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USE OF A CONVECTION-DIFFUSION MODEL TO UNDERSTAND GASTROINTESTINAL ABSORPTION OF ENVIRONMENTALLY-RELEVANT CHEMICALS
Citation:
Rigas, M L. AND E A. CohenHubal. USE OF A CONVECTION-DIFFUSION MODEL TO UNDERSTAND GASTROINTESTINAL ABSORPTION OF ENVIRONMENTALLY-RELEVANT CHEMICALS. Presented at Society for Risk Analysis 2000 Annual Meeting, Arlington, VA, December 3-6, 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:
Understanding the factors that affect the gastrointestinal absorption of chemicals is important to predicting the delivered systemic dose of chemicals following exposure in food, water, and other media. Two factors of particular interest are the effects of a matrix to which the chemical might be bound during ingestion as well as the effects of other material ingested along with the toxicant of interest. We use transport analysis to examine molecular absorption from the small intestine. This will provide quantitative estimates of these factors not normally addressed in the clinical physiologically-based pharmacokinetic (PBPK) modeling literature. The theoretical model is based on an analysis designed to investigate pharmaceutical absorption. It includes factors such as lumenal and membrane diffusion, convection, degradation and desorption/dissolution. Lumenal and systemic concentrations are predicted in humans for two small lipophillic molecules, ibuprofen, and the organophosphate insecticide chlorpyrifos. The simulation results are compared with experimental data from the literature. The solution of the model equations has led to a parametric analysis elucidating the importance of different factors affecting the intestinal absorption of chemicals. The solution also provides a method to predict intestinal membrane permeability, Kp using single-point peak plasma concentration data following a known administered dose. It is expected that further analysis using the model and comparison with experimental results will aid in the development of generalizations regarding the model complexity needed to predict the fraction and rate of absorption for less well-studied chemicals.
This work has been funded wholly or in part by the United States Environmental Protection Agency and has been approved for publication.