Implications of pharmacokinetic modeling in risk assessment analysis.

Physiologic pharmacokinetic models are a useful interface between exposure models and risk assessment models by providing a means to estimate tissue concentrations of reactive chemical species at the site of action. The models utilize numerous parameters that can be characterized as anatomical, such as body size or tissue volume; physiological, such as tissue blood perfusion rates, clearances, and metabolism; thermodynamic, such as partition coefficients; and transport, such as membrane permeabilities. The models provide a format to investigate how these parameters can influence the disposition of chemicals throughout the body, which is an important consideration in interpreting toxicity studies. Physiologic models can take into account nonlinear effects related to clearance, metabolism, or transport. They allow for extrapolation of tissue concentration from high dose to low dose experiments and from species to species and can account for temporal variations in dose.