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APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR ROUTE TO ROUTE DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)
Citation:
Blancato, J N., F. W. Power, J. W. Fisher, AND C. S. Scott. APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR ROUTE TO ROUTE DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE). Presented at Annual Meeting of Society of Toxicology, Philadelphia, PA, March 19-23, 2000.
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:
Route-to-route extrapolations are a crucial step in many risk assessments. Often the doses which result In toxicological end points in one route must be compared with doses resulting from typical environmental exposures by another route. In this case we used EPA's Dose Estimating Exposure Model (DEEM) to examine the route comparisons of different measures of internal dose after exposure to TCE. DEEM is a physiologically based model architecture for estimating internal tissue doses resulting from actual or simulated exposures. Because of different kinetic rates in the body not each possible measure of dose has the same quantitative relationship with exposure. Modeling shows that for different choices of internal dose the "equivalent" exposures are different, For example, we first chose the dose of interest to be the area under the curve (AUC) of the metabolite, trichloroacetic acid (TCA). In this case and with this model set-up an 8-hour 30 ppm exposure via inhalation was equivalent to drinking water intake of 50mg per day. For other measures of dose the point of equivalent exposure is far different. Thus, information about the mode of action and selection of internal dose is crucial before route to route extrapolations can be rationally made.
The U.S. Environmental Protection Agency (EPA). through Its Office of Research and Development, funded this research and approved this abstract as a basis for an oral presentation. The actual presentation has not been peer reviewed by the EPA.