You are here:
SIMULATION MODELING OF GASTROINTESTINAL ABSORPTION
Citation:
Rigas, M L., J N. Blancato, AND F. W. Power. SIMULATION MODELING OF GASTROINTESTINAL ABSORPTION. Presented at Interagency Conference on Toxicology and Risk Assessment, Wright-Patterson AFB, OH, April 12-15, 1999.
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:
Mathematical dosimetry models incorporate mechanistic determinants of chemical disposition in a living organism to describe relationships between exposure concentration and the internal dose needed for PBPK models and human health risk assessment. Because they rely on deterministic physical and chemical properties, dosimetry models can reduce the variability and uncertainty in describing dose and can reduce interspecies uncertainty.
The gastrointestinal tract represents a physically complex site of absorption. In the simplest sense, it can be modeled as a plug-flow chemical reactor in which substances move down a tube by convection and material passes through the walls into the bloodstream by diffusion. However, active processes exist to transport ions and other materials from the gastrointestinal lumen into the systemic circulation. Anatomical variations between segments of the tract create different capacities for transport at different locations, and changes in motility affect the residence time in these segments. Longitudinal gradients in pH will cause changes in the aqueous solubility of chemicals and will ultimately affect their absorption. Using a mathematical dosimetry model, we demonstrate how some of these parameters affect the systemic concentrations of compounds such as trichloroethylene (TCE) and chlorothiazide.
The U.S. Environmental Protection Agency (EPA), through its Office of Research and Development, funded this research. The abstract has been subjected to Agency review and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use