pharmacokinetic models for trichloroethylene. The pharmacokinetic models used in the U.S. Environmental Protection Agency (EPA 2001b) draft health risk assessment of trichloroethylene, several of the pharmacokinetic models published since that assessment, and a model later commissioned by EPA and the U.S. Air Force (USAF) to deal with some problems of the earlier health risk assessment are the focus of this chapter.

OVERVIEW OF PHARMACOKINETIC MODELS

Pharmacokinetic models mathematically describe the absorption, distribution, metabolism, and elimination of a chemical in an organism as a function of time. Similar descriptions for metabolites also can be incorporated into pharmacokinetic models for the parent compound. Pharmacokinetic models typically include compartments that represent specific organs and tissues as well as lumped tissue compartments and are represented by using systems of differential equations. Whether a specific tissue compartment is included in a pharmacokinetic model depends on how involved that tissue is in disposing of the compound (e.g., portals of entry or excretion, sites of metabolism, targets of toxicity) and on its utility as a biomarker of exposure or response. Pharmacokinetic model development is an iterative process; the mathematical model is used to simulate data and the simulated data are compared with real data to refine the mathematical model. “All models are wrong, but some models are useful” (attributed to G. Box [Kokko 2005]). There will never be a comprehensive model that perfectly describes all the exposure and response relationships for any chemical in laboratory animals or humans, but some models may be adequate for predicting useful internal dose metrics, and some models may provide better predictions than others.

Physiologically based pharmacokinetic (PBPK) models define model parameters in terms of directly interpretable anatomic, physiologic, or biochemical quantities. In a basic PBPK model, the tissue compartments are linked by blood flow and have associated physical volumes and partition coefficients that describe the relative degree to which a given chemical (e.g., trichloroethylene) is soluble in each of those tissues versus blood. Although the fundamental mathematical forms of pharmacokinetic and PBPK models with the same compartments may be identical, parameterization in terms of measurable physiologic quantities introduces several advantages (Gibaldi and Perrier 1982). For example, blood flow rates are well characterized in many species, providing a simple and rational method for adjusting a PBPK model to extrapolate across species (e.g., from laboratory animals to humans). Moreover, direct measurements can be independently obtained for some PBPK parameters, rather than relying solely on the results of dosing experiments.



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