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PROPOSED MODELS FOR ESTIMATING RELEVANT DOSE RESULTING FROM EXPOSURES BY THE GASTROINTESTINAL ROUTE
Citation:
Rigas, M L., W. L. Roth, AND A M. Jarabek. PROPOSED MODELS FOR ESTIMATING RELEVANT DOSE RESULTING FROM EXPOSURES BY THE GASTROINTESTINAL ROUTE. 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:
Simple first-order intestinal absorption commonly used in physiologically-based pharmacokinetic(PBPK) models can be made to fit many clinical administrations but may not provide relevant information to extrapolate to real-world exposure scenarios for risk assessment. Small hydrophilic molecules may be absorbed rapidly by solvent drag in areas of the intestinal tract where net water absorption occurs. Lipophilic molecules may be absorbed more readily via other mechanisms and perhaps will be more well-absorbed if exposure occurs in a lipid matrix. We have developed a suite of four models ranging from the simple one compartment first-order model to a more complex tubular representation of the GI tract accounting mathematically for both convection and diffusion. The suite is designed to provide flexibility to the risk assessment process by best utilizing the disparate available data. By applying dimensional analysis to the solution of a convection-diffusion model of GI absorption, we can provide information as to what models and data would improve the risk assessment if data is available. Some non-linear factors that may be incorporated into model structures include but are not limited to active transport into or out of the GI lumen by transporter proteins and metabolism within intestinal tissue, possibly leading to local toxicity.
This work has been funded wholly or in part by the United States Environmental Protection Agency and has been approved for publication.