detection limits for short term measurements, OSHA
could not determine the percentage of the STEL measurements that are
less than or equal to 0.5 [mu]g/m\3\.
Costs of Compliance
    As described in more detail in Section IX.E and reported, by
application group and NAICS code, in Table IX-7 of this preamble, the
total annualized cost of compliance with the proposed standard is
estimated to be about $37.6 million. The major cost elements associated
with the revisions to the standard are housekeeping ($12.6 million),
engineering controls ($9.5 million), training ($5.8 million), and
medical surveillance ($2.9 million).
    The compliance costs are expressed as annualized costs in order to
evaluate economic impacts against annual revenue and annual profits, to
be able to compare the economic impact of the rulemaking with other
OSHA regulatory actions, and to be able to add and track Federal
regulatory compliance costs and economic impacts in a consistent
manner. Annualized costs also represent a better measure for assessing
the longer-term potential impacts of the rulemaking. The annualized
costs were calculated by annualizing the one-time costs over a period
of 10 years and applying a discount rate of 3 percent (and an
alternative discount rate of 7 percent).
    The estimated costs for the proposed beryllium standard represent
the additional costs necessary for employers to achieve full
compliance. They do not include costs associated with current
compliance that has already been achieved with regard to the new
requirements or costs necessary to achieve compliance with existing
beryllium requirements, to the extent that some employers may currently
not be fully complying with applicable regulatory requirements.
Economic Impacts
    To assess the nature and magnitude of the economic impacts
associated with compliance with the proposed rule, OSHA developed
quantitative estimates of the potential economic impact of the new
requirements on entities in each of the affected industry sectors. The
estimated compliance costs were compared with industry revenues and
profits to provide an assessment of the economic feasibility of
complying with the revised standard and an evaluation of the potential
economic impacts.
    As described in greater detail in Section IX.F of this preamble and
in Chapter VI of the PEA, the costs of compliance with the proposed
rulemaking are not large in relation to the corresponding annual
financial flows associated with each of the affected industry sectors.
The estimated annualized costs of compliance represent about 0.11
percent of annual revenues and about 1.52 percent of annual profits, on
average, across all affected firms. Compliance costs do not represent
more than 1 percent of revenues or more than 16.25 percent of profits
in any affected industry.
    Based on its analysis of the relative inelasticity of demand for
beryllium-containing inputs and products and of possible international
trade effects, OSHA concluded that most or all costs arising from this
proposed beryllium rule would be passed on in higher prices rather than
absorbed in lost profits and that any price increases would result in
minimal loss of business to foreign competition.
    Given the minimal potential impact on prices or profits in the
affected industries, OSHA has preliminarily concluded that compliance
with the requirements of the proposed rulemaking would be economically
feasible in every affected industry sector.
Benefits, Net Benefits, and Cost-Effectiveness
    As described in more detail in Section VIII.G of this preamble,
OSHA estimated the benefits, net benefits, and incremental benefits of
the proposed beryllium rule. That section also contains a sensitivity
analysis to show how robust the estimates of net benefits are to
changes in various cost and benefit parameters. A full explanation of
the derivation of the estimates presented there is provided in Chapter
VII of the PEA for the proposed rule.
    OSHA estimated the benefits associated with the proposed beryllium
PEL of 0.2 [mu]g/m\3\ and, for analytical purposes to comply with OMB
Circular A-4, with alternative beryllium PELs of .1 [mu]g/m\3\ and .5
[mu]g/m\3\ by applying the dose-response relationship developed in the
Agency's preliminary risk assessment--summarized in Section VI of this
preamble--to current exposure levels. OSHA determined current exposure
levels by first developing an exposure profile for industries with
workers exposed to beryllium, using OSHA inspection and site-visit
data, and then applying this exposure profile to the total current
worker population. The industry-by-industry exposure profile is
summarized in Table IX-3 in Section IX.C of this preamble.
    By applying the dose-response relationship to estimates of current
exposure levels across industries, it is possible to project the number
of cases of the following diseases expected to occur in the worker
population given current exposure levels (the "baseline"):
     fatal cases of lung cancer,
     fatal cases of chronic beryllium disease (CBD), and
     morbidity related to chronic beryllium disease.
    Table IX-1 provides a summary of OSHA's best estimate of the costs
and benefits of the proposed rule. As shown, the proposed rule, once it
is fully effective, is estimated to prevent 96 fatalities and 50 non-
fatal beryllium-related illnesses annually, and the monetized
annualized benefits of the proposed rule are estimated to be $575.8
million using a 3-percent discount rate and $255.3 million using a 7-
percent discount rate. Also as shown in Table IX-1, the estimated
annualized cost of the rule is $37.6 million using a 3-percent discount
rate and $39.1 million using a 7-percent discount rate. The proposed
rule is estimated to generate net benefits of $538.2 million annually
using a 3-percent discount rate and $216.2 million annually using a 7-
percent discount rate. The estimated costs and benefits of the proposed
rule, disaggregated by industry sector, were previously presented in
Table I-1 in this preamble.

 Table IX-1--Annualized Costs, Benefits and Net Benefits of OSHA's Proposed Beryllium Standard of 0.2 [mu]g/m\3\
----------------------------------------------------------------------------------------------------------------

----------------------------------------------------------------------------------------------------------------
Discount Rate................................................                              3%                 7%
                                                                           -------------------------------------


Annualized Costs
    Engineering Controls.....................................                      $9,540,189        $10,334,036
    Respirators..............................................                         249,684            252,281
    Exposure Assessment......................................                       2,208,950          2,411,851
    Regulated Areas and Beryllium Work Areas.................                         629,031            652,823
    Medical Surveillance.....................................                       2,882,076          2,959,448
    Medical Removal..........................................                         148,826            166,054
    Exposure Control Plan....................................                       1,769,506          1,828,766
    Protective Clothing and Equipment........................                       1,407,365          1,407,365
    Hygiene Areas and Practices..............................                         389,241            389,891
    Housekeeping.............................................                      12,574,921         12,917,944
    Training.................................................                       5,797,535          5,826,975
                                                                           -------------------------------------
Total Annualized Costs (Point Estimate)......................                      37,597,325         39,147,434
Annual Benefits: Number of Cases Prevented
    Fatal Lung Cancer........................................          4.0
    CBD-Related Mortality....................................         92.0
    Total Beryllium Related Mortality........................         96.0       $572,981,864       $253,743,368
    Morbidity................................................         49.5          2,844,770          1,590,927
Monetized Annual Benefits (midpoint estimate)................                     575,826,633        255,334,295
Net Benefits.................................................                     538,229,308        216,186,861
----------------------------------------------------------------------------------------------------------------
Source: OSHA, Directorate of Standards and Guidance, Office of Regulatory Analysis.

Initial Regulatory Flexibility Analysis
    OSHA has prepared an Initial Regulatory Flexibility Analysis (IRFA)
in accordance with the requirements of the Regulatory Flexibility Act,
as amended in 1996. Among the contents of the IRFA are an analysis of
the potential impact of the proposed rule on small entities and a
description and discussion of significant alternatives to the proposed
rule that OSHA has considered. The IRFA is presented in its entirety
both in Chapter IX of the PEA and in Section IX.I of this preamble.
    The remainder of this section (Section IX) of the preamble is
organized as follows:

B. The Need for Regulation
C. Profile of Affected Industry
D. Technological Feasibility Analysis
E. Costs of Compliance
F. Economic Feasibility Analysis and Regulatory Flexibility
Determination
G. Benefits and Net Benefits
H. Regulatory Alternatives
I. Initial Regulatory Flexibility Analysis.

B. Need for Regulation

    Employees in work environments addressed by the proposed beryllium
rule are exposed to a variety of significant hazards that can and do
cause serious injury and death. As described in Chapter II of the PEA
in support of the proposed rule, the risks to employees are excessively
large due to the existence of various types of market failure, and
existing and alternative methods of overcoming these negative
consequences--such as workers' compensation systems, tort liability
options, and information dissemination programs--have been shown to
provide insufficient worker protection.
    After carefully weighing the various potential advantages and
disadvantages of using a regulatory approach to improve upon the
current situation, OSHA preliminarily concludes that, in the case of
beryllium exposure, the proposed mandatory standards represent the best
choice for reducing the risks to employees. In addition, rulemaking is
necessary in this case in order to replace older existing standards
with updated, clear, and consistent health standards.

C. Profile of Affected Industries

1. Introduction
    Chapter III of the PEA presents a profile of industries that use
beryllium, beryllium oxide, and/or beryllium alloys. The discussion
below summarizes the findings in that chapter. For each industry sector
identified, the Agency describes the uses of beryllium and estimates
the number of establishments and employees that may be affected by this
proposed rulemaking. Employee exposure to beryllium can also occur as a
result of certain processes such as welding that are found in many
industries. OSHA uses the umbrella term "application group" to refer
either to an industrial sector or a cross-industry group with a common
process. These groups are all mutually exclusive and are analyzed in
separate sections in Chapter III of the PEA. These sections briefly
describe each application group and then explain how OSHA estimated the
number of establishments working with beryllium and the number of
employees exposed to beryllium. Beryllium is rarely used by all
establishments in any particular application group because its unique
properties and relatively high cost typically result in only very
specific and limited usage within a portion of a group.
    The information in Chapter III of the PEA is based on reports
prepared under task order by Eastern Research Group (ERG), an OSHA
contractor; information collected during OSHA's Small Business Advocacy
Review Panel (OSHA 2008b); and Agency research and analysis.
Technological feasibility reports (summarized in Chapter IV of the PEA)
for each beryllium-using application group provide a detailed
presentation of processes and occupations with beryllium exposure,
including available sampling exposure measurements and estimates of how
many employees are affected in each specific occupation.
    OSHA has identified nine application groups that would be
potentially affected by the proposed beryllium standard:
    1. Beryllium Production
    2. Beryllium Oxide Ceramics and Composites
    3. Nonferrous Foundries
    4. Secondary Smelting, Refining, and Alloying
    5. Precision Turned Products
    6. Copper Rolling, Drawing, and Extruding
    7. Fabrication of Beryllium Alloy Products
    8. Welding
    9. Dental Laboratories
    These application groups are broadly defined, and some include
establishments in several North American Industrial Classification
System (NAICS) codes. For example, the Copper Rolling and Drawing,
and Extruding application group is made up both of NAICS 331421
Copper Rolling, Drawing, and Extruding and NAICS 331422 Copper
Wire Drawing. While an application group may contain numerous
NAICS six-digit industry codes, in most cases only a fraction of
the establishments in any individual six-digit NAICS industry use
beryllium and would be affected by the proposed rule. For example,
not all companies in the above application group work with copper
that contains beryllium.
    One application group, welding, reflects industrial activities or
processes that take place in various industry sectors. All of the
industries in which a given activity or process may result in worker
exposure to beryllium are identified in the sections on the application
group. The section on each application group describes the production
processes where occupational contact with beryllium can occur and
contains estimates of the total number of firms, employees, affected
establishments, and affected employees.
    Chapter III of the PEA presents formulas in the text, usually in
parentheses, to help explain the derivation of estimates. Because the
values used in the formulas shown in the text are sometimes rounded,
while the actual spreadsheet formulas used to create final costs are
not, the calculation using the presented formula will sometimes differ
slightly from the total presented in the text--which is the actual
total as shown in the tables.
    At the end of Chapter III in the PEA, OSHA discusses other industry
sectors that have reportedly used beryllium in the past or for which
there are anecdotal or informal reports of beryllium use. The Agency
was unable to verify beryllium use in these sectors that would be
affected by the proposed standard, and seeks further information in
this rulemaking on these or other industries where there may be
significant beryllium use and employee exposure.
2. Summary of Affected Establishments and Employers
    As shown in Table IX-2, OSHA estimates that a total of 35,051
workers in 4,088 establishments will be affected by the proposed
beryllium standard. Also shown are the estimated annual revenues for
these entities.

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3. Beryllium Exposure Profile of At-Risk Workers
    The technological feasibility analyses presented in Chapter IV of
the PEA contain data and discussion of worker exposures to beryllium
throughout industry. Exposure profiles, by job category, were developed
from individual exposure measurements that were judged to be
substantive and to contain sufficient accompanying description to allow
interpretation of the circumstance of each measurement. The resulting
exposure profiles show the job categories with current overexposures to
beryllium and, thus, the workers for whom beryllium controls would be
implemented under the proposed rule.
    Table IX-3 summarizes, from the exposure profiles, the number of
workers at risk from beryllium exposure and the distribution of 8-hour
TWA respirable beryllium exposures by affected job category and sector.
Exposures are grouped into the following ranges: Less than 0.1 [mu]g/
m\3\; >= 0.1 [mu]g/m\3\ and <= 0.2 [mu]g/m\3\; > 0.2 [mu]g/m\3\ and <=
0.5 [mu]g/m\3\; > 0.5 [mu]g/m\3\ and <= 1.0 [mu]g/m\3\; > 1.0 [mu]g/
m\3\ and <= 2.0 [mu]g/m\3\; and greater than 2.0 [mu]g/m\3\. These
frequencies represent the percentages of production employees in each
job category and sector currently exposed at levels within the
indicated range.
    Table IX-4 presents data by NAICS code on the estimated number of
workers currently at risk from beryllium exposure, as well as the
estimated number of workers at risk of beryllium exposure above 0
[mu]g/m\3\, at or above 0.1 [mu]g/m\3\, at or above 0.2 [mu]g/m\3\, at
or above 0.5 [mu]g/m\3\, at or above 1.0 [mu]g/m\3\, and at or above
2.0 [mu]g/m\3\. As shown, an estimated 12,101 workers currently have
beryllium exposures at or above the proposed action level of 0.1 [mu]g/
m\3\; and an estimated 8,091 workers currently have beryllium exposures
above the proposed PEL of 0.2 [mu]g/m\3\.

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D. Technological Feasibility Analysis of the Proposed Permissible
Exposure Limit to Beryllium Exposures

    This section summarizes the technological feasibility analysis
presented in Chapter IV of the PEA (OSHA, 2014). The technological
feasibility analysis includes information on current exposures,
descriptions of engineering controls and other measures to reduce
exposures, and a preliminary assessment of the technological
feasibility of compliance with the proposed standard, including a
reduction in OSHA's permissible exposure limits (PELs) in nine affected
application groups. The current PELs for beryllium are 2.0 [mu]g/m\3\
as an 8-hour time weighted average (TWA), and 5.0 [mu]g/m\3\ as an
acceptable ceiling concentration. OSHA is proposing a PEL of 0.2 [mu]g/
m\3\ as an 8-hour TWA and is additionally considering alternative TWA
PELs of 0.1 and 0.5 [mu]g/m\3\. OSHA is also proposing a 15-minute
short-term exposure limit (STEL) of 2.0 [mu]g/m\3\, and is considering
alternative STELs of 0.5, 1.0 and 2.5 [mu]g/m\3\.
    The technological feasibility analysis includes nine application
groups that correspond to specific industries or production processes
that OSHA has preliminarily determined fall within the scope of the
proposed standard. Within each of these application groups, exposure
profiles have been developed that characterize the distribution of the
available exposure measurements by job title or group of jobs.
Descriptions of existing engineering controls for operations that
create sources of beryllium exposure, and of additional engineering
and work practice controls that can be used to reduce exposure are
also provided. For each application group, a preliminary determination
is made regarding the feasibility of achieving the proposed permissible
exposure limits. For application groups in which the median exposures
for some jobs exceed the proposed TWA PEL, a more detailed analysis is
presented by job or group of jobs within the application group. The
analysis is based on the best information currently available to the
Agency, including a comprehensive review of the industrial hygiene
literature, National Institute for Occupational Safety and Health (NIOSH)
Health Hazard Evaluations and case studies of beryllium exposure,
site visits conducted by an OSHA contractor (Eastern Research Group (ERG)),
submissions to OSHA's rulemaking docket, and inspection data from
OSHA's Integrated Management Information System (IMIS). OSHA also
obtained information on production processes, worker exposures, and the
effectiveness of existing control measures from the primary beryllium
producer in the United States, Materion Corporation, and from
interviews with industry experts.
    The nine application groups included in this analysis were
identified based on information obtained during preliminary rulemaking
activities that included a SBRFA panel, a comprehensive review of the
published literature, stakeholder input, and an analysis of IMIS data
collected during OSHA workplace inspections where detectable airborne
beryllium was found. The nine application groups and their
corresponding section numbers in Chapter IV of the PEA are:
     Section 3--Beryllium Production,
     Section 4--Beryllium Oxide Ceramics and Composites,
     Section 5--Nonferrous Foundries,
     Section 6--Secondary Smelting, Refining, and Alloying,
     Section 7--Precision Turned Products,
     Section 8--Copper Rolling, Drawing, and Extruding,
     Section 9--Fabrication of Beryllium Alloy Products,
     Section 10--Welding, and
     Section 11--Dental Laboratories.
    OSHA developed exposure profiles by job or group of jobs using
exposure data at the application, operation or task level to the extent
that such data were available. In those instances where there were
insufficient exposure data to create a profile, OSHA used analogous
operations to characterize the operations. The exposure profiles
represent baseline conditions with existing controls for each operation
with potential exposure. For job groups where exposures were above the
proposed TWA PEL of 0.2 [mu]g/m\3\, OSHA identified additional controls
that could be implemented to reduce employee exposures to beryllium.
These included engineering controls, such as process containment, local
exhaust ventilation and wet methods for dust suppression, and work
practices, such as improved housekeeping and the prohibition of
compressed air for cleaning beryllium-contaminated surfaces.
    For the purposes of this technological feasibility assessment,
these nine application groups can be divided into three general
categories based on current exposure levels:
    (1) application groups in which current exposures for most jobs are
already below the proposed PEL of 0.2 [mu]g/m\3\;
    (2) application groups in which exposures for most jobs are below
the current PEL, but exceed the proposed PEL of 0.2 [mu]g/m\3\, and
therefore additional controls would be required; and
    (3) application groups in which exposures in one or more jobs
routinely exceed the current PEL, and therefore substantial reductions
in exposure would be required to achieve the proposed PEL.
    The majority of exposure measurements taken in the application
groups in the first category are already at or below the proposed PEL
of 0.2 [mu]g/m\3\, and most of the jobs with exposure to beryllium in
these four application groups have median exposures below the
alternative PEL of 0.1 [mu]g/m\3\ (See Table IX-5). These four
application groups include rolling, drawing, and extruding; fabrication
of beryllium alloy products; welding; and dental laboratories.
    The two application groups in the second category include:
precision turned products and secondary smelting. For these two groups,
the median exposures in most jobs are below the current PEL, but the
median exposure levels for some job groups currently exceed the
proposed PEL. Additional exposure controls and work practices could be
implemented that the Agency has preliminarily concluded would reduce
exposures to or below the proposed PEL for most jobs most of the time.
One exception is furnace operations in secondary smelting, in which the
median exposure exceeds the current PEL. Furnace operations involve
high temperatures that produce significant amounts of fumes and
particulate that can be difficult to contain. Therefore, the proposed
PEL may not be feasible for most furnace operations involved with
secondary smelting, and in some cases, respiratory protection would be
required to adequately protect furnace workers when exposures exceed
0.2 [mu]g/m\3\ despite the implementation of all feasible controls.
    Exposures in the third category of application groups routinely
exceed the current PEL for several jobs. The three application groups
in this category include: Beryllium production, beryllium oxide
ceramics production, and nonferrous foundries. The individual job
groups for which exposures exceed the current PEL are discussed in the
application group specific sections later in this summary, and
described in greater detail in the PEA. For the jobs that routinely
exceed the current PEL, OSHA identified additional exposure controls
and work practices that the Agency preliminarily concludes would reduce
exposures to or below the proposed PEL most of the time, with three
exceptions: Furnace operations in primary beryllium production and
nonferrous foundries, and shakeout operations at nonferrous foundries.
For these jobs, OSHA recognizes that even after installation of
feasible controls, respiratory protection may be needed to adequately
protect workers.
    In conclusion, the preliminary technological feasibility analysis
shows that for the majority of the job groups evaluated, exposures are
either already at or below the proposed PEL, or can be adequately
controlled with additional engineering and work practice controls.
Therefore, OSHA preliminarily concludes that the proposed PEL of 0.2
[mu]g/m\3\ is feasible for most operations most of the time. The
preliminary feasibility determination for the proposed PEL is also
supported by Materion Corporation, the sole primary beryllium
production company in the U.S., and by the United Steelworkers, who
jointly submitted a draft proposed standard that specified an exposure
limit of 0.2 [mu]g/m\3\ to OSHA (Materion and USW, 2012). The
technological feasibility analysis conducted for each application group
is briefly summarized below, and a more detailed discussion is
presented in Sections 3 through 11 of Chapter IV of the PEA (OSHA,
2014).
    Based on the currently available evidence, it is more difficult to
determine whether an alternative PEL of 0.1 [mu]g/m\3\ would also be
feasible in most operations. For some application groups, such as
fabrication of beryllium alloy products, a PEL of 0.1 [mu]g/m\3\
would almost certainly be feasible. In other application groups,
such as precision turned products, a PEL of 0.1 [mu]g/m\3\ appears
feasible, except for establishments working with high beryllium
content alloys. For application groups with the highest exposure,
the exposure monitoring data necessary to more fully evaluate the
effectiveness of exposure controls adopted after 2000 are not
currently available to OSHA, which makes it difficult to determine the
feasibility of achieving exposure levels at or below 0.1 [mu]g/m\3\.
    OSHA also evaluated the feasibility of a STEL of 2.0 [mu]g/m\3\,
and alternative STELs of 0.5 and 1.0 [mu]g/m\3\. An analysis of the
available short-term exposure measurements indicates that elevated
exposures can occur during short-term tasks such as those associated
with the operation and maintenance of furnaces at primary beryllium
production facilities, at nonferrous foundries, and at secondary
smelting operations. Peak exposure can also occur during the transfer
and handling of beryllium oxide powders. OSHA believes that in many
cases, reducing short-term exposures will be necessary to reduce
workers' TWA exposures to or below the proposed PEL. The majority of
the available short-term measurements are below 2.0 [mu]g/m\3\,
therefore OSHA preliminarily concludes that the proposed STEL of 2.0
[mu]g/m\3\ can be achieved for most operations most of the time. OSHA
recognizes that for a small number of tasks, short-term exposures may
exceed the proposed STEL, even after feasible control measures to
reduce TWA exposure to below the proposed PEL have been implemented,
and therefore assumes that the use of respiratory protection will
continue to be required for some short-term tasks. It is more difficult
based on the currently available evidence to determine whether the
alternative STEL of 1.0 [mu]g/m\3\ would also be feasible in most
operations based on lack of detail in the activities of the workers
presented in the data. OSHA expects additional use of respiratory
protection would be required for tasks in which peak exposures can be
reduced to less than 2.0 [mu]g/m\3\ but not less than 1.0 [mu]g/m\3\.
Due to limitations in the available sampling data and the higher
detection limits for short term measurements, OSHA could not determine
the percentage of the STEL measurements that are less than or equal to
0.5 [mu]g/m\3\. A detailed discussion of the STELs being considered by
OSHA is presented in Section 12 of Chapter IV of the PEA (OSHA, 2014).
    OSHA requests available exposure monitoring data and comments
regarding the effectiveness of currently implemented control measures
and the feasibility of the PELs under consideration, particularly the
proposed TWA PEL of 0.2 [mu]g/m\3\, the alternative TWA PEL of 0.1
[mu]g/m\3\, the proposed STEL of 2.0 [mu]g/m\3\, and the alternative
STEL of 1.0 [mu]g/m\3\ to inform the Agency's final feasibility
determinations.
Application Group Summaries
    This section summarizes the technological feasibility analysis for
each of the nine application groups affected by the proposed standard.
Chapter IV of the PEA, Technological Feasibility Analysis, identifies
specific jobs or job groups with potential exposure to beryllium, and
presents exposure profiles for each of these job groups (OSHA, 2014).
Control measures and work practices that OSHA believes can reduce
exposures are described along with preliminary conclusions regarding
the feasibility of the proposed PEL. Table IX-5, located at the end of
this summary, presents summary statistics for the personal breathing
zone samples taken to measure full-shift exposures to beryllium in each
application group. For the five application groups in which the median
exposure level for at least one job group exceeds the proposed PEL, the
sampling results are presented by job group. Table IX-5 displays the
number of measurements; the range, the mean and the median of the
measurement results; and the percentage of measurements less than 0.1
[mu]g/m\3\, less than or equal to the proposed PEL of 0.2 [mu]g/m\3\,
and less than or equal to the current PEL of 2.0 [mu]g/m\3\. A more
detailed discussion of exposure levels by job or job group for each
application group is provided in Chapter IV of the PEA, sections 3
through 11, along with a description of the available exposure
measurement data, existing controls, and additional controls that would
be required to achieve the proposed PEL.
Beryllium Production
    Only one primary beryllium production facility is currently in
operation in the United States, a plant owned and operated by Materion
Corporation,\15\ located in Elmore, Ohio. OSHA identified eight job
groups at this facility in which workers are exposed to beryllium.
These include: Chemical operations, powdering operations, production
support, cold work, hot work, site support, furnace operations, and
administrative work.
---------------------------------------------------------------------------

    \15\ Materion Corporation was previously named Brush Wellman. In
2011, subsequent to the collection of the information presented in
this chapter, the name changed. "Brush Wellman" is used whenever
the data being discussed pre-dated the name change.
---------------------------------------------------------------------------

    The Agency developed an exposure profile for each of these eight
job groups to analyze the distribution of exposure levels associated
with primary beryllium production. The job exposure profiles are based
primarily on full-shift personal breathing zone (PBZ) (lapel-type)
sample results from air monitoring conducted by Brush Wellman's primary
production facility in 1999 (Brush Wellman, 2004). Starting in 2000,
the company developed the Materion Worker Protection Program (MWPP), a
multi-faceted beryllium exposure control program designed to reduce
airborne exposures for the vast majority of workers to less than an
internally established exposure limit of 0.2 [mu]g/m\3\. According to
information provided by Materion, a combination of engineering
controls, work practices, and housekeeping were used together to reduce
average exposure levels to below 0.2 [mu]g/m\3\ for the majority of
workers (Materion Information Meeting, 2012). Also, two operations with
historically high exposures, the wet plant and pebble plants, were
decommissioned in 2000, thereby reducing average exposure levels.
Therefore, the samples taken prior to 2000 may overestimate current
exposures.
    Additional exposure samples were taken by NIOSH at the Elmore
facility from 2007 through 2008 (NIOSH, 2011). This dataset, which was
made available to OSHA by Materion, contains fewer samples than the
1999 survey. OSHA did not incorporate these samples into the exposure
profile due to the limited documentation associated with the sampling
data. The lack of detailed information for individual samples has made
it difficult for OSHA to correlate job classifications and identify the
working conditions associated with the samples. Sampling data provided
by Materion for 2007 and 2008 were not incorporated into the exposure
profiles because the data lacked specific information on jobs and
workplace conditions. In a meeting in May 2012 held between OSHA and
Materion Corporation at the Elmore facility, the Agency was able to
obtain some general information on the exposure control modifications
that Materion Corporation made between 1999 and 2007, but has been
unable to determine what specific controls were in place at the time
NIOSH conducted sampling (Materion Information Meeting, 2012).
    In five of the primary production job groups (i.e., hot work, cold
work, production support, site support, and administrative work), the
baseline exposure profile indicates that exposures are already lower
than the proposed PEL of 0.2 [mu]g/m\3\. Median exposure values for
these job groups range from nondetectable to 0.08 [mu]g/m\3\.
    For three of the job groups involved with primary beryllium
production, (i.e., chemical operations, powdering, and furnace
operations), the median exposure level exceeds the proposed PEL of 0.2
[mu]g/m\3\. Median exposure values for these job groups are 0.47, 0.37,
and 0.68 [mu]g/m\3\ respectively, and only 17 percent to 29 percent of
the available measurements are less than or equal to 0.2 [mu]g/m\3\.
Therefore, additional control measures for these job groups would be
required to achieve compliance with the proposed PEL. OSHA has
identified several engineering controls that the Agency preliminarily
concludes can reduce exposures in chemical processes and powdering
operations to less than or equal to 0.2 [mu]g/m\3\. In chemical
processes, these include fail-safe drum-handling systems, full
enclosure of drum-handling systems, ventilated enclosures around
existing drum positions, automated systems to prevent drum overflow,
and automated systems for container cleaning and disposal such as those
designed for hazardous powders in the pharmaceutical industry. Similar
engineering controls would reduce exposures in powdering operations. In
addition, installing remote viewing equipment (or other equally
effective engineering controls) to eliminate the need for workers to
enter the die-loading hood during die filling will reduce exposures
associated with this powdering task and reduce powder spills. Based on
the availability of control methods to reduce exposures for each of the
major sources of exposure in chemical operations, OSHA preliminarily
concludes that exposures at or below the proposed 0.2 [mu]g/m\3\ PEL
can be achieved in most chemical and powdering operations most of the
time. OSHA believes furnace operators' exposures can be reduced using
appropriate ventilation, including fume capture hoods, and other
controls to reduce overall beryllium levels in foundries, but is not
certain whether the exposures of furnace operators can be reduced to
the proposed PEL with currently available technology. OSHA requests
additional information on current exposure levels and the effectiveness
of potential control measures for primary beryllium production
operations to further refine this analysis.
Beryllium Oxide Ceramics Production
    OSHA identified seven job groups involved with beryllium oxide
ceramics production. These include: Material preparation operator,
forming operator, machining operator, kiln operator, production
support, metallization, and administrative work. Four of these jobs
(material preparation, forming operator, machining operator and kiln
operator) work directly with beryllium oxides, and therefore these jobs
have a high potential for exposure. The other three job groups
(production support work, metallization, and administrative work) have
primarily indirect exposure that occurs only when workers in these jobs
groups enter production areas and are exposed to the same sources to
which the material preparation, forming, machining and kiln operators
are directly exposed. However, some production support and
metallization activities do require workers to handle beryllium
directly, and workers performing these tasks may at times be directly
exposed to beryllium.
    The Agency developed exposure profiles for these jobs based on air
sampling data from four sources: (1) Samples taken between 1994 and
2003 at a large beryllium oxide ceramics facility, (2) air sampling
data obtained during a site visit to a primary beryllium oxide ceramics
producer, (3) a published report that provides information on beryllium
oxide ceramics product manufacturing for a slightly earlier time
period, and (4) exposure data from OSHA's Integrated Management
Information System (OSHA, 2009). The exposure profile indicates that
the three job groups with mostly indirect exposure (production support
work, metallization, and administrative work) already achieve the
proposed PEL of 0.2 [mu]g/m\3\. Median exposure sample values for these
job groups did not exceed 0.06 [mu]g/m\3\.
    The four job groups with direct exposure had higher exposures. In
forming operations and machining operations, the median exposure levels
of 0.18 and 0.15 ug/m\3\, respectively, are below the proposed PEL,
while the median exposure levels for material preparation and kiln
operations of 0.41 [mu]g/m\3\ and 0.25 [mu]g/m\3\, respectively, exceed
the proposed PEL.
    The profile for the directly exposed jobs may overestimate
exposures due to the preponderance of data from the mid-1990s, a time
period prior to the implementation of a variety of exposure control
measures introduced after 2000. In forming operations, 44 percent of
sample values in the exposure profile exceeded 0.2 ug/m\3\. However,
the median exposure levels for some tasks, such as small-press and
large-press operation, based on sampling conducted in 2003 were below
0.1 [mu]g/m\3\. The exposure profile for kiln operation was based on
three samples taken from a single facility in 1995, and are all above
0.2 ug/m\3\. Since then, exposures at the facility have declined due to
changes in operations that reduced the amount of time kiln operators
spend in the immediate vicinity of the kilns, as well as the
discontinuation of a nearby high-exposure process. More recent
information communicated to OSHA suggests that current exposures for
kiln operators at the facility are currently below 0.1 ug/m\3\.
Exposures in machining operations, most of which were already below 0.2
ug/m\3\ during the 1990s, may have been further reduced since then
through improved work practices and exposure controls (PEA Chapter IV,
Section 7). For forming, kiln, and machining operations, OSHA
preliminarily concludes that the installation of additional controls
such as machine interlocks (for forming) and improved enclosures and
ventilation will reduce exposures to or below the proposed PEL most of
the time. OSHA requests information on recent exposure levels and
controls in beryllium oxide forming and kiln operations to help the
Agency evaluate the effectiveness of available exposure controls for
this application group.
    In the exposure profile for material preparation, 73 percent of
sample values exceeded 0.2 ug/m\3\. As with other parts of the exposure
profile, exposure values from the mid-1990s may overestimate airborne
beryllium levels for current operations. During most material
preparation tasks, such as material loading, transfer, and spray
drying, OSHA preliminarily concludes that exposures can be reduced to
or below 0.2 [mu]g/m\3\ with process enclosures, ventilation hoods, and
improved housekeeping procedures. However, OSHA acknowledges that peak
exposures from some short-term tasks such as servicing of the spray
chamber might continue to drive the TWA exposures above 0.2 [mu]g/m\3\
on days when these material preparation tasks are performed.
Respirators may be needed to protect workers from exposures above the
proposed TWA PEL during these tasks.\16\ OSHA notes that material
preparation for production of beryllium oxide ceramics currently
takes place at only two facilities in the United States.
---------------------------------------------------------------------------

    \16\ One facility visited by ERG has reportedly modified this
process to reduce worker exposures, but OSHA has no data to quantify
the reduction.
---------------------------------------------------------------------------

Nonferrous Foundries
    OSHA identified eight job groups in aluminum and copper foundries
with beryllium exposure: Molding, material handling, furnace operation,
pouring, shakeout operation, abrasive blasting, grinding/finishing, and
maintenance. The Agency developed exposure profiles based on an air
monitoring survey conducted by NIOSH in 2007, a Health Hazard
Evaluation (HHE) conducted by NIOSH in 1975, a site visit by ERG in
2003, a site visit report from 1999 by the California Cast Metals
Association (CCMA); and two sets of data from air monitoring surveys
obtained from Materion in 2004 and 2010.
    The exposure profile indicates that in foundries processing
beryllium alloys, six of the eight job groups have median exposures
that exceed the proposed PEL of 0.2 [mu]g/m\3\ with baseline working
conditions. One exception is grinding/finishing operations, where the
median value is 0.12 [mu]g/m\3\ and 73 percent of exposure samples are
below 0.2 [mu]g/m\3\. The other exception is abrasive blasting. The
samples for abrasive blasting used in the exposure profile were
obtained during blasting operations using enclosed cabinets, and all 5
samples were below 0.2 [mu]g/m\3\. Exposures for other job groups
ranged from just below to well above the proposed PEL, including molder
(all samples above 0.2 [mu]g/m\3\), material handler (1 sample total,
above 0.2 [mu]g/m\3\), furnace operator (81.8 percent of samples above
0.2 [mu]g/m\3\), pouring operator (60 percent of samples above 0.2
[mu]g/m\3\), shakeout operator (1 sample total, above 0.2 [mu]g/m\3\),
and maintenance worker (50 percent of samples above 0.2 [mu]g/m\3\).
    In some of the foundries at which the air samples included in the
exposure profile were collected, there are indications that the
ventilation systems were not properly used or maintained, and dry
sweeping or brushing and the use of compressed air systems for cleaning
may have contributed to high dust levels. OSHA believes that exposures
in foundries can be substantially reduced by improving and properly
using and maintaining the ventilation systems; switching from dry
brushing, sweeping and compressed air to wet methods and use of HEPA-
filtered vacuums for cleaning molds and work areas; enclosing
processes; automation of high-exposure tasks; and modification of
processes (e.g., switching from sand-based to alternative casting
methods). OSHA preliminarily concludes that these additional
engineering controls and modified work practices can be implemented to
achieve the proposed PEL most of the time for molding, material
handling, maintenance, abrasive blasting, grinding/finishing, and
pouring operations at foundries that produce aluminum and copper
beryllium alloys.
    The Agency is less confident that exposure can be reliably reduced
to the proposed PEL for furnace and shakeout operators. Beryllium
concentrations in the proximity of the furnaces are typically higher
than in other areas due to the fumes generated and the difficulty of
controlling emissions during furnace operations. The exposure profile
for furnace operations shows a median beryllium exposure level of 1.14
[mu]g/m\3\. OSHA believes that furnace operators' exposures can be
reduced using local exhaust ventilation and other controls to reduce
overall beryllium levels in foundries, but it is not clear that they
can be reduced to the proposed PEL with currently available technology.
In foundries that use sand molds, the shakeout operation typically
involves removing the freshly cast parts from the sand mold using a
vibrating grate that shakes the sand from castings. The shakeout
equipment generates substantial amounts of airborne dust that can be
difficult to contain, and therefore shakeout operators are typically
exposed to high dust levels. During casting of beryllium alloys, the
dust may contain beryllium and beryllium oxide residues dislodged from
the casting during the shakeout process. The exposure profile for the
shakeout operations contains only one result of 1.3 [mu]g/m\3\. This
suggests that a substantial reduction would be necessary to achieve
compliance with a proposed PEL of 0.2 [mu]g/m\3\. OSHA requests
additional information on recent employee exposure levels and the
effectiveness of dust controls for shakeout operations for copper and
aluminum alloy foundries.
Secondary Smelting, Refining, and Alloying
    OSHA identified two job groups in this application group with
exposure to beryllium: Mechanical process operators and furnace
operations workers. Mechanical operators handle and treat source
material, and furnace operators run heating processes for refining,
melting, and casting metal alloy. OSHA developed exposure profiles for
these jobs based on exposure data from ERG site visits to a precious/
base metals recovery facility and a facility that melts and casts
beryllium-containing alloys, both conducted in 2003. The available
exposure data for this application group are limited, and therefore,
the exposure profile is supplemented in part by summary data presented
in secondary sources of information on beryllium exposures in this
application group.
    The exposure profile for mechanical processing operators indicates
low exposures (3 samples less than 0.2 [mu]g/m\3\), even though these
samples were collected at a facility where the ventilation system was
allowing visible emissions to escape exhaust hoods. Summary data from
studies and reports published in 2005-2009 showed that mechanical
processing operator exposures averaged between 0.01 and 0.04 [mu]g/m\3\
at facilities where mixed or electronic waste including beryllium alloy
parts were refined. Based on these results, OSHA preliminarily
concludes that the proposed PEL is already achieved for most mechanical
processing operations most of the time, and exposures could be further
reduced through improved ventilation system design and other measures,
such as process enclosures.
    As with furnace operations examined in other application groups,
the exposure profile indicates higher worker exposures for furnace
operators in the secondary smelting, refining, and alloying application
group (six samples with a median of 2.15 [mu]g/m\3\, and 83.3 percent
above 0.2 [mu]g/m\3\). The two lowest samples in this job's exposure
profile (0.03 and 0.5 [mu]g/m\3\) were collected at a facility engaged
in recycling and recovery of precious metals where work with beryllium-
containing material is incidental. At this facility, the furnace is
enclosed and fumes are ducted into a filtration system. The four higher
samples, ranging from 1.92 to 14.08 [mu]g/m\3\, were collected at a
facility engaged primarily in beryllium alloying operations, where
beryllium content is significantly higher than in recycling and
precious metal recovery activities, the furnace is not enclosed, and
workers are positioned directly in the path of the exhaust ventilation
over the furnace. OSHA believes these exposures could be reduced by
enclosing the furnace and repositioning the worker, but is not certain
whether the reduction achieved would be enough to bring exposures down
to the proposed PEL. Based on the limited number of samples in the
exposure profile and surrogate data from furnace operations, the
proposed PEL may not be feasible for furnace work in beryllium recovery and
alloying, and respirators may be necessary to protect employees
performing these tasks.
Precision Turned Products
    OSHA's preliminary feasibility analysis for precision turned
products focuses on machinists who work with beryllium-containing
alloys. The Agency also examined the available exposure data for non-
machinists and has preliminarily concluded that, in most cases,
controlling the sources of exposures for machinists will also reduce
exposures for other job groups with indirect exposure when working in
the vicinity of machining operations.
    OSHA developed exposure profiles based on exposure data from four
NIOSH surveys conducted between 1976 and 2008; ERG site visits to
precision machining facilities in 2002, 2003, and 2004; case study
reports from six facilities machining copper-beryllium alloys; and
exposure data collected between 1987 and 2001 by the U.S. Navy
Environmental Health Center (NEHC). Analysis of the exposure data
showed a substantial difference between the median exposure level for
workers machining pure beryllium and/or high-beryllium alloys compared
to workers machining low-beryllium alloys. Most establishments in the
precision turned products application group work only with low-
beryllium alloys, such as copper-beryllium. A relatively small number
of establishments (estimated at 15) specialize in precision machining
of pure beryllium and/or high-beryllium alloys.
    The exposure profile indicates that machinists working with low-
beryllium alloys have mostly low exposure to airborne beryllium.
Approximately 85 percent of the 80 exposure results are less than or
equal to 0.2 [mu]g/m\3\, and 74 percent are less than or equal to 0.1
[mu]g/m\3\. Some of the results below 0.1 [mu]g/m\3\ were collected at
a facility where machining operations were enclosed, and metal cutting
fluids were used to control the release of airborne contaminants.
Higher results (0.1 [mu]g/m\3\-1.07 [mu]g/m\3\) were found at a
facility where cutting and grinding operations were conducted in
partially enclosed booths equipped with LEV, but some LEV was not
functioning properly. A few very high results (0.77 [mu]g/m\3\-24
[mu]g/m\3\) were collected at a facility where exposure controls were
reportedly inadequate and poor work practices were observed (e.g.,
improper use of downdraft tables, use of compressed air for cleaning).
Based on these results, OSHA preliminarily concludes that exposures
below 0.2 [mu]g/m\3\ can be achieved most of the time for most
machinists at facilities dealing primarily with low-beryllium alloys.
OSHA recognizes that higher exposures may sometimes occur during some
tasks where exposures are difficult to control with engineering
methods, such as cleaning, and that respiratory protection may be
needed at these times.
    Machinists working with high-beryllium alloys have higher exposure
than those working with low-beryllium alloys. This difference is
reflected in the exposure profile for this job, where the median of
exposure is 0.31 [mu]g/m\3\ and 75 percent of samples exceed the
proposed PEL of 0.2 [mu]g/m\3\. The exposure profile was based on two
machining facilities at which LEV was used and machining operations
were performed under a liquid coolant flood. Like most facilities where
pure beryllium and high-beryllium alloys are machined, these facilities
also used some combination of full or partial enclosures, as well as
work practices to minimize exposure such as prohibiting the use of
compressed air and dry sweeping and implementing dust migration control
practices to prevent the spread of beryllium contamination outside
production areas. At one facility machining high-beryllium alloys,
where all machining operations were fully enclosed and ventilated,
exposures were mostly below 0.1 [mu]g/m\3\ (median 0.035 [mu]g/m\3\,
range 0.02-0.11 [mu]g/m\3\). Exposures were initially higher at the
second facility, where some machining operations were not enclosed,
existing LEV system were in need of upgrades, and some exhaust systems
were improperly positioned. Samples collected there in 2003 and 2004
were mostly below the proposed PEL in 2003 (median 0.1 [mu]g/m\3\) but
higher in 2004 (median 0.25 [mu]g/m\3\), and high exposure means in
both years (1.65 and 0.68 [mu]g/m\3\ respectively) show the presence of
high exposure spikes in the facility. However, the facility reported
that measures to reduce exposure brought almost all machining exposures
below 0.2 [mu]g/m\3\ in 2006. With the use of fully enclosed machines
and LEV and work practices that minimize worker exposures, OSHA
preliminarily concludes that the proposed PEL is feasible for the vast
majority of machinists working with pure beryllium and high-beryllium
alloys. OSHA recognizes that higher exposures may sometimes occur
during some tasks where exposures are difficult to control with
engineering methods, such as machine cleaning and maintenance, and that
respiratory protection may be needed at these times.
Copper Rolling, Drawing, and Extruding
    OSHA's exposure profile for copper rolling, drawing, and extruding
includes four job groups with beryllium exposure: strip metal
production, rod and wire production, production support, and
administrative work. Exposure profiles for these jobs are based on
personal breathing zone lapel sampling conducted at the Brush Wellman
Reading, Pennsylvania, rolling and drawing facility from 1977 to 2000.
    Prior to 2000, the Reading facility had limited engineering
controls in place. Equipment in use included LEV in some operations,
HEPA vacuums for general housekeeping, and wet methods to control loose
dust in some rod and wire production operations. The exposure profile
shows very low exposures for all four job groups. All had median
exposure values below 0.1 [mu]g/m\3\, and in strip metal production,
production support, and administrative work, over 90 percent of samples
were below 0.1 [mu]g/m\3\. In rod and wire production, 70 percent of
samples were below 0.1 [mu]g/m\3\.
    To characterize exposures in extrusion, OSHA examined the results
of an industrial hygiene survey of a copper-beryllium extruding process
conducted in 2000 at another facility. The survey reported eight PBZ
samples, which were not included in the exposure profile because of
their short duration (2 hours). Samples for three of the four jobs
involved with the extrusion process (press operator, material handler,
and billet assembler) were below the limit of detection (LOD) (level
not reported). The two samples for the press operator assistant, taken
when the assistant was buffing, sanding, and cleaning extrusion tools,
were very high (1.6 and 1.9 [mu]g/m\3\). Investigators recommended a
ventilated workstation to reduce exposure during these activities.
    In summary, exposures at or below 0.2 [mu]g/m\3\ have already been
achieved for most jobs in rolling, drawing, and extruding operations,
and OSHA preliminarily concludes that the proposed PEL of 0.2 [mu]g/
m\3\ is feasible for this application group. For jobs or tasks with
higher exposures, such as tool refinishing, use of exposure controls
such as local exhaust ventilation can help reduce workers' exposures.
The Agency recognizes the limitations of the available data, which were
drawn from two facilities and did not include full-shift PBZ samples
for extrusion. OSHA requests additional exposure data from other
facilities in this application group, especially data from facilities
where extrusion is performed.
Fabrication of Beryllium Alloy Products
    This application group includes the fabrication of beryllium alloy
springs, stampings, and connectors for use in electronics. The exposure
profile is based on a study conducted at four precision stamping
companies; a NIOSH report on a spring and stamping company; an ERG site
visit to a precision stamping, forming, and plating establishment; and
exposure monitoring results from a stamping facility presented at the
American Industrial Hygiene Conference and Exposition in 2007. The
exposure profiles for this application group include three jobs:
chemical processing operators, deburring operators, and assembly
operators. Other jobs for which all samples results were below 0.1
[mu]g/m\3\ are not shown in the profile.
    For the three jobs in the profile, the majority of exposure samples
were below 0.1 [mu]g/m\3\ (deburring operators, 79 percent; chemical
processing operators, 81 percent; assembly operators, 93 percent).
Based on these results, OSHA preliminarily concludes that the proposed
PEL is feasible for this application group. The Agency notes that a few
exposures above the proposed PEL were recorded for the chemical
processing operator (in plating and bright cleaning) and for deburring
(during corn cob deburring in an open tumbling mill). OSHA believes the
use of LEV, improved housekeeping, and work practice modifications
would reduce the frequency of excursions above the proposed PEL.
Welding
    Most of the samples in OSHA's exposure profile for welders in
general industry were collected between 1994 and 2001 at two of Brush
Wellman's alloy strip distribution centers, and in 1999 at Brush
Wellman's Elmore facility. At these facilities, tungsten inert gas
(TIG) welding was conducted on beryllium alloy strip. Seven samples in
the exposure profile came from a case study conducted at a precision
stamping facility, where airborne beryllium levels were very low (see
previous summary, Fabrication of Beryllium Alloy Products). At this
facility, resistance welding was performed on copper-beryllium parts,
and welding processes were automated and enclosed.
    Most of the sample results in the welding exposure profile were
below 0.2 [mu]g/m\3\. Of the 44 welding samples in the profile, 75
percent were below 0.2 [mu]g/m\3\ and 64 percent were below 0.1 [mu]g/
m\3\, with most values between 0.01 and 0.05 [mu]g/m\3\. All but one of
the 16 exposure samples above 0.1 [mu]g/m\3\ were collected in Brush
Wellman's Elmore facility in 1999. According to company
representatives, these higher exposure levels may have been due to
beryllium oxide that can form on the surface of the material as a
result of hot rolling. All seven samples from the precision stamping
facility were below the limit of detection. Based on these results,
OSHA preliminarily concludes that the proposed PEL of 0.2 [mu]g/m\3\ is
feasible for most welding operations in general industry.
Dental Laboratories
    OSHA's exposure profile for dental technicians includes sampling
results from a site visit conducted by ERG in 2003; a study of six
dental laboratories published by Rom et al. in 1984; a data set of
exposure samples collected between 1987 and 2001, on dental technicians
working for the U.S. Navy; and a docket submission from CMP Industries
including two samples from a large commercial dental laboratory using
nickel-beryllium alloy. Information on exposure controls in these
facilities suggests that controls in some cases may have been absent or
improperly used.
    The exposure profile indicates that 52 percent of samples are less
than or equal to 0.2 [mu]g/m\3\. However, the treatment of
nondetectable samples in the feasibility analysis may overestimate many
of the sample values in the exposure profile. Twelve of the samples in
the profile are nondetectable for beryllium. In the exposure profile,
these were assigned the highest possible value, the limit of detection
(LOD). For eight of the nondetectable samples, the LOD was reported as
0.2 [mu]g/m\3\. For the other four nondetectable samples, the LOD was
between 0.23 and 0.71 [mu]g/m\3\. If the true values for these four
nondetectable samples are actually less than or equal to the assigned
value of 0.2 [mu]g/m\3\, then the true percentage of profile sample
values less than or equal to 0.2 [mu]g/m\3\ is between 52 and 70
percent. Of the sample results with detectable beryllium above 0.2
[mu]g/m\3\, some were collected in 1984 at facilities studied by Rom et
al., who reported that they occurred during grinding with LEV that was
improperly used or, in one case, not used at all. Others were collected
at facilities where little contextual information was available to
determine what control equipment or work practices might have reduced
exposures.
    Based on this information, OSHA preliminarily concludes that
beryllium exposures for most dental technicians are already below 0.2
[mu]g/m\3\ most of the time. OSHA furthermore believes that exposure
levels can be reduced to or below 0.1 [mu]g/m\3\ most of the time via
material substitution, engineering controls, and work practices.
Beryllium-free alternatives for casting dental appliances are readily
available from commercial sources, and some alloy suppliers have
stopped carrying alloys that contain beryllium. For those dental
laboratories that continue to use beryllium alloys, exposure control
options include properly designed, installed, and maintained LEV
systems (equipped with HEPA filters) and enclosures; work practices
that optimize LEV system effectiveness; and housekeeping methods that
minimize beryllium contamination in the workplace. In summary, OSHA
preliminarily concludes that the proposed PEL is feasible for dental
laboratories.

                                   Table IX-5--Beryllium Full-Shift PBZ Samples by Application/Job Group ([mu]g/m\3\)
--------------------------------------------------------------------------------------------------------------------------------------------------------
      Application/Job group               N                Range               Mean           Median           %< 0.1          %<=0.2          %<=2.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
Be Production Operations (Section
 3)
    Furnace Operations...........             172  0.05 to 254                      3.80            0.68               5              17              82
    Chemical Operations..........              20  0.05 to 9.6                      1.02            0.47               5              15              95
    Powdering Operations.........              72  0.06 to 11.5                     0.82            0.37              11              29              94
    Production Support...........             861  0.02 to 22.7                     0.51            0.08              56              71              94
    Cold Work....................             555  0.04 to 24.9                     0.31            0.08              61              80              98
    Hot Work.....................             297  0.01 to 2.21                     0.12            0.06              69              88              99
    Site Support.................             879  0.05 to 4.22                     0.11            0.05              81              92              99
    Administrative...............             981  0.05 to 4.54                     0.10            0.05              85              94              99
Be Oxide Ceramics (Section 4)
    Material Preparation Operator              77  0.02 to 10.6                     1.01            0.41              13              27              90
    Forming Operator.............             408  0.02 to 53.2                     0.48            0.18              27              56              99
    Machining Operator...........             355  0.01 to 5.0                      0.32            0.15              37              63              98
    Kiln Operator................               3  0.22 to 0.36                     0.28            0.25               0               0             100
    Production Support Worker....             119  0.02 to 7.7                      0.21            0.05              68              88              98
    Metallization Worker.........              36  0.02 to 0.62                     0.15            0.06              55              69             100
    Administrative...............             185  0.02 to 1.2                      0.06            0.05              93              98             100
Aluminum and Copper Foundries
 (Section 5)
    Furnace Operator.............              11  0.2 to 19.76                     4.41            1.14               0              18              64
    Pouring Operator.............               5  0.2 to 2.2                       1.21            1.40               0              40              60
    Shakeout Operator............               1  1.3                              1.30            1.30               0               0             100
    Material Handler.............               1  0.93                             0.93            0.93               0               0             100
    Molder.......................               8  0.24 to 2.29                     0.67            0.45               0               0              88
    Maintenance..................              78  0.05 to 22.71                    0.87            0.21              15              50              96
    Abrasive Blasting Operator...               5  0.05 to 0.15                     0.11            0.12              40             100             100
    Grinding/finishing Operator..              56  0.01 to 4.79                     0.31            0.05              59              73              95
Secondary Smelting (Section 6)
    Furnace operations worker....               6  0.03 to 14.1                     3.85            2.15              17              17              50
    Mechanical processing                       3  0.03 to 0.2                      0.14            0.20              33             100             100
     operator.
Precision Turned Products
 (Section 7)
    High Be Content Alloys.......              80  0.02 to 7.2                      0.72            0.31              14              25              92
    Low Be Content Alloys........              59  0.005 to 24                      0.45            0.01              74              85              96
Rolling, Drawing, and Extruding               650  0.006 to 7.8                     0.11           0.024              86              93              99
 (Section 8)
Alloy Fabrication (Section 9)                  71  0.004 to 0.42                   0.056           0.025              83              94             100
Welding: Beryllium Alloy (Section              44  0.005 to 2.21                    0.19            0.02              64              75              98
 10)
Dental Laboratories (Section 11)               23  0.02 to 4.4                      0.74             0.2              13              52              87
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: OSHA, Directorate of Standards and Guidance, Office of Regulatory Analysis.

E. Costs of Compliance

    Chapter V of the PEA in support of the proposed beryllium rule
provides a detailed assessment of the costs to establishments in all
affected application groups of reducing worker exposures to beryllium
to an eight-hour time-weighted average (TWA) permissible exposure limit
(PEL) of 0.2 [mu]g/m\3\ and to the proposed short-term exposure limit
(STEL) of 2.0 [mu]g/m\3\, as well as of complying with the proposed
standard's ancillary provisions. OSHA describes its methodology and
sources in more detail in Chapter V. OSHA's preliminary cost assessment
is based on the Agency's technological feasibility analysis presented
in Chapter IV of the PEA; analyses of the costs of the proposed
standard conducted by OSHA's contractor, Eastern Research Group (ERG);
and the comments submitted to the docket in response to the request for
information (RFI) and as part of the SBREFA process.
    As shown in Table IX-7 at the end of this section, OSHA estimates
that the proposed standard would have an annualized cost of $37.6
million. All cost estimates are expressed in 2010 dollars and were
annualized using a discount rate of 3 percent, which--along with 7
percent--is one of the discount rates recommended by OMB.\17\
Annualization periods for expenditures on equipment are based on
equipment life, and one-time costs are annualized over a 10-year
period.
---------------------------------------------------------------------------

    \17\ Appendix V-A of the PEA presents costs by NAICS industry
and establishment size categories using, as alternatives, a 7
percent discount rate--shown in Table V-A-1--and a 0 percent
discount rate--shown in Table V-A-2.
---------------------------------------------------------------------------

    The estimated costs for the proposed beryllium rule represent the
additional costs necessary for employers to achieve full compliance.
They do not include costs associated with current compliance that may
already have been achieved with regard to existing beryllium
requirements or costs necessary to achieve compliance with existing
beryllium requirements, to the extent that some employers may currently
not be fully complying with applicable regulatory requirements.
    Throughout this section and in the PEA, OSHA presents cost formulas
in the text, usually in parentheses, to help explain the derivation of
cost estimates for individual provisions. Because the values used in
the formulas shown in the text are shown only to the second decimal
place, while the actual spreadsheet formulas used to create final costs
are not limited to two decimal places, the calculation using the
presented formula will sometimes differ slightly from the presented
total in the text, which is the actual and mathematically correct total
as shown in the tables.
1. Compliance With the Proposed PEL/STEL
    OSHA's estimate of the costs for affected employers to comply with
the proposed PEL of 0.2 [mu]g/m\3\ and the proposed STEL of 2.0 [mu]g/
m\3\ consists of two parts. First, costs are estimated for the
engineering controls, additional studies and custom design requirements
to implement those controls, work practices, and specific training
required for those work practices (as opposed to general training in
compliance with the rule) needed for affected employers to meet the
proposed PEL and STEL, as well as opportunity costs (lost productivity)
that may result from working with some of the new controls. In most
cases, the PEA breaks out these costs, but in other instances some or
all of the costs are shortened simply to "engineering controls" in
the text, for convenience. Second, for employers unable to meet the
proposed PEL and STEL using engineering controls and work practices
alone, costs are estimated for respiratory protection sufficient to
reduce worker exposure to the proposed PEL and STEL or below.
    In the technological feasibility analysis presented in Chapter IV
of the PEA, OSHA concluded that implementing all engineering controls
and work practices necessary to reach the proposed PEL will, except for
a small residual group (accounting for about 6 percent of all exposures
above the STEL), also reduce exposures below the STEL. However, based
on the nature of the processes this residual group is likely to be
engaged in, the Agency expects that employees would already be using
respirators to comply with the PEL under the proposed standard.
Therefore, with the proposed STEL set at ten times the proposed PEL,
the Agency has preliminarily determined that engineering controls, work
practices, and (when needed) respiratory protection sufficient to meet
the proposed PEL are also sufficient to meet the proposed STEL. For
that reason, OSHA has taken no additional costs for affected employers
to meet the proposed STEL. The Agency invites comment and requests that
the public provide data on this issue.
a. Engineering Controls
    For this preliminary cost analysis, OSHA estimated the necessary
engineering controls and work practices for each affected application
group according to the exposure profile of current exposures by
occupation presented in Chapter III of the PEA. Under the requirements
of the proposed standard, employers would be required to implement
engineering or work practice controls whenever beryllium exposures
exceed the proposed PEL of 0.2 [mu]g/m\3\ or the proposed STEL of 2.0
[mu]g/m\3\.
    In addition, even if employers are not exposed above the proposed
PEL or proposed STEL, paragraph (f)(2) of the proposed standard would
require employers at or above the action level to use at least one
engineering or work practice control to minimize worker exposure. Based
on the technological feasibility analysis presented in Chapter IV of
the PEA, OSHA has determined that, for only two job categories in two
application groups--chemical process operators in the Stamping, Spring
and Connection Manufacture application group and machinists in the
Machining application group--do the majority of facilities at or above
the proposed action level, but below the proposed PEL, lack the
baseline engineering or work controls required by paragraph (f)(2).
Therefore, OSHA has estimated costs, where appropriate, for employers
in these two application groups to comply with paragraph (f)(2).
    By assigning controls based on application group, the Agency is
best able to identify those workers with exposures above the proposed
PEL and to design a control strategy for, and attribute costs
specifically to, these groups of workers. By using this approach,
controls are targeting those specific processes, emission points, or
procedures that create beryllium exposures. Moreover, this approach
allows OSHA to assign costs for technologies that are demonstrated to
be the most effective in reducing exposures resulting from a particular
process.
    In developing cost estimates, OSHA took into account the wide
variation in the size or scope of the engineering or work practice
changes necessary to minimize beryllium exposures based on technical
literature, judgments of knowledgeable consultants, industry observers,
and other sources. The resulting cost estimates reflect the
representative conditions for the affected workers in each application
group and across all work settings. In all but a handful of cases (with
the exceptions noted in the PEA), all wage costs come from the 2010
Occupational Employment Statistics (OES) of the Bureau of Labor
Statistics (BLS, 2010a) and utilize the median wage for the appropriate
occupation. The wages used include a 30.35 percent markup for fringe
benefits as a percentage of total compensation, which is the average
percentage markup for fringe benefits for all civilian workers from the
2010 Employer Costs for Employee Compensation of the BLS (BLS, 2010b).
All descriptions of production processes are drawn from the relevant
sections of Chapter IV of the PEA.
    The specific engineering costs for each of the applications groups,
and the NAICS industries that contain those application groups, are
discussed in Chapter V of the PEA. Like the industry profile and
technological feasibility analysis presented in other PEA chapters,
Chapter V of the PEA presents engineering control costs for the
following application groups:

Beryllium Production
Beryllium Oxide, Ceramics & Composites Production
Nonferrous Foundries
Stamping, Spring and Connection Manufacture
Secondary Smelting, Refining, and Alloying
Copper Rolling, Drawing, and Extruding
Secondary Smelting, Refining, and Alloying
Precision Machining
Welding
    Dental Laboratories

    The costs within these application groups are estimated by
occupation and/or operation. One application group could have multiple
occupations, operations, or activities where workers are exposed to
levels of beryllium above the proposed PEL, and each will need its own
set of controls. The major types of engineering controls needed to
achieve compliance with the proposed PEL include ventilation equipment,
pharmaceutical-quality high-containment isolators, decontainment
chambers, equipment with controlled water sprays, closed-circuit remote
televisions, enclosed cabs, conveyor enclosures, exhaust hoods, and
portable local-exhaust-ventilation (LEV) systems. Capital costs and
annual operation and maintenance (O&M) costs, as well as any other
annual costs, are estimated for the set of engineering controls
estimated to be necessary for limiting beryllium exposures for each
occupation or operation within each application group.
    Tables V-2 through V-10 in Chapter V of the PEA summarize capital,
maintenance, and operating costs for each application group
disaggregated by NAICS code. Table IX-7 at the end of this section
breaks out the costs of engineering controls/work practices by
application group and NAICS code.
    Some engineering control costs are estimated on a per-worker basis
and then multiplied by the estimated number of affected workers--as
identified in Chapter III: Profile of Affected Industries in the PEA--
to arrive at a total cost for a particular control within a particular
application group. This worker-based method is necessary because--even
though OSHA has data on the number of firms in each affected industry,
the occupations and industrial activities that result in worker
exposure to beryllium, and the exposure profile of at-risk
occupations--the Agency does not have a way to match up these data at
the firm level. Nor does the Agency have establishment-specific data on
worker exposure to beryllium for all establishments, or even
establishment-specific data on the level of activity involving worker
exposure to beryllium. Thus, OSHA could not always directly estimate
per-affected-establishment costs, but instead first had to estimate
aggregate compliance costs (using an estimated per-worker cost
multiplied by the number of affected workers) and then calculate the
average per-affected-establishment costs by dividing those aggregate
costs by the number of affected establishments. This method, while
correct on average, may under- or over-state costs for certain firms.
For other controls that are implemented on a fixed-cost basis per
establishment (e.g., creating a training program, writing a control
program), the costs are estimated on an establishment basis, and these
costs were multiplied by the number of affected establishments in the
given application group to obtain total control costs.
    In developing cost estimates, the Agency sometimes had to make
case-specific judgments about the number of workers affected by each
engineering control. Because work environments vary within occupations
and across establishments, there are no definitive data on how many
workers are likely to have their exposures reduced by a given set of
controls. In the smallest establishments, especially those that might
operate only one shift per day, some controls would limit exposures for
only a single worker in one specific affected occupation. More
commonly, however, several workers are likely to benefit from each
enhanced engineering control. Many controls were judged to reduce
exposure for employees in multi-shift work or where workstations are
used by more than one worker per shift.
    In general, improving work practices involves operator training,
actual work practice modifications, and better enforcement or
supervision to minimize potential exposures. The costs of these process
improvements consist of the supervisor and worker time involved and
would include the time spent by supervisors to develop a training
program.
    Unless otherwise specified, OSHA viewed the extent to which
exposure controls are already in place to be reflected in the
distribution of exposures at levels above the proposed PEL among
affected workers. Thus, for example, if 50 percent of workers in a
given occupation are found to be exposed to beryllium at levels above
the proposed PEL, OSHA judged this equivalent to 50 percent of
facilities lacking adequate exposure controls. The facilities may have,
for example, the correct equipment installed but without adequate
ventilation to provide protection to workers exposed to beryllium. In
this example, the Agency would expect that the remaining 50 percent of
facilities to either have installed the relevant controls to reduce
beryllium exposures below the PEL or that they engage in activities
that do not require that the exposure controls be in place (for
example, they do not perform any work with beryllium-containing
materials). To estimate the need for incremental controls on a per-
worker basis, OSHA used the exposure profile information as the best
available data. OSHA recognizes that a very small percentage of
facilities might have all the relevant controls in place but are still
unable, for whatever reason, to achieve the proposed PEL through
controls alone. ERG's review of the industrial hygiene literature and
other source materials (ERG, 2007b), however, suggest that the large
majority of workplaces where workers are exposed to high levels of
beryllium lack at least some of the relevant controls. Thus, in
estimating the costs associated with the proposed standard, OSHA has
generally assumed that high levels of exposure to beryllium occur due
to the absence of suitable controls. This assumption likely results in
an overestimate of costs since, in some cases, employers may not need
to install and maintain new controls in order to meet the proposed PEL
but merely need to upgrade or better maintain existing controls, or to
improve work practices.
b. Respiratory Protection Costs
    Based on the findings of the technological feasibility analysis, a
small subset of employees working with a few processes in a handful of
application groups will need to use respirators, in addition to
required engineering controls and improved work practices, to reduce
employee exposures to meet the proposed PEL. Specifically, furnace
operators--both in non-ferrous foundries (both sand and non-sand) and
in secondary smelting, refining, and alloying--as well as welders in a
few other processes, will need to wear half-mask respirators.
In beryllium production, workers who rebuild or otherwise maintain
furnaces and furnace tools will need to wear full-face powered air-purifying
respirators. Finally, the Agency recognizes the possibility that, after all
feasible engineering and other controls are in place, there may still be a
residual group with potential exposure above the proposed PEL and/or STEL.
To account for these residual cases, OSHA estimates that 10 percent of the
workers, across all application groups and job categories, who are
above the proposed PEL before the beryllium proposed standard is in
place (according to the baseline exposure profile presented in Chapter
III of the PEA), would still be above the PEL after all feasible
controls are implemented and, hence, would need to use half-mask
respirators to achieve compliance with the proposed PEL.
    There are five primary costs for respiratory protection. First,
there is a cost per establishment to set up a written respirator
program in accordance with the respiratory protection standard (29 CFR
1910.134). The respiratory protection standard requires written
procedures for the proper selection, use, cleaning, storage, and
maintenance of respirators. As derived in the PEA, OSHA estimates that,
when annualized over 10 years, the annualized per-establishment cost
for a written respirator program is $207.
    For reasons unrelated to the proposed standard, certain
establishments will already have a respirator program in place. Table
V-11 in Chapter V of the PEA presents OSHA's estimates, by application
group, of current levels of compliance with the respirator program
provision of the proposed rule.
    The four other major costs of respiratory protection are the per-
employee costs for all aspects of respirator use: equipment, training,
fit-testing, and cleaning. Table V-12 of Chapter V in the PEA breaks
out OSHA's estimate of the unit costs for the two types of respirators
needed: A half-mask respirator and a full-face powered air-purifying
respirator. As derived in the PEA, the annualized per-employee cost for
a half-mask respirator would be $524 and the annualized per-employee
cost for a full-face powered air-purifying respirator would be $1,017.
    Table V-13 in Chapter V of the PEA presents the number of
additional employees, by application group and NAICS code, that would
need to wear respirators to comply with the proposed standard and the
cost to industry to comply with the respirator protection provisions in
the proposed rule. OSHA judges that only workers in Beryllium
Production work with processes that would require a full-face
respirator and estimates that there are 23 of those workers. Three
hundred and eighteen workers in other assorted application groups are
estimated to need half-mask respirators. A total of 341 employees would
need to wear some type of respirator, resulting in a total annualized
cost of $249,684 for affected industries to comply with the respiratory
protection requirements of the proposed standard. Table IX-7 at the end
of this section breaks out the costs of respiratory protection by
application group and NAICS code.
2. Ancillary Provisions
    This section presents OSHA's estimated costs for ancillary
beryllium control programs required under the proposed rule. Based on
the program requirements contained in the proposed standard, OSHA
considered the following cost elements in the following employer
duties: (a) Assess employees' exposure to airborne beryllium, (b)
establish regulated areas, (c) develop a written exposure control plan,
(d) provide protective work clothing, (e) establish hygiene areas and
practices, (f) implement housekeeping measures, (g) provide medical
surveillance, (h) provide medical removal for employees who have
developed CBD or been confirmed positive for beryllium sensitization,
and (i) provide appropriate training.
    The worker population affected by each program element varies by
several criteria discussed in detail in each subsection below. In
general, some elements would apply to all workers exposed to beryllium
at or above the action level. Other elements would apply to a smaller
set of workers who are exposed above the PEL. The training requirements
would apply to all employees who work in a beryllium work area (e.g.,
an area with any level of exposure to airborne beryllium). The
regulated area program elements triggered by exposures exceeding the
proposed PEL of 0.2 [mu]g/m\3\ would apply to those workers for whom
feasible controls are not adequate. In the earlier discussion of
respiratory protection, OSHA estimated that 10 percent of all affected
workers with current exposures above the proposed PEL would fall in
this category.
    Costs for each program requirement are aggregated by employment and
by industry. For the most part, unit costs do not vary by industry, and
any variations are specifically noted. The estimated compliance rate
for each provision of the proposed standard by application group is
presented in Table V-15 of the PEA.
a. Exposure Assessment
    Most establishments wishing to perform exposure monitoring would
require the assistance of an outside consulting industrial hygienist
(IH) to obtain accurate results. While some firms might already employ
or train qualified staff, OSHA judged that the testing protocols are
fairly challenging and that few firms have sufficiently skilled staff
to eliminate the need for outside consultants.
    The proposed standard requires that, after receiving the results of
any exposure monitoring where exposures exceed the TWA PEL or STEL, the
employer notify each such affected employee in writing of suspected or
known sources of exposure, and the corrective action(s) being taken to
reduce exposure to or below the PEL. Those workers exposed at or above
the action level and at or below the PEL must have their exposure
levels monitored annually.
    For costing purposes, OSHA estimates that, on average, there are
four workers per work area. OSHA interpreted the initial exposure
assessment as requiring first-year testing of at least one worker in
each distinct job classification and work area who is, or may
reasonably be expected to be, exposed to airborne concentrations of
beryllium at or above the action level.
    The proposed standard requires that whenever there is a change in
the production, process, control equipment, personnel, or work
practices that may result in new or additional exposures, or when the
employer has any reason to suspect that a change may result in new or
additional exposures, the employer must conduct additional monitoring.
The Agency has estimated that this provision would require an annual
sampling of 10 percent of the affected workers.
    OSHA estimates that an industrial hygienist (IH) would spend 1 day
each year to sample 2 workers, for a per worker IH fee of $257. This
exposure monitoring requires that three samples be taken per worker:
One TWA and two STEL for an annual IH fee per sample of $86. Based on
the 2000 EMSL Laboratory Testing Catalog (ERG, 2007b), OSHA estimated
that analysis of each sample would cost $137 in lab fees. When combined
with the IH fee, OSHA estimated the annual cost to obtain a TWA sample
to be $223 per sampled worker and the annual cost to obtain the two
STEL samples to be $445 per sampled worker. The direct exposure
monitoring unit costs are summarized in Table V-16 in Chapter V of the PEA.
    The cost of the sample also incorporates a productivity loss due to
the additional time for the worker to participate in the sampling (30
minutes per worker sampled) as well as for the associated recordkeeping
time incurred by a manager (15 minutes per worker sampled). The STEL
samples are assumed to be taken along with the TWA sample and, thus,
labor costs were not added to both unit costs. Including the costs
related to lost productivity, OSHA estimates the total annual cost of a
TWA sample to be $251, and 2 STEL samples, $445. The total annual cost
per worker for all sampling taken is then $696. OSHA estimates the
total annualized cost of this provision to be $2,208,950 for all
affected industries. The annualized cost of this provision for each
affected NAICS industry is shown in Table IX-6.
b. Beryllium Work Areas and Regulated Areas
    The proposed beryllium standard requires the employer to establish
and maintain a regulated area wherever employees are, or can reasonably
expected to be, exposed to airborne beryllium at levels above the TWA
PEL or STEL. Regulated areas require specific provisions that both
limit employee exposure within its boundaries and curb the migration of
beryllium outside the area. The Agency judged, based on the preliminary
findings of the technological feasibility analysis, that companies can
reduce establishment-wide exposure by ensuring that only authorized
employees wearing proper protective equipment have access to areas of
the establishment where such higher concentrations of beryllium exist,
or can be reasonably expected to exist. Workers in other parts of the
establishment are also likely to see a reduction in beryllium exposures
due to these measures since fewer employees would be traveling through
regulated areas and subsequently carrying beryllium residue to other
work areas on their clothes and shoes.
    Requirements in the proposed rule for a regulated area include:
Demarcating the boundaries of the regulated area as separate from the
rest of the workplace, limiting access to the regulated area, providing
an appropriate respirator to each person entering the regulated area
and other protective clothing and equipment as required by paragraph
(g) and paragraph (h), respectively.
    OSHA estimated that the total annualized cost per regulated area,
including set-up costs ($76), respirators ($1,768) and protective
clothing ($4,500), is $6,344.
    When establishments are in full compliance with the standard,
regulated areas would be required only for those workers for whom
controls could not feasibly reduce their exposures to or below the 0.2
[mu]g/m\3\ TWA PEL and the 2 [mu]g/m\3\ STEL. Based on the findings of
the technological feasibility analysis, OSHA estimated that 10 percent
of the affected workers would be exposed above the TWA PEL or STEL
after implementation of engineering controls and thus would require
regulated areas (with one regulated area, on average, for every four
workers exposed above the proposed TWA PEL or STEL).
    The proposed standard requires that all beryllium work areas are
adequately established and demarcated. ERG estimated that one work area
would need to be established for every 12 at-risk workers. OSHA
estimates that the annualized cost would be $33 per work area.
    OSHA estimates the total annualized cost of the regulated areas and
work areas is $629,031 for all affected industries. The cost for each
affected application group and NAICS code is shown in Table IX-6.
c. Written Exposure Control Plan
    The proposed standard requires that employers must establish and
maintain a written exposure control plan for beryllium work areas. The
written program must contain:
    1. An inventory of operations and job titles reasonably expected to
have exposure.
    2. An inventory of operations and job titles reasonably expected to
have exposure at or above the action level.
    3. An inventory of operations and job titles reasonably expected to
have exposure above the TWA PEL or STEL.
    4. Procedures for minimizing cross-contamination, including but not
limited to preventing the transfer of beryllium between surfaces,
equipment, clothing, materials and articles within beryllium work
areas.
    5. Procedures for keeping surfaces in the beryllium work area free
as practicable of beryllium.
    6. Procedures for minimizing the migration of beryllium from
beryllium work areas to other locations within or outside the
workplace.
    7. An inventory of engineering and work practice controls required
by paragraph (f)(2) of this standard.
    8. Procedures for removal, laundering, storage, cleaning,
repairing, and disposal of beryllium-contaminated personal protective
clothing and equipment, including respirators.
    The unit cost estimates take into account the judgment that (1)
most establishments have an awareness of beryllium risks and, thus,
should be able to develop or modify existing safeguards in an
expeditious fashion, and (2) many operations have limited beryllium
activities and these establishments need to make only modest changes in
procedures to create the necessary exposure control plan. ERG's experts
estimated that managers would spend eight hours per establishment to
develop and implement such a written exposure control plan, yielding a
total cost per establishment to develop and implement the written
control plan of $563.53 and an annualized cost of $66. In addition,
because larger firms with more affected workers will need to develop
more complicated written control plans, the development of a plan would
require an extra thirty minutes of a manager's time per affected
employee, for a cost of $35 per affected employee and an annualized
cost of $4 per employee. Managers would also need 12 minutes (0.2
hours) per affected employee per quarter, or 48 minutes per affected
employee per year to review and update the plan, for a recurring cost
of $56 per affected employee per year to maintain and update the plan.
Five minutes of clerical time would also be needed per employee for
providing each employee with a copy of the written exposure control
plan--yielding an annualized cost of $2 per employee. The total annual
per-employee cost for development, implementation, review, and update
of a written exposure control plan is then $62. The Agency estimates
the total annualized cost of this provision to be $1,769,506 for all
affected establishments. The breakdown of these costs by application
group and NAICS code is presented in Table IX-6.
d. Personal Protective Clothing and Equipment
    The proposed standard requires personal protective clothing and
equipment for workers:
    1. Whose exposure can reasonably be expected to exceed the TWA PEL
or STEL.
    2. When work clothing or skin may become visibly contaminated with
beryllium, including during maintenance and repair activities or during
non-routine tasks.
    3. Where employees' skin can reasonably be expected to be exposed
to soluble beryllium compounds.
    OSHA has determined that it would be necessary for employers to
provide reusable overalls and/or lab coats at a cost of $284 and $86,
respectively, for operations in the following application groups:

Beryllium Production
Beryllium Oxide, Ceramics & Composites
Nonferrous Foundries
Fabrication of Beryllium Alloy Products
Copper Rolling, Drawing & Extruding
Secondary Smelting, Refining and Alloying
Precision Turned Products
Dental Laboratories

    Chemical process operators in the spring and stamping application
group would require chemical resistant protective clothing at an annual
cost of $849. Gloves and/or shoe covers would be required when
performing operations in several different application groups,
depending on the process being performed, at an annual cost of $50 and
$78, respectively.
    The proposed standard requires that all reusable protective
clothing and equipment be cleaned, laundered, repaired, and replaced as
needed to maintain their effectiveness. This includes such safeguards
as transporting contaminated clothing in sealed and labeled impermeable
bags and informing any third party businesses coming in contact with
such materials of the risks associated with beryllium exposure. OSHA
estimates that the lowest cost alternative to satisfy this provision is
for an employer to rent and launder reusable protective clothing--at an
estimated annual cost per employee of $49. Ten minutes of clerical time
would also be needed per establishment with laundry needs to notify the
cleaners in writing of the potentially harmful effects of beryllium
exposure and how the protective clothing and equipment must be handled
in accordance with this standard--at a per establishment cost of $3.
    The Agency estimates the total annualized cost of this provision to
be $1,407,365 for all affected establishments. The breakdown of these
costs by application group and NAICS code is shown in Table IX-6.
e. Hygiene Areas and Practices
    The proposed standard requires employers to provide readily
accessible washing facilities to remove beryllium from the hands, face,
and neck of each employee working in a beryllium work area and also to
provide a designated change room in workplaces where employees would
have to remove their personal clothing and don the employer-provided
protective clothing. The proposed standard also requires that employees
shower at the end of the work shift or work activity if the employee
reasonably could have been exposed to beryllium at levels above the PEL
or STEL, and if those exposures could reasonably be expected to have
caused contamination of the employee's hair or body parts other than
hands, face, and neck.
    In addition to other forms of PPE costed previously, for processes
where hair may become contaminated, head coverings can be purchased at
an annual cost of $28 per employee. This could satisfy the requirement
to avoid contaminated hair. If workers are covered by protective
clothing such that no body parts (including their hair where necessary,
but not including their hands, face, and neck) could reasonably be
expected to have been contaminated by beryllium, and they could not
reasonably be expected to be exposed to beryllium while removing their
protective clothing, they would not need to shower at the end of a work
shift or work activity. OSHA notes that some facilities already have
showers, and the Agency judges that all employers either already have
showers where needed or will have sufficient measures in place to
ensure that employees could not reasonably be expected to be exposed to
beryllium while removing protective clothing. Therefore, OSHA has
preliminarily determined that employers will not need to provide any
new shower facilities to comply with the standard.
    The Agency estimated the costs for the addition of a change room
and segregated lockers based on the costs for acquisition of portable
structures. The change room is presumed to be used in providing a
transition zone from general working areas into beryllium-using
regulated areas. OSHA estimated that portable building, adequate for 10
workers per establishment can be rented annually for $3,251, and that
lockers could be procured for a capital cost of $407--or $48
annualized--per establishment. This results in an annualized cost of
$3,299 per facility to rent a portable change room with lockers. OSHA
estimates that the 10 percent of affected establishments unable to meet
the proposed TWA PEL would require change rooms. The Agency estimated
that a worker using a change room would need 2 minutes per day to
change clothes. Assuming 250 days per year, this annual time cost for
changing clothes is $185 per employee.
    The Agency estimates the total annualized cost of the provision on
hygiene areas and practices to be $389,241 for all affected
establishments. The breakdown of these costs by application group and
NAICS code can be seen in Table IX-6.
f. Housekeeping
    The proposed rule specifies requirements for cleaning and disposing
of beryllium-contaminated wastes. The employer shall maintain all
surfaces in beryllium work areas as free as practicable of
accumulations of beryllium and shall ensure that all spills and
emergency releases of beryllium are cleaned up promptly, in accordance
with the employer's written exposure control plan and using a HEPA-
filtered vacuum or other methods that minimize the likelihood and level
of exposure. The employer shall not allow dry sweeping or brushing for
cleaning surfaces in beryllium work areas unless HEPA-filtered
vacuuming or other methods that minimize the likelihood and level of
exposure have been tried and were not effective.
    ERG's experts estimated that each facility would need to purchase a
single vacuum at a cost of $2,900 for every five affected employees in
order to successfully integrate housekeeping into their daily routine.
The per-employee cost would be $580, resulting in an annualized cost of
$68 per worker. ERG's experts also estimated that all affected workers
would require an additional five minutes per work day (.083 hours) to
complete vacuuming tasks and to label and dispose of beryllium-
contaminated waste. While this allotment is modest, OSHA judged that
the steady application of this incremental additional cleaning, when
combined with currently conducted cleaning, would be sufficient in
average establishments to address dust or surface contamination
hazards. Assuming that these affected workers would be working 250 days
per year, OSHA estimates that the annual labor cost per employee for
additional time spent cleaning in order to comply with this provision
is $462.
    The proposed standard requires each disposal bag with contaminated
materials to be properly labeled. ERG estimated a cost of 10 cents per
label with one label needed per day for every five workers. With the
disposal of one labeled bag each day and 250 working days, the per-
employee annual cost would be $5. The annualized cost of a HEPA-
filtered vacuum, combined with the additional time needed to perform
housekeeping and the labeling of disposal bags, results in a total
annualized cost of $535 per employee.
    The Agency estimates the total annualized cost of this provision to
be $12,574,921 for all affected establishments. The breakdown of these
costs by application group and NAICS code is shown in Table IX-6.
g. Medical Surveillance
    The proposed standard requires the employer to make medical
surveillance available at no cost to the employee, and at a reasonable
time and place, for the following employees:
    1. Employees who have worked in a regulated area for more than 30
days in the last 12 months
    2. Employees showing signs or symptoms of chronic beryllium disease
(CBD)
    3. Employees exposed to beryllium during an emergency; and
    4. Employees exposed to airborne beryllium above 0.2 [mu]g/m\3\ for
more than 30 days in a 12-month period for 5 years or more.
    As discussed in the regulated areas section of this analysis of
program costs, the Agency estimates that approximately 10 percent of
affected employees would have exposure in excess of the PEL after the
standard goes into effect and would therefore be placed in regulated
areas. The Agency further estimates that a very small number of
employees will be affected by emergencies in a given year, likely less
than 0.1 percent of the affected population, representing a small
additional cost. The number of workers who would suffer signs and
symptoms of CBD after the rule takes effect is difficult to estimate,
but would likely substantially exceed those with actual cases of CBD.
    While the symptoms of CBD vary greatly, the first to appear are
usually chronic dry cough (generally defined as a nonproductive cough,
without phlegm or sputum, lasting two months or more) and shortness of
breath during exertion. Ideally, in developing these costs estimates,
OSHA would first estimate the percent of affected workers who might be
presenting with a chronic cough and/or experiencing shortness of
breath.
    Studies have found the prevalence of a chronic cough ranging from
10 to 38 percent across various community populations, with smoking
accounting for up to 18 percent of cough prevalence (Irwin, 1990;
Barbee, 1991). However, these studies are over 20 years old, and the
number of smokers has decreased substantially since then. It's also not
clear whether the various segments of the U.S. population studied are
similar enough to the population of workers exposed to beryllium such
that results of these studies could be generalized to the affected
worker population.
    A more recent study from a plant in Cullman, Alabama that works
with beryllium alloy found that about five percent of employees said
they were current smokers, with roughly 52 percent saying they were
previous smokers and approximately 43 percent stating they had never
smoked (Newman et al., 2001). This study does not, however, report on
the prevalence of chronic cough in this workplace.
    OSHA was unable to identify any studies on the general prevalence
of the other common early symptom of CBD, shortness of breath. Lacking
any better data to base an estimate on, the Agency used the studies
cited above (Irwin, 1990; Barbee, 1991) showing the prevalence of
chronic cough in the general population, adjusted to account for the
long term decrease in smoking prevalence (and hence, the amount of
overall cases of chronic cough), and estimated that 15 percent of the
worker population with beryllium exposure would exhibit a chronic cough
or other sign or symptom of CBD that would trigger medical
surveillance. The Agency welcomes comment and further data on this
question.
    According to the proposed rule, the initial (baseline) medical
examination would consist of the following:
    1. A medical and work history, with emphasis on past and present
exposure, smoking history and any history of respiratory system
dysfunction;
    2. A physical examination with emphasis on the respiratory tract;
    3. A physical examination for skin breaks and wounds;
    4. A pulmonary function test;
    5. A standardized beryllium lymphocyte proliferation test (BeLPT)
upon the first examination and within every two years from the date of
the first examination until the employee is confirmed positive for
beryllium sensitization;
    6. A CT scan, offered every two years for the duration of the
employee's employment, if the employee was exposed to airborne
beryllium at levels above 0.2 [mu]g/m\3\ for more than 30 days in a 12-
month period for at least 5 years. This obligation begins on the start-
up date of this standard, or on the 15th year after the employee's
first exposure above for more than 30 days in a 12-month period,
whichever is later; and
    7. Any other test deemed appropriate by the Physician or other
Licensed Health Care Professional (PLHCP).
    Table V-17 in Chapter V of the PEA lists the direct unit costs for
initial medical surveillance activities including: Work and medical
history, physical examination, pulmonary function test, BeLPT, CT scan,
and costs of additional tests. In OSHA's cost model, all of the
activities will take place during an employee's initial visit and on an
annual basis thereafter and involve a single set of travel costs,
except that: (1) The BeLPT tests will only be performed at two-year
intervals after the initial test, but will be conducted in conjunction
with the annual general examination (no additional travel costs); and
(2) the CT scans will typically involve different specialists and are
therefore treated as separate visits not encompassed by the general
exams (therefore requiring separate travel costs). Not all employees
would require CT scans, and employers would only be required to offer
them every other year.
    In addition to the fees for the annual medical exam, employers may
also incur costs for lost work time when their employees are
unavailable to perform their jobs. This includes time for traveling, a
health history review, the physical exam, and the pulmonary function
test. Each examination would require 15 minutes (or 0.25 hours) of a
human resource manager's time for recording the results of the exam and
tests and the PLHCP's written opinion for each employee and any
necessary post-exam consultation with the employee. There is also a
cost of 15 minutes of supervisor time to provide information to the
physician, five minutes of supervisor time to process a licensed
physician's written medical opinion, and five minutes for an employee
to receive a licensed physician's written medical opinion. The total
unit annual cost for the medical examinations and tests, excluding the
BeLPT test, and the time required for both the employee and the
supervisor is $297.
    The estimated fee for the BeLPT is $259. With the addition of the
time incurred by the worker to undergo the test, the total cost for a
BeLPT is $261. The standard requires a biennial BeLPT for each employee
covered by the medical surveillance provision, so most workers would
receive between two and five BeLPT tests over a ten year period
(including the BeLPT performed during the initial examination),
depending on whether the results of these tests were positive. OSHA
therefore estimates a net present value (NPV) of $1,417 for all five
tests. This NPV annualized over a ten year period is $166.
    Together, the annualized net present value of the BeLPT and the
annualized cost of the remaining medical surveillance produce an annual
cost of $436 per employee.
    The proposed standard requires that a helical tomography (CT scan)
be offered to employees exposed to airborne beryllium above 0.2 [mu]g/
m\3\ for more than 30 days in a 12-month period, for a period of 5
years or more. The five years do not need to be consecutive, and the
exposure does not need to occur after the effective date of the standard.
The CT scan shall be offered every 2 years starting on the 15th year
after the first year the employee was exposed above 0.2 [mu]g/m\3\ for
more than 30 days in a 12-month period, for the duration of their employment.
The total yearly cost for biennial CT scans consists of medical costs
totaling $1,020, comprised of a $770 fee for the scan and the cost of a
specialist to review the results, which OSHA estimates would cost $250.
The Agency estimates an additional cost of $110 for lost work time, for a
total of $1,131. The annualized yearly cost for biennial CT scans is $574.
    Based on OSHA's estimates explained earlier in this section, all
workers in regulated areas, workers exposed in emergencies, and an
estimated 15 percent of workers not in regulated areas who exhibit
signs and symptoms of CBD will be eligible for medical surveillance
other than CT scans. The estimate for the number of workers eligible to
receive CT scans is 25 percent of workers who are exposed above 0.2 in
the exposure profile. The estimate of 25 percent is based on the facts
that roughly this percentage of workers have 15-plus years of job
tenure in the durable manufacturing sector and the estimate that all
those with 15-plus years of job tenure and current exposure over 0.2
would have had at least 5 years of such exposure in the past.
    The costs estimated for this provision are likely to be
significantly overestimated, since not all affected employees offered
medical surveillance would necessarily accept the offer. At Department
of Energy facilities, only about 50 percent of eligible employees
participate in the voluntary medical surveillance tests, and a report
on an initial medical surveillance program at four aluminum manufacture
facilities found participation rates to be around 57 percent (Taiwo et
al., 2008). Where employers already offer equivalent health
surveillance screening, no new costs are attributable to the proposed
standard.
    Within 30 days after an employer learns that an employee has been
confirmed positive for beryllium sensitization, the employer's
designated licensed physician shall consult with the employee to
discuss referral to a CBD diagnostic center that is mutually agreed
upon by the employer and the employee. If, after this consultation, the
employee wishes to obtain a clinical evaluation at a CBD diagnostic
center, the employer must provide the evaluation at no cost to the
employee. OSHA estimates this consultation will take 15 minutes, with
an estimated total cost of $33.
    Table V-18 in Chapter V of the PEA lists the direct unit costs for
a clinical evaluation with a specialist at a CBD diagnostic center. To
estimate these costs, ERG contacted a healthcare provider who commonly
treats patients with beryllium-related disease, and asked them to
provide both the typical tests given and associated costs of an initial
examination for a patient with a positive BeLPT test, presented in
Table V-18 in Chapter V of the PEA. Their typical evaluation includes
bronchoscopy with lung biopsy, a pulmonary stress test, and a chest CAT
scan. The total cost for the entire suite of tests is $6,305.
    In addition, there are costs for lost productivity and travel. The
Agency has estimated the clinical evaluation would take three days of
paid time for the worker to travel to and from one of two locations:
Penn Lung Center at the Cleveland Clinic Foundation in Cleveland, Ohio
or National Jewish Medical Center in Denver, Colorado. OSHA estimates
lost work time is 24 hours, yielding total cost for the 3 days of $532.
    OSHA estimates that roundtrip air-fare would be available for most
facilities at $400, and the cost of a hotel room would be approximately
$100 per night, for a total cost of $200 for the hotel room. OSHA
estimates a per diem cost of $50 for three days, for a total of $150.
The total cost per trip for traveling expenses is therefore $750.
    The total cost of a clinical evaluation with a specialist at a CBD
diagnostic center is equal to the cost of the examination plus the cost
of lost work-time and the cost for the employee to travel to the CBD
diagnostic center, or $7,620.
    Based on the data from the exposure profile and the prevalence of
beryllium sensitization observed at various levels of cumulative
exposure,\18\ OSHA estimated the number of workers eligible for BeLPT
testing (4,181) and the percentage of workers who will be confirmed
positive for sensitization (two positive BeLPT tests, as specified in
the proposed standard) and referred to a CBD diagnostic center. During
the first year that the medical surveillance provisions are in effect,
OSHA estimates that 9.4 percent of the workers who are tested for
beryllium sensitization will be identified as sensitized. This
percentage is an average based on: (1) The number of employees in the
baseline exposure profile that are in a given cumulative exposure
range; (2) the expected prevalence for a given cumulative exposure
range (from Table VI-6 in Section VI of the preamble); and (3) an
assumed even distribution of employees by cumulative years of exposure
at a given level--20 percent having exposures at a given level for 5
years, 20 percent for 15 years, 20 percent for 25 years, 20 percent for
30 years, and 20 percent for 40 years.
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    \18\ See Table VI-6 in Section VI of the preamble, Preliminary
Risk Assessment.
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    OSHA did not assume that all workers with confirmed sensitization
would choose to undergo evaluation at a CBD diagnostic center, which
may involve invasive procedures and/or travel. For purposes of this
cost analysis, OSHA estimates that approximately two-thirds of workers
who are confirmed positive for beryllium sensitization will choose to
undergo evaluation for CBD. OSHA requests comment on the CBD evaluation
participation rate. OSHA estimates that about 264 of all non-dental lab
workers will go to a diagnostic center for CBD evaluation in the first
year.
    The calculation method described above applies to all workers
except dental technicians, who were analyzed with one modification. The
rates for dental technicians are calculated differently due to the
estimated 75 percent beryllium-substitution rate at dental labs, where
the 75 percent of labs that eliminate all beryllium use are those at
higher exposure levels. None of the remaining labs affected by this
standard had exposures above 0.1 [mu]g/m\3\. For the dental labs, the
same calculation was done as presented in the previous paragraph, but
only the remaining 25 percent of employees (2,314) who would still face
beryllium exposures were included in the baseline cumulative exposure
profile. With that one change, and all other elements of the
calculation the same, OSHA estimates that 9 percent of dental lab
workers tested for beryllium sensitization will be identified as
sensitized. The predicted prevalence of sensitization among those
dental lab workers tested in the first year after the standard takes
effect is slightly lower than the predicted prevalence among all other
tested workers combined. This slightly lower rate is not surprising
because only dental lab workers with exposures below 0.1 [mu]g/m\3\ are
included (after adjusting for substitution), and OSHA's exposure
profile indicates that the vast majority of non-dental workers exposed
to beryllium are also exposed at 0.1 [mu]g/m\3\ or lower. OSHA
estimates that 20 dental lab workers (out of 347 tested for
sensitization) would go to a diagnostic center for CBD evaluation in
the first year.
    In each year after the first year, OSHA relied on a 10 percent
worker turnover rate in a steady state (as discussed in Chapter VII of
the PEA) to estimate that the annual sensitization incidence rate is 10
percent of the first year's incidence rate. Based on that rate and the
number of workers in the medical surveillance program, the CBD
evaluation rate for workers other than those in dental labs would drop
to 0.63 percent (.063 x .10). The evaluation rate for dental labs
technicians is similarly estimated to drop to 0.58 percent (.058 x
.10).
    Based on these unit costs and the number of employees requiring
medical surveillance estimated above, OSHA estimates that the medical
surveillance and referral provisions would result in an annualized
total cost of $2,882,706. These costs are presented by application
group and NAICS code in Table IX-7.
h. Medical Removal Provision
    Once a licensed physician diagnoses an employee with CBD or the
employee is confirmed positive for sensitization to beryllium, that
employee is eligible for medical removal and has two choices:
    (a) Removal from current job, or
    (b) Remain in a job with exposure above the action level while
wearing a respirator pursuant to 29 CFR 1910.134.
    To be eligible for removal, the employee must accept comparable
work if such is available, but if not available the employer would be
required to place the employee on paid leave for six months or until
such time as comparable work becomes available, whichever comes first.
During that six-month period, whether the employee is re-assigned or
placed on paid leave, the employer must continue to maintain the
employee's base earnings, seniority and other rights, and benefits that
existed at the time of the first test.
    For purposes of this analysis, OSHA has conservatively estimated
the costs as if all employees will choose removal, rather than
remaining in the current job while wearing a respirator. In practice,
many workers may prefer to continue working at their current job while
wearing a respirator, and the employer would only incur the respirator
costs identified earlier in this chapter. The removal costs are
significantly higher over the same six-month period, so this analysis
likely overestimates the total costs for this provision.
    OSHA estimated that the majority of firms would be able to reassign
the worker to a job at least at the clerical level. The employer will
often incur a cost for re-assigning the worker because this provision
requires that, regardless of the comparable work the medically removed
worker is performing, the employee must be paid the full base earnings
for the previous position for six months. The cost per hour of
reassigning a worker to a clerical job is based on the wage difference
of a production worker of $22.16 and a clerical worker of $19.97, for a
difference of $2.19. Over the six-month period, the incremental cost of
reassigning a worker to a clerical position would be $2,190 per
employee. This estimate is based on the employee remaining in a
clerical position for the entire 6-month period, but the actual cost
would be lower if there is turnover or if the employee is placed in any
alternative position (for any part of the six-month period) that is
compensated at a wage closer to the employee's previous wage.
    Some firms may not have the ability to place the worker in an
alternate job. If the employee chooses not to remain in the current
position, the additional cost to the employer would be at most the cost
of equipping that employee with a respirator, which would be required
if the employee would continue to face exposures at or above the action
level. Based on the earlier discussion of respirator costs, that option
would be significantly cheaper than the alternative of providing the
employee with six months of paid leave. Therefore, in order to estimate
the maximum potential economic cost of the remaining alternatives, the
Agency has conservatively estimated the cost per worker based on the
cost of 6 months paid leave.
    Using the wage rate of a production worker of $22.16 for 6 months
(or 8 hours a day for 125 days), the total per-worker cost for this
provision when a firm cannot place a worker in an alternate job is
$22,161.
    OSHA has estimated an average medical removal cost per worker
assuming 75 percent of firms are able to find the employee an alternate
job, and the remaining 25 percent of firms would not. The weighted
average of these costs is $7,183. Based on these unit costs, OSHA
estimates that the medical removal provision would result in an
annualized total cost of $148,826. The breakdown of these costs by
application group and NAICS code is shown in Table IX-6.
i. Training
    As specified in the proposed standard and existing OSHA standard 29
CFR 1910.1200 on hazard communication, training is required for all
employees where there is potential exposure to beryllium. In addition,
newly hired employees would require training before starting work.
    OSHA anticipates that training in accordance with the requirements
of the proposed rule, which includes hazard communication training,
would be conducted by in-house safety or supervisory staff with the use
of training modules or videos. ERG estimated that this training would
last, on average, eight hours. (Note that this estimate does not
include the time taken for hazard communication training that is
already required by 29 CFR 1910.1200.) The Agency judged that
establishments could purchase sufficient training materials at an
average cost of $2 per worker, encompassing the cost of handouts, video
presentations, and training manuals and exercises. For initial and
periodic training, ERG estimated an average class size of five workers
with one instructor over an eight hour period. The per-worker cost of
initial training totals to $239.
    Annual retraining of workers is also required by the standard. OSHA
estimates the same unit costs as for initial training, so retraining
would require the same per-worker cost of $239.
    Finally, to calculate training costs, the Agency needs the turnover
rate of affected workers to know how many workers are receiving initial
training versus retraining. Based on a 26.3 percent new hire rate in
manufacturing, OSHA calculated a total net present value (NPV) of ten
years of initial and annual retraining of $2,101 per employee.
Annualizing this NPV gives a total annual cost for training of $246.
    Based on these unit costs, OSHA estimates that the training
requirements in the standard would result in an annualized total cost
of $5,797,535. The breakdown of these costs by application group and
NAICS code is presented in Table IX-6.

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[GRAPHIC] [TIFF OMITTED] TP07AU15.010


[GRAPHIC] [TIFF OMITTED] TP07AU15.011


Total Annualized Cost
    As shown in Table IX-7, the total annualized cost of the proposed
rule is estimated to be about $37.6 million. As shown, at $27.8
million, the program costs represent about 74 percent of the total
annualized costs of the proposed rule. The annualized cost of complying
with the PEL accounts for the remaining 26 percent, almost all of which
is for engineering controls and work practices. Respiratory protection,
at about $237,600, represents only 3 percent of the annualized cost of
complying with the PEL and less than 1 percent of the annualized cost
of the proposed rule.

[GRAPHIC] [TIFF OMITTED] TP07AU15.012


[GRAPHIC] [TIFF OMITTED] TP07AU15.013

F. Economic Feasibility Analysis and Regulatory Flexibility
Determination

    Chapter VI of the PEA, summarized here, investigates the economic
impacts of the proposed beryllium rule on affected employers. This
impact investigation has two overriding objectives: (1) To establish
whether the proposed rule is economically feasible for all affected
application groups/industries, and (2) to determine if the Agency can
certify that the proposed rule will not have a significant economic
impact on a substantial number of small entities.
    In the discussion below, OSHA first presents its approach for
achieving these objectives and next applies this approach to industries
with affected employers. The Agency invites comment on any aspect of
the methods, data, or preliminary findings presented here or in Chapter
VI of the PEA.
1. Analytic Approach
a. Economic Feasibility
    Section 6(b)(5) of the OSH Act directs the Secretary of Labor to
set standards based on the available evidence where no employee, over
his/her working life time, will suffer from material impairment of
health or functional capacity, even if such employee has regular
exposure to the hazard, "to the exent feasible" (29 U.S.C.
655(b)(5)). OSHA interpreted the phrase "to the extent feasible" to
encompass economic feasibility and was supported in this view by the
U.S. Court of Appeals for the D.C. Circuit, which has long held that
OSHA standards would satisfy the economic feasibility criterion even if
they imposed significant costs on regulated industries and forced some
marginal firms out of business, so long as they did not cause massive
economic dislocations within a particular industry or imperil the
existence of that industry. Am. Iron and Steel Inst. v. OSHA, 939 F.2d
975, 980 (D.C. Cir. 1991); United Steelworkers of Am., AFL-CIO-CLC v.
Marshall, 647 F.2d 1189, 1265 (D.C. Cir. 1980); Indus. Union Dep't v.
Hodgson, 499 F.2d 467 (D.C. Cir. 1974).
b. The Price Elasticity of Demand and Its Relationship to Economic
Feasibility
    In practice, the economic burden of an OSHA standard on an
industry--and whether the standard is economically feasible for that
industry--depends on the magnitude of compliance costs incurred by
establishments in that industry and the extent to which they are able
to pass those costs on to their customers. That, in turn, depends, to
a significant degree, on the price elasticity of demand for the products
sold by establishments in that industry.
    The price elasticity of demand refers to the relationship between
the price charged for a product and the demand for that product: The
more elastic the relationship, the less an establishment's compliance
costs can be passed through to customers in the form of a price
increase and the more the establishment has to absorb compliance costs
in the form of reduced profits. When demand is inelastic,
establishments can recover most of the costs of compliance by raising
the prices they charge; under this scenario, profit rates are largely
unchanged and the industry remains largely unaffected. Any impacts are
primarily on those customers using the relevant product. On the other
hand, when demand is elastic, establishments cannot recover all
compliance costs simply by passing the cost increase through in the
form of a price increase; instead, they must absorb some of the
increase from their profits. Commonly, this will mean reductions both
in the quantity of goods and services produced and in total profits,
though the profit rate may remain unchanged. In general, "[w]hen an
industry is subjected to a higher cost, it does not simply swallow it;
it raises its price and reduces its output, and in this way shifts a
part of the cost to its consumers and a part to its suppliers," in the
words of the court in Am. Dental Ass'n v. Sec'y of Labor (984 F.2d 823,
829 (7th Cir. 1993)).
    The court's summary is in accord with microeconomic theory. In the
long run, firms can remain in business only if their profits are
adequate to provide a return on investment that ensures that investment
in the industry will continue. Over time, because of rising real
incomes and productivity increases, firms in most industries are able
to ensure an adequate profit. As technology and costs change, however,
the long-run demand for some products naturally increases and the long-
run demand for other products naturally decreases. In the face of
additional compliance costs (or other external costs), firms that
otherwise have a profitable line of business may have to increase
prices to stay viable. Increases in prices typically result in reduced
quantity demanded, but rarely eliminate all demand for the product.
Whether this decrease in the total production of goods and services
results in smaller output for each establishment within the industry or
the closure of some plants within the industry, or a combination of the
two, is dependent on the cost and profit structure of individual firms
within the industry.
    If demand is perfectly inelastic (i.e., the price elasticity of
demand is zero), then the impact of compliance costs that are one
percent of revenues for each firm in the industry would be a one
percent increase in the price of the product, with no decline in
quantity demanded. Such a situation represents an extreme case, but
might be observed in situations in which there were few, if any,
substitutes for the product in question, or if the products of the
affected sector account for only a very small portion of the revenue or
income of its customers.
    If the demand is perfectly elastic (i.e., the price elasticity of
demand is infinitely large), then no increase in price is possible and
before-tax profits would be reduced by an amount equal to the costs of
compliance (net of any cost savings--such as reduced workers'
compensation insurance premiums--resulting from the proposed standard)
if the industry attempted to maintain production at the same level as
previously. Under this scenario, if the costs of compliance are such a
large percentage of profits that some or all plants in the industry
could no longer operate in the industry with hope of an adequate return
on investment, then some or all of the firms in the industry would
close. This scenario is highly unlikely to occur, however, because it
can only arise when there are other products--unaffected by the
proposed rule--that are, in the eyes of their customers, perfect
substitutes for the products the affected establishments make.
    A commonly-discussed intermediate case would be a price elasticity
of demand of one (in absolute terms). In this situation, if the costs
of compliance amount to one percent of revenues, then production would
decline by one percent and prices would rise by one percent. As a
result, industry revenues would remain the same, with somewhat lower
production, but with similar profit rates per unit of output (in most
situations where the marginal costs of production net of regulatory
costs would fall as well). Customers would, however, receive less of
the product for their (same) expenditures, and firms would have lower
total profits; this, as the court described in Am. Dental Ass'n v.
Sec'y of Labor, is the more typical case.
c. Variable Costs Versus Fixed Costs
    A decline in output as a result of an increase in price may occur
in a variety of ways: individual establishments could each reduce their
levels of production; some marginal plants could close; or, in the case
of an expanding industry, new entry may be delayed until demand equals
supply. In some situations, there could be a combination of these three
effects. Which possibility is most likely depends on the form that the
costs of the regulation take. If the costs are variable costs (i.e.,
costs that vary with the level of production at a facility), then
economic theory suggests that any reductions in overall output will be
the result of reductions in output at each affected facility, with few,
if any, plant closures. If, on the other hand, the costs of a
regulation primarily take the form of fixed costs (i.e., costs that do
not vary with the level of production at a facility), then reductions
in overall output are more likely to take the form of plant closures or
delays in new entry.
    Most of the costs of this regulation, as estimated in Chapter V of
the PEA, are variable costs in the sense that they will tend to vary by
production levels and/or employment levels. Almost all of the major
costs of program elements, such as medical surveillance and training,
will vary in proportion to the number of employees (which is a rough
proxy for the amount of production). Exposure monitoring costs will
vary with the number of employees, but do have some economies of scale
to the extent that a larger firm need only conduct representative
sampling rather than sample every employee. Finally, the costs of
operating and maintaining engineering controls tend to vary by usage--
which typically closely tracks the level of production and are not
fixed costs in the strictest sense.
    This leaves two kinds of costs that are, in some sense, fixed
costs--capital costs of engineering controls and certain initial costs.
The capital costs of engineering controls due to the standard--many of
which are scaled to production and/or employment levels--constitute a
relatively small share of the total costs, representing 10 percent of
total annualized costs (or approximately $870 per year per affected
establishment).
    Some ancillary provisions require initial costs that are fixed in
the sense that they do not vary by production activity or the number of
employees. Some examples are the costs to develop a training plan for
general training not currently required and to develop a written
exposure control plan.
    As a result of these considerations, OSHA expects it to be quite
likely that any reductions in total industry output would be due to
reductions in output at each affected facility rather than as a result
of plant closures. However, closures of some marginal plants or poorly
performing facilities are always possible.
d. Economic Feasibility Screening Analysis
    To determine whether a rule is economically feasible, OSHA begins
with two screening tests to consider minimum threshold effects of the
rule under two extreme cases: (1) All costs are passed through to
customers in the form of higher prices (consistent with a price
elasticity of demand of zero), and (2) all costs are absorbed by the
firm in the form of reduced profits (consistent with an infinite price
elasticity of demand).
    In the former case, the immediate impact of the rule would be
observed in increased industry revenues. While there is no hard and
fast rule, in the absence of evidence to the contrary, OSHA generally
considers a standard to be economically feasible for an industry when
the annualized costs of compliance are less than a threshold level of
one percent of annual revenues. Retrospective studies of previous OSHA
regulations have shown that potential impacts of such a small magnitude
are unlikely to eliminate an industry or significantly alter its
competitive structure,\19\ particularly since most industries have at
least some ability to raise prices to reflect increased costs, and
normal price variations for products typically exceed three percent a
year.
---------------------------------------------------------------------------

    \19\ See OSHA's Web page, http://www.osha.gov/dea/lookback.html#Completed, for a link to all completed OSHA lookback
reviews.
---------------------------------------------------------------------------

    In the latter case, the immediate impact of the rule would be
observed in reduced industry profits. OSHA uses the ratio of annualized
costs to annual profits as a second check on economic feasibility.
Again, while there is no hard and fast rule, in the absence of evidence
to the contrary, OSHA generally considers a standard to be economically
feasible for an industry when the annualized costs of compliance are
less than a threshold level of ten percent of annual profits. In the
context of economic feasibility, the Agency believes this threshold
level to be fairly modest, given that normal year-to-year variations in
profit rates in an industry can exceed 40 percent or more. OSHA also
considered whether this threshold would be adequate to assure that
upfront costs would not create major credit problems for affected
employers. To do this, OSHA examined a worst case scenario in which
annualized costs were ten percent of profits and all of the annualized
costs were the result of upfront costs. In this scenario, assuming a
three percent discount rate and a ten year life of equipment, total
costs would be 85 percent of profits \20\ in the year in which these
upfront costs were incurred. Because upfront costs would be less than
one year's profits in the year they were incurred, this means that an
employer could pay for all of these costs from that year's profits and
would not necessarily have to incur any new borrowing. As a result, it
is unlikely that these costs would create a credit crunch or other
major credit problems. It would be true, however, that paying
regulatory costs from profits might reduce investment from profits in
that year. OSHA's choice of a threshold level of ten percent of annual
profits is low enough that even if, in a hypothetical worst case, all
compliance costs were upfront costs, then upfront costs--assuming a
three percent discount rate and a ten-year time period--would be no
more than 85 percent of first-year profits and thus would be affordable
from profits without resort to credit markets. If the threshold level
were first-year costs of ten percent of annual profits, firms could
even more easily expect to cover first-year costs at the threshold
level out of current profits without having to access capital markets
and otherwise being threatened with short-term insolvency.
---------------------------------------------------------------------------

    \20\ At a discount rate of 3 percent over a life of investment
of 10 years, the present value of that stream of annualized costs
would be 8.53 times a single year's annualized costs. Hence, if
yearly annualized costs are 10 percent of profits, upfront costs
would be 85 percent of the profits in that first year. As a simple
example, assume annualized costs are $1 for each of the 10 years. If
annualized costs are 10 percent of profits, this translates to a
yearly profit of $10. The present value of that stream of $1 for
each year is $8.53. (The formula for this calculation is
($1*(1.03[caret]10)-1)/((.03)x(1.03)[caret]10).
---------------------------------------------------------------------------

    In general, because it is usually the case that firms would be able
to pass on to their customers some or all of the costs of the proposed
rule in the form of higher prices, OSHA will tend to give much more
weight to the ratio of industry costs to industry revenues than to the
ratio of industry costs to industry profits. However, if costs exceed
either the threshold percentage of revenue or the threshold percentage
of profits for an industry, or if there is other evidence of a threat
to the viability of an industry because of the proposed standard, OSHA
will examine the effect of the rule on that industry more closely. Such
an examination would include market factors specific to the industry,
such as normal variations in prices and profits, and any special
circumstances, such as close domestic substitutes of equal cost, which
might make the industry particularly vulnerable to a regulatory cost
increase.
    The preceding discussion focused on the economic viability of the
affected industries in their entirety. However, even if OSHA found that
a proposed standard did not threaten the survival of affected
industries, there is still the question of whether the industries'
competitive structure would be significantly altered. For example, if
the annualized costs of an OSHA standard were equal to 10 percent of an
industry's annual profits, and the price elasticity of demand for the
products in that industry were equal to one, then OSHA would not expect
the industry to go out of business. However, if the increase in costs
were such that most or all small firms in that industry would have to
close, it might reasonably be concluded that the competitive structure
of the industry had been altered. For this reason, OSHA also calculates
compliance costs by size of firm and conducts its economic feasibility
screening analysis for small and very small entities.
e. Regulatory Flexibility Screening Analysis
    The Regulatory Flexibility Act (RFA), Public Law 96-354, 94 Stat.
1164 (codified at 5 U.S.C. 601), requires Federal agencies to consider
the economic impact that a proposed rulemaking will have on small
entities. The RFA states that whenever a Federal agency is required to
publish general notice of proposed rulemaking for any proposed rule,
the agency must prepare and make available for public comment an
initial regulatory flexibility analysis (IRFA). 5 U.S.C. 603(a).
Pursuant to section 605(b), in lieu of an IRFA, the head of an agency
may certify that the proposed rule will not have a significant economic
impact on a substantial number of small entities. A certification must
be supported by a factual basis. If the head of an agency makes a
certification, the agency shall publish such certification in the
Federal Register at the time of publication of general notice of
proposed rulemaking or at the time of publication of the final rule. 5
U.S.C. 605(b).
    To determine if the Assistant Secretary of Labor for OSHA can
certify that the proposed beryllium rule will not have a significant
economic impact on a substantial number of small entities, the Agency
has developed screening tests to consider minimum threshold effects of
the proposed rule on small entities. These screening tests do not constitute
hard and fast rules and are similar in concept to those OSHA developed
above to identify minimum threshold effects for purposes of demonstrating
economic feasibility.
    There are, however, two differences. First, for each affected
industry, the screening tests are applied, not to all establishments,
but to small entities (defined as "small business concerns" by SBA)
and also to very small entities (as defined by OSHA as businesses with
fewer than 20 employees). Second, although OSHA's regulatory
flexibility screening test for revenues also uses a minimum threshold
level of annualized costs equal to one percent of annual revenues, OSHA
has established a minimum threshold level of annualized costs equal to
five percent of annual profits for the average small entity or very
small entity. The Agency has chosen a lower minimum threshold level for
the profitability screening analysis and has applied its screening
tests to both small entities and very small entities in order to ensure
that certification will be made, and an IRFA will not be prepared, only
if OSHA can be highly confident that a proposed rule will not have a
significant economic impact on a substantial number of small entities
or very small entities in any affected industry.
    Furthermore, certification will not be made, and an IRFA will be
prepared, if OSHA believes the proposed rule might otherwise have a
significant economic impact on a substantial number of small entities,
even if the minimum threshold levels are not exceeded for revenues or
profitability for small entities or very small entities in all affected
industries.
2. Impacts on Affected Industries
    In this section, OSHA applies its screening criteria and other
analytic methods, as needed, to determine (1) whether the proposed rule
is economically feasible for all affected industries within the scope
of this proposed rule, and (2) whether the Agency can certify that the
proposed rule will not have a significant economic impact on a
substantial number of small entities.
a. Economic Feasibility Screening Analysis: All Establishments
    To determine whether the proposed rule's projected costs of
compliance would threaten the economic viability of affected
industries, OSHA first compared, for each affected industry, annualized
compliance costs to annual revenues and profits per (average) affected
establishment. The results for all affected establishments in all
affected industries are presented in Table IX-8. Shown in the table for
each affected industry are the total number of establishments, the
total number of affected establishments, annualized costs per affected
establishment, annual revenues per establishment, the profit rate,
annual profits per establishment, annualized compliance costs as a
percentage of annual revenues, and annualized compliance costs as a
percentage of annual profits.
    The annualized costs per affected establishment for each affected
industry were calculated by distributing the industry-level
(incremental) annualized compliance costs among all affected
establishments in the industry, where annualized compliance costs
reflect a 3 percent discount rate. The annualized cost of the proposed
rule for the average affected establishment is estimated at $9,197 in
2010 dollars. It is clear from Table IX-8 that the estimates of the
annualized costs per affected establishment vary widely from industry
to industry. These estimates range from $1,257,214 for NAICS 331419
(Beryllium Production) and $120,372 for NAICS 327113a (Porcelain
Electrical Supply Manufacturing (primary)) to $1,636 for NAICS 621210
(Offices of Dentists) and $1,632 for NAICS 339116 (Dental
Laboratories).

[GRAPHIC] [TIFF OMITTED] TP07AU15.014


[GRAPHIC] [TIFF OMITTED] TP07AU15.015

    As previously discussed, OSHA has established a minimum threshold
level of annualized costs equal to one percent of annual revenues--and,
secondarily, annualized costs equal to 10 percent of annual profits--
below which the Agency has concluded that costs are unlikely to threaten
the economic viability of an affected industry. The results of OSHA's
threshold tests for all affected establishments are displayed in Table IX-8.
For all affected establishments, the estimated annualized cost of the
proposed rule is, on average, equal to 0.11 percent of annual revenue
and 1.52 percent of annual profit.
    As Table IX-8 shows, there are no industries in which the
annualized costs of the proposed rule exceed one percent of annual
revenues. However there are three six-digit NAICS industries where
annualized costs exceed ten percent of annual profits.
    NAICS 331525 (Copper foundries except die-casting) has the highest
cost impact as a percentage of profits. NAICS 331525 is made up of two
types of copper foundries: sand casting foundries and non-sand casting
foundries, incurring an annualized cost as a percent of profit of 16.25
percent and 14.92 percent, respectively. The other two six-digit NAICS
industries where annualized costs exceed ten percent of annual profits
are NAICS 331534: Aluminum foundries (except die-casting), 13.65
percent; and NAICS 811310: Commercial and industrial machinery and
equipment repair, 10.19 percent.
    OSHA believes that the beryllium-containing inputs used by these
industries have a relatively inelastic demand for three reasons. First,
beryllium has rare and unique characteristics, including low mass, high
melting temperature, dimensional stability over a wide temperature
range, strength, stiffness, light weight, and high elasticity
("springiness") that can significantly improve the performance of
various alloys. These characteristics cannot easily be replicated by
other materials. In economic terms, this means that the elasticity of
substitution between beryllium and non-beryllium inputs will be low.
Second, products which contain beryllium or beryllium-alloy components
typically have high-performance applications (whose performance depends
on the use of higher-cost beryllium). The lack of available competing
products with these performance characteristics suggests that the price
elasticity of demand for products containing beryllium or beryllium-
alloy components will be low. Third, components made of beryllium or
beryllium-containing alloys typically account for only a small portion
of the overall cost of the finished goods that these parts are used to
make. For example, the cost of brakes made of a beryllium-alloy used in
the production of a jet airplane represents a trivial percentage of the
overall cost to produce that airplane. As economic theory indicates,
the elasticity of derived demand for a factor of production (such as
beryllium) varies directly with the elasticity of substitution between
the input in question and other inputs; the price elasticity of demand
for the final product that the input is used to produce; and, in
general, the share of the cost of the final product that the input
accounts for. Applying these three conditions to beryllium points to
the relative inelastic derived demand for this factor of production and
the likelihood that cost increases resulting from the proposed rule
would be passed on to the consumer in the form of higher prices.
    A secondary point is that the establishments in an industry that
use beryllium may be more profitable than those that don't. This
follows from the prior arguments about beryllium's rare and desirable
characteristics and its valuable applications. For example, of the 208
establishments that make up NAICS 331525, OSHA estimated that 45
establishments (or 21 percent) work with beryllium. Of the 394
establishments that make up NAICS 331524, OSHA estimated that only 7
establishments (less than 2 percent) work with beryllium. Of the 21,960
establishments that make up NAICS 811310, OSHA estimated that 143 (0.7
percent) work with beryllium. However, when OSHA calculated the cost-
to-profit ratio, it used the average profit per firm for the entire
NAICs industry, not the average profit per firm for firms working with
beryllium.
(1) Normal Year-to-Year Variations in Prices and Profit Rates
    The United States has a dynamic and constantly changing economy in
which an annual percentage increase in industry revenues or prices of
one percent or more are common. Examples of year-to-year changes in an
industry that could cause such an increase in revenues or prices
include increases in fuel, material, real estate, or other costs; tax
increases; and shifts in demand.
    To demonstrate the normal year-to-year variation in prices for all
the manufacturers in general industry affected by the proposed rule,
OSHA developed in the PEA year-to-year producer price indices and year-
to-year percentage changes in producer prices, by industry, for the
years 1999-2010. For all of the industries estimated to be affected by
this proposed standard over the 12-year period, the average change in
producer prices was 4.4 percent a year--which is over 4 times as high
as OSHA's 1 percent cost-to-revenue threshold. For the industries found
to have the largest estimated potential annual cost impact as a
percentage of revenue shown in Chapter VI of the PEA are--NAICS 331524:
Aluminum Foundries (except Die-Casting), (0.71 percent); NAICS 331525(a
and b): Copper Foundries (except Die-Casting) (average of 0.81
percent); NAICS 332721a: Precision Turned Product Manufacturing of high
content beryllium (0.49 percent); \21\ and NAICS 811310: Commercial and
Industrial Machinery and Equipment (Except Automotive and Electronic)
Repair and Maintenance (0.55 percent)--the average annual changes in
producer prices in these industries over the 12-year period analyzed
were 3.1 percent, 8.2 percent, 3.6 percent and 2.3 percent,
respectively.
---------------------------------------------------------------------------

    \21\ By contrast, NAICS 332721b: Precision Turned Product
Manufacturing of low content beryllium alloys has a cost to revenue
ratio below 0.4 percent.
---------------------------------------------------------------------------

    Based on these data, it is clear that the potential price impacts
of the proposed rule in affected industries are all well within normal
year-to-year variations in prices in those industries. The maximum cost
impact of the proposed rule as a percentage of revenue in any affected
industry is 0.84 percent, while, as just noted, the average annual
change in producer prices for affected industries was 4.4 percent for
the period 1999-2010. In fact, Chapter VI of the PEA shows two of the
industries within the secondary smelting, refining, and alloying group,
for example, the prices rose over 60 percent in one year without
imperiling the existence of those industries. Thus, OSHA preliminarily
concludes that the potential price impacts of the proposal would not
threaten the economic viability of any industries affected by this
proposed standard.
    Profit rates are also subject to the dynamics of the U.S. economy.
A recession, a downturn in a particular industry, foreign competition,
or the increased competitiveness of producers of close domestic
substitutes are all easily capable of causing a decline in profit rates
in an industry of well in excess of ten percent in one year or for
several years in succession.
    To demonstrate the normal year-to-year variation in profit rates
for all the manufacturers affected by the proposed rule, OSHA presented
data in the PEA on year-to-year profit rates and year-to-year
percentage changes in profit rates, by industry, for the years 2002-
2009. For the industries that OSHA has estimated will be affected by
this proposed standard over the 8-year period, the average change in profit
rates is calculated to be 39 percent per year. For the industries with
the largest estimated potential annual cost impacts as a percentage of
profit--NAICS 331524: Aluminum foundries (except die-casting), (14
percent); NAICS 331525(a and b): Copper foundries (except die-casting)
(16 percent); NAICS 332721a: Precision Turned Product Manufacturing of
high content beryllium (8 percent); \22\ and NAICS 811310 Commercial
and Industrial Machinery and Equipment (Except Automotive and
Electronic) Repair and Maintenance (10 percent)--the average annual
changes in profit rates in these industries over the eight-year period
were 35 percent, 35 percent, 11 percent, and 5 percent, respectively.
---------------------------------------------------------------------------

    \22\ By contrast, NAICS 332721b: Precision Turned Product
Manufacturing of low content beryllium alloys has a cost to profit
ratio of 6 percent.
---------------------------------------------------------------------------

    A longer-term loss of profits in excess of 10 percent a year could
be more problematic for some affected industries and might conceivably,
under sufficiently adverse circumstances, threaten an industry's
economic viability. However, as previously discussed, OSHA's analysis
indicates that affected industries would generally not absorb the costs
of the proposed rule in reduced profits but, instead, would be able to
pass on most or all of those costs in the form of higher prices (due to
the relative price inelasticity of demand for beryllium and beryllium-
containing inputs). It is possible that such price increases will
result in some reduction in output, and the reduction in output might
be met through the closure of a small percentage of the plants in the
industry. The only realistic circumstance where an entire industry
would be significantly affected by small potential price increases
would be where there is a very close or perfect substitute product
available not subject to OSHA regulation. In most cases where beryllium
is used, there is no substitute product that could be used in place of
beryllium and achieve the same level of performance. The main potential
concern would be substitution by foreign competition, but the following
discussion reveals why such competition is not likely.
(2) International Trade Effects
    World production of beryllium is a thin market, with only a handful
of countries known to process beryllium ores and concentrates into
beryllium products, and characterized by a high degree of variation and
uncertainty. The United States accounts for approximately 65 percent of
world beryllium deposits and 90 percent of world production, but there
is also a significant stockpiling of beryllium materials in Kazakhstan,
Russia, China, and possibly other countries (USGS, 2013a). For the
individual years 2008-2012, the United States' net import reliance as a
percentage of apparent consumption (that is, imports minus exports net
of industry and government stock adjustments) ranged from 10 percent to
61 percent (USGS, 2013b). To assure an adequate stockpile of beryllium
materials to support national defense interests, the U.S. Department of
Defense, in 2005, under the Defense Production Act, Title III, invested
in a public-private partnership with the leading U.S. beryllium
producer to build a new $90.4 million primary beryllium facility in
Elmore, Ohio. Construction of that facility was completed in 2011
(USGS, 2013b).
    One factor of importance to firms working with beryllium and
beryllium alloys is to have a reliable supply of beryllium materials.
U.S. manufacturers can have a relatively high confidence in the
availability of beryllium materials relative to manufacturers in many
foreign countries, particularly those that do not have economic or
national security partnerships with the United States.
    Firms using beryllium in production must consider not just the cost
of the chemical itself but also the various regulatory costs associated
with the use, transport, and disposal of the material. For example, for
marine transport, metallic beryllium powder and beryllium compounds are
classified by the International Maritime Organization (IMO) as
poisonous substances, presenting medical danger. Beryllium is also
classified as flammable. The United Nations classification of beryllium
and beryllium compounds for the transport of dangerous goods is
"poisonous substance" and, for packing, a "substance presenting
medium danger" (WHO, 1990). Because of beryllium's toxicity, the
material is subject to various workplace restrictions as well as
international, national, and State requirements and guidelines
regarding beryllium content in environmental media (USGS, 2013a).
    As the previous discussion indicates, the production and use of
beryllium and beryllium alloys in the United States and foreign markets
appears to depend on the availability of production facilities;
beryllium stockpiles; national defense and political considerations;
regulations limiting the shipping of beryllium and beryllium products;
international, national, and State regulations and guidelines regarding
beryllium content in environmental media; and, of course, the special
performance properties of beryllium and beryllium alloys in various
applications. Relatively small changes in the price of beryllium would
seem to have a minor effect on the location of beryllium production and
use. In particular, as a result of this proposed rule, OSHA would
expect that, if all compliance costs were passed through in the form of
higher prices, a price increase of 0.11 percent, on average, for firms
manufacturing or using beryllium in the United States--and not
exceeding 1 percent in any affected industry--would have a negligible
effect on foreign competition and would therefore not threaten the
economic viability of any affected domestic industries.
(b) Economic Feasibility Screening Analysis: Small and Very Small
Businesses
    The preceding discussion focused on the economic viability of the
affected industries in their entirety. Even though OSHA found that the
proposed standard did not threaten the survival of these industries,
there is still the possibility that the competitive structure of these
industries could be significantly altered such as by small entities
exiting from the industry as a result of the proposed standard.
    To address this possibility, OSHA examined the annualized costs of
the proposed standard per affected small entity, and per affected very
small entity, for each affected industry. Again, OSHA used a minimum
threshold level of annualized compliance costs equal to one percent of
annual revenues--and, secondarily, annualized compliance costs equal to
ten percent of annual profits--below which the Agency has concluded
that the costs are unlikely to threaten the survival of small entities
or very small entities or, consequently, to alter the competitive
structure of the affected industries.
    Based on the results presented in Table IX-9, the annualized cost
of compliance with the proposed rule for the average affected small
entity is estimated to be $8,108 in 2010 dollars. Based on the results
presented in Table IX-10, the annualized cost of compliance with the
proposed rule for the average affected very small entity is estimated
to be $1,955 in 2010 dollars. These tables also show that there are no
industries in which the annualized costs of the proposed rule for small
entities or very small entities exceed one percent of annual revenues.
NAICS 331525b: Sand Copper Foundries (except die-casting) has the
highest estimated cost impact as a percentage of revenues for small
entities, 0.95 percent, and NAICS 336322b: Other motor vehicle
electrical and electronic equipment has the highest estimated cost
impact as a percentage of revenues for very small entities, 0.70 percent.
    Small entities in four industries--NAICS 331525: Sand and non-sand
foundries (except die-casting); NAICS 331524(a and b): Aluminum
foundries (except die-casting); NAICS 811310: Commercial and Industrial
Machinery and Equipment; and NAICS 331522: Nonferrous (except aluminum)
die-casting foundries--have annualized costs in excess of 10 percent of
annual profits (17.45 percent, 16.12 percent, 11.68 percent, and 10.64
percent, respectively). Very small entities in 7 industries are
estimated to have annualized costs in excess of 10 percent of annual
profit; NAICS 336322b: Other motor vehicle electrical and electronic
equipment (38.49 percent); \23\ NAICS 336322a: Other motor vehicle
electrical and electronic equipment, (18.18 percent); NAICS 327113:
Porcelain electrical Supply Manufacturing (13.82 percent); NAICS
811310: Commercial and Industrial Machinery and Equipment (Except
Automotive and Electronic) Repair and Maintenance (12.76 percent);
NAICS 332721a: Precision turned product manufacturing (10.50 percent);
NAICS 336214: Travel trailer and camper manufacturing (10.75 percent);
and NAICS 336399: All other motor vehicle parts manufacturing (10.38
percent).
---------------------------------------------------------------------------

    \23\ NAICS 336322 contains entities that fall into three
separate application groups. NAICS 336322b is in the Beryllium Oxide
Ceramics and Composites application group. NAICS 336322a (which
follows in the text) is in the Fabrication of Beryllium Alloy
Products application group.
---------------------------------------------------------------------------

    In general, cost impacts for affected small entities or very small
entities will tend to be somewhat higher, on average, than the cost
impacts for the average business in those affected industries. That is
to be expected. After all, smaller businesses typically suffer from
diseconomies of scale in many aspects of their business, leading to
less revenue per dollar of cost and higher unit costs. Small businesses
are able to overcome these obstacles by providing specialized products
and services, offering local service and better service, or otherwise
creating a market niche for themselves. The higher cost impacts for
smaller businesses estimated for this rule--other than very small
entities in NAICS 336322b: Other motor vehicle electrical and
electronic equipment--generally fall within the range observed in other
OSHA regulations and, as verified by OSHA's lookback reviews, have not
been of such a magnitude to lead to the economic failure of regulated
small businesses.
    The ratio of annualized costs to annual profit is a sizable 38.49
percent in NAICS 336322b: Other motor vehicle electrical and electronic
equipment. However, OSHA believes that the actual ratio is
significantly lower. There are 386 very small entities in NAICS 336322,
of which only 6, or 1.5 percent, are affected entities using beryllium.
When OSHA calculated the cost-to-profit ratio, it used the average
profit per firm for the entire NAICs industry, not the average profit
rate for firms working with beryllium. The profit rate for all
establishments in NAICS 336322b was estimated at 1.83 percent. If, for
example, the average profit rate for a very small entity in NAICS
336322b were equal to 5.95 percent, the average profit rate for its
application group, Beryllium Oxide Ceramics and Composites, then the
ratio of the very small entity's annualized cost of the proposed rule
to its annual profit would actually be 11.77 percent. OSHA tentatively
concludes the 6 establishments in the NAICS specializing in beryllium
production will have a higher than average profit rate and will be able
to pass much of the cost onto the consumer for three main reasons: (1)
The absence of substitutes containing the rare performance
characteristics of beryllium; (2) the relative price insensitivity of
(other) motor vehicles containing the special performance
characteristics of beryllium and beryllium alloys; and (3) the fact
that electrical and electronic components made of beryllium or
beryllium-containing alloys typically account for only a small portion
of the overall cost of the finished (other) motor vehicles. The
annualized compliance cost to annual revenue ratio for NAICS 336332b is
0.70 percent, 0.30 percent below the 1 percent threshold. Based on
OSHA's experience, price increases of this magnitude have not
historically been associated with the economic failure of small
businesses.

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(c) Regulatory Flexibility Screening Analysis
    To determine if the Assistant Secretary of Labor for OSHA can
certify that the proposed beryllium standard will not have a
significant economic impact on a substantial number of small entities,
the Agency has developed screening tests to consider minimum threshold
effects of the proposed standard on small entities. The minimum
threshold effects for this purpose are annualized costs equal to one
percent of annual revenues, and annualized costs equal to five percent
of annual profits, applied to each affected industry. OSHA has applied
these screening tests both to small entities and to very small
entities. For purposes of certification, the threshold level cannot be
exceeded for affected small entities or very small entities in any
affected industry.
    Tables IX-9 and Table IX-10, presented above, show that the
annualized costs of the proposed standard do not exceed one percent of
annual revenues for affected small entities or affected very small
entities in any affected industry. These tables also show that the
annualized costs of the proposed standard exceed five percent of annual
profits for affected small entities in 12 industries and for affected
very small entities in 30 industries. OSHA is therefore unable to
certify that the proposed standard will not have a significant economic
impact on a substantial number of small entities and must prepare an
Initial Regulatory Flexibility Analysis (IRFA). The IRFA is presented
in Chapter IX of the PEA and is reproduced in Section IX.I of this
preamble.

G. Benefits and Net Benefits

    In this section, OSHA presents a summary of the estimated benefits
and net benefits of the proposed beryllium rule. This section proceeds
in five steps. The first step estimates the numbers of diseases and
deaths prevented by comparing the current (baseline) situation to a
world in which the proposed PEL is adopted in a final standard to a
world in which employees are exposed at the level of the proposed PEL
throughout their working lives. The second step also assumes that the
proposed PEL is adopted, but uses the results from the first step to
estimate what would happen under a more realistic scenario in which
employees have been exposed for varying periods of time to the baseline
situation and will thereafter be exposed to the new PEL.
    The third step covers the monetization of benefits. Then, in the
fourth step, OSHA estimates the net benefits and incremental benefits
of the proposed rule by comparing the monetized benefits to the costs
presented in Chapter V of the PEA. The models underlying each step
inevitably need to make a variety of assumptions based on limited data.
In the fifth step, OSHA provides a sensitivity analysis to explore the
robustness of the estimates of net benefits with respect to many of the
assumptions made in developing and applying the underlying models. A
full explanation of the derivation of the estimates presented here is
provided in Chapter VII of the PEA for the proposed rule. OSHA invites
comments on any aspect of the data and methods used to estimate the
benefits and net benefits of this proposed rule. Because dental labs
constitute a significant source of both costs and benefits to the rule
(over 40 percent), OSHA is particularly interested in comments
regarding the appropriateness of the model, assumptions, and data to
estimating the benefits to workers in that industry.
    OSHA has added to the docket the spreadsheets used to calculate the
estimates of benefits outlined below (OSHA, 2015a). Those interested in
exploring the details and methodology of OSHA's benefits analysis, such
as how the life table referred to below was developed and applied,
should consult those spreadsheets.
Step 1--Estimation of the Steady-State Number of Beryllium-Related
Diseases Avoided
Methods of Estimation
    The first step in OSHA's development of the benefits analysis
compares the situation in which employees continue to be at baseline
exposure levels for their entire working lives to the situation in
which all employees have been exposed at a given PEL for their entire
working lives. This is a comparison of two steady-state situations. To
do this, OSHA must estimate both the risk associated with the baseline
exposure levels and the risk following the promulgation of a new
beryllium standard. OSHA's approach assumes for inputs such as the
turnover rate and the exposure response function that they are similar
across all workers exposed to beryllium, regardless of industry.
    An exposure-response model, discussed below, is used to estimate a
worker's risk of beryllium-related disease based on the worker's
cumulative beryllium exposure. The Agency used a lifetime risk model to
estimate the baseline risk and the associated number of cases for the
various disease endpoints. A lifetime risk model explicitly follows a
worker each year, from work commencement onwards, accumulating the
worker's beryllium exposure in the workplace and estimating outcomes
each year for the competing risks that can occur. To go from exposure
to number of cases, the Agency needs to estimate an exposure-response
relationship, and this is discussed below. The possible outcomes are no
change, or the various health endpoints OSHA has considered (beryllium
sensitization, CBD, lung cancer, and the mortality associated with
these endpoints). As part of the estimation discussion, OSHA will
mention specific parameters used in some of the estimation methods, but
will further discuss how these parameters were derived later in this
section.
    The baseline lifetime risk model is the most complicated part of
the analysis. The Agency only needs to make relatively simple
adjustments to this model to reflect changes in activities and
conditions due to the standard, which, working through the model, then
lead to changes in relevant health outcomes. There are three channels
by which the standard generates benefits. First are estimated benefits
due to the lowering of the PEL. Second are estimated benefits with
further exposure reductions from the substitution of non-beryllium for
beryllium-containing materials, ending workers' beryllium exposures
entirely. This potential source of benefits is particularly significant
with respect to OSHA's assumptions for how dental labs are likely to
reduce exposures (see below). Finally, the model estimates benefits due
to the ancillary programs that are required by the proposed standard.
The last channel affects CBD and sensitization, endpoints which may be
mitigated or prevented with the help of ancillary provisions such as
dermal protection and medical surveillance for early detection, and for
which the Agency has some information on the effects on risk of
ancillary provisions. The benefits of ancillary provisions are not
estimated for lung cancer because the benefits from reducing lung
cancer are considered to be the result of reducing airborne exposure
only and thus the ancillary provisions will have no separable effect on
airborne exposures. The discussion here will concentrate on CBD as
being the most important and complex endpoint, and most illustrative of
other endpoints: The structure for other endpoints is the same; only
the exposure response functions are different. Here OSHA will
discuss first the exposure-response model, then the structure of the
year-to-year changes for a worker, then the estimated exposure
distribution in the affected population and the risk model with the
lowering of the PEL, and, last, the other adjustments for the ancillary
benefits and the substitution benefits.
    The exposure response model is designed to translate beryllium
exposure to risk of adverse health endpoints. In the case of beryllium
sensitization and CBD, the Agency uses the cumulative exposure data
from a beryllium manufacturing facility. Specifically, OSHA uses the
quartile data from the Cullman plant that is presented in Table VI-7 of
the Preliminary Risk Assessment in the preamble. The raw data from this
study show cases of CBD with cumulative exposures that would represent
an average exposure level of less than 0.1 [micro]g/m\3\ if exposed for
10 years; show cases of CBD with exposures lasting less than one year;
and show cases of CBD with actual average exposure of less than 0.1
[micro]g/m\3\.
    Prevalence is defined as the percentage of persons with a condition
in a population at a given point in time. The quartile data in Table
VI-7 of the Preliminary Risk Assessment are prevalence percentages (the
number of cases of illness documented over several years in the 319
person cohort from the Cullman plant) at different cumulative exposure
levels. The Cullman data do not cover persons who left the work force
or what happened to persons who remained in the workforce after the
study was completed. For the lifetime risk model, the prevalence
percentages will be translated into incidence percentages--the
estimated number of new cases predicted to occur each year. For this
purpose OSHA assumed that the incidence for any given cumulative
exposure level is constant from year to year and continues after
exposure ceases.
    To calculate incidence from prevalence, OSHA assumed a steady state
in which both the size of the beryllium-exposed affected population,
exposure concentrations during employment and prevalence are constant
over time. If these conditions are met, and turnover among workers with
a condition is equal to turnover for workers without a condition, then
the incidence rate will be equal to the turnover rate multiplied by the
prevalence rate. If the turnover rate among persons with a condition is
higher than the turnover rate for workers without the condition, then
this assumption will underestimate incidence. This might happen if, in
addition to other reasons for leaving work, persons with a condition
leave a place of employment more frequently because their disabilities
cause them to have difficulty continuing to do the work. If the
turnover rate among persons with a condition is lower than the turnover
rate for workers without the condition, then this assumption will
overestimate incidence. This could happen if an employer provides
special benefits to workers with the condition, and the employer would
cease to provide these benefits if the employee left work.
    To illustrate, if 10 percent of the work force (including 10
percent of those with the condition) leave each year and if the overall
prevalence is at 20 percent, then a 2 percent (10 percent times 20
percent) incidence rate will be needed in order to keep a steady 20
percent group prevalence rate each year. OSHA's model assumes a
constant 10 percent turnover rate (see later in this section for the
rationale for this particular turnover rate). While turnover rates are
not available for the specific set of employees in question, for
manufacturing as a whole, the turnover rates are greater than 20
percent, and greater than 30 percent for the economy as a whole (BLS,
2013). For this analysis, OSHA assumed an effective turnover rate of 10
percent. Different turnover rates will result in different incidence
rates. The lower the turnover rate the lower the estimated incidence
rate. This is a conservative assumption for the industries where
turnover rates may be higher. However, some occupations/industries,
such as dental lab technicians, may have lower turnover rates than
manufacturing workers. Additionally, the typical dental technician even
if leaving one workplace, has significant likelihood of continuing to
work as a dental technician and going to another workplace that uses
beryllium. OSHA welcomes comments on its turnover estimates and on
sectors, such as dental laboratories, where turnover may be lower than
ten percent.
    Using Table VI-7 of the Preliminary Risk Assessment, when a
worker's cumulative exposure is below 0.147 ([mu]g/m\3\-years), the
prevalence of CBD is 2.5 percent and so the derived annual risk would
be 0.25 percent (0.10 x 2.5 percent). It will stay at this level until
the worker has reached a cumulative exposure of 1.468, where it will
rise to 0.80 percent.
    The model assumes a maximum 45-year (250 days per year) working
life (ages 20 through 65 or age of death or onset of CBD, whichever is
earlier) and follows workers after retirement through age 80. The 45-
year working life is based on OSHA's legal requirements and is longer
than the working lives of most exposed workers. A shorter working life
will be examined later in this section. While employed, the worker
accumulates beryllium exposure at a rate depending on where the worker
is in the empirical exposure profile presented in Chapter IV of the PEA
(i.e., OSHA calculates a general risk model which depends on the
exposure level and then plug in our empirical exposure distribution to
estimate the final number of cases of various health outcomes).
Following a worker's retirement, there is no increased exposure, just a
constant annual risk resulting from the worker's final cumulative
exposure.
    OSHA's model follows the population of workers each year, keeping
track of cumulative exposure and various health outcomes. Explicitly,
each year the model calculates: The increased cumulative exposure level
for each worker versus last year, the incidence at the new exposure
level, the survival rate for this age bracket, and the percentage of
workers who have not previously developed CBD in earlier years.
    For any individual year, the equation for predicting new cases of
CBD for workers at age t is:

    New CBD cases rate(t) = modeled incidence rate(t) * survival
rate(t) * (1- currently have CBD rate(t)), where the variables used
are:
    New CBD cases rate(t) is the output variable to be calculated;
    cumulative exposure(t) = cumulative exposure(t-1) + current
exposure;
    modeled incidence rate(t) is a function of cumulative exposure;
and
    survival rate(t) is the background survival rate from mortality
due to other causes in the national population.

    Then for the next year the model updates the survival rate (due to
an increase in the worker's age), incidence rate (due to any increased
cumulative exposure), and the rate of those currently having CBD, which
increases due to the new CBD case rate of the year before. This process
then repeats for all 60 years.
    It is important to note that this model is based on the assumption
that prevalence is explained by an underlying constant incidence, and
as a result, prevalence will be different depending on the average
number of years of exposure in the population examined and (though a
sensitivity analysis is provided later) on the assumption of a maximum
of 45 years of exposure. OSHA also examined (OSHA 2015c) a model in
which prevalence is constant at the levels shown in Table VI-7 of the
preliminary risk assessment, with a population age (and thus exposure)
distribution estimated based on an assumed constant turnover rate.
OSHA solicits comment on this and other alternative approaches to using
the available prevalence data to develop an exposure-response function
for this benefits analysis.
    In the next step, OSHA uses its model to take into account the
adoption of the lower proposed PEL. OSHA uses the exposure profile for
workers as estimated in Chapter IV of the PEA for each of the various
application groups. These exposure profiles estimate the number of
workers at various exposure levels, specifically the ranges less than
0.1 [mu]g/m\3\, 0.1 to 0.2, 0.2 to 0.5, 0.5 to 1.0, 1.0 to 2.0, and
greater than 2.0 [mu]g/m\3\. Translating these ranges into exposure
levels for the risk model, the model assumes an average exposure equal
to the midpoint of the range, except for the lower end, where it was
assumed to be equal to 0.1 [mu]g/m\3\, and the upper end, where it was
assumed to be equal to 2.0 [mu]g/m\3\.
    The model increases the workers' cumulative exposure each year by
these midpoints and then plugs these new values into the new case
equation. This alters the incidence rate as cumulative exposure crosses
a threshold of the quartile data. So then using the exposure profiles
by application group from Chapter IV of the PEA, the baseline exposure
flows through the life time risk model to give us a baseline number of
cases. Next OSHA calculated the number of cases estimated to occur
after the implementation of the proposed PEL of 0.2 [mu]g/m\3\. Here
OSHA simply takes the number of workers with current average exposure
above 0.2 [mu]g/m\3\ and set their exposure level at 0.2 [mu]g/m\3\;
all exposures for workers exposed below 0.2 [mu]g/m\3\ stay the same.
After adjusting the worker exposure profile in this way, OSHA goes
through all the same calculations and obtains a post-standard number of
CBD cases. Subtracting estimated post-standard CBD cases from estimated
pre-standard CBD cases gives us the number of CBD cases that would be
averted due to the proposed change in the PEL.
    Based on these methods, OSHA's estimate of benefits associated with
the proposed rule does not include benefits associated with current
compliance that have already been achieved with regard to the new
requirements, or benefits obtained from future compliance with existing
beryllium requirements. However, available exposure data indicate that
few employees are currently exposed above the existing standard's PEL
of 2.0 [mu]g/m\3\. To achieve consistency with the cost estimation
method in chapter V, all employees in the exposure profile that are
above 2.0 [mu]g/m\3\ are assumed to be at the 2.0 [mu]g/m\3\ level.
    There is also a component that applies only to dental labs. OSHA
has preliminarily assumed, based on the estimates of higher costs for
engineering controls than using substitutes presented in the cost
chapter, that rather than incur the costs of compliance with the
proposed standard, many dental labs are likely to stop using beryllium-
containing materials after the promulgation of the proposed
standard.\24\ OSHA estimated earlier in this PEA that, for the
baseline, only 25 percent of dental lab workers still work with
beryllium. OSHA estimates that, if OSHA adopts the proposed rule, 75
percent of the 25 percent still using beryllium will stop working with
beryllium; their beryllium exposure level will therefore drop to zero.
OSHA estimates that the 75 percent of workers will not be a random
sample of the dental lab exposure profile but instead will concentrate
among workers who are currently at the highest exposure levels because
it would cost more to reduce those higher exposures into compliance
with the proposed PEL. Under this judgment OSHA is estimating that the
rule would eliminate all cases of CBD in the 75 percent of dental lab
workers with the highest exposure levels. As discussed in the
sensitivity analysis below, dental labs constitute a significant source
of both costs and benefits to the rule (over 40 percent), and the
extent to which dental laboratories substitute other materials for
beryllium has significant effects on the benefits and costs of the
rule. To derive its baseline estimate of cases of CBD in dental
laboratories, OSHA (1) estimated baseline cases of CBD using the
existing rate of beryllium use in dental labs without a projection of
further substitution; (2) estimated cases of CBD with the proposed
regulation using an estimate that 75 percent of the dental labs with
higher exposure would switch to other materials and thus eliminate
exposure to beryllium; and (3) estimated that the turnover rate in the
industry is 10 percent. OSHA welcomes comments on all aspects of the
analysis of substitution away from beryllium in the dental laboratories
sector.
---------------------------------------------------------------------------

    \24\ In Chapter V (Costs) of the PEA, OSHA explored the cost of
putting in LEV instead of substitution. The Agency costed an
enclosure for 2 technicians: The Powder Safe Type A Enclosure, 32
inch wide with HEPA filter, AirClean Systems (2011), which including
operating and maintenance, was annualized at $411 per worker. This
is significantly higher than the annual cost for substitution of
$166 per worker, shown later in this section.
---------------------------------------------------------------------------

    Estimation results for both dental labs and non-dental workplaces
appear in the table below.

                                       CBD Case Estimates, 45-Year Totals, Baseline and With PEL of 0.2 [mu]g/m\3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                     Current beryllium exposure  ([mu]g/m\3\)
                                                                     ------------------------------------------------------------------------    Total
                                                                         < 0.1      0.1-0.2     0.2-0.5     0.5-1.0     1.0-2.0      > 2.0
--------------------------------------------------------------------------------------------------------------------------------------------------------
Baseline................................  Dental labs...............         827         636         432         608         155         466       3,124
                                          Non-dental................       5,912         631         738         287         112         214       7,893
                                                                     -----------------------------------------------------------------------------------
                                             Total..................       6,739       1,267       1,171         895         267         679      11,017
PEL = 0.2 [mu]g/m\3\....................  Dental labs...............         679           0           0           0           0           0         679
                                          Non-dental................       5,912         631         693         255          98         186       7,774
                                                                     -----------------------------------------------------------------------------------
                                             Total..................       6,591         631         693         255          98         186       8,454
Prevented by PEL reduction..............  Dental labs...............         148         636         432         608         155         466       2,444
                                          Non-dental................           0           0          45          32          14          27         119
                                                                     -----------------------------------------------------------------------------------
                                             Total..................         148         636         478         640         169         493       2,563
--------------------------------------------------------------------------------------------------------------------------------------------------------

    In contrast to this PEL component of the benefits, both the
ancillary program benefits calculation and the substitution benefits
calculation are relatively simple. Both are percentages of the
lifetime-risk-model CBD cases that still occur in the post-standard
world. OSHA notes that in the context of existing CBD prevention
programs, some ancillary-provision programs similar to those included
in OSHA's proposal have eliminated a significant percentage of the
remaining CBD cases (discussed later in this chapter). If the ancillary
provisions reduce remaining CBD cases by 90 percent for example, and if
the estimated baseline contains 120 cases of CBD, and post-standard
compliance with a lower PEL reduces the total to 100 cases of CBD, then
90 of those remaining 100 cases of CBD would be averted due to the
ancillary programs.
    OSHA assumed, based on the clinical experience discussed further
below, that approximately 65 percent of CBD cases ultimately result in
death. Later in this chapter, OSHA provides a sensitivity analysis of
the effects of different values for assuming this percentage at 50
percent and 80 percent on the number of CBD deaths prevented. OSHA
welcomes comment on this assumption. OSHA's exposure-response model for
lung cancer is based on lung cancer mortality data. Thus, all of the
estimated cases of lung cancer in the benefits analysis are cases of
premature death from beryllium-related lung cancer.
    Finally, in recognition of the uncertainty in this aspect of these
models, OSHA presents a "high" estimate, a "low" estimate, and uses
the midpoint of these two as our "primary" estimate. The low estimate
is simply those CBD fatalities prevented due to everything except the
ancillary provisions, i.e., both the reduction in the PEL and the
substitution by dental labs. The high estimate includes both of these
factors plus all the ancillary benefits calculated at an effectiveness
rate of 90 percent in preventing cases of CBD not averted by the
reduction of the PEL. The midpoint is the combination of reductions
attributed to adopting the proposed PEL, substitution by dental labs,
and the ancillary provisions calculated at an effectiveness rate of
only 45 percent.
a. Chronic Beryllium Disease
    CBD is a respiratory disease in which the body's immune system
reacts to the presence of beryllium in the lung, causing a progression
of pathological changes including chronic inflammation and tissue
scarring. Immunological sensitization to beryllium (BeS) is a precursor
that occurs before early-stage CBD. Only sensitized individuals can go
on to develop CBD. In early, asymptomatic stages of CBD, small
granulomatous lesions and mild inflammation occur in the lungs. As CBD
progresses, the capacity and function of the lungs decrease, which
eventually affects other organs and bodily functions as well. Over time
the spread of lung fibrosis (scarring) and loss of pulmonary function
cause symptoms such as: A persistent dry cough, shortness of breath,
fatigue, night sweats, chest and join pain, clubbing of fingers due to
impaired oxygen exchange, and loss of appetite. In these later stages
CBD can also impair the liver, spleen, and kidneys, and cause health
effects such as granulomas of the skin and lymph nodes, and cor
pulmonale (enlargement of the heart). The speed and extent of disease
progression may be influenced by the level and duration of exposure,
treatment with corticosteroids, and genetics, but these effects are not
fully understood.
    Corticosteroid therapy, in workers whose beryllium exposure has
ceased, has been shown to control inflammation, ease symptoms, and in
some cases prevent the development of fibrosis. However, corticosteroid
use can have adverse effects, including increased risk of infections;
accelerated bone loss or osteoporosis; psychiatric effects such as
depression, sleep disturbances, and psychosis; adrenal suppression;
ocular effects; glucose intolerance; excessive weight gain; increased
risk of cardiovascular disease; and poor wound healing. The effects of
CBD, and of common treatments for CBD, are discussed in detail in this
preamble at Section V, Health Effects, and Section VIII, Significance
of Risk.
    OSHA's review of the literature on CBD suggests three broad types
of CBD progression (see this preamble at Section V, Health Effects). In
the first, individuals progress relatively directly toward death
related to CBD. They suffer rapidly advancing disability and their
death is significantly premature. Medical intervention is not applied,
or if it is, does little to slow the progression of disease. In the
second type, individuals live with CBD for an extended period of time.
The progression of CBD in these individuals is naturally slow, or may
be medically stabilized. They may suffer significant disability, in
terms of loss of lung function--and quality of life--and require
medical oversight their remaining years. They would be expected to lose
some years of normal lifespan. As discussed previously, advanced CBD
can involve organs and systems beyond the respiratory system; thus, CBD
can contribute to premature death from other causes. Finally,
individuals with the third type of CBD progression do not die
prematurely from causes related to CBD. The disease is stabilized and
may never progress to a debilitating state. These individuals
nevertheless may experience some disability or loss of lung function,
as well as side effects from medical treatment, and may be affected by
the disease in many areas of their lives: Work, recreation, family,
etc.\25\
---------------------------------------------------------------------------

    \25\ As indicated in the Health Effects section of this
preamble: "It should be noted, however, that treatment with
corticosteroids has side-effects of their own that need to be
measured against the possibility of progression of disease (Gibson
et al., 1996; Zaki et al., 1987). Alternative treatments such as
azathiopurine and infliximab, while successful at treating symptoms
of CBD, have been demonstrated to have side-effects as well
(Pallavicino et al., 2013; Freeman, 2012)".
---------------------------------------------------------------------------

    In the analysis that follows, OSHA assumes, based on the clinical
experience discussed below, that 35 percent of workers who develop CBD
experience the third type of progression and do not die prematurely
from CBD. The remaining 65 percent were estimated to die prematurely,
whether from rapid disease progression (type 1) or slow (type 2).
Although the proportion of CBD patients who die prematurely as a result
of the disease is not well understood or documented at this time, OSHA
believes this assumption is consistent with the information submitted
in response to the RFI. Newman et al. (2003) presented a scenario for
what they considered to be the "typical" CBD patient:

    We have included an example of a life care plan for a typical
clinical case of CBD. In this example, the hypothetical case is
diagnosed at age 40 and assumed to live an additional 33.7 years
(approximately 5% reduced life expectancy in this model). In this
hypothetical example, this individual would be considered to have
moderate severity of chronic beryllium disease at the time of
initial diagnosis. They require treatment with prednisone and
treatment for early cor pulmonale secondary to CBD. They have
experienced some, but not all, of the side effects of treatment and
only the most common CBD-related health effects.

    In short, most workers diagnosed with CBD are expected to have
shortened life expectancy, even if they do not progress rapidly and
directly to death. It should be emphasized that this represents the
Agency's best estimate of the mortality related to CBD based upon the
current available evidence. As described in Section V, Health Effects,
there is a substantial degree of uncertainty as to the prognosis for
those contracting CBD, particularly as the relatively less severe
cases are likely not to be studied closely for the remainder of their
lives.
    As mentioned previously, OSHA used the Cullman data set for
empirical estimates of beryllium sensitization and CBD prevalence in
its exposure response model, which translates beryllium exposure to
risk of adverse health endpoints for the purpose of determining the
benefits that could be achieved by preventing those adverse health
endpoints.
    OSHA chose the cumulative exposure quartile data as the basis for
this benefits analysis. The choice of cumulative quartiles was based in
part on the need to use the cumulative exposure forecast developed in
the model, and in part on the fact that in statistically fitted models
for CBD, the cumulative exposure tended to fit the CBD data better than
other exposure variables. OSHA also chose the quartile model because
the outside expert who examined the logistic and proportional hazards
models believed statistical modeling of the data set to be unreliable
due to its small size. In addition, the proportional hazards model with
its dummy variables by year of detection is difficult to interpret for
purposes of this section. Of course regression analyses are often
useful in empirical analysis. They can be a useful compact
representation of a set of data, allow investigations of various
variable interactions and possible causal relationships, have added
flexibility due to covariate transformations, and under certain
conditions can be shown to be statistically "optimal." However, they
are only useful when used in the proper setting. The possibility of
misspecification of functional form, endogeneity, or incorrect
distributional assumptions are just three reasons to be cautious about
using regression analyses.
    On the other hand, the use of results produced by a quartile
analysis as inputs in a benefits assessment implies that the analytic
results are being interpreted as evidence of an exposure-response
causal relationship. Regression analysis is a more sophisticated
approach to estimating causal relationships (or even correlations) than
quartile or other quantile analysis, and any data limitations that may
apply to a particular regression-based exposure-response estimation
also apply to exposure-response estimation conducted with a quartile
analysis using the same data set. In this case, OSHA adopted the
quartile analysis because the logistic regression analysis yielded
extremely high prevalence rates for higher level of exposure over long
time periods that some might not find credible. Use of the quartile
analysis serves to show that there are significant benefits even
without using an extremely high estimate of prevalence for long periods
of exposure at high levels. As a check on the quartile model, the
Agency performed the same benefits calculation using the logit model
estimated by the Agency's outside expert, and these benefit results are
presented in a separate OSHA background document (OSHA, 2015b). The
difference in benefits between the two models is slight, and there is
no qualitative change in final outcomes. The Agency solicits comment on
these issues.
(1) Number of CBD Cases Prevented by the Proposed PEL
    To examine the effect of simply changing the PEL, including the
effect of the standard on some dental labs to discontinue their use of
beryllium, OSHA compared the number of CBD-related deaths (mortality)
and cases of non-fatal CBD (morbidity) that would occur if workers were
exposed for a 45-year working life to PELs of 0.1, 0.2, or 0.5 [mu]g/
m\3\ to the number of cases that would occur at levels of exposure at
or below the current PEL. The number of avoided cases over a
hypothetical working life of exposure for the current population at a
lower PEL is then equal to the difference between the number of cases
at levels of exposure at or below the current PEL for that population
minus the number of cases at the lower PEL. This approach represents a
steady-state comparison based on what would hypothetically happen to
workers who received a specific average level of occupational exposure
to beryllium during an entire working life. (Chapter VII in the PEA
modifies this approach by introducing a model that takes into account
the timing of benefits before steady state is reached.)
    As indicated in Table IX-11, the Agency estimates that there would
be 16,240 cases of beryllium sensitization, from which there would be
11,017, or about 70 percent, progressing to CBD. The Agency arrived at
these estimates by using the CBD and BeS prevalence values from the
Agency's preliminary risk analysis, the exposure profile at current
exposure levels (under an assumption of full, or fixed, compliance with
the existing beryllium PEL), and the model outlined in the previous
methods of estimation section after a working lifetime of exposure.
Applying the prior midpoint estimate, as explained above, that 65
percent of CBD cases cause or contribute to premature death, the Agency
predicts a total of 7,161 cases of mortality and 3,856 cases of
morbidity from exposure at current levels; this translates, annually,
to 165 cases of mortality and 86 cases of morbidity. At the proposed
PEL, OSHA's base model estimates that, due to the airborne factor only,
a total of 2,563 CBD cases would be avoided from exposure at current
levels, including 1,666 cases of mortality and 897 cases of morbidity--
or an average of 37 cases of mortality and 20 cases of morbidity
annually. OSHA has not estimated the quantitative benefits of
sensitization cases avoided.
    OSHA requests comment on this analysis, including feedback on the
data relied on and the approach and assumptions used. As discussed
earlier, based on information submitted in response to the RFI, the
Agency estimates that most of the workers with CBD will progress to an
early death, even if it comes after retirement, and has quantified
those cases prevented. However, given the evolving nature of science
and medicine, the Agency invites public comment on the current state of
CBD-related mortality.
    The proposed standard also includes provisions for medical
surveillance and removal. The Agency believes that to the extent the
proposal provides medical surveillance sooner and to more workers than
would have been the case in the absence of the proposed standard,
workers will be more likely to receive appropriate treatment and, where
necessary, removal from beryllium exposure. These interventions may
lessen the severity of beryllium-related illnesses, and possibly
prevent premature death. The Agency requests public comment on this
issue.
(2) CBD Cases Prevented by the Ancillary Provisions of the Proposed
Standard
    The nature of the chronic beryllium disease process should be
emphasized. As discussed in this preamble at Section V, Heath Effects,
the chronic beryllium disease process involves two steps. First,
workers become sensitized to beryllium. In most epidemiological studies
of CBD conducted to date, a large percentage of sensitized workers have
progressed to CBD. A certain percentage of the population has an
elevated risk of this occurring, even at very low exposure levels, and
sensitization can occur from dermal as well as inhalation exposure to
beryllium. For this reason, the threat of beryllium sensitization and
CBD persist to a substantial degree, even at very low levels of
airborne beryllium exposure. It is therefore desirable not only to
significantly reduce airborne beryllium exposure, but to avoid nearly
any source of beryllium exposure, so as to prevent beryllium sensitization.
    The analysis presented above accounted only for CBD-prevention
benefits associated with the proposed reduction of the PEL, from 2 ug/
m\3\ to 0.2 ug/m\3\. However, the proposed standard also includes a
variety of ancillary provisions--including requirements for respiratory
protection, personal protective equipment (PPE), housekeeping
procedures, hygiene areas, medical surveillance, medical removal, and
training--that the Agency believes would further reduce workers' risk
of disease from beryllium exposure. These provisions were described in
Chapter I of the PEA and discussed extensively in Section XVIII of this
preamble, Summary and Explanation of the Proposed Standard.
    The leading manufacturer of beryllium in the U.S., Materion
Corporation (Materion), has implemented programs including these types
of provisions in several of its plants and has worked with NIOSH to
publish peer-reviewed studies of their effectiveness in reducing
workers' risk of sensitization and CBD. The Agency used the results of
these studies to estimate the health benefits associated with a
comprehensive standard for beryllium.
    The best available evidence on comprehensive beryllium programs
comes from studies of programs introduced at Materion plants in
Reading, PA; Tucson, AZ; and Elmore, OH. These studies are discussed in
detail in this preamble at Section VI, Preliminary Risk Assessment, and
Section VIII, Significance of Risk. All three facilities were in
compliance with the current PEL prior to instituting comprehensive
programs, and had taken steps to reduce airborne levels of beryllium
below the PEL, but their medical surveillance programs continued to
identify cases of sensitization and CBD among their workers. Beginning
around 2000, these facilities introduced comprehensive beryllium
programs that used a combination of engineering controls, dermal and
respiratory PPE, and stringent housekeeping measures to reduce workers'
dermal exposures and airborne exposures. These comprehensive beryllium
programs have substantially lowered the risk of sensitization among
workers. At the times that studies of the programs were published,
insufficient follow-up time had elapsed to report directly on the
results for CBD. However, since only sensitized workers can develop
CBD, reduction of sensitization risk necessarily reduces CBD risk as
well.
    In the Reading, PA copper beryllium plant, full-shift airborne
exposures in all jobs were reduced to a median of 0.1 ug/m\3\ or below,
and dermal protection was required for production-area workers,
beginning in 2000-2001 (Thomas et al., 2009). In 2002, the process with
the highest exposures (with a median of 0.1 ug/m\3\) was enclosed, and
workers involved in that process were required to use respiratory
protection. Among 45 workers hired after the enclosure was built and
respiratory protection instituted, one was found to be sensitized (2.2
percent). This is more than an 80 percent reduction in sensitization
from a previous group of 43 workers hired after 1992, 11.5 percent of
whom had been sensitized by the time of testing in 2000.
    In the Tucson beryllium ceramics plant, respiratory and skin
protection was instituted for all workers in production areas in 2000
(Cummings et al., 2007). BeLPT testing in 2000-2004 showed that only 1
(1 percent) of 97 workers hired during that time period was sensitized
to beryllium. This is a 90 percent reduction from the prevalence of
sensitization in a 1998 BeLPT screening, which found that 6 (9 percent)
of 69 workers hired after 1992 were sensitized.
    In the Elmore, OH beryllium production and processing facility, all
new workers were required to wear loose-fitting powered air-purifying
respirators (PAPRs) in manufacturing buildings, beginning in 1999
(Bailey et al., 2010). Skin protection became part of the protection
program for new workers in 2000, and glove use was required in
production areas and for handling work boots, beginning in 2001. Bailey
et al. (2010) found that 23 (8.9 percent) of 258 workers hired between
1993 and 1999, before institution of respiratory and dermal protection,
were sensitized to beryllium. The prevalence of sensitization among the
290 workers who were hired after the respiratory protection and PPE
measures were put in place was about 2 percent, close to an 80 percent
reduction in beryllium sensitization.
    In a response to OSHA's 2002 Request for Information (RFI), Lee
Newman et al. from National Jewish Medical and Research Center (NJMRC)
summarized results of beryllium program effectiveness from several
sources. Said Dr. Newman (in response to Question #33):

    Q. 33. What are the potential impacts of reducing occupational
exposures to beryllium in terms of costs of controls, costs for
training, benefits from reduction in the number or severity of
illnesses, effects on revenue and profit, changes in worker
productivity, or any other impact measures than you can identify?
    A: From experience in [the Tucson, AZ facility discussed above],
one can infer that approximately 90 percent of beryllium
sensitization can be eliminated. Furthermore, the preliminary data
would suggest that potentially 100 percent of CBD can be eliminated
with appropriate workplace control measures.
    In a study by Kelleher 2001, Martyny 2000, Newman, JOEM 2001) in
a plant that previously had rates of sensitization as high as 9.7
percent, the data suggests that when lifetime weighted average
exposures were below 0.02 [mu]g per cu meter that the rate of
sensitization fell to zero and the rate of CBD fell to zero as well.
    In an unpublished study, we have been conducting serial
surveillance including testing new hires in a precision machining
shop that handles beryllium and beryllium alloys in the Southeast
United States. At the time of the first screening with the blood
BeLPT of people tested within the first year of hire, we had a rate
of 6.7 percent (4/60) sensitization and with 50 percent of these
individuals showing CBD at the time of initial clinical evaluation.
At that time, the median exposures in the machining areas of the
plant was 0.47 [mu]g per cu meter. Subsequently, efforts were made
to reduce exposures, further educate the workforce, and increase
monitoring of exposure in the plant. Ongoing testing of newly hired
workers within the first year of hire demonstrated an incremental
decline in the rate of sensitization and in the rate of CBD. For
example, at the time of most recent testing when the median airborne
exposures in the machining shop were 0.13 [mu]g per cu meter, the
percentage of newly hired workers found to have beryllium
sensitization or CBD was now 0 percent (0/55). Notably, we also saw
an incremental decline in the percentage of longer term workers
being detected with sensitization and disease across this time
period of exposure reduction and improved hygiene practices.
    Thus, in calculating the potential economic benefit, it's
reasonable to work with the assumption that with appropriate efforts
to control exposures in the work place, rates of sensitization can
be reduced by over 90 percent. (NJMRC, RFI Ex. 6-20)
    OSHA has reviewed these papers and is in agreement with Dr.
Newman's testimony. OSHA judges Dr. Newman's estimate to be an upper
bound of the effectiveness of ancillary programs and examined the
results of using Dr. Newman's estimate that beryllium ancillary
programs can reduce BeS by 90 percent, and potentially eliminate CBD
where sensitization is reduced, because CBD can only occur where there
is sensitization. OSHA applied this 90 percent reduction factor to all
cases of CBD remaining after application of the reductions due to
lowering the PEL alone. OSHA applied this reduction broadly because the
proposed standard would require housekeeping and PPE related to skin
exposure (18,000 of 28,000 employees will need PPE because of
possible skin exposure) to apply to all or most employees likely to
come in contact with beryllium and not just those with exposure above
the action level. Table IX-11 shows that there are 11,017 baseline
cases of CBD and that the proposed PEL of 0.2 [micro]g/m\3\ would
prevent 2,563 cases through airborne prevention alone. The remaining
number of cases of CBD is then 8,454 (11,017 minus 2,563).
If OSHA applies the full ninety percent reduction factor to
account for prevention of skin exposure ("non-airborne" protections),
then 7,609 (90 percent of 8,454 cases) additional cases of CBD
would be prevented.
    The Agency recognizes that there are significant differences
between the comprehensive programs discussed above and the proposed
standard. While the proposed standard includes many of the same
elements, it is generally less stringent. For example, the proposed
standard's requirements for respiratory protection and PPE are
narrower, and many provisions of the standard apply only to workers
exposed above the proposed TWA PEL or STEL. However, many provisions,
such as housekeeping and beryllium work areas, apply to all employers
covered by the proposed standard. To account for these differences,
OSHA has provided a range of benefits estimates (shown in Table IX-11),
first, assuming that there are no ancillary provisions to the standard,
and, second, assuming that the comprehensive standard achieves the full
90-percent reduction in risk documented in existing programs. The
Agency is taking the midpoint of these two numbers as its main estimate
of the benefits of avoided CBD due to the ancillary provisions of the
proposed standard. The results in Table IX-11 suggest that
approximately 60 percent of the beryllium sensitization cases and the
CBD cases avoided would be attributable to the ancillary provisions of
the standard. OSHA solicits comment on all aspects of this approach to
analyzing ancillary provisions and solicits additional data that might
serve to make more accurate estimates of the effects of ancillary
provisions. OSHA is interested in the extent of the effects of
ancillary provisions and whether these apply to all exposed employees
or only those exposed above or below a given exposure level.
(3) Morbidity Only Cases
    As previously indicated, the Agency does not believe that all CBD
cases will ultimately result in premature death. While currently strong
empirical data on this are lacking, the Agency estimates that
approximately 35 percent of cases would not ultimately be fatal, but
would result in some pain and suffering related to having CBD, and
possible side effects from steroid treatment, as well as the dread of
not knowing whether the disease will ultimately lead to premature
death. These would be described as "mild" cases of CBD relative to
the others. These are the residual cases of CBD after cases with
premature mortality have been counted. As indicated in Table IX-11, the
Agency estimates the standard will prevent 2,228 such cases (midpoint)
over 45 years, or an estimated 50 cases annually.
b. Lung Cancer
    In addition to the Agency's determinations with respect to the risk
of chronic beryllium disease, the Agency has preliminarily determined
that chronic beryllium exposure at the current PEL can lead to a
significantly elevated risk of (fatal) lung cancer. OSHA used the
estimation methodology outlined at the beginning of this section.
However, unlike with chronic beryllium disease, the underlying data
were based on incidence of lung cancer and thus there was no need to
address the possible limitations of prevalence data. The Agency also
used lifetime excess risk estimates of lung cancer mortality, presented
in Table VI-20 in Section VI of this preamble, Preliminary Risk
Assessment, to estimate the benefits of avoided lung cancer mortality.
The lung cancer risk estimates are derived from one of the best-fitting
models in a recent, high-quality NIOSH lung cancer study, and are based
on average exposure levels. The estimates of excess lifetime risk of
lung cancer were taken from the line in Table VI-20 in the risk
assessment labeled PWL (piecewise log-linear) not including
professional and asbestos workers. This model avoids possible
confounding from asbestos exposure and reduces the potential for
confounding due to smoking, as smoking rates and beryllium exposures
can be correlated via professional worker status. Of the three
estimates in the NIOSH study that excluded professional workers and
those with asbestos exposure, this model was chosen because it was at
the midpoint of risk results.
    Table IX-11 shows the number of avoided fatal lung cancers for PELs
of 0.2 [mu]g/m\3\, 0.1 [mu]g/m\3\, and 0.5 [mu]g/m\3\. At the proposed
PEL of 0.2 [mu]g/m\3\, an estimated 180 lung cancers would be prevented
over the lifetime of the current worker population. This is the
equivalent of 4.0 cases avoided annually, given a 45-year working life
of exposure.
    Combining the two major fatal health endpoints--for lung cancer and
CBD-related mortality--OSHA estimates that the proposed PEL would
prevent between 1,846 and 6,791 premature fatalities over the lifetime
of the current worker population, with a midpoint estimate of 4,318
fatalities prevented. This is the equivalent of between 41 and 151
premature fatalities avoided annually, with a midpoint estimate of 96
premature fatalities avoided annually, given a 45-year working life of
exposure.
    Note that the Agency based its estimates of reductions in the
number of beryllium-related diseases over a working life of constant
exposure for workers who are employed in a beryllium-exposed occupation
for their entire working lives, from ages 20 to 65. In other words,
workers are assumed not to enter or exit jobs with beryllium exposure
mid-career or to switch to other exposure groups during their working
lives. While the Agency is legally obligated to examine the effect of
exposures from a working lifetime of exposure and set its standard
accordingly,\26\ in an alternative analysis purely for informational
purposes, using the same underlying risk model for CBD, the Agency
examined, in Chapter VII of the PEA, the effect of assuming that
workers are exposed for a maximum of only 25 working years, as opposed
to the 45 years assumed in the main analysis. While all workers are
assumed to have less cumulative exposure under the 25-years-of-exposure
assumption, the effective exposed population over time is
proportionately increased.
---------------------------------------------------------------------------

    \26\ Section (6)(b)(5) of the OSH Act states: "The Secretary,
in promulgating standards dealing with toxic materials or harmful
physical agents under this subsection, shall set the standard which
most adequately assures, to the extent feasible, on the basis of the
best available evidence, that no employee will suffer material
impairment of health or functional capacity even if such employee
has regular exposure to the hazard dealt with by such standard for
the period of his working life." Given that it is necessary for
OSHA to reach a determination of significant risk over a working
life, it is a logical extension to estimate what this translates
into in terms of estimated benefits for the affected population over
the same period.
---------------------------------------------------------------------------

    A comparison of exposures over a maximum of 25 working years versus
over a potentially 45-year working life shows variations in the number
of estimated prevented cases by health outcome. For chronic beryllium
disease, there is a substantial increase in the number of estimated
baseline and prevented cases if one assumes that the typical maximum
exposure period is 25 years, as opposed to 45. This reflects the
relatively flat CBD risk function within the relevant exposure range,
given varying levels of airborne beryllium exposure--shortening the
average tenure and increasing the exposed population over time
translates into larger total numbers of people sensitized to beryllium.
This, in turn, results in larger populations of individuals contracting
CBD. Since the lung cancer model itself is based on average, as opposed
to cumulative, exposure, it is not adaptable to estimate exposures over
a shorter period of time. As a practical matter, however, over 90
percent of illness and mortality attributable to beryllium exposure in
this analysis comes from CBD.
    Overall, the 45-year-maximum-working-life assumption yields smaller
estimates of the number of cases of avoided fatalities and illnesses
than does the maximum-25-years-of-exposure assumption. For example, the
midpoint estimates of the number of avoided fatalities and illnesses
related to CBD under the proposed PEL of 0.2 [mu]g/m\3\ increases from
92 and 50, respectively, under the maximum-45-year-working-life
assumption to 145 and 78, respectively, under the maximum-25-year-
working-life assumption--or approximately a 57 to 58 percent
increase.\27\
---------------------------------------------------------------------------

    \27\ Technically, this analysis assumes that workers receive 25
years' worth of beryllium exposure, but that they receive it over 45
working years, as is assumed by the risk models in the risk
assessment. It also accounts for the turnover implied by 25, as
opposed to 45, years of work. However, it is possible that an
alternate analysis, which accounts for the larger number of post-
exposure worker-years implied by workers departing their jobs before
the end of their working lifetime, might find even larger health
effects for workers receiving 25 years' worth of beryllium exposure.

---------------------------------------------------------------------------

[GRAPHIC] [TIFF OMITTED] TP07AU15.022


Step 2--Estimating the Stream of Benefits Over Time
    Risk assessments in the occupational environment are generally
designed to estimate the risk of an occupationally related illness over
the course of an individual worker's lifetime. As demonstrated
previously in this section, the current occupational exposure profile
for a particular substance for the current cohort of workers can be
matched up against the expected profile after the proposed standard
takes effect, creating a "steady state" estimate of benefits.
However, in order to annualize the benefits for the period of time
after the beryllium rule takes effect, it is necessary to create a
timeline of benefits for an entire active workforce over that period.
    While there are various approaches that could be taken for modeling
the workforce, there seem to be two polar extremes. At one extreme, one
could assume that none of the benefits occur until after the worker
retires, or at least 45 years in the future. In the case of lung
cancer, that period would effectively be at least 55 years, since the
45 years of exposure must be added to a 10-year latency period during
which it is assumed that lung cancer does not develop.\28\ At the other
extreme, one could assume that the benefits occur immediately, or at
least immediately after a designated lag. However, based on the various
risk models discussed in this preamble at Section VI, Risk Assessment,
which reflect real-world experience with development of disease over an
extended period of time, it appears that the actual pattern occurs at
some point between these two extremes.
---------------------------------------------------------------------------

    \28\ This assumption is consistent with the 10-year lag
incorporated in the lung cancer risk models used in OSHA's
preliminary risk assessment.
---------------------------------------------------------------------------

    At first glance, the simplest intermediate approach would be to
follow the pattern of the risk assessments, which are based in part on
life tables, and observe that typically the risk of the illness grows
gradually over the course of a working life and into retirement. Thus,
the older the person exposed to beryllium, the higher the odds that
that person will have developed the disease.
    However, while this is a good working model for an individual
exposed over a working life, it is not very descriptive of the effect
of lowering exposures for an entire working population. In the latter
case, in order to estimate the benefits of the standard over time, one
has to consider that workers currently being exposed to beryllium are
going to vary considerably in age. Since the calculated health risks
from beryllium exposure depend on a worker's cumulative exposure over a
working lifetime, the overall benefits of the proposed standard will
phase in over several decades, as the cumulative exposure gradually
falls for all age groups, until those now entering the workforce reach
retirement and the annual stream of beryllium-related illnesses reaches
a new, significantly lowered "steady state." \29\ That said, the
near-term impact of the proposed rule estimated for those workers with
similar current levels of cumulative exposure will be greater for
workers who are now middle-aged or older. This conclusion follows in
part from the structure of the relative risk model used for lung cancer
in this analysis and the fact that the background mortality rates for
lung cancer increase with age.
---------------------------------------------------------------------------

    \29\ Technically, the RA lung cancer model is based on average
exposure, Nonetheless, as noted in the RA, the underlying studies
found lung cancer to be significantly related to cumulative
exposure. Particularly since the large majority of the benefits are
related to CBD, the Agency considers this fairly descriptive of the
overall phase-in of benefits from the standard.
---------------------------------------------------------------------------

    In order to characterize the magnitude of benefits before the
steady state is reached, OSHA created a linear phase-in model to
reflect the potential timing of benefits. Specifically, OSHA estimated
that, for all non-cancer cases, while the number of cases of beryllium-
related disease would gradually decline as a result of the proposed
rule, they would not reach the steady-state level until 45 years had
passed. The reduction in cases estimated to occur in any given year in
the future was estimated to be equal to the steady-state reduction (the
number of cases in the baseline minus the number of cases in the new
steady state) times the ratio of the number of years since the standard
was implemented and a working life of 45 years. Expressed
mathematically:

Nt = (C-S) x (t/45),

Where Nt is the number of non-malignant beryllium-related
diseases avoided in year t; C is the current annual number of non-
malignant beryllium-related diseases; S is the steady-state annual
number of non-malignant beryllium-related diseases; and t represents
the number of years after the proposed standard takes effect, with t
<= 45.

    In the case of lung cancer, the function representing the decline
in the number of beryllium-related cases as a result of the proposed
rule is similar, but there would be a 10-year lag before any reduction
in cancer cases would be achieved. Expressed mathematically, for lung
cancer:

Lt = (Cm-Sm) x ((t-10)/45)),

Where 10 <= t <= 55 and Lt is the number of lung cancer
cases avoided in year t as a result of the proposed rule;
Cm is the current annual number of beryllium-related lung
cancers; and Sm is the steady-state annual number of
beryllium-related lung cancers.

    This model was extended to 60 years for all the health effects
previously discussed in order to incorporate the 10-year lag, in the
case of lung cancer, and a maximum-45-year working life, as well as to
capture some occupationally-related disease that manifests itself after
retirement.\30\ As a practical matter, however, there is no overriding
reason for stopping the benefits analysis at 60 years. An internal
analysis by OSHA indicated that, both in terms of cases prevented, and
even with regard to monetized benefits, particularly when lower
discount rates are used, the estimated benefits of the standard are
larger on an annualized basis if the analysis extends further into the
future. The Agency welcomes comment on the merit of extending the
benefits analysis beyond the 60-years analyzed in the PEA.
---------------------------------------------------------------------------

    \30\ The left-hand columns in the tables in Appendix VII-A of
the PEA provide estimates using this model of the stream of
prevented fatalities and illnesses due to the proposed beryllium
rule.
---------------------------------------------------------------------------

    In order to compare costs to benefits, OSHA assumes that economic
conditions remain constant and that annualized costs--and the
underlying costs--will repeat for the entire 60-year time horizon used
for the benefits analysis (as discussed in Chapter V of the PEA). OSHA
welcomes comments on the assumption for both the benefit and cost
analysis that economic conditions remain constant for sixty years. OSHA
is particularly interested in what assumptions and time horizon should
be used instead and why.
Separating the Timing of Mortality
    In previous sections, OSHA modeled the timing and incidence of
morbidity. OSHA's benefit estimates are based on an underlying CBD-
related mortality rate of 65 percent. However, this mortality is not
simultaneous with the onset of morbidity. Although mortality from CBD
has not been well studied, OSHA believes, based on discussions with
experienced clinicians, that the average lag for a larger population
has a range of 10 to 30 years between morbidity and mortality. The
Agency's review of Workers Compensation data related to beryllium
exposure from the Office of Worker Compensation Programs (OWCP)
Division of Energy Employees Occupational Illness Compensation is
consistent with this range. Hence, for the purposes of this
proposal, OSHA estimates that mortality occurs on average 20 years
after the onset of CBD morbidity. Thus, for example, the prevented
deaths that would have occurred in year 21 after the promulgation of
the rule are associated with the CBD morbidity cases prevented in year
one. OSHA requests comment on this estimate and range.
    The Agency invites comment on each of these elements of the
analysis, particularly on the estimates of the expected life expectancy
of a patient with CBD.
Step 3--Monetizing the Benefits of the Proposed Rule
    To estimate the monetary value of the reductions in the number of
beryllium-related fatalities, OSHA relied, as OMB recommends, on
estimates developed from the willingness of affected individuals to pay
to avoid a marginal increase in the risk of fatality. While a
willingness-to-pay (WTP) approach clearly has theoretical merit, it
should be noted that an individual's willingness to pay to reduce the
risk of fatality would tend to underestimate the total willingness to
pay, which would include the willingness of others--particularly the
immediate family--to pay to reduce that individual's risk of fatality.
    For estimates using the willingness-to-pay concept, OSHA relied on
existing studies of the imputed value of fatalities avoided based on
the theory of compensating wage differentials in the labor market.
These studies rely on certain critical assumptions for their accuracy,
particularly that workers understand the risks to which they are
exposed and that workers have legitimate choices between high- and low-
risk jobs. These assumptions are far from obviously met in actual labor
markets.\31\ A number of academic studies, as summarized in Viscusi &
Aldy (2003), have shown a correlation between higher job risk and
higher wages, suggesting that employees demand monetary compensation in
return for a greater risk of injury or fatality. The estimated trade-
off between lower wages and marginal reductions in fatal occupational
risk--that is, workers' willingness to pay for marginal reductions in
such risk--yields an imputed value of an avoided fatality: The
willingness-to-pay amount for a reduction in risk divided by the
reduction in risk.\32\
---------------------------------------------------------------------------

    \31\ On the former assumption, see the discussion in Chapter II
of the PEA on imperfect information. On the latter, see, for
example, the discussion of wage compensation for risk for union
versus nonunion workers in Dorman and Hagstrom (1998).
    \32\ For example, if workers are willing to pay $90 each for a
1/100,000 reduction in the probability of dying on the job, then the
imputed value of an avoided fatality would be $90 divided by 1/
100,000, or $9,000,000. Another way to consider this result would be
to assume that 100,000 workers made this trade-off. On average, one
life would be saved at a cost of $9,000,000.
---------------------------------------------------------------------------

    OSHA has used this approach in many recent proposed and final
rules. Although this approach has been criticized for yielding results
that are less than statistically robust (see, for example, Hintermann,
Alberini and Markandya, 2010), a more recent WTP analysis, by Kniesner
et al. (2012), of the trade-off between fatal job risks and wages,
using panel data, seems to address many of the earlier econometric
criticisms by controlling for measurement error, endogeneity, and
heterogeneity. In conclusion, the Agency views the WTP approach as the
best available and will rely on it to monetize benefits.\33\ OSHA
welcomes comments on the use of willingness-to-pay measures and
estimates based on compensating wage differentials.
---------------------------------------------------------------------------

    \33\ Note that, consistent with the economics literature, these
estimates would be for reducing the risk of an acute (immediate)
fatality. They do not include an individual's willingness to pay to
avoid a higher risk of illness prior to fatality, which is
separately estimated in the following section.
---------------------------------------------------------------------------

    Viscusi & Aldy (2003) conducted a meta-analysis of studies in the
economics literature that use a willingness-to-pay methodology to
estimate the imputed value of life-saving programs and found that each
fatality avoided was valued at approximately $7 million in 2000
dollars. Using the GDP Deflator (U.S. BEA, 2010), this $7 million base
number in 2000 dollars yields an estimate of $8.7 million in 2010
dollars for each fatality avoided.\34\
---------------------------------------------------------------------------

    \34\ An alternative approach to valuing an avoided fatality is
to monetize, for each year that a life is extended, an estimate from
the economics literature of the value of that statistical life-year
(VSLY). See, for instance, Aldy and Viscusi (2007) for discussion of
VSLY theory and FDA (2003), pp. 41488-9, for an application of VSLY
in rulemaking. OSHA has not investigated this approach, but welcomes
comment on the issue.
---------------------------------------------------------------------------

    In addition to the benefits that are based on the implicit value of
fatalities avoided, workers also place an implicit value on
occupational injuries or illnesses avoided, which reflect their
willingness to pay to avoid monetary costs (for medical expenses and
lost wages) and quality-of-life losses as a result of occupational
illness. Chronic beryllium disease and lung cancer can adversely affect
individuals for years, or even decades, in non-fatal cases, or before
ultimately proving fatal. Because measures of the benefits of avoiding
these illnesses are rare and difficult to find, OSHA has included a
range based on a variety of estimation methods.
    For both CBD and lung cancer, there is typically some permanent
loss of lung function and disability, on-going medical treatments, side
effects of medicines, and major impacts on one's ability to work,
marry, enjoy family life, and quality of life.
    While diagnosis with CBD is evidence of material impairment of
health, placing a precise monetary value on this condition is
difficult, in part because the severity of symptoms may vary
significantly among individuals. For that reason, for this preliminary
analysis, the Agency employed a broad range of valuation, which should
encompass the range of severity these individuals may encounter.
    Using the willingness-to-pay approach, discussed in the context of
the imputed value of fatalities avoided, OSHA has estimated a range in
valuations (updated and reported in 2010 dollars) that runs from
approximately $62,000 per case--which reflects estimates developed by
Viscusi and Aldy (2003), based on a series of studies primarily
describing simple accidents--to upwards of $5 million per case--which
reflects work developed by Magat, Viscusi, and Huber (1996) for non-
fatal cancer. The latter number is based on an approach that places a
willingness-to-pay value to avoid serious illness that is calibrated
relative to the value of an avoided fatality. OSHA previously used this
approach in the Preliminary Economic Analysis (PEA) supporting its
respirable crystalline silica proposal (2013) and in the Final Economic
Analysis (FEA) supporting its hexavalent chromium final rule (2006),
and EPA (2003) used this approach in its Stage 2 Disinfection and
Disinfection Byproducts Rule concerning regulation of primary drinking
water. Based on Magat, Viscusi, and Huber (1996), EPA used studies on
the willingness to pay to avoid nonfatal lymphoma and chronic
bronchitis as a basis for valuing a case of nonfatal cancer at 58.3
percent of the value of a fatal cancer. OSHA's estimate of $5 million
for an avoided case of non-fatal cancer is based on this 58.3 percent
figure.
    The Agency believes this range of estimates, between $62,000 and $5
million, is descriptive of the value of preventing morbidity associated
with moderate to severe CBD that ultimately results in premature death.
\35\
---------------------------------------------------------------------------

    \35\ There are several benchmarks for valuation of health
impairment due to beryllium exposure, using a variety of techniques,
which provide a number of mid-range estimates between OSHA's high
and low estimates. For a fuller discussion of these benchmarks, see
Chapter VII of the PEA.

---------------------------------------------------------------------------

    While the Agency has estimated that 65 percent of CBD cases will
result in premature mortality, the Agency has also estimated that
approximately 35 percent of CBD cases will not result in premature
mortality. However, the Agency acknowledges that it is possible there
have been new developments in medicine and industrial hygiene related
to the benefits of early detection, medical intervention, and greater
control of exposure achieved within the past decade. For that reason,
as elsewhere, the Agency requests comment on these issues.
    Also not clear are the negative effects of the illness in terms of
lost productivity, medical costs, and potential side-effects of a
lifetime of immunosuppressive medication. Nonetheless, the Agency is
assigning a valuation of $62,000 per case, to reflect the WTP value of
a prevented injury not estimated to precede premature mortality. The
Agency believes this is conservative, in part because, with any given
case of CBD, the outcome is not known in advance, certainly not at the
point of discovery; indeed much of the psychic value of preventing the
cases may come from removing the threat of premature mortality. In
addition, as previously noted, some of these cases could involve
relatively severe forms of CBD where the worker died of other causes;
however, in those cases, the duration of the disease would be
shortened. While beryllium sensitization is a critical precursor of
CBD, this preliminary analysis does not attempt to assign a separate
value to sensitization itself.
    Particularly given the uncertainties in valuation on these
questions, the Agency is interested in public input on the issue of
valuing the cost to society of morbidity associated with CBD, both in
cases preceding mortality, and those that may not result in premature
mortality. The Agency is also interested in comments on whether it is
appropriate to assign a separate valuation to prevented sensitization
cases in their own right, and if so, how such cases should be valued.
a. Summary of Monetized Benefits
    Table IX-12 presents the estimated annualized (over 60 years, using
a 0 percent discount rate) benefits from each of these components of
the valuation, and the range of estimates, based on uncertainty of the
prevention factor (i.e., the estimated range of prevented cases,
depending on how large an impact the rule has on cases beyond an
airborne-only effect), and the range of uncertainty regarding valuation
of morbidity. (Mid-point estimates of the undiscounted benefits for
each of the first 60 years are provided in the middle columns of Table
VII-A-1 in Appendix VII-A at the end of Chapter VII in the PEA. The
estimates by year reach a peak of $3.5 billion in the 60th year. Note
that, by using a 60-year time-period, OSHA is not including any
monetized fatality benefits associated with reduced worker CBD cases
originating after year 40 because the 20-year lag takes these CBD
fatalities beyond the 60-year time horizon. To this extent, OSHA will
have underestimated benefits.)
    As shown in Table IX-12, the full range of monetized benefits,
undiscounted, for the proposed PEL of 0.2 [micro]g/m\3\ runs from $291
million annually, in the case of the lowest estimate of prevented cases
of CBD, and the lowest valuation for morbidity, up to $2.1 billion
annually, for the highest of both. Note that the value of total
benefits is more sensitive to the prevention factor used (ranging from
$430 million to $1.6 billion, given estimates at the midpoint of the
morbidity valuation) than to the valuation of morbidity (ranging from
$666 million to $1.3 billion, given estimates at the midpoint of
prevention factor).
    Also, the analysis illustrates that most of the morbidity benefits
are related to CBD and lung cancer cases that are ultimately fatal. At
the valuation and case frequency midpoint, $663 million in benefits are
related to mortality, $226 million are related to morbidity preceding
mortality, and $4.3 million are related to morbidity not preceding
mortality.

[GRAPHIC] [TIFF OMITTED] TP07AU15.023

b. Adjustment of WTP Estimates to Reflect Rising Real Income Over Time
    OSHA's estimates of the monetized benefits of the proposed rule are
based on the imputed value of each avoided fatality and each avoided
beryllium-related disease. As previously discussed, these, in turn, are
derived from a worker's willingness to pay to avoid a fatality (with an
imputed value per fatality avoided of $8.7 million in 2010 dollars) and
to avoid a beryllium-related disease (with an imputed value per disease
avoided of between $62,000 and $5 million in 2010 dollars). To this point,
these imputed values have been assumed to remain constant over time.
However, two related factors suggest that these values will tend to
increase over time.
    First, economic theory indicates that the value of reducing life-
threatening and health-threatening risks--and correspondingly the
willingness of individuals to pay to reduce these risks--will increase
as real per capita income increases. With increased income, an
individual's health and life becomes more valuable relative to other
goods because, unlike other goods, they are without close substitutes
and in relatively fixed or limited supply. Expressed differently, as
income increases, consumption will increase but the marginal utility of
consumption will decrease. In contrast, added years of life (in good
health) is not subject to the same type of diminishing returns--
implying that an effective way to increase lifetime utility is by
extending one's life and maintaining one's good health (Hall and Jones,
2007).
    Second, real per capita income has broadly been increasing
throughout U.S. history, including recent periods. For example, for the
period 1950 through 2000, real per capita income grew at an average
rate of 2.31 percent a year (Hall and Jones, 2007),\36\ although real
per capita income for the recent 25-year period 1983 through 2008 grew
at an average rate of only 1.3 percent a year (U.S. Census Bureau,
2010). More important is the fact that real U.S. per capita income is
projected to grow significantly in future years. For example, the
Annual Energy Outlook (AEO) projections, prepared by the Energy
Information Administration (EIA) in the Department of Energy (DOE),
show an average annual growth rate of per capita income in the United
States of 2.7 percent for the period 2011-2035.\37\ The U.S.
Environmental Protection Agency prepared its economic analysis of the
Clean Air Act using the AEO projections. OSHA believes that it is
reasonable to use the same AEO projections employed by DOE and EPA, and
correspondingly projects that per capita income in the United States
will increase by 2.7 percent a year.
---------------------------------------------------------------------------

    \36\ The results are similar if the historical period includes a
major economic downturn (such as the United States has recently
experienced). From 1929 through 2003, a period in U.S. history that
includes the Great Depression, real per capita income still grew at
an average rate of 2.22 percent a year (Gomme and Rupert, 2004).
    \37\ The EIA used DOE's National Energy Modeling System (NEMS)
to produce the Annual Energy Outlook (AEO) projections (EIA, 2011).
Future per capita GDP was calculated by dividing the projected real
gross domestic product each year by the projected U.S. population
for that year.
---------------------------------------------------------------------------

    On the basis of the predicted increase in real per capita income in
the United States over time and the expected resulting increase in the
value of avoided fatalities and diseases, OSHA has adjusted its
estimates of the benefits of the proposed rule to reflect the
anticipated increase in their value over time. This type of adjustment
has been recognized by OMB (2003), supported by EPA's Science Advisory
Board (EPA, 2000), and applied by EPA \38\. OSHA proposes to accomplish
this adjustment by modifying benefits in year i from [Bi] to
[Bi * (1 + k)\i\], where "k" is the estimated annual
increase in the magnitude of the benefits of the proposed rule.
---------------------------------------------------------------------------

    \38\ See, for example, EPA (2003, 2008).
---------------------------------------------------------------------------

    What remains is to estimate a value for "k" with which to
increase benefits annually in response to annual increases in real per
capita income, where "k" is equal to "(1+g) * ([eta])", "g" is
the expected annual percentage increase in real per capita income, and
"[eta]" is the income elasticity of the value of a statistical life.
Probably the most direct evidence of the value of "k" comes from the
work of Costa and Kahn (2003, 2004). They estimate repeated labor
market compensating wage differentials from cross-sectional hedonic
regressions using census and fatality data from the Bureau of Labor
Statistics for 1940, 1950, 1960, 1970, and 1980. In addition, with the
imputed income elasticity of the value of life on per capita GNP of 1.7
derived from the 1940-1980 data, they then predict the value of an
avoided fatality in 1900, 1920, and 2000. Given the change in the value
of an avoided fatality over time, it is possible to estimate a value of
"k" of 3.4 percent a year from 1900-2000; of 4.3 percent a year from
1940-1980; and of 2.5 percent a year from 1980-2000.
    Other, more indirect evidence comes from estimates in the economics
literature of "[eta]", the income elasticity of the value of a
statistical life. Viscusi and Aldy (2003) performed a meta-analysis on
0.2 wage-risk studies and concluded that the confidence interval upper
bound on the income elasticity did not exceed 1.0 and that the point
estimates across a variety of model specifications ranged between 0.5
and 0.6. Applied to a long-term increase in per capita income of about
2.7 percent a year, this would suggest a value of "k" of about 1.5
percent a year.
    More recently, Kniesner, Viscusi, and Ziliak (2010), using panel
data quintile regressions, developed an estimate of the overall income
elasticity of the value of a statistical life of 1.44. Applied to a
long-term increase in per capita income of about 2.7 percent a year,
this would suggest a value of "k" of about 3.9 percent a year.
    Based on the preceding discussion of these three approaches for
estimating the annual increase in the value of the benefits of the
proposed rule and the fact that the projected increase in real per
capita income in the United States has flattened in recent years and
could flatten in the long run, OSHA suggests a conservative value for
"k" of approximately two percent a year. The Agency invites comment
on this estimate and on estimates of the income elasticity of the value
of a statistical life.
    The Agency believes that the rising value, over time, of health
benefits is a real phenomenon that should be taken into account in
estimating the annualized benefits of the proposed rule. Table IX-13,
in the following section on discounting benefits, shows estimates of
the monetized benefits of the proposed rule (under alternative discount
rates) with this estimated increase in monetized benefits over time.
The Agency invites comment on this adjustment to monetized benefits.
c. The Discounting of Monetized Benefits
    As previously noted, the estimated stream of benefits arising from
the proposed beryllium rule is not constant from year to year, both
because of the 45-year delay after the rule takes effect until all
active workers obtain reduced beryllium exposure over their entire
working lives and because of, in the case of lung cancer, a 10-year
latency period between reduced exposure and a reduction in the
probability of disease. An appropriate discount rate \39\ is needed to
reflect the timing of benefits over the 60-year period after the rule
takes effect and to allow conversion to an equivalent steady stream of
annualized benefits.
---------------------------------------------------------------------------

    \39\ Here and elsewhere throughout this section, unless
otherwise noted, the term "discount rate" always refers to the
real discount rate--that is, the discount rate net of any
inflationary effects.
---------------------------------------------------------------------------

1. Alternative Discount Rates for Annualizing Benefits
    Following OMB (2003) guidelines, OSHA has estimated the annualized
benefits of the proposed rule using separate discount rates of 3
percent and 7 percent. Consistent with the Agency's own practices in
recent rulemakings, OSHA has also estimated, for benchmarking purposes,
undiscounted benefits--that is, benefits using a zero percent discount
rate.
    The question remains, what is the "appropriate" or "preferred"
discount rate to use to monetize health benefits? The choice of
discount rate is a controversial topic, one that has been the source of
scholarly economic debate for several decades. However, in simplest
terms, the basic choices involve a social opportunity cost of capital
approach or social rate of time preference approach.
    The social opportunity cost of capital approach reflects the fact
that private funds spent to comply with government regulations have an
opportunity cost in terms of foregone private investments that could
otherwise have been made. The relevant discount rate in this case is
the pre-tax rate of return on the foregone investments (Lind, 1982, pp.
24-32).
    The rate of time preference approach is intended to measure the
tradeoff between current consumption and future consumption, or in the
context of the proposed rule, between current benefits and future
benefits. The individual rate of time preference is influenced by
uncertainty about the availability of the benefits at a future date and
whether the individual will be alive to enjoy the delayed benefits. By
comparison, the social rate of time preference takes a broader view
over a longer time horizon--ignoring individual mortality and the
riskiness of individual investments (which can be accounted for
separately).
    The usual method for estimating the social rate of time preference
is to calculate the post-tax real rate of return on long-term, risk-
free assets, such as U.S. Treasury securities (OMB, 2003, p. 33). A
variety of studies have estimated these rates of return over time and
reported them to be in the range of approximately 1-4 percent.
    In accordance with OMB Circular A-4 (2003), OSHA presents benefits
and net benefits estimates using discount rates of 3 percent
(representing the social rate of time preference) and 7 percent (a rate
estimated using the social cost of capital approach). The Agency is
interested in any evidence, theoretical or applied, that would inform
the application of discount rates to the costs and benefits of a
regulation.
2. Summary of Annualized Benefits under Alternative Discount Rates
    Table IX-13 presents OSHA's estimates of the sum of the annualized
benefits of the proposed rule, using alternative discount rates of 0,
3, and 7 percent, with the suggested adjustment for increasing
monetized benefits in response to annual increases in per capita income
over time.
    Given that the stream of benefits extends out 60 years, the value
of future benefits is sensitive to the choice of discount rate. The
undiscounted benefits in Table IX-13 range from $291 million to $2.1
billion annually. Using a 7 percent discount rate, the annualized
benefits range from $60 million to $591 million. As can be seen, going
from undiscounted benefits to a 7 percent discount rate has the effect
of cutting the annualized benefits of the proposed rule by about 74
percent.
    Taken as a whole, the Agency's best preliminary estimate of the
total annualized benefits of the proposed rule--using a 3 percent
discount rate with an adjustment for the increasing value of health
benefits over time--is between $158 million and $1.2 billion, with a
mid-point value of $576 million.

[GRAPHIC] [TIFF OMITTED] TP07AU15.024

Step 4: Net Benefits of the Proposed Rule
    OSHA has estimated, in Table IX-14, the monetized and annualized
net benefits of the proposed rule (with a PEL of 0.2 [mu]g/m\3\), based
on the benefits and costs previously presented. Table IX-14 also
provides estimates of annualized net benefits for alternative PELs of
0.1 and 0.5 [mu]g/m\3\. Both the proposed rule and the alternatives PEL
options have the same ancillary provisions and an action level equal to
half of the PEL in both cases.
    Table IX-14 is being provided for informational purposes only. As
previously noted, the OSH Act requires the Agency to set standards
based on eliminating significant risk to the extent feasible. An
alternative criterion of maximizing net (monetized) benefits may result
in very different regulatory outcomes. Thus, this analysis of net
benefits has not been used by OSHA as the basis for its decision
concerning the choice of a PEL or of other ancillary requirements for
the proposed beryllium rule.
    Table IX-14 shows net benefits using alternative discount rates of
0, 3, and 7 percent for benefits and costs, having previously included
an adjustment to monetized benefits to reflect increases in real per
capita income over time. OSHA has relied on a uniform discount rate
applied to both costs and benefits. The Agency is interested in any
evidence, theoretical or applied, that would support or refute the
application of differential discount rates to the costs and benefits of
a regulation.
    As previously noted in this section, the choice of discount rate
for annualizing benefits has a significant effect on annualized
benefits. The same is true for net benefits. For example, the net
benefits using a 7 percent discount rate for benefits are considerably
smaller than the net benefits using a 3 percent discount rate,
declining by over half under all scenarios. (Conversely, as noted in
Chapter V of the PEA, the choice of discount rate for annualizing costs
has a relatively minor effect on annualized costs.)
    Based on the results presented in Table IX-14, OSHA finds:
     While the net benefits of the proposed rule vary
considerably--depending on the choice of discount rate used to
annualize benefits and on whether the benefits being used are in the
high, midpoint, or low range--benefits exceed costs for the proposed
0.2 [mu]g/m\3\ PEL in all cases that OSHA considered.
     The Agency's best estimate of the net annualized benefits
of the proposed rule--usin