Permeation of water contaminative phenols through hairless mouse skin.

As a means of determining the risk of absorption of water contaminative phenolic compounds through the skin, the permeat ion of a number of phenols, all on the U.S. Environmental Protection Agency ' s list of priority pollutants, through hairless mouse skin has been studied, using in vitro diffusion cell methods. Experimentally determined permeability coefficients through intact skin and stratum corneum denuded skin and permeability coefficients derived therefrom for the viable tissue layer and the stratum corneum, which are the tissue's major contributing substrata, have been correlated with their log Koctanol/wate r partition coefficients. Permeability coefficients for the whole skin and the stratum corneum systematically increased with increasing phenol lipophilicity to limiting values of about 0.15 and 0.30 cm/hr, respectively. The values of the permeability coefficients for the viable tissue were roughly the same for all compounds (~0.36 cm/hr). Because of the inductive effects of C1 and NO 2 substituents on the aromatic ring, phenolic analogs containing these moieties are acidic and, consequently, their overall skin permeabilities were highly pH-dependent in the range of pH values seen for surface waters. High fluxes were noted for such phenols at low pH, where they exist essentially in a non-ionized state. Though low, fluxes of the compounds were measurCurrent addresses: Squibb Institute for Medical Research, R O. Box 191, New Brunswick, NJ 08903. 2 Pharmacy Research Unit, The Upjohn Co., Kalamazoo, MI 49001. 3 To whom all correspondence should be addressed. 4 Kan tonssp i t a l B rude rho lz Pha rmaceu t i ca l Depar tmen t , CH-4101 Bruderholz BL, Switzerland. able at pH ' s >> pKa's, indicating that phenoJic anions also pass through the skin. With the exceptions of relatively polar phenol and the mono-nitro phenols, the free acid forms of all the phenols studied permeated skin with ease and at rates approaching those of denuded skin. The intact skin permeability coefficient of the free acid form of 4+ nitro phenol was exceptionally tow, which suggests that it might associate intermolecularly. Certain toxic compounds are found as contaminants of industrial waste streams and migrate into the aquifer and national watershed. By and large, it is unclear what risk trace levels of these pollutants present to individuals who unsuspectingly drink or bathe in the contaminated waters. The relative risk of absorption of such agents through the skin is especially difficult to put into proper perspective as the kinetics of skin permeation are unknown for all but a few of the compounds of interest. More than 101) compounds, many of them phenols, have been identified by the United States Environmental Protection Agency as significant waterborne pollutants and the potential extent of skin absorption relative to the potential of uptake by other modes of exposure needs to be established. The present study deals with pollutant phenols and was undertaken: (a) to determine the kinetics of skin permeation of phenol and certain of its analogs, (b) to investigate the pH dependency of the permeability of these compounds, (c) to put these compounds into a structure-permeability framework for eventual toxic risk assessment of all compounds of structural similarity and, finally, (d) to provide estimates of the possible skin uptake of the investigated compounds. The studies were made 558 A .S . Huq et al. with hairless mouse skin as the model skin for the assessment of the permeation kinetics. Permeability studies, using whole and stripped skin, were done to determine the separate diffusional resistance contributions of the stratum corneum and viable tissue layer to the skin permeation of each compound.