Academic journal article Environmental Health Perspectives

A Consistent Approach for the Application of Pharmacokinetic Modeling in Cancer and Noncancer Risk Assessment. (Articles)

Academic journal article Environmental Health Perspectives

A Consistent Approach for the Application of Pharmacokinetic Modeling in Cancer and Noncancer Risk Assessment. (Articles)

Article excerpt

Physiologically based pharmacokinetic 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 end point 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: a) exposure, b) tissue dosimetry/pharmacokinetics, c) toxicity process/pharmacodynamics, and d) 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 end points. Chemical risk assessments typically depend upon comparisons across species that often simplify to ratios reflecting the differences. In this paper we describe the uses of this ratio concept and discuss the advantages of a pharmacokinetic-based approach as compared to the use of default dosimetry. Key words: dose-response assessment, interspecies extrapolation, pharmacokinetics, physiologically based pharmacokinetic modeling, risk assessment, tissue dosimetry. Environ Health Perspect 110:85-93 (2002). [Online 18 December 2001]

http://ehpnet1.niehs.nih.gov/docs/2002/110p85-93clewell/abstract.html

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The process of assessing the health risks associated with human exposure to toxic environmental chemicals inevitably relies on a number of assumptions, estimates, and rationalizations. Some of the greatest challenges result from the necessity to extrapolate from the conditions in the studies providing evidence of the toxicity of the chemical to the anticipated conditions of exposure in the environment or workplace. For risk assessments based on animal data, the most obvious extrapolation that must be performed is from the tested animal species to humans; however, others are also generally required: from high dose to low dose, from one exposure route to another, and from one exposure time frame to another. Physiologically based pharmacokinetic (PBPK) modeling provides a powerful method for increasing the reliability of these extrapolations (1-3). The inherent capabilities of PBPK modeling are particularly advantageous for cross-species extrapolation: the physiological and biochemical parameters in the model can be changed from those for the test species to those that are appropriate for humans to provide a biologically meaningful animal-to-human extrapolation. However, it is important to recognize that a full PBPK model may not always be necessary to support a pharmacokinetic risk assessment. In some cases only a simple compartmental pharmacokinetic description is needed; an excellent example has been published for the case of cadmium (4-5).

Simple pharmacokinetic approaches have occasionally been used by regulatory agencies in cancer risk assessment; for example, the use of metabolized dose for trichloroethylene (6,7). The first case in which an agency has used a full PBPK approach was in the U.S. Environmental Protection Agency's (U.S. EPA) latest revision of its inhalation risk assessment for methylene chloride (8). The decision to use the PBPK approach in this case was made only after a period of considerable controversy, including a workshop sponsored by the National Academy of Sciences at which the usefulness of PBPK modeling for chemical risk assessment was discussed. The scientific consensus following the workshop was that "relevant PBPK data can be used to reduce uncertainty in extrapolation and risk assessment"(9). In 1989, after a detailed multiagency evaluation of the available PBPK information and a review by the U. …

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