Citation:

Okino, M S., F W. Power, J N. Blancato, W. Chiu, C. Chen, AND J. Lipscomb. HARMONIZATION AND COMMUNICATION OF PBPK MODELS USING THE EXPOSURE RELATED DOSE MODEL (ERDEM) SYSTEM: TRICHLOROETHYLENE. Presented at EPA Science Forum 2004, Washington, DC, June 1-3, 2004.

Impact/Purpose:

Research will be conducted to develop and apply integrated microenvironmental, and physiologically-based pharmacokinetic (PBPK) exposure-dose models and methods (that account for all media, routes, pathways and endpoints). Specific efforts will focus on the following areas:

1) Develop the Exposure Related Dose Estimating Model (ERDEM) System.

Includes: Updating the subsystems and compartments of the ERDEM models with those features needed for modeling chemicals of interest to risk assessors;

Designing and implementing the graphical user interface for added features.

Refining the exposure interface to handle various sources of exposure information;

Providing tools for post processing as well as for uncertainty and variability analyses;

Research on numerical and symbolic mathematical/statistical solution methods and computational algorithms/software for deterministic and stochastic systems analysis.

2) Apply ERDEM and other quantitative models to understand pharmacokinetics (PK) and significantly reduce the uncertainty in the dosimetry of specific compounds of regulatory interest.

Examples of the applications are:

exposure of children to pesticides

study design

route-to-route extrapolation

species extrapolation

experimental data analysis

relationship between parametric uncertainty and the distribution of model results

validity of scaling methods within species

validity of scaling methods from one species to another species

reduction of uncertainty factors for risk assessment

Description:

In support of the trichloroethylene (TCE) risk assessment for the Office of Air and Radiation, Office of Solid Waste and Emergency Response, and Office of Water, NERL and NCEA are developing an updated physiologically-based pharmacokinetic (PBPK) model. The PBPK modeling effort is in conjunction with a workgroup organized by TERA (Toxicology Excellence for Risk Assessment) that includes researchers from academia, the Air Force, and outside industry. PBPK models are powerful computational tools that can be used to link exposure to the internal concentrations of parent compounds and/or active metabolites at the target site(s) of toxicity. Challenges in model development are the comparison and harmonization of existing models, management of multiple diverse datasets, and characterization of the uncertainties. The implementation and documentation of a mathematical model in a general structure addresses these issues by managing the chemicals, compartments, and parameters in a consistent manner. The Exposure Related Dose Estimating Model (ERDEM) platform, developed by NERL, provides an appropriate structure. Also, the EPA Science Advisory Board has stressed the importance of transparency in the updated assessment of TCE. The development of the updated PBPK model in the ERDEM system addresses this charge through its graphical user interface (GUI), standard report generation, and availability to the public. Evaluation of the model can be done at a high level - standard reports or simulations of new scenarios through the GUI - and at varying levels of detail down to the actual FORTRAN code. This enables use and review by researchers of diverse backgrounds.

Although this work was reviewed by EPA and approved for publication, it may not necessarily reflect official Agency policy.

Record Details: