PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING OF BLOOD AND TISSUE EPOXIDE MEASUREMENTS FOR BUTADIENE

In vitro and in vivo butadiene (ED) metabolism data from laboratory an imals were integrated into a rodent physiologically based pharmacokine tic (PBPK) model with flow- and diffusion-limited compartments. The re sulting model describes experimental data from multiple sources under scenarios such as closed chamber inhalation and nose-only flow-through inhalation exposures. Incorporation of diurnal glutathione (GSH) vari ation allows accurate simulation of GSH changes observed in air contro l nose-only exposures and ED exposures. An isolated tissue model based on rate parameters determined in vitro predicts the decrease in epoxi de concentrations in intact animals during the time lag between exsang uination and tissue removal for tissues capable of epoxide biotransfor mation, providing a better indication of in vivo dosimetry. Further re finements of the model are required relative to model predictions of a n important ED metabolite, diepoxybutane.