Regulations (Preambles to Final Rules) - Table of Contents|
| Record Type:||Occupational Exposure to Methylene Chloride|
| 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 a 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." The Court added that the significant risk determination required by 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 "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 from body weight extrapolation (risks equivalent at equivalent body weights) to (body weight)(2/3) (risks equivalent at equivalent surface areas). 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. Body weight extrapolation is the least conservative. OSHA has generally used body weight extrapolation in assessing risks from animal data, our approach which tends to be significantly less conservative than the other methodologies and most likely is less conservative even than the central tendency of the plausible values.
Other examples in OSHA's risk assessment methodology where the Agency does not use a conservative approach are selection of the maximum likelihood estimator to parameterize the dose-response function rather than 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.
OSHA's overall analytic approach to regulating occupational exposure to particular substances is a four-step process consistent with recent court interpretations of the OSH Act, such as the Benzene decision, and rational, objective 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 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
The former OSHA standard for MC was designed to prevent irritation and injury to the neurological system of the employees exposed to MC. In 1985, the National Toxicology Program (NTP) released the results of their MC rodent lifetime bioassays. Those results indicated that MC is carcinogenic to rats and mice. As discussed in the Events Leading to the Final Standard section, based on the NTP findings, EPA now considers MC a probable human carcinogen, and NIOSH regards MC as a potential occupational carcinogen and recommends controlling the exposure to MC to the lowest feasible level. In 1988, ACGIH classified MC as an industrial substance suspected of carcinogenic potential for humans.
As discussed in the Health Effects section, OSHA has determined, based on the NTP data, that MC is a potential occupational carcinogen. This conclusion is supported by high-quality data in both rodent species. Having determined, as discussed in the Quantitative Risk Assessment section, that the NTP study provided suitable data for quantitative analysis, OSHA performed quantitative risk assessments to determine if MC exposure at the current PEL presents a significant risk.
As discussed in the Health Effects and Quantitative Risk Assessment sections, OSHA evaluated four MC rodent bioassays [Exs. 4-35, 4-25, 7-29, 7-30, 7-31] to select the most appropriate bioassay as the basis for a quantitative risk assessment. These bioassays were conducted in three rodent species (rat, mouse, and hamster) using two routes of administration (oral and inhalation). The NTP study (rat and mouse, inhalation) was chosen for a quantitative risk assessment because it provides the clearest toxicological and statistical evidence of the carcinogenicity of MC [Exs. 12, 7-127] and because the studies were of the highest data quality. In the NTP study, MC induced significant increases both in the incidence and multiplicity of alveolar/bronchiolar and hepatocellular neoplasms in male and female mice. In rats, dose-related, statistically significant increases in mammary tumors were also observed. OSHA chose the female mouse tumor response as the basis of its quantitative risk assessment, because of the high quality of data, the clear dose response of liver and lung tumors and the low background tumor incidence. OSHA chose female mouse lung tumors as the specific tumor site for its final quantitative risk assessment. There is no a priori reason to prefer the mouse lung tumor response over the liver tumor response because both data sets were of high quality, showed a clear dose-response relationship and had low background tumor incidence. In fact, in the NPRM, the Agency reported estimates of risk generated using both sites. However, to reduce the complexity of the final PBPK analysis, which required highly intensive computations, OSHA chose one site (the female mouse lung tumor response) for its final risk estimates. The risks calculated using the female mouse liver response would likely be only slightly lower than those calculated using the lung tumor response. On the other hand, pooling the total number of tumor-bearing animals having either a lung or liver tumor (or both) would have yielded risk estimates higher than OSHA's final values.
Once the alveolar/bronchiolar neoplasms in female mice were chosen as the most appropriate data set, the multistage model of carcinogenesis was used to predict a lifetime excess risk of cancer from occupational exposure to MC at several concentration levels. The multistage model is a mechanistic model based on the biological assumption that cancer is induced by carcinogens through a series of stages. The model may be conservative, in the sense that it risks error on the side of overprotection rather than underprotection, 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 this model conforms most closely to what we know of the etiology of cancer. There is no evidence that the multistage model is biologically incorrect, especially for genotoxic carcinogens, which MC most likely is. OSHA's preference is consistent with the position of the Office of Science and Technology Policy 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" [Ex. 7-227].
In the NPRM, OSHA solicited comment and testimony on the application of physiologically-based pharmacokinetic (PBPK) modeling to refine the MC risk assessment. There was an intensive discussion of pharmacokinetic issues during the hearings and in comments and briefs submitted to OSHA. PBPK modeling is used to account for metabolic and pharmacokinetic differences between rodents and humans and when extrapolating from high experimental doses to lower occupational exposures. OSHA has evaluated several risk assessments produced using pharmacokinetic models. Discussion of the major issues surrounding the use of PBPK in risk assessment can be found in the Quantitative Risk Assessment section. Although serious questions remain concerning the application of these models in the MC risk assessment, the Agency has used the estimates generated via PBPK modeling as its final estimate of the carcinogenic risk of MC exposure.
In accepting PBPK analysis, the Agency wanted to be able to utilize all of the data available and appropriate for the analysis. OSHA was also concerned that the uncertainties and inter-individual variabilities in PBPK models were insufficiently quantified to allow analysis of the impact of those uncertainties on the risk. Several rulemaking participants have conducted sensitivity and uncertainty analyses, the most extensive of which was that submitted by Mr. Harvey Clewell on behalf of the U.S. Navy. These analyses show the impact of the variability and uncertainty of the parameters which are used in the PBPK model and suggest methods of quantifying the impact of that uncertainty on the risk estimates.
OSHA has determined that the PBPK data are of sufficient weight to warrant reliance on PBPK modeling to develop a risk estimate in the specific case of MC, a chemical with more extensive information on metabolism than exists for most other substances. To that end, OSHA adopted a Bayesian approach in which all of the physiological and MC-specific data could be used to generate a distribution of estimates of the carcinogenic risks of MC. OSHA used the mean and the upper 95th percentile estimator of the distribution of human PBPK parameters, coupled with the maximum likelihood estimator of cancer potency, to generate its final estimates of risks.
As discussed in more detail in the Health Effects Section above, human data concerning the carcinogenicity of MC were presented in several epidemiology studies. In a study of cellulose triacetate fiber production (MC used as solvent) workers, an increased incidence of liver/biliary cancer [Ex. 7-260] was noted. Although the case numbers were small and the exposure information limited, this epidemiological evidence is consistent with findings from animal studies and indicates that there may be an association between human cancer risk and MC exposure. A study of workers in photographic film production was non-positive [7-163]. However, the exposures experienced by these workers were likely to have been much less than those in the cellulose triacetate fiber plant and, as discussed in the quantitative risk assessment section, the study lacked the power to detect the magnitude of the increase in cancer deaths that would have been predicted given only the bioassay results. A case-control study conducted by the National Cancer Institute showed a statistically significant association between occupational MC exposure and development of astrocytic brain cancer. Exposure levels could not be determined in this study. The results of the epidemiological studies summarized here were not inconsistent with the results of the animal-based cancer potency estimate.
C. Material Impairment of Health
MC is a potential occupational carcinogen. Cancer is a material impairment of health. OSHA has set the 8-hour TWA PEL primarily to reduce the risk to employees of developing cancer.
The STEL of 125 ppm averaged over 15 minutes is primarily designed to protect against MC's non-cancer risks. As discussed in the Health Effects section, there are substantial risks of CNS effects and cardiac toxicity resulting from acute exposure to MC and its metabolites. CNS effects have been demonstrated in workers at concentrations as low as 175 ppm [Ex. 7-153] and a STEL of 125 ppm for 15 minutes would thus be protective against the CNS effects described. Metabolism of MC to CO increases the body burden of COHb in exposed workers. Levels of COHb above 3% COHb may exacerbate angina symptoms and reduce exercise tolerance in workers with silent or symptomatic heart disease. Smokers are at higher risk for these effects because of the already increased COHb associated with smoking (COHb ranges from 2 to 10% in most smokers). Limiting short term exposure to 125 ppm for 15 minutes will keep COHb levels due to MC exposure below the 3% level, protecting the sub-population of workers with silent or symptomatic heart disease and also limiting the additional COHb burden in smokers.
In addition to protecting against CNS and cardiac effects, there is evidence that reducing the GST metabolite production by reducing short term exposure to high concentrations of MC may also lower the cancer risk. This is because metabolism by the MFO pathway (not generally believed to be associated with carcinogenesis) appears to saturate beginning around 100 ppm. This means that exposure to higher concentrations of MC would lead to increased metabolism by the GST pathway (the putative carcinogenic pathway) and therefore, greater than proportionally increased risk.
All of the health effects averted by reducing MC exposure are potentially or likely to be fatal, and this clearly represents "material impairment of health" as defined by the OSH Act and case law.
D. Risk Estimates
OSHA's final estimate of excess cancer risks at the current PEL of 500 ppm (8-hour TWA) is 126 per 1000. The risk at the new PEL of 25 ppm is 3.62 per 1000. The risk at 25 ppm is similar to the risk estimated in OSHA's preliminary quantitative risk assessment based on applied dose of MC on a mg/kg/day basis (2.3 per 1000 workers) and clearly supports a PEL of 25 ppm. Risks greater than or equal to 10(-3) are clearly significant and the Agency deems them unacceptably high. However, OSHA did not collect the data necessary to document the feasibility of a PEL below 25 ppm across all affected industry sectors, and so the Agency has set the PEL at 25 ppm in the final rule. OSHA intends in the future to gather more information pertaining to the feasibility of lower PELs.
E. "Significant Risk" Policy Issues
Further guidance for the Agency in evaluating significant risk and narrowing the million-fold range provided 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 MC at the current 8-hour TWA PEL (126 per 1000) 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. Moreover, a risk of 3.62 per 1000 at 25 ppm is also clearly significant; therefore, the PEL must be set at least as low as the level of 25 ppm documented as feasible across all industries.
Further, applying the rationale of the Benzene decision, the other risk assessments presented by OSHA and the risk estimates presented by rulemaking participants, including the HSIA (see Table VII-1, below), all support OSHA's conclusion that the human cancer risk for employees exposed to MC above 25 ppm as an 8-hour TWA is significant.
Table VII-1. -- Lifetime Excess Risk Estimates (per 1000) From Occupational Exposure Based on Female Mouse Lung Tumor Data ______________________________________________________________________ | MLE (UCL)(**) Model |________________________________________ | 25 ppm | 50 ppm | 500 ppm _____________________________|_____________|____________|_____________ OSHA NPRM Risk Assessment | 2.32 (2.97) | 4.64 (5.92)| 45.5 (57.7) (mg/kg/d, BW extrapolation) | | | without PBPK Adjustment. | | | PPM to PPM extrapolation | 11.3 (14.4) | 22.4 (28.5)| 203 (251) without PBPK Adjustment. | | | PBPK Reitz female mouse | 0.43 (0.53) | 0.93 (1.17)| 14.3 (17.9) lungs -- Reitz human | | | (HSIA assumptions). | | | PBPK Reitz female mouse | 0.81 (1.02) | 1.69 (2.12)| 15.0 (18.7) lung -- Dankovic average | | | human (NIOSH assumptions). | | | PBPK Clewell female mouse | 0.91 (1.14) | 1.88 (2.36)| 27.5 (34.2) lung -- Clewell human | | | (Navy assumptions)(*). | | | OSHA Final Risk Assessment | 3.62........| 7.47.......| 125.8 (femal mouse lung with | | | PBPK). | | | _____________________________|_____________|____________|_____________ Footnote(*) Upper 95th percentile of the GST metabolites distribution was used as input in the multistage model. Footnote(**) Maximum likelihood estimates are 95th percentile upper confidence limit (in parentheses) of the multistage dose-response function.
In addition to being 100 to 1000 times higher than the risk levels generally regarded by other Federal Agencies as on the boundary between significant and insignificant risk (see, e.g., Travis et al., 1987), and 1000 times higher than the "acceptable risk" level Congress set in the 1990 Clean Air Act Amendments, the level of 10(-3) is within the range where economic studies document a marked nonlinearity. In other words, individuals regard risks this high as qualitatively different from "smaller" risks. Although risks below 10(-3) are not unambiguously significant, depending on the size of the affected population, the benefits associated with the risky activity, and other factors, this policy determination is not relevant to this regulation, since OSHA's final risk estimate is substantially greater than 1 per 1000. Risks at or above 10(-3) are always significant by any empirical, legal or economic argument available.(2)
Footnote(2) OSHA also conducted an alternative PBPK analysis that uses all of the available human data on MC metabolism, despite the very limited quantity of data available and the additional bias introduced by adopting the "parallelogram" assumptions for interspecies scaling (see Quantitative Risk Assessment for a discussion of this analysis and the uncertainties and biases therein). The risk estimate using this alternative method, 1.2 per 1000, is also unambiguously significant.
Because of the lack of documented feasibility data for potential PELs of less than 25 ppm, OSHA has concluded that there is not enough information available to support lowering the 8-hour TWA PEL or STEL further at this time. However, OSHA has integrated other protective provisions into the final standard to further reduce the risk of developing cancer among employees exposed to MC. Employees exposed to MC at the 8-hour TWA PEL limit without the supplementary provisions would remain at 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 action level will encourage those employers for whom it is feasible to do so to lower exposures below 12.5 ppm to further reduce significant risk. 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 a result, OSHA concludes that its 8-hour TWA PEL of 25 ppm and associated action level (12.5 ppm) and STEL (125 ppm) will reduce significant risk and that employers who comply with the provisions of the standard will be taking reasonable steps to protect their employees from the hazards of MC.
The Agency notes that even at the final PELs, the risks to workers remain clearly significant. OSHA will be gathering information on the risks of, and feasibility of compliance with, PELs less than 25 ppm, to determine whether future rulemaking is appropriate in order to further reduce the MC risks to employees.
- [62 FR 1494, January 10, 1997]
|Regulations (Preambles to Final Rules) - Table of Contents|