1,3-Butadiene: II. Genotoxicity profile

Abstract

1,3-Butadiene’s (BD’s) major electrophilic metabolites 1,2-epoxy-3-butene (EB), 1,2-dihydroxy-3,4-epoxybutane (EBD), and 1,2,3,4-diepoxybutane (DEB) are responsible for both its mutagenicity and carcinogenicity. EB, EBD, and DEB are DNA reactive, forming a variety of adducts. All three metabolites are genotoxic in vitro and in vivo, with relative mutagenic potencies of DEB >> EB > EBD. DEB also effectively produces gene deletions and chromosome aberrations. BD’s greater mutagenicity and carcinogenicity in mice over rats as well as its failure to induce chromosome-level mutations in vivo in rats appear to be due to greater production of DEB in mice. Concentrations of EB and DEB in vivo in humans are even lower than in rats. Although most studies of BD-exposed humans have failed to find increases in gene mutations, one group has reported positive findings. Reasons for these discordant results are examined. BD-related chromosome aberrations have never been demonstrated in humans except for the possible production of micronuclei in lymphocytes of workers exposed to extremely high levels of BD in the workplace. The relative potencies of the BD metabolites, their relative abundance in the different species, and the kinds of mutations they can induce are major considerations in BD’s overall genotoxicity profile.