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

Area of Science:

• Dermatology and Pharmaceutical Sciences
• Biophysical Characterization of Skin
• In Vitro Testing Methodologies

Background:

• The in vitro permeation test (IVPT) using ex vivo human skin is crucial for assessing skin absorption of chemicals.
• Regulatory guidelines (FDA, OECD) mandate stratum corneum integrity screening before IVPT.
• Currently accepted methods include transepidermal water loss (TEWL), electrical resistance, and ³H₂O absorption.

Purpose of the Study:

• To retrospectively analyze the utility of ³H₂O absorption and TEWL as skin integrity tests.
• To evaluate the population attributes of a large dataset of human skin sections.
• To compare the effectiveness of integrity tests with actual drug permeation data.

Main Methods:

• Retrospective analysis of 17,330 skin sections from 459 donors.
• Comparison of ³H₂O absorption and TEWL data with permeation data for 25 topical drug products.
• Assessment of demographic factors (race, sex, age) on skin permeability.

Main Results:

• Water permeability varied by race (Blacks lower than Whites/Hispanics), sex (males higher), and age (decreased with age).
• ³H₂O absorption was a more sensitive indicator of permeability differences than TEWL.
• Correlation between ³H₂O absorption and drug absorption was minimal, with integrity tests failing to consistently identify drug outliers.

Conclusions:

• The findings question the reliability of the ³H₂O absorption test for predicting skin permeation in IVPT.
• The study suggests a critical reevaluation of the value of both ³H₂O and TEWL for ensuring stratum corneum integrity in IVPT.
• Current integrity screening methods may not adequately predict drug absorption outcomes.