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EVALUATING A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR USE IN RISK ASSESSMENT
Citation:
Clark, L. H., H A. Barton, AND R W. Setzer. EVALUATING A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR USE IN RISK ASSESSMENT. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13, 2003.
Description:
EVALUATING A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR USE IN RISK ASSESSMENT. L H Clark1, H A Barton1, and R W Setzer1. 1US EPA, ORD, NHEERL, ETD, Research Triangle Park, NC, USA.
Physiologically-based pharmacokinetic (PBPK) models are increasingly being used in evaluation of the effects of chemical exposures on human health. Due to the increased use of PBPK models, it is becoming more evident in the biological modeling community that a universal set of criteria should be used to evaluate the quality of a model before it is used in a human health risk assessment. The objective of this study was to develop a set of important criteria that can be used to evaluate PBPK models. We present the criteria here and note that this is not an exhaustive list but one that can be used as a starting point for further discussion. Increased confidence in PBPK model predictions of human health risks can be attained if the following criteria are satisfied: 1) the model must be biologically plausible (i.e. known physiological and biochemical properties of a chemical must be accounted for in the model and the appropriate mathematical descriptions should be used); 2) the computer algorithms describing the mathematical equations in the model should be implemented properly; 3) a consistent set of parameters should be used to reproduce available experimental data, including data that were not used to estimate the parameters; and 4) the model should exhibit the appropriate sensitivity to changes in each parameter value. In our study, we used an existing PBPK model for isopropanol (Clewell et al., Toxicol Sci, 63:160-172, 2001, Gentry et al., Regul Toxicol Pharmacol, in press) as a case study. This model has been proposed as a tool to perform the route-to-route and cross-species extrapolations, among other things, needed to evaluate the potential human health effects of isopropanol, based on studies in rats of systemic, developmental, reproductive, and neurobehavioral toxicities. The isopropanol model largely meets the above criteria and will be used here to illustrate the issues involved in evaluating the quality of a model. (This abstract does not reflect US EPA policy.)