Regulations (Preambles to Final Rules) - Table of Contents|
| Record Type:||Occupational Exposure to 1,3-Butadiene|
| Title:||Section 7 - VII. Significance of Risk|
VII. Significance of Risk
In the 1980 "Benzene Decision," the Supreme Court, in its discussion of the level of risk that Congress authorized OSHA to regulate, indicated its view of the boundaries of acceptable and unacceptable risk. The Court stated:
It is the Agency's responsibility to determine in the first instance what it considers to be a "significant" risk. Some risks are plainly acceptable and others are plainly unacceptable. If for example, the odds are one in a billion that a person will die from cancer by taking a drink of chlorinated water, the risk clearly could not be considered significant. On the other hand, if the odds are one in a thousand that regular inhalation of gasoline vapors that are 2 percent benzene will be fatal, a reasonable person might well consider the risk significant and take the appropriate steps to decrease or eliminate it. (I.U.D. v. A.P.I., 448 U.S. 607, 655).
So a risk of (1/1000) (10(-3)) is clearly significant. It represents the uppermost end of the million-fold range suggested by the Court, somewhere below which the boundary of acceptable versus unacceptable risk must fall.
The Court further stated that "while the Agency must support its findings that a certain level of risk exists with substantial evidence, we recognize that its determination that a particular level of risk is significant will be based largely on policy considerations." With regard to the methods used to determine the risk level present (as opposed to the policy choice of whether that level is "significant" or not), the Court added that assessment under the OSH Act is "not a mathematical straitjacket," and that "OSHA is not required to support its findings with anything approaching scientific certainty." The Court ruled that "a reviewing court [is] to give OSHA some leeway where its findings must be made on the frontiers of scientific knowledge [and that] * * * the Agency is free to use conservative assumptions in interpreting the data with respect to carcinogens, risking error on the side of overprotection rather than underprotection" (448 U.S. at 655, 656).
Nonetheless, OSHA has taken various steps that make it fairly confident its risk assessment methodology is not designed to be overly "conservative" (in the sense of erring on the side of overprotection). For example, there are several options for extrapolating human risks from animal data via interspecies scaling factors. The plausible factors range at least as widely as from body weight extrapolation at one extreme (risks equivalent at equivalent body weights, (mg/kg)(1)) to (body weight) (2/3) (risks equivalent at equivalent surface areas) at the other. Intermediate values have also been used, and the value of (body weight) (3/4), which is supported by physiological theory and empirical evidence, is generally considered to be the midpoint of the plausible values. (Body weight) (2/3) is the most conservative value in this series, while body weight extrapolation is the least conservative. OSHA has generally used body weight extrapolation in assessing risks from animal data, an approach that tends to be significantly less risk conservative than the other methodologies and is likely to be less conservative even than the central tendency of the plausible values.
Other steps in OSHA's risk assessment methodology where the Agency does not use the most conservative approach are selection of the maximum likelihood estimate (MLE) of the parameterized dose-response function rather than selection of the upper 95% confidence limit, and the use of site-specific tumor incidence, rather than pooled tumor response, in determining the dose-response function for a chemical agent.
Other aspects of OSHA's risk assessment methodology reflect more conservative choices, including: basing the risk estimate on the more sensitive species tested (the mouse); including lung tumors in the range of risks presented in the quantitative analysis, even though excess deaths from lung cancer have not been observed in any of the human studies; and, assuming workers will be exposed to butadiene at the maximum permissible level for 45 years. As discussed below, if workers are exposed to BD for fewer years, their estimated risks from BD will be less than indicated. This caveat, of course, does not address lifetime risks taking into account occupational exposure to other substances encountered at other jobs. For reasons already explained, OSHA believes these choices are appropriate for the BD risk assessment. OSHA also recognizes that use of the most conservative approach at every step of the risk assessment analysis could produce mathematical risk estimates which, because of the additive effect of multiple conservative assumptions, may overstate the likely risk. OSHA believes its quantitative risk assessment for BD strikes an appropriate balance.
Risk assessment is only one part of the process OSHA uses to regulate toxic substances in the workplace. OSHA's overall analytic approach to regulating occupational exposure to particular substances is a four-step process consistent with judicial interpretations of the OSH Act, such as the Benzene Decision, and rational policy formulation. In the first step, OSHA quantifies the pertinent health risks, to the extent possible, performing quantitative risk assessments. The Agency considers a number of factors to determine whether the substance to be regulated currently poses a significant risk to workers. These factors include the type of risk posed, the quality of the underlying data, the plausibility and precision of the risk assessment, the statistical significance of the findings and the magnitude of risk. (48 FR 1864, January 14, 1983) In the second step, OSHA considers which, if any, of the regulatory options being considered will substantially reduce the identified risks. In the third step, OSHA looks at the best available data to set permissible exposure limits that, to the extent possible, both protect employees from significant risks and are also technologically and economically feasible. In the fourth and final step, OSHA considers the most cost-effective way to fulfill its statutory mandate by crafting regulations that allow employers to reach the feasible PEL as efficiently as possible.
B. Review of Data Quality and Statistical Significance
As discussed in the Health Effects section, OSHA has concluded that butadiene is a probable human carcinogen. This conclusion is based on a body of evidence comprised of animal bioassays, human epidemiological investigations, and other experimental studies that together are both consistent in their findings and biologically plausible. First, OSHA has reviewed four rodent inhalation bioassays, two mouse bioassays conducted under the National Toxicology Program (designated NTP I and NTP II), a mouse study by Irons et al. in 1989, and a rat study sponsored by the IISRP. (Exs. 2-32, 23-1, 32-28D, 90, 96) All three mouse studies found a consistently high tumor response in BD-exposed mice, relative to control animals. Several target organs were identified, particularly by the NTP II study; however, all three studies found dose-related increases in the incidences of lymphocytic lymphoma and heart hemangiosarcomas associated with exposure to BD. Most significantly, the NTP II study reported statistically significant increases in tumor incidence among mice exposed to BD well below OSHA's current PEL of 1,000 ppm (exposure to as low as 6.25 ppm was associated with a statistically significant increase in tumors, e.g., lung tumors in female mice). There was also evidence for a dose-rate effect, meaning that the observed tumor incidence in mice exposed to high concentrations over short periods of time was higher than that observed in mice administered an equivalent cumulative concentration over a long period of time. The study employing BD-exposed rats also found increased incidences of several types of cancer, albeit at lower response rates than were observed in the mouse studies. The two major epoxide metabolites of BD have also been shown to be carcinogenic in rats and mice.
OSHA has also reviewed a number of human epidemiological studies that have examined the mortality experience of styrene-butadiene rubber (SBR) workers. These studies have consistently reported an elevated relative risk of leukemia-or lymphoma-related death among BD-exposed workers. The most recent of these, the study by Delzell et al., updated and expanded previous SBR worker mortality studies and found a positive and statistically significant dose-response relationship between cumulative exposure to BD and increased leukemia mortality, which remained statistically significant even after controlling for the potential confounder of concurrent styrene exposure. (Ex. 117-1) The Delzell et al. study thus provides further and more directly relevant evidence that an increased risk of leukemia-related death is associated with exposure to BD. Furthermore, other epidemiologic studies have reported finding an unusually short latency period (as little as 3 to 4 years from time of initial exposure to death) for exposure-related hematologic malignancies among workers who experienced exposures to BD in the past that were higher than exposures that prevail today. (Ex. 2-26, 3-34 Vol III H-1) Evidence for the carcinogenicity of BD is further strengthened by a collection of studies showing that the epoxide metabolites of BD are mutagenic in a wide variety of in vitro and in vivo test systems. Examination of cultured lymphocytes from BD-exposed workers has revealed the presence of chromosome aberrations, an elevated frequency of chromatid breaks, and various mutations, thereby providing direct evidence of genotoxicity in occupationally-exposed humans. (Exs. 118-2A, 118-2D) Furthermore, the finding of activated K-ras oncogenes in tumors of BD-exposed mice provides additional support for a mutagenic mode of action; this finding has particular relevance to human risk in that K-ras is the most commonly detected oncogene in human cancer. (Ex. 129) The findings from the animal bioassays and human epidemiologic studies identify the hematopoietic system as a primary target organ for BD-related carcinogenesis. Target organs for toxicity are not necessarily those for carcinogenicity. Other experimental findings are consistent with these observations. Studies in BD-exposed rodents have found concentration-dependent decreases in red blood cell counts, hemoglobin concentration, and other indicators of hematopoietic suppression. (Exs. 114, 32-38D, 23-12) There is also some suggestive evidence that workers exposed to BD at levels well below the current 1,000 ppm PEL exhibit hematological changes indicative of bone marrow depression. (Exs. 23-4, 2-28) Finally, many of the tumor types found in BD-exposed mice, including lymphocytic/hematopoietic cancer, lung cancer, mammary gland tumors, and possibly hemangiosarcomas, are tumors that are often found in association with exposure to other industrial chemicals known to cause lymphocytic/hematopoietic cancer in humans. Thus, OSHA finds that the body of scientific studies contained in the BD record, which includes well-conducted animal bioassays, human epidemiologic studies, and other experimental investigations, provides convincing evidence that BD is a probable human carcinogen.
This view is also held by other scientific organizations that have examined some or all of the same evidence. EPA considers BD to be a probable human carcinogen, and NIOSH regards BD as a potential occupational carcinogen and recommends controlling exposures to the lowest feasible level. In 1983, based on the findings of the first NTP bioassay alone, ACGIH classified BD as an animal carcinogen and, in the following year, recommended a new TLV of 10 ppm. In 1992, before the Delzell et al. study was released, IARC classified BD as a probable human carcinogen (Group 2A).
As discussed in the Quantitative Risk Assessment section, OSHA has selected the NTP II mouse bioassay for quantitative assessment of cancer risks for several reasons. Chief among these is that the NTP II study was conducted at BD concentrations that are representative of current exposure conditions and that the results demonstrated a strong dose-response relationship for several cancer sites. In addition, the study is of very high quality and pathology results from individual animals were available to the Agency, enabling OSHA to use a time-to-tumor model that could account for the early cancer-related deaths that occurred among the test animals (competing risks). OSHA also chose to base its risk estimates on the dose-response relationships for three cancer types: lung, ovarian, and lymphoma. The incidence of each was significantly elevated. It should be noted that pooling the total number of animals having any of these tumor types would have yielded risk estimates higher than OSHA's final values.
Because data were available on individual animals, including time of death, OSHA chose to use a Weibull time-to tumor form of the multistage model based on the biological assumption that cancer is induced by carcinogens through a series of events. This model has the advantage of accounting for competing risks.
The multistage model is most frequently used by OSHA; it is also a mechanistic model based on the biological assumption that cancer is induced by carcinogens through a series of independent stages. The model may be conservative, because it assumes no threshold for carcinogenesis and because it is approximately linear at low doses, although there are other plausible models of carcinogenesis which are more conservative. The Agency believes that the multistage model conforms most closely to what we know about the etiology of cancer, including the fact that linear-at-low-dose behavior is expected for exogenous agents, which increases the risk of cancer already posed by similar "background" processes. There is no evidence that the multistage model is biologically incorrect and abundant evidence supports its use, especially for genotoxic carcinogens, a category that most likely includes BD. OSHA's preference is consistent with the position of the Office of Science and Technology Policy of the Executive Office of the President, which recommends that "when data and information are limited, and when much uncertainty exists regarding the mechanisms of carcinogenic action, models or procedures that incorporate low-dose linearity are preferred when compatible with limited information." (OSTP, Chemical Carcinogens: A Review of the Science and Its Associated Principles. Federal Register, March 14, 1985, p. 10379) The BD record contained a great deal of commentary on the possible role of the principal epoxide metabolites of BD on the development of cancer in test animals, and on whether differences in BD metabolism, distribution, and excretion can explain the observed differences in cancer responses between BD-exposed mice and rats. In evaluating this information, OSHA explored the possibility of using a physiologically-based pharmacokinetic (PBPK) approach to estimate cancer risk among BD-exposed workers. In considering the use of PBPK modeling for estimating equivalent human dose in its final risk assessment for BD, OSHA considered several preselected criteria for judging whether the available data was adequate to permit OSHA to rely on a PBPK analysis in place of administered exposure levels. These are the same criteria that OSHA has recently used to rely on a PBPK-based analysis in its risk assessment of methylene chloride. The criteria included the following:
1. The predominant and all relevant minor metabolic pathways must be well described in several species, including humans.
4. The kinetics for the putative carcinogenic metabolic pathway must have been measured in test animals in vivo and in vitro and in corresponding human tissues at least in vitro.
5. The putative carcinogenic metabolic pathway must contain metabolites that are plausible proximate carcinogens.
6. The contribution to carcinogenesis via other pathways must be adequately modeled or ruled out as a factor.
7. The dose surrogate in target tissues used in PBPK modeling must correlate with tumor responses experienced by test animals.
8. All biochemical parameters specific to the compound, such as blood:air partition coefficients, must have been experimentally and reproducibly measured. This must especially be true for those parameters to which the PBPK model is sensitive.
9. The model must adequately describe experimentally measured physiological and biochemical phenomena.
10. The PBPK models must have been validated with other data (including human data) that were not used to construct the models.
11. There must be sufficient data, especially data from a broadly representative sample of humans, to assess uncertainty and variability in the PBPK modeling.
For the BD risk assessment, OSHA has chosen to use for animal-to-human dose equivalency mg/kg-day uptake based on the ppm exposure levels in the NTP II mouse study as the dose-metric.(7) While the body of data in the record leads OSHA to conclude that metabolism of BD to active metabolites is probably necessary for carcinogenicity, OSHA has chosen total body uptake rather than organ metabolic levels because the Agency was unable to determine from the record (a) which of the active metabolites are responsible for which observed tumors in the mice, (b) what the mouse and human metabolic equivalent doses were, (c) whether any of the PBPK models can successfully correlate with the tumor responses observed in mice and rats, and (d) whether local reactions in the mouse and human bone marrow were more important than total body burden. OSHA would have considered using BD metabolite body burden based on total human BD metabolites if the human chamber concentration data had been available, which would support estimating total human BD metabolism. Data of this type were available and used in OSHA's PBPK modeling for methylene chloride. In the absence of human chamber data or some better estimate of human equivalent dose, OSHA has chosen to use mg/kg-day BD uptake from the ppm inhalation exposure levels in the NTP II mouse bioassay as suitable for animal-to-human equivalency.
Footnote(7) A dose metric is the way in which dose is expressed in describing a dose-response relationship. A dose metric may be expressed as an applied dose, such as ppm concentration or mg of intake per kg body weight, or as an internal dose, such as mg per gram wet weight of an organ or mg of total metabolite formed per kg body weight.
C. Material Impairment of Health
The 1 ppm 8-hour TWA PEL is designed to reduce cancer risks among exposed workers. As mentioned above and in the Health Effects section, some epidemiological studies indicate that the increased risk of leukemia posed by BD exposure may occur within a short period after initial exposure. (This is supported by the NTP mouse bioassays, in which there was high early mortality resulting from the development of BD-induced cancers, especially lymphomas.) Therefore, OSHA believes these hematopoietic cancers are likely to be fatal, will result in substantially shortened worker lifespans, and clearly represent "material impairment of health" as defined in the OSH Act and case law.
OSHA has also concluded that exposure to BD is associated with a potential risk of adverse reproductive effects in both males and females. This conclusion is based on the two NTP animal bioassays, which found testicular atrophy in male mice exposed to 625 ppm BD and ovarian atrophy in female mice exposed to BD concentrations as low as 6.25 ppm, as well as other animal studies that have reported dominant lethal effects (indicating a genotoxic effect on germ cells) and abnormal sperm morphology in BD-exposed male mice. (Exs. 23-74, 23-75, 117-1) There is also evidence that BD exposure is associated with fetotoxicity in mice, and a teratogenic effect indicative of a transplacentally induced somatic cell mutation was observed in one mouse study. (Exs. 2-32, 23-72, 126) OSHA believes that teratogenic effects and gonadal atrophy would also unambiguously constitute "material impairment of health." Furthermore, although OSHA did not quantify reproductive risks that may be associated with exposure to BD, OSHA believes that reducing the 8-hour TWA PEL from 1,000 ppm to 1 ppm is likely to substantially reduce this risk.
D. Risk Estimates
OSHA's final estimate of excess cancer risks associated with exposure to 5 ppm BD (8-hour TWA) ranges from 11.2 to 59.4 per 1000, based on lymphomas, lung tumors and ovarian tumors seen in the NTP II mouse study (OSHA did not estimate the risks associated with exposure to the current PEL of 1,000 ppm, since workers are rarely, if ever, exposed to BD levels of that magnitude). Based on linear models the estimated risks at the new PEL of 1 ppm range from 1.3 to 8.1 per 1000, which represents a substantial reduction in risk from those associated with exposures to 5 ppm or greater.
OSHA's risk estimates for the 1 ppm PEL are similar in magnitude to, or lower than, most of the estimates contained in several risk assessments submitted to the BD record, which utilized a variety of models and dose metrics. Furthermore, NIOSH's quantitative assessment based on the Delzell et al. epidemiologic study of SBR workers yielded an estimate of 8 cancer deaths per 1,000 workers exposed to 1 ppm BD, a figure that is in close agreement with the upper end of the range of risks predicted by OSHA.
Risks greater than or equal to 10(-3) (1 per 1,000) are clearly significant and the Agency deems them unacceptably high. OSHA concludes that the new BD standard substantially lowers risk but does not reduce risk below the level of insignificance. The estimated levels of risk at 1 ppm are 1.3 to 8.1 per 1000. The ancillary provisions including the exposure goal program will further reduce risk from exposure to BD.
E. "Significant Risk" Policy Issues
Further guidance for the Agency in evaluating significant risk and narrowing the million-fold range described in the "Benzene Decision" is provided by an examination of occupational risk rates, legislative intent, and the academic literature on "acceptable risk" issues. For example, in the high risk occupations of mining and quarrying, the average risk of death from an occupational injury or an acute occupationally-related illness over a lifetime of employment (45 years) is 15.1 per 1,000 workers. The typical occupational risk of deaths for all manufacturing industries is 1.98 per 1,000. Typical lifetime occupational risk of death in an occupation of relatively low risk, like retail trade, is 0.82 per 1,000. (These rates are averages derived from 1984-1986 Bureau of Labor Statistics data for employers with 11 or more employees, adjusted to 45 years of employment, for 50 weeks per year).
Congress passed the Occupational Safety and Health Act of 1970 because of a determination that occupational safety and health risks were too high. Congress therefore gave OSHA authority to reduce significant risks when it is feasible to do so. Within this context, OSHA's final estimate of risk from occupational exposure to BD at levels of 2 ppm (2.5 to 16.2 deaths per 1,000 workers) or higher is substantially higher than other risks that OSHA has concluded are significant, is substantially higher than the risk of fatality in some high-risk occupations, and is substantially higher than the example presented by the Supreme Court in the benzene case. Moreover, a risk in the range of 1.3 to 8.1 per 1000 at 1 ppm is also clearly significant; therefore, the PEL must be set at least as low as the level of 1 ppm documented as feasible across all industries.
Because of technologic feasibility considerations, OSHA could not support promulgating a PEL below 1 ppm. However OSHA has integrated other protective provisions into the final standard to further reduce the risk of developing cancer among employees exposed to BD.
Based on OSHA's QRA, employees exposed to BD at the 8-hour TWA PEL limit, without the benefit of the supplementary provisions, would remain at significant risk of developing adverse health effects, so that inclusion of other protective provisions, such as medical surveillance and employee training, is both necessary and appropriate. The exposure goal program and action level trigger incorporated into the standard will encourage employers to lower exposures below 0.5 ppm to further reduce significant risk if it is feasible to do so in their workplaces. Consequently, the programs triggered by the action level will further decrease the incidence of disease beyond the predicted reductions attributable merely to a lower PEL.
As OSHA has explained, numerous issues arise in quantifying estimated risk to workers from BD. Such estimates are thus inherently uncertain; and, as more information becomes available, some of that uncertainty may be addressed and may substantially alter the risk estimate. Although OSHA believes the estimates fulfill its legal obligation to provide substantial evidence of significant risk the estimates should not be interpreted as a precise quantification of the cancer risk associated with the new PEL, or as demonstrated evidence of actual worker disease caused by BD.
OSHA's determination of significant risk is predicated, consistent with empirical evidence and the legal mandates of the OSHA Act, on determining the risk to a worker exposed to BD for a working lifetime (45 years) at the PEL. To the extent that future exposures to BD are (substantially) lower than 1 ppm, the estimated risks associated with those exposures will be (substantially) lower than the range presented in OSHA's QRA.
OSHA believes the final standard will reduce the risks of BD below those estimated using the mathematical model. The estimates of risk consider only exposures at the PEL, and do not take fully into account the other protective provisions of the standard such as medical surveillance, hazard communication, training, monitoring, and the exposure goal program. The decrease in risk to be achieved by additional provisions cannot be adequately quantified beyond a determination that they will add to the protection provided by the lower PEL alone. OSHA has determined that employers who fulfill the provisions of the standard as promulgated will provide protection for their employees from the hazards presented by occupational exposure to BD well beyond those which would be indicated solely by reduction of the PEL.
Furthermore, as discussed above and in the Health Effects section, there is evidence from the NTP bioassays that exposure to periodic high concentrations of BD may be associated with a higher cancer risk compared to an equivalent cumulative exposure administered over a longer time frame. OSHA has included a 5 ppm short-term exposure limit (STEL), averaged over 15 minutes, to provide protection to employees who are exposed to elevated BD concentrations during brief periods, such as in maintenance work.
As a result, OSHA concludes that its 8-hour TWA PEL of 1 ppm and associated action level (0.5 ppm) and STEL (5 ppm) will reduce significant risk and that employers who comply with the other provisions of the standard will be taking feasible, reasonable, and necessary steps to help protect their employees from the hazards of BD.
Regulations (Preambles to Final Rules) - Table of Contents|