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A COMPREHENSIVE APPROACH FOR PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM) SYSTEM
Citation:
Ruiz, A., A. Tsang, J. Licitra, F W. Power, J N. Blancato, AND C C. Dary. A COMPREHENSIVE APPROACH FOR PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM) SYSTEM. Presented at 43rd Annual Meeting of the Society of Toxicology, Baltimore, MD, March 21-25, 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:
The implementation of a comprehensive PBPK modeling approach resulted in ERDEM, a complex PBPK modeling system. ERDEM provides a scalable and user-friendly environment that enables researchers to focus on data input values rather than writing program code. ERDEM efficiently manages these inputs and provides reporting and model output assessment capabilities, for toxicologists, risk assessors, exposure scientists and managers. As PBPK models grow in complexity, the implementation of models, the preparation and maintenance of inputs, and the assessment of model output results has become more tedious and error prone.
Combining this experience with intensive research produced a comprehensive modeling approach for designing ERDEM and other PBPK modeling projects. The goal of this modeling approach is to improve the modeling process from planning to application for multi-media exposure assessments. The core activities for this approach include identification and implementation of the model design and performance criteria, the model hardware/software specifications, and the model testing and evaluation.
As a comprehensive modeling system, ERDEM contains a PBPK model engine component that can create scenario-based simulations and target dose estimates in multiple compartments for exposure of a species to multiple chemicals and metabolites. The input management component uses a Windows based graphical user interface and relational database, enabling the user to enter, edit, report, and export data sets of user assigned physiological information. The stochastic component evaluates the uncertainty associated with input parameters and output model results. ERDEM replaces the traditional program-oriented modeling approach, which is error prone, with a sophisticated and user-friendly model simulation and data management system.
This work has been funded by the United States Environmental Protection Agency. It has been subjected to Agency review and approved for publication.