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Prediction of dermal absorption from complex chemical mixtures: incorporation of vehicle effects and interactions into a QSPR framework.

Authors
Riviere-JE; Brooks-JD
Source
SAR QSAR Environ Res 2007 Jan-Mar; 18(1-2):31-44
NIOSHTIC No.
20031884
Abstract
Significant progress has been made on predicting dermal absorption/penetration of topically applied compounds by developing QSPR 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 or pharmaceutical exposure. We have explored using hybrid QSPR equations describing individual compound penetration based on the molecular descriptors for the compound modified by a mixture factor (MF) which accounts for the physicochemical 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 been applied to 12 different compounds in 24 mixtures for a total of 288 treatment combinations obtained from flow-through porcine skin diffusion cells and in an additional dataset of 10 of the same compounds in five mixtures for a total of 50 treatment combinations in the ex vivo isolated perfused porcine skin flap. The use of the MF in combination with a classic LFER based on penetrant properties significantly improved the ability to predict dermal absorption of compounds dosed in complex chemical mixtures.
Keywords
Synergism; Skin-exposure; Skin-absorption; Solvents; Mathematical-models; Pharmacodynamics; Chemical-properties
Contact
Jim Riviere, Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606
CODEN
SQERED
Publication Date
20070316
Document Type
Journal Article
Email Address
Jim_Riviere@ncsu.edu
Funding Amount
746428
Funding Type
Grant
Fiscal Year
2007
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-007555
Issue of Publication
1-2
ISSN
1062-936X
Priority Area
Work Environment and Workforce: Mixed Exposures
Source Name
SAR and QSAR in Environmental Research
State
NC
Performing Organization
North Carolina State University, Raleigh, North Carolina
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