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An introduction to the use of physiologically based pharmacokinetic models in risk assessment.

Authors
Bailer-AJ; Dankovic-DA
Source
Stat Methods Med Res 1997 Aug; 6(4):341-358
NIOSHTIC No.
20025217
Abstract
Many extrapolation issues surface in quantitative risk assessments. The extrapolation from high-dose animal studies to low-dose human exposures is of particular concern. Physiologically based pharmacokinetic (PBPK) models are often proposed as tools to mitigate the problems of extrapolation. These models provide a representation of the disposition, metabolism, and excretion of xenobiotics that are believed to possess the potential of inducing adverse human health responses. Given a model of xenobiotic disposition that is applicable for multiple species and appropriate for nonlinearity of the xenobiotic biotransformation process, better extrapolation may be possible. Unfortunately, the true structure of these models (e.g. number of compartments, type of metabolism, etc.) is seldom known, and attributes of these models (tissue volumes, partition coefficients, etc.) are often experimentally determined and often only central measures of these quantities are reported. We describe the use of PBPK models in risk assessment, the structural and parameter uncertainty in these models, and provide a simple illustration of how these characteristics can be incorporated in a statistical analysis of PBPK models. Additional complexity in the analysis of variability in the models is also outlined. This discussion is illustrated using data from methylene chloride.
Keywords
Risk-analysis; Risk-factors; Humans; Animal-studies; Animals; Physiological-testing; Physiological-measurements; Physiological-function; Physiological-effects; Humans; Human-factors-engineering; Statistical-analysis
CODEN
SMMRFQ
Publication Date
19970801
Document Type
Journal Article
Fiscal Year
1997
NTIS Accession No.
NTIS Price
Issue of Publication
4
ISSN
0962-2802
NIOSH Division
EID
Source Name
Statistical Methods in Medical Research
State
OH
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