Research strategy for assessing target tissue dosimetry of 1,3-butadiene in laboratory animals and humans.
1,3-Butadiene is carcinogenic to rats and mice, although mice are more sensitive than rats. It is not known if butadiene poses a carcinogenic risk to humans. Butadiene requires metabolic activation to reactive epoxides that can bind to DNA to initiate a series of events that lead to tumour formation. Species differences in activation and detoxification must be considered in estimating human risks from exposure to butadiene. A research strategy for assessing the role of metabolic factors in the carcinogenicity of butadiene involves studies in laboratory animals in vivo, supplemented with studies in vitro with tissues from both laboratory animals and humans. In experiments conducted on liver and lung tissues from Sprague-Dawley rats, B6C3F1 mice and humans, we characterized the oxidation of butadiene and butadiene monoepoxide by cytochrome P450-dependent mono-oxygenases and the detoxification of butadiene monoepoxide by epoxide hydrolases and glutathione transferases. B6C3F1 mouse liver microsomes displayed a capacity for butadiene oxidation exceeding that seen in either human or rat liver microsomes. Except in mice, oxidation of butadiene occurred at rates significantly lower with lung than with liver microsomes. In general, human liver microsomes hydrolysed butadiene monoepoxide at higher rates than either rats or mice. The capacity for glutathione conjugation with butadiene monoepoxide was higher in mice than in humans or rats. The ratios of butadiene activation (P450):detoxication (hydrolysis and conjugation) are markedly different in mouse (74:1), rat (6:1) and human (6:1) liver tissues. The differences in the ratios between mice and rats are consistent with the higher carcinogenic sensitivity of mice than rats to butadiene. Factors in addition to metabolism, however, probably play a role in the carcinogenicity of butadiene in rats and mice. Metabolic rate constants for butadiene and butadiene monoepoxide oxidation and for butadiene monoepoxide hydrolysis and conjugation with glutathione, determined from physiological pharmacokinetic model simulations of butadiene-exposed rats and mice, were for the most part similar to the constants determined in vitro. The same trends that were noted in vitro were seen in vivo. The physiological dosimetry model for butadiene that includes in-vitro vitro metabolic constants can stimulate behaviour in vivo and can be used to predict blood and tissue concentrations of butadiene and its monoepoxide.(ABSTRACT TRUNCATED AT 400 WORDS)
Bond
J A
JA
Chemical Industry Institute of Toxicology, Research Triangle Park, NC.
Csanády
G A
GA
Leavens
T
T
Medinsky
M A
MA
D000818:Animals; D002070:Butadienes / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000493:pharmacokinetics / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008168:Lung / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D002070:Butadienes; D004852:Epoxy Compounds; D009153:Mutagens; C024370:3,4-epoxy-1-butene; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; D005978:Glutathione; C031763:1,3-butadiene