MECHANISTIC STUDIES ON 1,3-BUTADIENE AND RELATED EPOXIDE-FORMING CHEMICALS

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Summary of Work: Inhalation carcinogenicity studies on two structural analogues of 1,3-butadiene, isoprene (2-methyl-1,3-butadiene) and chloroprene (2-chloro-1,3-butadiene), demonstrated multiple-organ carcinogenic effects including several sites that were targets of 1,3- butadiene carcinogenicity. Multiple research approaches have been taken to understand and quantify the effects of epoxide-forming chemicals that contribute to the carcinogenicity of this family of chemicals. Analyses of genetic alterations in ras protooncogenes in neoplasms induced by these chemicals revealed a predominance of A to T transversions at K-ras codon 61. Rate constants of the reactivity of specific epoxides (including the two epoxide intermediates of butadiene metabolism) with DNA and the kinetics of spontaneous release of epoxide-DNA adducts were determined. Using literature data, three PBPK models differing in their degree of anatomical detail were constructed and used to predict uptake of 1,3-bautadiene from closed chambers. Only when blood was distributed among arteries, veins, and tissue capillary beds would the model accurately reproduce the data, suggesting that the common assumption of flow-limited delivery to tissues may not be appropriate for this compound. The successful variant butadiene model was improved by accounting for a transient complex formed between the cytochrome P450 enzyme that produces epoxybutene and epoxide hydrolase, the enzyme that cartalyzes the hydolysis of this mutagenic intermedaite. This complex enhances the metabolic elimination of epoxybutene and corrected the over-prediction of blood epoxide concentrations that were predicted by less detailed models. A physiologically based toxicokinetic model of inhaled isoprene was constructed to provide an appropriate measure of dose for evaluations tumor dose-response data of isoprene in rats. Dose-response modeling of survival adjusted tumor data demonstrated that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene. - epoxides, carcinogenesis, DNA reactivity, depurination, ras protooncogenes, DNA repair, 1,3-butadiene, chloroprene, isoprene, ethylene oxide