1,3-Butadiene: I. Review of metabolism and the implications to human health risk assessment.

1,3-Butadiene (BD) is a multisite carcinogen in laboratory rodents following lifetime exposure, with mice demonstrating greater sensitivity than rats. In epidemiology studies of men in the styrene-butadiene rubber industry, leukemia mortality is associated with butadiene exposure, and this association is most pronounced for high-intensity BD exposures. Metabolism is an important determinant of BD carcinogenicity. BD is metabolized to several electrophilic intermediates, including epoxybutene (EB), diepoxybutane (DEB), and epoxybutane diol (EBD), which differ considerably in their genotoxic potency (DEB >> EB > EBD). Important species differences exist with respect to the formation of reactive metabolites and their subsequent detoxification, which underlie observed species differences in sensitivity to the carcinogenic effects of BD. The modes of action for human leukemia and for the observed solid tumors in rodents are both likely related to the genotoxic potencies for one or more of these metabolites. A number of factors related to metabolism can also contribute to nonlinearity in the dose-response relationship, including enzyme induction and inhibition, depletion of tissue glutathione, and saturation of oxidative metabolism. A quantitative risk assessment of BD needs to reflect these species differences and sources of nonlinearity if it is to reflect the current understanding of the disposition of BD.