Comparative metabolism of low concentrations of butadiene and its monoepoxide in human and monkey hepatic microsomes

The chronic (2-yr) inhalation toxicity of 1,3-butadiene (BD), a chemical us ed in large quantities to make rubber and plastics, differs greatly between mice and rats. Mice develop lung tumors after exposures to concentrations as low as 6.25 ppm, whereas rats der clop mammary rumors only after exposur es to 1000-8000 ppm ED. Extensive research has been carried our to determin e where humans lit into this susceptibility range. Species differences in r ates of metabolism of ED hale been noted but inconsistencies in metabolism data from different laboratories and some problems in the fit of physiologi cally based pharmacokinetic (PBPK) models with experimental data have left uncertainties. The experiments reported here are intended to clarify the is sue of human metabolism of ED and to determine ii metabolism of ED in cynom olgus monkeys is similar enough to metabolism in humans to use in vivo data from monkeys for PBPK modeling The results indicate that for the reactions studied (oxidation of BD to the mono- and diepoxide), BD is metabolized su bstantially the same in monkey and human hepatic microsomes. The human meta bolism data agreed with that reported earlier when the in vitro metabolism of ED las studied at low ED concentrations, Finally, ED at high concentrati ons was found to inhibit the further oxidation of its metabolite, the monoe poxide. Incorporation of li,is information on the competition between ED an d its first oxidation product for CYP2E1 should improve the fit of PBPK mod els.