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) and its oxidative metabolites in humans and rodents is reviewed with attention to newer data that have been published since the latest evaluation of BD by the International Agency for Research on Cancer (IARC). The oxidative metabolism of BD in mice, rats and humans is compared with emphasis on the major 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). Results from recent studies of DNA and hemoglobin adducts indicate that EBdiol may play a more significant role in the toxicity of BD than previously thought. 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. DEB is clearly 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 base pairs are critical events in the mutagenicity of BD. In-depth analyses of the mutational spectra induced by BD and/or its oxidative metabolites should help to clarify which metabolite(s) are associated with specific mutations in each animal species and which mutational events contribute to BD-induced carcinogenicity. While the quantitative relationship between exposure to BD, its genotoxicity, and the induction of cancer in occupationally exposed humans remains to be fully established, there is sufficient data currently available to demonstrate that 1,3-butadiene is a probable human carcinogen.
Jackson
M A
MA
Alpha-Gamma Technologies Inc., Raleigh, NC 27609, USA.
Stack
H F
HF
Rice
J M
JM
Waters
M D
MD
D000395:Air Pollutants, Occupational / Q000009:adverse effects; D000477:Alkylating Agents / Q000493:pharmacokinetics; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers; D001711:Biotransformation; D002070:Butadienes / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000633:toxicity; D002273:Carcinogens / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000633:toxicity; D065637:Cytochrome P-450 CYP2A6; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000187:drug effects; D018736:DNA Adducts; D004249:DNA Damage; D004852:Epoxy Compounds / Q000633:toxicity; D005260:Female; D006018:Glycols / Q000633:toxicity; D006454:Hemoglobins / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000378:metabolism; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009153:Mutagens / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000633:toxicity; D009374:Neoplasms, Experimental / Q000139:chemically induced; D016273:Occupational Exposure; D009928:Organ Specificity; D010084:Oxidation-Reduction; D011506:Proteins / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016037:Single-Blind Method; D012854:Sister Chromatid Exchange; D013045:Species Specificity
D000395:Air Pollutants, Occupational; D000477:Alkylating Agents; D015415:Biomarkers; D002070:Butadienes; D002273:Carcinogens; D018736:DNA Adducts; D004852:Epoxy Compounds; D006018:Glycols; D006454:Hemoglobins; D009153:Mutagens; D011506:Proteins; C080053:3,4-epoxybutane-1,2-diol; C024370:3,4-epoxy-1-butene; C007366:diepoxybutane; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A; C031763:1,3-butadiene