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PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODEL FOR PREDICTING THE DERMAL DOSE AND DISPOSITION OF ORGANOPHOSPHORUS INSECTICIDES
Citation:
Dary, C C., E J. Furtaw Jr., F W. Power, AND J N. Blancato. PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODEL FOR PREDICTING THE DERMAL DOSE AND DISPOSITION OF ORGANOPHOSPHORUS INSECTICIDES. Presented at Society for Risk Analysis Meeting, New Orleans, LA, December 8-11, 2002.
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:
Physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) models are particularly suited for interpretation of cumulative risk via the dermal route for which aggregate exposure must be assessed for chemicals having a common mechanism of toxicity. To this end, a quantitative structure-activity relationship (QSAR) database was compiled containing physicochemical descriptors and percutaneous absorption, pharmacokinetic, and metabolic parameter estimates, for 31 organophosphorus (OP) insecticides. The QSAR descriptors were obtained using molecular modeling software (HyperChem (registered) ChemPlus TM). Pharmacokinetic, metabolic, and percutaneous absorption parameter estimates were obtained from the published literature. Results indicate that QSAR techniques can provide reasonable estimates of pharmacokinetic, metabolic, and skin absorption parameter values for individual OP insecticides and mixtures for use in cumulative risk assessment. This approach holds great promise for advancing our understanding of a dynamic source-to-exposure-to-dose process involving aggregate exposure of infants and children to a broad range of organophosphorus (OP) insecticides with differing chemical structures. These dermal parameters were used in the Exposure Related Dose Estimating Model (a PBPK/PD model) to determine the relevant dose for exposure of children to OP insecticides, parathion, chlorpyrifos, and isofenphos.
The U.S. EPA Office of Research and Development funded this research. The abstract was reviewed and approved. The oral presentation has not been reviewed. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.