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Environmental Assessment

Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies (Final Report)

Report Information

This report summarizes some of the recent progress in characterizing uncertainty and variability in physiologically-based pharmacokinetic models and their predictions for use in risk assessment.

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Weihsueh Chiu
  • by phone at:   703-347-8607
  • by email at:  chiu.weihsueh@epa.gov

Background

Chemical risk and safety assessments increasingly rely upon tissue dosimetry estimates in animals and humans obtained from physiologically-based pharmacokinetic (PBPK) modeling. However, risk assessment also increasingly requires characterization of uncertainty and variability; such characterization for PBPK model predictions represents a continuing challenge to both modelers and users. Current practices show significant progress in specifying deterministic biological models and the non-deterministic (often statistical) models, estimating their parameters using diverse data sets from multiple sources, and using them to make predictions and characterize uncertainty and variability. This report summarizes some of the recent progress in this area that has been conducted or supported by the National Center for Environmental Assessment (NCEA). These include the identification of the state-of-the science on key issues in this area, as well as priority research or implementation needs. In addition, a number of case examples of chemical-specific applications have demonstrated some of the methods and issues associated with characterizing uncertainty and variability in PBPK modeling.

History/Chronology

Oct 2006Case studies using tetrachloroethylene and route-to-route extrapolation completed.
Oct/Nov 2006International Workshop on Uncertainty and Variability in PBPK Models
Apr 2007Case study on methyl tertiary butyl ether published.
Sep 2007Case study using 1,3-butadiene published.
Sep 2008EPA releases the final report.

Next Steps

This is the final report.

Citation

U.S. EPA. Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies (Final Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-08/090.

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