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Prediction of dermal absorption of chemical mixtures using both penetrant and mixture component properties in a hybrid quantitative structure permeability relationship (QSPR).

Riviere-JE; Brooks-JD
Toxicologist 2005 Mar; 84(Suppl 1):450
Occupational and environmental exposure to topical chemicals is usually in the form of complex chemical mixtures, yet risk assessment is based on experimentally derived data from individual chemical exposures or computed physiochemical properties. We present an approach using modified QSPR models where absorption through two systems (porcine skin flow-through diffusion cells-PSFT and isolated perfused porcine skin flaps-IPPSF) are well predicted using a QSPR model describing the individual penetrants, coupled with a mixture/vehicle factor (MF) that accounts for physicochemical properties of the vehicle/mixture components. The baseline equation is log Kp = c + mMF + rR + s + a + b + vV where R is molar refractivity, and V the McGowan molecular volume of the penetrants of interest; c, m, r, s, a, b and v are strength coefficients coupling these descriptors to skin permeability (Kp) in PSFT (12 penetrants in 24 mixtures) or to AUC of the absorption flux profile in IPPSF (8 penetrants in 4 mixtures). Mixtures consisted of different combinations of vehicles (water, ethanol, propylene glycol) and additives (sodium lauryl sulfate, methyl nicotinate). Across all exposures with no MF, R2 for absorption was 0.68 in IPPSF and 0.58 in PSFT. With the MF, correlations increased to 0.74 for IPPSF and 0.85 for PSFT. The initial MF is a function of the Henry Constant for the mixture components, although other factors are presently being investigated. The importance of these findings is that there is an approach whereby the effects of a mixture on absorption of a penetrant of interest can be quantitated in a standard QSPR model if physicochemical properties of the mixture are also taken into account. The good correlations obtained in the IPPSF, which has previously shown to be predictive of in vivo human absorption, suggests that this approach merits attention.
Quantitative-analysis; Absorption-rates; Chemical-analysis; Occupational-exposure; Environmental-exposure; Chemical-reactions; Chemical-composition; Risk-factors; Risk-analysis; In-vivo-studies; Models; Synergism; Skin-irritants; Skin-sensitivity; Skin-exposure
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Priority Area
Work Environment and Workforce: Mixed Exposures
Source Name
The Toxicologist. Society of Toxicology 44th Annual Meeting and ToxExpo, March 6-10, 2005, New Orleans, Louisiana
Performing Organization
North Carolina State University, Raleigh, North Carolina