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1,3-Butadiene (BD) is a carcinogen in both rats and mice with mice being substantially more sensitive than rats. It is not known if BD poses a carcinogenic risk for humans. Findings from exposure assessment studies indicate that potential industrial exposure to BD in monomer, polymer, and end-user industries is typically < 2 p.p.m. Epidemiologic studies of persons occupationally exposed to BD are inconclusive. In vitro metabolism of BD in rats, mice and human tissues indicate that there are significant quantitative species differences in the metabolic activation of BD to butadiene monoepoxide (BMO) and butadiene diepoxide (BDE) and the detoxication of BMO. Activation/detoxication ratios calculated using in vitro kinetic constants reveal that ratios in mice were 12-fold greater than rats and humans. In rats and mice exposed to BD, concentrations of BMO in blood and tissues of mice were up to 14-fold higher than in rats and BDE was only detected in mice thereby providing a strong argument for why mice are highly sensitive to BD carcinogenicity. The fact that human tissues do not appear to metabolize BMO to BDE to any significant extent suggest that humans may not be sensitive to BD carcinogenicity. In mice, BDE is a more potent carcinogen than BMO. BDE is mutagenic in vitro at the hprt locus in human TK6 lymphoblasts at concentrations that were 100-fold less than the concentration of BMO required to yield a similar mutation frequency. Importantly, the concentrations of BDE that were genotoxic in vitro are nearly identical to the concentrations of BDE measured in blood and tissues of mice exposed to BD by inhalation. BD is genotoxic in mice, but not rats, following inhalation exposure and this is paralleled by species differences in observed tumor susceptibility. BD is not genotoxic in occupationally-exposed workers. The genetic basis for BD carcinogenicity appears to be primarily through induction of point mutations and deletion events mediated via the potent genotoxic metabolite, BDE. The genotoxic endpoints induced by BDE (e.g., deletion and point mutations) rather than BMO (e.g., point mutations) likely represent the underlying mechanism responsible for the striking species differences observed in the genotoxicity and carcinogenicity of BD in mice versus rats.(ABSTRACT TRUNCATED AT 400 WORDS)