Assessment of the potential risk to workers from exposure to 1,3-butadiene

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 of the 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 of the 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.(ABSTRACT TRUNCATED AT 400 WORDS)