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A CONSISTENT APPROACH FOR THE APPLICATION OF PHARMACOKINETIC MODELING IN CANCER RISK ASSESSMENT
Citation:
Clewell, H., M. E. Andersen, AND H Barton. A CONSISTENT APPROACH FOR THE APPLICATION OF PHARMACOKINETIC MODELING IN CANCER RISK ASSESSMENT. ENVIRONMENTAL HEALTH PERSPECTIVES 110(1):85-93, (2001).
Description:
Physiologically based pharmacokinetic (PBPK) modeling provides important capabilities for improving the reliability of the extrapolations across dose, species, and exposure route that are generally required in chemical risk assessment regardless of the toxic endpoint being considered. Recently, there has been an increasing focus on harmonization of the cancer and noncancer risk assessment approaches used by regulatory agencies. Although the specific details of applying pharmacokinetic modeling within these two paradigms may differ, it is possible to identify important elements common to both. These elements expand on a four-part framework for describing the development of toxicity: i) exposure, ii) tissue dosimetry/pharmacokinetics, iii) toxicity process/pharmacodynamics, and iv) response. The middle two components constitute the mode of action. In particular, the approach described in this paper provides a common template for incorporating pharmacokinetic modeling to estimate tissue dosimetry into chemical risk assessment, whether for cancer or noncancer endpoints. Chemical risk assessments typically depend upon comparisons across species that often simplify to ratios reflecting the differences; uses of this ratio concept are described. The advantages of this pharmacokinetic-based approach as compared to the use of default dosimetry are discussed.