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A COMPARATIVE INVESTIGATION OF THE INFLUENCE OF DERMAL APPENDAGES (HAIR FOLLICLES) ON THE PERCUTANEOUS ABSORPTION OF ORGANOPHOSPHORUS (OP) INSECTICIDES USING QSAR AND PBPK/PD MODELS FOR HUMAN RISK ASSESSMENT
Citation:
TORNERO-VELEZ, R, C C. Dary, J. B. Knaak, F W. Power, AND M Dellarco. A COMPARATIVE INVESTIGATION OF THE INFLUENCE OF DERMAL APPENDAGES (HAIR FOLLICLES) ON THE PERCUTANEOUS ABSORPTION OF ORGANOPHOSPHORUS (OP) INSECTICIDES USING QSAR AND PBPK/PD MODELS FOR HUMAN RISK ASSESSMENT. Presented at International Society of Exposure Analysis, Stresa, Italy, September 21-25, 2003.
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:
The successful use of the Exposure Related Dose Estimating Model (ERDEM) for assessment of dermal exposure of humans to OP pesticides requires the input of representative and comparable input parameters. In the specific case of dermal exposure, regional anatomical variation in the rate of percutaneous absorption must be considered in order to make reasonable estimates of absorbed dose. To accomplish this assessment, estimates of hair follicle density were generated for various regions of the body including the scalp, forearms and hands. Quantitative Structure Activity Relationships (QSAR) were used to obtain Kp values (cm/h) for percutaneous absorption, skin/water and tissue/blood partition coefficients, and metabolic parameter values (Vmax and Km). Inhibition of the B-esterases (acetylcholin-, butyrylcholin- and carboxyl-) was used as the dose metric for the determination of margins of exposure (MOE) for exposure scenarios where various anatomical areas of the body may be implicated. Modeling results show the importance of considering regional variation in hair volume and density in exposure and risk assessment.
This work has been funded by the United States Environmental Protection Agency under Interagency Assistance Agreement (DW 47944301) to GSA. It has been subjected to Agency review and approved for publication.