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 a nd potentially DNA-reactive epoxides, including butadiene monoepoxide (BMO) and butadiene diepoxide. A physiological model containing five t issue groups (liver lung, fat, slowly perfused tissues and rapidly per fused tissues) and blood was developed to describe uptake and metaboli sm of inhaled BD and BMO. Maximal rates for hepatic and pulmonary meta bolism 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 we re identical to the values measured in vitro. Model simulations for BD and BMO uptake were compared to results from experiments in which gro ups of male Sprague-Dawley rats and B6C3F1 mice were exposed to initia l concentrations of 50-5000 p.p.m. BD in closed chamber experiments an d published data on BMO uptake by rats and mice. Metabolic rate consta nts extrapolated from in vitro data simulated both BMO and BD uptake f rom closed chambers. The V-max for hepatic metabolism of BD extrapolat ed 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 an d 22 for rats and mice, respectively. These results demonstrate the us efulness of data derived in vitro for predicting in vivo behavior. Mod el simulations were also conducted in which only hepatic metabolism of BD was incorporated. These simulations underestimated BD uptake for m ice, but not rats. Inclusion of in vitro-derived rates of pulmonary me tabolism of BD into the model improved the fit to the data for mice. S ince mice, but not rats, develop lung tumors after exposure to BD, the se results point to the need to further characterize the metabolic cap acity and target cells in the lung for BD and its metabolites. Once ch aracterized, these models can be extended to predict in vivo behavior of BD in humans.