Journal Article

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

Deborah A. Keys, James V. Bruckner, Srinivasa Muralidhara and Jeffrey W. Fisher

in Toxicological Sciences

Volume 76, issue 1, pages 35-50
Published in print November 2003 | ISSN: 1096-6080
Published online November 2003 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfg212
Tissue Dosimetry Expansion and Cross-Validation of Rat and Mouse Physiologically Based Pharmacokinetic Models for Trichloroethylene

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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.

Keywords: PBPK; TCE; cross-validation; lumping; liver

Journal Article.  11810 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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