Globally Harmonized In Vitro Skin Irritation Assay

说明(申请人提供)：确定皮肤刺激潜力与公共健康的相关性是对化学品危害识别/评估的国际法规要求，对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、配料和家居用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、标签和授权计划(REACH)、美国环保局高生产量(HPV)化学品挑战和欧盟“化妆品指令”禁止化妆品在动物身上进行测试，将极大地增加对体外皮肤刺激性评估方法的需求。为了满足对监管认可的体外皮肤刺激性测试方法的迫切需求，本拨款提案的目标是根据全球协调系统(GHS)验证Epiderm体外人体皮肤刺激性模型。将利用机构间替代方法验证协调委员会(ICCVAM)和欧洲替代方法验证中心(ECVAM)制定的验证指南。最初，已知体内皮肤刺激潜力的测试化学品将应用于Epiderm模型，以确定体外皮肤刺激生物标记物。将建立一个预测模型，将体外生物标记物的反应转换为体内GHS皮肤刺激分类(即刺激性、轻度刺激性和非刺激性)。模型和测试方法将用更大的化学品测试集进一步评估，以确定其有效性和总体预测能力。最后，其他测试将确定该分析方法的实验室内重复性和实验室间可转移性。这些第一阶段目标的成功完成将构成初步验证程序，以确定在第二阶段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对化学品危害识别/评估的一项国际法规要求，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估化妆品、配料和家居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、标签和授权计划(REACH)、美国环保局高生产量(HPV)化学品挑战和欧盟“化妆品指令”禁止化妆品在动物身上进行测试，将极大地增加对体外皮肤刺激性评估方法的需求。为了满足对监管认可的体外皮肤刺激性测试方法的迫切需求，本拨款提案的目标是根据全球协调系统(GHS)验证Epiderm体外人体皮肤刺激性模型。将利用机构间替代方法验证协调委员会(ICCVAM)和欧洲替代方法验证中心(ECVAM)制定的验证指南。最初，已知体内皮肤刺激潜力的测试化学品将应用于Epiderm模型，以确定体外皮肤刺激生物标记物。将建立一个预测模型，将体外生物标记物的反应转换为体内GHS皮肤刺激分类(即刺激性、轻度刺激性和非刺激性)。模型和测试方法将用更大的化学品测试集进一步评估，以确定其有效性和总体预测能力。最后，其他测试将确定该分析方法的实验室内重复性和实验室间可转移性。这些第一阶段目标的成功完成将构成初步验证程序，以确定在第二阶段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.