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Toxicological Sciences 69, 3-15 (2002)
Copyright © 2002 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETIC

A Physiologically Based Pharmacokinetic Model for Trichloroethylene in the Male Long-Evans Rat

J. E. Simmons*,1, W. K. Boyes*, P. J. Bushnell*, J. H. Raymer{dagger}, T. Limsakun{ddagger},2, A. McDonald*, Y. M. Sey* and M. V. Evans*

* National Health and Environmental Effects Research Laboratory, Office of Research and Development, U. S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; {dagger} Research Triangle Institute, Research Triangle Park, North Carolina 27709; and {ddagger} Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602

A physiologically based pharmacokinetic (PBPK) model for trichloroethylene (TCE) in the male Long-Evans (LE) rat was needed to aid in evaluation of neurotoxicity data collected in this rodent stock. The purpose of this study was to develop such a model with the greatest possible specificity for the LE rat. The PBPK model consisted of 5 compartments: brain, fat, slowly perfused tissue, rapidly perfused viscera, and liver. Partition coefficients (blood, fat, muscle, brain, liver) were determined for LE rats. The volumes of the brain, liver, and fat compartments were estimated for each rat, with tissue-specific regression equations developed from measurements made in LE rats. Vapor uptake data from LE rats were used for estimation of Vmaxc. As blood flow values for LE rats were not available, values from Sprague-Dawley (SD) and Fischer-344 (F344) rats were used in separate simulations. The resulting values of Vmaxc were used to simulate tissue (blood, liver, brain, fat) TCE concentrations, which were measured during (5, 20, 60 min) and after (60 min of TCE followed by 60 min of air) flow-through inhalation exposures of LE rats to 200, 2000, or 4000 ppm TCE. Simulation of the experimental data was improved by use of F-344 blood-flow values and the corresponding Vmaxc (8.68 mg/h/kg) compared to use of SD flows and the associated Vmaxc (7.34 mg/h/kg). Sensitivity analysis was used to determine those input parameters with the greatest influence on TCE tissue concentrations. Alveolar ventilation consistently (across exposure concentration, exposure duration, and target tissue) had the greatest impact on TCE tissue concentration. The PBPK model described here is being used to explore the relationship between measures of internal dose of TCE and neurotoxic outcome.

Key Words: physiologically based pharmacokinetic model; trichloroethylene; Long-Evans rat; Vmaxc.


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