Citation:

TORNERO-VELEZ, R, C C. Dary, M Dellarco, AND J Blancato. A PBPK MODEL OF PYRETHROID PESTICIDES FOR APPLICATION IN RISK ASSESSMENT. Presented at Exposure Assessment in a Changing Environment, Utrecht, The Netherlands, June 16-18, 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 are among the most potent and effective insecticides available, and are applied singly or in combination in agricultural and indoor insect control. The Food Quality Protection Act (FQPA) of 1996 requires the US EPA to consider the cumulative (multi-chemical) effects of exposure to pesticides having a 'common mechanism of toxicity'. For the risk assessment of pyrethroids, estimation of the extent of exposure and detailed knowledge of their kinetics is of prime importance. Towards this end, we have developed a physiologically-based pharmacokinetic (PBPK) model for evaluating dose resulting from residential and dietary exposures in humans. The application of PBPK models in risk assessment offers key benefits including: prediction of target dose, dose extrapolation in cases of non-linearity, and route of exposure extrapolation. In this project, studies examining the pharmacokinetics of permethrin and deltamethrin in rodents were used to derive the basic 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[Kow] and tissue composition. The model provides a systematic and quantitative framework for considering the impact of aggregate exposure routes (dermal, oral, inhalation). Human urinary excretion studies and computational methods were employed to derive parameters relevant to humans. The low coefficients of dermal permeability (Kp) of these highly lipophillic pesticides (Log[Kow]: 4.5-7) and their low volatility (Vapor Pressure: 10 -11 - 10 -7 mm Hg) suggest that the oral routes (dietary and oral non-dietary) and inhalation (aerosol) have greatest influence on target tissue dose. These preliminary findings will aid in shaping the development of a cumulative risk model of pyrethroids.

The opinions expressed in this manuscript are those of the author and do not reflect opinions or policy of the Environmental Protection Agency. Mention of trade names or commercial products does not constitute an endorsement or recommendation for use.

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