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ORD PYRETHROIDS PROJECT
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,
The Food Quality Protection Act (FQPA) of 1996 requires the Agency to consider the cumulative effects of pesticides and other substances that act by a common mechanism. Under the mandates of FQPA, the Agency conducted a cumulative risk assessment for the organophosphate pesticides and is currently conducting an assessment on n-methyl carbamate pesticides. The available data for the pyrethroid insecticides is currently being reviewed to determine if this class of pesticide warrants a cumulative assessment. To aid in this review and to strengthen the basis for a cumulative assessment, the Agency has promoted a multi-disciplinary effort which includes several laboratories at EPA's Office of Research and Development (ORD) and the Office of Pesticide Programs (OPP). Researchers at the National Exposure Research Laboratory (NERL) are refining and applying their exposure and dose modeling tools to conduct a cumulative assessment. SHEDS (the Stochastic Human Exposure and Dose Simulation model) is NERL's probabilistic human exposure model; ERDEM (Exposure Related Dose Estimating Model) is our dose modeling tool. Measurement studies, data analysis, and SHEDS exposure modeling will be used to identify and quantify critical routes and pathways of exposure for the pyrethroid pesticides, and to assess population estimates of aggregate and cumulative pyrethroids exposure. This work will also identify the mixtures of pyrethroid pesticides that individuals are exposed to in real world situations. To understand the relationship between exposure and internal dose, NERL investigators are working closely with scientists in the National Health and Ecological Research Laboratory (NHEERL) to develop human physiologically based pharmacokinetic (PBPK) models of pyrethroids. The PBPK models will be used to interpret the exposure data and compute integrated dose metrics related to toxic outcome for multiple routes of exposures to pyrethroid mixtures. Ultimately, the models developed under this task will be applied to support OPPA's risk assessment of pyrethroids.