Assessment of the Potential Risk to Workers from Exposure to 1,3-Butadiene

Abstract

The available epidemiologic data provide equivocal evidence that 1,3-butadiene is carcinogenic in humans; some available studies suggest that the lymphopoietic system is a target, but there are inconsistencies among studies in the types of tumors associated with 1,3-butadiene exposure, and there is no evidence of a relationship between length of exposure and cancer risk, as one might expect if there was a true causal relationship between 1,3-butadiene exposure and cancer risk. The available chronic animal studies, however, show an increase in tumor incidence associated with exposure to high concentrations of 1,3-butadiene. In addition to the general uncertainty ofthe relevance of animal data to humans, there are several additional reasons why the National Toxicology Program's mouse study may not be appropriate for assessing possible human risks. These include: a) the possible involvement of a species-specific tumor virus (MuLV) in the response in mice; b) apparent differences between mice and humans in the rate of metabolism of 1,3-butadiene to reactive epoxides that may be proximate carcinogens; c) use of high dose levels that caused excess early mortality; and d) exposure of animals to 1,3-butadiene for only about half their lifetime. While recognizing the uncertainty in using the available animal data for risk assessment, we have performed low-dose extrapolation ofthe data to examine the implications of the data if humans were as sensitive as rats or mice to 1,3-butadiene, and to examine how the predictions of the animal data compare to that observed in the epidemiologic studies. With the mouse data, because the study was of less than lifetime duration, we have used the Hartley-Sielken time-to-tumor model to permit estimation of lifetime risk from the less than lifetime exposure of the study. With the rat data, we have used three plausible models for assessing low-dose risk: the multistage model, the Weibull model, and the Mantel-Bryan probit model. With both the rat and mouse data, we used information on how much 1,3-butadiene is retained by animals exposed to various concentrations of the chemical. This improves the accuracy of the low-dose extrapolation. When extrapolated to low-dose levels, mice appear to be at greater risk (by a factor of 5-fold to 40-fold) than rats. Some of this difference (a factor 3-fold to 5-fold) may be due to the faster rate of metabolism of 1,3-butadiene to, and higher blood levels of, epoxide derivatives in mice than in rats. If humans, rats, and mice were at equal risk from equal average lifetime daily doses of retained 1,3-butadiene, the mouse and rat data would predict risks to occupationally exposed humans that are statistically inconsistent at the 95% level with the results of the available human data, unless human exposure in the past was very much lower than is believed to have been the case.

Cancer risk assessment of 1,3-butadiene.

“…The modeled exposure concentrations appears to be consistent with monitored off-site concentrations. Modeled estimates of fenceline concentrations and occupational monitoring of fenceline concentrations are also similar (30,31).…”

Using Epidemiological Studies to Check the Consistency of the Cancer Risks Predicted by High‐Dose Animal Experiments: A Methodological Review

“…For example, Turnbull et al (14) found only limited consistency when they compared animal results to the largest of three cohorts with exposure to 1,3-butadiene. The chosen study, (16) however, was the only one of the three that did not report an overall excess of lymphatic or hematopoietic cancer.…”

“…(14) In these instances, the exposure of concern has generally caused cancer at more than one site in rodents. We believe that the rationale for such a comparison is weak, because a single chemical exposure only occasionally produces excess tumors at multiple sites in people and rarely or never at all sites.…”

“…Other investigators have calculated predictions for both rats and mice, in order to give a range of possible values. (6,14) Recommendation: Comparing to one "key" rodent study is a reasonable approach and the only practical choice when direct validation of a regulatory guidance value is the goal. Presenting results from both rats and mice is appropriate when suitable results from both species are available and when there is no clear scientific consensus as to the most appropriate species to use for predicting risks to people.…”

On cancer risk estimation of urban air pollution

“…For that reason risk estimation from animal tests should be based on the doses of essential metabolites measured in both animal models and humans. For these reasons criticism of risk estimation of butadiene from experimental data is well-founded, particularly since comparison with epidemiological data indicate that such extrapolation leads to erroneous values (106).…”