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ToxSci Advance Access published online on March 31, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh117
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received October 28, 2003; accepted February 15, 2004
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.

Risk Assessment

Physiologically Based Pharmacokinetic Model for Developmental Exposures to TCDD in the Rat

Claude Emond 1, Linda S. Birnbaum 2, and Michael J. DeVito 2*

1 National Research Council, Washington DC; National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
2 National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711

* To whom correspondence should be addressed. E-mail: Devito.Mike{at}epa.gov.


  Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent developmental toxicant in rodents and these effects occur at exposures similar to background human body burdens. A physiologically based pharmacokinetic (PBPK) model can aid in quantitatively describing the relationship between exposure, dose and response. The aim of this work was the development a PBPK model to describe the relationship between maternal TCDD exposure and fetal TCDD concentrations during critical windows of susceptibility in the rat. This PBPK model is a modification of an eight-compartment model developed by Wang et al. (1997) that describes the adult female rat. The modified model reduces the compartments from eight to four maternal compartments (liver, fat, placenta and rest of the body). Activation of the placental compartment and a separate fetal compartment occurs during gestation. The systemic circulation connects the maternal compartments. The physiological and biochemical parameters were obtained from the literature. The model validation used experimental data from acute and subchronic exposures prior to and during gestation. The simulations predict the TCDD tissue concentrations of the maternal compartments within the standard deviation of the experimental data. The model slightly overestimates the fetal concentrations by approximately a factor of two at low subchronic exposures, but does predict the fetal tissue concentrations within the range of the experimental data at the higher exposures. This model may provide a framework for the development of a human PBPK model to estimate fetal TCDD concentrations in human health risk assessments.

Key Words: PBPK, TCDD, Rat, dioxin, developmental .


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