IN-VIVO METABOLISM OF BUTADIENE BY MICE AND RATS - A COMPARISON OF PHYSIOLOGICAL MODEL PREDICTIONS AND EXPERIMENTAL-DATA

1,3-Butadiene (BD), a rodent carcinogen, is metabolized to mutagenic and potentially DNA-reactive epoxides, including butadiene monoepoxide (BMO) and butadiene diepoxide. A physiological model containing five tissue groups (liver lung, fat, slowly perfused tissues and rapidly perfused tissues) and blood was developed to describe uptake and metabolism of inhaled BD and BMO. Maximal rates for hepatic and pulmonary metabolism of BD and hepatic metabolism of BMO incorporated into the model were extrapolated from in vitro data (Csanady et al., Carcinogenesis, 13, 1143-1153, 1992). Apparent enzyme affinities used in the model were identical to the values measured in vitro. Model simulations for BD and BMO uptake were compared to results from experiments in which groups of male Sprague-Dawley rats and B6C3F1 mice were exposed to initial concentrations of 50-5000 p.p.m. BD in closed chamber experiments and published data on BMO uptake by rats and mice. Metabolic rate constants extrapolated from in vitro data simulated both BMO and BD uptake from closed chambers. The V-max for hepatic metabolism of BD extrapolated from in vitro studies was 62 mu mol/kg/h for rats and 340 mu mol/kg/h for mice, while the V-max for pulmonary metabolism of BD was 1.0 and 22 for rats and mice, respectively. These results demonstrate the usefulness of data derived in vitro for predicting in vivo behavior. Model simulations were also conducted in which only hepatic metabolism of BD was incorporated. These simulations underestimated BD uptake for mice, but not rats. Inclusion of in vitro-derived rates of pulmonary metabolism of BD into the model improved the fit to the data for mice. Since mice, but not rats, develop lung tumors after exposure to BD, these results point to the need to further characterize the metabolic capacity and target cells in the lung for BD and its metabolites. Once characterized, these models can be extended to predict in vivo behavior of BD in humans.