[Federal Register: February 28, 2006 (Volume 71, Number 39)]
[Rules and Regulations]
[Page 10099-10385]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr28fe06-25]
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Part II
Department of Labor
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Occupational Safety and Health Administration
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29 CFR Parts 1910, 1915, et al.
Occupational Exposure to Hexavalent Chromium; Final Rule
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DEPARTMENT OF LABOR
Occupational Safety and Health Administration
29 CFR Parts 1910, 1915, 1917, 1918, and 1926
[Docket No. H054A]
RIN 1218-AB45
Occupational Exposure to Hexavalent Chromium
AGENCY: Occupational Safety and Health Administration (OSHA),
Department of Labor.
ACTION: Final rule.
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SUMMARY: The Occupational Safety and Health Administration (OSHA) is
amending the existing standard which limits occupational exposure to
hexavalent chromium (Cr(VI)). OSHA has determined based upon the best
evidence currently available that at the current permissible exposure
limit (PEL) for Cr(VI), workers face a significant risk to material
impairment of their health. The evidence in the record for this
rulemaking indicates that workers exposed to Cr(VI) are at an increased
risk of developing lung cancer. The record also indicates that
occupational exposure to Cr(VI) may result in asthma, and damage to the
nasal epithelia and skin.
The final rule establishes an 8-hour time-weighted average (TWA)
exposure limit of 5 micrograms of Cr(VI) per cubic meter of air (5
[mu]g/m\3\). This is a considerable reduction from the previous PEL of
1 milligram per 10 cubic meters of air (1 mg/10 m\3\, or 100 [mu]g/
m\3\) reported as CrO3, which is equivalent to a limit of 52
[mu]g/m\3\ as Cr(VI). The final rule also contains ancillary provisions
for worker protection such as requirements for exposure determination,
preferred exposure control methods, including a compliance alternative
for a small sector for which the new PEL is infeasible, respiratory
protection, protective clothing and equipment, hygiene areas and
practices, medical surveillance, recordkeeping, and start-up dates that
include four years for the implementation of engineering controls to
meet the PEL.
The final standard separately regulates general industry,
construction, and shipyards in order to tailor requirements to the
unique circumstances found in each of these sectors.
The PEL established by this rule reduces the significant risk posed
to workers by occupational exposure to Cr(VI) to the maximum extent
that is technologically and economically feasible.
DATES: This final rule becomes effective on May 30, 2006. Start-up
dates for specific provisions are set in Sec. 1910.1026(n) for general
industry; Sec. 1915.1026(l) for shipyards; and Sec. 1926.1126(l) for
construction. However, affected parties do not have to comply with the
information collection requirements in the final rule until the
Department of Labor publishes in the Federal Register the control
numbers assigned by the Office of Management and Budget (OMB).
Publication of the control numbers notifies the public that OMB has
approved these information collection requirements under the Paperwork
Reduction Act of 1995.
ADDRESSES: In compliance with 28 U.S.C. 2112(a), the Agency designates
the Associate Solicitor for Occupational Safety and Health, Office of
the Solicitor, Room S-4004, U.S. Department of Labor, 200 Constitution
Avenue, NW., Washington, DC 20210, as the recipient of petitions for
review of these standards.
FOR FURTHER INFORMATION CONTACT: Mr. Kevin Ropp, Director, OSHA Office
of Communications, Room N-3647, U.S. Department of Labor, 200
Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-
1999.
SUPPLEMENTARY INFORMATION: The following table of contents lays out the
structure of the preamble to the final standards. This preamble
contains a detailed description of OSHA's legal obligations, the
analyses and rationale supporting the Agency's determination, including
a summary of and response to comments and data submitted during the
rulemaking.
I. General
II. Pertinent Legal Authority
III. Events Leading to the Final Standard
IV. Chemical Properties and Industrial Uses
V. Health Effects
A. Absorption, Distribution, Metabolic Reduction and Elimination
1. Deposition and Clearance of Inhaled Cr(VI) From the
Respiratory Tract
2. Absorption of Inhaled Cr(VI) Into the Bloodstream
3. Dermal Absorption of Cr(VI)
4. Absorption of Cr(VI) by the Oral Route
5. Distribution of Cr(VI) in the Body
6. Metabolic Reduction of Cr(VI)
7. Elimination of Cr(VI) From the Body
8. Physiologically-Based Pharmacokinetic Modeling
9. Summary
B. Carcinogenic Effects
1. Evidence From Chromate Production Workers
2. Evidence From Chromate Pigment Production Workers
3. Evidence From Workers in Chromium Plating
4. Evidence From Stainless Steel Welders
5. Evidence From Ferrochromium Workers
6. Evidence From Workers in Other Industry Sectors
7. Evidence From Experimental Animal Studies
8. Mechanistic Considerations
C. Non-Cancer Respiratory Effects
1. Nasal Irritation, Nasal Tissue Ulcerations and Nasal Septum
Perforations
2. Occupational Asthma
3. Bronchitis
4. Summary
D. Dermal Effects
E. Other Health Effects
VI. Quantitative Risk Assessment
A. Introduction
B. Study Selection
1. Gibb Cohort
2. Luippold Cohort
3. Mancuso Cohort
4. Hayes Cohort
5. Gerin Cohort
6. Alexander Cohort
7. Studies Selected for the Quantitative Risk Assessment
C. Quantitative Risk Assessments Based on the Gibb Cohort
1. Environ Risk Assessments
2. National Institute for Occupational Safety and Health (NIOSH)
Risk Assessment
3. Exponent Risk Assessment
4. Summary of Risk Assessments Based on the Gibb Cohort
D. Quantitative Risk Assessments Based on the Luippold Cohort
E. Quantitative Risk Assessments Based on the Mancuso, Hayes,
Gerin, and Alexander Cohorts
1. Mancuso Cohort
2. Hayes Cohort
3. Gerin Cohort
4. Alexander Cohort
F. Summary of Risk Estimates Based on Gibb, Luippold, and
Additional Cohorts
G. Issues and Uncertainties
1. Uncertainty With Regard to Worker Exposure to Cr(VI)
2. Model Uncertainty, Exposure Threshold, and Dose Rate Effects
3. Influence of Smoking, Race, and the Healthy Worker Survivor
Effect
4. Suitability of Risk Estimates for Cr(VI) Exposures in Other
Industries
H. Conclusions
VII. Significance of Risk
A. Material Impairment of Health
1. Lung Cancer
2. Non-Cancer Impairments
B. Risk Assessment
1. Lung Cancer Risk Based on the Gibb Cohort
2. Lung Cancer Risk Based on the Luippold Cohort
3. Risk of Non-Cancer Impairments
C. Significance of Risk and Risk Reduction
VIII. Summary of the Final Economic Analysis and Regulatory
Flexibility Analysis
IX. OMB Review Under the Paperwork Reduction Act of 1995
X. Federalism
XI. State Plans
XII. Unfunded Mandates
XIII. Protecting Children from Environmental Health and Safety Risks
XIV. Environmental Impacts
XV. Summary and Explanation of the Standards
(a) Scope
(b) Definitions
(c) Permissible Exposure Limit (PEL)
(d) Exposure Determination
(e) Regulated Areas
(f) Methods of Compliance
(g) Respiratory Protection
(h) Protective Work Clothing and Equipment
(i) Hygiene Areas and Practices
(j) Housekeeping
(k) Medical Surveillance
(l) Communication of Chromium (VI) Hazards to Employees
(m) Recordkeeping
(n) Dates
XVI. Authority and Signature
XVII. Final Standards
I. General
This final rule establishes a permissible exposure limit (PEL) of 5
micrograms of Cr(VI) per cubic meter of air (5 [mu]g/m\3\) as an 8-hour
time-weighted average for all Cr(VI) compounds. After consideration of
all comments and evidence submitted during this rulemaking, OSHA has
made a final determination that a PEL of 5 [mu]g/m\3\ is necessary to
reduce the significant health risks posed by occupational exposures to
Cr(VI); it is the lowest level that is technologically and economically
feasible for industries impacted by this rule. A full explanation of
OSHA's rationale for establishing this PEL is presented in the
following preamble sections: V (Health Effects), VI (Quantitative Risk
Assessment), VII (Significance of Risk), VIII (Summary of the Final
Economic Analysis and Regulatory Flexibility Analysis), and XV (Summary
and Explanation of the Standard, paragraph (c), Permissible Exposure
Limit).
OSHA is establishing three separate standards covering occupational
exposures to Cr(VI) for: general industry (29 CFR 1910.1026); shipyards
(29 CFR 1915.1026), and construction (29 CFR 1926.1126). In addition to
the PEL, these three standards include ancillary provisions for
exposure determination, methods of compliance, respiratory protection,
protective work clothing and equipment, hygiene areas and practices,
medical surveillance, communication of Cr(VI) hazards to employees,
recordkeeping, and compliance dates. The general industry standard has
additional provisions for regulated areas and housekeeping. The Summary
and Explanation section of this preamble (Section XV, paragraphs (d)
through (n)) includes a full discussion of the basis for including
these provisions in the final standards.
Several major changes were made to the October 4, 2004 proposed
rule as a result of OSHA's analysis of comments and data received
during the comment periods and public hearings. The major changes are
summarized below and are fully discussed in the Summary and Explanation
section of this preamble (Section XV)
Scope. As proposed, the standards apply to occupational exposures
to Cr(VI) in all forms and compounds with limited exceptions. OSHA has
made a final determination to exclude from coverage of these final
standards exposures that occur in the application of pesticides
containing Cr(VI) (e.g., the treatment of wood with preservatives).
These exposures are already covered by the Environmental Protection
Agency. OSHA is also excluding exposures to portland cement and
exposures in work settings where the employer has objective data
demonstrating that a material containing chromium or a specific
process, operation, or activity involving chromium cannot release
dusts, fumes, or mists of Cr(VI) in concentrations at or above 0.5
[mu]g/m\3\ under any expected conditions of use. OSHA believes that the
weight of evidence in this rulemaking demonstrates that the primary
risk in these two exposure scenarios can be effectively addressed
through existing OSHA standards for personal protective equipment,
hygiene, hazard communication and the PELs for portland cement or
particulates not otherwise regulated (PNOR).
Permissible Exposure Limit. OSHA proposed a PEL of 1 [mu]g/m\3\ but
has now determined that a PEL 5 [mu]g/m\3\ is the lowest level that is
technologically and economically feasible.
Exposure Determination. OSHA did not include a provision for
exposure determination in the proposed shipyard and construction
standards, reasoning that the obligation to meet the proposed PEL would
implicitly necessitate performance-based monitoring by the employer to
ensure compliance with the PEL. However, OSHA was convinced by
arguments presented during the rulemaking that an explicit requirement
for exposure determination is necessary to ensure that employee
exposures are adequately characterized. Therefore OSHA has included a
provision for exposure determination for general industry, shipyards
and construction in the final rule. In order to provide additional
flexibility in characterizing employee exposures, OSHA is allowing
employers to choose between a scheduled monitoring option and a
performance-based option for making exposure determinations.
Methods of Compliance. Under the proposed rule employers were to
use engineering and work practice controls to achieve the proposed PEL
unless the employer could demonstrate such controls are not feasible.
In the final rule, OSHA has retained this exception but has added a
provision that only requires employers to use engineering and work
practice controls to reduce or maintain employee exposures to 25 [mu]g/
m\3\ when painting aircraft or large aircraft parts in the aerospace
industry to the extent such controls are feasible. The employer must
then supplement those engineering controls with respiratory protection
to achieve the PEL. As discussed more fully in the Summary of the Final
Economic Analysis and Regulatory Flexibility Analysis (Section VIII)
and the Summary and Explanation (Section XV) OSHA has determined that
this is the lowest level achievable through the use of engineering and
work practice controls alone for these limited operations.
Housekeeping. In the proposed rule, cleaning methods such as
shoveling, sweeping, and brushing were prohibited unless they were the
only effective means available to clean surfaces contaminated with
Cr(VI). The final standard has modified this prohibition to make clear
only dry shoveling, sweeping and brushing are prohibited so that
effective wet shoveling, sweeping, and brushing would be allowed. OSHA
is also adding a provision that allows the use of compressed air to
remove Cr(VI) when no alternative method is feasible.
Medical Surveillance. As proposed and continued in these final
standards, medical surveillance is required to be provided to employees
experiencing signs or symptoms of the adverse health effects associated
with Cr(VI) exposure or exposed in an emergency. In addition, for
general industry, employees exposed above the PEL for 30 or more days a
year were to be provided medical surveillance. In the final standard,
OSHA has changed the trigger for medical surveillance to exposure above
the action level (instead of the PEL) for 30 days a year to take into
account the existing risks at the new PEL. This provision has also been
extended to the standards for shipyards and construction since those
employers now will be required to perform an exposure determination and
thus will be able to determine which employees are exposed above the
action level 30 or more days a year.
Communication of Hazards. In the proposed standard, OSHA specified
the sign for the demarcation of regulated areas in general industry and
the label for contaminated work clothing or equipment and Cr(VI)
contaminated waste and debris. The proposed standard also listed the
various elements to be covered for employee training. In order to
simplify requirements under this section of the final standard and
reduce confusion between this standard and the Hazard Communication
Standard, OSHA has removed the requirement for special signs and labels
and the specification of employee training elements. Instead, the final
standard requires that signs, labels and training be in accordance with
the Hazard Communication Standard (29 CFR 1910.1200). The only
additional training elements required in the final rule are those
related specifically to the contents of the final Cr(VI) standards.
While the final standards have removed language in the communication of
hazards provisions to make them more consistent with OSHA's existing
Hazard Communication Standard, the employers obligation to mark
regulated areas (where regulated areas are required), to label Cr(VI)
contaminated clothing and wastes, and to train on the hazards of Cr(VI)
have not changed.
Recordkeeping. In the proposed standards for shipyards and
construction there were no recordkeeping requirements for exposure
records since there was not a requirement for exposure determination.
The final standard now requires exposure determination for shipyards
and construction and therefore, OSHA has also added provisions for
exposure records to be maintained in these final standards. In keeping
with its intent to be consistent with the Hazard Communication
Standard, OSHA has removed the requirement for training records in the
final standards.
Dates. In the proposed standard, the effective date of the standard
was 60 days after the publication date; the start-up date for all
provisions except engineering controls was 90 days after the effective
date; and the start-up date for engineering controls was two years
after the effective date. OSHA believes that it is appropriate to allow
additional time for employers, particularly small employers, to meet
the requirements of the final rule. The effective and start-up dates
have been extended as follows: the effective date for the final rule is
changed to 90 days after the publication date; the start-up date for
all provisions except engineering controls is changed to 180 days after
the effective date for employers with 20 or more employees; the start-
up date for all provisions except engineering controls is changed to
one year after the effective date for employers with 19 or fewer
employees; and the start-up date for engineering controls is changed to
four years after the effective date for all employers.
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 standard
regulating occupational exposure to Cr(VI), 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. 29
U.S.C. Sec. 655(b)(5).
The Supreme Court has held that before the Secretary can promulgate
any permanent health or safety standard, she 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"). 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." American Textile Mfrs. Inst.
v. Donovan, 425 U.S. 490, 509 (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. See The Lead case, 647 F.2d 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." Id.
[The] 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
Industrial Union Dept., 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 PEL's may enhance economic feasibility. Id.
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. The Cotton dust case, 453
U.S. at 509. Finally, unlike safety standards, health standards must
eliminate risk or reduce it to the maximum extent that is
technologically and economically feasible. See International Union,
United Automobile, Aerospace & Agricultural Implement Workers of
America, UAW v. OSHA, 938 F.2d 1310, 1313 (D.C. Cir. 1991); Control of
Hazardous Energy Sources (Lockout/Tagout), Final rule; supplemental
statement of reasons, (58 FR 16612, March 30, 1993).
III. Events Leading to the Final Standard
OSHA's previous standards for workplace exposure to Cr(VI) were
adopted in 1971, pursuant to section 6(a) of the Act, from a 1943
American National Standards Institute (ANSI) recommendation originally
tissues (36 FR at 10466, 5/29/71; Ex. 20-3). OSHA's general industry
standard set a permissible exposure limit (PEL) of 1 mg chromium
trioxide per 10 m\3\ air in the workplace (1 mg/10 m\3\
CrO3) as a ceiling concentration, which corresponds to a
concentration of 52 [mu]g/m\3\ Cr(VI). A separate rule promulgated for
the construction industry set an eight-hour time-weighted-average PEL
of 1 mg/10 m3 CrO3, also equivalent to 52 [mu]g/
m\3\ Cr(VI), adopted from the American Conference of Governmental
Industrial Hygienists (ACGIH) 1970 Threshold Limit Value (TLV) (36 FR
at 7340, 4/17/71).
Following the ANSI standard of 1943, other occupational and public
health organizations evaluated Cr(VI) as a workplace and environmental
hazard and formulated recommendations to control exposure. The ACGIH
first recommended control of workplace exposures to chromium in 1946,
recommending a time-weighted average Maximum Allowable Concentration
(later called a Threshold Limit Value) of 100 [mu]g/m\3\ for chromic
acid and chromates as Cr2O3 (Ex. 5-37), and later
classified certain Cr(VI) compounds as class A1 (confirmed human)
carcinogens in 1974. In 1975, the NIOSH Criteria for a Recommended
Standard recommended that occupational exposure to Cr(VI) compounds
should be limited to a 10-hour TWA of 1 [mu]g/m\3\, except for some
forms of Cr(VI) then believed to be noncarcinogenic (Ex. 3-92). The
National Toxicology Program's First Annual Report on Carcinogens
identified calcium chromate, chromium chromate, strontium chromate, and
zinc chromate as carcinogens in 1980 (Ex. 35-157).
During the 1980s, regulatory and standards organizations came to
recognize Cr(VI) compounds in general as carcinogens. The Environmental
Protection Agency (EPA) Health Assessment Document of 1984 stated that,
* * * using the IARC [International Agency for Research on Cancer]
classification scheme, the level of evidence available for the
combined animal and human data would place hexavalent chromium (Cr
VI) compounds into Group 1, meaning that there is decisive evidence
for the carcinogenicity of those compounds in humans (Ex. 19-1, p.
7-107).
In 1988 IARC evaluated the available evidence regarding Cr(VI)
carcinogenicity, concluding in 1990 that
* * * [t]here is sufficient evidence in humans for the
carcinogenicity of chromium[VI] compounds as encountered in the
chromate production, chromate pigment production and chromium
plating industries, [and] sufficient evidence in experimental
animals for the carcinogenicity of calcium chromate, zinc chromates,
strontium chromate and lead chromates (Ex. 18-3, p. 213).
In September 1988, NIOSH advised OSHA to consider all Cr(VI)
compounds as potential occupational carcinogens (Ex. 31-22-22). ACGIH
now classifies water-insoluble and water-soluble Cr(IV) compounds as
class A1 carcinogens (Ex. 35-207). Current ACGIH standards include
specific 8-hour time-weighted average TLVs for calcium chromate (1
[mu]g/m3), lead chromate (12 [mu]g/m3), strontium
chromate (0.5 [mu]g/m3), and zinc chromates (10 [mu]g/
m3), and generic TLVs for water soluble (50 [mu]g/
m3) and insoluble (10 [mu]g/m3) forms of
hexavalent chromium not otherwise classified, all measured as chromium
(Ex. 35-207).
In July 1993, OSHA was petitioned for an emergency temporary
standard to reduce occupational exposures to Cr(VI) compounds (Ex. 1).
The Oil, Chemical, and Atomic Workers International Union (OCAW) and
Public Citizen's Health Research Group (Public Citizen), citing
evidence that occupational exposure to Cr(VI) increases workers' risk
of lung cancer, petitioned OSHA to promulgate an emergency temporary
standard to lower the PEL for Cr(VI) compounds to 0.5 [mu]g/
m3 as an eight-hour time-weighted average (TWA). Upon review
of the petition, OSHA agreed that there was evidence of increased
cancer risk from exposure to Cr(VI) at the existing PEL, but found that
the available data did not show the "grave danger" required to
support an emergency temporary standard (Ex. 1-C). The Agency therefore
denied the request for an emergency temporary standard, but initiated
Section 6(b)(5) rulemaking and began performing preliminary analyses
relevant to the rule.
In 1997, Public Citizen petitioned the United States Court of
Appeals for the Third Circuit to compel OSHA to complete rulemaking
lowering the standard for occupational exposure to Cr(VI). The Court
denied Public Citizen's request, concluding that there was no
unreasonable delay and dismissed the suit. Oil, Chemical and Atomic
Workers Union and Public Citizen Health Research Group v. OSHA, 145
F.3d 120 (3rd Cir. 1998). Afterwards, the Agency continued its data
collection and analytic efforts on Cr(VI) (Ex. 35-208, p. 3). In 2002,
Public Citizen again petitioned the Court to compel OSHA to commence
rulemaking to lower the Cr(VI) standard (Ex. 31-24-1). Meanwhile on
August 22, 2002, OSHA published a Request for Information on Cr(VI) to
solicit additional information on key issues related to controlling
exposures to Cr(VI) (FR 67 at 54389), and on December 4, 2002 announced
its intent to proceed with developing a proposed standard (Ex. 35-306).
On December 24, 2002, the Court granted Public Citizen's petition, and
ordered the Agency to proceed expeditiously with a Cr(VI) standard. See
Public Citizen Health Research Group v. Chao, 314 F.3d 143 (3rd Cir.
2002)). In a subsequent order, the Court established a compressed
schedule for completion of the rulemaking, with deadlines of October 4,
2004 for publication of a proposed standard and January 18, 2006 for
publication of a final standard (Ex. 35-304).
In 2003, as required by the Small Business Regulatory Enforcement
Act (SBREFA), OSHA initiated SBREFA proceedings, seeking the advice of
small business representatives on the proposed rule. The SBREFA panel,
including representatives from OSHA, the Small Business Administration
(SBA), and the Office of Management and Budget (OMB), was convened on
December 23, 2003. The panel conferred with representatives from small
entities in chemical, alloy, and pigment manufacturing, electroplating,
welding, aerospace, concrete, shipbuilding, masonry, and construction
on March 16-17, 2004, and delivered its final report to OSHA on April
20, 2004. The Panel's report, including comments from the small entity
representatives (SERS) and recommendations to OSHA for the proposed
rule, is available in the Cr(VI) rulemaking docket (Ex. 34). The SBREFA
Panel made recommendations on a variety of subjects. The most important
recommendations with respect to alternatives that OSHA should consider
included: A higher PEL than the PEL of 1; excluding cement from the
scope of the standard; the use of SECALs for some industries; different
PELS for different Hexavalent chromium compounds; a multi-year phase-in
to the standards; and further consideration to approaches suited to the
special conditions of the maritime and construction industries. OSHA
has adapted many of these recommendations: The PEL is now 5; cement has
been excluded from the scope of the standard; a compliance alternative,
similar to a SECAL, has been used in aerospace industry; the standard
allows four years to phase in engineering controls; and a new
performance based monitoring approach for all industries, among other
changes, all of which should make it easier for all
industries with changing work place conditions to meet the standard in
a cost effective way. A full discussion of all of the recommendations,
and OSHA's responses to them, is provided in Section VIII of this
Preamble.
In addition to undertaking SBREFA proceedings, in early 2004, OSHA
provided the Advisory Committee on Construction Safety and Health
(ACCSH) and the Maritime Advisory Committee on Occupational Safety and
Health (MACOSH) with copies of the draft proposed rule for review. OSHA
representatives met with ACCSH in February 2004 and May 2004 to discuss
the rulemaking and receive their comments and recommendations. On
February 13, 2004, ACCSH recommended that portland cement should be
included within the scope of the proposed standard (Ex. 35-307, pp.
288-293) and that identical PELs should be set for construction,
maritime, and general industry (Ex. 35-307, pp. 293-297). On May 18,
2004, ACCSH recommended that the construction industry should be
included in the current rulemaking, and affirmed its earlier
recommendation regarding portland cement. OSHA representatives met with
MACOSH in March 2004. On March 3, 2004, MACOSH collected and forwarded
additional exposure monitoring data to OSHA to help the Agency better
evaluate exposures to Cr(VI) in shipyards (Ex. 35-309, p. 208). MACOSH
also recommended a separate Cr(VI) standard for the maritime industry,
arguing that maritime involves different exposures and requires
different means of exposure control than general industry and
construction (Ex. 35-309, p. 227).
In accordance with the Court's rulemaking schedule, OSHA published
the proposed standard for hexavalent chromium on October 4, 2004 (69 FR
at 59306). The proposal included a notice of public hearing in
Washington, DC (69 FR at 59306, 59445-59446). The notice also invited
interested persons to submit comments on the proposal until January 3,
2005. In the proposal, OSHA solicited public input on 65 issues
regarding the human health risks of Cr(VI) exposure, the impact of the
proposed rule on Cr(VI) users, and other issues of particular interest
to the Agency (69 FR at 59306-59312).
OSHA convened the public hearing on February 1, 2005, with
Administrative Law Judges John M. Vittone and Thomas M. Burke
presiding. At the conclusion of the hearing on February 15, 2005, Judge
Burke set a deadline of March 21, 2005, for the submission of post
hearing comments, additional information and data relevant to the
rulemaking, and a deadline of April 20, 2005, for the submission of
additional written comments, arguments, summations, and briefs. A wide
range of employees, employers, union representatives, trade
associations, government agencies and other interested parties
participated in the public hearing or contributed written comments.
Issues raised in their comments and testimony are addressed in the
relevant sections of this preamble (e.g., comments on the risk
assessment are discussed in section VI; comments on the benefits
analysis in section VIII). On December 22, 2005, OSHA filed a motion
with the U.S. Court of Appeals for the Third Circuit requesting an
extension of the court-mandated deadline for the publication of the
final rule by six weeks, to February 28, 2006 (Ex. 48-13). The Court
granted the request on January 17, 2006 (Ex. 48-15).
As mandated by the Act, the final standard on occupational exposure
to hexavalent chromium is based on careful consideration of the entire
record of this proceeding, including materials discussed or relied upon
in the proposal, the record of the hearing, and all written comments
and exhibits received.
OSHA has developed separate final standards for general industry,
shipyards, and the construction industry. The Agency has concluded that
excess exposure to Cr(VI) in any form poses a significant risk of
material impairment to the health of workers, by causing or
contributing to adverse health effects including lung cancer, non-
cancer respiratory effects, and dermal effects. OSHA determined that
the TWA PEL should not be set above 5 [mu]g/m3 based on the
evidence in the record and its own quantitative risk assessment. The
TWA PEL of 5 [mu]g/m3 reduces the significant risk posed to
workers by occupational exposure to Cr(VI) to the maximum extent that
is technologically and economically feasible. (See discussion of the
PEL in Section XV below.)
IV. Chemical Properties and Industrial Uses
Chromium is a metal that exists in several oxidation or valence
states, ranging from chromium (-II) to chromium (+VI). The elemental
valence state, chromium (0), does not occur in nature. Chromium
compounds are very stable in the trivalent state and occur naturally in
this state in ores such as ferrochromite, or chromite ore
(FeCr2O4). The hexavalent, Cr(VI) or chromate, is
the second most stable state. It rarely occurs naturally; most Cr(VI)
compounds are man made.
Chromium compounds in higher valence states are able to undergo
"reduction" to lower valence states; chromium compounds in lower
valence states are able to undergo "oxidation" to higher valence
states. Thus, Cr(VI) compounds can be reduced to Cr(III) in the
presence of oxidizable organic matter. Chromium can also be reduced in
the presence of inorganic chemicals such as iron.
Chromium does exist in less stable oxidation (valence) states such
as Cr(II), Cr(IV), and Cr(V). Anhydrous Cr(II) salts are relatively
stable, but the divalent state (II, or chromous) is generally
relatively unstable and is readily oxidized to the trivalent (III or
chromic) state. Compounds in valence states such as (IV) and (V)
usually require special handling procedures as a result of their
instability. Cr(IV) oxide (CrO2) is used in magnetic
recording and storage devices, but very few other Cr(IV) compounds have
industrial use. Evidence exists that both Cr(IV) and Cr(V) are formed
as transient intermediates in the reduction of Cr(VI) to Cr(III) in the
body.
Chromium (III) is also an essential nutrient that plays a role in
glucose, fat, and protein metabolism by causing the action of insulin
to be more effective. Chromium picolinate, a trivalent form of chromium
combined with picolinic acid, is used as a dietary supplement, because
it is claimed to speed metabolism.
Elemental chromium and the chromium compounds in their different
valence states have various physical and chemical properties, including
differing solubilities. Most chromium species are solid. Elemental
chromium is a steel gray solid, with high melting and boiling points
(1857 [deg]C and 2672 [deg]C, respectively), and is insoluble in water
and common organic solvents. Chromium (III) chloride is a violet or
purple solid, with high melting and sublimation points (1150 [deg]C and
1300 [deg]C, respectively), and is slightly soluble in hot water and
insoluble in common organic solvents. Ferrochromite is a brown-black
solid; chromium (III) oxide is a green solid; and chromium (III)
sulfate is a violet or red solid, insoluble in water and slightly
soluble in ethanol. Chromium (III) picolinate is a ruby red crystal
soluble in water (1 part per million at 25 [deg]C). Chromium (IV) oxide
is a brown-black solid that decomposes at 300 [deg]C and is insoluble
in water.
Cr(VI) compounds have mostly lemon yellow to orange to dark red
hues. They are typically crystalline, granular, or powdery although one
compound (chromyl chloride) exists in liquid form. For example, chromyl
chloride is a dark red liquid that decomposes into chromate ion and
hydrochloric acid in water. Chromic acids are dark red crystals that are
very soluble in water. Other examples of soluble chromates are sodium
chromate (yellow crystals) and sodium dichromate (reddish to bright orange
crystals). Lead chromate oxide is typically a red crystalline powder. Zinc
chromate is typically seen as lemon yellow crystals which decompose in
hot water and are soluble in acids and liquid ammonia. Other chromates
such as barium, calcium, lead, strontium, and zinc chromates vary in
color from light yellow to greenish yellow to orange-yellow and exist
in solid form as crystals or powder.
The Color Pigments Manufacturers Association (CPMA) provided
additional information on lead chromate and some other chromates used
in their pigments (Ex. 38-205, pp. 12-13). CPMA describes two main lead
chromate color groups: the chrome yellow pigments and the orange to red
varieties known as molybdate orange pigments. The chrome yellow
pigments are solid solution crystal compositions of lead chromate and
lead sulfate. Molybdate orange pigments are solid solution crystal
compositions of lead chromate, lead sulfate, and lead molybdate (Ex.
38-205, p. 12). CPMA also describes a basic lead chromate called
"chrome orange," and a lead chromate precipitated "onto a core" of
silica (Ex. 38-205, p. 13).
OSHA re-examined available information on solubility values in
light of comments from the CPMA and Dominion Color Corporation (DCC) on
qualitative solubility designations and CPMA's claim of low
bioavailability of lead chromate due to its extremely low solubility
(Exs. 38-201-1, p. 4; 38-205, p. 95). There was not always agreement or
consistency with the qualitative assignments of solubilities.
Quantitative values for the same compound also differ depending on the
source of information.
The Table IV-1 is the result of OSHA's re-examination of
quantitative water solubility values and qualitative designations.
Qualitative designations as well as quantitative values are listed as
they were provided by the source. As can be seen by the Table IV-1,
qualitative descriptions vary by the descriptive terminology chosen by
the source.
BILLING CODE 4510-26-P
Click here to view table IV-1
BILLING CODE 4510-26-C
OSHA has made some generalizations to describe the water
solubilities of chromates in subsequent sections of this Federal
Register notice. OSHA has divided Cr(VI) compounds and mixtures into
three categories based on solubility values. Compounds and mixtures
with water solubilities less than 0.01 g/l are referred to as water
insoluble. Compounds and mixtures between 0.01 g/l and 500 g/l are
referred to as slightly soluble. Compounds and mixtures with water
solubility values of 500 g/l or greater are referred to as highly
water soluble. It should be noted that these boundaries for insoluble,
slightly soluble, and highly soluble are arbitrary designations for the
sake of further description elsewhere in this document. Quantitative
values take precedence over qualitative designations. For example, zinc
chromates would be slightly soluble where their solubility values exceed 0.01 g/l.
Some major users of chromium are the metallurgical, refractory, and
chemical industries. Chromium is used by the metallurgical industry to
produce stainless steel, alloy steel, and nonferrous alloys. Chromium
is alloyed with other metals and plated on metal and plastic substrates
to improve corrosion resistance and provide protective coatings for
automotive and equipment accessories. Welders use stainless steel
welding rods when joining metal parts.
Cr(VI) compounds are widely used in the chemical industry in
pigments, metal plating, and chemical synthesis as ingredients and
catalysts. Chromates are used as high quality pigments for textile
dyes, paints, inks, glass, and plastics. Cr(VI) can be produced during
welding operations even if the chromium was originally present in
another valence state. While Cr(VI) is not intentionally added to
portland cement, it is often present as an impurity.
Occupational exposures to Cr(VI) can occur from inhalation of mists
(e.g., chrome plating, painting), dusts (e.g., inorganic pigments), or
fumes (e.g., stainless steel welding), and from dermal contact (e.g.,
cement workers).
There are about thirty major industries and processes where Cr(VI)
is used. These include producers of chromates and related chemicals
from chromite ore, electroplating, welding, painting, chromate pigment
production and use, steel mills, and iron and steel foundries. A
detailed discussion of the uses of Cr(VI) in industry is found in
Section VIII of this preamble.
V. Health Effects
This section summarizes key studies of adverse health effects
resulting from exposure to hexavalent chromium (Cr(VI)) in humans and
experimental animals, as well as information on the fate of Cr(VI) in
the body and laboratory research that relates to its toxic mode of
action. The primary health impairments from workplace exposure to
Cr(VI) are lung cancer, asthma, and damage to the nasal epithelia and
skin. While this chapter on health effects does not describe all of the
many studies that have been conducted on Cr(VI) toxicity, it includes a
selection of those that are relevant to the rulemaking and
representative of the scientific literature on Cr(VI) health effects.
A. Absorption, Distribution, Metabolic Reduction and Elimination
Although chromium can exist in a number of different valence
states, Cr(VI) is the form considered to be the greatest health risk.
Cr(VI) enters the body by inhalation, ingestion, or absorption through
the skin. For occupational exposure, the airways and skin are the
primary routes of uptake. The following discussion summarizes key
aspects of Cr(VI) uptake, distribution, metabolism, and elimination.
1. Deposition and Clearance of Inhaled Cr(VI) From the Respiratory
Tract
Various anatomical, physical and physiological factors determine
both the fractional and regional deposition of inhaled particulate
matter. Due to the airflow patterns in the lung, more particles tend to
deposit at certain preferred regions in the lung. It is therefore
possible to have a buildup of chromium at certain sites in the
bronchial tree that could create areas of very high chromium
concentration. A high degree of correspondence between the efficiency
of particle deposition and the frequency of bronchial tumors at sites
in the upper bronchial tree was reported in research by Schlesinger and
Lippman that compared the distribution of cancer sites in published
reports of primary bronchogenic tumors with experimentally determined
particle deposition patterns (Ex. 35-102).
Large inhaled particles (>5 [mu]m) are efficiently removed from the
air-stream in the extrathoracic region (Ex. 35-175). Particles greater
than 2.5 [mu]m are generally deposited in the tracheobronchial regions,
whereas particles less than 2.5 [mu]m are generally deposited in the
pulmonary region. Some larger particles (>2.5 [mu]m) can reach the
pulmonary region. The mucociliary escalator predominantly clears
particles that deposit in the extrathoracic and the tracheobronchial
region of the lung. Individuals exposed to high particulate levels of
Cr(VI) may also have altered respiratory mucociliary clearance.
Particulates that reach the alveoli can be absorbed into the
bloodstream or cleared by phagocytosis.
2. Absorption of Inhaled Cr(VI) Into the Bloodstream
The absorption of inhaled chromium compounds depends on a number of
factors, including physical and chemical properties of the particles
(oxidation state, size, solubility) and the activity of alveolar
macrophages (Ex. 35-41). The hexavalent chromate anions
(CrO4)2- enter cells via facilitated diffusion
through non-specific anion channels (similar to phosphate and sulfate
anions). As demonstrated in research by Suzuki et al., a portion of
water soluble Cr(VI) is rapidly transported to the bloodstream in rats
(Ex. 35-97). Rats were exposed to 7.3-15.9 mg Cr(VI)/m\3\ as potassium
dichromate for 2-6 hours. Following exposure to Cr(VI), the ratio of
blood chromium/lung chromium was 1.440.30 at 0.5 hours,
0.810.10 at 18 hours, 0.850.20 at 48 hours, and
0.960.22 at 168 hours after exposure.
Once the Cr(VI) particles reach the alveoli, absorption into the
bloodstream is greatly dependent on solubility. More soluble chromates
are absorbed faster than water insoluble chromates, while insoluble
chromates are poorly absorbed and therefore have longer resident time
in the lungs. This effect has been demonstrated in research by Bragt
and van Dura on the kinetics of three Cr(VI) compounds: highly soluble
sodium chromate, slightly soluble zinc chromate and water insoluble
lead chromate (Ex. 35-56). They instilled \51\chromium-labeled
compounds (0.38 mg Cr(VI)/kg as sodium chromate, 0.36 mg Cr(VI)/kg as
zinc chromate, or 0.21 mg Cr(VI)/kg as lead chromate) intratracheally
in rats. Peak blood levels of \51\chromium were reached after 30
minutes for sodium chromate (0.35 [mu]g chromium/ml), and after 24
hours for zinc chromate (0.60 [mu]g chromium/ml) and lead chromate
(0.007 [mu]g chromium/ml). At 30 minutes after administration, the
lungs contained 36, 25, and 81% of the respective dose of the sodium,
zinc, and lead chromate. On day six, >80% of the dose of all three
compounds had been cleared from the lungs, during which time the
disappearance from lungs followed linear first-order kinetics. The
residual amount left in the lungs on day 50 or 51 was 3.0, 3.9, and
13.9%, respectively. From these results authors concluded that zinc
chromate, which is less soluble than sodium chromate, is more slowly
absorbed from the lungs. Lead chromate was more poorly and slowly
absorbed, as indicated by very low levels in blood and greater
retention in the lungs. The authors also noted that the kinetics of
sodium and zinc chromates were very similar. Zinc chromate, which is
less soluble than sodium chromate, was slowly absorbed from the lung,
but the maximal blood levels were higher than those resulting from an
equivalent dose of sodium chromate. The authors believe that this was
probably the result of hemorrhages macroscopically visible in the lungs
of zinc chromate-treated rats 24 hours following intratracheal administration.
Boeing Corporation commented that this study does not show that the highly water
soluble sodium chromate is cleared more rapidly or retained in the lung for
shorter periods than the less soluble zinc chromate (Ex. 38-106-2, p.
18-19). This comment is addressed in the Carcinogenic Effects
Conclusion Section V.B.9 dealing with the carcinogenicity of slightly
soluble Cr(VI) compounds.
Studies by Langard et al. and Adachi et al. provide further
evidence of absorption of chromates from the lungs (Exs. 35-93; 189).
In Langard et al., rats exposed to 2.1 mg Cr(VI)/m\3\ as zinc chromate
for 6 hours/day achieved steady state concentrations in the blood after
4 days of exposure (Ex. 35-93). Adachi et al. studied rats that were
subject to a single inhalation exposure to chromic acid mist generated
from electroplating at a concentration of 3.18 mg Cr(VI)/m\3\ for 30
minutes which was then rapidly absorbed from the lungs (Ex. 189). The
amount of chromium in the lungs of these rats declined from 13.0 mg
immediately after exposure to 1.1 mg after 4 weeks, with an overall
half-life of five days.
Several other studies have reported absorption of chromium from the
lungs after intratracheal instillation (Exs. 7-9; 9-81; Visek et al.
1953 as cited in Ex. 35-41). These studies indicated that 53-85% of
Cr(VI) compounds (particle size < 5 [mu]m) were cleared from the lungs
by absorption into the bloodstream or by mucociliary clearance in the
pharynx; the rest remained in the lungs. Absorption of Cr(VI) from the
respiratory tract of workers has been shown in several studies that
identified chromium in the urine, serum and red blood cells following
occupational exposure (Exs. 5-12; 35-294; 35-84).
Evidence indicates that even chromates encapsulated in a paint
matrix may be released in the lungs (Ex. 31-15, p. 2). In a study of
chromates in aircraft spray paint, LaPuma et al. measured the mass of
Cr(VI) released from particles into water originating from three types
of paint particles: solvent-borne epoxy (25% strontium chromate
(SrCrO4)), water-borne epoxy (30% SrCrO4) and
polyurethane (20% SrCrO4) (Ex. 31-2-1). The mean fraction of
Cr(VI) released into the water after one and 24 hours for each primer
averaged: 70% and 85% (solvent epoxy), 74% and 84% (water epoxy), and
94% and 95% (polyurethane). Correlations between particle size and the
fraction of Cr(VI) released indicated that smaller particles (< 5 [mu]m)
release a larger fraction of Cr(VI) versus larger particles (>5 [mu]m).
This study demonstrates that the paint matrix only modestly hinders
Cr(VI) release into a fluid, especially with smaller particles. Larger
particles, which contain the majority of Cr(VI) due to their size,
appear to release proportionally less Cr(VI) (as a percent of total
Cr(VI)) than smaller particles. Some commenters suggested that the
above research shows that the slightly soluble Cr(VI) from aircraft
spray paint is less likely to reach and be absorbed in the
bronchoalveolar region of the lung than a highly soluble Cr(VI) form,
such as chromic acid aerosol (Exs. 38-106-2; 39-43, 44-33). This issue
is further discussed in the Carcinogenic Effects Conclusion Section
V.B.9.a and in the Quantitative Risk Assessment Section VI.G.4.a.
A number of questions remain unanswered regarding encapsulated
Cr(VI) and bioavailability from the lung. There is a lack of detailed
information on the efficiency of encapsulation and whether all of the
chromate molecules are encapsulated. The stability of the encapsulated
product in physiological and environmental conditions over time has not
been demonstrated. Finally, the fate of inhaled encapsulated Cr(VI) in
the respiratory tract and the extent of distribution in systemic
tissues has not been thoroughly studied.
3. Dermal Absorption of Cr(VI)
Both human and animal studies demonstrate that Cr(VI) compounds are
absorbed after dermal exposure. Dermal absorption depends on the
oxidation state of chromium, the vehicle and the integrity of the skin.
Cr(VI) readily traverses the epidermis to the dermis (Exs. 9-49; 309).
The histological distribution of Cr(VI) within intact human skin was
studied by Liden and Lundberg (Ex. 35-80). They applied test solutions
of potassium dichromate in petrolatum or in water as occluded circular
patches of filter paper to the skin. Results with potassium dichromate
in water revealed that Cr(VI) penetrated beyond the dermis and
penetration reached steady state with resorption by the lymph and blood
vessels by 5 hours. About 10 times more chromium penetrated when
potassium dichromate was applied in petrolatum than when applied in
water, indicating that organic solvents facilitate the absorption of
Cr(VI) from the skin. Research by Baranowska-Dutkiewicz also
demonstrated that the absorption rates of sodium chromate solutions
from the occluded forearm skin of volunteers increase with increasing
concentration (Ex. 35-75). The rates were 1.1 [mu]g Cr(VI)/cm\2\/hour
for a 0.01 molar solution, 6.4 [mu]g Cr(VI)/cm\2\/hour for a 0.1 molar
solution, and 10 [mu]g Cr(VI)/cm\2\/hour for a 0.2 molar solution.
Additional studies have demonstrated that the absorption of Cr(VI)
compounds can take place through the dermal route. Using volunteers,
Mali found that potassium dichromate penetrates the intact epidermis
(Exs. 9-49; 35-41). Wahlberg and Skog demonstrated the presence of
chromium in the blood, spleen, bone marrow, lymph glands, urine and
kidneys of guinea pigs dermally exposed to \51\chromium labeled Cr(VI)
compounds (Ex. 35-81).
4. Absorption of Cr(VI) by the Oral Route
Inhaled Cr(VI) can enter the digestive tract as a result of
mucocilliary clearance and swallowing. Studies indicate Cr(VI) is
absorbed from the gastrointestinal tract. For example, in a study by
Donaldson and Barreras, the six-day fecal and 24-hour urinary excretion
patterns of radioactivity in groups of six volunteers given Cr(VI) as
sodium chromate labeled with \51\chromium indicated that at least 2.1%
of the Cr(VI) was absorbed. After intraduodenal administration at least
10% of the Cr(VI) compound was absorbed. These studies also
demonstrated that Cr(VI) compounds are reduced to Cr(III) compounds in
the stomach, thereby accounting for the relatively poor
gastrointestinal absorption of orally administered Cr(VI) compounds
(Exs. 35-96; 35-41). In the gastrointestinal tract, Cr(VI) can be
reduced to Cr(III) by gastric juices, which is then poorly absorbed
(Underwood, 1971 as cited in Ex. 19-1; Ex. 35-85).
In a study conducted by Clapp et al., treatment of rats by gavage
with an unencapsulated lead chromate pigment or with a silica-
encapsulated lead chromate pigment resulted in no measurable blood
levels of chromium (measured as Cr(III), detection limit = 10 [mu]g/L)
after two or four weeks of treatment or after a two-week recovery
period. However, kidney levels of chromium (measured as Cr(III)) were
significantly higher in the rats that received the unencapsulated
pigment when compared to the rats that received the encapsulated
pigment, indicating that silica encapsulation may reduce the
gastrointestinal bioavailability of chromium from lead chromate
pigments (Ex. 11-5). This study does not address the bioavailability of
encapsulated chromate pigments from the lung where residence time could
be different.
5. Distribution of Cr(VI) in the Body
Once in the bloodstream, Cr(VI) is taken up into erythrocytes,
where it is reduced to lower oxidation states and forms chromium
protein complexes during reduction (Ex. 35-41). Once complexed with
protein, chromium cannot leave the cell and chromium ions are unable to
repenetrate the membrane and move back into the plasma (Exs. 7-6; 7-7;
19-1; 35-41; 35-52). Once inside the blood cell, the intracellular
Cr(VI) reduction to Cr(III) depletes Cr(VI) concentration in the red
blood cell (Ex. 35-89). This serves to enhance diffusion of Cr(VI) from
the plasma into the erythrocyte resulting in very low plasma levels of
Cr(VI). It is also believed that the rate of uptake of Cr(VI) by red
blood cells may not exceed the rate at which they reduce Cr(VI) to
Cr(III) (Ex. 35-99). The higher tissue levels of chromium after
administration of Cr(VI) than after administration of Cr(III) reflect
the greater tendency of Cr(VI) to traverse plasma membranes and bind to
intracellular proteins in the various tissues, which may explain the
greater degree of toxicity associated with Cr(VI) (MacKenzie et al.
1958 as cited in 35-52; Maruyama 1982 as cited in 35-41; Ex. 35-71).
Examination of autopsy tissues from chromate workers who were
occupationally exposed to Cr(VI) showed that the highest chromium
levels were in the lungs. The liver, bladder, and bone also had
chromium levels above background. Mancuso examined tissues from three
individuals with lung cancer who were exposed to chromium in the
workplace (Ex. 124). One was employed for 15 years as a welder, the
second and third worked for 10.2 years and 31.8 years, respectively, in
ore milling and preparations and boiler operations. The cumulative
chromium exposures for the three workers were estimated to be 3.45,
4.59, and 11.38 mg/m\3\-years, respectively. Tissues from the first
worker were analyzed 3.5 years after last exposure, the second worker
18 years after last exposure, and the third worker 0.6 years after last
exposure. All tissues from the three workers had elevated levels of
chromium, with the possible exception of neural tissues. Levels were
orders of magnitude higher in the lungs when compared to other tissues.
Similar results were also reported in autopsy studies of people who may
have been exposed to chromium in the workplace as well as chrome
platers and chromate refining workers (Exs. 35-92; 21-1; 35-74; 35-88).
Animal studies have shown similar distribution patterns after
inhalation exposure. For example, a study by Baetjer et al.
investigated the distribution of Cr(VI) in guinea pigs after
intratracheal instillation of slightly soluble potassium dichromate
(Ex. 7-8). At 24 hours after instillation, 11% of the original dose of
chromium from potassium dichromate remained in the lungs, 8% in the
erythrocytes, 1% in plasma, 3% in the kidney, and 4% in the liver. The
muscle, skin, and adrenal glands contained only a trace. All tissue
concentrations of chromium declined to low or nondetectable levels in
140 days, with the exception of the lungs and spleen.
6. Metabolic Reduction of Cr(VI)
Cr(VI) is reduced to Cr(III) in the lungs by a variety of reducing
agents. This serves to limit uptake into lung cells and absorption into
the bloodstream. Cr(V) and Cr(IV) are transient intermediates in this
process. The genotoxic effects produced by the Cr(VI) are related to
the reduction process and are further discussed in the section V.B.8 on
Mechanistic Considerations.
In vivo and in vitro experiments in rats indicated that, in the
lungs, Cr(VI) can be reduced to Cr(III) by ascorbate and glutathione. A
study by Suzuki and Fukuda showed that the reduction of Cr(VI) by
glutathione is slower than the reduction by ascorbate (Ex. 35-65).
Other studies have reported the reduction of Cr(VI) to Cr(III) by
epithelial lining fluid (ELF) obtained from the lungs of 15 individuals
by bronchial lavage. The average overall reduction capacity was 0.6
[mu]g Cr(VI)/mg of ELF protein. In addition, cell extracts made from
pulmonary alveolar macrophages derived from five healthy male
volunteers were able to reduce an average of 4.8 [mu]g Cr(VI)/10\6\
cells or 14.4 [mu]g Cr(VI)/mg protein (Ex. 35-83). Postmitochondrial
(S12) preparations of human lung cells (peripheral lung parenchyma and
bronchial preparations) were also able to reduce Cr(VI) to Cr(III) (De
Flora et al. 1984 as cited in Ex. 35-41).
7. Elimination of Cr(VI) From the Body
Excretion of chromium from Cr(VI) compounds is predominantly in the
urine, although there is some biliary excretion into the feces. In both
urine and feces, the chromium is present as low molecular weight
Cr(III) complexes. Absorbed chromium is excreted from the body in a
rapid phase representing clearance from the blood and at least two
slower phases representing clearance from tissues. Urinary excretion
accounts for over 50% of eliminated chromium (Ex. 35-41). Although
chromium is excreted in urine and feces, the intestine plays only a
minor part in chromium elimination, representing only about 5% of
elimination from the blood (Ex. 19-1). Normal urinary levels of
chromium in humans have been reported to range from 0.24-1.8 [mu]g/L
with a median level of 0.4 [mu]g/L (Ex. 35-79). Humans exposed to 0.01-
0.1 mg Cr(VI)/m\3\ as potassium dichromate (8-hour time-weighted
average) had urinary excretion levels from 0.0247 to 0.037 mg Cr(III)/
L. Workers exposed mainly to Cr(VI) compounds had higher urinary
chromium levels than workers exposed primarily to Cr(III) compounds. An
analysis of the urine did not detect Cr(VI), indicating that Cr(VI) was
rapidly reduced before excretion (Exs. 35-294; 5-48).
A half-life of 15-41 hours has been estimated for chromium in urine
for four welders using a linear one-compartment kinetic model (Exs. 35-
73; 5-52; 5-53). Limited work on modeling the absorption and deposition
of chromium indicates that adipose and muscle tissue retain chromium at
a moderate level for about two weeks, while the liver and spleen store
chromium for up to 12 months. The estimated half-life for whole body
chromium retention is 22 days for Cr(VI) (Ex. 19-1). The half-life of
chromium in the human lung is 616 days, which is similar to the half-
life in rats (Ex. 7-5).
Elimination of chromium was shown to be very slow in rats exposed
to 2.1 mg Cr(VI)/m\3\ as zinc chromate six hours/day for four days.
Urinary levels of chromium remained almost constant for four days after
exposure and then decreased (Ex. 35-93). After intratracheal
administration of sodium dichromate to rats, peak urinary chromium
concentrations were observed at six hours, after which the urinary
concentrations declined rapidly (Ex. 35-94). The more prolonged
elimination of the moderately soluble zinc chromate as compared to the
more soluble sodium dichromate is consistent with the influence of
Cr(VI) solubility on absorption from the respiratory tract discussed
earlier.
Information regarding the excretion of chromium in humans after
dermal exposure to chromium or its compounds is limited. Fourteen days
after application of a salve containing water soluble potassium
chromate, which resulted in skin necrosis and sloughing at the
application site, chromium was found at 8 mg/L in the urine and 0.61
mg/100 g in the feces of one individual (Brieger 1920 as cited in Ex.
19-1). A slight increase over background levels of urinary chromium was
observed in four subjects submersed in a tub of chlorinated water containing
22 mg Cr(VI)/L as potassium dichromate for three hours (Ex. 31-22-6). For
three of the four subjects, the increase in urinary chromium excretion
was less than 1 [mu]g/day over the five-day collection period. Chromium
was detected in the urine of guinea pigs after radiolabeled sodium
chromate solution was applied to the skin (Ex. 35-81).
8. Physiologically-Based Pharmacokinetic Modeling
Physiologically-based pharmacokinetic (PBPK) models have been
developed that simulate absorption, distribution, metabolism, and
excretion of Cr(VI) and Cr(III) compounds in humans (Ex. 35-95) and
rats (Exs. 35-86; 35-70). The original model (Ex. 35-86) evolved from a
similar model for lead, and contained compartments for the lung, GI
tract, skin, blood, liver, kidney, bone, well-perfused tissues, and
slowly perfused tissues. The model was refined to include two lung
subcompartments for chromium, one of which allowed inhaled chromium to
enter the blood and GI tract and the other only allowed chromium to
enter the GI tract (Ex. 35-70). Reduction of Cr(VI) to Cr(III) was
considered to occur in every tissue compartment except bone.
The model was developed from several data sets in which rats were
dosed with Cr(VI) or Cr(III) intravenously, orally or by intratracheal
instillation, because different distribution and excretion patterns
occur depending on the route of administration. In most cases, the
model parameters (e.g., tissue partitioning, absorption, reduction
rates) were estimated by fitting model simulations to experimental
data. The optimized rat model was validated against the 1978 Langard
inhalation study (Ex. 35-93). Chromium blood levels were overpredicted
during the four-day inhalation exposure period, but blood levels during
the post-exposure period were well predicted by the model. The model-
predicted levels of liver chromium were high, but other tissue levels
were closely estimated.
A human PBPK model recently developed by O'Flaherty et al. is able
to predict tissue levels from ingestion of Cr(VI) (Ex. 35-95). The
model incorporates differential oral absorption of Cr(VI) and Cr(III),
rapid reduction of Cr(VI) to Cr(III) in major body fluids and tissues,
and concentration-dependent urinary clearance. The model does not
include a physiologic lung compartment, but can be used to estimate an
upper limit on pulmonary absorption of inhaled chromium. The model was
calibrated against blood and urine chromium concentration data from a
group of controlled studies in which adult human volunteers drank
solutions of soluble Cr(III) or Cr(VI).
PBPK models are increasingly used in risk assessments, primarily to
predict the concentration of a potentially toxic chemical that will be
delivered to any given target tissue following various combinations of
route, dose level, and test species. Further development of the
respiratory tract portion of the model, specific Cr(VI) rate data on
extracellular reduction and uptake into lung cells, and more precise
understanding of critical pathways inside target cells would improve
the model value for risk assessment purposes.
9. Summary
Based on the studies presented above, evidence exists in the
literature that shows Cr(VI) can be systemically absorbed by the
respiratory tract. The absorption of inhaled chromium compounds depends
on a number of factors, including physical and chemical properties of
the particles (oxidation state, size, and solubility), the reduction
capacity of the ELF and alveolar macrophages and clearance by the
mucocliary escalator and phagocytosis. Highly water soluble Cr(VI)
compounds (e.g. sodium chromate) enter the bloodstream more readily
than highly insoluble Cr(VI) compounds (e.g. lead chromate). However,
insoluble compounds may have longer residence time in lung. Absorption
of Cr(VI) can also take place after oral and dermal exposure,
particularly if the exposures are high.
The chromate (CrO4) 2- enters cells via
facilitated diffusion through non-specific anion channels (similar to
phosphate and sulfate anions). Following absorption of Cr(VI) compounds
from various exposure routes, chromium is taken up by the blood cells
and is widely distributed in tissues as Cr(VI). Inside blood cells and
tissues, Cr(VI) is rapidly reduced to lower oxidation states and bound
to macromolecules which may result in genotoxic or cytotoxic effects.
However, in the blood a substantial proportion of Cr(VI) is taken up
into erythrocytes, where it is reduced to Cr(III) and becomes bound to
hemoglobin and other proteins.
Inhaled Cr(VI) is reduced to Cr(III) in vivo by a variety of
reducing agents. Ascorbate and glutathione in the ELF and macrophages
have been shown to reduce Cr(VI) to Cr(III) in the lungs. After oral
exposure, gastric juices are also responsible for reducing Cr(VI) to
Cr(III). This serves to limit the amount of Cr(VI) systemically
absorbed.
Absorbed chromium is excreted from the body in a rapid phase
representing clearance from the blood and at least two slower phases
representing clearance from tissues. Urinary excretion is the primary
route of elimination, accounting for over 50% of eliminated chromium.
Although chromium is excreted in urine and feces, the intestine plays
only a minor part in chromium elimination representing only about 5% of
elimination from the blood.
B. Carcinogenic Effects
There has been extensive study on the potential for Cr(VI) to cause
carcinogenic effects, particularly cancer of the lung. OSHA reviewed
epidemiologic data from several industry sectors including chromate
production, chromate pigment production, chromium plating, stainless
steel welding, and ferrochromium production. Supporting evidence from
animal studies and mechanistic considerations are also evaluated in
this section.
1. Evidence from Chromate Production Workers
The epidemiologic literature of workers in the chromate production
industry represents the earliest and best-documented relationship
between exposure to chromium and lung cancer. The earliest study of
chromate production workers in the United States was reported by Machle
and Gregorius in 1948 (Ex. 7-2). In the United States, two chromate
production plants, one in Baltimore, MD, and one in Painesville, OH,
have been the subject of multiple studies. Both plants were included in
the 1948 Machle and Gregorius study and again in the study conducted by
the Public Health Service and published in 1953 (Ex. 7-3). Both of
these studies reported the results in aggregate. The Baltimore chromate
production plant was studied by Hayes et al. (Ex. 7-14) and more
recently by Gibb et al. (Ex. 31-22-11). The chromate production plant
in Painesville, OH, has been followed since the 1950s by Mancuso with
his most recent follow-up published in 1997. The most recent study of
the Painesville plant was published by Luippold et al. (Ex. 31-18-4).
The studies by Gibb and Luippold present historical exposure data for
the time periods covered by their respective studies. The Gibb exposure
data are especially interesting since the industrial hygiene data were
collected on a routine basis and not for compliance purposes. These
routine air measurements may be more representative of those typically
encountered by the exposed workers. In Great Britain, three plants have been
studied repeatedly, with reports published between 1952 and 1991. Other
studies of cohorts in the United States, Germany, Italy and Japan are
also reported. The elevated lung cancer mortality reported in the great
majority of these cohorts and the significant upward trends with
duration of employment and cumulative exposure provide some of the
strongest evidence that Cr(VI) is carcinogenic to workers. A summary of
selected human epidemiologic studies in chromate production workers is
presented in Table V-1.
BILLING CODE 4510-26-P
Click here to view table V-1
BILLING CODE 4510-26-C
The basic hexavalent chromate production process involves milling
and mixing trivalent chromite ore with soda ash, sometimes in the
presence of lime (Exs. 7-103; 35-61). The mixture is 'roasted' at a
high temperature, which oxidizes much of the chromite to hexavalent
sodium chromate. Depending on the lime content used in the process, the
roast also contains other chromate species, especially calcium
chromate under high lime conditions. The highly water-soluble sodium
chromate is water-extracted from the water-insoluble trivalent chromite
and the less water-soluble chromates (e.g., calcium chromate) in the
'leaching' process. The sodium chromate leachate is reacted with
sulfuric acid and sodium bisulfate to form sodium dichromate. The
sodium dichromate is prepared and packaged as a crystalline powder to
be sold as final product or sometimes used as the starting material to
make other chromates such as chromic acid and potassium dichromate.
a. Cohort Studies of the Baltimore Facility. The Hayes et al. study of
the Baltimore, Maryland chromate production plant was designed to
determine whether changes in the industrial process at one chromium
chemical production facility were associated with a decreased risk of
cancer, particularly cancer of the respiratory system (Ex. 7-14). Four
thousand two hundred and seventeen (4,217) employees were identified as
newly employed between January 1, 1945 and December 31, 1974. Excluded
from this initial enumeration were employees who: (1) were working as
of 1945, but had been hired prior to 1945 and (2) had been hired since
1945 but who had previously been employed at the plant. Excluded from
the final cohort were those employed less than 90 days; women; those
with unknown length of employment; those with no work history; and
those of unknown age. The final cohort included 2,101 employees (1,803
hourly and 298 salaried).
Hayes divided the production process into three departments: (1)
The mill and roast or "dry end" department which consists of
grinding, roasting and leaching processes; (2) the bichromate
department which consists of the acidification and crystallization
processes; and (3) the special products department which produces
secondary products including chromic acid. The bichromate and special
products departments are referred to as the "wet end".
The construction of a new mill and roast and bichromate plant that
opened during 1950 and 1951 and a new chromic acid and special products
plant that opened in 1960 were cited by Hayes as "notable production
changes" (Ex. 7-14). The new facilities were designed to "obtain
improvements in process technique and in environmental control of
exposure to chromium bearing dusts * * *" (Ex. 7-14).
Plant-related work and health histories were abstracted for each
employee from plant records. Each job on the employee's work history
was characterized according to whether the job exposure occurred in (1)
a newly constructed facility, (2) an old facility, or (3) could not be
classified as having occurred in the new or the old facility. Those who
ever worked in an old facility or whose work location(s) could not be
distinguished based upon job title were considered as having a high or
questionable exposure. Only those who worked exclusively in the new
facility were defined for study purposes as "low exposure". Data on
cigarette smoking were abstracted from plant records, but were not
utilized in any analyses since the investigators thought them "not to
be of sufficient quality to allow analysis."
One thousand one hundred and sixty nine (1,169) cohort members were
identified as alive, 494 not individually identified as alive and 438
as deceased. Death certificates could not be located for 35 reported
decedents. Deaths were coded to the 8th revision of the International
Classification of Diseases.
Mortality analysis was limited to the 1,803 hourly employees
calculating the standardized mortality ratios (SMRs) for specific
causes of death. The SMR is a ratio of the number of deaths observed in
the study population to the number that would be expected if that study
population had the same specific mortality rate as a standard reference
population (e.g., age-, gender-, calendar year adjusted U.S.
population). The SMR is typically multiplied by 100, so a SMR greater
than 100 represents an elevated mortality in the study cohort relative
to the reference group. In the Hayes study, the expected number of
deaths was based upon Baltimore, Maryland male mortality rates
standardized for age, race and time period. For those where race was
unknown, the expected numbers were derived from mortality rates for
whites. Cancer of the trachea, bronchus and lung accounted for 69% of
the 86 cancer deaths identified and was statistically significantly
elevated (O=59; E=29.16; SMR=202; 95% CI: 155-263).
Analysis of lung cancer deaths among hourly workers by year of
initial employment (1945-1949; 1950-1959 and 1960-1974), exposure
category (low exposure or questionable/high exposure) and duration of
employment (short term defined as 90 days-2 years; long term defined as
3 years +) was also conducted. For those workers characterized as
having questionable/high exposure, the SMRs were significantly elevated
for the 1945-1949 and the 1950-1959 hire periods and for both short-
and long-term workers (not statistically significant for the short-term
workers initially hired 1945-1949). For those characterized as low
exposure, there was an elevated SMR for the long-term workers hired
between 1950 and 1959, but based only on three deaths (not
statistically significant). No lung cancer cases were observed for
workers hired 1960-1974.
Case-control analyses of (1) a history of ever having been employed
in selected jobs or combinations of jobs or (2) a history of specified
morbid conditions and combinations of conditions reported on plant
medical records were conducted. Cases were defined as decedents (both
hourly and salaried were included in the analyses) whose underlying or
contributing cause of death was lung cancer. Controls were defined as
deaths from causes other than malignant or benign tumors. Cases and
controls were matched on race (white/non-white), year of initial
employment (+/-3 years), age at time of initial employment (+/-5 years)
and total duration of employment (90 days-2 years; 3-4 years and 5
years +). An odds ratio (OR) was determined where the ratio is the odds
of employment in a job involving Cr(VI) exposure for the cases relative
to the controls.
Based upon matched pairs, analysis by job position showed
significantly elevated odds ratios for special products (OR=2.6) and
bichromate and special products (OR=3.3). The relative risk for
bichromate alone was also elevated (OR=2.1, not statistically
significant).
The possible association of lung cancer and three health conditions
(skin ulcers, nasal perforation and dermatitis) as recorded in the
plant medical records was also assessed. Of the three medical
conditions, only the odds ratio for dermatitis was statistically
significant (OR=3.0). When various combinations of the three conditions
were examined, the odds ratio for having all three conditions was
statistically significantly elevated (OR=6.0).
Braver et al. used data from the Hayes study discussed above and
the results of 555 air samples taken during the period 1945-1950 by the
Baltimore City Health Department, the U.S. Public Health Service, and
the companies that owned the plant, in an attempt to examine the
relationship between exposure to Cr(VI) and the occurrence of lung
cancer (Ex. 7-17). According to the authors, methods for determining
the air concentrations of Cr(VI) have changed since the industrial
hygiene data were collected at the Baltimore plant between 1945 and
1959. The authors asked the National Institute for Occupational Safety
and Health (NIOSH) and the Occupational Safety and Health
Administration (OSHA) to review the available documents on the methods
of collecting air samples, stability of Cr(VI) in the sampling media
after collection and the methods of analyzing Cr(VI) that were used to
collect the samples during that period.
Air samples were collected by both midget impingers and high volume
samplers. According to the NIOSH/OSHA review, high volume samplers
could have led to a "significant" loss of Cr(VI) due to the reduction
of Cr(VI) to Cr(III) by glass or cellulose ester filters, acid
extraction of the chromate from the filter, or improper storage of
samples. The midget impinger was "less subject" to loss of Cr(VI)
according to the panel since neither filters nor acid extraction from
filters was employed. However, if iron was present or if the samples
were stored for too long, conversion from Cr(VI) to Cr(III) may have
occurred. The midget impinger can only detect water soluble Cr(VI). The
authors noted that, according to a 1949 industrial hygiene survey by
the U.S. Public Health Service, very little water insoluble Cr(VI) was
found at the Baltimore plant. One NIOSH/OSHA panel member characterized
midget impinger results as "reproducible" and "accuracy * * * fairly
solid unless substantial reducing agents (e.g., iron) are present"
(Ex. 7-17, p. 370). Based upon the panel's recommendations, the authors
used the midget impinger results to develop their exposure estimates
even though the panel concluded that the midget impinger methods "tend
toward underestimation" of Cr(VI).
The authors also cite other factors related to the industrial
hygiene data that could have potentially influenced the accuracy of
their exposure estimates (either overestimating or underestimating the
exposure). These include: Measurements may have been taken primarily in
"problem" areas of the plant; the plants may have been cleaned or
certain processes shut down prior to industrial hygiene monitoring by
outside groups; respirator use; and periodic high exposures (due to
infrequent maintenance operations or failure of exposure control
equipment) which were not measured and therefore not reflected in the
available data.
The authors estimated exposure indices for cohorts rather than for
specific individuals using hire period (1945-1949 or 1950-1959) and
duration of exposure, defined as short (at least 90 days but less than
three years) and long (three years or more). The usual exposure to
Cr(VI) for both the short- and long-term workers hired 1945-1949 was
calculated as the average of the mean annual air concentration for
1945-1947 and 1949 (data were missing for 1948). This was estimated to
be 413 [mu]g/m3. The usual exposure to Cr(VI) was estimated
to be 218 [mu]g/m3 for the short and long employees hired
between 1950 and 1959 based on air measurements in the older facility
in the early 1950s.
Cumulative exposure was calculated as the usual exposure level
times average duration. Short-term workers, regardless of length of
employment, were assumed to have received 1.6 years of exposure
regardless of hire period. For long-term workers, the average length of
exposure was 12.3 years. Those hired 1945-1949 were assigned five years
at an exposure of 413 [mu]g/m3 and 7.3 years at an exposure
of 218 [mu]g/m3. For the long-term workers hired between
1950 and 1959, the average length of exposure was estimated to be 13.4
years. The authors estimated that the cumulative exposures at which
"significant increases in lung cancer mortality" were observed in the
Hayes study were 0.35, 0.67, 2.93 and 3.65 mg/m3--years. The
association seen by the authors appears more likely to be the result of
duration of employment rather than the magnitude of exposure since the
variation in the latter was small.
Gibb et al. relied upon the Hayes study to investigate mortality in
a second cohort of the Baltimore plant (Ex. 31-22-11). The Hayes cohort
was composed of 1,803 hourly and 298 salaried workers newly employed
between January 1, 1945 and December 31, 1974. Gibb excluded 734
workers who began work prior to August 1, 1950 and included 990 workers
employed after August 1, 1950 who worked less than 90 days, resulting
in a cohort of 2,357 males followed for the period August 1, 1950
through December 31, 1992. Fifty-one percent (1,205) of the cohort was
white; 36% (848) nonwhite. Race was unknown for 13% (304) of the
cohort. The plant closed in 1985.
Deaths were coded according to the 8th revision of the
International Classification of Diseases. Person years of observation
were calculated from the beginning of employment until death or
December 31, 1992, whichever came earlier. Smoking data (yes/no) were
available for 2,137 (93.3%) of the cohort from company records.
Between 1950 and 1985, approximately 70,000 measurements of
airborne Cr(VI) were collected utilizing several different sampling
methods. The program of routine air sampling for Cr(VI) was initiated
to "characterize 'typical/usual exposures' of workers" (Ex. 31-22-11,
p. 117). Area samples were collected during the earlier time periods,
while both area and personal samples were collected starting in 1977.
Exposure estimates were derived from the area sampling systems and were
adjusted to "an equivalent personal exposure estimate using job-
specific ratios of the mean area and personal sampling exposure
estimates for the period 1978-1985 * * *" (Ex. 31-22-11, p. 117).
According to the author, comparison of the area and personal samples
showed "no significant differences" for about two-thirds of the job
titles. For several job titles with a "significant point source of
contamination" the area sampling methods "significantly
underestimated" personal exposure estimates and were adjusted "by the
ratio of the two" (Ex. 31-22-11, p. 118).
A job exposure matrix (JEM) was constructed, where air sampling
data were available, containing annual average exposure for each job
title. Data could not be located for the periods 1950-1956 and 1960-
1961. Exposures were modeled for the missing data using the ratio of
the measured exposure for a job title to the average of all measured
job titles in the same department. For the time periods where
"extensive" data were missing, a simple straight line interpolation
between years with known exposures was employed.
To estimate airborne Cr(III) concentrations, 72 composite dust
samples were collected at or near the fixed site air monitoring
stations about three years after the facility closed. The dust samples
were analyzed for Cr(VI) content using ion chromatography. Cr(III)
content was determined through inductively coupled plasma spectroscopic
analysis of the residue. The Cr(III):Cr(VI) ratio was calculated for
each area corresponding to the air sampling zones and the measured
Cr(VI) air concentration adjusted based on this ratio. Worker exposures
were calculated for each job title and weighted by the fraction of time
spent in each air-monitoring zone. The Cr(III):Cr(VI) ratio was derived
in this manner for each job title based on the distribution of time
spent in exposure zones in 1978. Cr(VI) exposures in the JEM were
multiplied by this ratio to estimate Cr(III) exposures.
Information on smoking was collected at the time of hire for
approximately 90% of the cohort. Of the 122 lung cancer cases, 116 were
smokers and four were non smokers at the time of hire. Smoking status
was unknown for two lung cancer cases. As discussed below, these data
were used by the study authors to adjust for smoking in their
proportional hazards regression models used to determine whether lung
cancer mortality in the worker cohort increased with increasing cumulative
Cr(VI) exposure.
A total of 855 observed deaths (472 white; 323 nonwhite and 60 race
unknown) were reported. SMRs were calculated using U.S. rates for
overall mortality. Maryland rates (the state in which the plant was
located) were used to analyze lung cancer mortality in order to better
account for regional differences in disease fatality. SMRs were not
adjusted for smoking. In the public hearing, Dr. Gibb explained that it
was more appropriate to adjust for smoking in the proportional hazards
models than in the SMRs, because the analyst must make more assumptions
to adjust the SMRs for smoking than to adjust the regression model (Tr.
124).
A statistically significant lung cancer SMR, based on the national
rate, was found for whites (O=71; SMR=186; 95% CI: 145-234); nonwhites
(O=47; SMR=188; 95% CI: 138-251) and the total cohort (O=122; SMR=180;
95% CI: 149-214). The ratio of observed to expected lung cancer deaths
(O/E) for the entire cohort stratified by race and cumulative exposure
quartile were computed. Cumulative exposure was lagged five years (only
exposure occurring five years before a given age was counted). The cut
point for the quartiles divided the cohort into four equal groups based
upon their cumulative exposure at the end of their working history (0-
0.00149 mgCrO\3\/m3-yr; 0.0015-0.0089 mgCrO3/m\3\-yr; 0.009-
0.0769 mgCrO3/m\3\-yr; and 0.077-5.25 mgCrO3/
m\3\-yr). For whites, the relative risk of lung cancer was
significantly elevated for the second through fourth exposure quartiles
with O/E values of 0.8, 2.1, 2.1 and 1.7 for the four quartiles,
respectively. For nonwhites, the O/E values by exposure quartiles were
1.1, 0.9, 1.2 and 2.9, respectively. Only the highest exposure quartile
was significantly elevated. For the total cohort, a significant
exposure-response trend was observed such that lung cancer mortality
increased with increasing cumulative Cr(VI) exposure.
Proportional hazards models were used to assess the relationship
between chromium exposure and the risk of lung cancer. The lowest
exposure quartile was used as the reference group. The median exposure
in each quartile was used as the measure of cumulative Cr(VI) exposure.
When smoking status was included in the model, relative lung cancer
risks of 1.83, 2.48 and 3.32 for the second, third and fourth exposure
quartiles respectively were estimated. Smoking, Cr(III) exposure, and
work duration were also significant predictors of lung cancer risk in
the model.
The analysis attempted to separate the effects into two
multivariate proportionate hazards models (one model incorporated the
log of cumulative Cr(VI) exposure, the log of cumulative Cr(III)
exposure and smoking; the second incorporated the log of cumulative
Cr(VI), work duration and smoking). In either regression model, lung
cancer mortality remained significantly associated (p < .05) with
cumulative Cr(VI) exposure even after controlling for the combination
of smoking and Cr(III) exposure or the combination of smoking and work
duration. On the other hand, lung cancer mortality was not
significantly associated with cumulative Cr(III) or work duration in
the multivariate analysis indicating lung cancer risk was more strongly
correlated with cumulative Cr(VI) exposure than the other variables.
Exponent, as part of a larger submission from the Chrome Coalition,
submitted comments on the Gibb paper prior to the publication of the
proposed rule. These comments asked that OSHA review methodological
issues believed by Exponent to impact upon the usefulness of the Gibb
data in a risk assessment analysis. While Exponent states that the Gibb
study offers data that "are substantially better for cancer risk than
the Mancuso study * * * they believe that further scrutiny of some of
the methods and analytical procedures is necessary (Ex. 31-18-15-1, p.
5).
The issues raised by Exponent and the Chrome Coalition (Ex. 31-18-
14) concerning the Gibb paper are: selection of the appropriate
reference population for compilation of expected numbers for use in the
SMR analysis; inclusion of short term workers (< 1 year); expansion of
the number of exposure groupings to evaluate dose response trends;
analyzing dose response by peak JEM exposure levels; analyzing dose-
response at exposures above and below the current PEL and calculating
smoking-adjusted SMRs for use in dose-response assessments. Exponent
obtained the original data from the Gibb study. The data were
reanalyzed to address the issues cited above. Exponent's findings are
presented in Exhibit 31-18-15-1 and are discussed below.
Exponent suggested that Gibb's use of U.S. and Maryland mortality
rates for developing expectations for the SMR analysis was
inappropriate. It suggested that Baltimore city mortality rates would
have been the appropriate standard to select since those mortality
rates would more accurately reflect the mortality experience of those
who worked at the plant. Exponent reran the SMR analysis to compare the
SMR values reported by Gibb (U.S. mortality rates for SMR analysis)
with the results of an SMR analysis using Maryland mortality rates and
Baltimore mortality rates. Gibb reported a lung cancer SMR of 1.86 (95%
CI: 1.45-2.34) for white males based upon 71 lung cancer deaths using
U.S. mortality rates. Reanalysis of the data produced a lung cancer SMR
of 1.85 (95% CI: 1.44-2.33) for white males based on U.S. mortality
rates, roughly the same value obtained by Gibb. When Maryland and
Baltimore rates are used, the SMR drops to 1.70 and 1.25 respectively.
Exponent suggested conducting sensitivity analysis that excludes
short-term workers (defined as those with one year of employment) since
the epidemiologic literature suggests that the mortality of short-term
workers is different than long-term workers. Short-term workers in the
Gibb study comprise 65% of the cohort and 54% of the lung cancers. The
Coalition also suggested that data pertaining to short-term employees'
information are of "questionable usefulness for assessing the
increased cancer risk from chronic occupational exposure to Cr(VI)"
(Ex. 31-18-15-1, p. 5).
Lung cancer SMRs were calculated for those who worked for less than
one year and for those who worked one year or more. Exponent defined
short-term workers as those who worked less than one year "because it
is consistent with the inclusion criteria used by others studying
chromate chemical production worker cohorts" (Ex. 31-18-15-1, p. 12).
Exponent also suggested that Gibb's breakdown of exposure by quartile
was not the most "appropriate" way of assessing dose-response since
cumulative Cr(VI) exposures remained near zero until the 50th to 60th
percentile, "so there was no real distinction between the first two
quartiles * * * (Ex. 31-18-15-1, p. 24). They also suggested that
combining "all workers together at the 75th quartile * * * does not
properly account for the heterogeneity of exposure in this group" (Ex.
31-18-15-1, p. 24). The Exponent reanalysis used six cumulative
exposure levels of Cr(VI) compared with the four cumulative exposure
levels of Cr(VI) in the Gibb analysis. The lower levels of exposure
were combined and "more homogeneous" categories were developed for
the higher exposure levels.
Using these re-groupings and excluding workers with less than one
year of employment, Exponent reported that the highest SMRs are seen in
the highest exposure group (1.5-< 5.25 mg CrO3/m\3\-years) for both white
and nonwhite, based on either the Maryland or the Baltimore mortality rates.
The authors did not find "that the inclusion of short-term workers had a
significant impact on the results, especially if Baltimore rates are used
in the SMR calculations' (Ex. 31-18-15-1, p. 28).
Analysis of length of employment and "peak" (i.e., highest
recorded mean annual) exposure level to Cr(VI) was conducted. Exponent
reported that approximately 50% of the cohort had "only very low"
peak exposure levels (<7.2 [mu]g CrO3/m\3\ or approximately
3.6 [mu]g/m\3\ of Cr(VI)). The majority of the short-term workers had
peak exposures of <100 [mu]g CrO3/m\3\. There were five peak
Cr(VI) exposure levels (<7.2 [mu]g CrO3/m\3\; 7.2-<19.3
[mu]g CrO3/m\3\; 19.3-<48.0 [mu]g CrO3/m\3\;
48.0-<105 [mu]g CrO3/m\3\; 105-<182 [mu]g CrO3/
m\3\; and 182-<806 [mu]g CrO3/m\3\) included in the
analyses. Overall, the lung cancer SMRs for the entire cohort grouped
according to the six peak exposure categories were slightly higher
using Maryland reference rates compared to Baltimore reference rates.
The Exponent analysis of workers who were ever exposed above the
current PEL versus those never exposed above the current PEL produced
slightly higher SMRs for those ever exposed, with the SMRs higher using
the Maryland standard rather than the Baltimore standard. The only
statistically significant result was for all lung cancer deaths
combined.
Assessment was made of the potential impact of smoking on the lung
cancer SMRs since Gibb did not adjust the SMRs for smoking. Exponent
stated that the smoking-adjusted SMRs are more appropriate for use in
the risk assessment than the unadjusted SMRs. It should be noted that
smoking adjusted SMRs could not be calculated using Baltimore reference
rates. As noted by the authors, the smoking adjusted SMRs produced
using Maryland reference rates are, by exposure, "reasonably
consistent with the Baltimore-referenced SMRs" (Ex. 31-18-15-1, p.
41).
Gibb et al. included workers regardless of duration of employment,
and the cohort was heavily weighted by those individuals who worked
less than 90 days. In an attempt to clarify this issue, Exponent
produced analyses of short-term workers, particularly with respect to
exposures. Exponent redefined short-term workers as those who worked
less than one year, to be consistent with the definition used in other
studies of chromate producers. OSHA finds this reanalysis excluding
short-term workers to be useful. It suggests that including cohort
workers employed less than one year did not substantively alter the
conclusions of Gibb et al. with regard to the association between
Cr(VI) exposure and lung cancer mortality. It should be noted that in
the Hayes study of the Baltimore plant, the cohort is defined as anyone
who worked 90 days or more.
Hayes et al. used Baltimore mortality rates while Gibb et al. used
U.S. mortality rates to calculate expectations for overall SMRs. To
calculate expectations for the analysis of lung cancer mortality and
exposure, Gibb et al. used Maryland state mortality rates. The SMR
analyses provided by Exponent using both Maryland and Baltimore rates
are useful. The data showed that using Baltimore rates raised the
expected number of lung cancer deaths and, thus, lowered the SMRs.
However, there remained a statistically significant increase in lung
cancer risk among the exposed workers and a significant upward trend
with cumulative Cr(VI) exposure. The comparison group should be as
similar as possible with respect to all other factors that may be
related to the disease except the determinant under study. Since the
largest portion of the cohort (45%) died in the city of Baltimore, and
even those whose deaths occurred outside of Baltimore (16%) most likely
lived in proximity to the city, the use of Baltimore mortality rates as
an external reference population is preferable.
Gibb's selection of the cut points for the exposure quartiles was
accomplished by dividing the workers in the cohort into four equal
groups based on their cumulative exposure at the end of their working
history. Using the same method but excluding the short-term workers
would have resulted in slightly different cumulative exposure
quartiles. Exponent expressed a preference for a six-tiered exposure
grouping. The impact of using different exposure groupings is further
discussed in section VI.C of the quantitative risk assessment.
The exposure matrix of Gibb et al. utilizes an unusually high-
quality set of industrial hygiene data. Over 70,000 samples taken to
characterize the "typical/usual" working environment is more
extensive industrial hygiene data then is commonly available for most
exposure assessments. However, there are several unresolved issues
regarding the exposure assessment, including the impact of the
different industrial hygiene sampling techniques used over the sampling
time frame, how the use of different sampling techniques was taken into
account in developing the exposure assessment and the use of area vs.
personal samples.
Exponent and the Chrome Coalition also suggested that the SMRs
should have been adjusted for smoking. According to Exponent, smoking
adjusted SMRs based upon the Maryland mortality rates produced SMRs
similar to the SMRs obtained using Baltimore mortality rates (Ex. 31-
18-15-1). The accuracy of the smoking data is questionable since it
represents information obtained at the time of hire. Hayes abstracted
the smoking data from the plant medical records, but "found it not to
be of sufficient quality to allow analysis." One advantage to using
the Baltimore mortality data may be to better control for the potential
confounding of smoking.
The Gibb study is one of the better cohort mortality studies of
workers in the chromium production industry. The quality of the
available industrial hygiene data and its characterization as
"typical/usual" makes the Gibb study particularly useful for risk
assessment.
b. Cohort Studies of the Painesville Facility. The Ohio Department of
Health conducted epidemiological and environmental studies at a plant
in Painesville that manufactured sodium bichromate from chromite ore.
Mancuso and Hueper (Ex. 7-12) reported an excess of respiratory cancer
among chromate workers when compared to the county in which the plant
was located. Among the 33 deaths in males who had worked at the plant
for a minimum of one year, 18.2% were from respiratory cancer. In
contrast, the expected frequency of respiratory cancer among males in
the county in which the plant was located was 1.2%. Although the
authors did not include a formal statistical comparison, the lung
cancer mortality rate among the exposed workers would be significantly
greater than the county rate.
Mancuso (Ex. 7-11) updated his 1951 study of 332 chromate
production workers employed during the period 1931-1937. Age adjusted
mortality rates were calculated by the direct method using the
distribution of person years by age group for the total chromate
population as the standard. Vital status follow-up through 1974 found
173 deaths. Of the 66 cancer deaths, 41 (62.1%) were lung cancers. A
cluster of lung cancer deaths was observed in workers with 27-36 years
since first employment.
Mancuso used industrial hygiene data collected in 1949 to calculate
weighted average exposures to water-soluble (presumed to be Cr(VI)),
insoluble (presumed to be principally Cr(III)) and
total chromium (Ex. 7-98). The age-adjusted lung cancer death rate
increased from 144.6 (based upon two deaths) to 649.6 (based upon 14
deaths) per 100,000 in five exposure categories ranging from a low of
0.25-0.49 to a high of 4.0+ mg/m\3\-years for the insoluble Cr(III)
exposures. For exposure to soluble Cr(VI), the age adjusted lung cancer
rates ranged from 80.2 (based upon three deaths) to 998.7 (based upon
12 deaths) in five exposure categories ranging from < 0.25 to 2.0+ mg/
m\3\-years. For total chromium, the age-adjusted death rates ranged
from 225.7 (based upon three deaths) to 741.5 (based upon 16 deaths)
for exposures ranging from 0.50-0.99 mg/m\3\-years to 6.0+ mg/m\3\-
years.
Age-adjusted lung cancer death rates also were calculated by
classifying workers by the levels of insoluble Cr(III) and total
chromium exposure. From the data presented, it appears that for a fixed
level of insoluble Cr(III), the lung cancer risk appears to increase as
the total chromium increases (Ex. 7-11).
Mancuso (Ex. 23) updated the 1975 study. As of December 31, 1993,
283 (85%) cohort members had died and 49 could not be found. Of the 102
cancer deaths, 66 were lung cancers. The age-adjusted lung cancer death
rate per 100,000 ranged from 187.9 (based upon four deaths) to 1,254.1
(based upon 15 deaths) for insoluble Cr(III) exposure categories
ranging from 0.25-0.49 to 4.00-5.00 mg/m\3\ years. For the highest
exposure to insoluble Cr(III) (6.00+ mg/m\3\ years) the age-adjusted
lung cancer death rate per 100,000 fell slightly to 1,045.5 based upon
seven deaths.
The age-adjusted lung cancer death rate per 100,000 ranged from
99.7 (based upon five deaths) to 2,848.3 (based upon two deaths) for
soluble Cr(VI) exposure categories ranging from < 0.25 to 4.00+ mg/m\3\
years. For total chromium, the age-adjusted lung cancer death rate per
100,000 ranged from 64.7 (based upon two deaths) to 1,106.7 (based upon
21 deaths) for exposure categories ranging from < 0.50 to 6.00+ mg/m\3\
years.
To investigate whether the increase in the lung cancer death rate
was due to one form of chromium compound (presumed insoluble Cr(III) or
soluble Cr(VI)), age-adjusted lung cancer mortality rates were
calculated by classifying workers by the levels of exposure to
insoluble Cr(III) and total chromium. For a fixed level of insoluble
Cr(III), the lung cancer rate appears to increase as the total chromium
increases for each of the six total chromium exposure categories,
except for the 1.00-1.99 mg/m\3\-years category. For the fixed exposure
categories for total chromium, increasing exposures to levels of
insoluble Cr(III) showed an increased age-adjusted death rate from lung
cancer in three of the six total chromium exposure categories.
For a fixed level of soluble Cr(VI), the lung cancer death rate
increased as total chromium categories of exposure increased for three
of the six gradients of soluble Cr(VI). For the fixed exposure
categories of total chromium, the increasing exposure to specific
levels of soluble Cr(VI) led to an increase in two of the six total
chromium exposure categories. Mancuso concluded that the relationship
of lung cancer is not confined solely to either soluble or insoluble
chromium. Unfortunately, it is difficult to attribute these findings
specifically to Cr(III) [as insoluble chromium] and Cr(VI) [as soluble
chromium] since it is likely that some slightly soluble and insoluble
Cr(VI) as well as Cr(III) contributed to the insoluble chromium
measurement.
Luippold et al. conducted a retrospective cohort study of 493
former employees of the chromate production plant in Painesville, Ohio
(Ex. 31-18-4). This Painesville cohort does not overlap with the
Mancuso cohort and is defined as employees hired beginning in 1940 who
worked for a minimum of one year at Painesville and did not work at any
other facility owned by the same company that used or produced Cr(VI).
An exception to the last criterion was the inclusion of workers who
subsequently were employed at a company plant in North Carolina (number
not provided). Four cohort members were identified as female. The
cohort was followed for the period January 1, 1941 through December 31,
1997. Thirty-two percent of the cohort worked for 10 or more years.
Information on potential confounders was limited. Smoking status
(yes/no) was available for only 35% of the cohort from surveys
administered between 1960 and 1965 or from employee medical files. For
those employees where smoking data were available, 78% were smokers
(responded yes on at least one survey or were identified as smokers
from the medical file). Information on race also was limited, the death
certificate being the primary source of information.
Results of the vital status follow-up were: 303 deaths; 132
presumed alive and 47 vital status unknown. Deaths were coded to the
9th revision of the International Classification of Diseases. Cause of
death could not be located for two decedents. For five decedents the
cause of death was only available from data collected by Mancuso and
was recoded from the 7th to the 9th revision of the ICD. There were no
lung cancer deaths among the five recoded deaths.
SMRs were calculated based upon two reference populations: The U.S.
(white males) and the state of Ohio (white males). Lung cancer SMRs
stratified by year of hire, duration of exposure, time since first
employment and cumulative exposure group also were calculated.
Proctor et al. analyzed airborne Cr(VI) levels throughout the
facility for the years 1943 to 1971 (the plant closed April 1972) from
800 area air sampling measurements from 21 industrial hygiene surveys
(Ex. 35-61). A job exposure matrix (JEM) was constructed for 22
exposure areas for each month of plant operation. Gaps in the matrix
were completed by computing the arithmetic mean concentration from area
sampling data, averaged by exposure area over three time periods (1940-
1949; 1950-1959 and 1960-1971) which coincided with process changes at
the plant (Ex. 31-18-1)
The production of water-soluble sodium chromate was the primary
operation at the Painesville plant. It involved a high lime roasting
process that produced a water insoluble Cr(VI) residue (calcium
chromate) as byproduct that was transported in open conveyors and
likely contributed to worker exposure until the conveyors were covered
during plant renovations in 1949. The average airborne soluble Cr(VI)
from industrial hygiene surveys in 1943 and 1948 was 0.72 mg/m\3\ with
considerable variability among departments. During these surveys, the
authors believe the reported levels may have underestimated total
Cr(VI) exposure by 20 percent or less for some workers due to the
presence of insoluble Cr(VI) dust.
Reductions in Cr(VI) levels over time coincided with improvements
in the chromate production process. Industrial hygiene surveys over the
period from 1957 to 1964 revealed average Cr(VI) levels of 270 [mu]g/
m\3\. Another series of plant renovations in the early 1960s lowered
average Cr(VI) levels to 39 [mu]g/m\3\ over the period from 1965 to
1972. The highest Cr(VI) concentrations generally occurred in the
shipping, lime and ash, and filtering operations while the locker
rooms, laboratory, maintenance shop and outdoor raw liquor storage
areas had the lowest Cr(VI) levels.
The average cumulative Cr(VI) exposure (mg/m\3\-yrs) for the cohort
was 1.58 mg/m\3\-yrs and ranged from 0.006 to 27.8 mg/m\3\-yrs. For
those who died from lung cancer, the average Cr(VI) exposure was 3.28
mg/m\3\-yrs and ranged from 0.06 to 27.8 mg/m\3\-yrs.
According to the authors, 60% of the cohort accumulated an estimated
Cr(VI) exposure of 1.00 mg/m\3\-yrs or less.
Sixty-three per cent of the study cohort was reported as deceased
at the end of the follow-up period (December 31, 1997). There was a
statistically significant increase for the all causes of death category
based on both the national and Ohio state standard mortality rates
(national: O=303; E=225.6; SMR=134; 95% CI: 120-150; state: O=303;
E=235; SMR=129; 95% CI: 115-144). Fifty-three of the 90 cancer deaths
were cancers of the respiratory system with 51 coded as lung cancer.
The SMR for lung cancer is statistically significant using both
reference populations (national O= 51; E=19; SMR 268; 95% CI: 200-352;
state O=51; E=21.2; SMR 241; 95% CI: 180-317).
SMRs also were calculated by year of hire, duration of employment,
time since first employment and cumulative Cr(VI) exposure, mg/m\3\-
years. The highest lung cancer SMRs were for those hired during the
earliest time periods. For the period 1940-1949, the lung cancer SMR
was 326 (O=30; E=9.2; 95% CI: 220-465); for 1950-1959, the lung cancer
SMR was 275 (O=15; E=5.5; 95% CI: 154-454). For the period 1960-1971,
the lung cancer SMR was just under 100 based upon six deaths with 6.5
expected.
Lung cancer SMRs based upon duration of employment (years)
increased as duration of employment increased. For those with one to
four years of employment, the lung cancer SMR was 137 based upon nine
deaths (E=6.6; 95% CI: 62-260); for five to nine years of employment,
the lung cancer SMR was 160 (O=8; E=5.0; 95% CI: 69-314). For those
with 10-19 years of employment, the lung cancer SMR was 169 (O=7;
E=4.1; 95% CI: 68-349), and for those with 20 or more years of
employment, the lung cancer SMR was 497 (O=27; E=5.4; 95% CI: 328-723).
Analyses of cumulative Cr(VI) exposure found the lung cancer SMR
(based upon the Ohio standard) in the highest exposure group (2.70-
27.80 mg/m\3\-yrs) was 463 (O=20; E=4.3; 95% CI: 183-398). In the 1.05-
2.69 mg/m\3\-yrs cumulative exposure group, the lung cancer SMR was 365
based upon 16 deaths (E=4.4; 95% CI: 208-592). For the cumulative
exposure groups 0.49-1.04, 0.20-0.48 and 0.00-0.19, the lung cancer
SMRs were 91 (O=4; E=4.4; 95% CI: 25-234; 184 (O=8; E=4.4; 95% CI: 79-
362) and 67 (O=3; E=4.5; 95% CI: 14-196). A test for trend showed a
strong relationship between lung cancer mortality and cumulative Cr(VI)
exposure (p=0.00002). The authors claim that the SMRs are also
consistent with a threshold effect since there was no statistically
significant trend for excess lung cancer mortality with cumulative
Cr(VI) exposures less than about 1 mg/m\3\-yrs. The issue of whether
the cumulative Cr(VI) exposure-lung cancer response is best represented
by a threshold effect is discussed further in preamble section VI on
the quantitative risk assessment.
The Painesville cohort is small (482 employees). Excluded from the
cohort were six employees who worked at other chromate plants after
Painesville closed. However, exceptions were made for employees who
subsequently worked at the company's North Carolina plant (number not
provided) because exposure data were available from the North Carolina
plant. Subsequent exposure to Cr(VI) by other terminated employees is
unknown and not taken into account by the investigators. Therefore, the
extent of the bias introduced is unknown.
The 10% lost to follow-up (47 employees) in a cohort of this size
is striking. Four of the forty-seven had "substantial" follow-up that
ended in 1997 just before the end date of the study. For the remaining
43, most were lost in the 1950s and 1960s (most is not defined). Since
person-years are truncated at the time individuals are lost to follow
up, the potential implication of lost person years could impact the
width of the confidence intervals.
The authors used U.S. and Ohio mortality rates for the standards to
compute the expectations for the SMRs, stating that the use of Ohio
rates minimizes bias that could occur from regional differences in
mortality. It is unclear why county rates were not used to address the
differences in regional mortality.
c. Other Cohort Studies. The first study of cancer of the respiratory
system in the U.S. chromate producing industry was reported by Machle
and Gregorius (Ex. 7-2). The study involved a total of 11,000 person-
years of observation between 1933 and 1947. There were 193 deaths; 42
were due to cancer of the respiratory system. The proportion of
respiratory cancer deaths among chromate workers was compared with
proportions of respiratory cancer deaths among Metropolitan Life
Insurance industrial policyholders. A non-significant excess
respiratory cancer among chromate production workers was found. No
attempt was made to control for confounding factors (e.g., age). While
some exposure data are presented, the authors state that one cannot
associate tumor rates with tasks (and hence specific exposures) because
of "shifting of personnel" and the lack of work history records.
Baetjer reported the results of a case-control study based upon
records of two Baltimore hospitals (Ex. 7-7). A history of working with
chromates was determined from these hospital records and the proportion
of lung cancer cases determined to have been exposed to chromates was
compared with the proportion of controls exposed. Of the lung cancer
cases, 3.4% had worked in a chromate manufacturing plant, while none of
the controls had such a history recorded in the medical record. The
results were statistically significant and Baetjer concluded that the
data confirmed the conclusions reached by Machle and Gregorius that
"the number of deaths due to cancer of the lung and bronchi is greater
in the chromate-producing industry than would normally be expected"
(Ex. 7-7, p. 516).
As a part of a larger study carried out by the U.S. Public Health
Service, the morbidity and mortality of male workers in seven U.S.
chromate manufacturing plants during the period 1940-1950 was reported
(Exs. 7-1; 7-3). Nearly 29 times as many deaths from respiratory cancer
(excluding larynx) were found among workers in the chromate industry
when compared to mortality rates for the total U.S. for the period
1940-1948. The lung cancer risk was higher at the younger ages (a 40-
fold risk at ages 15-45; a 30-fold risk at ages 45-54 and a 20-fold
risk at ages 55-74). Analysis of respiratory cancer deaths (excluding
larynx) by race showed an observed to expected ratio of 14.29 for white
males and 80 for nonwhite males.
Taylor conducted a mortality study in a cohort of 1,212 chromate
workers followed over a 24 year (1937-1960) period (Ex. 7-5). The
workers were from three chromate plants that included approximately 70%
of the total population of U.S. chromate workers in 1937. In addition,
the plants had been in continuous operation for the study period
(January 1, 1937 to December 31, 1960). The cohort was followed
utilizing records of Old Age and Survivors Disability Insurance
(OASDI). Results were reported both in terms of SMRs and conditional
probabilities of survival to various ages comparing the mortality
experience of chromate workers to the U.S. civilian male population. No
measures of chromate exposure were reported although results are
provided in terms of duration of employment. Taylor concluded that not
only was there an excess in mortality from respiratory cancer, but from
other causes as well, especially as duration of employment increased.
In a reanalysis of Taylor's data, Enterline excluded those workers
born prior to 1889 and analyzed the data by follow-up period using U.S.
rates (Ex. 7-4). The SMR for respiratory cancer for all time periods
showed a nine-fold excess (O=69 deaths; E=7.3). Respiratory cancer
deaths comprised 28% of all deaths. Two of the respiratory cancer
deaths were malignant neoplasms of the maxillary sinuses, a number
according to Enterline, "greatly in excess of that expected based on
the experience of the U.S. male population." Also slightly elevated
were cancers of the digestive organs (O=16; E=10.4) and non-malignant
respiratory disease (O=13; E=8.9).
Pastides et al. conducted a cohort study of workers at a North
Carolina chromium chemical production facility (Ex. 7-93). Opened in
1971, this facility is the largest chromium chemical production
facility in the United States. A low-lime process was used since the
plant began operation. Three hundred and ninety eight workers employed
for a minimum of one year between September 4, 1971 and December 31,
1989 comprised the study cohort. A self-administered employee
questionnaire was used to collect data concerning medical history,
smoking, plant work history, previous employment and exposure to other
potential chemical hazards. Personal air monitoring results for Cr(VI)
were available from company records for the period February 1974
through April 1989 for 352 of the 398 cohort members. A job matrix
utilizing exposure area and calendar year was devised. The exposure
means from the matrix were linked to each employee's work history to
produce the individual exposure estimates by multiplying the mean
Cr(VI) value from the matrix by the duration (time) in a particular
exposure area (job). Annual values were summed to estimate total
cumulative exposure.
Personal air monitoring indicated that TWA Cr(VI) air
concentrations were generally very low. Roughly half the samples were
less than 1 [mu]g/m3, about 75 percent were below 3 [mu]g/
m3, and 96 percent were below 25 [mu]g/m3. The
average worker's age was 42 years and mean duration of employment was
9.5 years. Two thirds of the workers had accumulated less than 0.01
[mu]g/m3-yr cumulative Cr(VI) exposure. SMRs were computed
using National, State (not reported) and county mortality rates (eight
adjoining North Carolina counties, including the county in which the
plant is located). Two of the 17 recorded deaths in the cohort were
from lung cancers. The SMRs for lung cancer were 127 (95% CI: 22-398)
and 97 (95% CI: 17-306) based on U.S. and North Carolina county
mortality rates, respectively. The North Carolina cohort is still
relatively young and not enough time has elapsed to reach any
conclusions regarding lung cancer risk and Cr(VI) exposure.
In 2005, Luippold et al. published a study of mortality among two
cohorts of chromate production workers with low exposures (Ex. 47-24-
2). Luippold et al. studied a total of 617 workers with at least one
year of employment, including 430 at the North Carolina plant studied
by Pastides et al. (1994) ("Plant 1") and 187 hired after the 1980
institution of exposure-reducing process and work practice changes at a
second U.S. plant ("Plant 2"). A high-lime process was never used at
Plant 1, and workers drawn from Plant 2 were hired after the
institution of a low lime process, so that exposures to calcium
chromate in both cohorts were likely minimal. Personal air-monitoring
measures available from 1974 to 1988 for the first plant and from 1981
to 1998 for the second plant indicated that exposure levels at both
plants were low, with overall geometric mean concentrations below 1.5
[mu]g/m3 and area-specific average personal air sampling
values not exceeding 10 [mu]g/m3 for most years (Ex. 47-24-
2, p. 383).
Workers were followed through 1998. By the end of follow-up, which
lasted an average of 20.1 years for workers at Plant 1 and 10.1 years
at Plant 2, 27 cohort members (4%) were deceased. There was a 41%
deficit in all-cause mortality when compared to all-cause mortality
from age-specific state reference rates, suggesting a strong healthy
worker effect. Lung cancer was 16% lower than expected based on three
observed vs. 3.59 expected cases, also using age-specific state
reference rates (Ex. 47-24-2, p. 383). The authors stated that "[t]he
absence of an elevated lung cancer risk may be a favorable reflection
of the postchange environment", but cautioned that longer follow-up
allowing an appropriate latency for the entire cohort would be required
to confirm this conclusion (Ex. 47-24-2, p. 381). OSHA received several
written testimony regarding this cohort during the post-hearing comment
period. These are discussed in section VI.B.7 on the quantitative risk
assessment.
A study of four chromate producing facilities in New Jersey was
reported by Rosenman (Ex. 35-104). A total of 3,408 individuals were
identified from the four facilities over different time periods (plant
A from 1951-1954; plant B from 1951-1971; plant C from 1937-1964 and
plant D 1937-1954). No Cr(VI) exposure data was collected for this
study. Proportionate mortality ratios (PMRs) and proportionate cancer
mortality ratios (PCMRs), adjusted by race, age, and calendar year,
were calculated for the three companies (plants A and B are owned by
one company). Unlike SMRs, PMRs are not based on the expected mortality
rates in a standardized population but, instead, merely represent the
proportional distribution of deaths in the cohort relative to the
general U.S. population. Analyses were done evaluating duration of work
and latency from first employment.
Significantly elevated PMRs were seen for lung cancer among white
males (170 deaths, PMR=1.95; 95% CI: 1.67-2.27) and black males (54
deaths, PMR=1.88; 95% CI: 1.41-2.45). PMRs were also significantly
elevated (regardless of race) for those who worked 1-10, 11-20 and >20
years and consistently higher for white and black workers 11-20 years
and >20 years since first hire. The results were less consistent for
those with 10 or fewer years since first hire.
Bidstrup and Case reported the mortality experience of 723 workers
at three chromate producing factories in Great Britain (Ex. 7-20). Lung
cancer mortality was 3.6 times that expected (O=12; E=3.3) for England
and Wales. Alderson et al. conducted a follow-up of workers from the
three plants in the U.K. (Bolton, Rutherglen and Eaglescliffe)
originally studied by Bidstrup (Ex. 7-22). Until the late 1950s, all
three plants operated a "high-lime" process. This process potentially
produced significant quantities of calcium chromate as a by-product as
well as the intended sodium dichromate. Process changes occurred during
the 1940s and 1950s. The major change, according to the author, was the
introduction of the "no-lime" process, which eliminated unwanted
production of calcium chromate. The no-lime process was introduced at
Eaglescliffe 1957-1959 and by 1961 all production at the plant was by
this process. Rutherglen operated a low-lime process from 1957/1959
until it closed in 1967. Bolton never changed to the low lime process.
The plant closed in 1966. Subjects were eligible for entry into the
study if they had received an X-ray examination at work and had been
employed for a minimum of one year between 1948 and 1977. Of the 3,898
workers enumerated at the three plants, 2,715 met the cohort entrance
criteria, (alive: 1,999; deceased: 602; emigrated: 35; and lost to
follow-up: 79). Those lost to follow-up were not included in the
analyses. Eaglescliffe contributed the greatest number of subjects to
the study (1,418). Rutherglen contributed the largest number of total
deaths (369, or 61%). Lung cancer comprised the majority of cancer deaths
and was statistically significantly elevated for the entire cohort
(O=116; E=47.96; SMR= 240; p < 0.001). Two deaths from nasal cancer were
observed, both from Rutherglen.
SMRs were computed for Eaglescliffe by duration of employment,
which was defined based upon plant process updates (those who only
worked before the plant modification, those who worked both before and
after the modifications, or those who worked only after the
modifications were completed). Of the 179 deaths at the Eaglescliffe
plant, 40 are in the pre-change group; 129 in the pre-/post-change and
10 in the post-change. A total of 36 lung cancer deaths occurred at the
plant, in the pre-change group O=7; E=2.3; SMR=303; in the pre-/post-
change group O=27; E=13; SMR=2.03 and in the post-change group O=2;
E=1.07; SMR=187.
In an attempt to address several potential confounders, regression
analysis examined the contributions of various risk factors to lung
cancer. Duration of employment, duration of follow-up and working
before or after plant modification appear to be greater risk factors
for lung cancer, while age at entry or estimated degree of chromate
exposure had less influence.
Davies updated the work of Alderson, et al. concerning lung cancer
in the U.K. chromate producing industry (Ex. 7-99). The study cohort
included payroll employees who worked a minimum of one year during the
period January 1, 1950 and June 30, 1976 at any of the three facilities
(Bolton, Eaglescliffe or Rutherglen). Contract employees were excluded
unless they later joined the workforce, in which case their contract
work was taken into account.
Based upon the date of hire, the workers were assigned to one of
three groups. The first, or "early" group, consists of workers hired
prior to January 1945 who are considered long term workers, but do not
comprise a cohort since those who left or died prior to 1950 are
excluded. The second group, "pre-change" workers, were hired between
January 1, 1945 to December 31, 1958 at Rutherglen or to December 31,
1960 at Eaglescliffe. Bolton employees starting from 1945 are also
termed pre-change. The cohort of pre-change workers is considered
incomplete since those leaving 1946-1949 could not be included and
because of gaps in the later records. For those who started after 1953
and for all men staying 5+ years, this subcohort of pre-change workers
is considered complete. The third group, "post-change" workers,
started after the process changes at Eaglescliffe and Rutherglen became
fully effective and are considered a "complete" cohort. A "control"
group of workers from a nearby fertilizer facility, who never worked in
or near the chromate plant, was assembled.
A total of 2,607 employees met the cohort entrance criteria. As of
December 31, 1988, 1,477 were alive, 997 dead, 54 emigrated and 79
could not be traced (total lost to follow-up: 133). SMRs were
calculated using the mortality rates for England and Wales and the
mortality rates for Scotland. Causes of death were ascertained for all
but three decedents and deaths were coded to the revision of the
International Classification of Diseases in effect at the time of
death. Lung cancer in this study is defined as those deaths where the
underlying cause of death is coded as 162 (carcinoma of the lung) or
239.1 (lung neoplasms of unspecified nature) in the 9th revision of the
ICD. Two deaths fell into the latter category. The authors attempted to
adjust the national mortality rates to allow for differences based upon
area and social class.
There were 12 lung cancer deaths at Bolton, 117 at Rutherglen, 75
at Eaglescliffe and one among staff for a total of 205 lung cancer
deaths. A statistically significant excess of lung cancer deaths (175
deaths) among early and pre-change workers is seen at Rutherglen and
Eaglescliffe for both the adjusted and unadjusted SMRs. For Rutherglen,
for the early period based upon 68 observed deaths, the adjusted SMR
was 230 while the unadjusted SMR was 347 (for both SMRs p< 0.001). For
the 41 pre-change lung cancer deaths at Rutherglen, the adjusted SMR
was 160 while the unadjusted SMR was 242 (for both SMRs p< 0.001). At
Eaglescliffe, there were 14 lung cancer deaths in the early period
resulting in an adjusted SMR of 196 and an unadjusted SMR of 269 (for
both SMRs p< 0.05). For the pre-change period at Eaglescliffe, the
adjusted SMR was 195 and the unadjusted was 267 (p< 0.001 for both
SMRs). At Bolton there is a non-significant excess among pre-change
men. There are no apparent excesses in the post-change groups, the
staff groups or in the non-exposed fertilizer group.
There is a highly significant overall excess of nasal cancers with
two cases at Eaglescliffe and two cases at Rutherglen (O=4,
Eadjusted=0.26; SMR=1538). All four men with nasal cancer had more than
20 years of exposure to chromates.
Aw reported on two case-control studies conducted at the previously
studies Eaglescliffe plant (Ex. 245). In 1960, the plant, converted
from a "high-lime" to a "no-lime" process, reducing the likelihood
of calcium chromate formation. As of March 1996, 2,672 post-change
workers had been employed, including 891 office personnel. Of the post-
change plant personnel, 56% had been employed for more than one year.
Eighteen lung cancer cases were identified among white male post-change
workers (13 deceased; five alive). Duration of employment for the cases
ranged from 1.5 to 25 years with a mean of 14.4. Sixteen of the lung
cancer cases were smokers.
In the first case-control study reported, the 15 lung cancer cases
identified up to September 1991 were matched to controls by age and
hire date (five controls per case). Cases and controls were compared
based upon their job categories within the plant. The results showed
that cases were more likely to have worked in the kiln area than the
controls. Five of the 15 cases had five or more years in the kiln area
where Cr(VI) exposure occurred vs. six of the 75 controls. A second
case-control study utilized the 18 lung cancer cases identified in post
change workers up to March 1996. Five controls per case were matched by
age (+/-5 years), gender and hire date. Both cases and controls had a
minimum of one year of employment. A job exposure matrix was being
constructed that would allow the investigators to "estimate exposure
to hexavalent chromates for each worker in the study for all the jobs
done since the start of employment at the site until 1980." Starting
in 1970 industrial hygiene sampling was performed to determine exposure
for all jobs at the plant. Cr(VI) exposure levels for the period
between 1960 and 1969 were being estimated based on the recall of
employees regarding past working conditions relative to current
conditions from a questionnaire. The author stated that preliminary
analysis suggests that the maximum recorded or estimated level of
exposure to Cr(VI) for the cases was higher than that of the controls.
However, specific values for the estimated Cr(VI) exposures were not
reported.
Korallus et al. conducted a study of 1,140 active and retired
workers with a minimum of one year of employment between January 1,
1948 and March 31, 1979 at two German chromate production plants (Ex.
7-26). Workers employed prior to January 1, 1948 (either active or
retired) and still alive at that date were also included in the cohort.
The primary source for determining cause of death was medical
records. Death certificates were used only when medical records could
not be found. Expected deaths were calculated using the male population
of North Rhineland-Westphalia. Elevated SMRs for cancer of the
respiratory system (50 lung cancers and one laryngeal cancer) were seen
at both plants (O=21; E=10.9; SMR=192 and O=30; E=13.4; SMR=224).
Korallus et al. reported an update of the study. The cohort
definition was expanded to include workers with one year of employment
between January 1, 1948 and December 31, 1987 (Ex. 7-91). One thousand
four hundred and seventeen workers met the cohort entrance criteria and
were followed through December 31, 1988. While death certificates were
used, where possible, to obtain cause of death, a majority of the cause
of death data was obtained from hospital, surgical and general
practitioner reports and autopsies because of Germany's data protection
laws. Smoking data for the cohort were incomplete.
Process modifications at the two plants eliminated the high-lime
process by January 1, 1958 at one location and January 1, 1964 at the
second location. In addition, technical measures were introduced which
led to reductions in the workplace air concentrations of chromate
dusts. Cohort members were divided into pre- and post-change cohorts,
with subcohorts in the pre-change group. SMRs were computed with the
expected number of deaths derived from the regional mortality rates
(where the plants are located). One plant had 695 workers (279 in the
pre-change group and 416 in the post change group). The second plant
had 722 workers (460 in the pre-change group and 262 in the post-change
group). A total of 489 deaths were ascertained (225 and 264 deaths). Of
the cohort members, 6.4% were lost to follow-up.
Lung cancer is defined as deaths coded 162 in the 9th revision of
the International Classification of Diseases. There were 32 lung cancer
deaths at one plant and 43 lung cancer deaths at the second plant. Lung
cancer SMRs by date of entry (which differ slightly by plant) show
elevated but declining SMRs for each plant, possibly due to lower
Cr(VI) exposure as a result of improvements in production process. The
lung cancer SMR for those hired before 1948 at Plant 1 is statistically
significant (O=13; SMR=225; 95% CI: 122-382). The overall lung cancer
SMR for Plant 1 is also statistically significantly elevated based upon
32 deaths (SMR=175; 95% CI: 120-246). At Plant 2, the only lung cancer
SMR that is not statistically significant is for those hired after 1963
(based upon 1 death). Lung cancer SMRs for those hired before 1948
(O=23; SMR=344; 95% CI: 224-508) and for those hired between 1948 and
1963 (O=19; SMR=196; 95% CI: 1.24-2.98) are statistically significantly
elevated. The overall lung cancer SMR at Plant 2 based upon 43 deaths
is 239 (95% CI: 177-317). No nasal cavity neoplasms were found. A
statistically significant SMR for stomach cancer was observed at Plant
2 (O=12; SMR=192; 95% CI: 104-324).
Recently, the mortality experience of the post-change workers
identified by Korallus et al. was updated in a study by Birk et al.
(Ex. 48-4). The study cohort consisted of 901 post-change male workers
from two German chromate production plants (i.e. 472 workers and 262
workers, respectively) employed for at least one year. Review of
employment records led to the addition of employees to the previous
Korallus cohort. Mortality experience of the cohort was evaluated
through 1998. A total of 130 deaths were ascertained, of which 22 were
due to cancer of the lung. Four percent of the cohort was lost to
follow-up. Specific cause of death could not be determined for 14
decedents. The mean duration of Cr(VI) exposure was 10 years and the
mean time since first exposure was 17 years. The proportion of workers
who ever smoked was 65 percent.
The cohort lacked sufficient job history information and air
monitoring data to develop an adequate job-exposure matrix required to
estimate individual airborne exposures (Ex. 48-1-2). Instead, the
researchers used the over 12,000 measurements of urinary chromium from
routine biomonitoring of plant employees collected over the entire
study period to derive individual cumulative urinary chromium estimates
as an exposure surrogate. The approximate geometric average of all
urinary chromium measurements in the two German plants from 1960 to
1998 was 7-8 [mu]g/dl (Ex. 48-1-2, Table 5). There was a general plant-
wide decline in average urinary chromium over time from 30 to 50 [mu]g/
dl in the 1960s to less than 5 [mu]g/dl in the 1990s (Ex. 48-4, Figure
1). However, there was substantial variation in urinary chromium by
work location and job group.
The study reported a statistically significant deficit in all cause
mortality (SMR=80 95% CI: 67-95) and mortality due to heart disease
(SMR=66 95% CI: 45-93) based on the age- and calendar year-adjusted
German national population rates indicating a healthy worker
population. However, the SMR for lung cancer mortality was elevated
(SMR=148 95% CI: 93-225) against the same reference population (Ex. 48-
4, Table 2). There was a statistically significant two-fold excess lung
cancer mortality (SMR=209; 95% CI: 108-365; 12 observed lung cancer
deaths) among workers in the highest cumulative exposure grouping (i.e.
>200 [mu]g Cr/L-yr). There was no increase in lung cancer mortality in
the lower exposure groups, but the number of lung cancer deaths was
small (i.e. < =5 deaths) and the confidence intervals were wide.
There were no obvious trends in lung cancer mortality with
employment duration or time since first employed, but the results were,
again, limited by the small number of study subjects per group.
Logistic regression analysis showed that cumulative urinary chromium >=
200 [mu]g Cr/L-yr was associated with a significantly higher risk of
lung cancer death (OR=6.9; 95% CI: 2.6-18.2) when compared against
workers exposed to lower cumulative urinary chromium exposures. This
risk was unchanged after controlling for smoking status indicating that
the elevated risks were unlikely to be confounded by smoking. Including
a peak exposure score to the regression analysis did not result in
additional risk beyond that associated with cumulative exposure alone.
Some commenters felt this German post-change cohort provided evidence
for an exposure threshold below which there is no risk of lung cancer.
This issue is addressed in Section VI.B.7 of the quantitative risk
assessment.
DeMarco et al. conducted a cohort study of chromate production
workers in northern Italy to assess the existence of excess risk of
respiratory cancer, specifically lung cancer (Ex. 7-54). The cohort was
defined as males who worked for a minimum of one year from 1948 to 1985
and had at least 10 years of follow-up. Five hundred forty workers met
the cohort definition. Vital status follow-up, carried out through June
30, 1985, found 427 cohort members alive, 110 dead and three lost to
follow-up. Analysis utilizing SMRs based on Italian national rates was
conducted. Of the 110 deaths, 42 were cancer deaths. The statistically
significant SMR for lung cancer based upon 14 observed deaths with 6.46
expected was 217 (95% CI: 118-363).
Exposure estimates were based upon the duration of cumulative
exposure and upon a risk score (low, medium, high and not assessed)
assigned to the department in which the worker was primarily employed.
A committee assigned the scores, based upon knowledge of the production
process or on industrial hygiene surveys taken in 1974, 1982 and 1984.
The risk score is a surrogate for the workplace concentrations of Cr(VI)
in the different plant departments. Since no substantial changes had been
made since World War II, the assumption was made that exposures remained
relatively stable. Lung cancer SMRs based upon type of exposure increased
with level of exposure (Low: O=1; E=1.43; SMR=70; Medium: O=5; E=202; SMR=2.48;
High: O=6; E=1.4; SMR=420; Not Assessed: O=2; E=1.6; SMR=126). Only the SMR
for those classified as having worked in departments characterized as high
exposure was statistically significant at the p< 0.05 level.
A cohort study of workers at a chromium compounds manufacturing
plant in Tokyo, Japan by Satoh et al. included males employed between
1918 and 1975 for a minimum of one year and for whom the necessary data
were available (Ex. 7-27). Date and cause of death data were obtained
from the death certificate (85%) or from other "reliable" written
testimony (15%). Of the 1,061 workers identified, 165 were excluded
from the study because information was missing. A total of 896 workers
met the cohort inclusion criteria and were followed through 1978. The
causes of 120 deaths were ascertained. SMRs based on age-cause specific
mortality for Japanese males were calculated for four different time
periods (1918-1949; 1950-1959; 1960-1969 and 1970-1978) and for the
entire follow-up period (1918-1978). An elevated SMR for lung cancer is
seen for the entire follow-up period (O=26; E=2.746; SMR=950). A
majority of the lung cancer deaths (20) occurred during the 1970-1978
interval.
Results from the many studies of chromate production workers from
different countries indicate a relationship between exposure to
chromium and malignant respiratory disease. The epidemiologic studies
done between 1948 and 1952 by Machle and Gregorius (Ex. 7-2), Mancuso
and Hueper (Ex. 7-12) and Brinton, et al. (Ex. 7-1) suggest a risk for
respiratory cancer among chromate workers between 15 and 29 times
expectation. Despite the potential problems with the basis for the
calculations of the expectations or the particular statistical methods
employed, the magnitude of the difference between observed and expected
is powerful enough to overcome these potential biases.
It is worth noting that the magnitude of difference in the relative
risks reported in a mortality study among workers in three chromate
plants in the U.K. (Ex.7-20) were lower than the relative risks
reported for chromate workers in the U.S. during the 1950s and 1960s.
The observed difference could be the result of a variety of factors
including different working conditions in the two countries, a shorter
follow-up period in the British study, the larger lost-to-follow-up in
the British study or the different statistical methods employed. While
the earlier studies established that there was an excess risk for
respiratory cancer from exposure to chromium, they were unable to
specify either a specific chromium compound responsible or an exposure
level associated with the risk. Later studies were able to use superior
methodologies to estimate standardized lung cancer mortality ratios
between chromate production cohorts and appropriate reference
populations (Exs. 7-14; 7-22; 7-26; 7-99; 7-91). These studies
generally found statistically increased lung cancer risk of around two-
fold. The studies usually found trends with duration of employment,
year of hire, or some production process change that tended to
implicate chromium exposure as the causative agent.
Some of the most recent studies were able to use industrial hygiene
data to reconstruct historical Cr(VI) exposures and show statistically
significant associations between cumulative airborne Cr(VI) and lung
cancer mortality (Exs. 23; 31-22-11; Ex. 31-18-4). Gibb et al. found
the significant association between Cr(VI) and lung cancer was evident
in models that accounted for smoking. The exposure'response
relationship from these chromate production cohorts provide strong
evidence that occupational exposure to Cr(VI) dust can increase cancer
in the respiratory tract of workers.
The Davies, Korallus, (German cohort), Luippold (2003), and
Luippold (2005) studies examine mortality patterns at chromate
producing facilities where one production process modification involved
conversion from a high-lime to a low-lime or a lime-free process (Exs.
7-99; 7-91; 31-18-4). In addition to process modification, technical
improvements also were implemented that lowered Cr(VI) exposure. One of
the plants in the Davies study retained the high-lime process and is
not discussed. The lung cancer SMRs for one British plant and both of
the German plants decline from early, to pre-change to post change time
periods. In the remaining British plants, the lung cancer SMR is
basically identical for the early and pre-change period, but does
decline in the post-change time period. The lung cancer SMR in the
Luippold 2003 cohort also declined over time as the amount of lime was
reduced in the roasting process. Other modifications at the Painesville
plant that reduced airborne Cr(VI) exposure, such as installation of
covered conveyors and conversion from batch to continuous process,
occurred at the same time (Ex. 35-61). The workers in the Luippold
(2005) study were not exposed to Cr(VI) in facilities using a high-lime
process. This study did not show excess risk; however, this may be a
consequence of short follow-up time (< 20 years for most workers) or
the small size of the study (< 4 expected lung cancers), as discussed
further in Section VI.B.7. In general, it is not clear whether reduced
levels of the high-lime byproduct, calcium chromate, or the roasting/
leaching end product, sodium dichromate, that resulted from the various
process changes is the reason for the decrease in lung cancer SMRs in
these cohorts. It should be noted that increased lung cancer risk was
experienced by workers at the Baltimore plant (e.g., Hayes and Gibb
cohorts) even though early air monitoring studies suggest that a high
lime process was probably not used at this facility (Ex. 7-17).
2. Evidence From Chromate Pigment Production Workers
Chromium compounds are used in the manufacture of pigments to
produce a wide range of vivid colors. Lead and zinc chromates have
historically been the predominant hexavalent chromium pigments,
although others such as strontium and barium chromate have also been
produced. These chromates vary considerably in their water solubility
with lead and barium chromates being the most water insoluble. All of
the above chromates are less water-soluble than the highly water-
soluble sodium chromate and dichromate that usually serve as the
starting material for chromium pigment production. The reaction of
sodium chromate or dichromate with the appropriate zinc or lead
compound to form the corresponding lead or zinc chromate takes place in
solution. The chromate pigment is then precipitated, separated, dried,
milled, and packaged. Worker exposures to chromate pigments are
greatest during the milling and packaging stages.
There have been a number of cohort studies of chromate pigment
production workers from the United States, the United Kingdom, France,
Germany, the Netherlands, Norway and Japan. Most of the studies found
significantly elevated lung cancers in workers exposed to Cr(VI)
pigments over many years when compared against standardized reference
populations. In general, the studies of chromate pigment workers lack
the historical exposure data found in some of the chromate production
cohorts. The consistently higher lung cancers across several worker
cohorts exposed to the less water-soluble Cr(VI) compounds complements
the lung cancer findings from the studies of workers producing highly
water soluble chromates and adds to the further evidence that occupational
exposure to Cr(VI) compounds should be regarded as carcinogenic. A summary
of selected human epidemiologic studies in chromate production workers is
presented in Table V-2.
BILLING CODE 4510-26-P
Click here to view table V-2
BILLING CODE 4510-26-C
Langard and Vigander updated a cohort study of lung cancer
incidence in 133 workers employed by a chromium pigment production
company in Norway (Ex. 7-36). The cohort was originally studied by
Langard and Norseth (Ex. 7-33). Twenty four men had more than three
years of exposure to chromate dust. From 1948, when the company was
founded, until 1951, only lead chromate pigment was produced.
From 1951 to 1956, both lead chromate and zinc chromate pigments were
produced and from 1956 to the end of the study period in 1972 only zinc
chromate was produced. Workers were exposed to chromates both as the
pigment and its raw material, sodium dichromate.
The numbers of expected lung cancers in the workers were calculated
using the age-adjusted incidence rates for lung cancer in the Norwegian
male population for the period 1955-1976. Follow-up using the Norwegian
Cancer Registry through December 1980, found the twelve cancers of
which seven were lung cancers. Six of the seven lung cancers were
observed in the subcohort of 24 workers who had been employed for more
than three years before 1973. There was an increased lung cancer
incidence in the subcohort based on an observed to expected ratio of 44
(O=6; E=0.135). Except for one case, all lung cancer cases were exposed
to zinc chromates and only sporadically to other chromates. Five of the
six cases were known to be smokers or ex-smokers. Although the authors
did not report any formal statistical comparisons, the extremely high
age-adjusted standardized incidence ratio suggests that the results
would likely be statistically significant.
Davies reported on a cohort study of English chromate pigment
workers at three factories that produced chromate pigments since the
1920s or earlier (Ex. 7-41). Two of the factories produced both zinc
and lead chromate. Both products were made in the same sheds and all
workers had mixed exposure to both substances. The only product at the
third factory was lead chromate.
Cohort members are defined as males with a minimum of one year of
employment first hired between 1933 and 1967 at plant A; 1948 and 1967
at plant B and 1946-1961 at plant C. The analysis excludes men who
entered employment later than 1967 because of the short follow-up
period. Three hundred and ninety six (396) men from Factory A, 136 men
from Factory B and 114 men from Factory C were followed to mid-1977.
Ninety-four workers with 3-11 months employment during 1932-1945 at
Factory A were also included. Expectations were based upon calendar
time period-, gender- and age-specific national cancer death rates for
England and Wales. The author adjusted the death rates for each factory
for local differences, but the exact methods of adjustment were not
explicit.
Exposure to chromates was assigned as high for those in the dry
departments where pigments were ground, blended and packed; medium for
those in the wet departments where precipitates were washed, pressed
and stove dried and in maintenance or cleaning which required time in
various departments; or low for those jobs which the author states
involved "slight exposure to chromates such as most laboratory jobs,
boiler stoking, painting and bricklaying" (Ex. 7-41, p. 159). The high
and medium exposure categories were combined for analytical purposes.
For those entering employment from 1932 to 1954 at Factory A, there
were 18 lung cancer deaths in the high/medium exposure group, with 8.2
deaths expected. The difference is significant at p< .01. In the low
exposure group, the number of observed and expected lung cancer deaths
was equal (two deaths). There were no lung cancer deaths at Factory A
for those hired between 1955-1960 and 1961-1967.
For those entering employment between 1948 and 1967 at Factory B,
there were seven observed lung cancer deaths in the high/medium
exposure group with 1.4 expected which is statistically significant at
p< .001. At Factory C (which manufactured only lead chromate), there was
one death in the high/medium exposure group and one death in the low
exposure group for those beginning employment between 1946 and 1967.
The author points out that:
There has been no excess lung cancer mortality amongst workers
with chromate exposure rated as "low", nor among those exposed
only to lead chromate. High and medium exposure-rated workers who in
the past had mixed exposure to both lead and zinc chromate have
experienced a marked excess of lung cancer deaths, even if employed
for as little as one year (Ex. 7-41, p. 157).
It is the author's opinion that the results "suggest that the
manufacture of zinc chromate may involve a lung cancer hazard" (Ex. 7-
41, p. 157).
Davies updated the lung cancer mortality at the three British
chromate pigment production factories (Ex. 7-42). The follow-up was
through December 31, 1981. The cohort was expanded to include all male
workers completing one year of service by June 30, 1975 but excluded
office workers.
Among workers at Factory A with high and medium exposure, mortality
was statistically significantly elevated over the total follow-up
period among entrants hired from 1932 to 1945 (O/E=2.22). A similar,
but not statistically significant, excess was seen among entrants hired
from 1946 to 1954 (O/E=2.23). The results for Factory B showed
statistically significantly elevated lung cancer mortality among
workers classified with medium exposures entering service during the
period from 1948 to 1960 (O/E=3.73) and from 1961 to 1967 (O/E=5.62).
There were no lung cancer deaths in the high exposure group in either
time period. At Factory C, analysis by entry date (early entrant and
the period 1946-1960) produced no meaningful results since the number
of deaths was small. When the two periods are combined, the O/E was
near unity. The author concluded that in light of the apparent absence
of risk at Factory C, "it seems reasonable to suggest that the hazard
affecting workers with mixed exposures at factories A and B * * * is
attributable to zinc chromates" (Ex. 7-42, p. 166). OSHA disagrees
with this conclusion, as discussed in section V.9.
Davies also studied a subgroup of 57 chromate pigment workers,
mostly employed between 1930 and 1945, who suffered clinical lead
poisoning (Ex. 7-43). Followed through 1981, there was a statistically
significantly elevated SMR for lung cancer based upon four cases (O=4;
E=2.8; SMR=145).
Haguenoer studied 251 French zinc and lead chromate pigment workers
employed for six months or more between January 1, 1958 and December
31, 1977 (Ex. 7-44). As of December 31, 1977, 50 subjects were
identified as deceased. Cause of death was obtained for 30 of the 50
deaths (60%). Lung cancer mortality was significantly elevated based on
11 fatalities (SMR=461; 95% CI: 270-790). The mean time from first
employment until detection of cancer was 17 years. The mean duration of
employment among cases was 15 years.
The Haguenoer cohort was followed up in a study by Deschamps et al.
(Ex. 234). Both lead and zinc chromate pigments were produced at the
plant until zinc chromate production ceased in 1986. The cohort
consisted of 294 male workers employed for at least six months between
1958 and 1987. At the end of the follow-up, 182 cohort members were
alive, 16 were lost to follow-up and 96 were dead. Because of French
confidentiality rules, the cause of death could not be obtained from
the death certificate; instead physicians and hospital records were
utilized. Using cause of death data from sources other than death
certificates raises the potential for misclassification bias. Cause of
death could not be obtained for five decedents. Data on smoking habits
was not available for a number of workers and was not used in the
analysis.
Since individual work histories were not available, the authors
made the assumption that the exposure level was the same for all
workers during their employment at the plant. Duration of employment
was used as a surrogate for exposure. Industrial hygiene measurements
taken in 1981 provide some idea of the exposure levels at the plant.
In the filtration department, Cr(VI) levels were between 2 and 3 [mu]g/m\3\;
in the grinding department between 6 and 165 [mu]g/m\3\; in the drying and
sacking department between 6 and 178 [mu]g/m\3\; and in the sacks
marking department more than 2000 [mu]g/m\3\.
The expected number of deaths for the SMR analysis was computed
from age-adjusted death rates in the northern region of France where
the plant was located. There was a significant increase in lung cancer
deaths based on 18 fatalities with five expected (SMR=360; 95% CI: 213-
568). Using duration of employment as a surrogate for exposure,
statistically significant SMRs were seen for the 10-15 years of
exposure (O=6, SMR=720, 95% CI: 264-1568), 15-20 years (O=4, SMR=481,
95% CI: 131-1231), and 20+ years (O=6, SMR=377, 95% CI: 1.38-8.21) time
intervals. There was a significantly elevated SMR for brain cancer
based upon two deaths (SMR=844, 95% CI: 102-3049). There was a non-
statistically significant increase for digestive tract cancer (O=9,
SMR=130) consisting of three esophageal cancers, two stomach cancers
and four colon cancers.
Equitable Environmental Health, Inc., on behalf of the Dry Color
Manufacturers Association, undertook a historical prospective mortality
study of workers involved in the production of lead chromate (Exs. 2-D-
3; 2-D-1). The cohort was defined as male employees who had been
exposed to lead chromate for a minimum of six months prior to December
1974 at one of three facilities in West Virginia, Kentucky or New
Jersey. The New Jersey facility had a unit where zinc chromate was
produced dating back to 1947 (Ex. 2-D-3). Most workers rotated through
this unit and were exposed to both lead and zinc chromates. Two men
were identified at the New Jersey facility with exposure solely to lead
chromate; no one with exposure only to zinc chromate was identified.
Subsequent review of the data found that the Kentucky plant also
produced zinc chromates from the late 1930s to early 1964. During the
period 1961-1962, zinc chromates accounted for approximately 12% of
chromate production at the plant. In addition, strontium chromate and
barium chromate also were produced at the plant.
The cohort consisted of 574 male employees from all three plants
(Ex. 2-D-1). Eighty-five deaths were identified with follow up through
December 1979. Six death certificates were not obtained. SMRs were
reported based on U.S. white male death rates. There were 53 deaths
from the New Jersey plant including a statistically significant SMR for
cancer of the trachea, bronchus and lung based upon nine deaths (E=3.9;
SMR=231; 95% CI: 106-438). One lung cancer decedent worked solely in
the production of lead chromates. Three of the lung cancer deaths were
black males. In addition, there were six deaths from digestive system
cancers, five of which were stomach cancers reported at the New Jersey
plant. The SMR for stomach cancer was statistically significantly
elevated (O=5; E=0.63; SMR=792; 99% CI: 171-2243). There were 21 deaths
from the West Virginia plant, three of which were cancer of the
trachea, bronchus and lung (E=2.3; SMR=130; 95% CI: 27-381). There were
11 deaths at the Kentucky plant, two of which were cancer of the
trachea, bronchus and lung (E=0.9; SMR=216; 95% CI: 26-780).
Sheffet et al. examined the lung cancer mortality among 1,946 male
employees in a chromate pigment factory in Newark, NJ, who were exposed
to both lead chromate and zinc chromate pigments (Ex. 7-48). The men
worked for a minimum of one month between January 1, 1940 and December
31, 1969. As of March 31, 1979, a total of 321 cohort members were
identified as deceased (211 white males and 110 non-white males). Cause
of death could not be ascertained for 37 white males and 12 non-white
males. The proportion of the cohort lost to follow up was high (15% of
white males and 20% of non-white males).
Positions at the plant were classified into three categories
according to intensity of exposure: high (continuous exposure to
chemical dust), moderate (occasional exposure to chemical dust or to
dry or wet pigments) and low (infrequent exposure by janitors or office
workers). Positions were also classified by type of chemical exposure:
chromates, other inorganic substances, and organics. The authors state
that in almost all positions individuals "who were exposed to any
chemicals were also exposed to hexavalent chromium in the form of
airborne lead and zinc chromates (Ex. 7-48, p. 46)." The proportion of
lead chromate to zinc chromate was approximately nine to one.
Calculations, based upon air samples during later years, give an
estimate for the study period of more than 2000 [mu]g airborne
chromium/m\3\ for the high exposure category, between 500 and 2000
[mu]g airborne chromium/m\3\ and less than 100 [mu]g airborne chromium/
m\3\ for the low exposure category. Other suspected carcinogens present
in the workplace air at much lower levels were nickel sulfate and
nickel carbonate.
Because of the large proportion of workers lost to follow-up (15%
of white males and 20% of non-white males) and the large numbers of
unknown cause of death (21% of white males and 12% of non-white males),
the authors calculated three separate mortality expectations based upon
race-, gender-, age-, and time-specific U.S. mortality ratios. The
first expectation was calculated upon the assumption that those lost to
follow-up were alive at the end of the study follow-up period. The
second expectation was calculated on the assumption that those whose
vital status was unknown were lost to follow-up as of their employment
termination date. The third expectation was calculated excluding those
of unknown vital status from the cohort. Deaths with unknown cause were
distributed in the appropriate proportions among known causes of death
which served as an adjustment to the observed deaths. The adjusted
deaths were used in all of the analyses.
A statistically significant ratio for lung cancer deaths among
white males (O/E=1.6) was observed when using the assumption that
either the lost to follow-up were assumed lost as of their termination
date or were excluded from the cohort (assumptions two and three
above). The ratio for lung cancer deaths for non-white males results in
an identical O/E of 1.6 for all three of the above scenarios, none of
which was statistically significant.
In addition, the authors also conducted Proportionate Mortality
Ratio (PMR) and Proportionate Cancer Mortality Ratio (PCMR) analyses.
For white males, the lung cancer PMR was 200 and the lung cancer PCMR
was 160 based upon 25.5 adjusted observed deaths (21 actual deaths).
Both were statistically significantly elevated at the p< .05 level. For
non-white males, the lung cancer PMR was 200 and the lung cancer PCMR
was 150 based upon 11.2 adjusted observed deaths (10 actual deaths).
The lung cancer PMR for non-white males was statistically significantly
elevated at the p< .05 level. Statistically significantly elevated PMRs
and PCMRs for stomach cancer in white males were reported (PMR=280;
PCMR=230) based upon 6.1 adjusted observed deaths (five actual).
The Sheffet cohort was updated in a study by Hayes et al. (Ex. 7-
46). The follow up was through December 31, 1982. Workers employed as
process operators or in other jobs which involved direct exposure to
chromium dusts were classified as having exposure to chromates. Airborne
chromium concentrations taken in "later years" were estimated to be
>500 [mu]g g/m\3\ for "exposed" jobs and >2000 [mu]g/m\3\ for
"highly exposed" jobs.
The cohort included 1,181 white and 698 non-white males. Of the 453
deaths identified by the end of the follow-up period, 41 were lung
cancers. For the entire study group, no statistically significant
excess was observed for lung cancer (SMR=116) or for cancer at any
other site. Analysis by duration of employment found a statistically
significant trend (p=.04) for lung cancer SMRs (67 for those employed
< 1 year; 122 for those employed 1-9 years and 151 for those employed
10+ years).
Analysis of lung cancer deaths by duration of employment in
chromate dust associated jobs found no elevation in risk for subjects
who never worked in these jobs (SMR=92) or for subjects employed less
than one year in these jobs (SMR=93). For those with cumulative
employment of 1-9 and 10+ years in jobs with chromate dust exposure,
the SMRs were 176 (nine deaths) and 194 (eight deaths) respectively.
Frentzel-Beyme studied the mortality experience of 1,396 men
employed for more than six months in one of five factories producing
lead and zinc chromate pigments located in Germany and the Netherlands
(Ex. 7-45). The observed deaths from the five factories were compared
with the expected deaths calculated on the basis of mortality figures
for the region in which the plant was located. Additional analysis was
conducted on relevant cohorts which included workers with a minimum of
10 years exposure, complete records for the entire staff, and exclusion
of foreign nationals. Jobs were assigned into one of three exposure
categories: High (drying and milling of the filtered pigment paste),
medium (wet processes including precipitation of the pigment, filtering
and maintenance, craftsmen and cleaning) and low or trivial exposure
(storage, dispatch, laboratory personnel and supervisors).
There were 117 deaths in the entire cohort of which 19 were lung
cancer deaths (E=9.3). The lung cancer SMRs in the relevant cohort
analyses were elevated at every plant; however, in only one instance
was the increased lung cancer SMR statistically significant, based upon
three deaths (SMR=386, p< 0.05). Analysis by type of exposure is not
meaningful due to the small number of lung cancer deaths per plant per
exposure classification.
Kano et al. conducted a study of five Japanese manufacturers who
produced lead chromates, zinc chromate, and/or strontium chromate to
assess if there was an excess risk of lung cancer (Ex. 7-118). The
cohort consisted of 666 workers employed for a minimum of one year
between 1950 and 1975. At the end of 1989, 604 subjects were alive,
five lost to follow-up and 57 dead. Three lung cancer deaths were
observed in the cohort with 2.95 expected (SMR=102; 95% CI: 0.21-2.98).
Eight stomach cancer deaths were reported with a non-statistically
significant SMR of 120.
Following the publication of the proposed rule, the Color Pigment
Manufacturers Association requested that OSHA reconsider its
preliminary conclusions with respect to the health effects of lead
chromate color pigments (Ex. 38-205). They relied on the Davies (Ex. 7-
43), Cooper [Equitable Environmental Health, Inc] (Ex. 2-D-1) and Kano
(Ex. 14-1-B) epidemiologic studies as the only available data on worker
cohorts exposed to lead chromate in the absence of other chromates
commonly found in pigment production (e.g., zinc chromate). The CPMA's
comments regarding the Davies, Cooper and Kano studies and OSHA's
response to them are discussed in section V.B.9.a.
3. Evidence from Workers in Chromium Plating
Chrome plating is the process of depositing chromium metal onto the
surface of an item using a solution of chromic acid. The items to be
plated are suspended in a diluted chromic acid bath. A fine chromic
acid mist is produced when gaseous bubbles, released by the
dissociation of water, rise to the surface of the plating bath and
burst. There are two types of chromium electroplating. Decorative or
"bright" involves depositing a thin (0.5-1 [mu]m) layer of chromium
over nickel or nickel-type coatings to provide protective, durable,
non-tarnishable surface finishes. Decorative chrome plating is used for
automobile and bicycle parts. Hard chromium plating produces a thicker
(exceeding 5 [mu]m) coating which makes it resistant and solid where
friction is usually greater, such as in crusher propellers and in
camshafts for ship engines. Limited air monitoring indicates that
Cr(VI) levels are five to ten times higher during hard plating than
decorative plating (Ex. 35-116).
There are fewer studies that have examined the lung cancer
mortality of chrome platers than of soluble chromate production and
chromate pigment production workers. The largest and best described
cohort studies investigated chrome plating cohorts in the United
Kingdom (Exs. 7-49; 7-57; 271; 35-62). They generally found elevated
lung cancer mortality among the chrome platers, especially those
engaged in chrome bath work, when compared to various reference
populations. The studies of British chrome platers are summarized in
Table V-3.
BILLING CODE 4510-26-P
Click here to view table V-3
BILLING CODE 4510-26-C
Cohort studies of chrome platers in Italy, the United States, and
Japan are also discussed in this subsection. Co-exposure to nickel,
another suspected carcinogen, during plating operations can complicate
evaluation of an association between Cr(VI) and an increased risk of
lung cancer in chrome platers. Despite this, the International Agency
for Research on Cancer concluded that the epidemiological
studies provide sufficient evidence for carcinogenicity of Cr(VI) as
encountered in the chromium plating industry; the same conclusion
reached for chromate production and chromate pigment production (Exs.
18-1; 35-43). The findings implicate the highly water-soluble chromic
acid as an occupational carcinogen. This adds to the weight of evidence
that water-soluble (e.g., sodium chromates, chromic acid) and water-
insoluble forms (e.g., lead and zinc chromates) of Cr(VI) are able to
cause cancer of the lower respiratory tract.
Royle reported on a cohort mortality study of 1,238 chromium
platers employed for a minimum of three consecutive months between
February 20, 1969 and May 31, 1972 in 54 plating plants in West Riding,
Yorkshire, England (Ex. 7-49). A control population was enumerated from
other departments of the larger companies where chromium plating was
only a portion of the companies' activities and from the former and
current employees of two industrial companies in York where information
on past workers was available. Controls were matched for gender, age
(within two years) and date last known alive. In addition, 229 current
workers were matched for smoking habits.
As of May 1974, there were 142 deaths among the platers (130 males
and 12 females) and 104 deaths among the controls (96 males and 8
females). Among the male platers, there were 24 deaths from cancer of
the lung and pleura compared to 13 deaths in the control group. The
difference was not statistically significant. There were eight deaths
from gastrointestinal cancer among male platers versus four deaths in
the control group. The finding was not statistically significant.
The Royle cohort was updated by Sorahan and Harrington (Ex. 35-62).
Chrome plating was the primary activity at all 54 plants, however 49 of
the plants used nickel and 18 used cadmium. Also used, but in smaller
quantities according to the authors, were zinc, tin, copper, silver,
gold, brass or rhodium. Lead was not used at any of the plants. Four
plants, including one of the largest, only used chromium. Thirty-six
chrome platers reported asbestos exposure versus 93 comparison workers.
Industrial hygiene surveys were carried out at 42 plants during
1969-1970. Area air samples were done at breathing zone height. With
the exception of two plants, the chromic acid air levels were less than
30 [mu]g/m\3\. The two exceptions were large plants, and in both the
chromic acid levels exceeded 100 [mu]g/m\3\.
The redefined cohort consisted of 1087 platers (920 men and 167
women) from 54 plants employed for a minimum of three months between
February 1969 and May 31, 1972 who were alive on May 31, 1972.
Mortality data were also available for a comparison group of 1,163
workers (989 men and 174 women) with no chromium exposure. Both groups
were followed for vital status through 1997.
The lung cancer SMR for male platers was statistically significant
(O=60; E=32.5; SMR=185; 95% CI: 141-238). The lung cancer SMR for the
comparison group, while elevated, was not statistically significant
(O=47; E=36.9; SMR=127; 95% CI: 94-169). The only statistically
significant SMR in the comparison group was for cancer of the pleura
(O=7; E=0.57; SMR=1235; 95% CI: 497-2545).
Internal regression analyses were conducted comparing the mortality
rates of platers directly with those of the comparison workers. For
these analyses, lung cancers mentioned anywhere on the death
certificate were considered cases. The redefinition resulted in four
additional lung cancer cases in the internal analyses. There was a
statistically significant relative risk of 1.44 (p< 0.05) for lung
cancer mortality among chrome platers that was slightly reduced to 1.39
after adjustment for smoking habits and employment status. There was no
clear trend between lung cancer mortality and duration of Cr(VI)
exposure. However, any positive trend may have been obscured by the
lack of information on worker employment post-1972 and the large
variation in chromic acid levels among the different plants.
Sorahan reported the experience of a cohort of 2,689 nickel/
chromium platers from the Midlands, U.K. employed for a minimum of six
months between 1946 and 1975 and followed through December 1983 (Ex. 7-
57). There was a statistically significant lung cancer SMR for males
(O=63; E=40; SMR=158; p< 0.001). The lung cancer SMR for women, while
elevated (O=9; E=8.1; SMR=111), was not statistically significant.
Other statistically significant cancer SMRs for males included: stomach
(O=21; E=11.3; SMR=186; p< 0.05); liver (O=4; E=0.6; SMR=667; p< 0.01);
and nasal cavities (O=2; E=0.2; SMR=1000; p< 0.05). While there were
several elevated SMRs for women, none were statistically significant.
There were nine lung cancers and one nasal cancer among the women.
Analysis by type of first employment (i.e., chrome bath workers vs.
other chrome work) resulted in a statistically significant SMR for lung
cancer of 199 (O=46; E=23.1; p< 0.001) for chrome bath workers and a SMR
of 101 for other chrome work. The SMR for cancer of the stomach for
male chrome bath workers was also statistically significantly elevated
(O=13; E=6.3; SMR=206; p< 0.05); for stomach cancer in males doing other
chrome work, the SMR was 160 with 8 observed and 5 expected. Both of
the nasal cancers in males and the one nasal cancer in women were
chrome bath workers. The nasal cancer SMR for males was statistically
significantly elevated (O=2; E=0.1; SMR=2000; p< 0.05).
Regression analysis was used to examine evidence of association of
several types of cancers and Cr(VI) exposure duration among the cohort.
There was a significant positive association between lung cancer
mortality and exposure duration as a chrome bath worker controlling for
gender as well as year and age at the start of employment. There was no
evidence of an association between other cancer types and duration of
Cr(VI) exposure. There was no positive association between duration of
exposure to nickel bath work and cancer of the lung. The two largest
reported SMRs were for chrome bath workers 10-14 years (O=13; E=3.8;
SMR=342; p< 0.001) and 15-19 years (O=12; E=4.9; SMR=245; p< 0.01) after
starting employment. The positive associations between lung cancer
mortality and duration of chrome bath work suggests Cr(VI) exposure may
be responsible for the excess cancer risk.
Sorahan et al. reported the results of a follow-up to the nickel/
chromium platers study discussed above (Ex. 271). The cohort was
redefined and excluded employees whose personnel records could not be
located (650); those who started chrome work prior to 1946 (31) and
those having no chrome exposure (236). The vital status experience of
1,762 workers (812 men and 950 women) was followed through 1995. The
expected number of deaths was based upon the mortality of the general
population of England and Wales.
There were 421 deaths among the men and 269 deaths among the women,
including 52 lung cancers among the men and 17 among the women. SMRs
were calculated for different categories of chrome work: Period from
first chrome work; year of starting chrome work, and cumulative
duration of chrome work categories. Poison regression modeling was
employed to investigate lung cancer in relation to type of chrome work
and cumulative duration of work.
A significantly elevated lung cancer SMR was seen for male workers
with some period of chrome bath work (O=40; E=25.4; SMR=157; 95% CI: 113-
214, p< 0.01). Lung cancer was not elevated among male workers engaged
in other chrome work away from the chromic acid bath (O=9; E=13.7;
SMR=66; 95% CI: 30-125). Similar lung cancer mortality results were
found for female chrome bath workers (O=15; E=8.6; SMR=175; 95% CI: 98-
285; p< 0.06). After adjusting for sex, age, calendar year, year
starting chrome work, period from first chrome work, and employment
status, regression modeling showed a statistically significant positive
trend (p< 0.05) between duration of chrome bath work and lung cancer
mortality risk. The relative lung cancer risk for chrome bath workers
with more than five years of Cr(VI) exposure (i.e., relative to the
risk of those without any chrome bath work) was 4.25 (95% CI: 1.83-
9.37).
Since the Sorahan cohort consists of nickel/chromium workers, the
question arises of the potential confounding of nickel. In the earlier
study, 144 of the 564 employees with some period of chrome bath work
had either separate or simultaneous periods of nickel bath employment.
According to the authors, there was no clear association between cancer
deaths from stomach, liver, respiratory system, nose and larynx, and
lung and bronchus and the duration of nickel bath employment. In the
follow-up report, the authors re-iterate this result stating,
"findings for lung cancer in a cohort of nickel platers (without any
exposure to chrome plating) from the same factory are unexceptional"
(Ex. 35-271, p. 241).
Silverstein et al. reported the results of a cohort study of hourly
employees and retirees with at least 10 years of credited pension
service in a Midwestern plant manufacturing hardware and trim
components for use primarily in the automobile industry (Ex. 7-55). Two
hundred thirty eight deaths occurred between January 1, 1974 and
December 31, 1978. Proportional Mortality Ratio (PMR) analysis adjusted
for race, gender, age and year of death was conducted. For white males,
the PMR for cancer of the lung and pleura was 1.91 (p< 0.001) based upon
28 deaths. For white females, the PMR for cancer of the lung and pleura
was 3.70 (p< 0.001) based upon 10 deaths.
White males who worked at the plant for less than 15 years had a
lung cancer PMR of 1.65. Those with 15 or more years at the plant had a
lung cancer PMR of 2.09 (p< 0.001). For white males with less than 22.5
years between hire and death (latency) the lung cancer PMR was 1.78
(p< 0.05) and for those with 22.5 or more years, the PMR was 2.11
(p< 0.01).
A case-control analysis was conducted on the Silverstein cohort to
examine the association of lung cancer risk with work experience.
Controls were drawn from cardiovascular disease deaths (ICD 390-458,
8th revision). The 38 lung cancer deaths were matched to controls for
race and gender. Odds ratios (ORs) were calculated by department
depending upon the amount of time spent in the department (ever/never;
more vs. less than one year; and more vs. less than five years). Three
departments showed increasing odds ratios with duration of work;
however, the only statistically significant result was for those who
worked more than five years in department 5 (OR=9.17, p=0.04, Fisher's
exact test). Department 5 was one of the major die-casting and plating
areas of the plant prior to 1971.
Franchini et al. conducted a mortality study of employees and
retirees from nine chrome plating plants in Parma, Italy (Ex. 7-56).
Three plants produced hard chrome plating. The remaining six plants
produced decorative chromium plates. A limited number of airborne
chromium measurements were available. Out of a total of 10 measurements
at the hard chrome plating plants, the air concentrations of chromium
averaged 7 [mu]g/m\3\ (range of 1-50 [mu]g/m\3\) as chromic acid near
the baths and 3 [mu]g/m\3\ (range of 0-12 [mu]g/m\3\) in the middle of
the room.
The cohort consisted of 178 males (116 from the hard chromium
plating plants and 62 from the bright chromium plating plants) who had
worked for at least one year between January 1, 1951 and December 31,
1981. In order to allow for a 10-year latency period, only those
employed before January 1972 were included in further analysis. There
were three observed lung cancer deaths among workers in the hard chrome
plating plants, which was significantly greater than expected (O=3;
E=0.6; p< 0.05). There were no lung cancer deaths among decorative
chrome platers.
Okubo and Tsuchiya conducted a study of plating firms with five or
more employees in Tokyo (Exs. 7-51; 7-52). Five hundred and eighty nine
firms were sent questionnaires to ascertain information regarding
chromium plating experience. The response rate was 70.5%. Five thousand
one hundred seventy platers (3,395 males and 1,775 females) met the
cohort entrance criteria and were followed from April 1, 1970 to
September 30, 1976. There were 186 deaths among the cohort; 230 people
were lost to follow-up after retirement. The cohort was divided into
two groups: Chromium platers who worked six months or more and a
control group with no exposure to chromium (clerical, unskilled
workers). There were no deaths from lung cancer among the chromium
platers.
The Okubo cohort was updated by Takahashi and Okubo (Ex. 265). The
cohort was redefined to consist of 1,193 male platers employed for a
minimum of six months between April 1970 and September 1976 in one of
415 Tokyo chrome plating plants and who were alive and over 35 years of
age on September 30, 1976. The only statistically significant SMR was
for lung cancer for all platers combined (O=16; E=8.9; SMR=179; 95% CI:
102-290). The lung cancer SMR for the chromium plater subcohort was 187
based upon eight deaths and 172 for the nonchromium plater subcohort,
also based upon eight deaths. The cohort was followed through 1987.
Itoh et al. updated the Okubo metal plating cohort through December
1992 (Ex. 35-163). They reported a lung cancer SMR of 118 (95% CI: 99-
304).
4. Evidence From Stainless Steel Welders
Welding is a term used to describe the process for joining any
materials by fusion. The fumes and gases associated with the welding
process can cause a wide range of respiratory exposures which may lead
to an increased risk of lung cancer. The major classes of metals most
often welded include mild steel, stainless and high alloy steels and
aluminum. The fumes from stainless steel, unlike fumes from mild steel,
contain nickel and Cr(VI). There are several cohort and case-control
studies as well as two meta analyses of welders potentially exposed to
Cr(VI). In general, the studies found an excess number of lung cancer
deaths among stainless steel welders. However, few of the studies found
clear trends with Cr(VI) exposure duration or cumulative Cr(VI). In
most studies, the reported excess lung cancer mortality among stainless
steel welders was no greater than mild steel welders, even though
Cr(VI) exposure is much greater during stainless steel welding. This
weak association between lung cancer and indices of exposure limits the
evidence provided by these studies. Other limitations include the co-
exposures to other potential lung carcinogens, such as nickel,
asbestos, and cigarette smoke, as well as possible healthy worker
effects and exposure misclassification in some studies, which may
obscure a relationship betweeen Cr(VI) and lung cancer risk. These
limitations are discussed further in sections VI.B.5, VI.E.3, and
VI.G.4.
Nevertheless, these studies add some further support to the much
stronger link between Cr(VI) and lung cancer found in soluble chromate
production workers, chromate pigment production workers, and chrome
platers. The key studies are summarized in Table V-4.
BILLING CODE 4510-26-P
Click here to view table V-4
BILLING CODE 4510-26-C
Sjogren et al. reported on the mortality experience in two cohorts
of welders (Ex. 7-95). The cohort characterized as "high exposure"
consisted of 234 male stainless steel welders with a minimum of 5 years
of employment between 1950 and 1965. An additional criterion for
inclusion in the study was assurance from the employer that asbestos
had not been used or had been used only occasionally and never in a
dust-generating way. The cohort characterized as "low exposure"
consisted of 208 male railway track welders working at the Swedish
State Railways for at least 5 years between 1950 and 1965. In 1975, air
pollution in stainless steel welding was surveyed in Sweden. The median
time weighted average (TWA) value for Cr(VI) was 110 [mu]g
CrO3/m\3\ (57 [mu]g/m\3\ measured as CrVI). The highest
concentration was 750 [mu]g CrO3/m\3\ (390 [mu]g/m\3\
measured as CrVI) found in welding involving coated electrodes. For
gas-shielded welding, the median Cr(VI) concentration was 10 [mu]g
CrO3/m\3\ (5.2 [mu]g/m\3\ measured as CrVI) with the highest
concentration measured at 440 [mu]g CrO3/m\3\ (229 [mu]g/
m\3\ measured as CrVI). Follow-up for both cohorts was through December
1984. The expected number of deaths was based upon Swedish male death
rates. Of the 32 deaths in the "high exposure" group, five were
cancers of the trachea, bronchus and lung (E=2.0; SMR=249; 95% CI:
0.80-5.81). In the low exposure group, 47 deaths occurred, one from
cancer of the trachea, bronchus and lung.
Polednak compiled a cohort of 1,340 white male welders who worked
at the Oak Ridge nuclear facilities from 1943 to 1977 (Ex. 277). One
thousand fifty-nine cohort members were followed through 1974. The
cohort was divided into two groups. The first group included 536
welders at a facility where nickel-alloy pipes were welded; the second
group included 523 welders of mild steel, stainless steel and aluminum
materials. Smoking data were available for 33.6% of the total cohort.
Expectations were calculated based upon U.S. mortality rates for white
males. There were 17 lung cancer deaths in the total cohort (E=11.37;
SMR=150; 95% CI: 87-240). Seven of the lung cancer deaths occurred in
the group which routinely welded nickel-alloy materials (E=5.65;
SMR=124; 95% CI: 50-255) versus 10 lung cancer deaths in the "other"
welders (E=6.12; SMR=163; 95% CI: 78-300).
Becker et al. compiled a cohort of 1,213 stainless steel welders
and 1,688 turners from 25 German metal processing factories who had a
minimum of 6 months employment during the period 1950-1970 (Exs. 227;
250; 251). The data collected included the primary type of welding
(e.g., arc welding, gas-shielded welding, etc.) used by each person,
working conditions, average daily welding time and smoking status. The
most recent follow-up of the cohort was through 1995. Expected numbers
were developed using German mortality data. There were 268 deaths among
the welders and 446 deaths among the turners. An elevated, but non-
statistically significant, lung cancer SMR (O=28; E=23; SMR=121.5; 95%
CI: 80.7-175.6) was observed among the welders. There were 38 lung
cancer deaths among the turners with 38.6 expected, resulting in a SMR
slightly below unity. Seven deaths from cancer of the pleura (all
mesotheliomas) occurred among the welders with only 0.6 expected
(SMR=1,179.9; 95% CI: 473.1-2,430.5), compared to only one death from
cancer of the pleura among the turners, suggesting that the welders had
exposure to asbestos. Epidemiological studies have shown that asbestos
exposure is a primary cause of pleural mesotheliomas.
The International Agency for Research on Cancer (IARC) and the
World Health Organization (WHO) cosponsored a study on welders. IARC
and WHO compiled a cohort of 11,092 male welders from 135 companies in
nine European countries to investigate the relationship between the
different types of exposure occurring in stainless steel, mild steel
and shipyard welding and various cancer sites, especially lung cancer
(Ex. 7-114). Cohort entrance criteria varied by country. The expected
number of deaths was compiled using national mortality rates from the
WHO mortality data bank.
Results indicated the lung cancer deaths were statistically
significant in the total cohort (116 cases; E=86.81; SMR=134; 95% CI:
110-160). Cohort members were assigned to one of four subcohorts based
upon type of welding activity. While the lung cancer SMRs were elevated
for all of the subcohorts, the only statistically significant SMR was
for the mild steel-only welders (O=40; E=22.42; SMR=178; 95% CI: 127-
243). Results for the other subgroups were: shipyard welders (O=36;
E=28.62; SMR=126; 95% CI: 88-174); ever stainless steel welders (O=39;
E=30.52; SMR=128; 95% CI: 91-175); and predominantly stainless steel
welders (O=20; E=16.25; SMR=123; 95% CI: 75-190). When analyzed by
subcohort and time since first exposure, the SMRs increased over time
for every group except shipyard welders. For the predominantly
stainless steel welder subcohort, the trend to increase with time was
statistically significant (p < .05).
An analysis was conducted of lung cancer mortality in two stainless
steel welder subgroups (predominantly and ever) with a minimum of 5
years of employment. Cumulative Cr(VI) was computed from start of
exposure until 20 years prior to death. A lung cancer SMR of 170, based
upon 14 cases, was observed in the stainless steel ever subgroup for
those welders with >=0.5 mg-years/m\3\ Cr(VI) exposure; the lung cancer
SMR for those in the < 0.5 mg-years/m\3\ Cr(VI) exposure group was 123
(based upon seven cases). Neither SMR was statistically significant.
For the predominantly stainless steel welders, which is a subset of the
stainless steel ever subgroup, the corresponding SMRs were 167 (>=0.5
mg-years/m\3\ Cr(VI) exposure) based upon nine cases and 191 (< 0.5 mg-
years/m\3\ Cr(VI) exposure) based upon three cases. Neither SMR was
statistically significant.
In conjunction with the IARC/WHO welders study, Gerin et al.
reported the development of a welding process exposure matrix relating
13 combinations of welding processes and base metals used to average
exposure levels for total welding fumes, total chromium, Cr(VI) and
nickel (Ex. 7-120). Quantitative estimates were derived from the
literature supplemented by limited monitoring data taken in the 1970s
from only 8 of the 135 companies in the IARC/WHO mortality study. An
exposure history was constructed which included hire and termination
dates, the base metal welded (stainless steel or mild steel), the
welding process used and changes in exposure over time. When a detailed
welding history was not available for an individual, the average
company welding practice profile was used. In addition, descriptions of
activities, work force, welding processes and parameters, base metals
welded, types of electrodes or rods, types of confinement and presence
of local exhaust ventilation were obtained from the companies.
Cumulative dose estimates in mg/m\3\ years were generated for each
welder's profile (number of years and proportion of time in each
welding situation) by applying a welding process exposure matrix
associating average concentrations of welding fumes (mg/m\3\) to each
welding situation. The corresponding exposure level was multiplied by
length of employment and summed over the various employment periods
involving different welding situations. No dose response relationship
was seen for exposure to Cr(VI) for either those who were "ever
stainless steel welders" or those who were "predominantly stainless
steel welders". The authors note that if their exposure estimates are
correct, the study had the power to detect a significant result in the
high exposure group for Cr(VI). However, OSHA believes that there is
likely to be substantial exposure misclassification in this study, as
discussed further in section VI.G.4.
The IARC/WHO multicenter study is the sole attempt to undertake
even a semi-quantified exposure analysis of stainless steel welders'
potential exposure to nickel and Cr(VI) for <5 and >=0.5 mg-years/
m3 Cr(VI) exposures. The IARC/WHO investigators noted that
there was more than a twofold increase in SMRs between the long (>=20
years since first exposure) and short (< 20 years since first exposure)
observation groups for the predominantly stainless steel welders
"suggesting a relation of lung cancer mortality with the occupational
environment for this group" (Ex. 7-114, p. 152). The authors conclude
that the increase in lung cancer mortality does not appear to be
related to either duration of exposure or cumulative exposure to total
fume, chromium, Cr(VI) or nickel.
Moulin compiled a cohort of 2,721 French male welders and an
internal comparison group of 6,683 manual workers employed in 13
factories (including three shipyards) with a minimum of one year of
employment from 1975 to 1988 (Ex. 7-92). Three controls were selected
at random for each welder. Smoking data were abstracted from medical
records for 86.6% of welders and 86.5% of the controls. Smoking data
were incorporated in the lung cancer mortality analysis using methods
suggested by Axelson. Two hundred and three deaths were observed in the
welders and 527 in the comparison group. A non-statistically
significant increase was observed in the lung cancer SMR (O=19;
E=15.33; SMR=124; 95% CI: 0.75-1.94) for the welders. In the control
group, the lung cancer SMR was in deficit (O=44; E=46.72; SMR=94; 95%
CI: 0.68-1.26). The resulting relative risk was a non-significant 1.3.
There were three deaths from pleural cancer in the comparison group and
none in the welders, suggesting asbestos exposure in the comparison
group. The welders were divided into four subgroups (shipyard welders,
mild steel only welders, ever stainless steel welders and stainless
steel predominantly Cr(VI) welders). The highest lung cancer SMR was
for the mild steel welders O=9; SMR of 159). The lowest lung cancer
SMRs were for ever stainless steel welders (O=3; SMR= 92) and for
stainless steel predominantly Cr(VI) welders (O=2; SMR= 103). None of
the SMRs are statistically significant.
Hansen conducted a study of cancer incidence among 10,059 male
welders, stainless steel grinders and other metal workers from 79
Danish companies (Ex. 9-129). Cohort entrance criteria included: alive
on April 1, 1968; born before January 1, 1965; and employed for at
least 12 months between April 1, 1964 and December 31, 1984. Vital
status follow-up found 9,114 subjects alive, 812 dead and 133
emigrated. A questionnaire was sent to subjects and proxies for
decedents/emigrants in an attempt to obtain information about lifetime
occupational exposure, smoking and drinking habits. The overall
response rate was 83%. The authors stated that no major differences in
smoking habits were found between exposure groups with or without a
significant excess of lung cancer.
The expected number of cancers was based on age-adjusted national
cancer incidence rates from the Danish Cancer Registry. There were
statistically significantly elevated Standardized Incidence Ratios
(SIRs) for lung cancer in the welding (any kind) group (O=51; E=36.84;
SIR=138; 95% CI: 103-181) and in the mild steel only welders (O=28;
E=17.42; SIR=161; 95% CI: 107-233). The lung cancer SIR for mild steel
ever welders was 132 (O=46; E=34.75; 95% CI: 97-176); for stainless
steel ever welders 119 (O=23; E=19.39; 95% CI: 75-179) and for
stainless steel only welders 238 (O=5; E=2.10; 95% CI: 77-555).
Laurtitsen reported the results of a nested case-control conducted
in conjunction with the Hansen cancer incidence study discussed above
(Exs. 35-291; 9-129). Cases were defined as the 94 lung cancer deaths.
Controls were defined as anyone who was not a case, but excluded deaths
from respiratory diseases other than lung cancer (either as an
underlying or a contributing cause of death), deaths from "unknown
malignancies" and decedents who were younger than the youngest case.
There were 439 decedents eligible for use as controls.
The crude odds ratio (OR) for welding ever (yes/no) was 1.7 (95%
CI: 1.0-2.8). The crude OR for mild steel welding only was 1.3 (95% CI:
0.8-2.3) and for stainless steel welding only the crude OR was 1.3 (95%
CI: 0.3-4.3). When analyzed by number of years exposed, "ever"
stainless steel welding showed no relationship with increasing number
of years exposed. The highest odds ratio (2.9) was in the lowest
category (1-5 years) based upon seven deaths; the lowest odds ratio was
in the highest category (21+ years) based upon three deaths.
Kjuus et al. conducted a hospital-based case-control study of 176
male incident lung cancer cases and 186 controls (matched for age, +/-5
years) admitted to two county hospitals in southeast Norway during
1979-1983 (Ex. 7-72). Subjects were classified according to exposure
status of main occupation and number of years in each exposure category
and assigned into one of three exposure groups according to potential
exposure to respiratory carcinogens and other contaminants. A
statistically significantly elevated risk ratio for lung cancer
(adjusted for smoking) for the exposure factor "welding, stainless,
acid proof" of 3.3 (p< 0.05) was observed based upon 16 lung cancer
deaths. The unadjusted odds ratio is not statistically significant
(OR=2.8). However, the appropriateness of the analysis is questionable
since the exposure factors are not discrete (a case or a control may
appear in multiple exposure factors and therefore is being compared to
himself). In addition, the authors note that several exposure factors
were highly correlated and point out specifically that one-half of the
cases "exposed to either stainless steel welding fumes or fertilizers
also reported moderate to heavy asbestos exposure." When put into a
stepwise logistic regression model, exposure to stainless steel fumes,
which was initially statistically significant, loses its significance
when smoking and asbestos are first entered into the model.
Hull et al. conducted a case-control study of lung cancer in white
male welders aged 20-65 identified through the Los Angeles County tumor
registry (Southern California Cancer Surveillance Program) for the
period 1972 to 1987 (Ex. 35-243). Controls were welders 40 years of age
or older with non-pulmonary malignancies. Interviews were conducted to
obtain information about sociodemographic data, smoking history,
employment history and occupational exposures to specific welding
processes, metals welded, asbestos and confined space welding.
Interviews were completed for 90 (70%) of the 128 lung cancer cases and
116 (66%) of the controls. Analysis was conducted using 85 deceased
cases and 74 deceased controls after determining that the subject's
vital status influenced responses to questions concerning occupational
exposures. The crude odds ratio (ever vs. never exposed) for stainless
steel welding, based upon 34 cases, was 0.9 (95% CI: 0.3-1.4). For
manual metal arc welding on stainless steel, the crude odds ratio
was 1.3 (95% CI: 0.6-2.3) based upon 61 cases.
While the relative risk estimates in both cohort and case-control
of stainless steel welders are elevated, none are statistically
significant. However, when combined in two meta-analyses, a small but
statistically significant increase in lung cancer risk was reported.
Two meta-analyses of welders have been published. Moulin carried out a
meta-analysis of epidemiologic studies of lung cancer risk among
welders, taking into account the role of asbestos and smoking (Ex. 35-
285). Studies published between 1954 and 1994 were reviewed. The
inclusion criteria were clearly defined: only the most recent updates
of cohort studies were used and only the mortality data from mortality/
morbidity studies were included. Studies that did not provide the
information required by the meta-analysis were excluded.
Five welding categories were defined (shipyard welding, non-
shipyard welding, mild steel welding, stainless steel welding and all
or unspecified welding). The studies were assigned to a welding
category (or categories) based upon the descriptions provided in the
paper's study design section. The combined relative risks (odds ratios,
standardized mortality ratios, proportionate mortality ratios and
standardized incidence ratios) were calculated separately for the
population-based studies, case-control studies, and cohort studies, and
for all the studies combined.
Three case-control studies (Exs. 35-243; 7-120; 7-72) and two
cohort studies (Exs. 7-114; 35-277) were included in the stainless
steel welding portion of the meta-analysis. The combined relative risk
was 2.00 (O=87; 95% CI: 1.22-3.28) for the case-control studies and
1.23 (O=27; 95% CI: 0.82-1.85) for the cohort studies. When all five
studies were combined, the relative risk was 1.50 (O=114; 95% CI: 1.10-
2.05).
By contrast, the combined risk ratio for the case-control studies
of mild steel welders was 1.56 (O=58; 95% CI: 0.82-2.99) (Exs. 7-120;
35-243). For the cohort studies, the risk ratio was 1.49 (O=79; 95% CI:
1.15-1.93) (Exs. 35-270; 7-114). For the four studies combined, the
risk ratio was 1.50 (O=137; 95% CI: 1.18-191). The results for the
stainless steel welders and the mild steel welders are basically the
same.
The meta-analysis by Sjogren of exposure to stainless steel welding
fumes and lung cancer included studies published between 1984 and 1993,
which took smoking and potential asbestos exposure into account (Ex. 7-
113). Five studies met the author's inclusion criteria and were
included in the meta-analysis: two cohort studies, Moulin et al. (Ex.
35-283) and Sjogren et al. (Ex. 7-95); and three case-control studies,
Gerin, et al. (Ex. 7-120, Hansen et al. (Ex. 9-129) and Kjuus et al.
(Ex. 7-72). The calculated pooled relative risk for welders exposed to
stainless steel welding fumes was 1.94 (95% CI: 1.28-2.93).
5. Evidence from Ferrochromium Workers
Ferrochromium is produced by the electrothermal reduction of
chromite ore with coke in the presence of iron in electric furnaces.
Some of the chromite ore is oxidized into Cr(VI) during the process.
However, most of the ore is reduced to chrome metal. The manufacture of
ferroalloys results in a complex mixture of particles, fumes and
chemicals including nickel, Cr(III) and Cr(VI). Polycyclic aromatic
hydrocarbons (PAH) are released during the manufacturing process. The
co-exposure to other potential lung carcinogens combined with the lack
of a statistically significant elevation in lung cancer mortality among
ferrochromium workers were limitations in the key studies.
Nevertheless, the observed increase in the relative risks of lung
cancer add some further support to the much stronger link between
Cr(VI) and lung cancer found in soluble chromate production workers,
chromate pigment production workers, and chrome platers. The key
studies are summarized in Table V-5.
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Langard et al. conducted a cohort study of male workers producing
ferrosilicon and ferrochromium for more than one year between 1928 and
1977 at a plant located on the west coast of Norway (Exs. 7-34; 7-37). The
cohort and study findings are summarized in Table V.5. Excluded from
the study were workers who died before January 1, 1953 or had an
unknown date of birth. The cohort was defined in the 1980 study as 976
male employees who worked for a minimum of one year prior to January 1,
1960. In the 1990 study, the cohort definition was expanded to include
those hired up to 1965.
Production of ferrosilicon at the plant began in 1928 and
ferrochromium production began in 1932. Job characterizations were
compiled by combining information from company personnel lists and
occupational histories contained in medical records and supplemented
with information obtained via interview with long-term employees. Ten
occupational categories were defined. Workers were assigned to an
occupational category based upon the longest time in a given category.
Industrial hygiene studies of the plant from 1975 indicated that
both Cr(III) and Cr(VI) were present in the working environment. The
ferrochromium furnance operators were exposed to measurements of 0.04-
0.29 mg/m3 of total chromium. At the charge floor the mean
concentration of total chromium was 0.05 mg/m3, 11-33% of
which was water soluble. The water soluble chromium was considered to
be in the hexavalent state.
Both observed and expected cases of cancer were obtained via the
Norwegian Cancer Registry. The observation period for cancer incidence
was January 1, 1953 to December 31, 1985. Seventeen incident lung
cancers were reported in the 1990 study (E=19.4; SIR=88). A deficit of
lung cancer incidence was observed in the ferrosilicon group (O=2;
E=5.8; SIR=35). In the ferrochromium group there were a significant
excess of lung cancer; 10 observed lung cancers with 6.5 expected
(SIR=154).
Axelsson et al. conducted a study of 1,932 ferrochromium workers to
examine whether exposure in the ferrochromium industry could be
associated with an increased risk of developing tumors, especially lung
cancer (Ex. 7-62). The study cohort and findings are summarized in
Table V.5. The study cohort was defined as males employed at a
ferrochromium plant in Sweden for at least one year during the period
January 1, 1930 to December 31, 1975.
The different working sites within the industry were classified
into four groups with respect to exposure to Cr(VI) and Cr(III).
Exposure was primarily to metallic and trivalent chromium with
estimated levels ranging from 0-2.5 mg/m3. Cr(VI) was also
present in certain operations with estimated levels ranging from 0-0.25
mg/m3. The highest exposure to Cr(VI) was in the arc-furnace
operations. Cr(VI) exposure also occurred in a chromate reduction
process during chromium alum production from 1950-1956. Asbestos-
containing materials had been used in the plant. Cohort members were
classified according to length and place of work in the plant.
Death certificates were obtained and coded to the revision of the
International Classification of Diseases in effect at the time of
death. Data on cancer incidence were obtained from the Swedish National
Cancer Registry. Causes of death in the cohort for the period 1951-1975
were compared with causes of death for the age-adjusted male population
in the county in which the plant was located.
There were seven cases of cancers of the trachea, bronchus and lung
and the pleura with 5.9 expected (SIR=119) for the period 1958-1975.
Four of the seven cases in the lung cancer group were maintenance
workers and two of the four cases were pleural mesotheliomas. In the
arc furnace group, which was thought to have the highest potential
exposure to both Cr(III) and Cr(VI), there were two cancers of the
trachea, bronchus and lung and the pleura. One of the cases was a
mesothelioma. Of the 380 deaths that occurred during the period 1951-
1975, five were from cancer of the trachea, bronchus and lung and the
pleura (E=7.2; SMR=70). For the "highly" exposed furnace workers,
there was one death from cancer of the trachea, bronchus and lung and
the pleura.
Moulin et al. conducted a cohort mortality study in a French
ferrochromium/stainless steel plant to determine if exposure to
chromium compounds, nickel compounds and polycyclic aromatic
hydrocarbons (PAHs) results in an increased risk of lung cancer (Ex.
282). The cohort was defined as men employed for at least one year
between January 1, 1952 and December 31, 1982; 2,269 men met the cohort
entrance criteria. No quantitative exposure data were available and no
information on the relative amounts of Cr(VI) and Cr(III) was provided.
In addition, some workers were also exposed to other carcinogens, such
as silica and asbestos. The authors estimated that 75.7% of the cohort
had been exposed to combinations of PAH, nickel and chromium compounds.
Of the 137 deaths identified, the authors determined 12 were due to
cancer of the trachea, bronchus and lung (E=8.56; SMR=140; 95% CI:
0.72-2.45). Eleven of the 12 lung cancers were in workers employed for
at least one year in the ferrochromium or stainless steel production
workshops (E=5.4; SMR=204; 95% CI: 1.02-3.64).
Pokrovskaya and Shabynina conducted a cohort mortality study of
male and female workers employed "some time" between 1955 and 1969 at
a chromium ferroalloy production plant in the U.S.S.R (Ex. 7-61).
Workers were exposed to both Cr(III) and Cr(VI) as well as to benzo [a]
pyrene. Neither the number of workers nor the number of cancer deaths
by site were provided. Death certificates were obtained and the deaths
were compared with municipal mortality rates by gender and 10 year age
groups. The investigators state that they were able to exclude those in
the comparison group who had chromium exposures in other industries.
The lung cancer SMR for male chromium ferroalloy workers was 440 in the
30-39 year old age group and 660 in the 50-59 year old age group
(p=0.001). There were no lung cancer deaths in the 40-49 and the 60-69
year old age groups. The data suggest that these ferrochromium workers
may have been had an excess risk of lung cancer.
The association between Cr(VI) exposure in ferrochromium workers
and the incidence of respiratory tract cancer these studies is
difficult to assess because of co-exposures to other potential
carcinogens (e.g., asbestos, PAHs, nickel, etc.), absence of a clear
exposure-response relationship and lack of information on smoking.
There is suggestive evidence of excess lung cancer mortality among
Cr(VI)-exposed ferrochromium workers in the Norwegian (Langard) cohort
when compared to a similar unexposed cohort of ferrosilicon workers.
However, there is little consistency for this finding in the Swedish
(Axelsson) or French (Moulin) cohorts.
6. Evidence From Workers in Other Industry Sectors
There are several other epidemiological studies that do not fit
into the five industry sectors previously reviewed. These include
worker cohorts in the aerospace industry, paint manufacture, and
leather tanning operations, among others. The two cohorts of aircraft
manufacturing workers are summarized in Table V-6. All of the cohorts
had some Cr(VI) exposure, but certain cohorts may have included a
sizable number of workers with little or no exposure to Cr(VI). This
creates an additional complexity in assessing whether the study
findings support a Cr(VI) etiology for cancer of the respiratory system.
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Alexander et al. conducted a cohort study of 2,429 aerospace
workers with a minimum of six months of cumulative employment in jobs
involving chromate exposure during the period 1974 through 1994 (Ex. 31-16-3).
Exposure estimates were based on industrial hygiene measurements and work
history records. Jobs were classified into categories of "high"
(spray painters, decorative painters), "moderate" (sanders/maskers,
maintenance painters) and "low" (chrome platers, surface processors,
tank tenders, polishers, paint mixers) exposure. Each exposure category
was assigned a summary TWA exposure based upon the weighted TWAs and
information from industrial hygienists. The use of respiratory
protection was accounted for in setting up the job exposure matrix. The
index of cumulative total chromium exposure (reported as [mu]g/m\3\
chromate TWA-years) was computed by multiplying the years in each job
by the summary TWAs for each exposure category.
In addition to cumulative chromate exposure, chromate exposure jobs
were classified according to the species of chromate. According to the
authors, in painting operations the exposure is to chromate pigments
with moderate and low solubility such as zinc chromate, strontium
chromate and lead chromate; in sanding and polishing operations the
same chromate pigments exist as dust; while platers and tank tenders
are exposed to chromium trioxide, which is highly soluble.
Approximately 26% of the cohort was lost to follow-up. Follow-up on
the cohort was short (average 8.9 years per cohort member). Cases were
identified through the Cancer Surveillance System (CSS) at the Fred
Hutchinson Cancer Research Center in Seattle, Washington. CSS records
primary cancer diagnoses in 13 counties in western Washington. Expected
numbers were calculated using race-, gender-, age- and calendar-
specific rates from the Puget Sound reference population for 1974
through 1994. Fifteen lung cancer cases were identified with an overall
standardized incidence ratio (SIR) of 80 (95% CI: 0.4-1.3). The SIRs
for lung cancer by cumulative years of employment in the "high
exposure" painting job category were based upon only three deaths in
each of the cumulative years categories (<5 and >=5); years of
employment was inversely related to the risk of lung cancer. For those
in the "low exposure" category, the SIRs were 130 for those who
worked less than five years in that category (95% CI: 0.2-4.8) and 190
for those who worked five years or more (95% CI: 0.2-6.9). However,
there were only two deaths in each category. The SIR for those who
worked >=5 years was 270 (95% CI: 0.5-7.8), but based only on three
deaths.
Boice et al. conducted a cohort mortality study of 77,965 workers
employed for a minimum of one year on or after January 1960 in aircraft
manufacturing (Ex. 31-16-4). Routine exposures to Cr(VI) compounds
occurred primarily while operating plating and coating process
equipment or when using chromate based primers or paints. According to
the authors, 3,634 workers, or 8% of the cohort, had the potential for
routine exposure to chromate and 3,809 workers, or 8.4%, had the
potential for intermittent exposure to chromate. Limited chromate air
sampling was conducted between 1978 and 1991. The mean full shift air
measurement was 1.5 [mu]g CrO3/m\3\ (0.78 [mu]g Cr(VI)/m\3\)
indicating fairly low airborne Cr(VI) in the plant (Ex. 47-19-5).
Follow up of the cohort was through 1996. Expectations were
calculated based on the general population of California for white
workers, while general population rates for the U.S. were used for non-
white workers. For the 3,634 cohort members who had potential for
routine exposure to chromates, the lung cancer SMR (race and gender
combined) was 102 based upon 87 deaths (95% CI: 82-126). There was a
slight non-significant positive trend (p value >2.0) for lung cancer
with duration of potential exposure. The SMR was 108 (95% CI: 75-157)
for workers exposed to chromate for >=5 years. Among the painters,
there were 41 deaths from lung cancer yielding a SMR of 111 (95% CI:
80-151). For those who worked as a process operator or plater the SMR
for lung cancer was 103 based upon 38 deaths (95% CI: 73-141).
OSHA believes the Alexander (Ex. 31-16-3) and the Boice et al. (Ex.
31-16-4) studies have several limitations. The Alexander cohort has few
lung cancers (due in part to the young age of the population) and lacks
smoking data. The authors note that these factors "[limit] the overall
power of the study and the stability of the risk estimates, especially
in exposure-related subanalyses" (Ex. 31-16-3, p. 1256). Another
limitation of the study is the 26.3% of cohort members lost to follow-
up. Boice et al. is a large study of workers in the aircraft
manufacturing industry, but was limited by a lack of Cr(VI) exposure
measurement during the 1960s and most of the 1970s. I was also limited
by a substantial healthy worker survivor effect that may have masked
evidence of excess lung cancer mortality in Cr(VI) exposed workers (Ex.
31-16-4). These studies are discussed further in section VI, including
section VI.B.6 (Alexander cohort) and section VI.G.4.a (Alexander and
Boice cohorts).
Dalager et al. conducted a proportionate mortality study of 977
white male spray painters potentially exposed to zinc chromate in the
aircraft maintenance industry who worked at least three months and
terminated employment within ten years prior to July 31, 1959 (Ex. 7-
64). Follow-up was through 1977. The expected numbers of deaths were
obtained by applying the cause-specific proportionate mortality of U.S.
white males to the total numbers of deaths in the study group by five
year age groups and five year time intervals. Two hundred and two
deaths were observed. There were 21 deaths from cancer of the
respiratory system (PMR=184), which was statistically significant. The
Proportionate Cancer Mortality Ratio for cancer of the respiratory
system was not statistically significant (PCMR= 146). Duration of
employment as a painter with the military as indicated on the service
record was used as an estimate of exposure to zinc chromate pigments,
which were used as a metal primer. The PMRs increased as duration of
employment increased (< 5 years, O=9, E=6.4, PMR=141; 5-9 years, O=6,
E=3, PMR=200; and 10+ years, O=6, E=2, PMR=300) and were statistically
significant for those who worked 10 or more years.
Bertazzi et al. studied the mortality experience of 427 workers
employed for a minimum of six months between 1946 and 1977 in a plant
manufacturing paint and coatings (Ex. 7-65). According to the author,
chromate pigments represented the "major exposure" in the plant. The
mortality follow-up period was 1954-1978. There were eight deaths from
lung cancer resulting in a SMR of 227 on the local standard (95% CI:
156-633) and a SMR of 334 on the national standard (95% CI: 106-434).
The authors were unable to differentiate between exposures to different
paints and coatings. In addition, asbestos was used in the plant and
may be a potential confounding exposure.
Morgan conducted a cohort study of 16,243 men employed after
January 1, 1946 for at least one year in the manufacture of paint or
varnish (Ex. 8-4). Analysis was also conducted for seven subcohorts,
one of which was for work with pigments. Expectations were calculated
based upon the mortality experience of U.S. white males. The SMR for
cancer of the trachea, bronchus and lung was below unity based upon 150
deaths. For the pigment subcohort, the SMR for cancer of the trachea,
bronchus and lung was 117 based upon 43 deaths. In a follow-up study of
the subcohorts, case-control analyses were conducted for several causes
of death including lung cancer (Ex. 286). The details of matching were not
provided. The authors state that no significant excesses of lung cancer
risk by job were found. No odds ratios were presented.
Pippard et al. conducted a cohort mortality study of 833 British
male tannery workers employed in 1939 and followed through December 31,
1982 (Ex. 278). Five hundred and seventy three men worked in tanneries
making vegetable tanned leathers and 260 men worked in tanneries that
made chrome tanned leathers. The expected number of deaths was
calculated using the mortality rates of England and Wales as a whole.
The lung cancer SMR for the vegetable tanned leather workers was in
deficit (O=31; E=32.6; 95% CI: 65-135), while the lung cancer SMR for
the chrome tanned leather workers was slightly elevated but not
statistically significant (O=13; E=12; SMR=108; 95% CI: 58-185).
In a different study of two U.S. tanneries, Stern et al.
investigated mortality in a cohort of all production workers employed
from January 1, 1940 to June 11, 1979 at tannery A (N=2,807) and from
January 1, 1940 to May 1, 1980 at tannery B (N=6,558) (Ex. 7-68). Vital
status was followed through December 31, 1982. There were 1,582 deaths
among workers from the two tanneries. Analyses were conducted employing
both U.S. mortality rates and the mortality rates for the state in
which the plant is located. There were 18 lung/pleura cancer deaths at
tannery A and 42 lung/pleura cancer deaths at tannery B. The lung
cancer/pleura SMRs were in deficit on both the national standard and
the state standard for both tanneries. The authors noted that since the
1940s most chrome tanneries have switched to the one-bath tanning
method in which Cr(VI) is reduced to Cr(III).
Blot et al. reported the results of a cohort study of 51,899 male
workers of the Pacific Gas & Electric Company alive in January 1971 and
employed for at least six months before the end of 1986 (Ex. 239). A
subset of the workers were involved in gas generator plant operations
where Cr(VI) compounds were used in open and closed systems from the
1950s to early 1980s. One percent of the workers (513 men) had worked
in gas generator jobs, with 372 identified from post-1971 listing at
the company's three gas generator plants and 141 from gas generator job
codes. Six percent of the cohort members (3,283) had trained at one of
the gas generator plants (Kettleman).
SMRs based on national and California rates were computed. Results
in the paper are based on the California rates, since the overall
results reportedly did not differ substantially from those using the
national rates. SMRs were calculated for the entire cohort and for
subsets defined by potential for gas generator plant exposure. No
significant cancer excesses were observed and all but one cancer SMR
was in deficit. There were eight lung cancer deaths in the gas
generator workers (SMR=81; 95% CI: 0.35-1.60) and three lung cancer
deaths among the Kettleman trainees (SMR=57; 95% CI: 0.12-1.67). There
were no deaths from nasal cancer among either the gas generator workers
or the Kettleman trainees. The risk of lung cancer did not increase
with length of employment or time since hire.
Rafnsson and Johannesdottir conducted a study of 450 licensed
masons (cement finishers) in Iceland born between 1905 and 1945,
followed from 1951 through 1982 (Ex. 7-73). Stonecutters were excluded.
Expectations were based on the male population of Iceland. The SMR for
lung cancer was 314 and is statistically significant based upon nine
deaths (E=2.87; 95% CI: 1.43-5.95). When a 20 year latency was factored
into the analysis, the lung cancer SMR remained statistically
significant (O=8; E=2.19; SMR=365; 95% CI: 1.58-7.20).
Svensson et al. conducted a cohort mortality study of 1,164 male
grinding stainless steel workers employed for three months or more
during the period 1927-1981 (Ex.266). Workers at the facility were
reportedly exposed to chromium and nickel in the stainless steel
grinding process. Records provided by the company were used to assign
each worker to one of three occupational categories: those considered
to have high exposure to chromium, nickel as well as total dust, those
with intermediate exposure, and those with low exposure. Mortality
rates for males in Blekinge County, Sweden were used as the reference
population. Vital status follow-up was through December 31, 1983. A
total of 194 deaths were observed (SMR=91). No increased risk of lung
cancer was observed (SMR=92). The SMR for colon/rectum cancer was 2.47,
but was not statistically significant.
Cornell and Landis studied the mortality experience of 851 men who
worked in 26 U.S. nickel/chromium alloy foundries between 1968 and 1979
(Ex. 7-66). Standardized Proportionate Mortality Ratio (SPMR) analyses
were done using both an internal comparison group (foundry workers not
exposed to nickel/chromium) and the mortality experience of U.S. males.
The SPMR for lung cancer was 105 (O=60; E=56.9). No nasal cancer deaths
were observed.
Brinton et al. conducted a case-control study of 160 patients
diagnosed with primary malignancies of the nasal cavity and sinuses at
one of four hospitals in North Carolina and Virginia between January 1,
1970 and December 31, 1980 (Ex. 8-8). For each case determined to be
alive at the time of interview, two hospital controls were selected
matched on vital status, hospital, year of admission (2
years), age (5 years), race and state economic area or
county or usual residence. Excluded from control selection were
malignant neoplasms of the buccal cavity and pharynx, esophagus, nasal
cavity, middle ear and accessory sinuses, larynx, and secondary
neoplasms. Also excluded were benign neoplasms of the respiratory
system, mental disorders, acute sinusitis, chronic pharyngitis and
nasopharyngitis, chronic sinusitis, deflected nasal septum or nasal
polyps. For those cases who were deceased at the time of interview, two
different controls were selected. One control series consisted of
hospital controls as described previously. The second series consisted
of decedents identified through state vital statistics offices matched
for age (5 years), sex, race, county of usual residence and
year of death. A total of 193 cases were identified and 160 case
interviews completed. For those exposed to chromates, the relative risk
was not significantly elevated (OR=5.1) based upon five cases.
According to the authors, chromate exposure was due to the use of
chromate products in the building industry and in painting, rather than
the manufacture of chromates.
Hernberg et al. reported the results of a case-control study of 167
living cases of nasal or paranasal sinus cancer diagnosed in Denmark,
Finland and Sweden between July 1, 1977 and December 31, 1980 (Exs. 8-
7; 7-71). Controls were living patients diagnosed with malignant tumors
of the colon and rectum matched for country, gender and age at
diagnosis (3 years) with the cases. Both cases and controls
were interviewed by telephone to obtain occupational histories.
Patients with work-related exposures during the ten years prior to
their illness were excluded. Sixteen cases reported exposure to
chromium, primarily in the "stainless steel welding" and "nickel"
categories, versus six controls (OR=2.7l; 95% CI: 1.1-6.6).
7. Evidence From Experimental Animal Studies
Most of the key animal cancer bioassays for chromium compounds were
conducted before 1988. These studies have been critically reviewed by the
IARC in the Monograph Chromium, Nickel, and Welding (Ex. 35-43). OSHA
reviewed the key animal cancer bioassays in the NPRM (69 FR at 59341-59347)
and requested any additional data in experimental animals that were considered
important to evaluating the carcinogenicity of Cr(VI). The discussion below
describes these studies along with any new study information received
during the public hearing and comment periods.
In the experimental studies, Cr(VI) compounds were administered by
various routes including inhalation, intratracheal instillation,
intrabronchial implantation, and intrapleural injection, as well as
intramuscular and subcutaneous injection. For assessing human health
effects from occupational exposure, the most relevant route is
inhalation. However, as a whole, there were very few inhalation
studies. In addition to inhalation studies, OSHA is also relying on
intrabronchial implantation and intratracheal instillation studies for
hazard identification because these studies examine effects directly
administered to the respiratory tract, the primary target organ of
concern, and they give insight into the relative potency of different
Cr(VI) compounds. In comparison to studies examining inhalation,
intrabronchial implantation, and intratracheal instillation, studies
using subcutaneous injection and intramuscular administration of Cr(VI)
compounds were of lesser significance but were still considered for
hazard identification.
In its evaluation, OSHA took into consideration the exposure
regimen and experimental conditions under which the experiments were
performed, including the exposure level and duration; route of
administration; number, species, strain, gender, and age of the
experimental animals; the inclusion of appropriate control groups; and
consistency in test results. Some studies were not included if they did
not contribute to the weight of evidence, lacked adequate
documentation, were of poor quality, or were less relevant to
occupational exposure conditions (e.g., some intramuscular injection
studies).
The summarized animal studies are organized by Cr(VI) compound in
order of water solubility as defined in section IV on Chemical
Properties (i.e., Cr(VI) compounds that are highly soluble in water;
Cr(VI) compounds that are slightly soluble in water, and Cr(VI)
compounds that insoluble in water). Solubility is an important factor
in determining the carcinogenicity of Cr(VI) compounds (Ex. 35-47).
a. Highly Water Soluble Cr(VI) Compounds
Multiple animal carcinogenicity studies have been conducted on
highly water soluble sodium dichromate and chromic acid. The key
studies are summarized in Table V-7.
BILLING CODE 4510-26-P
Click here to view table V-7
BILLING CODE 4510-26-C
Chromic acid (Chromium trioxide). In a study by Adachi et al., ICR/JcI
mice were exposed by inhalation to 3.63 mg/m\3\ for 30 minutes per day,
two days per week for up to 12 months (Ex. 35-26-1). The mice were
observed for an additional six months. The authors used a miniaturized
chromium electroplating system to generate chromic acid for the study.
The authors found there were elevations in lung adenomas at 10-14
months (3/14 vs. 0/10) and lung adenocarcinomas at 15-18 months (2/19
vs. 0/10), but the results were not statistically significant. The
small number of animals (e.g. 10-20 per group) used in this study
limited its power to detect all but a relatively high tumor incidence
(e.g. >20%) with statistical precision. Statistically significant
increases in nasal papillomas were observed in another study by Adachi
et al., in which C57B1 mice were exposed by inhalation to 1.81 mg/m\3\
chromic acid for 120 min per day, two days per week for up to 12 months
(Ex. 35-26). At 18 months, the tumor incidence was 6/20 in exposed
animals vs. 0/20 in the control animals (p< 0.05).
In separate but similar studies, Levy et al. and Levy and Venitt,
using similar exposure protocol, conducted bronchial implantation
experiments in which 100 male and female Porton-Wistar rats were dosed
with single intrabronchial implantations of 2 mg chromic acid (1.04 mg
Cr(VI)) mixed 50:50 with cholesterol in stainless steel mesh pellets
(Exs. 11-2; 11-12). The authors found no statistically significant
increases in lung tumors, although Levy et al. found a bronchial
carcinoma incidence of 2/100 in exposed rats compared with 0/100 in
control rats. Levy and Venitt found a bronchial carcinoma incidence of
1/100 accompanied by a statistically significant increase in squamous
metaplasia, a lesion believed capable of progressing to carcinoma.
There was no statistically significant increase in the incidence of
squamous metaplasia in control rats or rats treated with Cr(III)
compounds in the same study. This finding suggests that squamous
metaplasia is specific to Cr(VI) and is not evoked by a non-specific
stimuli, the implantation procedure itself, or treatment with Cr(III)
containing materials.
Similar to Levy et al. and Levy and Venitt studies, Laskin et al.
gave a single intrabronchial implantation of 3-5 mg chromic acid mixed
50:50 with cholesterol in stainless steel mesh pellets to 100 male and
female Porton-Wistar rats (Ex. 10-1). The rats were observed for 2
years. No tumors were identified in the treated or control animals (0/
100 vs. 0/24).
Sodium dichromate. Glaser et al. exposed male Wistar rats to
aerosolized sodium dichromate by inhalation for 22-23 hours per day,
seven days per week for 18 months (Exs. 10-10; 10-11). The rats were
held for an additional 12 months at which point the study was
terminated. Lung tumor incidences among groups exposed to 25, 50, and
100 [mu]g Cr(VI)/m\3\ were 0/18, 0/18, and 3/19, respectively, vs. 0/37
for the control animals. Histopathology revealed one adenocarcinoma and
two adenomas in the highest group. The slightly elevated tumor
incidence at the highest dose was not statistically significant. A
small number of animals (20 per group) were used in this study limiting
its power to detect all but a relatively high tumor incidence (e.g.
>20%) with statistical precision. In addition, the administered doses
used in this study were fairly low, such that the maximum tolerated
dose (i.e., the maximum dose level that does not lead to moderate
reduction in body weight gain) may not have been achieved. Together,
these factors limit the interpretation of the study.
In an analysis prepared by Exponent and submitted by the Chrome
Coalition, Exponent stated that "inhalation studies of Glaser et al.
support a position that exposures to soluble Cr(VI) at concentrations
at least as high as the current PEL (i.e., 52 [mu]g/m\3\) do not cause
lung cancer" (Ex. 31-18-1, page 2). However, it should be noted that
the Glaser et al. studies found that 15% (\3/19\) of the rats exposed
to an air concentration just above the current PEL developed lung
tumors, and that the elevated tumor incidence was not statistically
significant in the highest dose group because the study used a small
number of animals. OSHA believes the Glaser study lacks the statistical
power to state with sufficient confidence that Cr(VI) exposure does not
cause lung cancer at the current PEL, especially when given the
elevated incidence of lung tumors at the next highest dose level.
Steinhoff et al. studied the carcinogenicity of sodium dichromate
in Sprague-Dawley rats (Ex. 11-7). Forty male and 40 female Sprague-
Dawley rats were divided into two sets of treatment groups. In the
first set, doses of 0.01, 0.05 or 0.25 mg/kg body weight in 0.9% saline
were instilled intratracheally five times per week. In the second set
of treatment groups, 0.05, 0.25 or 1.25 mg/kg body weight in 0.9%
saline doses were instilled intratracheally once per week. Duration of
exposure in both treatment groups was 30 months. The total cumulative
dose for the lowest treatment group of animals treated once per week
was the same as the lowest treatment group treated five times per week.
Similarly, the medium and high dose groups treated once per week had
total doses equivalent to the medium and high dose animals treated five
times per week, respectively. No increased incidence of lung tumors was
observed in the animals dosed five times weekly. However, in the
animals dosed once per week, tumor incidences were 0/80 in control
animals, 0/80 in the 0.05 mg/kg exposure group, 1/80 in the 0.25 mg/kg
exposure group and 14/80 in the 1.25 mg/kg exposure group (p < 0.01).
The tumors were malignant in 12 of the 14 animals in the 1.25 mg/kg
exposure group. Tracheal instillation at the highest dose level (i.e.
1.25 mg/kg) caused emphysematous lesions and pulmonary fibrosis in the
lungs of Cr(VI)-treated rats. A similar degree of lung damage did not
occur at the lower dose levels. Exponent commented that the Steinhoff
and Glaser results are evidence that the risk of lung cancer from
occupational exposure does not exist below a threshold Cr(VI) air
concentration of approximately 20 [mu]g/m\3\ (Ex. 38-233-4). This
comment is addressed in Section VI.G.2.c.
In separate but similar studies, Levy et al. and Levy and Venitt
implanted stainless steel mesh pellets filled with a single dose of 2
mg sodium dichromate (0.80 mg Cr(VI)) mixed 50:50 with cholesterol in
the bronchi of male and female Porton-Wistar rats (Exs. 11-2; 11-12).
Control groups (males and females) received blank pellets or pellets
loaded with cholesterol. The rats were observed for two years. Levy et
al. and Levy and Venitt reported a bronchial tumor incidence of 1/100
and 0/89, respectively, for exposed rats. However, the latter study
reported a statistically significant increase in squamous metaplasia, a
lesion believed capable of progressing to carcinoma, among exposed rats
when compared to unexposed rats. There were no bronchial tumors or
squamous metaplasia in any of the control animals and no significant
increases in lung tumors were observed in the two studies.
b. Slightly Water Soluble Cr(VI) Compounds
Animal carcinogenicity studies have been conducted on slightly
water soluble calcium chromate, strontium chromate, and zinc chromates.
The key studies are summarized in Table V-8.
BILLING CODE 4510-26-P
Click here to view table V-8
BILLING CODE 4510-26-C
Calcium chromate. Nettesheim et al. conducted the only available
inhalation carcinogenicity study with calcium chromate showing
borderline statistical significance for increased lung adenomas in
C57B1/6 mice exposed to 13 mg/m\3\ for 5 hours per day, 5 days per week
over the life of the mice. The tumor incidences were 6/136 in exposed
male mice vs. 3/136 in control male mice and 8/136 in exposed female
mice vs. 2/136 in control female mice (Ex. 10-8).
Steinhoff et al. observed a statistically significant increase in
lung tumors in Sprague-Dawley rats exposed by intratracheal
instillation to 0.25 mg/kg body weight calcium chromate in 0.9% saline
five times weekly for 30 months (Ex. 11-7). Tumors were found in 6/80
exposed animals vs. 0/80 in unexposed controls (p< 0.01). Increased
incidence of lung tumors was also observed in those rats exposed to
1.25 mg/kg calcium chromate once per week (14/80 vs. 0/80 in controls)
for 30 months. At the highest dose, the authors observed 11 adenomas,
one adenocarcinoma, and two squamous carcinomas. The total administered
doses for both groups of dosed animals (1 x 1.25 mg/kg and 5 x 0.25 mg/
kg) were equal, but the tumor incidence in the rats exposed once per
week was approximately double the incidence in rats exposed to the same
weekly dose divided into five smaller doses. The authors suggested that
the dose-rate for calcium chromate compounds may be important in
determining carcinogenic potency and that limiting higher single
exposures may offer greater protection against carcinogenicity than
reducing the average exposure alone.
Snyder et al. administered Cr(VI)-contaminated soil of defined
aerodynamic diameter (2.9 to 3.64 micron) intratracheally to male
Sprague-Dawley rats (Ex. 31-18-12). For the first six weeks of
treatment, the rats were instilled with weekly suspensions of 1.25 mg
of material per kg body weight, followed by 2.5 mg/kg every other week,
until treatments were terminated after 44 weeks. The investigation
included four exposure groups: control animals (50 rats), rats
administered Cr(VI)-contaminated soil (50 rats), rats administered
Cr(VI)-contaminated soil supplemented with calcium chromate (100 rats),
and rats administered calcium chromate alone (100 rats). The total
Cr(VI) dose for each group was: control group (0.000002 mg Cr(VI)/kg),
soil alone group (0.324 mg Cr(VI)/kg), soil plus calcium chromate group
(7.97 mg Cr(VI)/kg), and calcium chromate alone group (8.70 mg Cr(VI)/
kg). No primary tumors were observed in the control group or the
chromium contaminated soil group. Four primary tumors of the lung were
found in the soil plus calcium chromate group and one primary lung
tumor was observed in the group treated with calcium chromate alone;
however, these incidences did not reach statistical significance.
Statistically significant increases in the incidence of bronchial
carcinoma in rats exposed to calcium chromate through intrabronchial
instillation were reported by Levy et al. (Ex. 11-2) and Levy and
Venitt (Ex. 11-12). These studies, using a similar protocol, implanted
a single dose of 2 mg calcium chromate (0.67 mg Cr(VI)) mixed 50:50
with cholesterol in stainless steel pellets into the bronchi of Porton-
Wistar rats. Levy et al. and Levy and Venitt found bronchial carcinoma
incidences of 25/100 and 8/84, respectively, following a 24-month
observation. The increased incidences were statistically significant
when compared to the control group. Levy and Venitt also reported
statistically significant increases in squamous metaplasia in the
calcium chromate-treated rats (Ex. 11-12).
Laskin et al. observed 8/100 tumors in rats exposed to a single
dose of 3-5 mg calcium chromate mixed with cholesterol in stainless
steel mesh pellets implanted in the bronchi (Ex. 10-1). Animals were
observed for a total of 136 weeks. The sex, strain, and species of the
rats were not specified in the study. Tumor incidence in control
animals was 0/24. Although tumor incidence did not reach statistical
significance in this study, OSHA agrees with the IARC evaluation that
the incidences are due to calcium chromate itself rather than
background variation.
Strontium chromate. Strontium chromate was tested by intrabronchial
implantation and intrapleural injection. In a study by Levy et al., two
strontium chromate compounds mixed 50:50 with cholesterol in stainless
steel mesh pellets were administered by intrabronchial instillation of
a 2 mg (0.48 mg Cr(VI)) dose into 100 male and female Porton-Wistar
rats (Ex. 11-2). Animals were observed for up to 136 weeks. The
strontium chromate compounds induced bronchial carcinomas in 43/99 (Sr,
42.2%; CrO4, 54.1%) and 62/99 rats (Sr, 43.0%; Cr, 24.3%)],
respectively, compared to 0/100 in the control group. These results
were statistically significant. The strontium chromates produced the
strongest carcinogenic response out of the 20 Cr(VI) compounds tested
by the intrabronchial implantation protocol. Boeing Corporation
commented that the intrabronchial implantation results with strontium
chromate should not be relied upon in an evaluation of carcinogenicity
and that the data is inconsistent with other Cr(VI) studies (Ex. 38-
106-2, p. 26). This comment is discussed in the Carcinogenic Effects
Conclusion Section V.B.9 dealing with the carcinogenicity of slightly
soluble Cr(VI) compounds.
In the study by Hueper, strontium chromate was administered by
intrapleural injection (doses unspecified) lasting 27 months (Ex. 10-
4). Local tumors were observed in 17/28 treated rats vs. 0/34 for the
untreated rats. Although the authors did not examine the statistical
significance of tumors, the results clearly indicate a statistical
significance.
Zinc chromate compounds. Animal studies have been conducted to
examine several zinc chromates of varying water solubilities and
composition. In separate, but similarly conducted studies, Levy et al.
and Levy and Venitt studied two zinc chromate powders, zinc potassium
chromate, and zinc tetroxychromate (Exs. 11-2; 11-12). Two milligrams
of the compounds were administered by intrabronchial implantation to
100 male and female Porton-Wistar rats. Zinc potassium chromate (0.52
mg Cr(VI)) produced a bronchial tumor incidence of 3/61 which was
statistically significant (p< 0.05) when compared to a control group
(Ex. 11-12). There was also an increased incidence of bronchial tumors
(5/100, p=0.04; 3/100, p=0.068) in rats receiving the zinc chromate
powders (0.44 mg Cr(VI)). Zinc tetroxychromate (0.18 mg Cr(VI)) did not
produce a statistically significant increase in tumor incidence (1/100)
when compared to a control group. These studies show that most slightly
water soluble zinc chromate compounds elevated incidences of tumors in
rats.
Basic potassium zinc chromate was administered to mice, guinea pigs
and rabbits via intratracheal instillation (Ex. 35-46). Sixty-two
Strain A mice were given six injections of 0.03 ml of a 0.2% saline
suspension of the zinc chromate at six week intervals and observed
until death. A statistically significant increase in tumor incidence
was observed in exposed animals when compared to controls (31/62 vs. 7/
18). Statistically significant effects were not observed among guinea
pigs or rabbits. Twenty-one guinea pigs (sex and strain not given)
received six injections of 0.3 ml of a 1% suspension of zinc chromate
at three monthly intervals and observed until death. Results showed
pulmonary adenomas in only 1/21 exposed animals vs. 0/18 in controls.
Seven rabbits (sex and strain not given) showed no increase in lung
tumors when given 3-5 injections of 1 ml of a saline suspension of 10
mg zinc chromate at 3-month intervals. However, as noted by IARC, the
small numbers of animals used in the guinea pig and rabbit experiments
(as few as 13 guinea pigs and 7 rabbits per group) limit the power of
the study to detect increases in cancer incidence.
Hueper found that intrapleural injection of slightly water soluble
zinc yellow (doses were unspecified) resulted in statistically significant
increases in local tumors in rats (sex, strain, and age of rat
unspecified; dose was unspecified). The incidence of tumors in exposed
rats was 22/33 vs. 0/34 in controls (Ex. 10-4).
Maltoni et al. observed increases in the incidence of local tumors
after subcutaneous injection of slightly water soluble zinc yellow in
20 male and 20 female Sprague-Dawley rats (statistical significance was
not evaluated) (Ex. 8-37). Tumor incidences were 6/40 in 20%
CrO3 dosed animals at 110 weeks and 17/40 in 40%
CrO3 dosed animals at 137 weeks compared to 0/40 in control
animals.
c. Water Insoluble Cr(VI) Compounds
There have been a number of animal carcinogenicity studies
involving implantation or injection of principally water insoluble
zinc, lead, and barium chromates. The key studies are summarized in
Table V-9.
BILLING CODE 4510-26-P
Click here to view table V-9
BILLING CODE 4510-26-C
Lead chromate and lead chromate pigments. Levy et al. examined the
carcinogenicity of lead chromate and several lead chromate-derived
pigments in 100 male and female Porton-Wistar rats after a single
intrabronchial implantation followed by a two year observation period
(Ex. 11-12). The rats were dosed with two mg of a lead chromate
compound and lead chromate pigments, which were mixed 50:50 with
cholesterol in stainless steel mesh pellets and implanted in the
bronchi of experimental animals. The lead chromate and lead chromate
pigment compositions consisted of the following: lead chromate (35.8%
CrO4; 0.32 mg Cr(VI)), primrose chrome yellow (12.6% Cr;
0.25 mg Cr(VI)), molybdate chrome orange (12.9% Cr; 0.26 mg Cr(VI)),
light chrome yellow (12.5% Cr; 0.25 mg Cr(VI)), supra LD chrome yellow
(26.9% CrO3; 0.28 mg Cr(VI)), medium chrome yellow (16.3%
Cr; 0.33 mg Cr(VI)) and silica encapsulated medium chrome yellow (10.5%
Cr; 0.21 mg Cr(VI)). No statistically significant tumors were observed
in the lead chromate group compared to controls (1/98 vs. 0/100),
primrose chrome yellow group (1/100 vs. 0/100), and supra LD chrome
yellow group (1/100 vs. 0/100). The authors also noted no tumors in the
molybdate chrome orange group, light chrome yellow group, and silica
encapsulated medium chrome yellow group.
Maltoni (Ex. 8-25), Maltoni (Ex. 5-2), and Maltoni et al. (Ex. 8-
37) examined the carcinogenicity of lead chromate, basic lead chromate
(chromium orange) and molybdenum orange in 20 male and 20 female
Sprague-Dawley rats by a single subcutaneous administration of the lead
chromate compound in water. Animals were observed for 117 to 150 weeks.
After injection of 30 mg lead chromate, local injection site sarcomas
were observed in 26/40 exposed animals vs. 0/60 and 1/80 in controls.
Although the authors did not examine the statistical significance of
sarcomas, the results clearly indicate a statistical significance.
Animals injected with 30 mg basic lead chromate (chromium orange) were
found to have an increased incidence of local injection site sarcomas
(27/40 vs. 0/60 and 1/80 in controls). Animals receiving 30 mg
molybdenum orange in 1 ml saline were also found to have an increased
incidence of local injection site sarcomas (36/40 vs. 0/60 controls).
Carcinogenesis was observed after intramuscular injection in a
study by Furst et al. (Ex. 10-2). Fifty male and female Fischer 344
rats were given intramuscular injections of 8 mg lead chromate in
trioctanoin every month for nine months and observed up to 24 months.
An increase in local tumors at the injection site (fibrosarcomas and
rhabdomyosarcomas) was observed (31/47 in treated animals vs. 0/22 in
controls). These rats also had an increased incidence of renal
carcinomas (3/23 vs. 0/22 in controls), but IARC noted that the renal
tumors may be related to the lead content of the compound. In the same
study, 3 mg lead chromate was administered to 25 female NISH Swiss
weanling mice via intramuscular injection every 4 months for up to 24
months. In the exposed group, the authors observed three lung
alveologenic carcinomas after 24 months of observation and two
lymphomas after 16 months of observation. Two control groups were used:
an untreated control group (22 rats) and a vehicle injected control
group (22 rats). The authors noted that one alveologenic carcinoma and
one lymphoma were observed in each control group. The Color Pigment
Manufacturers Association (CPMA) commented that the lack of elevated
tumor incidence in the intrabronchial implantation studies confirmed
that lead chromate was not carcinogenic and that the positive injection
studies by the subcutaneous, intrapleural, and intramuscular routes
were of questionable relevance (Ex. 38-205, p. 93). This comment is
further discussed in the Carcinogenic Effects Conclusion Section V.B.9
dealing with the carcinogenicity of lead chromate.
Barium chromate. Barium chromate was tested in rats via
intrabronchial, intrapleural and intramuscular administration. No
excess lung or local tumors were observed (Ex. 11-2; Ex. 10-4; Ex. 10-
6).
d. Summary. Several Cr(VI) compounds produced tumors in laboratory
animals under a variety of experimental conditions using different
routes of administration. The animals were generally given the test
material(s) by routes other than inhalation (e.g., intratracheal
administration, intramuscular injection, intrabronchial implantation,
and subcutaneous injection). Although the route of administration may
have differed from that found in an occupational setting, these studies
have value in the identification of potential health hazards associated
with Cr(VI) and in assessing the relative potencies of various Cr(VI)
compounds.
OSHA believes that the results from Adachi et al. (Ex. 35-26-1),
Adachi et al. (Ex. 35-26), Glaser et al. (Ex. 10-4), Glaser et al. (Ex.
10-10), Levy et al. (Ex. 11-2), and Steinhoff et al. (Ex. 11-7) studies
provide valuable insight on the carcinogenic potency of Cr(VI)
compounds in laboratory animals. Total dose administered, dose rate,
amount of dosage, dose per administration, number of times
administered, exposure duration and the type of Cr(VI) compound are
major influences on the observed tumor incidence in animals. It was
found that slightly water soluble calcium, strontium, and zinc
chromates showed the highest incidence of lung tumors, as indicated in
the results of the Steinhoff and Levy studies, even when compared to
similar doses of the more water soluble sodium chromates and chromic
acid compounds. The highly insoluble lead chromates did not produce
lung tumors by the intrabronchial implantation procedure but did
produce tumors by subcutaneous injection and intramuscular injection.
8. Mechanistic Considerations
Mechanistic information can provide insight into the biologically
active form(s) of chromium, its interaction with critical molecular
targets, and the resulting cellular responses that trigger neoplastic
transformation. There has been considerable scientific study in recent
years of Cr(VI)-initiated cellular and molecular events believed to
impact development of respiratory carcinogenesis. Much of the research
has been generated using in vitro techniques, cell culture systems, and
animal administrations. The early mechanistic data were reviewed by
IARC in 1990 (Ex. 35-43). Recent experimental research has identified
several biological steps critical to the mode of action by which Cr(VI)
transforms normal lung cells into a neoplastic phenotype. These are:
(a) Cellular uptake of Cr(VI) and its extracellular reduction, (b)
intracellular Cr(VI) reduction to produce biologically active products,
(c) damage to DNA, and (d) activation of signaling pathways in response
to cellular stress. Each step will be described in detail below.
a. Cellular Uptake and Extracellular Reduction. The ability of
different Cr(VI) particulate forms to be taken up by the
bronchoalveolar cells of the lung is an essential early step in the
carcinogenic process. Particle size and solubility are key physical
factors that influence uptake into these cells. Large particulates (>10
[mu]m) are generally deposited in the upper nasopharygeal region of the
respiratory tract and do not reach the bronchoalveolar region of the
lungs. Smaller Cr(VI) particulates will increasingly reach these lower
regions and come into contact with target cells.
Once deposited in the lower respiratory tract, solubility of Cr(VI)
particulates becomes a major influence on disposition. Highly water
soluble Cr(VI), such as sodium chromate and chromic acid, rapidly
dissolves in the fluids lining the lung epithelia and can be taken up
by lung cells via facilitated diffusion mediated by sulfate/phosphate
anion transport channels (Ex. 35-148). This is because Cr(VI) exists in
a tetrahedral configuration as a chromate oxyanion similar to the
physiological anions, sulfate and phosphate (Ex. 35-231). Using cultured
human epithelial cells, Liu et al. showed that soluble Cr(VI) uptake was
time- and dose-dependant over a range of 1 to 300 [mu]m in the medium with
30 percent of the Cr(VI) transported into the cells within two hours and
67 percent at 16 hours at the lowest concentration (Ex. 31-22-18).
Water insoluble Cr(VI) particulates do not readily dissolve into
epithelial lining fluids of the bronchoalveolar region. This has led to
claims that insoluble chromates, such as lead chromate pigments, are
not bioavailable and, therefore, are unable to cause carcinogenesis
(Ex. 31-15). However, several scientific studies indicate that
insoluble Cr(VI) particulates can come in close contact with the
bronchoalveolar epithelial cell surface, allowing enhanced uptake into
cells. Wise et al. showed that respirable lead chromate particles
adhere to the surface of rodent cells in culture causing cell-enhanced
dissolution of the chromate ion as well as phagocytosis of lead
chromate particles (Exs. 35-68; 35-67). The intracellular accumulation
was both time- and dose-dependant. Cellular uptake resulted in damage
to DNA, apoptosis (i.e., form of programmed cell death), and neoplastic
transformation (Ex. 35-119). Singh et al. showed that treatment of
normal human lung epithelial cells with insoluble lead chromate
particulates (0.4 to 2.0 [mu]g/cm\2\) or soluble sodium chromate (10
[mu]M) for 24 hours caused Cr(VI) uptake, Cr-DNA adduct formation, and
apoptosis (Ex. 35-66). The proximate genotoxic agent in these cell
systems was determined to be the chromate rather than the lead ions
(Ex. 35-327). Elias et al. reported that cell-enhanced particle
dissolution and uptake was also responsible for the cytotoxicity and
neoplastic transformation in Syrian hamster embryo cells caused by
Cr(VI) pigments, including several complex industrial chrome yellow and
molybdate orange pigments (Ex. 125). These studies are key experimental
evidence in the determination that water-insoluble Cr(VI) compounds, as
well as water soluble Cr(VI) compounds, are to be regarded as
carcinogenic agents. This determination is further discussed in the
next section (see V.B.9).
Reduction to the poorly permeable Cr(III) in the epithelial lining
fluid limits cellular uptake of Cr(VI). Ascorbic acid and glutathione
(GSH) are believed to be the key molecules responsible for the
extracellular reduction. Cantin et al. reported high levels of GSH in
human alveolar epithelial lining fluid and Susuki et al. reported
significant levels of ascorbic acid in rat lung lavage fluids (Exs. 35-
147; 35-143). Susuki and Fukuda studied the kinetics of soluble Cr(VI)
reduction with ascorbic acid and GSH in vitro and following
intratracheal instillation (Ex. 35-90). They reported that the rate of
reduction was proportional to Cr(VI) concentration with a half-life of
just under one minute to several hours. They found the greatest
reduction rates with higher levels of reductants. Ascorbic acid was
more active than GSH. Cr(VI) reduction was slower in vivo than
predicted from in vitro and principally involved ascorbic acid, not
GSH. This research indicates that extracellular Cr(VI) reduction to
Cr(III) is variable depending on the concentration and nature of the
reductant in the epithelial fluid lining regions of the respiratory
tract. De Flora et al. determined the amount of soluble Cr(VI) reduced
in vitro by human bronchiolar alveolar fluid and pulmonary alveolar
macrophage fractions over a short period and used these specific
activities to estimate an "overall reducing capacity" of 0.9-1.8 mg
Cr(VI) and 136 mg Cr(VI) per day per individual, respectively (Ex. 35-
140).
De Flora, Jones, and others have interpreted the extracellular
reduction data to mean that very high levels of Cr(VI) are required to
"overwhelm" the reductive defense mechanism before target cell uptake
can occur and, as such, impart a "threshold" character to the
exposure-response (Exs. 35-139; 31-22-7). However, the threshold
capacity concept does not consider that facilitated lung cell uptake
and extracellular reduction are dynamic and parallel processes that
happen concurrently. If their rates are comparable then some cellular
uptake of Cr(VI) would be expected, even at levels that do not
"overwhelm" the reductive capacity. Based on the in vitro kinetic
data, it would appear that such situations are plausible, especially
when concentrations of ascorbic acid are low. Unfortunately, there has
been little systematic study of the dose-dependence of Cr(VI) uptake in
the presence of physiological levels of ascorbate and GSH using
experimental systems that possess active anion transport capability.
The implications of extracellular reduction on the shape of Cr(VI)
dose--lung cancer response curve is further discussed in Section
VI.G.2.c.
Wise et al. did study uptake of a single concentration of insoluble
lead chromate particles (0.8 [mu]g/cm2) and soluble sodium
chromate (1.3 [mu]M) in Chinese hamster ovary cells co-treated with a
physiological concentration (1mM) of ascorbate (Ex. 35-68). They found
that the ascorbate substantially reduced, but did not eliminate,
chromate ion uptake over a 24 hour period. Interestingly, ascorbate did
not affect phagocytic uptake of lead chromate particles, although it
eliminated the Cr(VI)-induced clastogenesis (e.g., DNA strand breakage
and chromatid exchange) as measured under their experimental
conditions.
Singh et al. suggested that cell surface interactions with
insoluble lead chromate particulates created a concentrated
microenvironment of chromate ions resulting in higher intracellular
levels of chromium than would occur from soluble Cr(VI) (Ex. 35-149).
Cell membrane-enhanced uptake of Cr(VI) is consistent with the
intratracheal and intrabronchial instillation studies in rodents that
show greater carcinogenicity with slightly soluble (e.g., calcium
chromate and strontium chromate) than with the highly water-soluble
chromates (e.g., sodium chromate and chromic acid) (Ex. 11-2).
Finally, Cr(VI) deposited in the tracheobronchial and alveolar
regions of the respiratory tract is cleared by the mucocilliary
escalator (soluble and particulate Cr(VI)) and macrophage phagocytosis
(particulate Cr(VI) only). In most instances, these clearance processes
take hours to days to completely clear Cr(VI) from the lung, but it can
take considerably longer for particulates deposited at certain sites.
For example, Ishikawa et al. showed that some workers had substantial
amounts of chromium particulates at the bifurcations of the large
bronchii for more than two decades after cessation of exposure (Ex. 35-
81). Mancuso reported chromium in the lungs of six chromate production
workers who died from lung cancer (as cited in Ex. 35-47). The interval
between last exposure to Cr(VI) until autopsy ranged from 15 months to
16 years. Using hollow casts of the human tracheobronchial tree and
comparing particle deposition with reported occurrence of bronchogenic
tumors, Schlesinger and Lippman were able to show good correlations
between sites of greatest deposition and increased incidence of
bronchial tumors (Ex. 35-102).
b. Intracellular Reduction of Cr(VI). Once inside the cell, the
hexavalent chromate ion is rapidly reduced to intermediate oxidation
states, Cr(V) and Cr(IV), and the more chemically stable Cr(III).
Unlike Cr(VI), these other chromium forms are able to react with DNA
and protein to generate a variety of adducts and complexes. In
addition, reactive oxygen species (ROS) are produced during the
intracellular reduction of Cr(VI) that are also capable of damaging
DNA. These reactive intermediates, and not Cr(VI) itself, are considered
to be the ultimate genotoxic agents that initiate the carcinogenic process.
After crossing the cell membrane, Cr(VI) compounds can be non-
enzymatically converted to Cr(III) by several intracellular reducing
factors (Ex. 35-184). The most plentiful electron donors in the cell
are GSH, and other thiols, such as cysteine, and ascorbate. Connett and
Wetterhahn showed that a Cr(VI)-thioester initially forms in the
presence of GSH (Ex. 35-206). A two-phase reduction then occurs with
rapid conversion to Cr(V) and glutathionyl radical followed by
relatively slower reduction to Cr(III) that requires additional
molecules of GSH. Depletion of cellular GSH and other thiols is
believed to retard complete reduction of Cr(VI) to Cr(III), allowing
buildup of intermediates Cr(V) and Cr(IV). The molecular kinetics of
the Cr(VI) to Cr(III) reduction with ascorbate is less well understood
but can also involve intermediate formation of Cr(V) and free radicals
(Ex. 35-184).
Another important class of intracellular Cr(VI) reductions are
catalyzed by flavoenzymes, such as GSH reductase, lipoyl dehydrogenase,
and ferredoxin-NADP oxidoreductase. The most prominent among these is
GSH reductase that uses NADPH as a cofactor in the presence of
molecular oxygen (O2) to form Cr(V)-NADPH complexes. During
the reaction, O2 undergoes one electron reduction to the
superoxide radical (O2-) which produces hydrogen
peroxide (H2O2) through the action of the enzyme
superoxide dismutase. The Cr(V)-NADPH can then react with
H2O2 to regenerate Cr(VI) giving off hydroxyl
radicals, a highly reactive oxygen species, by a Fenton-like reaction.
It is, therefore, possible for a single molecule of Cr(VI) to produce
many molecules of potentially DNA damaging ROS through a repeated
reduction/oxidation cycling process. Shi and Dalal used electron spin
resonance (ESR) to establish formation of Cr(V)-NADPH and hydroxyl
radical in an in vitro system (Ex. 35-169; 35-171). Sugiyama et al.
reported Cr(V) formation in cultured Chinese hamster cells treated with
soluble Cr(VI) (Ex.35-133). Using a low frequency ESR, Liu et al.
provided evidence of Cr(V) formation in vivo in mice injected with
soluble Cr(VI) (Ex. 35-141-28).
Several studies have documented that Cr(VI) can generate Cr(V) and
ROS in cultured human lung epithelial cells and that this reduction/
oxidation pathway leads to DNA damage, activation of the p53 tumor
suppressor gene and stress-induced transcription factor NF-[kappa]B,
cell growth arrest, and apptosis (Exs. 35-125; 35-142; 31-22-18; 35-
135). Leonard et al. used ESR spin trapping, catalase, metal chelators,
free radical scavengers, and O2-free atmospheres to show
that hydroxyl radical generation involves a Fenton-like reaction with
soluble potassium dichromate (Ex. 31-22-17) and insoluble lead chromate
(Ex.35-137) in vitro. Liu et al. showed that the Cr(IV)/Cr(V) compounds
are also able to generate ROS with H2O2 in a
Fenton reduction/oxidation cycle in vitro (Ex. 35-183).
Although most intracellular reduction of Cr(VI) is believed to
occur in the cytoplasm, Cr(VI) reduction can also occur in mitochondria
and the endoplasmic reticulum. Cr(VI) reduction can occur in the
mitochondria through the action of the electron transport complex (Ex.
35-230). The microsomal cytochrome P-450 system in the endoplasmic
reticulum also enzymatically reduces Cr(VI) to Cr(V), producing ROS
through reduction/oxidation cycling as described above (Ex. 35-171).
c. Genotoxicity and Damage to DNA. A large number of studies have
examined multiple types of genotoxicity in a wide range of experimental
test systems. Many of the specific investigations have been previously
reviewed by IARC (Ex. 35-43), Klein (Ex. 35-134), ATSDR (Ex. 35-41),
and the K.S. Crump Group (Ex. 35-47) and will only be briefly
summarized here. The body of evidence establishes that both soluble and
insoluble forms of Cr(VI) cause structural DNA damage that can lead to
genotoxic events such as mutagenisis, clastogenisis, inhibition of DNA
replication and transcription, and altered gene expression, all of
which probably play a role in neoplastic transformation. The reactive
intermediates and products that occur from intracellular reduction of
Cr(VI) cause a wide variety of DNA lesions. The type(s) of DNA damage
that are most critical to the carcinogenic process is an area of active
investigation.
Many Cr(VI) compounds are mutagenic in bacterial and mammalian test
systems (Ex. 35-118). In the bacterial Salmonella typhimurium strains,
soluble Cr(VI) caused base pair substitutions at A-T sites as well as
frame shift mutations (Ex. 35-161). Nestmann et al. also reported
forward and frame shift mutations in Salmonella typhimurium with pre-
solubilized lead chromate (Ex. 35-162). Several Cr(VI) compounds have
produced mutagenic responses at various genetic loci in mammalian cells
(Ex. 12-7). Clastogenic damage, such as sister chromatid exchange and
chromosomal aberrations, have also been reported for insoluble Cr(VI)
and soluble Cr(VI) (Exs. 35-132; 35-115). Mammalian cells undergo
neoplastic transformation following treatment with soluble Cr(VI) or
insoluble Cr(VI), including a number of slightly soluble zinc and
insoluble lead chromate pigments (Exs. 12-5; 35-186).
Genotoxicity has been reported from Cr(VI) administration to
animals in vivo. Soluble Cr(VI) induced micronucleated erythrocytes in
mice following intraperitoneal (IP) administration (Ex. 35-150). It
also increased the mutation frequency in liver and bone marrow
following IP administration to lacZ transgenic mice (Exs. 35-168; 35-
163). Izzotti et al. reported DNA damage in the lungs of rats exposed
to soluble Cr(VI) by intratracheal instillation (Ex. 35-170).
Intratracheal instillation of soluble Cr(VI) produced a time- and dose-
dependant elevation in mutant frequency in the lung of Big Blue
transgenic mice (Ex. 35-174). Oral administration of soluble Cr(VI) in
animals did not produce genotoxicity in several studies probably due to
route-specific differences in absorption. OSHA is not aware of
genotoxicity studies from in vivo administration of insoluble Cr(VI).
Studies of chromosomal and DNA damage in workers exposed to Cr(VI) vary
in their findings. Some studies reported higher levels of chromosomal
aberrations, sister chromatid exchanges, or DNA strand breaks in
peripheral lymphocytes of stainless steel welders (Exs. 35-265; 35-160)
and electroplaters (Ex. 35-164). Other studies were not able to find
excess damage in DNA from the blood lymphocytes of workers exposed to
Cr(VI) (Exs. 35-185; 35-167). These reports are difficult to interpret
since co-exposure to other genotoxic agents (e.g., other metals,
cigarette smoke) likely existed and the extent of Cr(VI) exposures were
not known.
Because of the consistent positive response across multiple assays
in a wide range of experimental systems from prokaryotic organisms
(e.g., bacteria) to human cells in vitro and animals in vivo, OSHA
regards Cr(VI) as an agent able to induce carcinogenesis through a
genotoxic mode of action. Both soluble and insoluble forms of Cr(VI)
are reported to cause genotoxicity and neoplastic transformation. On
the other hand, Cr(III) compounds do not easily cause genotoxicity in
intact cellular systems, presumably due to the inability of Cr(III) to
penetrate cell membranes (Exs. 12-7; 35-186).
There has been a great deal of research to identify the types of
damage to DNA caused by Cr(VI), the reactive intermediates that are
responsible for the damage, and the specific genetic lesions critical to
carcinogenesis. It was shown that Cr(VI) was inactive in DNA binding assays
with isolated nuclei or purified DNA (Ex. 35-47). However, Cr(III) was able
to produce DNA protein cross-links, sister chromatid exchanges, and chromosomal
aberrations in an acellular system. Zhitkovich et al. showed that incubation of
Chinese hamster ovary cells with soluble Cr(VI) produced ternary complexes of
Cr(III) cross-linked to cysteine, other amino acids, or glutathione and
the DNA phosphate backbone (Ex. 312). Utilizing the pSP189 shuttle
vector plasmid, they showed these DNA-Cr(III)-amino acid cross-links
were mutagenic when introduced in human fibroblasts (Ex. 35-131).
Another research group showed that plasmid DNA treated with Cr(III)
produced intrastrand crosslinks and the production of these lesions
correlated with DNA polymerase arrest (Ex. 35-126). The same
intrastrand crosslinks and DNA polymerase arrest could also be induced
by Cr(VI) in the presence of ascorbate as a reducing agent to form
Cr(III) (Ex. 35-263). These results were confirmed in a cell system by
treating human lung fibroblasts with soluble Cr(VI), isolating genomic
DNA, and demonstrating dose-dependent guanine-specific arrest in a DNA
polymerase assay (Ex. 35-188). Cr(V) may also form intrastrand
crosslinks since Cr(V) interacts with DNA in vitro (Ex. 35-178). The
Cr(V)-DNA crosslinks are probably readily reduced to Cr(III) in cell
systems. Intrastrand crosslinks have also been implicated in inhibition
of RNA polymerase and DNA topoisomerase, leading to cell cycle arrest,
apoptosis and possibly other disturbances in cell growth that
contribute to the carcinogenic pathway (Ex. 35-149).
DNA strand breaks and oxidative damage result from the one electron
reduction/oxidation cycling of Cr(VI), Cr(V), and Cr(IV). Shi et al.
showed that soluble Cr(VI) in the presence of ascorbate and
H2O2 caused DNA double strand breaks and 8-
hydroxy deoxyguanine (8-OHdG, a marker for oxidative DNA damage) in
vitro (Ex. 35-129). Leonard et al. showed that the DNA strand breaks
were reduced by several experimental conditions including an
O2-free atmosphere, catabolism of H2O2
by catalase, ROS depletion by free radical scavengers, and chelation of
Cr(V). They concluded that the strand breaks and 8-OHdG resulted from
DNA damage caused by hydroxyl radicals from Cr(VI) reduction/oxidation
cycling (Ex. 31-22-17). Generation of ROS-dependant DNA damage could
also be shown with insoluble Cr(VI) (Ex. 35-137). DNA strand breaks and
related damage caused by soluble Cr(VI) have been reported in Chinese
hamster cells (Ex. 35-128), human fibroblasts (Ex. 311), and human
prostate cells (Ex. 35-255). Pretreatment of Chinese hamster cells with
a metal chelator suppressed Cr(V) formation from Cr(VI) and decreased
DNA strand breaks (Ex. 35-197). Chinese hamster cells that developed
resistance to H2O2 damage also had reduced DNA
strand breaks from Cr(VI) treatment compared to the normal phenotype
(Ex. 35-176).
Several researchers have been able to modulate Cr(VI)-induced DNA
damage using cellular reductants such as ascorbate, GSH and the free
radical scavenger tocopherol (vitamin E). This has provided insight
into the relationships between DNA damage, reduced chromium forms and
ROS. Sugiyama et al. showed that Chinese hamster cells pretreated with
ascorbate decreased soluble Cr(VI)-induced DNA strand damage (e.g.,
alkali-labile sites), but enhanced DNA-amino acid crosslinks (Ex. 35-
133). Standeven and Wetterhahn reported that elimination of ascorbate
from rat lung cytosol prior to in vitro incubation with soluble Cr(VI)
completely inhibited Cr-DNA binding (Ex. 35-180). However, not all
types of Cr-DNA binding are enhanced by ascorbate. Bridgewater et al.
found that high ratios of ascorbate to Cr(VI) actually decreased
intrastrand crosslinks in vitro while low ratios induced their
formation (Ex. 35-263). This finding is consistent with research by
Stearns and Watterhahn who showed that excessive ascorbate relative to
Cr(VI) leads to two-electron reduction of Cr(III) and formation of
Cr(III)-DNA monoadducts and DNA-Cr(III)-amino acid crosslinks (Ex. 35-
166). Low amounts of ascorbate primarily cause one-electron reduction
to intermediates Cr(V) and Cr(IV) that form crosslinks with DNA and ROS
responsible for DNA strand breaks, alkali-labile sites, and clastogenic
damage. This explains the apparent paradox that extracellular Cr(VI)
reduction by ascorbate to Cr(III) reduces Cr(VI)-induced DNA binding
but intracellular Cr(VI) reduction by ascorbate to Cr(III) enhances Cr-
DNA binding. The aforementioned studies used soluble forms of Cr(VI),
but Blankenship et al. showed that ascorbate pretreatment inhibited
chromosomal aberrations in Chinese hamster ovary cells caused by both
insoluble lead chromate particles as well as soluble Cr(VI) (Ex. 35-
115). Pretreatment with the free radical scavenger tocopherol also
inhibits chromosomal aberrations and alkali-labile sites in Cr(VI)-
treated cells (Exs. 35-115; 35-128).
Studies of the different types of DNA damage caused by Cr(VI) and
the modulation of that damage inside the cell demonstrate that Cr(VI)
itself is not biologically active. Cr(VI) must undergo intracellular
reduction to Cr(V), Cr(IV), and Cr(III) before the damage to DNA can
occur. The evidence suggests that Cr(III) can cause DNA-Cr-amino acid,
DNA-Cr-DNA crosslinks and Cr-DNA monoadducts. Cr(V) and possibly Cr(IV)
contribute to intrastrand crosslinks and perhaps other Cr-DNA binding.
ROS generated during intracellular reduction of Cr(VI) lead to lesions
such as chromosomal aberrations, DNA strand breaks, and oxidative DNA
damage. The specific DNA lesions responsible for neoplastic
transformation have yet to be firmly established so all forms of DNA
damage should, at this time, be regarded as potential contributors to
carcinogenicity.
d. Cr(VI)-induced Disturbances in the Regulation of Cell
Replication. Recent research has begun to elucidate how Cr(VI)-induced
oxidative stress and DNA lesions trigger cell signaling pathways that
regulate the cell growth cycle. The complex regulation of the cell
growth cycle by Cr(VI) involves activation of the p53 protein and other
transcription factors that respond to oxidative stress and DNA damage.
The cellular response ranges from a temporary pause in the cell cycle
to terminal growth arrest (i.e., viable cells that have lost the
ability to replicate) and a programmed form of cell death, known as
apoptosis. Apoptosis involves alterations in mitochondrial
permeability, release of cytochrome c and the action of several kinases
and caspases. Less is known about the molecular basis of terminal
growth arrest. Terminal growth arrest and apoptosis serve to eliminate
further growth of cells with unrepaired Cr(VI)-induced genetic damage.
However, it is believed that cells which escape these protective
mechanisms and regain replicative competence eventually become
resistant to normal growth regulation and can transform to a neoplastic
phenotype (Exs. 35-121; 35-122; 35-120).
Blankenship et al. first described apoptosis as the primary mode of
cell death following a two hour treatment of Chinese hamster ovary
cells with high concentrations (>150 [mu]M) of soluble Cr(VI) (Ex. 35-
144). Apoptosis also occurs in human lung cells following short-term
treatment with soluble Cr(VI)(Ex. 35-125) as well as longer term treatment
(e.g., 24 hours) with lower concentrations of soluble Cr(VI) (e.g., 10 [mu]M)
and insoluble Cr(VI) in the form of lead chromate (Ex. 35-166). Ye et al.
found that the Cr(VI) treatment that caused apoptosis also activated expression
of p53 protein (Ex. 35-125). This apoptotic response was substantially
reduced in a p53-deficient cell line treated with Cr(VI), suggesting
that the p53 activation was required for apoptosis. Other studies using
p53 null cells from mice and humans confirmed that Cr(VI)-induced
apoptosis is p53-dependent (Ex. 35-225).
The p53 protein is a transcription factor known to be activated by
DNA damage, lead to cell cycle arrest, and regulate genes responsible
for either DNA repair or apoptosis. Therefore, it is likely that the
p53 activation is a response to the Cr(VI)-induced DNA damage.
Apoptosis (i.e., programmed cell death) is triggered once the Cr(VI)-
induced DNA damage becomes too extensive to successfully repair. In
this manner, apoptosis serves to prevent replication of genetically
damaged cells.
Several researchers have gone on to further elucidate the molecular
pathways involved in Cr(VI)-induced apoptosis. ROS produced by
intracellular Cr(VI) reduction/oxidation cycling have been implicated
in the activation of p53 and apoptosis (Exs. 35-255; 35-122). Using
specific inhibitors, Pritchard et al. showed that mitochondrial release
of cytochrome c is critical to apoptotic death from Cr(VI) (Ex. 35-
159). Cytochrome c release from mitochondria could potentially result
from either direct membrane damage caused by Cr(VI)-induced ROS or
indirectly by enhanced expression of the p53-dependent apoptotic
proteins, Bax and Nova, known to increase mitochondrial membrane
permeability.
Cr(VI) causes cell cycle arrest and reduces clonogenic potential
(i.e., normal cell growth) at very low concentrations (e.g., 1 [mu]M)
where significant apoptosis is not evident. Xu et al. showed that human
lung fibroblasts treated with low doses of Cr(VI) caused guanine-
guanine intrastrand crosslinks, guanine-specific polymerase arrest, and
inhibited cell growth at the G1/S phase of the cell cycle
(Ex. 35-188). Zhang et al. described a dose-dependent increase in
growth arrest at the G2/M phase of the cell cycle in a human
lung epithelial cell line following 24 hour Cr(VI) treatment over a
concentration range of 1 to 10 [mu]M (Ex. 35-135). The cell cycle
arrest could be partially eliminated by reducing production of Cr(VI)-
induced ROS. Apoptosis was not detected in these cells until a
concentration of 25 [mu]M Cr(VI) had been reached. These data suggest
that low cellular levels of Cr(VI) are able to cause DNA damage and
disrupt the normal cell growth cycle.
Pritchard et al. studied the clonogenicity over two weeks of human
fibroblasts treated 24 hours with soluble Cr(VI) concentrations from 1
to 10 [mu]M (Ex. 35-120). They reported a progressive decline in cell
growth with increasing Cr(VI) concentration. Terminal growth arrest
(i.e., viable cells that have lost the ability to replicate) was
primarily responsible for the decrease in clonogenic survival below 4
[mu]M Cr(VI). At higher Cr(VI) concentrations, apoptosis was
increasingly responsible for the loss in clonogenicity. Pritchard et
al. and other research groups have suggested that a subset of cells
that continue to replicate following Cr(VI) exposure could contain
unrepaired genetic damage or could have become intrinsically resistant
to processes (e.g., apoptosis, terminal growth arrest) that normally
control their growth (Exs. 35-121; 35-122; 35-120). These surviving
cells would then be more prone to neoplastic progression and have
greater carcinogenic potential.
e. Summary. Respirable chromate particulates are taken up by target
cells in the bronchoalveolar region of the lung, become intracellularly
reduced to several reactive genotoxic species able to damage DNA,
disrupt normal regulation of cell division and cause neoplastic
transformation. Scientific studies indicate that both water soluble and
insoluble Cr(VI) can be transported into the cell. In fact, cell
surface interactions with slightly soluble and insoluble chromates may
create a concentrated microenvironment of chromate ion, especially in
the case of the slightly soluble Cr(VI) compounds that more readily
dissociate. The higher concentration of chromate ion in close proximity
to the lung cells will likely result in higher intracellular Cr(VI)
than would occur from the highly water-soluble chromates. This is
consistent with the studies of respiratory tract carcinogenesis in
animals that indicate the most tumorigenic chromates had low to
moderate water solubility. Once inside the cell, Cr(VI) is converted to
several lower oxidation forms able to bind to and crosslink DNA. ROS
are produced during intracellular reduction/oxidation of Cr(VI) that
further damage DNA. These structural lesions are functionally
translated into a impaired DNA replication, mutagenesis, and altered
gene expression that ultimately lead to neoplastic transformation.
9. Conclusion
In the NRPM, OSHA preliminarily concluded that the weight of
evidence supports the determination that all Cr(VI) compounds should be
regarded as carcinogenic to workers (69 FR at 59351). This conclusion
included the highly water soluble chromates, such as sodium chromate,
sodium dichromate, and chromic acid; chromates of slight and
intermediate water solubility such as calcium chromate, strontium
chromates, and many zinc chromates (e.g. zinc yellow); and chromates
that have very low water solubility and are generally considered to be
water insoluble such as barium chromate and lead chromates. The
strongest evidence supporting this conclusion comes from the many
cohort studies reporting excess lung cancer mortality among workers
engaged in the production of soluble chromates (Exs. 7-14; 31-22-11;
23; 31-18-4), chromate pigments (Exs. 7-36; 7-42; 7-46), and chrome
plating (Exs. 35-62; 35-271). Chromate production workers were
principally exposed to the highly soluble sodium chromate and
dichromate (Ex. 35-61) although lesser exposure to other chromates,
such as highly soluble chromic acid and slightly soluble calcium
chromate probably occurred. Pigment production workers were principally
exposed Cr(VI) in the form of lead and zinc chromates. Significantly
elevated lung cancer mortality was found in two British chromium
electroplating cohorts (Exs. 35-62; 35-271). These workers were exposed
to Cr(VI) in the form of chromic acid mist. Therefore, significantly
elevated lung cancer rates have been observed in working populations
exposed to a broad range of Cr(VI) compounds.
Cellular research has shown that both highly water soluble (e.g.
sodium chromate) Cr(VI) and water insoluble (e.g. lead chromate) Cr(VI)
enter lung cells (see Section V.8.a) and undergo intracellular
reduction to several lower oxidation forms able to bind to and
crosslink DNA as well as generate reactive oxygen species that can
further damage DNA (see Section V.8.b). Soluble and insoluble Cr(VI)
compounds are reported to cause mutagenesis, clastogenesis, and
neoplastic transformation across multiple assays in a wide range of
experimental systems from prokaryotic organisms to human cells in vitro
and animals in vivo (see Section V.8.c).
The carcinogenicity of various Cr(VI) compounds was examined after
instillation in the respiratory tract of rodents. Slightly water
soluble Cr(VI) compounds, strontium chromate, calcium chromate, and some
zinc chromates produced a greater incidence of respiratory tract tumors than
highly water soluble (e.g. sodium dichromate and chromic acid) and
water insoluble (e.g. barium chromate and lead chromates) Cr(VI)
compounds under similar experimental protocol and conditions (see
Section V.7). This likely reflects the greater tendency for chromates
of intermediate water solubility to provide a persistent high local
concentration of solubilized Cr(VI) in close proximity to the target
cell. Highly soluble chromates rapidly dissolve and diffuse in the
aqueous fluid lining the epithelia of the lung. Thus, these chromates
are less able to achieve the higher local concentrations within close
proximity of the lung cell surface than the slightly water soluble
chromates. However, it has been shown that water-soluble Cr(VI) can
still enter lung cells, damage DNA, and cause cellular effects
consistent with carcinogenesis (Ex. 31-22-18; 35-125; 35-135; 35-142).
Like the slightly water soluble chromates, water insoluble Cr(VI)
particulates are able to come in close contact with the lung cell
surface and slowly dissolve into readily absorbed chromate ion. For
example, water insoluble lead chromate has been shown to enter human
airway cells both through extracellular solubilization as chromate ion
(Exs. 35-66; 35-327; 47-12-3) as well as internalization as
unsolubilized particulate (Exs. 35-66; 47-19-7). However, the rate of
solubilization and uptake of water insoluble Cr(VI) is expected to be
more limited than chromates with moderate solubility. Once chromate ion
is inside lung cells, studies have shown that similar cellular events
believed critical to initiating neoplastic transformation occur
regardless of whether the source is a highly soluble or insoluble
Cr(VI) compound (Ex. 35-327).
a. Public Comment on the Carcinogenicity of Cr(VI) Compounds
In the NRPM, OSHA requested comment on whether currently available
epidemiologic and experimental studies supported the determination that
all Cr(VI) compounds possess carcinogenic potential and solicited
additional information that should be considered in evaluating relative
carcinogenic potency of the different Cr(VI) compounds (69 FR 59307).
Several comments supported the view that sufficient scientific evidence
exists to regard all Cr(VI) compounds as potential occupational
carcinogens (Exs. 38-106-2; 38-222; 39-73-2; 40-10-2; 42-2). The AFL-
CIO stated that " * * * the agency has fully demonstrated that Cr(VI)
is a human carcinogen and that exposed workers are at risk of
developing lung cancer" (Ex. 38-222). NIOSH stated that "the
epidemiologic and experimental studies cited by OSHA support the
carcinogenic potential of all Cr(VI) compounds (i.e. water soluble,
insoluble, and slightly soluble)" (Ex. 40-10-2, p. 4). Peter Lurie of
Public Citizen testified:
As we heard repeatedly in the course of this hearing, scientific
experts, in fact, agree. They agree that the most reasonable
approach to the regulation is to consider them all [Cr(VI)
compounds] to be carcinogenic (Tr. 710).
Several commenters agreed that the evidence supported the
qualitative determination that Cr(VI) compounds were carcinogenic but
wished to make clear that the information was inadequate to support
quantitative statements about relative potency of the individual
chromates (Exs. 38-106-2; 40-10-2; 42-2). For example, the Boeing
Company in their technical comments stated:
The available data does support the conclusion that the low
solubility hexavalent chromium compounds [e.g. strontium chromate]
can cause cancer but evidence to support a quantitative comparison
of carcinogenic potency based on differences in solubility is
lacking (Ex. 38-106-2, p. 18).
Pigment Manufacturers' Comments on Carcinogenicity of Lead Chromate--
One group that did not regard all Cr(VI) compounds as occupational
carcinogens was the color pigment manufacturers who manufacture and
market lead chromate pigments which are primarily used in industrial
coatings and colored plastic articles. The color pigment manufacturers
maintain that their lead chromate products are unreactive in biological
systems, are not absorbed into the systemic circulation by any route,
and can not enter lung cells (Ex. 38-205, p. 14). Their principal
rationale is that lead chromate is virtually insoluble in water, is
unable to release chromate ion into aqueous media, and therefore, is
incapable of interacting with biological systems (Exs. 38-205, p. 95;
38-201-1, p. 9). The color pigment manufacturers assert that their lead
chromate pigment products are double encapsulated in a resin/plastic
matrix surrounded by a silica coating and that the encapsulated pigment
becomes even less "bioavailable" than unencapsulated "less
stabilized" lead chromates. They believe the extreme stability and
non-bioavailable nature of their products makes them a non-carcinogenic
form of Cr(VI) (Ex. 38-205, p. 106).
According to the Color Pigment Manufacturers Association (CPMA),
several pieces of scientific evidence support their position, namely,
the lack of a significant excess of lung cancer mortality in three
cohorts of pigment workers engaged in the production of water-insoluble
lead chromate (Ex. 38-205, pp. 88-91) and the lack of statistically
significant elevated tumor incidence following a single instillation of
lead chromate in the respiratory tract of rats (Ex. 38-205, pp. 88-92).
They dismiss as irrelevant other animal studies that produced
statistically significant increases in tumors when lead chromate was
repeatedly injected by other routes. In addition, CPMA claims that the
lead chromate used in cellular studies that report genotoxicity was
reagent grade, was contaminated with soluble chromate, and was
inappropriately solubilized using strong acids and bases prior to
treatment (Exs. 38-205, pp. 93-94; 47-31, pp. 9-13). They are
especially critical of studies conducted by the Environmental and
Genetic Toxicology group at the University of Southern Maine that
report lead chromate particulates to be clastogenic in human lung cells
(Exs. 34-6-1; 38-205, pp. 98-102 & appendix D; 47-22). Instead, they
rely on two in vitro studies of lead chromate pigments that report a
lack of genotoxicity in cultured bacterial and hamster ovary cells,
respectively (Exs. 47-3 Appendix C; 38-205, p. 94).
OSHA addresses many of the CPMA claims in other sections of the
preamble. The bioavailability issue of encapsulated lead chromate is
addressed in Section V.A.2. The CPMA request to consider the lack of
excess lung cancer mortality among pigment workers exposed exclusively
to lead chromate is discussed in Section V.B.2. The CPMA assertions
that animal studies are evidence that lead chromates are not
carcinogenic to workers are addressed in Section V.B.7. The studies
documenting uptake of lead chromate into lung cells are described in
Section V.B.8.a. Section V.B.8.c describes evidence that lead chromate
is genotoxic. As requested by CPMA, OSHA will pull these responses
together and expand on their concerns below.
Lung Cancer Mortality in Pigments Workers Exposed to Lead
Chromate--Comments and testimony from NIOSH and others cite evidence of
excess lung cancer among pigment workers and support the results of
OSHA's preliminary risk assessment for color pigments in general and
for lead chromate in particular (Tr. 135-146, 316, 337, Ex. 40-18-1, p.
2). However, comments submitted by the CPMA and the Dominion Colour
Corporation (DCC) attributed the excess lung cancer risk observed in
pigment worker studies to zinc chromate (Tr. 1707, 1747, Exs. 38-201-1,
p. 13; 38-205, p. 90; 40-7, p. 92). For example, the CPMA stated that:
When lead chromate and zinc chromate exposures occur
simultaneously, there appears to be a significant cancer hazard.
However, when lead chromate pigments alone are the source of
chromium exposure, a significant carcinogenic response has never
been found (Ex. 40-7, p. 92).
The latter statement refers to the Davies et al. (1984) study of
British pigment workers, the Cooper et al. (1983) study of U.S. pigment
workers, and the Kano et al. (1993) study of pigment workers in Japan,
all of which calculated separate observed and expected lung cancer
deaths for workers exposed exclusively to lead chromate (Ex. 38-205, p.
89). DCC and the Small Business Administration's Office of Advocacy
similarly stated that the excess lung cancer risk observed among
workers exposed to both zinc chromate and lead chromate cannot
necessarily be attributed to lead chromate (Exs. 38-201-1, p. 13; 38-7,
p. 4).
OSHA agrees with CPMA and DCC that the excess lung cancer observed
in most pigment worker studies taken alone cannot be considered
conclusive evidence that lead chromate is carcinogenic. Given that the
workers were exposed to both zinc chromate and lead chromate, it is not
possible to draw strong conclusions about the effects of either
individual compound using only these studies. However, based on the
overall weight of available evidence, OSHA believes that the excess
lung cancer found in these studies is most likely attributable to lead
chromate as well as zinc chromate exposure. Lead chromate was the
primary source of Cr(VI) for several worker cohorts with excess lung
cancer (e.g., Davies et al. (1984), Factory A; Hayes et al. (1989); and
Deschamps et al. (1995)) (Exs. 7-42; 7-46; 35-234), and as previously
discussed, there is evidence from animal and mechanistic studies
supporting the carcinogenicity of both zinc chromate and lead chromate.
Considered in this context, the elevated risk of lung cancer observed
in most chromate pigment workers is consistent with the Agency's
determination that all Cr(VI) compounds--including lead chromate--
should be regarded as carcinogenic.
Moreover, OSHA disagrees with the CPMA and DCC interpretation of
the data on workers exposed exclusively to lead chromate. In the
Preamble to the Proposed Rule, OSHA stated that "[t]he number of lung
cancer deaths [in the Davies, Cooper, and Kano studies] is too small to
be meaningful" with respect to the Agency's determination regarding
the carcinogenicity of lead chromate (FR 69 at 59332). The CPMA
subsequently argued that:
[b]y this rationale, OSHA could never conclude that a compound
such as lead chromate pigment exhibits no carcinogenic potential
because there can never be enough lung cancer deaths to produce a
"meaningful" result. This is an arbitrary and obviously biased
assessment which creates an insurmountable barrier. Since the lead
chromate pigments did not create an excess of lung cancer, there
cannot be a significant enough mortality from lung cancer to be
meaningful (Ex. 38-205, p. 90).
OSHA believes that these comments reflect a misunderstanding of the
sense in which the Davies, Cooper, and Kano studies are too small to be
meaningful, and also a misunderstanding of the Agency's position.
Contrary to CPMA's argument, a study with no excess in lung cancer
mortality can provide evidence of a lack of carcinogenic effect if the
confidence limits for the measurement of effect are close to the null
value. In other words, the measured effect must be close to the null
and the study must have a high level of precision. In the case of the
Davies, Cooper, and Kano studies, the standardized mortality ratio
(SMR) is the measurement of interest and the null value is an SMR of 1.
Table V.10 below shows that the SMRs for these study populations are
near or below 1; however, the 95% confidence intervals for the SMRs are
quite wide, indicating that the estimated SMRs are imprecise. The Kano
data, for example, are statistically consistent with a "true" SMR as
low as 0.01 or as high as 2.62. The results of these studies are too
imprecise to provide evidence for or against the hypothesis that lead
chromate is carcinogenic.
Click here to view table V-10
This lack of precision may be partly explained by the small size of
the studies, as reflected in the low numbers of expected lung cancers.
However, it is the issue of precision, and not the number of lung
cancer deaths per se, that led OSHA to state in the preamble to the
proposed rule that the Davies, Cooper, and Kano studies cannot serve as
the basis of a meaningful analysis of lead chromate carcinogenicity
(Exs. 7-42; 2-D-1; 7-118). In contrast, a study population that has
confidence limits close to or below 1 would provide evidence to support
the DCC claim that " * * * if lead chromate pigments possess any
carcinogenic potential at all, it must be extremely small" (Ex. 38-
201-1, p. 14) at the exposure levels experienced by that population.
While this standard of evidence has not been met in the epidemiological
literature for pigment workers exposed exclusively to lead chromate
(i.e., the Davies, Cooper, and Kano studies), it is hardly an
"insurmountable barrier" that sets up an impossible standard of proof
for those who contend that lead chromate is not carcinogenic.
Some comments suggested that the Davies, Cooper, and Kano studies
should be combined to derive a summary risk measure for exposure to
lead chromate (see e.g. Ex. 38-201-1, pp. 13-14). However, OSHA
believes that these studies do not provide a suitable basis of meta-analysis.
There is little information with which to assess factors recognized by
epidemiologists as key to meta-analysis, for example sources of bias or
confounding in the individual studies and comparability of exposures and
worker characteristics across studies, and to verify certain conditions
required for comparability of SMRs across these studies (see e.g. Modern
Epidemiology, Rothman and Greenland, p. 655). In addition, the
inclusion criteria and length of follow-up differ across the three
studies. Finally, each of the studies is extremely small. Even if it
were appropriate to calculate a 'summary' SMR based on them, the
precision of this SMR would not be much improved compared to those of
the original studies.
In their written testimony, DCC suggested that OSHA should
aggregate the data from the Davies, Cooper, and Kano studies in order
to determine whether there is a discrepancy between the results of
these three studies, taken together, and OSHA's preliminary risk
assessment (Ex. 38-201-1, pp. 13-14). DCC performed a calculation to
compare OSHA's risk model with the observed lung cancer in the three
cohorts. DCC stated that:
OSHA estimates a chromate worker's risk of dying from lung
cancer due to occupational exposure as about one chance in four * *
* [Assuming that there were about] 200 workers in the Kano study,
the total in the three studies would be 600. A calculation of one
quarter would be 150 deaths. To compensate for a working life of
less than OSHA's 45 years [an assumption of 20 years] provides * * *
a refined estimate of about 70 deaths. An observed number less than
this could be due either to exposures already in practice averaging
much less than the current PEL of 52, or to lead chromate having
much less potential (if any) for carcinogenicity than other
chromates. In any event the actual incidence of death from lung
cancer would appear to be no more than one tenth of OSHA's best
estimate (Ex. 38-201-1, pp. 15-16).
The method suggested by DCC is not an appropriate way to assess the
carcinogenicity of lead chromate, to identify a discrepancy between the
pigment cohort results and OSHA's risk estimates, or to determine an
exposure limit for lead chromate. Among other problems, DCC's
calculation does not make a valid comparison between OSHA's risk
estimates and the results of the Davies, Cooper, and Kano studies.
OSHA's 'best estimate' of lung cancer risk for any given Cr(VI)-exposed
population depends strongly on factors including exposure levels,
exposure duration, population age, and length of follow-up. The 'one in
four' prediction cited by DCC applies to one specific risk scenario
(lifetime risk from 45 years of occupational exposure at the previous
PEL of 52 [mu]g/m\3\). OSHA's best estimate of risk would be lower for
a population with lower exposures (as noted by DCC), shorter duration
of exposure, or less than a lifetime of follow-up. Without adequate
information to adjust for each of these factors, a valid comparison
cannot be drawn between OSHA's risk predictions and the results of the
lead chromate cohort studies.
The importance of accounting for cohort age and follow-up time may
be illustrated using information provided in the Cooper et al. study.
As shown in Table V-11 below, approximately three-fourths of the Cooper
et al. Plant 1 cohort members were less than 60 years old at the end of
follow-up.
Click here to view table V-11
For a population of 600 with approximately the same distribution of
follow-up time as described in the Cooper et al. publication (e.g.,
0.4% of workers are followed to age 84, 2% to age 79, etc.), OSHA's
risk model predicts about 3-15 excess lung cancers (making the DCC
assumption that workers are exposed for 20 years at 52 [mu]g/m\3\),
rather than the 70 deaths calculated by the DCC. If the workers were
typically exposed for less than 20 years or at levels lower than 52
[mu]g/m\3\, OSHA s model would predict still lower risk. A precise
comparison between OSHA's risk model and the observed lung cancer risk
in the Davies, Cooper and Kano cohorts is not possible without
demographic, work history and exposure information on the lead chromate
workers. (In particular, note that year 2000 background lung cancer
rates were used in the calculation above, as it was not feasible to
reconstruct appropriate reference rates without work history
information on the cohorts.) However, this exercise illustrates that
DCC's assertion of a large discrepancy between OSHA's risk model and
the available data on workers exposed exclusively to lead chromate is
not well-founded. To make a valid comparison between the OSHA risk
model and the lung cancer observed in the lead chromate cohorts would
require more information on exposure and follow-up than is available
for these cohorts.
OSHA received comments and testimony from NIOSH and others
supporting of the Agency's interpretation of the epidemiological
literature on Cr(VI) color pigments, including lead chromate (Tr. 135-
146, 316, 337, Ex. 40-18-1, p. 2). At the hearing, Mr. Robert Park of
NIOSH stated that the available studies of workers exposed to chromate
pigments show " * * * a general pattern of excess [lung cancer] * * *
" and pointed out that "[i]n several of the studies, lead [chromate]
was by far the major component of production, like 90 percent * * * So
I don't think there is any epidemiological evidence at this point that
gets lead off the hook" (Tr. 337). Regarding the lack of statistically
significant excess lung cancer in several pigment worker cohorts, Mr.
Park identified study attributes that may have obscured an excess in
lung cancer, such as the high percentage of workers lost to follow-up
among immigrant workers in the Davies et al. study (Tr. 337) or a
healthy worker effect in the Hayes et al. study (Tr. 316). Dr. Paul
Schulte of NIOSH explained that
* * * a lot of these studies that appear to be negative were
either of low power or had [some] other kind of conflicting
situation [so] that we can't really consider them truly negative
studies (Tr. 338).
Dr. Herman Gibb testified that the epidemiological studies relied on by
CPMA and DCC to question the carcinogenicity of lead chromate have very
low expected numbers of lung cancer deaths, so they " * * * really
don't have a lot of ability to be able to detect a risk" (Tr. 135-
136). Public Citizen agreed with OSHA's preliminary conclusion that
lead chromate is carcinogenic. Based on the major pigment worker
cohorts identified by OSHA in the Preamble to the Proposed Rule, Public
Citizen's Health Research Group concluded that
* * * inadequately-powered studies, the standardized mortality
ratios for exposed workers are significantly elevated (range 1.5-
4.4) and a relationship between extent of exposure (whether measured
by duration of exposure or factory) generally emerges; [moreover,]
[t]hese studies must be placed in the context * * * of the animal
carcinogenicity studies * * * and the mechanistic studies reviewed
by OSHA (Ex. 40-18-1, p. 2).
Tumor Incidence in Experimental Animals Administered Lead Chromate--
CPMA also claims that the absence of evidence for carcinogenicity found
among the three cited cohorts of lead chromate pigment workers " * * *
is further confirmed by the rat implantation studies of Levy" (Ex. 38-
205, p. 98). They argue that these studies which involved implantation
into rat lungs " * * * indicated no increased incidence of tumors for
lead chromate pigment, although more soluble chromates exhibited
varying degrees of carcinogenicity" (Ex. 38-205, p. 93). They
dismissed other animal studies involving intramuscular and subcutaneous
injection of lead chromate which did report increased incidence of
tumors because they believe these techniques
* * * are of questionable relevance in relation to human
workplace exposure conditions in industry, whereas tests involving
implantation in rat lung * * * are relevant to inhalation in
industrial exposures (Ex. 38-205, p. 93).
In a more recent submission, CPMA remarked that the intramuscular and
subcutaneous injection studies with lead chromate were contradictory
and " * * * problematic in that false positive results frequently
occur during the study procedure (Ex. 47-31, p. 13).
The rat implantation studies of Levy involved the surgical
placement of a Cr(VI)-containing pellet in the left bronchus of an
anesthetized rat (Exs. 10-1; 11-12; 11-2). This pellet procedure was an
attempt to deliver Cr(VI) compounds directly to the bronchial
epithelium and mimic continuous chronic in vivo dosing at the tissue
target site in order to assess the relative ability of different Cr(VI)
compounds to induce bronchogenic carcinoma. Histopathological
evaluation of the rat lung was conducted after a two year exposure
time. In most cases, approximately 100 rats were implanted with a
single pellet for each Cr(VI) test compound. The total lifetime dose of
Cr(VI) received by the animal was generally between 0.2 and 1.0 mg
depending on the compound. The amount of Cr(VI) that actually leached
from the cholesterol pellet and remained near the lung tissue was never
determined. At least 20 different commercially relevant Cr(VI)
compounds ranging from water insoluble to highly water soluble were
tested using this intrabronchial implantation protocol.
The results of these studies are described in preamble section
V.B.7 and tables V-7, V-8, and V-9. Reagent grade lead chromate and six
different lead chromate pigments were tested. The lead chromate
pigments were a variety of different chrome yellows, including a silica
encapsulated chrome yellow, and molybdenum orange. The incidence of
bronchogenic cancer in the rats under this set of experimental
conditions was one percent or less for all the lead chromates tested.
This incidence was not statistically different from the negative
controls (i.e. rats implanted with a cholesterol pellet containing no
test compound) or rats administered either the water-insoluble barium
chromate or the highly soluble chromic acid and sodium dichromate. The
percent incidence of bronchogenic cancer in lead chromate-treated rats
was substantially less than that of rats treated with slightly soluble
strontium chromates (about 52 percent) and calcium chromate (24
percent). The type of bronchogenic cancer induced in these experiments
was almost entirely squamous cell carcinomas.
OSHA does not agree with the CPMA position that absence of a
significant tumor incidence in the intrabronchial implantation studies
confirms that lead chromates lack carcinogenic activity and, therefore,
should not be subject to the OSHA Cr(VI) standard. The bioassay
protocol used approximately 100 test animals per experimental group.
This small number of animals limits the power of the bioassay to detect
tumor incidence below three to four percent with an acceptable degree
of statistical confidence. Three of the lead chromates, in fact,
produced a tumor incidence of about one percent (e.g. 1 tumor in 100
rats examined) which was not statistically significant. The researchers
only applied a single 2 mg [approximately 0.3 mg Cr(VI)] dose of lead
chromate to the bronchus of the rats. Since it was not experimentally
confirmed that the lead chromate pigments were able to freely leach
from the cholesterol pellet, the amount of Cr(VI) actually available to
the lung tissue is not entirely clear. Therefore, OSHA believes a more
appropriate interpretation of the study findings is that lead chromates
delivered to the respiratory tract at a dose of about 0.3 mg Cr(VI)
(maybe lower) lead to a less than three percent tumor incidence.
However, OSHA agrees that the intrabronchial implantation protocol
does provide useful information regarding the relative carcinogenicity
of different Cr(VI) compounds once they are delivered and deposited in
the respiratory tract. No other study examines the carcinogenicity of
such a broad range of commercial Cr(VI) compounds under the same
experimental conditions in the relevant target organ to humans (i.e.
respiratory tract) following in vivo administration. OSHA agrees with
CPMA that the results of this study provide credible
evidence that water insoluble lead chromates are less carcinogenic than
some of the more moderately soluble chromates. Specifically, this
includes the slightly soluble zinc chromates (e.g. zinc yellow, zinc
potassium chromates, basic zinc chromates) as well as strontium
chromate and calcium chromate. Intrabronchial implantation of chromic
acid and other highly soluble Cr(VI) salts, such as sodium chromates,
did not induce a significant number of tumors. Therefore, these
experiments do not indicate lead chromate are less carcinogenic than
the highly water soluble Cr(VI) compounds.
If the histopathology data from the intrabronchial implantation is
examined more closely, all lead chromates increased the incidence of
squamous metaplasia relative to controls, and, for some lead chromates,
squamous dysplasia of the bronchial epithelium occurred (Table 2, Ex.
11-2). Squamous metaplasia and dysplasia are generally considered to be
transformed cellular states from which a neoplasm (e.g. carcinomas) can
arise (Ex. 11-12). Increased squamous metaplasia was common among all
tested Cr(VI) compounds but not among Cr(III)-containing materials or
the negative controls (Ex. 11-12). The increased metaplasia induced by
lead chromates is unlikely to be due to bronchial inflammation since
the degree of inflammation was no greater than that observed in the
cholesterol-implanted controls (Table 2, Ex. 11-2).
The squamous metaplasia and dysplasia in the rat lung model
following low dose lead chromate administration is consistent with a
low carcinogenic response (e.g. incidence of one percent or less) not
able to be detected under the conditions of the animal bioassay. This
explanation is supported by studies (discussed later in the section)
that show lead chromate can enter lung cells, damage DNA, and cause
genotoxic events leading to neoplastic transformation.
Lead chromate carcinogenicity is also supported by the animal
studies that CPMA dismisses as problematic and of questionable
relevance. These studies administered lead chromates to rodents by
either the subcutaneous (Exs. 8-25, 5-2, 8-37) or intramuscular routes
(Ex. 10-2). While OSHA agrees that these routes may be less relevant to
occupational inhalation than implantation in the respiratory tract, the
studies exposed rats to a larger dose of lead chromate. The higher
amounts of Cr(VI) produced a significant incidence of tumors at the
injection site (see section V.B.7.c).
The lead chromate pigments, chrome yellow and chrome orange,
induced injection site rhabdomyosarcomas and fibrosarcomas in 65
percent of animals following a single 30 mg injection in a saline
suspension (Ex. 8-37). The rats received a roughly ten fold higher dose
of Cr(VI) than in the intrabronchial bioassay. Rats injected with
saline alone did not develop injection site tumors. Only two percent or
less of rats receiving equal quantities of the inorganic pigments iron
yellow and iron red developed these tumors. The iron oxides are not
considered to be carcinogenic and do not give a significant neoplastic
response in this bioassay. OSHA has no reason to believe the
experimental procedure was problematic or given to frequent false
positives.
A similarly high incidence (i.e. 70 percent) of the same injection
site sarcomas were found in an independent study in which rats were
injected intramuscularly with reagent grade lead chromate once a month
for nine months (Ex. 10-2). Each injection contained approximately 1.3
mg of Cr(VI) and the total dose administered was over 30 times higher
than the intrabronchial implantation. The lead chromate was
administered in a glycerin vehicle. The vehicle produced less than a
two percent incidence of injection site sarcomas when administered
alone.
Contrary to statements by Eurocolour (Ex. 44-3D), lead chromate did
produce a low incidence of site-of-contact tumors in rats in an earlier
study when administered by either intramuscular or intrapleural
implantation (Ex. 10-4). There was no tumor incidence in the control
animals. The dose of lead chromate in this early publication was not
stated.
Based on the increase in pre-neoplastic changes from the single low
dose intrabronchial implantation and the high incidence of malignant
tumors resulting from larger doses administered by subcutaneous and
intramuscular injection, it is scientifically reasonable to expect that
larger doses of lead chromate may have produced a higher incidence of
tumors in the more relevant intrabronchial implantation procedure. The
highly soluble sodium dichromate produced a small (statistically
insignificant) incidence of squamous cell carcinoma (i.e. one percent)
upon single low dose intrabronchial implantation similar to the lead
chromates (Ex. 11-2). In another study, sodium dichromate caused a
significant 17 percent increase in the incidence of respiratory tract
tumors when instilled once a week for 30 months in the trachea of rats
(Ex. 11-7). The weekly-administered dose for this repeated instillation
was about \1/5\th the dose of that used in the intrabronchial
implantation assay but the total administered dose after 30 months was
about 25 times higher. Rats that received a lower total dose of sodium
dichromate or the same total dose in more numerous instillations (i.e.
lower dose rate) developed substantially fewer tumors that were
statistically indistinguishable from the saline controls. A third study
found a 15 percent increase (not statistically significant) in lung
tumor incidence when rats repeatedly inhaled aerosolized sodium
dichromate for 18 months at the highest air concentrations tested (Ex.
10-11). These sodium dichromate studies are further described in
section V.B.7.a. The findings suggest that the lack of significant
carcinogenic activity in the intrabronchial implantation study
reflects, in part, the low administered dose employed in the bioassay.
In his written testimony to OSHA, Dr. Harvey Clewell directly
addressed the issue of interpreting the absence of carcinogenicity in
an animal study as it relates to significant risk.
First, the ability to detect an effect depends on the power of
the study design. A statistically-based No Observed Adverse Effect
Level (NOAEL) in a toxicity study does not necessarily mean that
there is no risk of adverse effect. For example, it has been
estimated that a NOAEL in a typical animal study can actually be
associated with the presence of an effect in as many as 10% to 30%
of the animals. Thus the failure to observe a statistically
significant increase in tumor incidence at a particular exposure
does not rule out the presence of a substantial carcinogenic effect
at that exposure * * *. Similarly the failure of Levy et al. (1986)
to detect an increase in tumors following intrabronchial
instillation of lead chromate does not in itself demonstrate a lack
of carcinogenic activity for that compound. It only demonstrates a
lower activity than for other compounds that showed activity in the
same experimental design. Presumably this lower activity is
primarily due to its low solubility; evidence of solubilization,
cellular uptake, and carcinogenic activity of this compound [i.e.
lead chromate] is provided in other studies (Maltoni et al. 1974,
Furst et al., 1976, Blankenship et al., 1997; Singh et al., 1999;
Wise et al., 2004) (Ex. 44.5, p. 13-14).
OSHA agrees with Dr. Clewell that the inability to detect a
statistically significant incidence of tumors in one study that
administers a single low dose of lead chromate to a limited number of
animals is not evidence that this Cr(VI) compound lacks carcinogenic
activity. This is especially true when there exists an elevation in
pre-neoplastic lesions and other studies document significant
tumor incidence in animals administered higher doses of lead chromate.
Cellular Uptake and Genotoxicity of Lead Chromate--CPMA disputes
the many studies that report lead chromate to be genotoxic or
clastogenic in cellular test systems (Exs. 35-162; 12-5; 35-119; 35-
188; 35-132; 35-68; 35-67; 35-115; 35-66; 47-22-1; 47-12-3; 35-327; 35-
436). They claim that the studies inappropriately solubilized the lead
chromate " * * * in non-biological conditions such as strong alkali or
strong acid that causes the chemical breakdown of the lead chromate
crystal" (Ex. 38-205, p. 94) and the "lead chromate had been
dissolved * * * using aggressive substances" (Ex. 38-205, p. 99). In a
later submission, CPMA states state that some of the cellular studies
used reagent grade lead chromate that is only >=98 percent pure and may
contain up to 2 percent soluble chromate (Ex. 47-31, p. 11). They
speculate that the interactions (e.g. chromate ion uptake, chromosomal
aberrations, DNA adducts, etc.) described in studies using cell
cultures treated with lead chromate are either due to the presumed
contamination of soluble chromate or some other undefined "reactive
nature" of lead chromate. CPMA adds that " * * * the studies
referenced by OSHA [that use reagent grade lead chromate] have no
relevance to occupational exposures to commercial lead chromate
pigments" (Ex. 38-205, p. 11-12).
OSHA agrees that studies involving lead chromate pre-solubilized in
solutions of hydrochloric acid, sodium hydroxide or other strong acids
and bases prior to treatment with cells are not particularly relevant
to the inhalation of commercial lead chromate particulates. However,
several relevant cellular studies have demonstrated that lead chromate
particulates suspended in biological media and not can enter lung
cells, damage DNA, and cause altered gene expression as described
below.
Beginning in the late 1980s, there has been a consistent research
effort to characterize the genotoxic potential of lead chromate
particulate in mammalian cells. The lead chromate was not pre-
solubilized prior to cell treatment in any of these investigations. In
most of the studies, lead chromate particles were rinsed with water and
then acetone. The rinses cleansed the particles of water- and acetone-
soluble contaminants before cell treatment. This served to remove any
potential water-soluble Cr(VI) present that might confound the study
results. In most instances, the lead chromate particles were filtered,
stirred or sonicated in suspension to break up the aggregated particles
into monomeric lead chromate particulates. These lead chromate
particulates were primarily less than 5 [mu]m in diameter. This is
consistent with the inhaled particle size expected to deposit in the
bronchial and alveolar regions of the lung where lung cancer occurs.
Air-dried lead chromate particulates were introduced to the cell
cultures in a suspension of either saline-based media or acetone. Lead
chromate particulate is considered to be insoluble in both solvents so
significant solubilization is not expected during the process of
creating a homogenous suspension.
The initial research showed that lead chromate particulate
morphologically transformed mouse and hamster embryo cells (Exs. 35-
119; 12-5). One study tested a variety of lead chromate pigments of
different types (e.g. chrome yellows, chrome oranges, molybdate
oranges) as well as reagent grade lead chromate (Ex. 12-5). The
transformed cells displayed neoplastic properties (e.g. growth in soft
agar) and were tumorigenic when injected into animals (Ex. 35-119; 12-
5). While lead chromate particulate transformed mouse embryo cells, it
is important to note that lead chromate particulate was not found to be
mutagenic in these cells suggesting that other types of genetic lesions
(e.g. clastogenicity) may be involved (Ex. 35-119).
Follow-on research established that lead chromate particulate
caused DNA-protein crosslinks, DNA strand breaks, and chromosomal
aberrations (i.e. chromatid deletions and achromatic lesions combined)
in mammalian cells rather than DNA nucleotide binding often associated
with base substitution and frameshift mutations captured in a standard
Ames assay (Exs. 35-132; 35-188). This distinguishes lead chromate
particulate from high concentrations of soluble Cr(VI) compounds or
pre-solubilized lead chromate which can cause these mutations.
Lead chromate particulate enters mammalian embryo cells by two
distinct pathways (Ex. 35-68). It partially dissolves in the culture
medium (i.e. biological saline solution) to form chromate ion, which is
then transported into the cell. The rate of particle dissolution was
shown to be time- and concentration-dependent. The measured chromate
ion concentration was consistent with that predicted from the lead
chromate solubility constant in water. Lead chromate particulates were
shown to adhere to the embryo cell surface enhancing chromate ion
solubilization leading to sustained intracellular chromium levels and
measurable chromosomal damage (Ex. 35-67).
Lead chromate particulates are also internalized into embryo cells,
without dissolution, by a phagocytic process (Ex. 35-68). The lead
chromate particles appeared to remain undissolved in tight vacuoles
(i.e. phagosomes) within the cell over a 24 hour period. Treatment of
embryo cells with lead chromate particulates in the presence of a
reducing agent (i.e. ascorbate) substantially reduced cellular uptake
of dissolved chromate ions and the chromosomal damage, but did not
impact the internalization of lead chromate particulates (Ex. 35-68).
This suggests that chromosomal damage by lead chromate was the result
of extracellular particle dissolution and not internalization under the
particular experimental conditions. Embryo cell treatment with large
amounts of lead glutamate that produced high intracellular lead in the
absence of Cr(VI) did not cause chromosomal damage further implicating
intracellular chromium as the putative clastogenic agent (Ex. 35-67).
As the ability to maintain human tissue cells in culture improved
in the 1990s, dissolution and internalization of lead chromate
particulates, uptake of chromate ion, and the resulting chromosomal
damage were verified in human lung cells (Exs. 35-66; 47-22-1; 47-12-3;
35-327; 35-436). Lead chromate particulates are internalized, form
chromium adducts with DNA, and trigger dose-dependent apoptosis in
human small airway epithelial cells (Ex. 35-66). They also cause dose-
dependent increases in intracellular chromium, internalized lead
chromate particulates and chromosomal damage in human lung fibroblasts
(Exs. 47-22-1; 47-12-3). The chromosomal damage from lead chromate in
these human lung cells is dependent on the extracellular dissolution
and cell uptake of the chromate, rather than lead, in a manner similar
to dilute concentrations of the highly soluble sodium chromate (Ex. 47-
12-3; 35-327). Another water insoluble Cr(VI) compound, barium chromate
particulate, produces very similar responses in human lung fibroblasts
(Ex. 35-328). Human lung macrophages can phagocytize lead chromate
particulates and trigger oxidation-reduction of Cr(VI) to produce
reactive oxygen species capable of damaging DNA and altering gene
expression (Ex. 35-436).
OSHA finds these recent studies to be carefully conceived and
executed by reputable academic laboratories. The scientific findings
have been published in well-respected peer reviewed
molecular cancer and toxicology journals, such as Carcinogenesis (Exs.
12-5, 35-68), Cancer Research (Ex. 35-119), Toxicology and Applied
Pharmacology (Exs. 35-66; 25-115), and Mutation Research (Exs. 35-132;
47-22-1; 35-327). Contrary to statements by CPMA, the results indicate
that lead chromate particulates are able to dissociate in the presence
of biological media without the aid of aggressive substances. The
resulting chromate ion is bioavailable to enter lung cells, damage
genetic material and initiate events critical to carcinogenesis. These
effects can not be attributed to small amounts of soluble chromate
contaminants since these substances are usually removed as part of the
test compound preparation prior to cell treatment.
As one of the study authors, Dr. John Wise of the University of
Southern Maine, stated in his post-hearing comments:
At no time did we dissolve lead chromate particles prior to
administration. At the initial onset of the administration of lead
chromate particles in our studies, the cells encountered intact lead
chromate particles. Any dissolution that occurred was the natural
result of the fate of lead chromate particles in a biological
environment (Ex. 47-12, p. 3).
Other scientists concurred that the methods and findings of the
cellular research with lead chromate were reasonable. Dr. Kathleen
MacMahon, a biologist from NIOSH stated:
NIOSH believes that the methods that were used in the [lead
chromate] studies were credible and we support the results and
conclusions from those studies (Tr. 342).
Dr. Clewell said:
As I recall, it [lead chromate particles] was suspended in
acetone and ultrasonically shaken to reduce it to submicron
particles, which seems like a reasonably good thing to do. There are
actually a couple of studies besides the Wise studies that have
looked at the question of the uptake of lead chromate. I have looked
at those studies and I don't really see any basic flaws in what they
did. It is obviously a challenge to reproduce inhalation exposure in
vitro (Tr. 180-181).
Chromosal Aberrations and Lead Chromate--Several submissions contained
testimony from another researcher, Dr. Earle Nestmann of CANTOX Health
Sciences International, that criticized the methodology and findings of
a study published by the research group at the University of Southern
Maine (Exs. 34-6-1; 38-205D; 47-12-1; 47-22). Dr. Nestmann viewed as
inappropriate the practice of combining the chromatid deletions and
achromatic lesions together as chromosomal aberrations. He indicated
the standard practice was to score these two types of lesions
separately and that only the deletions had biological relevance.
According to Dr. Nestmann, achromatic lesions are chromatid gaps (i.e.
lesion smaller than the width of one chromatid) that have no
clastogenic significance and serve to inflate the percentage of cells
with chromosomal aberrations (i.e. chromatid deletions or breaks). Dr.
Nestmann criticized the studies for not including a positive control
group that shows the experimental system responds to a 'true'
clastogenic effect (i.e. a compound that clearly increases chromosomal
deletions without contribution from chromatid gaps).
Dr. John Wise, the Director of the research laboratory at the
University of Southern Maine, responded that distinguishing chromatid
gaps from breaks is a subjective distinction (e.g. requiring judgment
as to the width of a lesion relative to the width of a chromatid) and
pooling these lesions simply reduces this potential bias (Ex. 47-12;
47-12-1). He stated that there is no consensus on whether gaps should
or should not be scored as a chromosomal aberration and that gaps have
been included as chromosomal aberrations in other publications. Dr.
Wise also points out that achromatic lesions have not been shown to
lack biological significance and that the most recent research
indicates that they may be related to DNA strand breaks, a
scientifically accepted genotoxic endpoint. Dr. Wise further believed
that a positive control was unnecessary in his experiments since the
purpose was not to determine whether lead chromate was a clastogenic
agent, which had already been established by other research. Rather,
the purpose of his studies was to assess Cr(VI) uptake and chromosomal
damage caused by water-insoluble lead chromate compared to that of
highly water soluble sodium chromate using a relevant in vitro cell
model (i.e. human lung cells).
OSHA is not in a position to judge whether achromatic lesions
should be scored as a chromosomal aberration. However, OSHA agrees with
Dr. Nestmann that combining gaps and breaks together serves to increase
the experimental response rate in the studies. Given the lack of
consensus on the issue, it would have been of value to record these
endpoints separately. OSHA is not aware of data that show achromatic
gaps to be of no biological significance. The experimental data cited
above indicate that soluble and insoluble Cr(VI) compounds clearly
increase achromatic gaps in a concentration-dependent manner. The
chromatid lesions (gaps and breaks) may be chromosomal biomarkers
indicative of genetic damage that is critical to neoplastic
transformation. Furthermore, OSHA agrees with Dr. Wise that other
evidence establishes lead chromate as an agent able to cause DNA damage
and transform cells. The Agency considers the use of sodium chromate-
treated cells in the above set of experiments to be the appropriate
comparison group and does not find the absence of an additional
positive control group to be a technical deficiency of the studies.
OSHA considers the research conducted at the University of Southern
Maine documenting chromosomal damage in human lung cells following
treatment with lead chromate particulates to be consistent with results
from other studies (see Section V.B.8) and, thus, contributes to the
evidence that water insoluble lead chromate, like other chromates, is
able to enter lung cells and damage DNA.
In post-hearing comments, CPMA provided a Canadian research
laboratory report that tested the lead chromate Pigment Yellow 34 for
chromosomal aberrations in a hamster embryo cell system (Ex. 47-3,
appendix C). The research was sponsored by DCC and its representative
Dr. Nestmann. Lead chromate particles over the concentration range of
0.1 [mu]/cm2 to 10 [mu]/cm2 were reported to not
induce chromosomal aberrations under the experimental test conditions.
Chromatid structural and terminal gaps were not scored as aberrations
in this study, even though the percentage of cells with these lesions
increased in a dose-dependent manner from two percent in the absence of
lead chromate to over thirteen percent in cells treated with 1 [mu]/
cm2 lead chromate pigment particles.
This result is consistent with other experimental data that show
lead chromate particulates cause chromosomal lesions when administered
to mammalian embryo cells (Exs. 35-188; 35-132; 35-68; 35-67). The key
difference is how the various researchers interpreted the data. The
George Washington University group (i.e. Pateirno, Wise, Blankenship et
al.) considered the dose-dependent achromatic lesions (i.e. chromatid
gaps) as a clastogenic event and included them as chromosomal damage.
The Canadian test laboratory (i.e. Nucrotechnics) reported achromatic
lesions but did not score them as chromosomal aberrations. Reporting
achromatic lesions but not scoring them as chromosomal aberrations is
consistent with regulatory test guidelines as currently recommended by
EPA and OECD. The Nucrotechnics data suggest that the tested lead chromate
pigment caused a similar degree of chromosomal damage (i.e. dose-dependent
achromatic lesions and chromosomal aberrations combined) in mammalian cells.
This result was similar to results produced by reagent grade lead chromate in
previous studies.
Mutagenicity and Lead Chromate--CPMA also relied on a study that
reported a lack of mutagenicity for lead chromate pigments in a
bacterial assay using Salmonella Typhimurium TA 100 (Ex. 11-6). As
previously mentioned, this assay specifically measures point and
frameshift mutations usually caused by DNA adduct formation. The assay
is not sensitive to chromosomal damage, DNA strand breaks, or DNA
crosslinks most commonly found with low concentrations of Cr(VI)
compounds. Large amounts (50 to 500 [mu]g/plate) of highly soluble
sodium dichromate and slightly soluble calcium, strontium, and zinc
chromates, were found to be mutagenic in the study, but not the water
insoluble barium chromate and lead chromate pigments. However,
mutagenicity was observed when the acidic chelating agent,
nitrilotriacetic acid (NTA), was added to the assay to help solubilize
the water insoluble Cr(VI) compounds. The chelating agent was unable to
solubilize sufficient amounts of lead chromate pigments to cause
bacterial mutagenicity, if these pigments were more than five percent
encapsulated (weight to weight) with amorphous silica.
OSHA finds the results of this study to be consistent with the
published literature that shows Cr(VI) mutagenicity requires high
concentrations of solubilized chromate ion (Exs. 35-118; 35-161). Large
amounts of water-soluble and slightly soluble Cr(VI) compounds produce
a mutagenic response in most studies since these Cr(VI) compounds can
dissociate to achieve a high concentration of chromate ion. Insoluble
lead chromate usually needs to be pre-solubilized under acidic or
alkaline conditions to achieve sufficient chromate ion to cause
mutagenicity (Ex. 35-162). The above study found highly and slightly
soluble chromates to be mutagenic as well as water insoluble lead
chromate pigments pre-solubilized with NTA. The lack of mutagenicity
for silica encapsulated lead chromate pigments under these experimental
conditions is likely the result of their greater resistance to acidic
digestion than unencapsulated lead chromate pigment.
Failure to elicit a mutagenic response in a bacterial assay, with
or without NTA, is not a convincing demonstration that chromate ion can
not partially dissociate from encapsulated lead chromate in biological
media, enter mammalian cells, and elicit other types of genotoxicity.
As described above, chromosomal damage, believed to result from DNA
strand breaks and crosslinks, appears to be the critical genotoxic
endpoint for low concentrations of Cr(VI) compounds. Research has shown
that lead chromate and lead chromate pigment particulates in biological
media can cause chromosomal lesions and cell transformation without the
aid of strongly acidic or basic substances (Exs. 12-5; 35-119; 35-188;
35-132; 35-68; 35-67; 47-12-3; 35-327). While silica-encapsulated lead
chromate pigments have not been as thoroughly investigated as the
unencapsulated pigments or reagent grade lead chromate, one study
reported that lead silicochromate particles did have low solubility in
biological culture media and transformed hamster embryo cells (Ex. 12-
5).
Information is not available in the record to adequately
demonstrate the efficiency and stability of the encapsulation process,
despite OSHA statements that such information would be of value in its
health effects evaluation and its request for such information (69 FR
59315-59316, 10/4/2004; Ex. 2A). In the absence of data to the
contrary, OSHA believes it prudent and plausible that encapsulated lead
chromate pigments are able to partially dissociate into chromate ion
available for lung cell uptake and/or be internalized in a manner
similar to other lead chromate particulates. The resulting
intracellular Cr(VI) leads to genotoxic damage and cellular events
critical to carcinogenesis.
Public Comments on Carcinogenicity of Slightly Water Soluble Cr(VI)
Compounds--In its written comments to the NPRM, Boeing Corporation
stated that "there is no persuasive scientific evidence for OSHA's
repeated assertion that low solubility hexavalent chromium compounds
[e.g. strontium and zinc chromates] are more potent carcinogens than
[highly] soluble [Cr(VI)] compounds" (Ex. 38-106, p. 2). Boeing and
others in the aerospace industry are users of certain slightly soluble
Cr(VI) compounds, particularly strontium chromate, found in the
protective coatings applied to commercial and military aircraft.
Boeing argues that OSHA, along with IARC, ACGIH and others, have
exclusively relied on intrabronchial implantation studies in animals
that are both not representative of inhalation exposures in the
workplace and are not consistent with the available animal inhalation
data (Ex. 38-106-2, p. 26). Boeing asserts that there is no evidence
that slightly soluble chromates behave differently in terms of their
absorption kinetics than highly soluble chromates when instilled in the
lungs of rats (Ex. 38-106-2, p. 19). Boeing believes the OSHA position
that slightly soluble Cr(VI) compounds are retained in the lung,
associate with cells, and cause high uptake or high local
concentrations to be inconsistent with other data showing these Cr(VI)
compounds quickly disperse in water (Ex. 38-106-2, p. 26). Boeing
concludes:
There is no basis for the conclusion that low solubility [i.e.
slightly soluble] chromates could be more potent than [highly]
soluble, and some evidence the opposite may be the case. As a worst
case OSHA should conclude that there is inadequate evidence to
conclude that [highly] soluble and low-solubility compounds differ
in carcinogenic potency. It is critical that OSHA maintain a
distinction between low-solubility chromates and highly insoluble
chromates based on this data. (Ex. 38-106-2, p. 26)
As noted earlier, OSHA as well as other commenters agree with
Boeing that the animal intrabronchial and intratracheal instillation
studies are not appropriate for quantitatively predicting lung cancer
risk to a worker breathing Cr(VI) dust and aerosols. However, many
stakeholders disagreed with the Boeing view and believed these animal
studies can be relied upon as qualitative evidence of relative
carcinogenic potency. CPMA, which relies on the rat intrabronchial
implantation results as evidence that lead chromate is non-
carcinogenic, states "tests involving implantation in rat lung, as
carried out by Levy et al. in 1986, are relevant to inhalation in
industrial exposures" (Ex. 38-205, p. 93). In their opening statement
NIOSH agreed with the preliminary OSHA determination that "the less
water soluble [Cr(VI)] compounds may be more potent than the more water
soluble [Cr(VI)] compounds" (Tr. 299). NIOSH identified the rat
intrabronchial implantation findings as the basis for their position
that the slightly soluble Cr(VI) compounds appear to be more
carcinogenic than the more soluble and insoluble Cr(VI) compounds (Tr.
334). Dr. Clewell testified that:
Some animal studies suggest the solubility of hexavalent
chromium compounds influences their carcinogenic potency with
slightly soluble compounds having the higher potencies than highly
soluble or insoluble compounds. However, the evidence is inadequate
to conclude that specific hexavalent chromium compounds are not
carcinogenic. Moreover the designs of the studies were not
sufficient to quantitatively estimate comparative potencies (Ex. 44-5, p. 15).
Respiratory Tract Instillation of Slightly Soluble Cr(VI) Compounds in
Rats--OSHA agrees that animal intrabronchial and intratracheal
implantation studies provide persuasive evidence that slightly soluble
Cr(VI) are more carcinogenic than the highly soluble Cr(VI) compounds.
As mentioned previously, these studies provide useful information
regarding the relative carcinogenicity of different Cr(VI) compounds
once they are delivered and deposited in the respiratory tract. For
example, one study examined the carcinogenicity of over twenty
different Cr(VI) compounds in rats, spanning a broad range of
solubilities, under the same experimental conditions in the relevant
target organ to humans (i.e. respiratory tract) following in vivo
administration (Ex. 11-2). A single administration of each Cr(VI) test
compound was instilled in the lower left bronchus of approximately 100
rats. The results were dramatic. Roughly 50 and 25 percent of the rats
receiving the slightly soluble strontium and calcium chromates,
respectively, developed bronchogenic carcinoma. No other Cr(VI)
compounds produced more than five percent tumor incidence. The highly
soluble sodium dichromate under the same experimental conditions caused
bronchogenic carcinoma in only a single rat.
The higher relative potency of the slightly soluble calcium
chromate compared to the highly soluble sodium dichromate was confirmed
in another study in which each test compound was instilled at a low
dose level (i.e., 0.25 mg/kg) in the trachea of 80 rats five times
weekly for 30 months (Ex. 11-7). Using this experimental protocol, 7.5
percent of the slightly soluble calcium chromate-treated animals
developed brochioalveolar adenomas while none of the highly soluble
sodium dichromate-treated rats developed tumors. The tumor incidence at
this lower dose level occurred in the absence of serious lung pathology
and is believed to reflect the tumorigenic potential of the two Cr(VI)
compounds at workplace exposures of interest to OSHA. On the other
hand, a five-fold higher dose level that caused severe damage and
chronic inflammation to the rat lungs produced a similar fifteen
percent lung tumor incidence in both calcium and sodium chromate
treated rats. OSHA, as well as the study authors, believe the later
tumor response with the higher dose level did not result from direct
Cr(VI) interaction with cellular genes, but, instead, was primarily
driven by the cellular hyperplasia secondary to the considerable damage
to the lung tissue. Boeing also seems to attribute this result to
tissue damage stating "most of the tumors were found in areas of
chronic inflammation and scarring, suggesting an effect that is
secondary to tissue damage" (Ex. 38-106-2, p. 21).
OSHA does not agree with some study interpretations advanced by
Boeing in support of their position that slightly soluble Cr(VI)
compounds are no more carcinogenic than highly soluble Cr(VI). For
example, Boeing claims that the intrabronchial implantation experiments
cannot be relied upon because the results do not correspond to findings
from animal inhalation studies (Ex. 38-106-2, p. 24-25). The primary
basis for the Boeing comparison were two rodent bioassays that reported
tumor incidence from the inhalation of different Cr(VI) compounds (Exs.
10-8; 10-11). In one study over 200 mice inhaled slightly soluble
calcium chromate powder for five hours per day, five days per week for
roughly two years (Ex. 10-8). In the other study, 19 rats inhaled an
aqueous sodium dichromate liquid aerosol virtually around the clock for
22 hours a day, seven days a week for eighteen months (Ex. 10-11). The
two studies reported a similar tumor incidence despite the lower total
weekly Cr(VI) dose of sodium dichromate in the second study. OSHA
believes the vastly different experimental protocols employed in these
studies do not allow for a legitimate comparison of carcinogenic
potency between Cr(VI) compounds. First, mouse and rat strains can
differ in their susceptibility to chemical-induced lung tumors. Second,
the proportion of respirable Cr(VI) may differ between a liquid aerosol
of aqueous sodium dichromate mist and an aerosol solid calcium chromate
particles suspended in air. Third, the opportunity for Cr(VI) clearance
will undoubtedly differ between a Cr(VI) dose inhaled nearly
continuously (e.g., 22 hours per day, seven days a week) and inhaled
intermittently (e.g., five hours a day, five days a week) over the
course of a week. These experimental variables can be expected to have
a major influence on tumor response and, thus, will obscure a true
comparison of carcinogenic potency. Boeing acknowledges that "these
[inhalation] studies used very different protocols and are not directly
comparable" (Ex. 38-106-2, p.24). On the other hand, slightly soluble
Cr(VI) compounds were found to cause a greater incidence of lung tumors
than highly soluble Cr(VI) compounds in two independent studies in
which the test compounds were instilled under the same dosing regime in
the same rodent models in research specifically designed to assess
relative Cr(VI) carcinogenic potency (Exs. 11-2; 11-7). Therefore, OSHA
believes any apparent lack of correspondence between animal inhalation
and instillation studies is due to an inability to compare inhalation
data from vastly different experimental protocols and should not
diminish the relevance of the instillation findings.
Epidemiological Studies of Slightly Soluble Cr(VI) Compounds--
Boeing further argues that the greater carcinogenic potency experienced
by rats intrabronchially instilled with slightly soluble chromates
compared to rats instilled with highly soluble and water-insoluble
Cr(VI) compounds "do not correspond qualitatively to observed lung
cancer in occupational exposure" (Ex. 38-106-2, p. 21). Several other
industry stakeholders disagree. In explaining the excess lung cancer
mortality among pigment production workers, CPMA commented:
[water-insoluble] Lead chromate pigments must be differentiated
from [slightly soluble] zinc chromate corrosion inhibitor additives,
which are consistently shown to be carcinogenic in various studies.
When [water insoluble] lead chromate and [slightly soluble] zinc
chromate exposures occur simultaneously, there appears to be a
significant cancer hazard. However, when lead chromate pigments
alone are the source of chromium exposure, a significant cancer
response has never been found (Ex. 38-205, p. 91).
In explaining the excess lung cancer mortality among chromate
production workers in the Gibb and Luippold cohorts, the Electric Power
Research Institute states that:
One important distinction is that workers of the historical
chromate production industry were exposed to sparingly soluble forms
of calcium chromate in the roast mix, which are recognized to have
greater carcinogenic potential as compared to soluble forms of
Cr(VI) based on animal implantation studies (Ex. 38-8, p. 12).
Deborah Proctor of Exponent also testified:
Several studies of chromate production worker cohorts have
demonstrated that the excess cancer risk is reduced when less lime
is added to the roast mixture, reducing worker exposure to the
sparingly soluble calcium chromate compounds" (Ex. 40-12-5).
OSHA believes there is merit to the above comments that workplace
exposure to slightly soluble Cr(VI) compounds may have contributed to
the higher lung cancer mortality in both pigments workers producing
mixed zinc and lead chromate pigments as well as
chromate production workers exposed to calcium chromate from high lime
production processes in the 1930s and 1940s. Other factors, such as
greater Cr(VI) exposure, probably also contributed to the higher lung
cancer mortality observed in these cohorts. In any case, these
epidemiological findings support the Boeing contention that the
epidemiological findings are inconsistent with the results from animal
intrabronchial implantation studies (Ex. 38-106-2, p. 26).
Clearance, Retention, and Dissolution of Slightly Soluble Cr(VI)
Compounds in the Lung--Boeing argues that animal experiments that
examined the absorption, distribution and excretion of Cr(VI) compounds
after intratracheal instillation of Cr(VI) compounds in rats do not
show that highly soluble Cr(VI) is cleared more rapidly or retained in
the lung for shorter periods than slightly soluble Cr(VI) compounds
(Ex. 38-106-2, p. 18-19). The results of one study found that larger
amounts of water-insoluble lead chromate were retained in the lungs of
rats at both 30 minutes and at 50 days after instillation than for
highly soluble sodium chromate or slightly soluble zinc chromate (Ex.
35-56). Although the authors concluded that slightly soluble zinc
chromate was more slowly absorbed from the lung than the highly soluble
sodium chromate, the excretion and distribution of the absorbed
chromium from the zinc and sodium chromate instillations was similar.
Furthermore, there was little difference in the amounts of zinc and
sodium chromate retained by the lung at the two extreme time points
(e.g., 30 minutes and 50 days) measured in the study. OSHA agrees with
Boeing that these findings indicate slower clearance and longer
retention in the lung of the water insoluble lead chromate relative to
highly soluble sodium chromate, but not in the case of the slightly
soluble zinc chromate. Slower clearance and longer residence time in
the lung will generally enhance carcinogenic potential assuming other
dosimetric variables such as lung deposition, Cr(VI) concentration at
the lung cell surface, and dissociation into chromate ion are
unchanged.
Boeing asserts that a study of strontium chromate dissociation from
paint primer contradicts the notion that slightly soluble are more
likely than highly soluble Cr(VI) compounds to concentrate and
dissociate at the lung cell surface (Ex. 38-106-2, p. 25). This
experimental research found that roughly 75 and 85 percent of strontium
chromate contained in metal surface primer coating particles was
solubilized in water after one and 24 hours, respectively (Ex. 31-2-1).
The primer particles were generated using a high volume, low pressure
spray gun according to manufacturer specifications, and collected in
water impingers. The authors concluded that their study demonstrated
that chromate dissociation from primer particles into the aqueous fluid
lining lung cells would be modestly hindered relative to highly water
soluble Cr(VI) aerosols.
The slower dissociation of the slightly soluble Cr(VI) compound,
strontium chromate, plausibly explains its higher carcinogenicity in
animal implantation studies. The 'modest hindrance' allows the
undissociated chromate to achieve higher concentrations at the surface
of the lung cells facilitating chromate transport into the cell. The
unhindered, instantaneous dispersion of highly water soluble chromates
in aqueous fluid lining of the respiratory tract is less likely to
achieve a high chromate concentration at the lung cell membrane. OSHA
believes the results of the above study support, not contradict, that
slightly soluble Cr(VI) may lead to higher chromium uptake into lung
cells than highly soluble Cr(VI) compounds.
In summary, slightly soluble Cr(VI) compounds have consistently
caused higher lung tumor incidence in animal instillation studies
specifically designed to examine comparative carcinogenic potency in
the respiratory tract. The higher carcinogenic activity of slightly
soluble Cr(VI) is consistent with cellular studies that indicate that
chromate dissociation in close proximity to the lung cell surface may
be a critical feature to efficient chromate ion uptake. This is
probably best achieved by Cr(VI) compounds that have intermediate water
solubility rather than by highly water-soluble Cr(VI) that rapidly
dissolves and diffuses in the aqueous fluid layers lining the
respiratory tract. The higher carcinogenicity of slightly soluble
Cr(VI) may contribute, along with elevated Cr(VI) workplace exposures,
to the greater lung cancer mortality in certain occupational cohorts
exposed to both slightly soluble and other forms of Cr(VI). The vastly
different study protocols employed in the few animal inhalation
bioassays do not allow a valid comparison of lung tumor incidence
between slightly soluble and highly soluble Cr(VI) compounds.
b. Summary of Cr(VI) Carcinogenicity
After carefully considering all the epidemiological, animal and
mechanistic evidence presented in the rulemaking record, OSHA regards
all Cr(VI) compounds as agents able to induce carcinogenesis through a
genotoxic mode of action. This position is consistent with findings of
IARC, EPA, and ACGIH that classified Cr(VI) compounds as known or
confirmed human carcinogens. Based on the above animal and experimental
evidence, OSHA believes that slightly soluble Cr(VI) compounds are
likely to exhibit a greater degree of carcinogenicity than highly water
soluble or water insoluble Cr(VI) when the same dose is delivered to
critical target cells in the respiratory tract of the exposed worker.
In its evaluation of different Cr(VI) compounds, ACGIH recommended
lower occupational exposure limits for the slightly soluble strontium
chromate (TLV of 0.5 [mu]g/m\3\) and calcium chromate (TLV of 1 [mu]g/
m\3\) than either water insoluble (TLV of 10 [mu]g/m\3\) or water
soluble (TLV of 50 [mu]g/m\3\) forms of Cr(VI) based on the animal
instillation studies cited above. While these animal instillation
studies are useful for hazard identification and qualitative
determinations of relative potency, they cannot be used to determine a
reliable quantitative estimate of risk for human workers breathing
these chromates during occupational exposure. This was due to use of
inadequate number of dose levels (e.g., single dose level) or a less
appropriate route of administration (e.g., tracheal instillation).
It is not clear from the animal or cellular studies whether the
carcinogenic potency of water insoluble Cr(VI) compounds would be
expected to be more or less than highly water soluble Cr(VI). However,
it was found that a greater percentage of water insoluble lead chromate
remains in the lungs of rats for longer periods than the highly water
soluble sodium chromate when instilled intratracheally at similar doses
(Ex. 35-56). Since water insoluble lead chromate can persist for long
periods in the lung and increase intracellular levels of Cr and damage
DNA in human lung cells at low doses (e.g., 0.1 [mu]g/cm\2\), OSHA
believes that based on the scientific evidence discussed above it is
reasonable to regard the water insoluble Cr(VI) to be of similar
carcinogenic potency to highly soluble Cr(VI) compounds. No convincing
scientific evidence was introduced into the record that shows lead
chromate to be less carcinogenic than highly soluble chromate
compounds.
C. Non-cancer Respiratory Effects
The following sections describe the evidence from the literature on
nasal irritation, nasal ulcerations, nasal perforations, asthma, and
bronchitis following inhalation exposure to water
soluble Cr(VI) compounds. The evidence clearly demonstrates that
workers can develop impairment to the respiratory system (nasal
irritation, nasal ulceration, nasal perforation, and asthma) after
workplace exposure to Cr(VI) compounds below the previous PEL.
It is very clear from the evidence that workers may develop nasal
irritation, nasal tissue ulcerations, and nasal septum perforations at
occupational exposures level at or below the current PEL of 52 [mu]g/
m\3\. However, it is not clear what occupational exposure levels lead
to the development of occupational asthma or bronchitis.
1. Nasal Irritation, Nasal Tissue Ulcerations and Nasal Septum
Perforations
Occupational exposure to Cr(VI) can lead to nasal tissue
ulcerations and nasal septum perforations. The nasal septum separates
the nostrils and is composed of a thin strip of cartilage. The nostril
tissue consists of an overlying mucous membrane known as the mucosa.
The initial lesion after Cr(VI) exposure is characterized by localized
inflammation or a reddening of the affected mucosa, which can later
lead to atrophy. This may progress to an ulceration of the mucosa layer
upon continued exposure (Ex. 35-1; Ex. 7-3). If exposure is
discontinued, the ulcer progression will stop and a scar may form. If
the tissue damage is sufficiently severe, it can result in a
perforation of the nasal septum, sometimes referred to chrome hole.
Individuals with nasal perforations may experience a range of signs and
symptoms, such as a whistling sound, bleeding, nasal discharge, and
infection. Some individuals may experience no noticeable effects.
Several cohort and cross-sectional studies have described nasal
lesions from airborne exposure to Cr(VI) at various electroplating and
chrome production facilities. Most of these studies have been reviewed
by the Center for Disease Control's Agency for Toxic Substances and
Disease Registry (ATSDR) toxicological profile for chromium (Ex. 35-
41). OSHA reviewed the studies summarized in the profile, conducted its
own literature search, and evaluated studies and comments submitted to
the rulemaking record. In its evaluation, OSHA took into consideration
the exposure regimen and experimental conditions under which the
studies were performed, including exposure levels, duration of
exposure, number of animals, and the inclusion of appropriate control
groups. Studies were not included if they did not contribute to the
weight of evidence either because of inadequate documentation or
because of poor quality. This section only covers some of the key
studies and reviews. OSHA has also identified two case reports
demonstrating the development of nasal irritation and nasal septum
perforations, and these case reports are summarized as well. One case
report shows how a worker can develop the nasal perforations from
direct contact (i.e., touching the inner surface of the nose with
contaminated fingers).
Lindberg and Hedenstierna examined the respiratory symptoms and
effects of 104 Swedish electroplaters (Ex. 9-126). Of the 104
electroplaters, 43 were exposed to chromic acid by inhalation. The
remaining 61 were exposed to a mixture of chromic acid and nitric acid,
hydrochloric acid, boric acid, nickel, and copper salts. The workers
were evaluated for respiratory symptoms, alterations in the condition
of the nasal tissue, and lung function. All workers were asked to fill
out a detailed questionnaire on their history of respiratory symptoms
and function. Physicians performed inspections of the nasal passages of
each worker. Workers were given a pulmonary function test to assess
lung function. For those 43 workers exposed exclusively to chromic
acid, the median exposure time was 2.5 years, ranging from 0.2 to 23.6
years. The workers were divided into two groups, a low exposure group
(19 workers exposed to eight-hour time weighted average levels below 2
[mu]g/m\3\) and a high exposure group (24 workers exposed to eight-hour
time weighted average levels above 2 [mu]g/m\3\). Personal air sampling
was conducted on 11 workers for an entire week at stations close to the
chrome baths to evaluate peak exposures and variations in exposure on
different days over the week. Nineteen office employees who were not
exposed to Cr(VI) were used as controls for nose and throat symptoms,
and 119 auto mechanics (no car painters or welders) whose lung function
had been evaluated using similar techniques to those used on Cr(VI)
exposed workers were used as controls for lung function.
The investigators reported nasal tissue ulcerations and septum
perforations in a group of workers exposed to chromic acid as Cr(VI) at
peak exposure ranging from 20 [mu]g/m\3\ to 46 [mu]g/m\3\. The
prevalence of ulceration/perforation was statistically higher than the
control group. Of the 14 individuals in the 20-46 [mu]g/m\3\ exposure
group, 7 developed nasal ulcerations. In addition to nasal ulcerations,
2 of the 7 also had nasal perforations. Three additional individuals in
this group developed nasal perforations in the absence of ulcerations.
None of the 14 workers in the 20-46 [mu]g/m\3\ exposure group were
reported to have nasal tissue atrophy in the absence of the more
serious ulceration or perforation.
At average exposure levels from 2 [mu]g/m\3\ to 20 [mu]g/m\3\, half
of the workers complained of "constantly running nose," "stuffy
nose," or "there was a lot to blow out." (Authors do not provide
details of each complaint). Nasal tissue atrophy, in the absence of
ulcerations or perforations, was observed in 66 percent of
occupationally exposed workers (8 of 12 subjects) at relatively low
peak levels ranging from 2.5 [mu]g/m\3\ to 11 [mu]g/m\3\. No one
exposed to levels below 1 [mu]g/m\3\ (time-weighted average, TWA)
complained of respiratory symptoms or developed lesions.
The authors also reported that in the exposed workers, both forced
vital capacity and forced expiratory volume in one second were reduced
by 0.2 L, when compared to controls. The forced mid-expiratory flow
diminished by 0.4 L/second from Monday morning to Thursday afternoon in
workers exposed to chromic acid as Cr(VI) at daily TWA average levels
of 2 [mu]g/m\3\ or higher. The effects were small, not outside the
normal range and transient. Workers recovered from the effects after
two days. There was no difference between the control and exposed group
after the weekend. The workers exposed to lower levels (2 [mu]g/m\3\ or
lower, TWA) showed no significant changes.
Kuo et al. evaluated nasal septum ulcerations and perforations in
189 electroplaters in 11 electroplating factories (three factories used
chromic acid, six factories used nickel-chromium, and two factories
used zinc) in Taiwan (Ex. 35-10). Of the 189 workers, 26 used Cr(VI),
129 used nickel-chromium, and 34 used zinc. The control group consisted
of electroplaters who used nickel and zinc. All workers were asked to
fill out a questionnaire and were given a nasal examination including a
lung function test by a certified otolaryngologist. The authors
determined that 30% of the workers (8/26) that used chromic acid
developed nasal septum perforations and ulcerations and 38% (10/26)
developed nasal septum ulcers. Using the Mantel Extension Test for
Trends, the authors also found that chromium electroplaters had an
increased likelihood of developing nasal ulcers and perforations
compared to electroplating workers using nickel-chromium and zinc.
Personal sampling of airborne Cr(VI) results indicated the highest
levels (32 [mu]g/m\3\ 35 [mu]g/m\3\, ranging from 0.1
[mu]g/m\3\-119 [mu]g/m\3\) near the electroplating tanks of the Cr(VI)
electroplating
factories (Ex. 35-11). Much lower personal sampling levels were
reported in the "other areas in the manufacturing area" and in the
"administrative area" (TWA 0.16 0.10 [mu]g/m\3\) of the
Cr(VI) electroplating plant. The duration of sampling was not
indicated. The lung function tests showed that Cr(VI) electroplaters
had significantly lower forced vital capacity and forced expiratory
volume when compared to other exposure groups.
Cohen et al. examined respiratory symptoms of 37 electroplaters
following inhalation exposure to chromic acid (Ex. 9-18). The mean
length of employment for the 37 electroplaters was 26.9 months (range
from 0.3 to 132 months). Fifteen workers employed in other parts of the
plant were randomly chosen for the control group (mean length of
employment was 26.1 months; range from 0.1 to 96). All workers were
asked to fill out a questionnaire on their respiratory history and to
provide details about their symptoms. An otolaryngologist then examined
each individual's nasal passages and identified ulcerations and
perforations. Air samples to measure Cr(VI) were collected for
electroplaters. The air sampling results of chromic acid as Cr(VI)
concentrations for electroplaters was a mean of 2.9 [mu]g/m\3\ (range
from non-detectable to 9.1 [mu]g/m\3\). The authors found that 95% of
the electroplaters developed pathologic changes in nasal mucosa.
Thirty-five of the 37 workers who were employed for more than 1 year
had nasal tissue damage. None of these workers reported any previous
job experience involving Cr(VI) exposure. Four workers developed nasal
perforations, 12 workers developed ulcerations and crusting of the
septal mucosa, 11 workers developed discoloration of the septal mucosa,
and eight workers developed shallow erosion of septal mucosa. The
control group consisted of 15 workers who were not exposed to Cr(VI) at
the plant. All but one had normal nasal mucosa. The one individual with
an abnormal finding was discovered to have had a previous Cr(VI)
exposure while working in a garment manufacturing operation as a fabric
dyer for three years. In addition to airborne exposure, the authors
observed employees frequently wiping their faces and picking their
noses with contaminated hands and fingers. Many did not wear any
protective gear, such as gloves, glasses, or coveralls.
Lucas and Kramkowsi conducted a Health Hazard Evaluation (HHE) on
11 chrome platers in an industrial electroplating facility (Ex. 3-84).
The electroplaters worked for about 7.5 years on average. Physicians
evaluated each worker for chrome hole scars, nasal septum ulceration,
mucosa infection, nasal redness, perforated nasal septum, and wheezing.
Seventeen air samples for Cr(VI) exposure were collected in the chrome
area. Cr(VI) air concentrations ranged from 1 to 20 [mu]g/m\3\, with an
average of 4 [mu]g/m\3\. In addition to airborne exposure, the authors
observed workers being exposed to Cr(VI) by direct "hand to nose"
contact, such as touching the nose with contaminated hands. Five
workers had nasal mucosa that became infected, two workers had nasal
septum ulcerations, two workers had atrophic scarring (author did not
provide explanation), possibly indicative of presence of past
ulcerations, and four workers had nasal septum perforations.
Gomes evaluated 303 employees from 81 electroplating operations in
Sao Paulo, Brazil (Ex. 9-31). Results showed that more than two-thirds
of the workers had nasal septum ulcerations and perforations following
exposure to chromic acid at levels greater than 100 [mu]g/m\3\, but
less than 600 [mu]g/m\3\ (precise duration of exposure was not stated).
These effects were observed within one year of employment.
Lin et al. examined nasal septum perforations and ulcerations in 79
electroplating workers from seven different chromium electroplating
factories in Taipei, Taiwan (Ex.35-13). Results showed six cases of
nasal septum perforations, four having scar formations, and 38 cases of
nasal septum ulcerations following inhalation exposure to chromic acid.
Air sampling near the electroplating tanks had the highest range of
chromic acid as Cr(VI) (mean of 28 [mu]g/m\3\; range from 0.7 to 168.3
[mu]g/m\3\). In addition to airborne exposures, the authors also
observed direct "hand to nose" contact where workers placed
contaminated fingers in their nose. The authors attributed the high
number of cases to poor industrial hygiene practices in the facilities.
Five of the seven factories did not have adequate ventilation systems
in place. Workers did not wear any PPE, including respirators.
Bloomfield and Blum evaluated nasal tissue damage and nasal septum
perforations in 23 workers employed at six chromium electroplating
plants (Ex. 9-13). They found that daily exposure to chromic acid as
Cr(VI) at levels of 52 [mu]g/m\3\ or higher can lead to nasal tissue
damage. Three workers developed nasal ulcerations, two workers had
nasal perforations, nine workers had nose bleeds, and nine workers had
inflamed mucosa.
Kleinfeld and Rosso found that seven out of nine of chrome
electroplaters had nasal septum ulcerations (Ex. 9-41). The nine
workers were exposed to chromic acid as Cr(VI) by inhalation at levels
ranging from 93 [mu]g/m\3\ to 728 [mu]g/m\3\. Duration of exposure
varied from two weeks to one year. Nasal septum ulcerations were noted
in some workers who had been employed for only one month.
Royle, using questionnaire responses from 997 British
electroplaters exposed to chromic acid, reported a significant increase
in the prevalence of nasal ulcerations. The prevalence increased the
longer the worker was exposed to chromic acid (e.g., from 14 cases with
exposure less than one year to 62 cases with exposure over five years)
(Ex. 7-50). In all but 2 cases, air samples revealed chromic acid
concentrations of 0.03 mg/m\3\ (i.e., 30 [mu]g/m\3\).
Gibb et al. reported nasal irritations, nasal septum bleeding,
nasal septum ulcerations and perforations among a cohort of 2,350
chrome production workers in a Baltimore plant (Ex. 31-22-12). A
description of the cohort is provided in detail in the cancer health
effects section V.B. of this preamble. The authors found that more than
60% of the cohort had experienced nasal ulcerations and irritations,
and that the workers developed these effects for the first time within
the first three months of being hired (median). Gibb et al. found that
the median annual exposure to Cr(VI) during first diagnosis of
irritated and/or ulcerated nasal septum was 10 [mu]g/m\3\. About 17% of
the cohort reported nasal perforations. Based on historical data, the
authors believe that the nasal findings are attributable to Cr(VI)
exposure.
Gibb et al. also used a Proportional Hazard Model to evaluate the
relationship between Cr(VI) exposure and the first occurrence of each
of the clinical findings. Cr(VI) data was entered into the model as a
time dependent variable. Other explanatory variables were calendar year
of hire and age of hire. Results of the model indicated that airborne
Cr(VI) exposure was associated with the occurrence of nasal septum
ulceration (p = 0.0001). The lack of an association between airborne
Cr(VI) exposure and nasal perforation and bleeding nasal septum may
reflect the fact that Cr(VI) concentrations used in the model represent
annual averages for the job, in which the worker was involved in at the
time of the findings, rather than a short-term average. Annual averages
do not factor in day-to-day fluctuations or extreme episodic
occurrences. Also, the author believed that poor housekeeping
and hygiene practices may have contributed to these health effects as
well as Cr(VI) air borne concentrations.
Based on their hazard model, Gibb et al. estimated the relative
risks for nasal septum ulcerations would increase 1.2 for each 52 [mu]g
of Cr(VI)/m\3\ increase in Cr(VI) air levels. They found a reduction in
the incidence of nasal findings in the later years. They found workers
from the earlier years who did not wear any PPE had a greater risk of
developing respiratory problems. They believe that the reduction in
ulcerations was possibly due to an increased use of respirators and
protective clothing and improved industrial hygiene practices at the
facility.
The U.S. Public Health Service conducted a study of 897 chrome
production workers in seven chromate producing plants in the early
1950s (Ex. 7-3). The findings of this study were used in part as
justification for the current OSHA PEL. Workers were exposed by
inhalation to various water soluble chromates and bichromate compounds.
The total mean exposure to the workers was a TWA of 68 [mu]g/m\3\. Of
the 897 workers, 57% (or 509 workers) were found to have nasal septum
perforations. Nasal septum perforations were even observed in workers
during their first year on the job.
Case reports provide further evidence that airborne exposure and
direct "hand to nose" contact of Cr(VI) compounds lead to the
development of nasal irritation and nasal septum perforations.
For example, a 70-year-old man developed nasal irritation,
incrustation, and perforation after continuous daily exposure by
inhalation to chromium trioxide (doses were not specified, but most
likely quite high given the nature of his duties). This individual
inhaled chromium trioxide daily by placing his face directly over an
electroplating vessel. He worked in this capacity from 1934 to 1982.
His symptoms continued to worsen after he stopped working. By 1991, he
developed large perforations of the nasal septum and stenosis (or
constriction) of both nostrils by incrustation (Ex. 35-8).
Similarly, a 30-year-old female jigger (a worker who prepares the
items prior to electroplating by attaching the items to be plated onto
jigs or frames) developed nasal perforation in her septum following
continuous exposure (doses in this case were not provided) to chromic
acid mists. She worked adjacent to the automated Cr(VI) electroplating
shop. She was also exposed to chromic acid from direct contact when she
placed her contaminated fingers in her nose. Her hands became
contaminated by handling wet components in the jigging and de-jigging
processes (Ex. 35-24).
Evidence of nasal septum perforations has also been demonstrated in
experimental animals. Adachi exposed 23 C57BL mice to chromic acid by
inhalation at concentrations of 1.81 mg Cr(VI)/m\3\ for 120 min per
day, twice a week and 3.63 mg Cr(VI)/m\3\ for 30 minutes per day, two
days per week for up to 12 months (Ex. 35-26). Three of the 23 mice
developed nasal septum perforations in the 12 month exposure group.
Adachi et al. also exposed 50 ICR female mice to chromic acid by
inhalation at concentrations of 3.18 mg Cr(VI)/m\3\ for 30 minutes per
day, two days per week for 18 months (Ex. 35-26-1). The authors used a
miniaturized chromium electroplating system to mimic electroplating
processes and exposures similar to working experience. Nasal septum
perforations were found in six mice that were sacrificed after 10
months of exposure. Of those mice that were sacrificed after 18 months
of exposure, nasal septum perforations were found in three mice.
2. Occupational Asthma
Occupational asthma is considered "a disease characterized by
variable airflow limitation and/or airway hyperresponsiveness due to
causes and conditions attributable to a particular occupational
environment and not to stimuli encountered outside the workplace" (Ex.
35-15). Asthma is a serious illness that can damage the lungs and in
some cases be life threatening. The common symptoms associated with
asthma include heavy coughing while exercising or when resting after
exercising, shortness of breath, wheezing sound, and tightness of chest
(Exs. 35-3; 35-6).
Cr(VI) is considered to be an airway sensitizer. Airway sensitizers
cause asthma through an immune response. The sensitizing agent
initially causes production of specific antibodies that attach to cells
in the airways. Subsequent exposure to the sensitizing agent, such as
Cr(VI), can trigger an immune-mediated narrowing of the airways and
onset of bronchial inflammation. All exposed workers do not become
sensitized to Cr(VI) and the asthma only occurs in sensitized
individuals. It is not clear what occupational exposure levels of
Cr(VI) compounds lead to airway sensitization or the development of
occupational asthma.
The strongest evidence of occupational asthma has been demonstrated
in four case reports. OSHA chose to focus on these four case reports
because the data from other occupational studies do not exclusively
implicate Cr(VI). The four case reports have the following in common:
(1) The worker has a history of occupational exposure exclusively to
Cr(VI); (2) a physician has confirmed a diagnosis that the worker has
symptoms consistent with occupational asthma; and (3) the worker
exhibits functional signs of air restriction (e.g., low forced
expiratory volume in one second or low peak expiratory flow rate) upon
bronchial challenge with Cr(VI) compounds. These case reports
demonstrate, through challenge tests, that exposure to Cr(VI) compounds
can cause asthmatic responses. The other general case reports below did
not use challenge tests to confirm that Cr(VI) was responsible for the
asthma; however, these reports came from workers similarly exposed to
Cr(VI) such that Cr(VI) is likely to have been a contributing factor in
the development of their asthmatic symptoms.
DaReave reported the case of a 48-year-old cement floorer who
developed asthma from inhaling airborne Cr(VI) (Ex. 35-7). This worker
had been exposed to Cr(VI) as a result of performing cement flooring
activities for more than 20 years. The worker complained of dyspnea,
shortness of breath, and wheezing after work, especially after working
in enclosed spaces. The Cr(VI) content in the cement was about 12 ppm.
A bronchial challenge test with potassium dichromate produced a 50%
decrease in forced expiratory volume in one second. The occupational
physician concluded that the worker's asthmatic condition, triggered by
exposure to Cr(VI) caused the worker to develop bronchial constriction.
LeRoyer reported a case of a 28-year-old roofer who developed
asthma from breathing dust while sawing material made of corrugated
fiber cement containing Cr(VI) for nine years (Ex. 35-12). This worker
demonstrated symptoms such as wheezing, shortness of breath, coughing,
rhinitis, and headaches while working. Skin prick tests were all
negative. Several inhalation challenges were performed by physicians
and immediate asthmatic reactions were observed after nebulization of
potassium dichromate. A reduction (by 20%) in the forced expiratory
volume in one second after exposure to fiber cement dust was noted.
Novey et al. reported a case of a 32-year-old electroplating worker
who developed asthma from working with chromium sulfate and nickel
salts (Ex. 35-16). He began experiencing coughs,
wheezing, and dyspnea within the first week of exposure. Separate
inhalation challenge tests given by physicians using chromium sulfate
and nickel salts resulted in positive reactions. The worker immediately
had difficulty breathing and started wheezing. The challenges caused
the forced expiratory volume in 1 second to decrease by 22% and the
forced expiratory volume in 1 second/forced vital capacity ratio to
decrease from 74.5% to 60.4%. The author believes the worker's
bronchial asthma was induced from inhaling chromium sulfate and nickel
salts. Similar findings were reported in a different individual by
Sastre (Ex.35-20).
Shirakawa and Morimoto reported a case of a 50-year-old worker who
developed asthma while working at a metal-electroplating plant (Ex. 35-
21). Bronchial challenge by physicians produced positive results when
using potassium bichromate, followed by a rapid recovery within 5
minutes, when given no exposures. The worker's forced expiratory volume
in one second dropped by 37% after inhalation of potassium bichromate.
The individual immediately began wheezing, coughing with dyspnea, and
recovered without treatment within five minutes. The author believes
that the worker developed his asthma from inhaling potassium
bichromate.
In addition to the case reports confirming that Cr(VI) is
responsible for the development of asthma using inhalation challenge
tests, there are several other case reports of Cr(VI) exposed workers
having symptoms consistent with asthma where the symptoms were never
confirmed by using inhalation challenge tests.
Lockman reported a case of a 41-year-old woman who was
occupationally exposed to potassium dichromate during leather tanning
(Ex. 35-14). The worker developed an occupational allergy to potassium
dichromate. This allergy involved both contact dermatitis and asthma.
The physicians considered other challenge tests using potassium
dichromate as the test agent (i.e., peak expiratory flow rate, forced
expiratory volume in 1 second and methacholine or bronchodilator
challenge), but the subject changed jobs before the physicians could
administer these tests. Once the subject changed jobs, all her symptoms
disappeared. It was not confirmed whether the occupational exposure to
Cr(VI) was the cause of the asthma.
Williams reported a 23-year-old textile worker who was
occupationally exposed to chromic acid. He worked near two tanks of
chromic acid solutions (Ex. 35-23) and inhaled fumes while frequently
walking through the room with the tanks. He developed both contact
dermatitis and asthma. He believes the tank was poorly ventilated and
was the source of the fumes. He stopped working at the textile firm on
the advice of his physician. After leaving, his symptoms improved
greatly. No inhalation bronchial challenge testing was conducted to
confirm that chromic acid was causing his asthmatic attacks. However,
as noted above, chromic acid exposure has been shown to lead to
occupational asthma, and thus, chromic acid was likely to be a
causative agent in the development of asthma.
Park et al. reported a case of four workers who worked in various
occupations involving exposure to either chromium sulfate or potassium
dichromate (Ex. 35-18). Two worked in a metal electroplating factory,
one worked at a cement manufacturer, and the other worked in
construction. All four developed asthma. One individual had a positive
response to a bronchial provocation test (with chromium sulfate as the
test agent). This individual developed an immediate reaction,
consisting of wheezing, coughing and dyspnea, upon being given chromium
sulfate as the test agent. Peak expiratory flow rate decreased by about
20%. His physician determined that exposure to chromium sulfate was
contributing to his asthma condition. Two other individuals had
positive reactions to prick skin tests with chromium sulfate as the
test agent. Two had positive responses to patch tests using potassium
dichromate as the testing challenge agent. Only one out of four
underwent inhalation bronchial challenge testing (with a positive
result to chromium sulfate) in this report.
3. Bronchitis
In addition to nasal ulcerations, nasal septum perforations, and
asthma, there is also limited evidence from reports in the literature
of bronchitis associated with Cr(VI) exposure. It is not clear what
occupational exposure levels of Cr(VI) compounds would lead to the
development of bronchitis.
Royle found that 28% (104/288) of British electroplaters developed
bronchitis upon inhalation exposure to chromic acid, as compared to 23%
(90/299) controls (Ex. 7-50). The workers were considered to have
bronchitis if they had symptoms of persistent coughing and phlegm
production. In all but two cases of bronchitis, air samples revealed
chromic acid at levels of 0.03 mg/m\3\. Workers were asked to fill out
questionnaires to assess respiratory problems. Self-reporting poses a
problem in that the symptoms and respiratory health problems identified
were not medically confirmed by physicians. Workers in this study
believe they were developing bronchitis, but it is not clear from this
study whether the development of bronchitis was confirmed by
physicians. It is also difficult to assess the bronchitis health
effects of chromic acid from this study because the study results for
the exposed (28%) and control groups (23%) were similar.
Alderson et al. reported 39 deaths of chromate production workers
related to chronic bronchitis from three chromate producing factories
(Bolton, Eaglescliffe, and Rutherglen) from 1947 to 1977 (Ex. 35-2).
Neither the specific Cr(VI) compound nor the extent or frequency with
which the workers were exposed were specified. However, workers at all
three factories were exposed to sodium chromate, chromic acid, and
calcium chromate at one time or another. The authors did not find an
excess number of bronchitis related deaths at the Bolton and
Eaglescliffe factories. At Rutherglen, there was an excess number of
deaths (31) from chronic bronchitis with a ratio of observed/expected
of 1.8 (p< 0.001). It is difficult to assess the respiratory health
effects of Cr(VI) compounds from this study because there are no
exposure data, there are no data on smoking habits, nor is it clear the
extent, duration, and amount of specific Cr(VI) compound to which the
workers were exposed during the study.
While the evidence supports an association between bronchitis and
Cr(VI) exposure is limited, studies in experimental animals demonstrate
that Cr(VI) compounds can cause lung irritation, inflammation in the
lungs, and possibly lung fibrosis at various exposure levels. Glaser et
al. examined the effects of inhalation exposure of chromium (VI) on
lung inflammation and alveolar macrophage function in rats (Ex. 31-18-
9). Twenty, 5-week-old male TNO-W-74 Wistar rats were exposed via
inhalation to 25-200 [mu]g Cr(VI)/m3 as sodium dichromate
for 28 days or 90 days for 22 hours per day, 7 days per week in
inhalation chambers. Twenty, 5-week-old male TNO-W-74 Wistar rats also
served as controls. All rats were killed at the end of the inhalation
exposure period. The authors found increased lung weight in the 50-200
[mu]g/m3 groups after the 90-day exposure period. They also
found that 28-day exposure to levels of 25 and 50 [mu]g/m3
resulted in "activated" alveolar macrophages with stimulated
phagocytic activities. A more pronounced effect on the activation of
alveolar macrophages was seen during the 90-day exposure period of 25
and 50 [mu]g/m3.
Glaser et al. exposed 150 male, 8-week-old Wistar rats (10 rats per
group) continuously by inhalation to aerosols of sodium dichromate at
concentrations of 50, 100, 200, and 400 [mu]g Cr(VI)/m3 for
22 hours per day, 7 days a week, for continuous exposure for 30 days or
90 days in inhalation chambers (Ex. 31-18-11). Increased lung weight
changes were noticeable even at levels as low as 50 and 100 [mu]g
Cr(VI)/m3 following both 30 day and 90 day exposures.
Significant accumulation of alveolar macrophages in the lungs was noted
in all of the exposure groups. Lung fibrosis occurred in eight rats
exposed to 100 [mu]g Cr(VI)/m3 or above for 30 days. Most
lung fibrosis disappeared after the exposure period had ceased. At 50
[mu]g Cr(VI)/m3 or higher for 30 days, a high incidence of
hyperplasia was noted in the lung and respiratory tract. The total
protein in bronchoalveolar lavage (BAL) fluid, albumin in BAL fluid,
and lactate dehydrogenase in BAL fluid were significant at elevated
levels of 200 and 400 [mu]g Cr(VI)/m3 in both the 30 day and
90 day exposure groups (as compared to the control group). These
responses are indicative of severe injury in the lungs of animals
exposed to Cr(VI) dose levels of 200 [mu]g Cr(VI)/m3 and
above. At levels of 50 and 100 [mu]g Cr(VI)/m3, the
responses are indicative of mild inflammation in the lungs. The authors
concluded that these results suggest that the severe inflammatory
reaction may lead to more chronic and obstructive lesions in the lung.
4. Summary
Overall, there is convincing evidence to indicate that Cr(VI)
exposed workers can develop nasal irritation, nasal ulcerations, nasal
perforations, and asthma. There is also some limited evidence that
bronchitis may occur when workers are exposed to Cr(VI) compounds at
high levels. Most of the studies involved exposure to water-soluble
Cr(VI) compounds. It is very clear that workers may develop nasal
irritations, nasal ulcerations, and nasal perforations at levels below
the current PEL of 52 [mu]g/m3. However, it is not clear
what occupational exposure levels lead to disorders like asthma and
bronchitis.
There are numerous studies in the literature showing nasal
irritations, nasal perforations, and nasal ulcerations resulting from
Cr(VI) inhalation exposure. It also appears that direct hand-to-nose
contact (i.e., by touching inner nasal surfaces with contaminated
fingers) can contribute to the incidence of nasal damage. Additionally,
some studies show that workers developed these nasal health problems
because they did not wear any PPE, including respiratory protection.
Inadequate area ventilation and sanitation conditions (lack of
cleaning, dusty environment) probably contributed to the adverse nasal
effects.
There are several well documented case reports in the literature
describing occupational asthma specifically triggered by Cr(VI) in
sensitized workers. All involved workers who frequently suffered
symptoms typical of asthma (e.g. dyspnea, wheezing, coughing, etc.)
while working in jobs involving airborne exposure to Cr(VI). In some of
the reports, a physician diagnosed bronchial asthma triggered by Cr(VI)
after specific bronchial challenge with a Cr(VI) aerosol produced
characteristic symptoms and asthmatic airway responses. Several
national and international bodies, such as the National Institute for
Occupational Safety and Health, the World Health Organization's
International Programme on Chemical Safety, and the United Kingdom
Health and Safety Executive have recognized Cr(VI) as an airway
sensitizer that can cause occupational asthma. Despite the widespread
recognition of Cr(VI) as an airway sensitizer, OSHA is not aware of any
well controlled occupational survey or epidemiological study that has
found a significantly elevated prevalence of asthma among Cr(VI)-
exposed workers. The level of Cr(VI) in the workplace that triggers the
asthmatic condition and the number of workers at risk are not known.
The evidence that workers breathing Cr(VI) can develop respiratory
disease that involve inflammation, such as asthma and bronchitis is
supported by experimental animal studies. The 1985 and 1990 Glaser et
al. studies show that animals experience irritation and inflammation of
the lungs following repeated exposure by inhalation to water-soluble
Cr(VI) at air concentrations near the previous PEL of 52 [mu]g/
m3.
D. Dermal Effects
Occupational exposure to Cr(VI) is a well-established cause of
adverse health effects of the skin. The effects are the result of two
distinct processes: (1) Irritant reactions, such as skin ulcers and
irritant contact dermatitis, and (2) delayed hypersensitivity
(allergic) reactions. Some evidence also indicates that exposure to
Cr(VI) compounds may cause conjunctivitis.
The mildest skin reactions consist of erythema (redness), edema
(swelling), papules (raised spots), vesicles (liquid spots), and
scaling (Ex. 35-313, p. 295). The lesions are typically found on
exposed areas of the skin, usually the hands and forearms (Exs. 9-9; 9-
25). These features are common to both irritant and allergic contact
dermatitis, and it is generally not possible to determine the etiology
of the condition based on histopathologic findings (Ex. 35-314).
Allergic contact dermatitis can be diagnosed by other methods, such as
patch testing (Ex. 35-321, p. 226). Patch testing involves the
application of a suspected allergen to the skin, diluted in petrolatum
or some other vehicle. The patch is removed after 48 hours and the skin
examined at the site of application to determine if a reaction has
occurred.
Cr(VI) compounds can also have a corrosive, necrotizing effect on
living tissue, forming ulcers, or "chrome holes" (Ex. 35-315). This
effect is apparently due to the oxidizing properties of Cr(VI)
compounds (Ex. 35-318, p. 623). Like dermatitis, chrome ulcers
generally occur on exposed areas of the body, chiefly on the hands and
forearms (Ex. 35-316). The lesions are initially painless, and are
often ignored until the surface ulcerates with a crust which, if
removed, leaves a crater two to five millimeters in diameter with a
thickened, hardened border. The ulcers can penetrate deeply into tissue
and become painful. Chrome ulcers may penetrate joints and cartilage
(Ex. 35-317, p. 138). The lesions usually heal in several weeks if
exposure to Cr(VI) ceases, leaving a flat, atrophic scar (Ex. 35-318,
p.623). If exposure continues, chrome ulcers may persist for months
(Ex. 7-3).
It is generally believed that chrome ulcers do not occur on intact
skin (Exs. 35-317, p. 138; 35-315; 35-25). Rather, they develop readily
at the site of small cuts, abrasions, insect bites, or other injuries
(Exs. 35-315; 35-318, p. 138). In experimental work on guinea pigs,
Samitz and Epstein found that lesions were never produced on undamaged
skin (Ex. 35-315). The degree of trauma, as well as the frequency and
concentration of Cr(VI) application, was found to influence the
severity of chrome ulcers.
The development of chrome ulcers does not appear to be related to
the sensitizing properties of Cr(VI). Edmundson provided patch tests to
determine sensitivity to Cr(VI) in 56 workers who exhibited either
chrome ulcers or scars (Ex. 9-23). A positive response to the patch
test was found in only two of the workers examined.
Parkhurst first identified Cr(VI) as a cause of allergic contact
dermatitis in 1925 (Ex. 9-55). Cr(VI) has since been
confirmed as a potent allergen. Kligman (1966) used a maximization test
(a skin test for screening possible contact allergens) to assess the
skin sensitizing potential of Cr(VI) compounds (Ex. 35-327). Each of
the 23 subjects was sensitized to potassium dichromate. On a scale of
one to five, with five being the most potent allergen, Cr(VI) was
graded as five (i.e., an extreme sensitizer). This finding was
supported by a guinea pig maximization test, which assigned a grade of
four to potassium chromate using the same scale (Ex. 35-328).
1. Prevalence of Dermal Effects
Adverse skin effects from Cr(VI) exposure have been known since at
least 1827, when Cumin described ulcers in two dyers and a chromate
production worker (Ex. 35-317, p. 138). Since then, skin conditions
resulting from Cr(VI) exposure have been noted in a wide range of
occupations. Work with cement is regarded as the most common cause of
Cr(VI)-induced dermatitis (Exs. 35-313, p. 295; 35-319; 35-320). Other
types of work where Cr(VI)-related skin effects have been reported
include chromate production, chrome plating, leather tanning, welding,
motor vehicle assembly, manufacture of televisions and appliances,
servicing of railroad locomotives, aircraft production, and printing
(Exs. 31-22-12; 7-50; 9-31; 9-100; 9-63; 9-28; 9-95; 9-54; 35-329; 9-
97; 9-78; 9-9; 35-330). Some of the important studies on Cr(VI)-related
dermal effects in workers are described below.
a. Cement Dermatitis
Many workers develop cement dermatitis, including masons, tile
setters, and cement workers (Ex. 35-318, p. 624). Cement, the basic
ingredient of concrete, may contain several possible sources of
chromium (Exs. 35-317, p.148; 9-17). Clay, gypsum, and chalk that serve
as ingredients may contain traces of chromium. Ingredients may be
crushed using chrome steel grinders that, with wear, contribute to the
chromium content of the concrete. Refractory bricks in the kiln and ash
residues from the burning of coal or oil to heat the kiln serve as
additional sources. Trivalent chromium from these sources can be
converted to Cr(VI) in the kiln (Ex. 35-317. p. 148).
The prevalence of cement dermatitis in groups of workers with
regular contact with wet cement has been reported to be from 8 to 45
percent depending on the countries of origin, type of construction
industry, and criteria used to diagnose dermatitis (Exs. 46-74, 9-131;
35-317, 9-57, 40-10-10). Cement dermatitis can be caused by direct
irritation of the skin, by sensitization to Cr(VI), or both (Ex. 35-
317, p. 147). The reported proportion of allergic and irritant contact
dermatitis varies considerably depending on the information source. In
a review of 16 different data sets, Burrows (1983) found that, on
average, 80% of cement dermatitis cases were sensitized to Cr(VI) (Ex.
35-317, p. 148). The studies were mostly conducted prior to 1970 on
European construction workers. More recent occupational studies suggest
that Cr(VI) allergy may make up a smaller proportion of all dermatitis
in construction workers, depending on the Cr(VI) content of the cement.
For example, examination of 1238 German and Austrian construction
workers in dermatitis units found about half those with occupational
dermatitis were skin sensitized to Cr(VI) (Ex. 40-10-10). Several other
epidemiological investigations conducted in the 1980s and 1990s also
reported that allergic contact dermatitis made up 50 percent or less of
all dermatitis cases in various groups of construction workers exposed
to wet cement (Ex. 46-74).
Cement is alkaline, abrasive, and hydroscopic (water-absorbing),
and it is likely that the irritant effect resulting from these
properties interferes with the skin's defenses, permitting penetration
and sensitization to take place more readily (Ex. 35-318, p. 624). Dry
cement is considered relatively innocuous because it is not as alkaline
as wet cement (Exs. 35-317, p. 147; 9-17). When water is mixed with
cement the water liberates calcium hydroxide, causing a rise in pH (Ex.
35-317, p. 147).
Flyvholm et al. (1996) noted a correlation between the Cr(VI)
concentration in the local cement and the frequency of allergic contact
dermatitis (Ex. 35-326, p. 278). Because the Cr(VI) content depends
partially upon the chromium concentration in raw materials, there is a
great variability in the Cr(VI) content in cement from different
geographical regions. In locations with low Cr(VI) content, the
prevalence of Cr(VI)-induced allergic contact dermatitis was reported
to be approximately one percent, while in regions with higher chromate
concentrations the prevalence was reported to rise to between 9 to 11%
of those exposed (Ex. 35-326, p. 278). For example, only one of 35 U.S.
construction workers with confirmed cement dermatitis was reported to
have a positive Cr(VI) patch test in a 1970 NIOSH study (Ex. 9-57).
However, the same study revealed a low Cr(VI) content in 42
representative cement samples from U.S. companies (e.g 80 percent of
the samples with C(VI) < 2 [mu]g/g).
The relationship between Cr(VI) content in cement and the
prevalence of Cr(VI)-induced allergic contact dermatitis is supported
by the findings of Avnstorp (1989) in a study of Danish workers who had
daily contact with wet cement during the manufacture of pre-fabricated
concrete products (Ex. 9-131). Beginning in September of 1981, low
concentrations of ferrous sulfate were added to all cement sold in
Denmark to reduce Cr(VI) to trivalent chromium. Two hundred and twenty
seven workers were examined in 1987 for Cr(VI)-related skin effects.
The findings from these examinations were compared to the results from
190 workers in the same plants who were examined in 1981. The
prevalence of hand eczema had declined from 11.7% to 4.4%, and the
prevalence of Cr(VI) sensitization had declined from 10.5% to 2.6%.
While the two-to four-fold drop in prevalence was statistically
significant, the magnitude of the reduction may be overstated because
the amount of exposure time was less in the 1987 than the 1981 group.
There is also the possibility that other factors, in addition to
ferrous sulfate, may have led to less dermal contact to Cr(VI), such as
greater automation or less construction work. However, the study found
no significant change in the frequency of irritant dermatitis.
Another study also found lower prevalence of allergic contact
dermatitis among Finish construction workers following the 1987
decision to reduce Cr(VI) content of cement used in Finland to less
than 2 ppm (Ex. 48-8). Ferrous sulfate was typically added to the
cement to meet this requirement. There was a significantly decreased
risk of allergic Cr(VI) contact dermatitis reported to the Finnish
Occupational Disease Registry post-1987 as compared to pre-1987
(OR=0.4, 95% CI: 0.2-0.7) indicating the occurrence of disease dropped
one-third after use of the low Cr(VI) content cement. On the other
hand, the occurrence of irritant dermatitis remained stable throughout
the study period. Time of exposure was not a significant explanatory
variable in the analysis. However, the findings may have been somewhat
confounded by changes in diagnostic procedure over time. The Finnish
study retested patients previously diagnosed with prior patch test
protocols and found several false positives (i.e. false diagnosis of
Cr(VI) allergy).
In 2003, the Norwegian National Institute of Occupational Health
sponsored an expert peer review of 24
key epidemiological investigations addressing; (1) whether exposure to
wet cement containing water soluble Cr(VI) caused allergic contact
dermatitis, and (2) whether there was a causal association between
reduction of Cr(VI) in cement and reduction in the prevalence of the
disease (Ex. 46-74). The panel of four experts concluded that, despite
the documented limitations of each individual study, the collective
evidence was consistent in supporting "fairly strong associations
between Cr(VI) content in cement and the occurrence of allergic
dermatitis * * * it seems unlikely that all these associations reported
in the reviewed papers are due to systematic errors only" (Ex. 46-74,
p. 42).
Even though the Norwegian panel felt that the available evidence
indicated a relationship between reduced Cr(VI) content of wet cement
and lower occurrence of allergic dermatitis, they stated that the
epidemiological literature was "not sufficient to conclude that there
is a causal association" (Ex. 46-74, p. 42). This is somewhat
different than the view expressed in a written June 2002 opinion by the
Scientific Committee on Toxicity, Ecotoxicity and the Environment
(CSTEE) to the European Commission, Directorate for General Health and
Consumer Protection (Ex. 40-10-7). In responding to the question of
whether it is scientifically justified to conclude that cement
containing less than 2 ppm Cr(VI) content could substantially reduce
the risk of skin sensitization, the CSTEE stated that "the available
information clearly demonstrates that reduction of chromium VI in
cement to less than 2 ppm * * * will reduce the prevalence of allergic
contact eczema in workers" (Ex. 40-10-7, p. 5)
b. Dermatitis Associated With Cr(VI) From Sources Other Than Cement
In 1953 the U.S. Public Health Service reported on hazards
associated with the chromium-producing industry in the United States
(Ex. 7-3). Workers were examined for skin effects from Cr(VI) exposure.
Workers' eyes were also examined for possible effects from splashes of
Cr(VI)-containing compounds that had been observed in the plants. Of
the 897 workers examined, 451 had skin ulcers or scars of ulcers.
Seventeen workers were reported to have skin lesions suggestive of
chrome dermatitis. The authors noted that most plants provided adequate
washing facilities, and had facilities for providing clean work
clothes. A statistically significant increase in congestion of the
conjunctiva was also reported in Cr(VI)-exposed workers when compared
with non-exposed workers (38.7% vs. 25.8%).
In the Baltimore, Maryland chromate production plant examined by
Gibb et al. (2000), a substantial number of workers were reported to
have experienced adverse skin effects (Ex. 31-22-12). The authors
identified a cohort of 2,357 workers first employed at the plant
between 1950 and 1974. Clinic and first aid records were examined to
identify findings of skin conditions. These clinical findings were
identified by a physician as a result of routine examinations or visits
to the medical clinic by members of the cohort. Percentages of the
cohort with various clinical findings were as follows:
Irritated skin: 15.1%
Dermatitis: 18.5%
Ulcerated skin: 31.6%
Conjunctivitis: 20.0%
A number of factors make these results difficult to interpret. The
reported findings are not specifically related to Cr(VI) exposure. They
may have been the result of other workplace exposures, or non-workplace
factors. The report also indicates the percentage of workers who were
diagnosed with a condition during their tenure at the plant; however,
no information is presented to indicate the expected incidence of these
conditions in a population that is not exposed to Cr(VI).
Measurements of Cr(VI) air concentrations by job title were used to
estimate worker exposures. Based on these estimates, the authors used a
proportional hazards model to find a statistically significant
correlation (p=0.004) between ulcerated skin and airborne Cr(VI)
exposure. Statistically significant correlations between year of hire
and findings of ulcerated skin and dermatitis were also reported.
Exposures to Cr(VI) in the plant had generally dropped over time.
Median exposure to Cr(VI) at the time of occurrence for most of the
findings was said to be about 10 [mu]g/m\3\ Cr(VI) (reported as 20
[mu]g/m\3\ CrO3). It is unclear, however, what contribution
airborne Cr(VI) exposures may have had to dermal effects. Direct dermal
contact with Cr(VI) compounds in the plant may have been a contributing
factor in the development of these conditions.
Mean and median times on the job prior to initial diagnosis were
also reported. The mean time prior to diagnosis of skin or eye effects
ranged from 373 days for ulcerated skin to 719 days for irritated skin.
Median times ranged from 110 days for ulcerated skin to 221 days for
conjunctivitis. These times are notable because many workers in the
plant stayed for only a short time. Over 40% worked for less than 90
days. Because these short-term workers did not remain in the workplace
for the length of time that was typically necessary for these effects
to occur, the results of this study may underestimate the incidence
that would occur with a more stable worker population.
Lee and Goh (1988) examined the skin condition of 37 workers who
maintained chrome plating baths and compared these workers with a group
of 37 control subjects who worked in the same factories but were not
exposed to Cr(VI) (Ex. 35-316). Mean duration of employment as a chrome
plater was 8.1 (SD7.9) years. Fourteen (38%) of the chrome
platers had some occupational skin condition; seven had chrome ulcers,
six had contact dermatitis and one had both. A further 16 (43%) of the
platers had scars suggestive of previous chrome ulcers. Among the
control group, no members had ulcers or scars of ulcers, and three had
dermatitis.
Where ulcers or dermatitis were noted, patch tests were
administered to determine sensitization to Cr(VI) and nickel. Of the
seven workers with chrome ulcers, one was allergic to Cr(VI). Of the
six workers with dermatitis, two were allergic to Cr(VI) and one to
nickel. The worker with ulceration and dermatitis was not sensitized to
either Cr(VI) or nickel. Although limited by a relatively small study
population, this report clearly indicates that Cr(VI)-exposed workers
face an increased risk of adverse skin effects. The fact that the
majority of workers with dermatitis were not sensitized to Cr(VI)
indicates that irritant factors play an important role in the
development of dermatitis in chrome plating operations.
Royle (1975) also investigated the occurrence of skin conditions
among workers involved in chrome plating (Ex. 7-50). A questionnaire
survey completed by 997 chrome platers revealed that 21.8% had
experienced skin ulcers, and 24.6% had suffered from dermatitis. No
information was presented to indicate the expected incidence in a
comparable population that was not exposed to Cr(VI). Of the 54 plants
involved in the study, 49 used nickel, another recognized cause of
allergic contact dermatitis.
The author examined the relationship between the incidence of these
conditions and length of exposure. The plater population was divided
into three groups: those with less than one year of Cr(VI) exposure,
those with one to five years of Cr(VI) exposure, and those with over
five years of Cr(VI) exposure. A statistically significant trend was
found between length of Cr(VI) exposure and incidence of skin ulcers. The
incidence of dermatitis, on the other hand, bore no relationship to
length of exposure.
In 1973, researchers from NIOSH reported on the results of a health
hazard investigation of a chrome plating establishment (Ex. 3-5). In
the plating area, airborne Cr(VI) concentrations ranged from less than
0.71 to 9.12 [mu]g/m\3\ (mean 3.24 [mu]g/m\3\; SD=2.48 [mu]g/m\3\). Of
the 37 exposed workers who received medical examinations, five were
reported to have chrome-induced lesions on their hands. Hygiene and
housekeeping practices in this facility were reportedly deficient, with
the majority of workers not wearing gloves, not washing their hands
before eating or leaving the plant, and consuming food and beverages in
work areas.
Gomes (1972) examined Cr(VI)-induced skin lesions among
electroplaters in Sao Paulo, Brazil (Ex. 9-31). A clinical examination
of 303 workers revealed 88 (28.8%) had skin lesions, while 175 (58.0%)
had skin and mucus membrane lesions. A substantial number of employers
(26.6%) also did not provide personal protective equipment to workers.
The author attributed the high incidence of skin ulcers on the hands
and arms to inadequate personal protective equipment, and lack of
training for employees regarding hygiene practices.
Fleeger and Deng (1990) reported on an outbreak of skin ulcerations
among workers in a facility where enamel paints containing chromium
were applied to kitchen range parts (Ex. 9-97). A ground coat of paint
was applied to the parts, which were then placed on hooks and
transported through a curing oven. In some cases, small parts were
places on hooks before paint application. Tiny holes in the oven coils
apparently resulted in improper curing of the paint, leaving sharp
edges and a Cr(VI)-containing residue on the hooks. Most of the workers
who handled the hooks reportedly did not wear gloves, because the
gloves were said to reduce dexterity and decrease productivity. As a
result, cuts from the sharp edges allowed the Cr(VI) to penetrate the
skin, leading to ulcerations (Ex. 9-97).
2. Prognosis of Dermal Effects
Cr(VI)-related dermatitis tends to become more severe and
persistent with continuing exposure. Once established, the condition
may persist even if occupational exposure ceases. Fregert followed up
on cases of occupational contact dermatitis diagnosed over a 10-year
period by a dermatology service in Sweden. Based on responses to
questionnaires completed two to three years after treatment, only 7% of
women and 10% of men with Cr(VI)-related allergic contact dermatitis
were reported to be healed (Ex. 35-322). Burrows reviewed the condition
of patients diagnosed with work-related dermatitis 10-13 years earlier.
Only two of the 25 cases (8%) caused by exposure to cement had cleared
(Ex. 35-323).
Hogan et al. reviewed the literature regarding the prognosis of
contact dermatitis, and reported that the majority of patients had
persistent dermatitis (Ex. 35-324). It was reported that job changes
did not usually lead to a significant improvement for most patients.
The authors surveyed contact dermatitis experts around the world to
explore their experience with the prognosis of patients suffering from
occupational contact dermatitis of the hands. Seventy-eight percent of
the 51 experts who responded to the survey indicated that chromate was
one of the allergens associated with the worst possible prognosis.
Halbert et al. reviewed the experience of 120 patients diagnosed
with occupational chromate dermatitis over a 10-year period (Ex. 35-
320). The time between initial diagnosis and the review ranged from a
minimum of six months to a maximum of nine years. Eighty-four (70%) of
patients were reviewed two or more years after initial diagnosis, and
40 (33%) after five years or more. In the majority of cases (78, or
65%), the dermatitis was attributed to work with cement. For the study
population as a whole, 76% had ongoing dermatitis at the time of the
review.
When the review was conducted, 62 (58%) patients were employed in
the same occupation as when initially diagnosed. Fifty-five (89%) of
these workers continued to suffer from dermatitis. Fifty-eight patients
(48%) changed occupations after their initial diagnosis. Each of these
individuals indicated that they had changed occupations because of
their dermatitis. In spite of the change, dermatitis persisted in 40
members of this group (69%).
Lips et al. found a somewhat more favorable outcome among 88
construction workers with occupational chromate dermatitis who were
removed from Cr(VI) exposure (Ex. 35-325). Follow-up one to five years
after removal indicated that 72% of the patients no longer had
dermatitis. The authors speculated that this result might be due to
strict avoidance of Cr(VI) contact. Nonetheless, the condition
persisted in a substantial portion of the affected population.
3. Thresholds for Dermal Effects
In a response to OSHA's RFI submitted on behalf of the Chrome
Coalition, Exponent indicated that the findings of Fowler et al. (1999)
and others provide evidence of a threshold for elicitation of allergic
contact dermatitis (Ex. 31-18-1, p. 27). Exponent also stated that
because chrome ulcers did not develop in the Fowler et al. study,
"more aggressive" exposures appear to be necessary for the
development of chrome ulcers.
The Fowler et al. study involved the dermal exposure of 26
individuals previously sensitized to Cr(VI) who were exposed to water
containing 25 to 29 mg/L Cr(VI) as potassium dichromate (pH 9.4) (Ex.
31-18-5). Subjects immersed one arm in the Cr(VI) solution, while the
other arm was immersed in an alkaline buffer solution as a control.
Exposure lasted for 30 minutes and was repeated on three consecutive
days. Based on examination of the skin, the authors concluded that the
skin response experienced by subjects was not consistent with either
irritant or allergic contact dermatitis.
The exposure scenario in the Fowler et al. study, however, does not
take into account certain skin conditions often encountered in the
workplace. While active dermatitis, scratches, and skin lesions served
as criteria for excluding both initial and continuing participation in
the study, it is reasonable to expect that individuals with these
conditions will often continue to work. Cr(VI)-containing mixtures and
compounds used in the workplace may also pose a greater challenge to
the integrity of the skin than the solution used by Fowler et al. Wet
cement, for example, may have a pH higher than 9.4, and may be capable
of abrading or otherwise damaging the skin. As damaged skin is liable
to make exposed workers more susceptible to Cr(VI)-induced skin
effects, the suggested threshold is likely to be invalid. The absence
of chrome ulcers in the Fowler et al. study is not unexpected, because
subjects with "fissures or lesions" on the skin were excluded from
the study (Ex. 31-18-5). As discussed earlier, chrome ulcers are not
believed to occur on intact skin.
4. Conclusions
OSHA believes that adverse dermal effects from exposure to Cr(VI),
including irritant contact dermatitis, allergic contact dermatitis, and
skin ulceration, have been firmly established. The available evidence
is not sufficient to relate these effects to any given Cr(VI) air
concentration. Rather, it appears that direct dermal contact with
Cr(VI) is the most relevant factor in the development of dermatitis and
ulcers. Based on the findings of Gibb et al. (Ex. 32-22-12) and U.S.
Public Health Service (Ex. 7-3), OSHA believes that conjunctivitis may
result from direct eye contact with Cr(VI).
OSHA does not believe that the available evidence is sufficient to
establish a threshold concentration of Cr(VI) below which dermal
effects will not occur in the occupational environment. This finding is
supported not only by the belief that the exposure scenario of Fowler
et al. is not consistent with occupational exposures, but by experience
in the workplace as well. As summarized by Flyvholm et al. (1996),
numerous reports have indicated that allergic contact dermatitis occurs
in cement workers exposed to Cr(VI) concentrations below the threshold
suggested by Fowler et al. (1999). OSHA considers the evidence of
Cr(VI)-induced allergic contact dermatitis in these workers to indicate
that the threshold for elicitation of response suggested by Fowler et
al. (1999) is not applicable to the occupational environment.
E. Other Health Effects
OSHA has examined the possibility of health effect outcomes
associated with Cr(VI) exposure in addition to such effects as lung
cancer, nasal ulcerations and perforations, occupational asthma, and
irritant and allergic contact dermatitis. Unlike the Cr(VI)-induced
toxicities cited above, the data on other health effects do not
definitively establish Cr(VI)-related impairments of health from
occupational exposure at or below the previous OSHA PEL.
There is some positive evidence that workplace inhalation of Cr(VI)
results in gastritis and gastrointestinal ulcers, especially at high
exposures (generally over OSHA's previous PEL) (Ex. 7-12). This is
supported by ulcerations in the gastrointestinal tract of mice
breathing high Cr(VI) concentration for long periods (Ex. 10-8). Other
studies reported positive effects but significant information was not
reported or the confounders made it difficult to draw positive
conclusions (Ex. 3-84; Sassi 1956 as cited in Ex. 35-41). Other studies
reported negative results (Exs. 7-14; 9-135).
Likewise, several studies reported increases in renal proteins in
the urine of chromate production workers and chrome platers (Exs. 35-
107; 5-45; 35-105; 5-57). The Cr(VI) air levels recorded in these
workers were usually below the previous OSHA PEL (Exs. 35-107; 5-45).
Workers with the highest urinary chromium levels tended to also have
the largest elevations in renal markers (Ex. 35-107). One study
reported no relationship between chromium in urine and renal function
parameters, no relationship with age or with duration of exposure, and
no relationship between the presence of chromium skin ulcers and
chromium levels in urine or renal function parameters (Ex. 5-57). In
most studies, the elevated renal protein levels were restricted to only
one or two proteins out of several examined per study, generally
exhibited small increases (Ex. 35-105) and the effects appeared to be
reversible (Ex. 5-45). In addition, it has been stated that low
molecular weight proteinuria can occur from other reasons and cannot by
itself be considered evidence of chronic renal disease (Ex. 35-195).
Other human inhalation studies reported no changes in renal markers
(Exs. 7-27; 35-104). Animal inhalation studies did not report kidney
damage (Exs. 9-135; 31-18-11; 10-11; 31-18-10; 10-10). Some studies
with Cr(VI) administered by drinking water or gavage were positive for
increases in renal markers as well as some cell and tissue damage (Exs.
9-143; 11-10). However, it is not clear how to extrapolate such
findings to workers exposed to Cr(VI) via inhalation. Well-designed
studies of effects in humans via ingestion were not found.
OSHA did not find information to clearly and sufficiently
demonstrate that exposures to Cr(VI) result in significant impairment
to the hepatic system. Two European studies, positive for an excess of
deaths from cirrhosis of the liver and hepatobiliarity disorders, were
not able to separate chromium exposures from exposures to the many
other substances present in the workplace. The authors also could not
rule out the role of alcohol use as a possible contributor to the
disorder (Ex. 7-92; Sassi as cited in Ex. 35-41). Other studies did not
report any hepatic abnormalities (Exs. 7-27; 10-11).
The reproductive studies showed mixed results. Some positive
reproductive effects occurred in some welding studies. However, it is
not clear that Cr(VI) is the causative agent in these studies (Exs. 35-
109; 35-110; 35-108; 35-202; 35-203). Other positive studies were
seriously lacking in information. Information was not given on
exposures, the nature of the reproductive complications, or the women's
tasks (Shmitova 1980, 1978 as cited in Ex. 35-41, p. 52). ATSDR states
that because these studies were generally of poor quality and the
results were poorly reported, no conclusions can be made on the
potential for chromium to produce adverse reproductive effects in
humans (Ex. 35-41, p. 52). In animal studies, where Cr(VI) was
administered through drinking water or diet, positive developmental
effects occurred in offspring (Exs. 9-142; 35-33; 35-34; 35-38).
However, the doses administered in drinking water or given in the diet
were high (i.e., 250, 500, and 750 ppm). Furthermore, strong studies
showing reproductive or developmental effects in other situations where
employees were working exclusively with Cr(VI) were not found. In fact,
the National Toxicology Program (NTP) (Exs. 35-40; 35-42; 35-44)
conducted an extensive multigenerational reproductive assessment by
continuous breeding where the chromate was administered in the diet.
The assessment yielded negative results (Exs. 35-40; 35-42; 35-44).
Animal inhalation studies were also negative (Exs. 35-199; 9-135; 10-
10; Glaser 1984 as cited in Ex. 31-22-33;). Thus, it cannot be
concluded that Cr(VI) is a reproductive toxin for normal working
situations.
VI. Quantitative Risk Assessment
A. Introduction
The Occupational Safety and Health (OSH) Act and some landmark
court cases have led OSHA to rely on quantitative risk assessment,
where possible, 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 Act states that "The
Secretary [of Labor], in promulgating standards dealing with toxic
materials or harmful 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. 651 et seq.)
In a further interpretation of the risk requirements for OSHA
standard setting, the United States Supreme Court, in the 1980
"benzene" decision, (Industrial Union Department, AFL-CIO v. American
Petroleum Institute, 448 U.S. 607 (1980)) 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 he 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" [448 U.S. 642]. The Court also stated "that
the Act does not limit the Secretary's power to require the elimination
of significant risks" [488 U.S. 644]. While the Court indicated that
the use of quantitative risk analysis was an appropriate means to
establish significant risk, they made clear that "OSHA is not required
to support its finding that a significant risk exists with anything
approaching scientific certainty."
The Court in the Cotton Dust case, (American Textile Manufacturers
Institute v. Donovan, 452 U.S. 490 (1981)) found that Section 6(b)(5)
of the OSH Act places benefits to worker health above all other
considerations except those making attainment of the health benefits
unachievable and, therefore, only feasibility analysis of OSHA health
standards is required and not cost-benefit analysis. It reaffirmed its
previous position in the "benzene" case, however, that a risk
assessment is not only appropriate but should be used to identify
significant health risk in workers and to determine if a proposed
standard will achieve a reduction in that risk. Although the Court did
not require OSHA to perform a quantitative risk assessment in every
case, the Court implied, and OSHA as a matter of policy agrees, that
assessments should be put into quantitative terms to the extent
possible.
The determining factor in the decision to perform a quantitative
risk assessment is the availability of suitable data for such an
assessment. As reviewed in section V.B. on Carcinogenic Effects, there
are a substantial number of occupational cohort studies that reported
excess lung cancer mortality in workers exposed to Cr(VI) in several
industrial operations. Many of these found that workers exposed to
higher levels of airborne Cr(VI) for a longer period of time had
greater standardized mortality ratios (SMRs) for lung cancer.
OSHA believes that two recently studied occupational cohorts by
Gibb et al. (Ex. 31-22-11) and Luippold et al. (Ex. 33-10) have the
strongest data sets on which to quantify lung cancer risk from
cumulative Cr(VI) exposure (i.e., air concentration x exposure
duration). A variety of exposure-response models were fit to these
data, including linear relative risk, quadratic relative risk, log-
linear relative risk, additive risk, and Cox proportional hazards
models. Using a linear relative risk model on these data to predict
excess lifetime risk, OSHA estimated that the lung cancer risk from a
45 year occupational exposure to Cr(VI) at an 8-hour TWA at the
previous PEL of 52 [mu]g/m\3\ is 101 to 351 excess deaths per 1000.
Quantitative lifetime risk estimates from a working lifetime exposure
at several lower alternative PELs under consideration by the Agency
were also estimated. The sections below discuss the selection of the
appropriate data sets and risk models, the estimation of lung cancer
risks based on the selected data sets and models, the uncertainty in
the risk estimates, and the key issues that were raised in comments
received during the public hearing process.
A preliminary quantitative risk assessment was previously published
in the Notice of Proposed Rulemaking (69 FR at 59306, 10/4/2004). This
was peer-reviewed by three outside experts in the fields of
occupational epidemiology and risk assessment. Their comments were
discussed in the NPRM (69 FR at 59385-59388). They commented on the
suitability of several occupational data sets for exposure-response
analysis, the choice of exposure metric and risk model, the
appropriateness of the risk estimates, and the characterization of key
issues and uncertainties. The reviewers agreed that the soluble
chromate production cohorts described by Gibb et al. and Luippold et
al. provided the strongest data sets for quantitative risk assessment.
They concurred that a linear model using cumulative exposure based on
time-weighted average Cr(VI) air concentrations by job title and
employment history was the most reasonable risk assessment approach.
The experts showed less enthusiasm for average monthly Cr(VI) air
concentrations as an appropriate exposure metric or for an exposure
threshold below which there is no lung cancer risk. They found the
range of excess lifetime lung cancer risks presented by OSHA to be
sound and reasonable. They offered suggestions regarding issues such as
the impact of cigarette smoking and the healthy worker effect on the
assessment of risk. OSHA revised the preliminary quantitative risk
assessment in several respects based on these peer review comments.
In contrast to the more extensive occupational cohort data on
Cr(VI) exposure-response, data from experimental animal studies are
less suitable for quantitative risk assessment of lung cancer. Besides
the obvious species difference, most of the animal studies administered
Cr(VI) to the respiratory tract by less relevant routes, such as
instillation or implantation. The few available inhalation studies in
animals were limited by a combination of inadequate exposure levels,
abbreviated durations, and small numbers of animals per dose group.
Despite these limitations, the animal data do provide semi-quantitative
information with regard to the relative carcinogenic potency of
different Cr(VI) compounds. A more detailed discussion can be found in
sections V.B.7 and V.B.9.
The data that relate non-cancer health impairments, such as damage
to the respiratory tract and skin, to Cr(VI) exposure are also not well
suited for quantitative assessment. There are some data from cross-
sectional studies and worker surveys that group the prevalence and
severity of nasal damage by contemporary time-weighted average (TWA)
Cr(VI) air measurements. However, there are no studies that track
either incidence or characterize exposure over time. Nasal damage is
also more likely influenced by shorter-term peak exposures that have
not been well characterized. While difficult to quantify, the data
indicate that the risk of damage to the nasal mucosa will be
significantly reduced by lowering the previous PEL, discussed further
in section VII on Significance of Risk.
There are even less suitable exposure-response data to assess risk
for other Cr(VI)-induced impairments (e.g., mild renal damage,
gastrointestinal ulceration). With the possible exception of
respiratory tract effects (e.g., nasal damage, occupational asthma),
the risk of non-cancer adverse effects that result from inhaling Cr(VI)
are expected to be very low, except as a result of long-term regular
airborne exposure around or above the previous PEL (52 [mu]g/m\3\).
Since the non-cancer effects occur at relatively high Cr(VI) air
concentrations, OSHA has concluded that lowering the PEL to reduce the
risk of developing lung cancer over a working lifetime will also
eliminate or reduce the risk of developing these other health
impairments. As discussed in section V.E., adverse effects to the skin
primarily result from dermal rather than airborne exposure.
B. Study Selection
The more than 40 occupational cohort studies reviewed in Section
VI.B on carcinogenic effects were evaluated to determine the adequacy
of the exposure-response information for the quantitative assessment of
lung cancer risk associated with Cr(VI) exposure. The key criteria were
data that allowed for estimation of input variables,
specifically levels of exposure and duration of exposure (e.g.,
cumulative exposure in mg/m\3\-yr); observed numbers of cancers (deaths
or incident cases) by exposure category; and expected (background)
numbers of cancer deaths by exposure category.
Additional criteria were applied to evaluate the strengths and
weaknesses of the available epidemiological data sets. Studies needed
to have well-defined cohorts with identifiable cases. Features such as
cohort size and length of follow-up affect the ability of the studies
to detect any possible effect of Cr(VI) exposure. Potential confounding
of the responses due to other exposures was considered. Study
evaluation also considered whether disease rates from an appropriate
reference population were used to derive expected numbers of lung
cancers. One of the most important factors in study evaluation was the
ascertainment and use of exposure information (i.e., well-documented
historical exposure data). Both level and duration of exposure are
important in determining cumulative dose, and studies are often
deficient with respect to the availability or use of such information.
Two recently studied cohorts of chromate production workers, the
Gibb cohort and the Luippold cohort, were found to be the strongest
data sets for quantitative assessment (Exs. 31-22-11; 33-10). Of the
various studies, these two had the most extensive and best documented
Cr(VI) exposures spanning three or four decades. Both cohort studies
characterized observed and expected lung cancer mortality and reported
a statistically significant positive association between lung cancer
risk and cumulative Cr(VI) exposure. For the remainder of this preamble
the Gibb and Luippold cohorts are referred to as the "preferred
cohorts", denoting that they are the cohorts used to derive OSHA's
model of lung cancer risk from exposure to Cr(VI).
Four other cohorts (Mancuso, Hayes et al., Gerin et al., and
Alexander et al.) had less satisfactory data for quantitative
assessments of lung cancer risk (Exs. 7-11; 23; 7-14; 7-120; 31-16-3).
These cohorts include chromate production workers, stainless steel
welders, and aerospace manufacturing workers. While the lung cancer
response in these cohorts was stratified across multiple exposure
groups, there were limitations to these data that affected their
reliability for quantitative risk assessment. OSHA therefore did not
consider them to be preferred cohorts (i.e., they were not used to
derive OSHA's model of lung cancer risk from exposure to Cr(VI)).
However, OSHA believes that quantitative analysis of these cohorts
provides valuable information to the risk assessment, especially for
the purpose of comparison with OSHA's risk model based on the preferred
Gibb and Luippold cohorts. Analyses based on the Mancuso, Hayes et al.,
Gerin et al., and Alexander et al. cohorts, referred to as "additional
cohorts" for the remainder of this preamble, were compared with the
assessments based on the Gibb and Luippold cohorts. The strengths and
weaknesses of all six cohorts as a basis for exposure-response analysis
are discussed in more detail below.
1. Gibb Cohort
The Gibb et al. study was a particularly strong study for
quantitative risk assessment, especially in terms of cohort size and
historical exposure data (Exs. 31-22-11; 33-11). Gibb et al. studied an
updated cohort from the same Baltimore chromate production plant
previously studied by Hayes et al. (see section VI.B.4). The cohort
included 2357 male workers (white and non-white) first employed between
1950 and 1974. Follow-up was through the end of 1992 for a total of
70,736 person-years and an average length of 30 years per cohort
member. Smoking status and amount smoked in packs per day at the start
of employment was available for the majority of the cohort members.
A significant advantage of the Gibb data was the availability of a
large number of personal and area sampling measurements from a variety
of locations and job titles which were collected over the years during
which the cohort members were exposed (from 1950 to 1985, when the
plant closed). Using these concentration estimates, a job exposure
matrix was constructed giving annual average exposures by job title.
Based on the job exposure matrix and work histories for the cohort
members, Gibb et al. computed the person-years of observation, the
observed numbers of lung cancer deaths, and the expected numbers of
lung cancer deaths categorized by cumulative Cr(VI) exposure and age of
death. They found that cumulative Cr(VI) exposure was a significant
predictor of lung cancer risk over the exposure range of 0 to 2.76
(meanSD = 0.702.75) mg/m\3\-yr. This included a
greater than expected number of lung cancer deaths among relatively
young workers. For example, chromate production workers between 40 and
50 years of age with mean cumulative Cr(VI) exposure of 0.41 mg
CrO3/m\3\-yr (equivalent to 0.21 mg Cr(VI)/m\3\-yr) were
about four times more likely to die of lung cancer than a State of
Maryland resident of similar age (Ex. 31-22-11, Table V).
The data file containing the demographic, exposure, smoking, and
mortality data for the individual cohort members was made available to
OSHA (Ex. 295). These data were used in several reanalyses to produce
several different statistical exposure-response models and to explore
various issues raised in comments to OSHA, such as the use of linear
and nonlinear exposure-response models, the difference between modern
and historical levels of Cr(VI) exposure, and the impact of including
or excluding short-term workers from the exposure-response analysis.
The Agency's access to the dataset and to reanalyses of it performed by
several different analysts has been a tremendous advantage in its
consideration of these and other issues in the development of the final
risk assessment.
2. Luippold Cohort
The other well-documented exposure-response data set comes from a
second cohort of chromate production workers. Luippold et al. studied a
cohort of 482 predominantly white, male employees who started work
between 1940 and 1972 at the same Painesville, Ohio plant studied
earlier by Mancuso (Ex. 33-10) (see subsection VI.B.3). Mortality
status was followed through 1997 for a total of 14,048 person-years.
The average worker had 30 years of follow-up. Cr(VI) exposures for the
Luippold cohort were based on 21 industrial hygiene surveys conducted
at the plant between 1943 and 1971, yielding a total of more than 800
area samples (Ex. 35-61). A job exposure matrix was computed for 22
exposure areas for each month of plant operation starting in 1940 and,
coupled with detailed work histories available for the cohort members,
cumulative exposures were calculated for each person-year of
observation. Luippold et al. found significant dose-related trends for
lung cancer SMRs as a function of year of hire, duration of employment,
and cumulative Cr(VI) exposure. Risk assessments on the Luippold et al.
study data performed by Crump et al. had access to the individual data
and, therefore, had the best basis for analysis of this cohort (Exs.
31-18-1; 35-205; 35-58).
While the Luippold cohort was smaller and less racially diverse
than the Gibb cohort, the workforce contained fewer transient, short-
term employees. The Luippold cohort consisted entirely of workers
employed over one year. Fifty-five percent worked
for more than five years. In comparison, 65 percent of the Gibb cohort
worked for less than a year and 15 percent for more than five years at
the Baltimore plant. There was less information about the smoking
behavior (smoking status available for only 35 percent of members) of
the Luippold cohort than the Gibb cohort.
One aspect that the Luippold cohort had in common with the Gibb
cohort was extensive and well-documented air monitoring of Cr(VI). The
quality of exposure information for both the Gibb and Luippold cohorts
was considerably better than that for the Mancuso, Hayes et al., Gerin
et al., and Alexander et al. cohorts. The cumulative Cr(VI) exposures
for the Luippold cohort, which ranged from 0.003 to 23 (mean< plus-
minus>SD = 1.582.50) mg Cr(VI)/m\3\-yr, were generally
higher but overlapped those of the Gibb cohort. The use of individual
work histories to define exposure categories and presentation of mean
cumulative doses in the exposure groups provided a strong basis for a
quantitative risk assessment. The higher cumulative exposure range and
the longer work duration of the Luippold cohort serve to complement
quantitative data available on the Gibb cohort.
3. Mancuso Cohort
Mancuso (Ex. 7-11) studied the lung cancer incidence of an earlier
cohort of 332 white male employees drawn from the same plant in
Painesville, Ohio that was evaluated by the Luippold group. The Mancuso
cohort was first employed at the facility between 1931 and 1937 and
followed up through 1972, when the plant closed. Mancuso (Ex. 23) later
extended the follow-up period through 1993, yielding a total of 12,881
person-years of observation for an average length of 38.8 years and a
total of 66 lung cancer deaths. Since the Mancuso workers were first
employed in the 1930s and the Luippold workers were first employed
after 1940, the two cohorts are completely different sets of
individuals.
A major limitation of the Mancuso study is the uncertainty of the
exposure data. Mancuso relied exclusively on the air monitoring
reported by Bourne and Yee (Ex. 7-98) conducted over a single short
period of time during 1949. Bourne and Yee presented monitoring data as
airborne insoluble chromium, airborne soluble chromium, and total
airborne chromium by production department at the Painesville plant.
The insoluble chromium was probably Cr(III) compounds with some
slightly water-soluble and insoluble chromates. The soluble chromium
was probably highly water-soluble Cr(VI). Mancuso (Exs. 7-11; 23)
calculated cumulative exposures (mg/m\3\-yr) for each cohort member
based on the 1949 mean chromium concentrations, by production
department, under the assumption that those levels reflect exposures
during the entire duration of employment for each cohort member, even
though employment may have begun as early as 1931 and may have extended
to 1972. Due to the lack of air measurements spanning the full period
of worker exposure and the lack of adequate methodology to distinguish
chromium valence states (i.e., Cr(VI) vs. Cr(III)), the exposure data
associated with the Mancuso cohort were not as well characterized as
data from the Luippold or Gibb cohorts.
Mancuso (Exs. 7-11; 23)reported cumulative exposure-related
increases in age-adjusted lung cancer death rates for soluble,
insoluble, or total chromium. Within a particular range of exposures to
insoluble chromium, lung cancer death rates also tended to increase
with increasing total cumulative chromium. However, the study did not
report whether these tendencies were statistically significant, nor did
it report the extent to which exposures to soluble and insoluble
chromium were correlated. Thus, it is possible that the apparent
relationship between insoluble chromium (e.g., primarily Cr(III)) and
lung cancer may have arisen because both insoluble chromium
concentrations and lung cancer death rates were positively correlated
with Cr(VI) concentrations. Further discussion with respect to
quantitative risk estimation from the Mancuso cohort is provided in
section VI.E.1 on additional risk assessments.
4. Hayes Cohort
Hayes et al. (Ex. 7-14) studied a cohort of employees at the same
chromate production site in Baltimore examined by Gibb et al. The Hayes
cohort consisted of 2101 male workers who were first hired between 1945
and 1974, excluding those employed for less than 90 days. The Gibb
cohort had different but partially overlapping date criteria for first
employment (1950-1974) and no 90 day exclusion. Hayes et al. reported
SMRs for respiratory tract cancer based on workers grouped by time of
hire, employment duration, and high or low exposure groups. Workers who
had ever worked at an older plant facility and workers whose location
of employment could not be determined were combined into a single
exposure group referred to as "high or questionable" exposure.
Workers known to have been employed exclusively at a newer renovated
facility built in 1950 and 1951 were considered to have had "low"
exposure. A dose-response was observed in the sense that higher SMRs
for respiratory cancer were observed among long-term workers (workers
who had worked for three or more years) than among short-term workers.
Hayes et al. did not quantify occupational exposure to Cr(VI) at
the time the cohort was studied, but Braver et al. (Ex. 7-17) later
estimated average cumulative soluble chromium (presumed by the authors
to be Cr(VI)) exposures for four subgroups of the Hayes cohort first
employed between 1945 and 1959. The TWA Cr(VI) concentrations were
determined from a total of 555 midget impinger air measurements that
were collected at the older plant from 1945 to 1950. The cumulative
exposures for the subgroups were estimated from the yearly average
Cr(VI) exposure for the entire plant and the subgroups' average
duration of employment rather than job-specific Cr(VI) concentrations
and individual work histories. Such "group level" estimation of
cumulative exposure is less appropriate than the estimation based on
individual experiences as was done for the Gibb and Luippold cohorts.
A more severe limitation of this study is that exposures attributed
to many workers in the newly renovated facility at the Baltimore site
throughout the 1950s were based on chromium measurements from an
earlier period (i.e., 1949-1950) at an older facility. Samples
collected at the new facility and reviewed by Gibb et al. (Exs. 25, 31-
22-12) show that the exposures in the new facility were substantially
lower than assumed by Braver et al. Braver et al. (Ex. 7-17) discussed
a number of other potential sources of uncertainty in the Cr(VI)
exposure estimates, such as the possible conversion to Cr(III) during
sample collection and the likelihood that samples may have been
collected mainly in potential problem areas.
5. Gerin Cohort
Gerin et al. (Ex. 7-120) developed a job exposure matrix that was
used to estimate cumulative Cr(VI) exposures for male stainless steel
welders who were part of the International Agency for Research on
Cancer's (IARC) multi-center historical cohort study (Ex. 7-114). The
IARC cohort included 11,092 welders. However, the number of cohort
members who were stainless steel welders, for which Cr(VI) exposures
were estimated, could not be determined from their report. Gerin et al.
used occupational hygiene surveys reported in the published literature,
including a limited amount of data collected from 8 of the 135
companies that employed welders in the cohort, to estimate typical eight-hour
TWA Cr(VI) breathing zone concentrations for various combinations of
welding processes and base metal. The resulting exposure matrix was
then combined with information about individual work history, including
time and length of employment, type of welding, base metal welded, and
information on typical ventilation status for each company (e.g.,
confined area, use of local exhaust ventilation, etc.) to estimate the
cumulative Cr(VI) exposure. Individual work histories were not
available for about 25 percent of the stainless steel welders. In these
cases, information was assumed based on the average distribution of
welding practices within the company. The lack of Cr(VI) air
measurements from most of the companies in the study and the
limitations in individual work practice information for this cohort
raise questions concerning the accuracy of the exposure estimates.
Gerin et al. reported no upward trend in lung cancer mortality
across four cumulative Cr(VI) exposure categories for stainless steel
welders, each accumulating between 7,000 and 10,000 person-years of
observation. The welders were also known to be exposed to nickel,
another potential lung carcinogen. Co-exposure to nickel may obscure or
confound the Cr(VI) exposure-response relationship. As discussed
further in Sections VI.E.3 and VI.G.4, exposure misclassification in
this cohort may obscure an exposure-response relationship. This is the
primary reason that the Gerin et al. cohort was not considered a
preferred cohort (i.e., it was not used to derive OSHA's quantitative
risk estimates), although a quantitative analysis of this cohort was
performed for comparison with the preferred cohorts.
6. Alexander Cohort
Alexander et al. (Ex. 31-16-3) conducted a retrospective cohort
study of 2429 aerospace workers employed in jobs entailing chromate
exposure (e.g., spray painting, sanding/polishing, chrome plating,
etc.) between 1974 and 1994. The cohort included workers employed as
early as 1940. Follow-up time was short, averaging 8.9 years per cohort
member; in contrast, the Gibb and Luippold cohorts accumulated an
average 30 or more years of follow-up. Long-term follow-up of cohort
members is particularly important for determining the risk of lung
cancer, which typically has an extended latency period of twenty years
or more.
Industrial hygiene data collected between 1974 and 1994 were used
to classify jobs in categories of "high" exposure, "moderate"
exposure, or "low" exposure to Cr(VI). The use of respiratory
protection was accounted for when setting up the job exposure matrix.
These exposure categories were assigned summary TWA concentrations and
combined with individual job history records to estimate cumulative
exposures for cohort members over time. As further discussed in section
VI.E.4, it was not clear from the study whether exposures are expressed
in units of Cr(VI) or chromate (CrO3). Exposures occurring
before 1974 were assumed to be at TWA levels assigned to the interval
from 1974 to 1985.
Alexander et al. presented lung cancer incidence data for four
cumulative chromate exposure categories based on worker duration and
the three (high, moderate, low) exposure levels. Lung cancer incidence
rates were determined using a local cancer registry, part of the
National Cancer Institute (NCI) Surveillance Epidemiology and End
Results (SEER) program. The authors reported no positive trend in lung
cancer incidence with increasing Cr(VI) exposure. Limitations of this
cohort study include the young age of the cohort members (median = 42)
and lack of information on smoking. As discussed above, the follow-up
time (average < 9 years) was probably too short to capture lung cancers
resulting from Cr(VI) exposure. Finally, the available Cr(VI) air
measurement data did not span the entire employment period of the
cohort (e.g., no data for 1940 to 1974) and was heavily grouped into a
relatively small number of "summary" TWA concentrations that may not
have fully captured individual differences in workplace exposures to
Cr(VI). For the above reasons, in particular the insufficient follow-up
time for most cohort members, the Alexander cohort was not considered a
preferred dataset for OSHA's quantitative risk analysis. However, a
quantitative analysis of this cohort was performed for comparison with
the preferred cohorts.
7. Studies Selected for the Quantitative Risk Assessment
The epidemiologic database is quite extensive and contains several
studies with exposure and response data that could potentially be used
for quantitative risk assessment. OSHA considers certain studies to be
better suited for quantitative assessment than others. The Gibb and
Luippold cohorts are the preferred sources for quantitative risk
assessment because they are large, have extensive follow-up, and have
documentation of historical Cr(VI) exposure levels superior to the
Mancuso, Hayes, Gerin and Alexander cohorts. In addition, analysts have
had access to the individual job histories of cohort members and
associated exposure matrices. OSHA's selection of the Gibb and Luippold
cohorts as the best basis of exposure-response analysis for lung cancer
associated with Cr(VI) exposure was supported by a variety of
commenters, including for example NIOSH (Tr. 314; Ex. 40-10-2, p. 4),
EPRI (Ex. 38-8, p.6), and Exponent (Ex. 38-215-2, p. 15). It was also
supported by the three external peer reviewers who reviewed OSHA's
preliminary risk assessment, Dr. Gaylor (Ex. 36-1-4-1, p. 24), Dr.
Smith (Ex. 36-1-4-2 p. 28), and Dr. Hertz-Picciotto (Ex. 36-1-4-4, pp.
41-42).
The Mancuso cohort and the Hayes cohort were derived from workers
at the same plants as Luippold and Gibb, respectively, but have
limitations associated with the reporting of quantitative information
and exposure estimates that make them less suitable for risk
assessment. Similarly, the Gerin and Alexander cohorts are less
suitable, due to limitations in exposure estimation and short follow-
up, respectively. For these reasons, OSHA did not rely upon the
Mancuso, Hayes, Gerin, and Alexander cohorts to derive its exposure-
response model for the risk of lung cancer from Cr(VI).
Although the Agency did not rely on the Mancuso, Hayes, Gerin, and
Alexander studies to develop its exposure-response model, OSHA believes
that evaluating risk among several different worker cohorts and
examining similarities and differences between them adds to the overall
completeness and quality of the assessment. The Agency therefore
analyzed these datasets and compared the results with the preferred
Gibb and Luippold cohorts. This comparative analysis is discussed in
Section VI.E. In light of the extensive worker exposure-response data,
there is little additional value in deriving quantitative risk
estimates from tumor incidence results in rodents, especially
considering the concerns with regard to route of exposure and study
design.
OSHA received a variety of public comments regarding the overall
quality of the Gibb and Luippold cohorts and their suitability as the
preferred cohorts in OSHA's quantitative risk analysis. Some commenters
raised concerns about the possible impact of short-term workers in the
Gibb cohort on the risk assessment (Tr. 123; Exs. 38-106, p. 10, 21;
40-12-5, p. 9). The Gibb cohort's inclusion of many workers employed
for short periods of time was cited as a
"serious flaw" by one commenter, who suggested that many lung cancers
among short-term workers in the study were caused by unspecified other
factors (Ex. 38-106, p. 10, p. 21). Another commenter stated that the
Davies cohort of British chromate production workers "gives greater
credence to the Painesville cohort as it showed that brief exposures
(as seen in a large portion of the Baltimore cohort) did not have an
increased risk of lung cancer" (Ex. 39-43, p. 1). However, separate
analyses of the short-term (< 1 year employment) and longer-term ( 1
year) Gibb cohort members indicated that restriction of the cohort to
workers with tenures of at least one year did not substantially impact
estimates of excess lung cancer mortality (Ex. 31-18-15-1 , p. 29). At
the public hearing, Ms. Deborah Proctor of Exponent, Inc. stated that
"the short term workers did not affect the results of the study" (Tr.
1848). OSHA agrees with Ms. Proctor's conclusion, and does not believe
that the inclusion of short term workers in the Gibb cohort is a source
of substantial uncertainty in the Agency's risk estimates.
Some commenters expressed concern that the Gibb study did not
control for smoking (Exs. 38-218, pp. 20-21; 38-265, p. 28; 39-74, p.
3). However, smoking status at the time of employment was ascertained
for approximately 90% of the cohort (Ex. 35-435) and was used in
statistical analyses by Gibb et al., Environ Inc., and Exponent Inc. to
adjust for the effect of smoking on lung cancer in the cohort (Exs. 25;
31-18-15-1; 35-435). NIOSH performed similar analyses using more
detailed information on smoking level (packs per day) that was
available for 70% of the cohort (Ex. 35-435, p.1100). OSHA believes
that these analyses appropriately addressed the potential confounding
effect of smoking in the Gibb cohort. Issues and analyses related to
smoking are further discussed in Section VI.G.3.
Other issues and uncertainties raised about the Gibb and Luippold
cohorts include a lack of information necessary to estimate deposited
dose of Cr(VI) for workers in either cohort and a concern that the
Luippold exposure data were based on exposures to "airborne total
soluble and insoluble chromium* * * rather than exposures to Cr(VI)"
(Ex. 38-218, pp. 20-21). However, the exposure estimates for the
Luippold (2003) cohort were recently developed by Proctor et al. using
measurements of airborne Cr(VI), not the total chromium measurements
used previously in Mancuso et al.'s analysis (Exs. 35-58, p. 1149; 35-
61). And, while it is true that the Gibb and Luippold (2003) datasets
do not lend themselves to construction of deposited dose measures, the
extensive Cr(VI) air monitoring data available on these cohorts are
more than adequate for quantitative risk assessment. In the case of the
Gibb cohort, the exposure dataset is extraordinarily comprehensive and
well-documented (Tr. 709-710; Ex. 44-4, p.2), even "exquisite"
according to one NIOSH expert (Tr. 312). Further discussion of the
quality and reliability of the Gibb and Luippold (2003) exposure data
and related comments appears in Section VI.G.1.
OSHA received several comments regarding a new epidemiological
study conducted by Environ, Inc. for the Industrial Health Foundation,
Inc. of workers hired after the institution of process changes and
industrial hygiene practices designed to limit exposure to Cr(VI) in
two chromate production plants in the United States and two plants in
Germany (Exs. 47-24-1; 47-27, pp. 15-16; 47-35-1, pp. 7-8). These
commenters suggested that OSHA should use these cohorts to model risk
of lung cancer from low exposures to Cr(VI). Unfortunately, the public
did not have a chance to comment on this study because documents
related to it were submitted to the docket after the time period when
new information should have been submitted. However, OSHA reviewed the
study and comments that were submitted to the docket. Based on the
information submitted, the Agency does not believe that quantitative
analysis of these studies would provide additional information on risk
from low exposures to Cr(VI).
A cohort analysis based on the U.S. plants is presented in an April
2005 publication by Luippold et al. (Ex. 47-24-2). Luippold et al.
studied a total of 617 workers with at least one year of employment,
including 430 at a plant built in the early 1970s ("Plant 1") and 187
hired after the 1980 institution of exposure-reducing process and work
practice changes in a second plant ("Plant 2"). Workers were followed
through 1998. Personal air-monitoring measures available from 1974 to
1988 for the first plant and from 1981 to 1998 for the second plant
indicated that exposure levels at both plants were low, with overall
geometric mean concentrations below 1.5 [mu]g/m3 and area-
specific average personal air sampling values not exceeding 10 [mu]g/
m3 for most years (Ex. 47-24-2, p. 383). By the end of
follow-up, which lasted an average of 20.1 years for workers at Plant 1
and 10.1 years at Plant 2, 27 cohort members (4%) were deceased. There
was a 41% deficit in all-cause mortality when compared to all-cause
mortality from age-specific state reference rates, suggesting a strong
healthy worker effect. Lung cancer was 16% lower than expected based on
three observed vs. 3.59 expected cases, also using age-specific state
reference rates (Ex. 47-24-2, p. 383). The authors concluded that
"[t]he absence of an elevated lung cancer risk may be a favorable
reflection of the postchange environment. However, longer follow-up
allowing an appropriate latency for the entire cohort will be needed to
confirm this conclusion" (Ex. 47-24-2, p. 381).
OSHA agrees with the study authors that the follow-up in this study
was not sufficiently long to allow potential Cr(VI)-related lung cancer
deaths to occur among many cohort members. The mean times since first
exposure of 10 and 20 years for Plant 1 and Plant 2 employees,
respectively, suggest that most workers in the cohort may not have
completed the " * * * typical latency period of 20 years or more"
that Luippold et al. suggest is required for occupational lung cancer
to emerge (Ex. 47-24-2, p. 384). Other important limitations of this
study include the striking healthy worker effect on the SMR analysis,
and the relatively young age of most workers at the end of follow-up
(approximately 90% < 60 years old) (Ex. 47-24-2, p. 383). OSHA also
agrees with the study authors' statements that " * * * the few lung
cancer deaths in this cohort precluded * * * [analyses to] evaluate
exposure-response relationships * * * " (Ex. 47-24-2, p. 384).
Although OSHA's model predicts high excess lung cancer risk for
highly exposed individuals (e.g., workers exposed for 45 years at the
previous PEL of 52 [mu]g/m3), the model would predict much
lower risks for workers with low exposures, as in the Luippold (2005)
cohorts. To provide a point of comparison between the results of the
Luippold et al. (2005) 'post-change' study and OSHA's risk model, the
Agency used its risk model to generate an estimate of lung cancer risk
for a population with exposure characteristics approximately similar to
the 'post-change' cohorts described in Luippold et al. (2005). It
should be noted that since this comparative analysis used year 2000
U.S. reference rates were rather than the state-, race-, and gender-
specific historical reference mortality rates used by Luippold et al.
(2005), this risk calculation provides only a rough estimate of
expected excess lung cancer risk for the cohort. The derivation of
OSHA's risk model (based on the preferred Gibb and Luippold
(2003) cohorts) is described in Sections VI.C.1 and VI.C.2.
It is difficult to tell from the publication what the average level
or duration of exposure was for the cohort. However, personal sampling
data reported by Luippold et al. (2005) had annual geometric mean 8-
hour TWA concentrations "much less" than 1.5 [mu]g/m3 in
most years (Ex. 47-24-2, p. 383). Most workers also probably had less
than 20 years of exposure, given the average follow-up periods of 20
and 10 years reported for the Luippold (2005) Plant 1 and Plant 2,
respectively. OSHA assumed that workers had TWA exposures of 1.5 [mu]g/
m3 for 20 years, with the understanding that this assumption
would lead to somewhat higher estimates of risk than OSHA s model would
predict if the average exposure of the cohort was known. Using these
assumptions, OSHA's model predicts a 2-9% excess lung cancer risk due
to Cr(VI) exposure, or less than four cancers in the population the
size and age of the Luippold 2005 cohort.
Since this analysis used year 2000 U.S. reference rates rather than
the state-, race-, and gender-specific historical reference mortality
rates used by Luippold et al. (2005), this risk calculation provides
only a rough estimate of the lung cancer risk that OSHA's model would
predict for the cohort. Nevertheless, it illustrates that for a
relatively young population with low exposures, OSHA's risk model
(derived from the preferred Gibb and Luippold 2003 cohorts) predicts
lung cancer risk similar to that observed in the low-exposure Luippold
2005 cohort. The small number of lung cancer deaths observed in
Luippold 2005 should not be considered inconsistent with the risk
estimates derived using models developed by OSHA based on the Gibb and
Luippold (2003) cohorts (Ex. 47-24-2, p. 383).
Some commenters believed that analysis of the unpublished German
cohorts would demonstrate that lung cancer risk was only increased at
the highest Cr(VI) levels and, therefore, could form the basis for an
exposure threshold (Exs. 47-24-1; 47-35-1). Although no data were
provided to corroborate their comments, the Society of the Plastics
Industry requested that OSHA obtain and evaluate the German study as
"new and available evidence which may suggest a higher PEL than
proposed" (Ex. 47-24-1, p. 4).
Following the close of the comment period, OSHA gained access to a
2002 final contract report by Applied Epidemiology Inc. prepared for
the Industrial Health Foundation (Ex. 48-1-1; 48-1-2) and a 2005
prepublication by ENVIRON Germany (Ex. 48-4). The 2002 report contained
detailed cohort descriptions, exposure assessments, and mortality
analyses of 'post-change' workers from the two German chromate
production plants referred to above and two U.S. chromate production
plants, one of which is plant 1 discussed in the 2005 study by Luippold
et al. The mortality and multivariate analyses were performed on a
single combined cohort from all four plants. The 2005 prepublication
contained a more abbreviated description and analysis of a smaller
cohort restricted to the two German plants only. The cohorts are
referred to as 'post-change' because the study only selected workers
employed after the participating plants switched from a high-lime to a
no-lime (or very low lime facility, in the case of U.S. plant 1)
chromate production process and implemented industrial hygiene
improvements that considerably reduced Cr(VI) air levels in the
workplace.
The German cohort consisted of 901 post-change male workers from
two chromate production plants employed for at least one year.
Mortality experience of the cohort was evaluated through 1998. The
study found elevated lung cancer mortality (SMR=1.48 95% CI: 0.93-2.25)
when compared to the age- and calendar year-adjusted German national
population rates (Ex. 48-4). The cohort lacked sufficient job history
information and air monitoring data to develop an adequate job-exposure
matrix required to estimate individual airborne exposures (Ex. 48-1-2).
Instead, the researchers used the large amount of urinary chromium data
from routine biomonitoring of plant employees to analyze lung cancer
mortality using cumulative urinary chromium as an exposure surrogate,
rather than the conventional cumulative Cr(VI) air concentrations. The
study reported a statistically significant two-fold excess lung cancer
mortality (SMR=2.09; 95% CI: 1.08-3.65; 12 observed lung cancer deaths)
among workers in the highest cumulative exposure grouping (i.e. >200
[mu]g Cr/L--yr). There was no increase in lung cancer mortality in the
lower exposure groups, but the number of lung cancer deaths was small
(i.e. < 5 deaths) and the confidence intervals were wide. Logistic
regression modeling in the multi-plant cohort (i.e. German and U.S.
plants combined) showed an increased risk of lung cancer in the high
(OR=20.2; 95% CI: 6.2-65.4; 10 observed deaths) and intermediate
(OR=4.9; 95% CI: 1.5-16.0; 9 deaths) cumulative exposure groups when
compared to the low exposure group (Ex. 48-1-2, Table 18). The lung
cancer risks remained unchanged when smoking status was controlled for
in the model, indicating that the elevated risks were unlikely to be
confounded by smoking in this study.
OSHA does not believe that the results of the German study provide
a basis on which to establish a threshold exposure below which no lung
cancer risk exists. Like the U.S. post-change cohort (i.e., Luippold
(2005) cohort) discussed above, small cohort size, few lung cancer
cases (e.g., 10 deaths in the three lowest exposure groups combined)
and limited follow-up (average 17 years) severely limit the power to
detect small increases in risk that may be present with low cumulative
exposures. The limited power of the study is reflected in the wide
confidence intervals associated with the SMRs. For example, there is no
apparent evidence of excess lung cancer (SMR=0.95; 95% CI: 0.26-2.44)
in workers exposed to low cumulative urine chromium levels between 40-
100 [mu]g Cr/L--yr. However, the lack of precision in this estimate is
such that a two-fold increase in lung cancer mortality can not be ruled
out with a high degree of confidence. Although the study authors state
that the data suggest a possible threshold effect, they acknowledge
that "demonstrating a clear (and statistically significant) threshold
response in epidemiological studies is difficult especially [where], as
in this study, the number of available cases is relatively small, and
the precise estimation of small risks requires large numbers" (Ex. 48-
4, p. 8). OSHA agrees that the number of lung cancer cases in the study
is too small to clearly demonstrate a threshold response or precisely
estimate small risks.
OSHA has relied upon a larger, more robust cohort study for its
risk assessment than the German cohort. In comparison, the Gibb cohort
has about five times the person-years of observation (70736 vs. 14684)
and number of lung cancer cases (122 vs. 22). The workers, on average,
were followed longer (30 vs. 17 years) and a greater proportion of the
cohort is deceased (36% vs. 14%). Limited air monitoring from the
German plants indicate that average plant-wide airborne Cr(VI) roughly
declined from about 35 [mu]g Cr(VI)/m\3\ in the mid 1970s to 5 [mu]g
Cr(VI)/m\3\ in the 1990s (2002 report; Ex. 7-91). This overlaps the
Cr(VI) air levels in the Baltimore plant studied by Gibb et al. (Ex.
47-8). Furthermore, cumulative exposure estimates for members of the
Gibb cohort were individually reconstructed
from job histories and Cr(VI) air monitoring data. These airborne
Cr(VI) exposures are better suited than urinary chromium for evaluating
occupational risk at the permissible exposure limits under
consideration by OSHA. An appropriate conversion procedure that
credibly predicts time-weighted average Cr(VI) air concentrations in
the workplace from urinary chromium measurements is not evident and,
thus, would undoubtedly generate additional uncertainty in the risk
estimates. For the above reasons, OSHA believes the Gibb cohort
provides a stronger dataset than the German cohort on which to assess
the existence of a threshold exposure. This and other issues pertaining
to the relationship between the cumulative exposure and lung cancer
risk are further discussed in section VI.G.1.a.
C. Quantitative Risk Assessments Based on the Gibb Cohort
Quantitative risk assessments were performed on the exposure-
response data from the Gibb cohort by three groups: Environ
International (Exs. 33-15; 33-12) under contract with OSHA; the
National Institute for Occupational Safety and Health (Ex. 33-13); and
Exponent (Ex. 31-18-15-1) for the Chrome Coalition. All reported
similar risks for Cr(VI) exposure over a working lifetime despite using
somewhat different modeling approaches. The exposure-response data,
risk models, statistical evaluation, and risk estimates reported by
each group are discussed below.
1. Environ Risk Assessments
In 2002, Environ International (Environ) prepared a quantitative
analysis of the association between Cr(VI) exposure and lung cancer
(Ex. 33-15) , which was described in detail in the Preamble to the
Proposed Rule (69 FR at 59364-59365). After the completion of the 2002
Environ analysis, individual data for the 2357 men in the Gibb et al.
cohort became available. The new data included cumulative Cr(VI)
exposure estimates, smoking information, date of birth, race, date of
hire, date of termination, cause of death, and date of the end of
follow-up for each individual (Ex. 35-295). The individual data allowed
Environ to do quantitative risk assessments based on (1) redefined
exposure categories, (2) alternate background reference rates for lung
cancer mortality, and (3) Cox proportional hazards modeling (Ex. 33-
12). These are discussed below and in the 2003 Environ analysis (Ex.
33-12).
The 2003 Environ analysis presented two alternate groupings with
ten cumulative Cr(VI) exposure groups each, six more than reported by
Gibb et al. and used in the 2002 analysis. One alternative grouping was
designed to divide the person-years of follow-up fairly evenly across
groups. The other alternative allocated roughly the same number of
observed lung cancers to each group. These two alternatives were
designed to remedy the uneven distribution of observed and expected
cases in the Gibb et al. categories, which may have caused parameter
estimation problems due to the small number of cases in some groups.
The new groupings assigned adequate numbers of observed and expected
lung cancer cases to all groups and are presented in Table VI-1.
Environ used a five-year lag to calculate cumulative exposure for
both groupings. This means that at any point in time after exposure
began, an individual's cumulative exposure would equal the product of
chromate concentration and duration of exposure, summed over all jobs
held up to five years prior to that point in time. An exposure lag is
commonly used in exposure-response analysis for lung cancer since there
is a long latency period between first exposure and the development of
disease. Gibb et al. found that models using five- and ten-year lags
provided better fit to the mortality data than lags of zero, two and
twenty years (Ex. 31-22-11).
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The 2003 Environ analysis also derived expected cases using lung
cancer rates from alternative reference populations. In addition to the
State of Maryland lung cancer rates that were used by Gibb et al.,
Environ used age- and race-specific rates from the city of Baltimore,
where the plant was located. Baltimore may represent a more appropriate
reference population because most of the cohort members
resided in Baltimore and Baltimore residents may be more similar to the
cohort members than the Maryland or U.S. populations in their co-
exposures and lifestyle characteristics, especially smoking habits and
urban-related risk factors. On the other hand, Baltimore may not be the
more appropriate reference population if the higher lung cancer rates
in the Baltimore population primarily reflect extensive exposure to
industrial carcinogens. This could lead to underestimation of risk
attributable to Cr(VI) exposure.
The 2003 analysis used two externally standardized models, a
relative risk model (model E1 below) and an additive risk model (model
E2) defined as follows:
E1. Ni = C0 * Ei * (1 + C1Di + C2Di\2\)
E2. Ni = C0 * Ei + PYi * (C1Di + C2Di\2\)
where Ni is the predicted number of lung cancers in the i
th group; PYi is the number of person-years for
group i; Ei is the expected number of lung cancers in that
group, based on the reference population; Di is the mean
cumulative dose for that group; and C0, C1, and
C2 are parameters to be estimated. Both models initially
included quadratic exposure terms (C2Di\2\ ) as
one way to test for nonlinearity in the exposure-response. Model E1 is
a relative risk model, whereas Model E2 is an additive risk model. In
the case of additive risk models, the exposure-related estimate of
excess risk is the same regardless of the age- and race-specific
background rate of lung cancer. For relative risk models, a dose term
is multiplied by the appropriate background rate of lung cancer to
derive an exposure-related estimate of risk, so that excess risk always
depends on the background.
Maximum likelihood techniques were used to estimate the parameters
C0, C1, and C2. Likelihood ratio tests
were used to determine which of the model parameters contributed
significantly to the fit of the model. Parameters were sequentially
added to the model, starting with C1, when they contributed
significantly (p < 0.05) to improving the fit. Parameters that did not
contribute significantly, including the quadratic exposure terms
(C2Di\2\ ), were removed from the models.
Two Cox proportional hazards models were also fit to the individual
exposure-response data. The model forms were:
C1. h(t;z;D) = h0(t)*exp([beta]1z +
[beta]2D)
C2. h(t;z;D) = h0(t)*[exp([beta]1z)][1 +
[beta]2D]
where h is the hazard function, which expresses the age-specific rate
of lung cancer among workers, as estimated by the model. In addition, t
is age, z is a vector of possible explanatory variables other than
cumulative dose, D is cumulative dose, h0(t) is the baseline
hazard function (a function of age only), [beta]2 is the
cumulative dose coefficient, and [beta]1 is a vector of
coefficients for other possible explanatory variables--here, cigarette
smoking status, race, and calendar year of death (Ex. 35-57). Cox
modeling is an approach that uses the experience of the cohort to
estimate an exposure-related effect, irrespective of an external
reference population or exposure categorization. Because they are
internally standardized, Cox models can sometimes eliminate concerns
about choosing an appropriate reference population and may be
advantageous when the characteristics of the cohort under study are not
well matched against reference populations for which age-related
background rates have been tabulated. Model C1 assumes the lung cancer
response is nonlinear with cumulative Cr(VI) exposure, whereas C2
assumes a linear lung cancer response with Cr(VI) exposure. For the Cox
proportional hazards models, C1 and C2, the other possible explanatory
variables considered were cigarette smoking status, race, and calendar
year of death.
The externally standardized models E1 and E2 provided a good fit to
the data (p>=0.40). The choice of exposure grouping had little effect
on the parameter estimates of either model E1 or E2. However, the
choice of reference rates had some effect, notably on the
"background" parameter, C0, which was included as a fitted
parameter in the models to adjust for differences in background lung
cancer rates between cohort members and the reference populations. For
example, values of C0 greater than one "inflate" the base
reference rates, reducing the magnitude of excess risks in the model.
Such an adjustment was necessary for the Maryland reference population
(the maximum likelihood estimate of C0 was significantly
higher than one), but not for the Baltimore city reference population
(C0 was not significantly different from one). This result
suggests that the Maryland lung cancer rates may be lower than the
cohort's background lung cancer rates, but the Baltimore city rates may
adequately reflect the cohort background rates. The inclusion of the
C0 parameter yielded a cumulative dose coefficient that
reflected the effect of exposure and not the effect of differences in
background rates, and was appropriate.
The model results indicated a relatively consistent cumulative dose
coefficient, regardless of reference population. The coefficient for
cumulative dose in the models ranged from 2.87 to 3.48 per mg/m\3\-yr
for the relative risk model, E1, and from 0.0061 to 0.0071 per mg/m\3\-
person-yr for the additive risk model, E2. These coefficients determine
the slope of the linear cumulative Cr(VI) exposure-lung cancer response
relationship. In no case did a quadratic model fit the data better than
a linear model.
Based on comparison of the models' AIC values, Environ indicated
that the linear relative risk model E1 was preferred over the additive
risk model E2. OSHA agrees with Environ's conclusion. The relative risk
model is also preferred over an additive risk model because the
background rate of lung cancer varies with age. It may not be
appropriate to assume, as an additive model does, that increased lung
cancer risk at age 25, where background risk is relatively low, would
be the same (for the same cumulative dose) as at age 65, where
background rates are much higher.
The Cox proportional hazards models, C1 and C2, also fit the data
well (although the fit was slightly better for model C2 than C1).
Recall that for the Cox proportional hazards models, C1 and C2, the
other possible explanatory variables considered were cigarette smoking
status, race, and calendar year of death. For both models, addition of
a term for smoking status significantly improved the fit of the models
to the data (p< 0.00001). The experience with model C1 indicated that
race (p=0.15) and year of death (p=0.4) were not significant
contributors when cumulative dose and smoking status were included in
the model. Based on results for model C1, race and year of death were
not considered by Environ in the linear model C2. The cumulative dose
coefficient, [beta]2, was 1.00 for model C1 and 2.68 for
model C2. A more complete description of the models and variables can
be found in the 2003 Environ analysis (Ex. 33-12, p. 10).
Lifetable calculations were made of the number of extra lung
cancers per 1000 workers exposed to Cr(VI) based on models E1, E2, C1,
and C2, assuming a constant exposure from age 20 through a maximum of
age 65. The lifetable accounted for both lung cancer risk and competing
mortality through age 100. Rates of lung cancer and other mortality for
the lifetable calculations were based, respectively, on 2000 U.S. lung
cancer and all-cause mortality rates for both sexes and all races. In
addition to the maximum likelihood estimates, 95% confidence intervals
for the excess lifetime risk were derived. Details about the procedures
used to estimate parameters, model fit, lifetable calculations, and
confidence intervals are described in the 2003 Environ report (Ex. 33-12, p. 8-9).
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Table VI-2 shows each model's predictions of excess lifetime lung
cancer risk from a working lifetime of exposure to various Cr(VI) air
levels. The estimates are very consistent regardless of model, exposure
grouping, or reference population. The model that appears to generate
results least similar to the others is C1, which yielded one of the
higher risk estimates at 52 [mu]g/m3, but estimated the
lowest risks for exposure levels of 10 [mu]g/m3 or lower.
The change in magnitude, relative to the other models, is a result of
the nonlinearity of this model. Confidence limits for all models,
including C1, tend to overlap, suggesting a fair degree of statistical
consistency.
2. National Institute for Occupational Safety and Health (NIOSH) Risk
Assessment
NIOSH (Ex. 33-13) developed a risk assessment from the Gibb cohort.
The NIOSH analysis, like the 2003 Environ assessment, used the cohort
individual data files to compute cumulative Cr(VI) exposure. However,
NIOSH also explored some other exposure-related assumptions. For
example, they performed the dose-response analysis with lag times in
addition to the 5-year lag used by Environ. NIOSH also analyzed dose-
response using as many as 50 exposure categories, although their report
presents data in five cumulative Cr(VI) exposure groupings.
NIOSH incorporated information on the cohort smoking behavior in
their quantitative assessments. They estimated (packs/day)-years of
cumulative smoking for each individual in the cohort, using information
from a questionnaire that was administered at the time of each cohort
member's date of hire. To estimate cumulative smoking, NIOSH assumed
that the cohort members maintained the level of smoking reported in the
questionnaire from the age of 18 through the end of follow-up.
Individuals with unknown smoking status were assigned a value equal to
the average smoking level among all individuals with known smoking
levels (presumably including non-smokers). Individuals who were known
to smoke but for whom the amount was unknown were assigned a smoking
level equal to the average of all smokers.
NIOSH considered six different relative risk models, fit to the
Gibb cohort data by Poisson regression methods. They did not consider
additive risk models. The six relative risk models were externally
standardized using age- and race-specific U.S. lung cancer rates. Their
background coefficients, C0, explicitly included smoking,
race, and age terms to adjust for differences between the cohort and
the reference population. These models are described as follows:
NIOSH1a: Ni = C0 * Ei * exp(C1Di)
NIOSH1b: Ni = C0 * Ei * exp(C1Di\1/2\\)
NIOSH1c: Ni = C0 * Ei * exp(1 + C1Di + C2Di2)
NIOSH1d: Ni = C0 * Ei * (1 + Di)[alpha]
NIOSH1e: Ni = C0 * Ei * (1 + C1Di)
NIOSH1f: Ni = C0 * Ei * (1 + C1Di[alpha])
where the form of the equation has been modified to match the format
used in the Environ reports. In addition, NIOSH fit Cox proportional
hazard models (not presented) to the lung cancer mortality data using
the individual cumulative Cr(VI) exposure estimates.
NIOSH reported that the linear relative risk model 1e generally
provided a superior fit to the exposure-response data when compared to
the various log linear models, 1a-d. Allowing some non-linearity (e.g.,
model 1f) did not significantly improve the goodness-of-fit, therefore,
they considered the linear relative risk model form 1e (analogous to
the Environ model E1) to be the most appropriate for determining their
lifetime risk calculations. A similar fit could be achieved with a log-
linear power model (model 1d) using log-transformed cumulative Cr(VI)
and a piece-wise linear specification for the cumulative smoking term.
The dose coefficient (C1) for the linear relative risk
model 1e was estimated by NIOSH to be 1.444 per [mu]g CrO3/
m3-yr (Ex. 33-13, Table 4). If the exposures were converted
to units of [mu]g Cr(VI)/m3-yr, the estimated cumulative
dose coefficient would be 2.78 (95% CI: 1.04 to 5.44) per [mu]g/
m3-yr. This value is very close to the estimates derived in
the Environ 2003 analysis (maximum likelihood estimates ranging from
2.87 to 3.48 for model E1, depending on the exposure grouping and the
reference population). Lifetime risk estimates based on the NIOSH-
estimated dose coefficient and the Environ lifetable method using 2000
U.S. rates for lung cancer and all cause mortality are shown in Table
VI-3. The values are very similar to the estimates predicted by the
Environ 2003 analysis (Table VI-3). The small difference may be due to
the NIOSH adjustment for smoking in the background coefficient. NIOSH
found that excess lifetime risks for a 45-year occupational exposure to
Cr(VI) predicted by the best-fitting power model gave very similar
risks to the preferred linear relative risk model at TWA Cr(VI)
concentrations between 0.52 and 52 [mu]g/m3 (Ex. 33-13,
Table 5). Although NIOSH did not report the results, they stated that
Cox modeling produced risk estimates similar to the Poisson regression.
The consistency between Cox and Poisson regression modeling is
discussed further in section VI.C.4.
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Click here to view table VI-3
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NIOSH reported a significantly higher dose-response coefficient for
nonwhite workers than for white workers. That is, nonwhite workers in
the Gibb cohort are estimated to have a higher excess risk of lung
cancer than white workers, given equal cumulative exposure to Cr(VI).
In contrast, no significant race difference was found in the Cox
proportional hazards analysis reported by 2003 Environ.
3. Exponent Risk Assessment
In response to OSHA's Request For Information, Exponent prepared an
analysis of lung cancer mortality from the Gibb cohort. Like the 2003
Environ and NIOSH analyses, the Exponent analysis relied on the
individual worker data. Exponent performed their dose-response analyses
based on three different sets of exposure categories using two
reference populations and 70,808 person-years of follow-up. A total of
four analyses were completed, using (1) Maryland reference rates and
the four Gibb et al. exposure categories; (2) Baltimore reference rates
and the four Gibb et al. exposure categories; (3) Baltimore reference
rates and six exposure groups defined by Exponent; and (4) Baltimore
City reference rates and five exposure categories, obtained by removing
the highest of the six groups defined by Exponent from the dose-
response analysis. A linear relative risk model without a background
correction term (the term C0 used by Environ and NIOSH) was
applied in all of these cases and cumulative exposures were lagged five
years (as done by Environ and NIOSH). The analyses showed excess
lifetime risk between 6 and 14 per 1000 for workers exposed to 1 [mu]g/
m\3\ Cr(VI) for 45 years.
The analysis using Maryland reference lung cancer rates and the
Gibb et al. four-category exposure grouping yielded an excess lifetime
risk of 14 per 1000. This risk, which is higher than the excess
lifetime risk estimates by Environ and NIOSH for the same occupational
exposure, probably results from the absence of a background rate
coefficient (C0) in Exponent's model. As reported in the
Environ 2002 and 2003 analyses, the Maryland reference lung cancer
rates require a background rate coefficient greater than 1 to achieve
the best fit to the exposure-response data. The unadjusted Maryland
rates probably underestimate the cohort's background lung cancer rate,
leading to overestimation of the risk attributable to cumulative Cr(VI)
exposure.
The two analyses that used Baltimore reference rates and either
Exponent's six-category exposure grouping or the Gibb et al. four-
category grouping both resulted in an excess lifetime unit risk of 9
per 1000 for workers exposed to 1 [mu]g/m\3\ Cr(VI) for 45 years (Ex.
31-18-15-1, p. 41). This risk is close to estimates reported by Environ
using their relative risk model (E1) and Baltimore reference rates for
the same occupational exposure (Table VI-2). The Environ analysis
showed that, unlike the Maryland-standardized model discussed above,
the Baltimore-standardized models had background rate coefficients very
close to 1, the "default" value assumed by the Exponent relative risk
model. This suggests that the Baltimore reference rates may represent
the background lung cancer rate for this cohort more accurately than
the Maryland reference rates.
The lowest excess lifetime unit risk for workers exposed to 1
[mu]g/m\3\ Cr(VI) for 45 years reported by Exponent, at 6 per 1000, was
derived from the analysis that excluded the highest of Exponent's six
exposure groups. While this risk value is close to the Environ and
NIOSH unit risk estimates, the analysis merits some concern. Exponent
eliminated the highest exposure group on the basis that most cumulative
exposures in this group were higher than exposures usually found in
current workplace conditions. However, eliminating this group could
exclude possible long-term exposures (e.g., >15 years) below the
previous OSHA PEL (52 [mu]g/m\3\ ) from the risk analysis. Moreover, no
matter what current exposures might be, data on higher cumulative
exposures are relevant for understanding the dose-response
relationships.
In addition, the Exponent six category cumulative exposure grouping
may have led to an underestimate of the dose effect. The definition of
Exponent's six exposure groups was not related to the distribution of
cumulative exposure associated with individual person-years, but rather
to the distribution of cumulative exposure among the workers at the end
of their employment. This division does not result in either a uniform
distribution of person-years or observed lung cancer cases among
exposure categories. In fact, the six category exposure groupings of
both person-years and observed lung cancers were very uneven, with a
preponderance of both allocated to the lowest exposure group. This
skewed distribution of person-years and observed cases puts most of the
power for detecting significant differences from background cancer
rates at low exposure levels, where these differences are expected to
be small, and reduces the power to detect any significant differences
from background at higher exposure concentrations.
4. Summary of Risk Assessments Based on the Gibb Cohort
OSHA finds remarkable consistency among the risk estimates from the
various quantitative analyses of the Gibb cohort. Both Environ and
NIOSH determined that linear relative risk models generally provided a
superior fit to the data when compared to other relative risk models,
although the confidence intervals in the non-linear Cox model reported
by Environ overlapped with the confidence intervals in their linear
models. The Environ 2003 analysis further suggested that a linear
additive risk model could adequately describe the observed dose-
response data. The risk estimates for NIOSH and Environ's best-fitting
models were statistically consistent (compare Tables VI-2 and VI-3).
The choice of reference population had little impact on the risk
estimates. NIOSH used the entire U.S. population as the reference, but
included adjustment terms for smoking, age and race in its models. The
Environ 2003 analysis used both Maryland and Baltimore reference lung
cancer rates, and included a generic background coefficient
C0 to adjust for potential differences in background risk
between the reference population and the worker cohort. This term was
significant in the fitted model when Maryland rates were used for
external standardization, but not when Baltimore rates were used. Since
no adjustment in the model background term was required to better fit
the exposure-response data using Baltimore City lung cancer rates, they
may best represent the cohort's true background lung cancer incidence.
OSHA considers the inclusion of such adjustment factors, whether
specific to smoking, race, and age (as defined by NIOSH), or generic
(as defined by Environ), to be appropriate and believes they contribute
to accurate risk estimation by helping to correct for confounding risk
factors. The Cox proportional hazard models, especially the linear Cox
model, yielded risk estimates that were generally consistent with the
externally standardized models.
Finally, the number of exposure categories used in the analysis had
little impact on the risk estimates. When an appropriate adjustment to
the background rates was included, the four exposure groups originally
defined by Gibb et al. and analyzed in the 2002 Environ report, the six
exposure groups defined by Exponent, the two alternate sets of ten
exposure categories as defined in the 2003 Environ analysis, and the
fifty groups defined and aggregated by NIOSH all gave essentially the
same risk estimates. The robustness of the results to various
categorizations of cumulative exposure adds credence to the risk
projections.
Having reviewed the analyses described in this section, OSHA finds
that the best estimates of excess lung cancer risk to workers exposed
to the previous PEL (52 [mu]g Cr(VI)/m3) for a
working lifetime are about 300 to 400 per thousand based on data from
the Gibb cohort. The best estimates of excess lung cancer risks to
workers exposed to other TWA exposure concentrations are presented in
Table VI-2. These estimates are consistent with predictions from
Environ, NIOSH and Exponent models that applied linear relative and
additive risk models based on the full range of cumulative Cr(VI)
exposures experienced by the Gibb cohort and used appropriate
adjustment terms for the background lung cancer mortality rates.
D. Quantitative Risk Assessments Based on the Luippold Cohort
As discussed earlier, Luippold et al. (Exs. 35-204; 33-10) provided
information about the cohort of workers employed in a chromate
production plant in Painesville, Ohio. Follow-up for the 482 members of
the Luippold cohort started in 1940 and lasted through 1997, with
accumulation of person-years for any individual starting one year after
the beginning of his first exposure. There were 14,048 total person-
years of follow-up for the cohort. The person-years were then divided
into five exposure groups that had approximately equal numbers of
expected lung cancers in each group. Ohio reference rates were used to
compute expected numbers of deaths. White male rates were used because
the number of women was small (4 out of 482) and race was known to be
white for 241 of 257 members of the cohort who died and for whom death
certificates were available. The 1960-64 Ohio rates (the earliest
available) were assumed to hold for the time period from 1940 to 1960.
Rates from 1990-94 were assumed to hold for the period after 1994. For
years between 1960 and 1990, rates from the corresponding five-year
summary were used. There were significant trends for lung cancer SMR as
a function of year of hire, duration of employment, and cumulative
Cr(VI) exposure. The cohort had a significantly increased SMR for lung
cancer deaths of 241 (95% C.I. 180 to 317).
Click here to view table VI-4
Environ conducted a risk assessment based on the cumulative Cr(VI)
exposure-lung cancer mortality data from Luippold et al. and presented
in Table VI-4 (Ex. 33-15). Cumulative Cr(VI) exposures were categorized
into five groups with about four expected lung cancer deaths in each
group. In the absence of information to the contrary, Environ assumed
Luippold et al. did not employ any lag time in determining the
cumulative exposures. The calculated
and expected numbers of lung cancers were derived from Ohio reference
rates. Environ applied the relative and additive risk models, E1 and
E2, to the data in Table VI-4.
Linear relative and additive risk models fit the Luippold cohort
data adequately (p>=0.25). The final models did not include the
quadratic exposure coefficient, C2, or the background rate
parameter, C0, as they did not significantly improve the fit
of the models. The maximum likelihood estimates for the Cr(VI)
exposure-related parameter, C1, of the linear relative and
additive risk models were 0.88 per mg/m3-yr and 0.0014 per
mg/m3-person-yr, respectively. The C1 estimates
based on the Luippold cohort data were about 2.5-fold lower than the
parameter estimates based on the Gibb cohort data. The excess lifetime
risk estimate calculated by Environ for a 45-year working-lifetime
exposure to 1 [mu]g Cr(VI)/m3 (e.g., the unit risk) for both
models was 2.2 per 1000 workers (95% confidence intervals from 1.3 to
3.5 per 1000 for the relative risk model and 1.2 to 3.4 per 1000 for
the additive risk model) using a lifetable analysis with 1998 U.S.
mortality reference rates. These risks were 2.5 to 3-fold lower than
the projected unit risks based on the Gibb data set for equivalent
cumulative Cr(VI) exposures.
Crump et al. (Exs. 33-15; 35-58; 31-18) also performed an exposure-
response analysis from the Painesville data. In a Poisson regression
analysis, cumulative exposures were grouped into ten exposure
categories with approximately two expected lung cancer deaths in each
group. The observed and expected lung cancer deaths by Cr(VI) exposure
category are shown in Table VI-5. Ohio reference rates were used in
calculating the expected lung cancer deaths and cumulative exposures
were lagged five years.
Click here to view table VI-5
The Crump et al. analysis used the same linear relative risk and
additive risk models as Environ on the individual data categorized into
the ten cumulative exposure groups (Ex. 35-58). Tests for systematic
departure from
linearity were non-significant for both models (p>=0.11). The
cumulative dose coefficient determined by the maximum likelihood method
was 0.79 (95% CI: 0.47 to 1.19) per mg/m3-yr for the
relative risk model and 0.0016 (95% CI: 0.00098 to 0.0024) per mg/
m3-person-yr for the additive risk model, respectively. The
authors noted that application of the linear models to five and seven
exposure groups resulted in no significant difference in dose
coefficients, although the results were not presented. The exposure
coefficients reported by Crump et al. were very similar to those
obtained by Environ above, although different exposure groups were used
and Crump et al. used a five-year lag for the cumulative exposure
calculation. The authors noted that the linear models did not fit the
exposure data grouped into ten categories very well (goodness-of-fit
p< =0.01) but fit the data much better with seven exposure groups
(p>0.3), replacing the many lower exposure categories where there were
few observed and expected cancers with more stable exposure groupings
with greater numbers of cancers. The reduction in number of exposure
groups did not substantially change the fitted exposure coefficients.
The maximum likelihood estimate for the cumulative exposure
coefficient using the linear Cox regression model C2 was 0.66 (90% CI:
0.11 to 1.21), which was similar to the linear [Poisson regression]
relative risk model. When the Cox analysis was restricted to the 197
workers with known smoking status and a smoking variable in the model,
the dose coefficient for Cr(VI) was nearly identical to the estimate
without controlling for smoking. This led the authors to conclude that
"the available smoking data did not suggest that exposure to Cr(VI)
was confounded with smoking in this cohort, or that failure to control
for smoking had an appreciable effect upon the estimated carcinogenic
potency of Cr(VI)" (Ex. 35-58, p. 1156).
Given the similarity in results, OSHA believes it is reasonable to
use the exposure coefficients reported by Crump et al. based on their
groupings of the individual cumulative exposure data to estimate excess
lifetime risk from the Luippold cohort. Table VI-6 presents the excess
risk for a working lifetime exposure to various TWA Cr(VI) levels as
predicted by Crump et al.'s relative and additive risk models using a
lifetable analysis with 2000 U.S. rates for all causes and lung cancer
mortality. The resulting maximum likelihood estimates indicate that
working lifetime exposures to the previous Cr(VI) PEL would result in
excess lifetime lung cancer risks around 100 per 1000 (95% C.I. approx.
60-150). The risk estimates based on the Luippold cohort are lower than
the risk estimates based on the Gibb cohort, as discussed further in
section VI.F.
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Click here to view table VI-6
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E. Quantitative Risk Assessments Based on the Mancuso, Hayes, Gerin,
and Alexander Cohorts
In addition to the preferred data sets analyzed above, there are
four other cohorts with available data sets for estimation of
additional lifetime risk of lung cancer. These are the Mancuso cohort,
the Hayes cohort, the Gerin cohort, and the Alexander cohort. Environ
did exposure-response analysis for all but the Hayes cohort (Ex. 33-
15). Several years earlier, the K.S. Crump Division did quantitative
assessments on data from the Mancuso and Hayes cohort, under contract
with OSHA (Ex.13-5). The U.S. EPA developed quantitative risk
assessments from the Mancuso cohort data for its Integrated Risk
Information System (Exs. 19-1; 35-52). The California EPA (Ex. 35-54),
Public Citizen Health Research Group (Ex. 1), and the U.S. Air Force
Armstrong Laboratory (AFAL) for the Department of Defense (Ex. 35-51)
performed assessments from the Mancuso data using the 1984 U.S. EPA
risk estimates as their starting point. The U.S. EPA also published a
risk assessment based on the Hayes cohort data (Ex. 7-102). Until the
cohort studies of Gibb et al. and Luippold et al. became available,
these earlier assessments provided the most current projected cancer
risks from airborne exposure to Cr(VI). The previous risk assessments
were extensively described in the NPRM sections VI.E.1 and VI.E.2 (69
FR at 59375-59378). While the risk estimates from Mancuso, Hayes,
Gerin, and Alexander data sets are associated with a greater degree of
uncertainty, it is nevertheless valuable to compare them to the risk
estimates from the higher quality Gibb and Luippold data sets in order
to determine if serious discrepancies exist between them. OSHA believes
evaluating consistency in risk among several worker cohorts adds to the
overall quality of the assessment.
The Mancuso and Luippold cohorts each worked at the Painesville
plant but the worker populations did not overlap due to different
selection criteria. Exposure estimates were also based on different
industrial hygiene surveys. The Hayes and Gibb cohorts both worked at
the Baltimore plant. Even though Cr(VI) exposures were reconstructed
from monitoring data measured at different facilities resulting in
significantly different exposure-response functions (see section VI.F),
there was some overlap in the two study populations. As a result, the
projected risks from these data sets can not strictly be viewed as
independent estimates. The Gerin and Alexander cohorts were not
chromate production workers and are completely independent from the
Gibb and Luippold data sets. The quantitative assessment of the four
data sets and comparison with the risk assessments based on the Gibb
and Luippold cohorts are discussed below.
1. Mancuso Cohort
As described in subsection VII.B.3, the Mancuso cohort was
initially defined in 1975 and updated in 1997. The cohort members were
hired between 1931 and 1937 and worked at the same Painesville facility
as the Luippold cohort workers. However, there was no overlap between
the two cohorts since all Luippold cohort workers were hired after
1939. The quantitative risk assessment by Environ used data reported in
the 1997 update (Ex. 23, Table XII) in which lung cancer deaths and
person-years of follow-up were classified into four groups of
cumulative exposure to soluble chromium, assumed to represent Cr(VI)
(Ex. 33-15). The mortality data and person-years were further broken
down by age of death in five year increments starting with age interval
40 to 44 years and going up to >75 years. No expected numbers of lung
cancers were computed, either for the cohort as a whole or for specific
groups of person-years. Environ applied an indirect method based on the
recorded median age and year of entry into the cohort to estimate age
information necessary to derive expected numbers of age- and calendar
year-adjusted lung cancers deaths required to complete the risk
assessment.
Observed and expected lung cancer deaths by age and cumulative
exposure (mg/m\3\-yr) are presented in Table 3 of the 2002 Environ
report (Ex. 33-15, p. 39). The mean cumulative exposures to soluble
Cr(VI) were assumed to be equal to the midpoints of the tabulated
ranges. No lag was used for calculating the cumulative exposures.
Environ applied externally standardized risk models to these data,
similar to those described in section VI.C.1 but using an age-related
parameter, as discussed in the 2002 report (Ex. 33-15, p. 39). The
externally-standardized linear relative risk model with an age-
dependent exposure term provided a superior fit over the other models.
The predicted excess risk of lung cancer from a 45-year working
lifetime of exposure to Cr(VI) at the previous OSHA PEL using the best-
fitting linear relative risk model is 293 per 1000 workers (95% C.I.
188 to 403). The maximum likelihood estimate from working lifetime
exposure to new PEL of 5.0 [mu]g/m\3\ Cr(VI) is 34 per 1000 workers
(95% C.I. 20 to 52 per 1000). These estimates are close to those
predicted from the Gibb cohort but are higher than predicted from the
Luippold cohort.
There are uncertainties associated with both the exposure estimates
and the estimates of expected numbers of lung cancer deaths for the
1997 Mancuso data set. The estimates of exposure were derived from a
single set of measurements obtained in 1949 (Ex. 7-98). Although little
prior air monitoring data were available, it is thought that the 1949
air levels probably understate the Cr(VI) concentrations in the plant
during some of the 1930s and much of the 1940s when chromate production
was high to support the war. The sampling methodology used by Bourne
and Yee only measured soluble Cr(VI), but it is believed that the
chromate production process employed at the Painesville plant in these
early years yielded slightly soluble and insoluble Cr(VI) compounds
that would not be fully accounted for in the sampling results (Ex. 35-
61). This would imply that risks would be overestimated by use of
concentration estimates that were biased low. However, it is possible
that the 1949 measurements did not underestimate the Cr(VI) air levels
in the early 1930s prior to the high production years. Some older
cohort members were also undoubtedly exposed to less Cr(VI) in the
1950s than measured in 1949 survey.
Another uncertainty in the risk assessment for the Mancuso cohort
is associated with the post-hoc estimation of expected numbers of lung
cancer deaths. The expected lung cancers were derived based on
approximate summaries of the ages and assumed start times of the cohort
members. Several assumptions were dictated by reliance on the published
groupings of results (e.g., ages at entry, calendar year of entry, age
at end of follow-up, etc.) as well as by the particular choices for
reference mortality rates (e.g., U.S. rates, in particular years close
to the approximated time at which the person-years were accrued). Since
the validity of these assumptions could not be tested, the estimates of
expected numbers of lung cancer deaths are uncertain.
There is also a potential healthy worker survivor effect in the
Mancuso cohort. The cohort was identified as workers first hired in the
1930s based on employment records surveyed in the late 1940s (Ex. 2-
16). The historical company files in this time period were
believed to be sparse and more likely to only identify employees still
working at the plant in the 1940s (Ex. 33-10). If there was a sizable |
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