Observations on the Tritiated Water and TEWL Skin Integrity Tests: Relevance to In Vitro Permeation Testing (IVPT).

Background: The in vitro permeation test (IVPT) using ex vivo human skin is a sensitive and robust model system that has been vital in elucidating the fundamental parameters surrounding the absorption of both therapeutic agents and industrial chemicals through skin. FDA and OECD IVPT Guidances recommend that each skin section selected for study should be screened prior to use to ensure that the stratum corneum integrity is retained. Three methods are currently considered acceptable: 1) transepidermal water loss (TEWL), 2) electrical resistance, and 3) tritiated water (³H₂O) absorption.

Methods: A retrospective analysis of data from the authors' laboratory has been performed with the objective of addressing a number of questions regarding the ³H₂O and TEWL integrity tests, and the population attributes of a large database consisting of 17,330 individual skin sections obtained from 459 skin donors. The applicability and usefulness of these tests, when compared to companion permeation data obtained from 25 topical drug products, has also been examined.

Results: Both integrity tests found water permeability to be equal in White and Hispanic races but higher than in Blacks, ³H₂O being more discriminating than TEWL. Male skin is more permeable than female and there is a slight decrease in permeability with advancing age in both groups. Correlation between ³H₂O absorption and drug absorption revealed a minimal relationship between the two in most cases, the Pearson correlation coefficient ranging from -0.417 to 0.953. Additionally, drug outliers were not always identified with a failing integrity test.

Conclusion: The results call for a critical reexamination of the value of the ³H₂O integrity test, and by extension, TEWL, for use in IVPT studies.