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Towards a Generic PBPK Model of Pyrethroid Pesticides: Modeling Deltamethrin and Permethrin in the Rat

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Abstract: Pyrethroids have emerged as a major class of insecticide due to their selective potency in insects and their relatively low potency in mammalian studies. Pyrethroids exert toxicity by binding to voltage-gated sodium channels, thereby eliciting excitatory neurotoxicity. The Food Quality Protection Act (FQPA) of 1996 requires the US EPA to consider the cumulative effects (multiple chemicals by aggregate routes of exposure) of pesticides having a common mechanism of toxicity. In such evaluations it is necessary to accurately estimate the dose available to critical tissues. Towards this end, studies examining the pharmacokinetics of permethrin and deltamethrin in rodents were used to derive a common PBPK model structure. The model included skin, fat, liver, brain, and lumped tissue compartments. Physiological values were obtained from the literature. Tissue-blood partition coefficients were based on Log P and tissue composition. Diffusion-limited tissue uptake in all tissues provided a better visual fit to the data than flow-limited kinetics. Apparent coefficients of permeability were held constant for both pyrethroids at 5% of tissue flow for fat and muscle tissues, 2% for brain tissue, and 0.2% for richly perfused tissue. While the terminal half life of deltamethrin in blood was 2.5 times longer than permethrin, the kinetics of these two pyrethroids were adequately described by the same model structure. This initial modeling exercise suggests that the kinetics of other pyrethroids may be described by a common model structure. This may allow the development of a single unified PBPK model for use in the cumulative risk assessment of pyrethroid pesticides.

This work has been funded by the United States Environmental Protection Agency. It has been subjected to Agency review and approved for publication.
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Citation:Tornero-Velez, R., H. P. Nichols, M. V. Evans, M. J. Devito, C. C. Dary, M. Dellarco, and J. Blancato. Towards a Generic PBPK Model of Pyrethroid Pesticides: Modeling Deltamethrin and Permethrin in the Rat. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
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Contact: Liz Hope - (919) 541-2785 or hope.elizabeth@epa.gov
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Division: Human Exposure & Atmospheric Sciences Division
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Branch: Exposure & Dose Research Branch
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Product Type: Abstrct/Oral
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Presented: 03/23/2004
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Related Entries:
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Bullet Item Models and Modeling Methods for Assessing Human Exposure and Dose to Toxic Chemicals and Pollutants
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Last Updated on Monday, October 22, 2007
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