Globally Harmonized In Vitro Skin Irritation Assay

描述（由申请人提供）：公共卫生相关性皮肤刺激潜力的测定是化学品危害识别/评估的国际法规要求，对于建立化学品和化学混合物的安全处理、包装、标签和运输程序以及评价化妆品、成分和家用产品的刺激潜力非常重要。最近颁布的立法，包括欧盟化学品注册、标签和授权（REACH）计划、美国环保署高产量（HPV）化学品挑战和欧盟禁止在动物身上测试化妆品的“化妆品指令”，将大大增加对体外皮肤刺激评估方法的需求。为了满足监管机构对可接受的体外皮肤刺激试验方法的迫切需求，本赠款提案的目标是根据“全球协调制度”（GHS）验证EpiDerm体外人体皮肤模型的皮肤刺激性。将使用替代方法验证机构间协调委员会（ICCVAM）和欧洲替代方法验证中心（ECVAM）制定的验证指南。最初，将具有已知体内皮肤刺激潜力的测试化学品应用于EpiDerm模型，以识别体外皮肤刺激生物标志物。将建立一个预测模型，用于将体外生物标志物反应转换为体内GHS皮肤刺激分类（即刺激性、轻度刺激性和非刺激性）。将使用更大的化学品测试集对模型和测试方法进行进一步评估，以确定其有效性和总体预测能力。最后，额外的检测将确定试验方法的实验室内重现性和实验室间可转移性。这些I期目标的成功完成将构成预验证过程，以确定在II期研究中进行全面正式验证的可行性。皮肤刺激潜力的测定是化学品危害识别/评估的国际法规要求，在建立化学品和化学混合物的安全处理、包装、标签和运输程序以及评估化妆品、成分和家用产品的刺激潜力方面非常重要。最近颁布的立法，包括欧盟化学品注册、标签和授权（REACH）计划、美国环保署高产量（HPV）化学品挑战和欧盟禁止在动物身上测试化妆品的“化妆品指令”，将大大增加对体外皮肤刺激评估方法的需求。为了满足监管机构对可接受的体外皮肤刺激试验方法的迫切需求，本赠款提案的目标是根据“全球协调制度”（GHS）验证EpiDerm体外人体皮肤模型的皮肤刺激性。将使用替代方法验证机构间协调委员会（ICCVAM）和欧洲替代方法验证中心（ECVAM）制定的验证指南。最初，将具有已知体内皮肤刺激潜力的测试化学品应用于EpiDerm模型，以识别体外皮肤刺激生物标志物。将建立一个预测模型，用于将体外生物标志物反应转换为体内GHS皮肤刺激分类（即刺激性、轻度刺激性和非刺激性）。将使用更大的化学品测试集对模型和测试方法进行进一步评估，以确定其有效性和总体预测能力。最后，额外的检测将确定试验方法的实验室内重现性和实验室间可转移性。这些I期目标的成功完成将构成预验证过程，以确定在II期研究中进行全面正式验证的可行性。

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.