Abstract

Significant advances have been made in the development of Adverse Outcome Pathways (AOPs) over the last decade, mainly focused on the toxicity mechanisms of chemicals. These AOPs, although relevant to manufactured nanomaterials (MNs), do not currently capture the reported roles of size-associated properties of MNs on toxicity. Moreover, some AOs of relevance to airborne exposures to MNs such as lung inflammation and fibrosis shown in animal studies may not be targeted in routine regulatory decision making. The primary objective of the present study was to establish an approach to advance the development of AOPs of relevance to MNs using existing, publicly available, nanotoxicology literature. A systematic methodology was created for curating, organizing and applying the available literature for identifying key events (KEs). Using a case study approach, the study applied the available literature to build the biological plausibility for ‘tissue injury’, a KE of regulatory relevance to MNs. The results of the analysis reveal the various endpoints, assays and specific biological markers used for assessing and reporting tissue injury. The study elaborates on the limitations and opportunities of the current nanotoxicology literature and provides recommendations for the future reporting of nanotoxicology results that will expedite not only the development of AOPs for MNs but also aid in application of existing data for decision making.

摘要

在过去十年中，不利结果途径 (AOP) 的发展取得了重大进展，主要集中在化学品的毒性机制上。这些 AOPs 虽然与人造纳米材料 (MNs) 相关，但目前并未捕捉到报道的 MNs 尺寸相关特性对毒性的作用。此外，动物研究中显示的一些与空气中暴露于 MN 相关的 AO，例如肺部炎症和纤维化，可能不会成为常规监管决策的目标。本研究的主要目的是建立一种方法，利用现有的、可公开获得的纳米毒理学文献来推进与 MN 相关的 AOP 的开发。创建了一个系统的方法来策划、组织和应用可用的文献来识别关键事件 (KE)。该研究采用案例研究方法，应用现有文献来建立“组织损伤”的生物学合理性，这是与 MN 监管相关的 KE。分析结果揭示了用于评估和报告组织损伤的各种终点、测定和特定生物标志物。该研究详细阐述了当前纳米毒理学文献的局限性和机会，并为未来报告纳米毒理学结果提供了建议，这不仅将加快 MN 的 AOP 的开发，而且有助于将现有数据应用于决策。用于评估和报告组织损伤的检测和特定生物标志物。该研究详细阐述了当前纳米毒理学文献的局限性和机会，并为未来报告纳米毒理学结果提供了建议，这不仅将加快 MN 的 AOP 的开发，而且有助于将现有数据应用于决策。用于评估和报告组织损伤的检测和特定生物标志物。该研究详细阐述了当前纳米毒理学文献的局限性和机遇，并为未来报告纳米毒理学结果提供了建议，这不仅将加快 MN 的 AOP 的开发，而且有助于将现有数据应用于决策。