Environmental Health Science and Research Bureau, Health Canada, Ottawa, K1A0K9, Canada.
Department of Biology, University of Ottawa, Ottawa, K1N6N5, Canada.
Small. 2021 Apr;17(15):e2007628. doi: 10.1002/smll.202007628. Epub 2021 Feb 9.
Faster, cheaper, sensitive, and mechanisms-based animal alternatives are needed to address the safety assessment needs of the growing number of nanomaterials (NM) and their sophisticated property variants. Specifically, strategies that help identify and prioritize alternative schemes involving individual test models, toxicity endpoints, and assays for the assessment of adverse outcomes, as well as strategies that enable validation and refinement of these schemes for the regulatory acceptance are needed. In this review, two strategies 1) the current nanotoxicology literature review and 2) the adverse outcome pathways (AOPs) framework, a systematic process that allows the assembly of available mechanistic information concerning a toxicological response in a simple modular format, are presented. The review highlights 1) the most frequently assessed and reported ad hoc in vivo and in vitro toxicity measurements in the literature, 2) various AOPs of relevance to inhalation toxicity of NM that are presently under development, and 3) their applicability in identifying key events of toxicity for targeted in vitro assay development. Finally, using an existing AOP for lung fibrosis, the specific combinations of cell types, exposure and test systems, and assays that are experimentally supported and thus, can be used for assessing NM-induced lung fibrosis, are proposed.
需要更快、更便宜、更敏感的基于机制的动物替代方法来满足越来越多的纳米材料（NM）及其复杂特性变体的安全性评估需求。具体来说，需要帮助识别和优先考虑替代方案的策略，这些方案涉及单独的测试模型、毒性终点和用于评估不良后果的检测，以及能够验证和完善这些方案以获得监管机构认可的策略。在这篇综述中，介绍了两种策略：1）当前纳米毒理学文献综述和 2） 不良结局途径（AOPs）框架，这是一个系统的过程，允许以简单的模块化格式组装关于毒性反应的可用机制信息。该综述重点介绍了 1）文献中最常评估和报告的特定体内和体外毒性测量，2）与 NM 吸入毒性相关的各种正在开发的 AOPs，以及 3）它们在识别靶向体外检测发展的毒性关键事件方面的适用性。最后，使用现有的肺纤维化 AOP，提出了实验支持的特定细胞类型、暴露和测试系统以及检测组合，可用于评估 NM 诱导的肺纤维化。
