DEVELOPMENT OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR PERCHLOROETHYLENE USING TISSUE CONCENTRATION-TIME DATA

The tissue disposition of perchloroethylene (PCE) was characterized ex perimentally in rats in order to (1) obtain input parameters from in v ivo data for the development of a physiologically based pharmacokineti c (PBPK) model, and (2) use the PBPK model to predict the deposition o f PCE in a variety of tissues following inhalation exposure. For the d erivation of model input parameters, male Sprague-Dawley rats received a single bolus of 10 mg PCE/kg body wt in polyethylene glycol 400 by ia injection through an indwelling carotid arterial cannula. Other mal e Sprague-Dawley rats inhaled 500 ppm PCE for 2 hr in dynamic exposure inhalation chambers. Serial samples of brain, liver, kidney, lung, he art, skeletal muscle, perirenal fat, and blood were taken for up to 72 hr following ia injection, during the 2-hr inhalation exposure, and f or up to 72 hr postexposure. Blood and tissue PCE concentrations were analyzed using a gas chromatography headspace technique. Following ia administration, the tissues exhibited similar terminal elimination hal f-lives (t(1/2)). As comparable tissue t(1/2)s are consistent with a b lood-flow-limited model, tissue:blood partition coefficients were calc ulated for noneliminating compartments by division of the area under t he tissue concentration-time curve (AUC) by the blood AUC. Liver PCE c oncentration versus time data were employed in the calculation of in v ivo metabolic rate constants. A PBPK model was developed using these p arameters derived from the ia data set and used to predict tissue PCE concentrations during and following PCE inhalation. Predicted tissue l evels were in close agreement with the levels measured over time in th e seven tissues and in blood. Tissue concentration-time data can thus provide valuable input for parameter estimation and for validation of PBPK model simulations, as long as independent in vivo data sets are u sed for each step. (C) 1994 Academic Press, Inc.