Globally Harmonized In Vitro Skin Irritation Assay

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DESCRIPTION (provided by applicant):PUBLIC HEALTH RELEVANCE Determination of skin irritation potential is an international regulatory requirement for hazard identification/assessment of chemicals, and is important in establishing procedures for the safe handling, packaging, labeling and transport of chemicals and chemical mixtures, as well as evaluation of irritation potential of cosmetic products, ingredients and household productions. Recently enacted legislation including the European Union Registration, Labeling and Authorization of Chemicals (REACH) program, the US EPA High Production Volume (HPV) Chemical Challenge and EU "cosmetics directive" ban on the testing of cosmetics on animals will dramatically increase the need for in vitro skin irritation assessment methods. To fulfill the urgent need for a regulatory accepted in vitro skin irritation test method, the goal of the present grant proposal is to validate the EpiDerm in vitro human skin model for skin irritation according to the "Globally Harmonized System" (GHS). Validation guidelines developed by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and European Center for the Validation of Alternative Methods (ECVAM) will be utilized. Initially, test chemicals with known in vivo skin irritation potential will be applied to the EpiDerm model to identify in vitro skin irritation biomarkers. A prediction model will be established for converting in vitro biomarker responses into in vivo GHS skin irritation classifications (i.e. irritant, mild irritant and non-irritants). The model and test methods will be further evaluated with a larger test set of chemicals to determine its validity and overall predictive ability. Finally, additional tests will determine intra-laboratory reproducibility and inter-laboratory transferability of the assay method. Successful completion of these Phase I Aims will constitute the pre-validation process for establishing the feasibility of proceeding to full formal validation in Phase II studies. Determination of skin irritation potential is an international regulatory requirement for hazard identification/assessment of chemicals, and is important in establishing procedures for the safe handling, packaging, labeling and transport of chemicals and chemical mixtures, as well as evaluation of irritation potential of cosmetic products, ingredients and household productions. Recently enacted legislation including the European Union Registration, Labeling and Authorization of Chemicals (REACH) program, the US EPA High Production Volume (HPV) Chemical Challenge and EU "cosmetics directive" ban on the testing of cosmetics on animals will dramatically increase the need for in vitro skin irritation assessment methods. To fulfill the urgent need for a regulatory accepted in vitro skin irritation test method, the goal of the present grant proposal is to validate the EpiDerm in vitro human skin model for skin irritation according to the "Globally Harmonized System" (GHS). Validation guidelines developed by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and European Center for the Validation of Alternative Methods (ECVAM) will be utilized. Initially, test chemicals with known in vivo skin irritation potential will be applied to the EpiDerm model to identify in vitro skin irritation biomarkers. A prediction model will be established for converting in vitro biomarker responses into in vivo GHS skin irritation classifications (i.e. irritant, mild irritant and non-irritants). The model and test methods will be further evaluated with a larger test set of chemicals to determine its validity and overall predictive ability. Finally, additional tests will determine intra-laboratory reproducibility and inter- laboratory transferability of the assay method. Successful completion of these Phase I Aims will constitute the pre-validation process for establishing the feasibility of proceeding to full formal validation in Phase II studies.