A review of the genetic and related effects of 1,3-butadiene in rodents and humans

In this paper, the metabolism and genetic toxicity of 1,3-butadiene (BD) an d its oxidative metabolites in humans and rodents is reviewed with attentio n to newer data that have been published since the latest evaluation of ED by the International Agency for Research on Cancer (IARC). The oxidative me tabolism of ED in mice, rats and humans is compared with emphasis on the ma jor pathways leading to the reactive intermediates 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBdiol). Result s from recent studies of DNA and hemoglobin adducts indicate that EBdiol ma y play a more significant role in the toxicity of ED than previously though t. All three metabolites are capable of reacting with macromolecules, such as DNA and hemoglobin, and have been shown to induce a variety of genotoxic effects in mice and rats as well as in human cells in vitro. DEE is clearl y the most potent of these genotoxins followed by EB, which in turn is more potent than EBdiol. Studies of mutations in lacI and lacZ mice and of the Hprt mutational spectrum in rodents and humans show that mutations at G:C b ase pairs are critical events in the mutagenicity of BD. In-depth analyses of the mutational spectra induced by ED and/or its oxidative metabolites sh ould help to clarify which metabolite(s) are associated with specific mutat ions in each animal species and which mutational events contribute to ED-in duced carcinogenicity. While the quantitative relationship between exposure to ED, its genotoxicity, and the induction of cancer in occupationally exp osed humans remains to be fully established, there is sufficient data curre ntly available to demonstrate that 1,3-butadiene is a probable human carcin ogen. Published by Elsevier Science B.V.