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

Authors
Riviere-JE; Brooks-JD
Source
Toxicologist 2007 Mar; 96(1):433
NIOSHTIC No.
20031940
Abstract
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.
Keywords
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
Publication Date
20070301
Document Type
Abstract
Funding Amount
746428
Funding Type
Grant
Fiscal Year
2007
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
The Toxicologist. Society of Toxicology 46th Annual Meeting and ToxExpo, March 25-29, 2007, Charlotte, North Carolina
State
NC
Performing Organization
North Carolina State University, Raleigh, North Carolina
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