Probabilistic modeling of percutaneous absorption for risk-based exposure assessments and transdermal drug delivery

1 Chemical transport through human skin can play a significant role in human exposure to toxic 2 chemicals in the workplace, as well as to chemical/biological warfare agents in the battlefield. 3 The viability of transdermal drug delivery also relies on chemical transport processes through the 4 skin. Models of percutaneous absorption are needed for risk-based exposure assessments and drug5 delivery analyses, but previous mechanistic models have been largely deterministic. A probabilistic, 6 transient, three-phase model of percutaneous absorption of chemicals has been developed to assess 7 the relative importance of uncertain parameters and processes that may be important to risk8 based assessments. Penetration routes through the skin that were modeled include the following: 9 (1) intercellular diffusion through the multiphase stratum corneum; (2) aqueous-phase diffusion 10 through sweat ducts; and (3) oil-phase diffusion through hair follicles. Uncertainty distributions 11 were developed for the model parameters, and a Monte Carlo analysis was performed to simulate 12 probability distributions of mass fluxes through each of the routes. Sensitivity analyses using stepwise 13 linear regression were also performed to identify model parameters that were most important to 14 the simulated mass fluxes at different times. This probabilistic analysis of percutaneous absorption 15 (PAPA) method has been developed to improve risk-based exposure assessments and transdermal 16 drug-delivery analyses, where parameters and processes can be highly uncertain. 17 © 2004 Elsevier B.V. All rights reserved. 18