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Incorporation of complex chemical mixture effects into a QSAR model of dermal absorption.

Riviere-JE; Brooks-JD
Toxicologist 2007 Mar; 96(1):433
Significant progress has been made on predicting dermal absorption/penetration of topically applied compounds by developing quantitative structure activity relationship (QSAR) models based on linear free energy relations (LFER). However, all of these efforts have employed compounds applied to the skin in aqueous or single solvent systems, a dosing scenario that does not mimic occupational, environmental nor pharmaceutical exposure. We have explored using hybrid QSAR equations describing individual compound penetration based on the molecular descriptors for the compound modified by a mixture factor (MF) which accounts for the physiochemical properties of the vehicle/mixture components. The MF is calculated based on percentage composition of the vehicle/mixture components and physical chemical properties selected using principal components analysis. This model has previously been applied to 12 different compounds in 24 mixtures for a total of 288 treatment combinations obtained from flow-through porcine skin diffusion cells (Toxicol. Appl. Pharmacol. 208:99-110, 2005). The data reported here includes using three fundamentally different LFER models (Abraham, Potts and Guy, Hostynek and Magee) on this diffusion cell dataset as well as applying them to a new experimental dataset in the ex vivo isolated perfused porcine skin flap model consisting of 10 of the same compounds in 5 mixtures for a total of 50 treatment combinations. The use of the MF in combination with classic LFERs based on penetrant properties significantly improved the ability to predict dermal absorption of compounds dosed in complex chemical mixtures across three different LFER models and two biological systems.
Skin-absorption; Skin-disorders; Skin-exposure; Skin-irritants; Skin-sensitivity; Dermatitis; Dermatosis; Mathematical-models; Statistical-analysis; Skin-exposure; Chemical-properties; Physical-properties; Chemical-composition; Models; Cell-morphology; Cellular-reactions; Cellular-transport-mechanism
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Work Environment and Workforce: Mixed Exposures
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The Toxicologist. Society of Toxicology 46th Annual Meeting and ToxExpo, March 25-29, 2007, Charlotte, North Carolina
Performing Organization
North Carolina State University, Raleigh, North Carolina
Page last reviewed: September 2, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division