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ToxSci Advance Access originally published online on August 12, 2003
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Toxicological Sciences 76, 35-50 (2003)
Copyright © 2003 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Tissue Dosimetry Expansion and Cross-Validation of Rat and Mouse Physiologically Based Pharmacokinetic Models for Trichloroethylene

Deborah A. Keys*,1, James V. Bruckner{dagger}, Srinivasa Muralidhara{dagger} and Jeffrey W. Fisher*

* Department of Environmental Health Science, and {dagger} Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, Georgia 30602

Trichloroethylene (TCE), a volatile liquid used as a degreasing agent, is a common environmental pollutant. In 2001, the EPA published a draft risk assessment for TCE that incorporates dosimetry predictions of physiologically based pharmacokinetic (PBPK) models. The current modeling effort represents an expansion and extensive tissue dosimetry validation of rodent PBPK models for TCE. The pharmacokinetics of TCE in male Sprague-Dawley (S-D) rats were characterized (1) during and after inhalation exposure to 50 or 500 ppm TCE, (2) following administration of 8 mg/kg TCE PO, and (3) following intra-arterial injection of 8 mg/kg TCE. Blood and tissues (including liver, kidney, fat, skeletal muscle, heart, spleen, gastrointestinal tract, and brain) were collected at selected time-points from 5 min up to 24 h post initial exposure. The fat compartment was modified to be diffusion-limited to predict the observed slow release of TCE from the fat. The addition of a deep liver compartment was necessary to accurately predict the slower hepatic clearance of TCE for all three exposure routes. Simulations of liver concentrations following gavage of male B6C3F1 mice with 300–2000 mg/kg TCE were also improved with the addition of a deep liver compartment. Liver predictions were calibrated and validated using a cross-validation technique novel to PBPK modeling. Splitting of compartments did not significantly affect predictions of TCE concentrations in the liver, fat, or venous blood. This model expansion and validation increases both the utility and our confidence in the current use of rodent TCE PBPK models in human health risk assessment.

Key Words: PBPK; TCE; cross-validation; lumping; liver.


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