The Tritiated Water Skin Barrier Integrity Test: Considerations for Acceptance Criteria with and Without .sup.14C-Octanol

Purpose A study was designed to assess barrier integrity simultaneously using separate compounds (probes) for polar and non-polar pathways through the skin, .sup.3H.sub.2O and .sup.14C-octanol, respectively; and to determine whether the two probe approach could better define barrier integrity. Methods A 5-min dose of water containing .sup.3H.sub.2O and .sup.14C -octanol was applied to ex vivo human skin mounted in Franz diffusion cells. The receptor solution was sampled at 30 min, analyzed for .sup.3H and .sup.14C content, and the correlation between water and octanol absorption was determined by statistical tests suitable for non-normally distributed data. This study was conducted on skin from 37 donors with from 3 to 30 replicate skin sections per donor (a total of 426 sections). Results The correlation between .sup.3H.sub.2O and .sup.14C-octanol absorption was low (Pearson correlation coefficient = 0.3485). The .sup.3H.sub.2O absorption cutoff used in this study to select for a normal skin barrier rejected some sections in which .sup.14C-octanol absorption was within normal limits and accepted others in which .sup.14C-octanol absorption was abnormally high. The converse was true for .sup.3H.sub.2O absorption when the .sup.14C-octanol-based cutoff was used. Conclusions The results of the .sup.3H.sub.2O test or of similar tests that primarily assess the permeability of polar pathways through the skin may not necessarily provide information relevant to the absorption of highly lipophilic compounds. Octanol, or another molecule that more closely matches the physicochemical attributes of the test compound, may characterize properties of the skin barrier that are more relevant to compounds of low water solubility.