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PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF PERMETHRIN IN THE RAT
TORNERO-VELEZ, R., E. SCOLLON, J. M. STARR, M. F. HUGHES, M. J. DEVITO, AND C. C. DARY. PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF PERMETHRIN IN THE RAT. Presented at 2007 Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
A physiologically-based pharmacokinetic (PBPK) model was used to describe pharmacokinetics of permethrin and calibrated using experimental data on the concentration time-course of cis- and trans-permethrin in rat blood and brain tissues following oral administration.
The overall goal of this task is to develop state-of-the-art exposure and dose modeling tools to support OPP'S risk assessment of pyrethroids. Measurement data will be developed and analyzed both to provide inputs to and to evaluate the models. Combined exposure and dose models will permit an evaluation of the simultaneous exposures of pyrethroid pesticides that lead to cumulative risk. Specific objectives include:
(Subtask 1): Application of NERL's refined exposure model, SHEDS, to estimate exposures to pyrethroid pesticides. SHEDS will first be applied to conduct a probabilistic aggregate assessment for permethrin, which will be compared to other model predictions. SHEDS version 3 focuses on aggregate (single chemical, multiple pathway, co-occurrences of applications) exposures; version 4 will extend the aggregate version to cumulative (multiple chemical, multiple pathway, co-occurrences of applications) exposures to multiple pesticides over time. Both versions are expected to be completed in the summer of 2006. Analysis will be conducted on the available field measurement data (e.g., CTEPP, CHAMACOS, and Jacksonville studies) to develop inputs for SHEDS and to conduct model/model component evaluation. Collaboration with OPP will assist in collecting the best available application and label data to use in the fugacity module of SHEDS for predicting indoor residential concentrations. Usage data from the Residential Exposure Joint Venture (REJV) will also be used in SHEDS to assist with predicting population exposures.:
(Subtask 2): Evaluation of the fate and transport of pyrethroid pesticides in the indoor environment. The spatial and temporal distributions of four insecticides (cypermethrin, fipronil, permethrin and propoxur) will be examined in the Indoor Air Quality Research House following a simulated crack and crevice application. Measurements will provide information on airborne and surface concentrations resulting from the application. The findings will help to characterize the dispersion of insecticides with a house across their differing physio-chemical properties. In addition, the measures will contribute towards the evaluation of the source-to-concentration module (a fuagacity model) in SHEDS.:
(Subtask 3): Development of dosimetry, pharmacokinetic, pharmacodynamic models for pyrethroid pesticides. A provisional structure for a PBPK model of deltamethrin in the rodent has been developed in collaboration with the University of Georgia. The model is written in both ACSL and in Matlab. The model was developed using flow-limited (rapidly-perfused tissues) and diffusion-limited (brain, fat, and slowly-perfused tissues) differential equations to describe the pharmacokinetics of the insecticide. Metabolism of deltamethrin was accounted for in the liver and plasma. The PBPK model was robust in that its predictions compared favorably to experimental blood, plasma, brain, and fat deltamethrin profiles for most published datasets. We will employ the same model structure to evaluate the disposition of other pyrethroid in the rat. The studies serve an important role in developing PBPK models of pyrethroid disposition in humans. Due to paucity of human PK data for pyrethroids, models of pyrethroid disposition in humans will be developed based on human in vitro data and scaling from the rodent model. :
(Subtask 4): Evaluation of the importance of the dietary route for pyrethroid pesticides. Under FQPA, all pesticide food uses must be "safe"; that is, EPA must be able to conclude with "reasonable certainty that no harm will result from aggregate exposure" to each pesticide from dietary and other sources. As an estimate of general exposure to pyrethroids we will consider the levels of urinary metabolites of pyrethroids reported in the 2001-2002 U.S. National Health and Nutrition Examination Survey (NHANES). To estimate dietary exposure to these pyrethroids in the general population,
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL EXPOSURE RESEARCH LAB
HUMAN EXPOSURE AND ATMOSPHERIC SCIENCES DIVISION
EXPOSURE & DOSE RESEARCH BRANCH