Validation of an In Vitro Human Airway Model

描述（由申请人提供）：危害评估，包括急性吸入毒性潜力评价，是国际商业中使用的化学品的强制性国际监管要求。急性吸入毒性或刺激可能性是制定化学品和化学品混合物的安全处理、包装、标签和运输程序以及制定紧急接触情况应对措施时的一个重要考虑因素。最近颁布的立法，包括欧盟（EU）化学品注册、标签和授权（REACH）计划，以及美国环保局高产量（HPV）化学品挑战，将大大增加对吸入毒性信息的需求。本资助提案的目标是验证EpiAirway体外人体气道模型，以根据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）指南预测体内人体吸入毒性危害潜力。第一阶段的实验产生了几个预测模型，将在目前的第二阶段项目中进一步测试。II期验证项目中将使用100种具有可用的人体或动物体内吸入毒性数据以及由NIOSH确定的对生命或健康有立即危险（IDLH）浓度的化学品。还将在4个实验室中使用从II期研究期间最初检测的100种化学品中选择的30种化学品子集评价该方法的实验室间可转移性。然后将提交研究数据进行独立统计分析，并将最终结果和报告提交给监管机构（即ICCVAM），以支持监管机构的认可。在目前的第二阶段提案中有待验证的技术将解决在全球范围内执行化学品吸入毒性测试要求的关键障碍，以及迫切需要但目前不存在的技术能力。开发的方法将提供一种变革性技术，促进从体内啮齿动物到体外人吸入毒理学试验的范式转变，这在最近的国家研究理事会报告“21世纪世纪的毒性试验：愿景和战略”中有所设想。 公共卫生相关性：危害评估，包括急性吸入毒性潜力的评价，是对国际商业中使用的化学品的强制性国际管制要求。急性吸入毒性或刺激可能性是制定化学品和化学品混合物的安全处理、包装、标签和运输程序以及制定紧急接触情况应对措施时的一个重要考虑因素。在目前的第二阶段提案中有待验证的技术将解决在全球范围内执行化学品吸入毒性测试要求的关键障碍，并提供迫切需要但目前不存在的技术能力。

DESCRIPTION (provided by applicant): Hazard assessment, including evaluation of acute inhalation toxicity potential, is a mandatory international regulatory requirement for chemicals utilized in international commerce. Acute inhalation toxicity or irritation potential is an important consideration in establishing procedures for the safe handling, packaging and labeling and transport of chemicals and chemical mixtures, and in formulating responses to emergency exposure situations. Recently enacted legislation including the European Union (EU) Registration, Labeling and Authorization of Chemicals (REACH) program, and the US EPA High production Volume (HPV) Chemical Challenge will dramatically increase the need for inhalation toxicity information. The goal of the present grant proposal is to validate the EpiAirway in vitro human airway model for prediction of in vivo human inhalation toxicity hazard potential following Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and European Center for Validation of Alternative Methods (ECVAM) guidelines. Phase I experiments produced several prediction models that will be further tested in the current Phase II project. One hundred chemicals that have available in vivo human or animal inhalation toxicity data and established immediately Dangerous to Life or health (IDLH) concentrations established by NIOSH will be utilized in the Phase II validation project. Interlaboratory transferability of the method will also be evaluated in 4 laboratories using a subset of 30 chemicals chosen from the original 100 tested during the Phase II study. The study data will then be submitted for independent statistical analysis and the final results and report will be submitted to regulatory agencies (i.e. ICCVAM) in support of regulatory acceptance. The technology to be validated in the current Phase II proposal will address a critical barrier to implementation of worldwide requirements for inhalation toxicity testing of chemicals, and a technical capacity that is urgently needed but that does not presently exist. The methodology developed will provide a transformative technology that will facilitate the paradigm shift from in vivo rodent to in vitro human inhalation toxicology testing envisioned in the resent National Research Council Report "Toxicity Testing in the 21st Century: A Vision and a Strategy". PUBLIC HEALTH RELEVANCE: Hazard assessment, including evaluation of acute inhalation toxicity potential, is a mandatory international regulatory requirement for chemicals utilized in international commerce. Acute inhalation toxicity or irritation potential is an important consideration in establishing procedures for the safe handling, packaging and labeling and transport of chemicals and chemical mixtures, and in formulating responses to emergency exposure situations. The technology to be validated in the current Phase II proposal will address a critical barrier to implementation of worldwide requirements for inhalation toxicity testing of chemicals, and provide a technical capability that is urgently needed but that does not presently exist.