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Predicting skin permeability from complex chemical mixtures: the impact of biological skin model systems on quantitative structure permeation relationships (QSPR).
Toxicologist 2011 Mar; 120(Suppl 2):136
Dermal absorption of topically applied chemicals usually occurs from complex chemical mixtures, yet most attempts to predict dermal permeability use data collected from aqueous binary mixtures. The focus of this research was to develop absorption from mixtures through skin using two different in vitro porcine skin biological systems. A total of 16 diverse chemicals were applied in 384 treatment combinations in pig skin flow-through diffusion cells (PSFT) and 20 chemicals in 119 treatment combinations in the isolated perfused porcine skin flap (IPPSF). Apparent permeability coefficient (kp*) was calculated using chemical flux into perfusate in the PSFT, while area under the curve (AUC) was calculated for the IPPSF. These data were then fit with a modified Abraham and Martin dermal QSPR model including a sixth term called a mixture factor (MF) to account for mixture interactions based on physico-chemical properties of the mixture components. Goodness of fit was assessed using correlation coefficients (r2), internal and external validation metrics q2(LOO') q2(L25%') q2(EXT), and applicable chemical domain. Different mixture factors were needed for each model system. Based on standard deviation and p-values of the model parameters greater than alpha=0.05, the Abraham and Martin model could be reduced to four terms plus the MF for each biological system. The term which could be eliminated from each model differed in the PSFT (hydrogen-bond acceptor basicity) and in the IPPSF (dipolarity/polarizability). These findings suggest that a QSPR model for estimating apparent kp* as a function of chemical mixture composition is possible and that the nature of the QSPR model selected is dependent upon the biological level of the in vitro test system used. Both of these findings having implications when dermal absorption data is used for in vivo risk assessments.
Biological-effects; Cell-function; Cellular-function; Cellular-reactions; Exposure-assessment; Exposure-levels; Immune-reaction; Laboratory-testing; Physiological-effects; Quantitative-analysis; Risk-analysis; Risk-factors; Skin-absorption; Skin-exposure; Skin-irritants; Skin-sensitivity; Statistical-analysis
Work Environment and Workforce: Mixed Exposures
The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC
North Carolina State University, Raleigh, North Carolina
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