SIMULATION OF TOLUENE KINETICS IN THE RAT BY A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL WITH APPLICATION OF BIOTRANSFORMATION PARAMETERSDERIVED INDEPENDENTLY IN-VITRO AND IN-VIVO

The biokinetic behavior of toluene was modeled in the rat with a physi ologically based pharmacokinetic (PB-PK) model. The model was paramete rized by using reference physiological parameter values and partition coefficients that were reported earlier from in vitro studies. Biotran sformation parameters for toluene, reported from two in vivo and six i n vitro studies, were subsequently substituted in the model while keep ing all other model parameters constant. Simulations of toluene kineti cs, based on these eight biotransformation parameter sets, were compar ed with empirical data reported on toluene uptake in blood and/or brai n tissue after inhalation exposure. It was observed that most empirica l data on toluene blood concentrations were adequately predicted by th e model for almost each of the eight biotransformation parameter sets. It was also observed that differences between model predictions, base d on either in vivo- or in vitro-derived biotransformation parameters, were generally small. It is concluded that the results from most in v itro studies on toluene biotransformation can be applied successfully to predict the kinetics of toluene in vivo. It is also concluded that the brain-blood partition coefficient may be at least as important for the outcome of the model as the biotransformation parameters are. The se results support earlier reported Bindings in the literature on appl ication of in vitro techniques to derive parameters for PB-PK models. (C) 1996 Society of Toxicology