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. 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.
| Hong, H H; Devereux, T R; Melnick, R L et al. (2000) Mutations of ras protooncogenes and p53 tumor suppressor gene in cardiac hemangiosarcomas from B6C3F1 mice exposed to 1,3-butadiene for 2 years. Toxicol Pathol 28:529-34 |
| Sills, R C; Hong, H L; Melnick, R L et al. (1999) High frequency of codon 61 K-ras A-->T transversions in lung and Harderian gland neoplasms of B6C3F1 mice exposed to chloroprene (2-chloro-1,3-butadiene) for 2 years, and comparisons with the structurally related chemicals isoprene and 1,3-butadiene. Carcinogenesis 20:657-62 |
| Melnick, R L; Sills, R C; Portier, C J et al. (1999) Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in mice. Carcinogenesis 20:867-78 |
