Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA.
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, Washington, USA.
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021 Sep;13(5):e1708. doi: 10.1002/wnan.1708. Epub 2021 Mar 25.
The Adverse Outcome Pathway (AOP) framework is serving as a basis to integrate new data streams in order to enhance the power of predictive toxicology. AOP development for engineered nanomaterials (ENM), including silver nanoparticles (AgNP), is currently lagging behind other chemicals of regulatory interest due to our limited understanding of the mechanism by which underlying genetics or diseases directly modify host response to AgNP exposures. This also highlights the importance of considering the Aggregate Exposure Pathway (AEP) framework, which precedes the AOP framework and outlines source to target site exposure. The AEP and AOP frameworks interface at the target site, where a molecular initiating event (MIE) occurs and is followed by key events (KE) for adverse cellular and organ responses along a biological pathway and ends with the adverse organism response. The primary goal of this study is to use AgNP to interrogate the AEP-AOP framework by organizing and integrating in vitro dose-response data and in vivo exposure-response data from previous studies to evaluate the effects of interactions between host genetic and acquired factors, or gene × environment interactions (G × E), on AgNP toxicity in the respiratory system. Using this framework will help us to identify plausible key event relationships (KER) between MIE and adverse organism responses when KE are not measured using the same assay in order to derive future predictive models, guide research, and support development of tools for making risk-based, regulatory decisions on ENM. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.
不良结局途径 (AOP) 框架可作为整合新数据流的基础，以增强预测毒理学的能力。由于我们对潜在遗传或疾病如何直接改变宿主对 AgNP 暴露的反应机制的理解有限，因此用于工程纳米材料 (ENM) 的 AOP 开发，包括银纳米颗粒 (AgNP)，目前落后于其他具有监管意义的化学物质。这也突出了考虑聚合暴露途径 (AEP) 框架的重要性，该框架先于 AOP 框架，并概述了从源到靶部位的暴露。AEP 和 AOP 框架在靶部位接口，在该部位发生分子起始事件 (MIE)，随后是沿着生物途径的不良细胞和器官反应的关键事件 (KE)，并以不良机体反应结束。本研究的主要目标是使用 AgNP 通过组织和整合来自先前研究的体外剂量反应数据和体内暴露反应数据来检验 AEP-AOP 框架，以评估宿主遗传和获得性因素之间的相互作用或基因 × 环境相互作用 (G × E) 对呼吸系统中 AgNP 毒性的影响。使用该框架将有助于我们在使用相同测定法未测量 KE 的情况下，确定 MIE 和不良机体反应之间的合理关键事件关系 (KER)，以便得出未来的预测模型，指导研究并支持开发用于基于风险的 ENM 监管决策的工具。本文属于以下类别：纳米药物毒理学和监管问题 > 纳米材料毒理学纳米药物毒理学和监管问题 > 纳米药物的监管和政策问题。
