A primary route of occupational exposure to toxic chemicals is often through the skin. Exposure to complex mixtures of chemicals is the norm in most of these settings. Although the mechanism of absorption of a single chemical has been well studied, effects of co-administered chemicals on absorption of a systemic toxicant may ultimately determine whether this potential toxicity is ever realized. Estimating exposure for risk assessment purposes under this scenario is difficult, as available databases are based on single chemical exposure. Our group has previously studied the nature of chemical interactions within a mixture that could modulate absorption across the skin. The objective of this present grant was to extend the analysis of chemical mixture interactions that affect percutaneous absorption to define the physical chemical characteristics of the mixture that allow significant mixture interactions to be detected. The ability of mixture components to modulate a chemical's rate and extent of percutaneous absorption and/or cutaneous deposition is dependent upon the physical chemical properties of the chemical that make it susceptible to specific chemical interactions; as well as the mechanism of percutaneous absorption that determines whether changes in skin permeability or vascular perfusion could further alter disposition. Such interactions that occur in the dosing solution and with the stratum corneum membrane are termed solvatochromatic and are susceptible to developing quantitative structure permeability relationships (QSPRs) using linear free energy relationships (LFERs). This grant studied the nature of mixture interactions using 12 compounds selected for physiochemical diversity as well as being representative of toxicologically significant classes': Substituted Phenols: nonylphenol, pentachlorophenol (PCP), phenol, p nitrophenol (PNP); Organophosphate Pesticides: chlorpyrifos, ethylparathion, fenthion, methylparathion; Triazines: atrazine, propazine, simazine, triazine. Mixtures consisted of three solvent systems (water, ethanol, propylene glycol) to which the surfactant sodium lauryl sulfate or methyl nicotinate were added. Complete factorial experiments were conducted in three model systems of increasing biological complexity: inert silastic and in vitro porcine skin diffusion cells, and ex vivo isolated perfused porcine skin flaps (IPPSF). Statistical techniques were used to define significant mixture interactions. QSPR of dermal absorption were formulated using LFER equations that account for solvatochromatic properties of the penetrants. A number of significant interactions were detected across all model systems that altered the normally linear relationship between a compound's octanol/water partition coefficient arid dermal permeability. Close examination of these data suggested that such effects may be predictable from the properties of the mixture in which the chemical was dosed. Surfactant and ethanol effects on absorption were closely examined. A correlation between the straltum corneum/mixture partition coefficient and ultimate dermal absorption across mixtures was determined, a finding that lends credence to developing LFER models of dermal absorption across mixtures. A modified LFER model based on molecular descriptors of the penetrants and physical properties of the mixtures was formulated. Mixture component interactions are quantitated as a Mixture Factor that is related to certain solution properties of the mixture components. This model resulted in better correlations (R2 of 0.76 versus 0.58) to absorption in both porcine skin model systems than was seen when a factor to account for mixture components was not included. Preliminary analysis indicate that half of the variability in the mixture factor could be accounted for using parameters describing the mixture [e.g. log (1/Henry Constant), vapor pressure, refractive index of the mixture, etc]. In conclusion, these data clearly demonstrate that mixture effects of compound absorption are reproducible across mixtures and compound classes. Dermal absorption of toxicologically relevant compounds can be predicted using generally accepted QSPR equations based on LFER principles if the presence of mixture components are accounted for in a modified equation. These data open up the potential for risk assessment strategies to incorporate a mixture's effect on compound absorption using a framework that is well accepted for single chemical dermal absorption estimation.