Chemical exposure in most occupational settings is to complex chemical mixtures rather than to individual chemicals. The estimation of dermal exposure for risk assessment purposes under this scenario is difficult, as most research is based on absorption of single chemicals. The existing grant upon which this renewal is based assessed the relationship of a compound's dermal penetration in three in vitro model systems to their stratum corneum/mixture and octanol/water partition coefficients, the latter being the primary parameter used in regulatory risk assessment models to predict dermal absorption. 12 chemicals of 3 classes were investigated in 3 solvent systems to which 2 additional chemical components were added. Mixture interactions changed the relationship between partitioning and absorption, suggesting that this risk assessment approach may not be optimal for mixture exposures. Based upon these results, this renewal proposes to explore this phenomenon in greater depth by expanding the data set to include another 12 chemicals chosen to reflect greater diversity of physical chemical properties. Disposition in mixtures containing surfactants and or water/ethanol gradients will be studied in more detail using additional physical chemical endpoints. A promising new tool to measure multiple partition coefficients under different mixture exposure scenarios, the membrane coated fiber, will also be utilized as it correlates to, and thus could replace, the more cumbersome diffusion cell experimental models used in the original research. The isolated perfused porcine skin flap model (IPPSF), previously shown to be predictive of chemical absorption in humans, will be the model used to assess the biological relevance of the interactions detected. This research should help develop a more quantitative and reproducible approach for assessing complex chemical mixture exposure, using novel humane alternative animal model systems with direct relevance to predicting dermal absorption in humans. ? ?
