Toxicology of 1,3-butadiene, chloroprene, and isoprene

Abstract

The diene monomers, 1,3-butadiene, chloroprene, and isoprene, respectively, differ only in substitution of a hydrogen, a chlorine, or a methyl group at the second of the four unsaturated carbon atoms in these linear molecules. Literature reviewed in the preceding sections indicates that these chemicals have important uses in synthesis of polymers, which offer significant benefits within modern society. Additionally, studies document that these monomers can increase the tumor formation rate in various organs of rats and mice during chronic cancer bioassays. The extent of tumor formation versus animal exposure to these monomers varies significantly across species, as well among strains within species. These studies approach, but do not resolve, important questions of human risk from inhalation exposure. Each of these diene monomers can be activated to electrophilic epoxide metabolites through microsomal oxidation reactions in mammals. These epoxide metabolites are genotoxic through reactions with nucleic acids. Some of these reactions cause mutations and subsequent cancers, as noted in animal experiments. Significant differences exist among the compounds, particularly in the extent of formation of highly mutagenic diepoxide metabolites, when animals are exposed. These metabolites are detoxified through hydrolysis by epoxide hydrolase enzymes and through conjugation with glutathione with the aid of glutathione S-transferase. Different strains and species perform these reactions with varying efficacy. Mice produce these electrophilic epoxides more rapidly and appear to have less adequate detoxification mechanisms than rats or humans. The weight of evidence from many studies suggests that the balance of activation versus detoxification offers explanation of differing sensitivities of animals to these carcinogenic actions. Other aspects, including molecular biology of the many processes that lead through specific mutations to cancer, are yet to be understood. Melnick and Sills (2001) compared the carcinogenic potentials of these three dienes, along with that of ethylene oxide, which also acts through an epoxide intermediate. From the number of tissue sites where experimental animal tumors were detected, butadiene offers greatest potential for carcinogenicity of these dienes. Chloroprene and then isoprene appear to follow in this order. Comparisons among these chemicals based on responses to external exposures are complicated by differences among studies and of species and tissue susceptibilities. Physiologically based pharmacokinetic models offer promise to overcome these impediments to interpretation. Mechanistic studies at the molecular level offer promise for understanding the relationships among electrophilic metabolites and vital genetic components. Significant improvements in minimization of industrial worker exposures to carcinogenic chemicals have been accomplished after realization that vinyl chloride caused hepatic angiosarcoma in polymer production workers (Creech and Johnson 1974; Falk et al. 1974). Efforts continue to minimize disease, particularly cancer, from exposures to chemicals such as these dienes. Industry has responded to significant challenges that affect the health of workers through efforts that minimize plant exposures and by sponsorship of research, including animal and epidemiological studies. Governmental agencies provide oversight and have developed facilities that accomplish studies of continuing scientific excellence. These entities grapple with differences in perspective, objectives, and interpretation as synthesis of knowledge develops through mutual work. A major challenge remains, however, in assessment of significance of environmental human exposures to these dienes. Such exposure levels are orders of magnitude less than exposures studied in experimental or epidemiological settings, but exposures may persist much longer and may involve unknown but potentially significant sensitivities in the general population. New paradigms likely will be needed for toxicological evaluation of these human exposures, which are ongoing but as yet are not interpreted.