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A physiologically based pharmacokinetic model of organophosphate dermal absorption.

Authors
van der Merwe-D; Brooks-JD; Gehring-R; Baynes-RE; Monteiro-Riviere-NA; Riviere-JE
Source
Toxicol Sci 2006 Jan; 89(1):188-204
NIOSHTIC No.
20029237
Abstract
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 microg/cm2 for parathion; 0.8-23.6 microg/cm2 for fenthion; 1.6-39.3 microg/cm2 for methyl parathion), different solvents (ethanol, 2-propanol and acetone), different solvent volumes (5-120 microl for ethanol; 20-80 microl 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.
Keywords
Models; Toxins; Toxic-effects; Risk-analysis; Pesticides; Pesticides-and-agricultural-chemicals; Absorption-rates; Solvents
CODEN
TOSCF2
Publication Date
20060101
Document Type
Journal Article
Funding Amount
746428
Funding Type
Grant
Fiscal Year
2006
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-007555
Issue of Publication
1
ISSN
1096-6080
Priority Area
Work Environment and Workforce: Mixed Exposures
Source Name
Toxicological Sciences
State
NC
Performing Organization
North Carolina State University, Raleigh, North Carolina
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