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

EPA announced the availability of the final report, Uncertainty and Variability in Physiologically-Based Pharmacokinetic (PBPK) Models: Key Issues and Case Studies. 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.

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.

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.

History/Chronology

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

This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.