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ToxSci Advance Access originally published online on October 12, 2005
Toxicological Sciences 2006 89(1):188-204; doi:10.1093/toxsci/kfj014
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A Physiologically Based Pharmacokinetic Model of Organophosphate Dermal Absorption

D. van der Merwe, J. D. Brooks, R. Gehring, R. E. Baynes, N. A. Monteiro-Riviere and J. E. Riviere1

Center for Chemical Toxicology Research and Pharmacokinetics, College of Veterinary Medicine, NC State University, Raleigh, North Carolina, 27606

Received August 10, 2005; accepted September 29, 2005

The rate and extent of dermal absorption are important in the analysis of risk from dermal exposure to toxic chemicals and for the development of topically applied drugs, barriers, insect repellents, and cosmetics. In vitro flow-through cells offer a convenient method for the study of dermal absorption that is relevant to the initial processes of dermal absorption. This study describes a physiologically based pharmacokinetic (PBPK) model developed to simulate the absorption of organophosphate pesticides, such as parathion, fenthion, and methyl parathion through porcine skin with flow-through cells. Parameters related to the structure of the stratum corneum and solvent evaporation rates were independently estimated. Three parameters were optimized based on experimental dermal absorption data, including solvent evaporation rate, diffusivity, and a mass transfer factor. Diffusion cell studies were conducted to validate the model under a variety of conditions, including different dose ranges (6.3–106.9 µg/cm2 for parathion; 0.8–23.6 µg/cm2 for fenthion; 1.6–39.3 µg/cm2 for methyl parathion), different solvents (ethanol, 2-propanol and acetone), different solvent volumes (5–120 µl for ethanol; 20–80 µl for 2-propanol and acetone), occlusion versus open to atmosphere dosing, and corneocyte removal by tape-stripping. The study demonstrated the utility of PBPK models for studying dermal absorption, which can be useful as explanatory and predictive tools that may be used for in silico hypotheses generation and limited hypotheses testing. The similarity between the overall shapes of the experimental and model-predicted flux/time curves and the successful simulation of altered system conditions for this series of small, lipophilic compounds indicated that the absorption processes that were described in the model successfully simulated important aspects of dermal absorption in flow-through cells. These data have direct relevance to topical organophosphate pesticide risk assessments.

Key Words: dermal absorption; PBPK model; parathion; fenthion; methyl parathion.


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