PBPK model for butadiene metabolism to epoxides: quantitative species differences in metabolism

We have developed a physiologically based pharmacokinetic (PBPK) model for 1,3-butadiene (BD) and its first reactive metabolite 1,2-epoxybutene-3 (EB). This model contrasts with other published ones, in that it incorporates three important features: (I) reduced alveolar ventilation, based on experimental observations on a number of vapors and gases; (II) intrahepatic first-pass hydrolysis of EB, based on experimental observations with BD-EB, ethylene-ethylene oxide, and styrene-styrene oxide; (III) a two-substrate Michealis-Menten kinetic description of EB conjugation with GSH. We believe these features are essential for a correct toxicokinetic description of BD. The model was validated against a number of published experimental observations on BD, EB, and liver glutathione (GSH), kinetics made in vivo with rats and mice, including EB exhalation upon BD exposure and liver GSH depletion at high exposure levels of BD. According to our model, the relative internal doses of EB (expressed as the relation between steady-state concentrations or AUCs in mixed venous blood) are: mouse 1.6, rat 1.0, man 0.3. In the mouse, GSH depletion occurs after 6-9 h exposure at high concentrations resulting in a shift of the relative internal dose from 1.6 to between 2 and 3. The clear but relatively small mouse-rat difference in internal EB doses can only partly explain the marked species difference in cancer response between mice and rats exposed to BD.