EPIDEMIOLOGIC AND MECHANISTIC DATA SUGGEST THAT 1,3-BUTADIENE WILL NOT BE CARCINOGENIC TO HUMANS AT EXPOSURES LIKELY TO BE ENCOUNTERED IN THE ENVIRONMENT OR WORKPLACE

1,3-Butadiene (BD) is a carcinogen in both rats and mice with mice bei ng substantially more sensitive than rats. It is not known if BD poses a carcinogenic risk for humans. Findings from exposure assessment stu dies indicate that potential industrial exposure to BD in monomer, pol ymer, and end-user industries is typically <2 p.p.m. Epidemiologic stu dies of persons occupationally exposed to BD are inconclusive. In vitr o metabolism of BD in rats, mice and human tissues indicate that there are significant quantitative species differences in the metabolic act ivation of BD to butadiene monoepoxide (BMO) and butadiene diepoxide ( BDE) and the detoxication of BMO. Activation/detoxication ratios calcu lated 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 providi ng a strong argument for why mice are highly sensitive to BD carcinoge nicity. The fact that human tissues do not appear to metabolize BMO to BDE to any significant extent suggest that humans may not be sensitiv e 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 lymphob lasts at concentrations that were 100-fold less than the concentration of BMO required to yield a similar mutation frequency. Importantly, t he concentrations of BDE that were genotoxic in vitro are nearly ident ical to the concentrations of BDE measured in blood and tissues of mic e exposed to BD by inhalation. BD is genotoxic in mice, but not rats, following inhalation exposure and this is paralleled by species differ ences in observed tumor susceptibility. BD is not genotoxic in occupat ionally-exposed workers. The genetic basis for BD carcinogenicity appe ars to be primarily through induction of point mutations and deletion events mediated via the potent genotoxic metabolite, BDE. The genotoxi c endpoints induced by BDE (e.g., deletion and point mutations) rather than BMO (e.g., point mutations) likely represent the underlying mech anism responsible for the striking species differences observed in the genotoxicity and carcinogenicity of BD in mice versus rats. In summar y, the preponderance of evidence which includes both epidemiological a nd mechanistic data in mice, rats, and humans strongly suggests that B D wilt not be carcinogenic to humans at occupational or environmental exposures. Any cancer risk assessment for BD should use in vitro human tissue metabolic data and in vitro and in vivo rat data for estimatio n of human cancer risks.