Physiologically-based Population Pharmacokinetic Models for Risk Assessment

EPA Grant Number: R824755
Title: Physiologically-based Population Pharmacokinetic Models for Risk Assessment
Investigators: Bois, Frederic Y.
Institution: Ernest Orlando Lawrence Berkeley National Lab
EPA Project Officer: Manty, Dale
Project Period: November 27, 1995 through September 30, 1996
Project Amount: $68,633
RFA: Human Health Risk Assessment (1995) RFA Text |  Recipients Lists
Research Category: Health Effects , Human Health Risk Assessment , Health


There is currently no method for rigorous statistical validation of physiologically-based pharmacokinetic (PBPK) models. This study proposes to develop methods which will bring these important health risk assessment models to the level of statistical quality and reliability required from any scientific activity. These methods will ultimately address model parametrization, optimal experimental designs, and linkage with input time series. Bayesian statistical theory and techniques will be used. This approach will allow the combination of two forms of information essential for PBPK modeling: prior knowledge from the scientific literature, and data from pharmacokinetic experiments. In addition, new methods to measure the human variability which affect the results of toxicokinetic data will be developed. A general Bayesian population pharmacokinetic model will be designed to account for inter- and intra-individual variability as well as data and input measurement uncertainty. A specific model will be developed to describe both trichloroethylene (TRI) and tetrachloroethylene (PERC) pharmacokinetics in humans. This project will therefore offer two validated PBPK models, with statistically sound estimates of uncertainty and population variability in the metabolism of PERC and TRI. More generally, this project will directly benefit regulatory agencies, the regulated communities and the general population, since the statistical validation of PBPK exposure models will lead to improved risk assessments.

Supplemental Keywords:

Health, Scientific Discipline, PHYSICAL ASPECTS, Toxics, Toxicology, Health Risk Assessment, Risk Assessments, Biochemistry, Physical Processes, 33/50, toxicokinetic, PBPK model, Tetrachloroethylene, exposure, Trichloroethylene, metabolic activation, human exposure, metabolism, statistical validation, physiologically based model, Bayesian statistical theory, model parametrization, trichloroethylene (TRI), tetrachloroethylene (PERC), human health risk, pharmokinetic models