EVALUATION OF THE USEFULNESS OF 3-D MODELS OF RECONSTITUTED HUMAN SKIN AND EPIDERMIS IN APPLICATIONS OF REGULATORY SKIN TOXICOLOGY: PREVALIDATION, VALIDATION, CATCH-UP VALIDATION, AND REGULATORY ACCEPTANCE.

In 1991 we evaluated a model of full human skin (Skin2, ATS, La Jolla) for phototoxicity testing. The test developed showed promising results as an adjunct to a test performed with Balb/c 3T3 cells. While it detected acute phototoxins correctly, it classified those chemicals negative, that are known photoallergic in humans, but are not phototoxic after single application (e.g., musk ambrette, 6-methycoumarin). The test was later evaluated in a blind trial with 30 chemicals with promising outcome. When the production of Skin2 was terminated in 1996, we evaluated together with P&G (Cincinnati, OH) and Beiersdorf AG (Hamburg, Germany) if human reconstituted epidermis, EpiDerm, (MatTek, Ashland, USA) could replace the full skin model. The outcome was excellent, confirming reproducibility between labs, and over time, as well as high predictivity. Currently, we are evaluating, if the EpiDerm test can sufficiently be used for photosafety testing of formulations and for testing of phototoxic potency. In a European validation study of four in vitro tests for predicting corrosive potential to the skin, two tests provided good predictivity, and have meanwhile gained full acceptance in the EU for regulatory applications. One of the accepted tests is using EPISKIN, a human reconstituted epidermis model. Since EPISKIN is currently not available, we have performed a ‘catch-up validation study’ together with two laboratories, BASF (Ludwigshafen, Germany) and HLS (Huntingdon, UK) to prove equivalence of EpiDerm with regard to structure and performance criteria. This study has meanwhile led to EU acceptance of the test. Current attempts to evaluate the use of 3D skin/epidermis models for skin irritancy testing and for assessment of percutaneous absorption will be addressed.

3-D, 3-Dimensional, BASF, Cutaneous irritancy, Cutaneous irritation, Cutaneous toxicity, Dermal absorption, Dermal irritancy, Dermal irritancy testing, Dermal irritation, Dermal penetration, Dermal permeation, EpiDerm, EpiSkin, European acceptance, HLS, Huntingdon, Percutaneous absorption, Percutaneous penetration, Photoallergens, Phototoxicity, Pre-validation, Prevalidation, Reconstructed human skin equivalents, Regulatory acceptance, Reproducibility, Reproducible, Skin irritancy, Skin irritation, Sun screens, Transdermal, UVA, UVB, Validation