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 used 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 develop mammary tumors only after exposures to 1000-8000 ppm BD. Extensive research has been carried out to determine where humans fit into this susceptibility range. Species differences in rates of metabolism of BD have been noted, but inconsistencies in metabolism data from different laboratories and some problems in the fit of physiologically based pharmacokinetic (PBPK) models with experimental data have left uncertainties. The experiments reported here are intended to clarify the issue of human metabolism of BD and to determine if metabolism of BD in cynomolgus 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 substantially the same in monkey and human hepatic microsomes. The human metabolism data agreed with that reported earlier when the in vitro metabolism of BD was studied at low BD concentrations. Finally, BD at high concentrations was found to inhibit the further oxidation of its metabolite, the monoepoxide. Incorporation of this information on the competition between BD and its first oxidation product for CYP2E1 should improve the fit of PBPK models.