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USE OF PBPK MODELS FOR ASSESSING ABSORBED DOSE AND CHE INHIBITION FROM AGGREGATE EXPOSURE OF INFANTS AND CHILDREN TO ORGANOPHOSPHORUS INSECTICIDES
Citation:
Blancato, J N., J. B. Knaak, F. W. Power, AND C C. Dary. USE OF PBPK MODELS FOR ASSESSING ABSORBED DOSE AND CHE INHIBITION FROM AGGREGATE EXPOSURE OF INFANTS AND CHILDREN TO ORGANOPHOSPHORUS INSECTICIDES. Presented at ISEA 2000 Exposure Analysis in the 21st Century: Integrating Science, Policy and Quality of Life, Monterey Peninsula, CA, October 24-27, 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:
A physiological pharmacokinetic (PBPK) modeling framework has been established to assess cumulative risk of dose and injury of infants and children to organophosphorus (OP) insecticides from aggregate sources and routes. Exposure inputs were drawn from all reasonable sources, primarily food and drinking water, inhaled air, and from dermal absorption of transferred surface residues. Michaelis-Menten kinetics were used to describe hydrolysis and activation of P=S containing OP insecticides to their corresponding oxons. Biomolecular rate constants were used to describe cholinesterase inhibition, a typical biomarker for these compounds. The disposition of products of activation and metabolism were traced in tissues, organs, fluid compartments and excreta. Mass balance summaries were generated to compare routes of exposure and sources of OP contamination. The assumption of "reasonable certainty of no harm" as expressed under the Food Quality Protection Act (FQPA) was examined based on the dynamic processing of modeling data.
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.