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.

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:

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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