Toxicity testing and regulation of advanced materials at the nanoscale, i.e. nanosafety, is challenged by the growing number of nanomaterials and their property variants requiring assessment for potential human health impacts. The existing animal-reliant toxicity testing tools are onerous in terms of time and resources and are less and less in line with the international effort to reduce animal experiments. Thus, there is a need for faster, cheaper, sensitive and effective animal alternatives that are supported by mechanistic evidence. More importantly, there is an urgency for developing alternative testing strategies that help justify the strategic prioritization of testing or targeting the most apparent adverse outcomes, selection of specific endpoints and assays and identifying nanomaterials of high concern. The Adverse Outcome Pathway (AOP) framework is a systematic process that uses the available mechanistic information concerning a toxicological response and describes causal or mechanistic linkages between a molecular initiating event, a series of intermediate key events and the adverse outcome. The AOP framework provides pragmatic insights to promote the development of alternative testing strategies. This review will detail a brief overview of the AOP framework and its application to nanotoxicology, tools for developing AOPs and the role of toxicogenomics, and summarize various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development. The review also presents a network of AOPs derived from connecting all AOPs, which shows that several adverse outcomes induced by nanomaterials originate from a molecular initiating event that describes the interaction of nanomaterials with lung cells and involve similar intermediate key events. Finally, using the example of an established AOP for lung fibrosis, the review will discuss various in vitro tests available for assessing lung fibrosis and how the information can be used to support a tiered testing strategy for lung fibrosis. The AOPs and AOP network enable deeper understanding of mechanisms involved in inhalation toxicity of nanomaterials and provide a strategy for the development of alternative test methods for hazard and risk assessment of nanomaterials.

中文翻译：

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不良结果途径作为设计测试策略的工具，以支持纳米级新兴先进材料的安全评估。


纳米级先进材料的毒性测试和监管（即纳米安全）受到越来越多的纳米材料及其特性变体的挑战，需要评估潜在的人类健康影响。现有的动物毒性测试工具在时间和资源方面都非常繁重，并且越来越不符合国际上减少动物实验的努力。因此，需要有机械证据支持的更快、更便宜、敏感和有效的动物替代品。更重要的是，迫切需要制定替代测试策略，以帮助证明测试的战略优先顺序或针对最明显的不良结果、选择特定终点和测定以及识别高度关注的纳米材料。不良结果途径（AOP）框架是一个系统过程，它使用有关毒理学反应的可用机制信息，并描述分子起始事件、一系列中间关键事件和不良结果之间的因果或机制联系。 AOP 框架提供了实用的见解来促进替代测试策略的开发。本综述将详细介绍 AOP 框架及其在纳米毒理学中的应用、开发 AOP 的工具以及毒物基因组学的作用，并总结与目前处于不同开发阶段的纳米材料吸入毒性相关的各种 AOP。 该综述还提出了一个源自连接所有 AOP 的 AOP 网络，该网络表明纳米材料引起的几种不良后果源于描述纳米材料与肺细胞相互作用的分子起始事件，并涉及类似的中间关键事件。最后，以已建立的肺纤维化 AOP 为例，该综述将讨论可用于评估肺纤维化的各种体外测试，以及如何使用这些信息来支持肺纤维化的分层测试策略。 AOP 和 AOP 网络使人们能够更深入地了解纳米材料吸入毒性的机制，并为开发纳米材料危害和风险评估的替代测试方法提供策略。