Development of a Cumulative Dermal Absorption Model by Linkage to a PBPK Model for Chlorpyrifos and Diazinon

Abstract

WM3-PD-12 Introduction: In light of the Food Quality Protection Act of 1996, it has become increasingly important to assess cumulative exposure to pesticides having the same toxicologic endpoint. For some pesticides, the dermal route might be dominant. Most current mathematical skin absorption models treat the skin as one membrane. However, we have previously presented a dermal absorption model with 2 distinct membranes (ie, stratum corneum and viable epidermis). This 2-layer, time-variant dermal absorption model has been linked to a cumulative physiologically based pharmacokinetic (PBPK) model for diazinon and chlorpyrifos, allowing body burden estimates of parent compounds and metabolites. Methods: Separate PBPK models were developed for diazinon and chlorpyrifos to characterize their body distribution. Additional modules were added to the PBPK models to characterize the common metabolites (dialkyl phosphates [DAPs]) of diazinon and chlorpyrifos. These modules are linked to the main models through metabolism in the liver and blood. The dermal absorption model is linked to the PBPK models through blood flow to the exposed skin. To assess the distribution of common metabolites after cumulative exposure events, the PBPK models for diazinon and chlorpyrifos were linked through their common metabolite modules. Model parameters include diffusivities in skin layers, partition coefficients, and physiologic and metabolic parameters. Outputs include time course profiles of blood, urine, and tissue concentrations of the parent compounds and metabolites. Results: Input parameters were estimated using several methods. Validation of linked dermal absorption PBPK models was conducted separately for diazinon and chlorpyrifos. In each case, the model was used to simulate multiple human exposure studies available in experimental literature. In these studies, a known amount of the pesticide was applied to skin, and urine metabolite concentrations were measured over time. For diazinon, with refinement of a few input parameter estimation techniques, both the shape and amplitude of the urine time profile for the metabolites were successfully simulated. In the experimental study, dermal absorption resulted in excretion of 1550 nmol of DAPs in 70 hours, or 0.47% of the applied dose. Model estimates were 1380 nmol DAPs or 0.42% of applied dose. Similar success was achieved for chlorpyrifos. Discussion: The validated cumulative dermal absorption PBPK model for chlorpyrifos and diazinon is helpful in assessing the importance of the dermal exposure route. For dermal exposure to chlorpyrifos and diazinon, it can be used to assess their relative contributions to urine metabolite levels. However, simulations are limited by input parameter accuracy and experimental study uncertainty used for validation.