Scientific Direction of Chemical and Physical Health Risks, Sciensano, Brussels, Belgium.
Laboratory of Toxicology, Unit of Environment and Health, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.
ALTEX. 2024 Jan 9;41(1):76-90. doi: 10.14573/altex.2305011. Epub 2023 Aug 21.
The adverse outcome pathway (AOP) framework plays a crucial role in the paradigm shift of toxicity testing towards the development and use of new approach methodologies. AOPs developed for chemicals are in theory applicable to nanomaterials (NMs). However, only initial efforts have been made to integrate information on NM-induced toxicity into existing AOPs. In a previous study, we identified AOPs in the AOP-Wiki associated with the molecular initiating events (MIEs) and key events (KEs) reported for NMs in scientific literature. In a next step, we analyzed these AOPs and found that mitochondrial toxicity plays a significant role in several of them at the molecular and cellular levels. In this study, we aimed to generate hypothesis-based AOPs related to NM-induced mitochondrial toxicity. This was achieved by integrating knowledge on NM-induced mitochondrial toxicity into all existing AOPs in the AOP-Wiki, which already includes mitochondrial toxicity as a MIE/KE. Several AOPs in the AOP-Wiki related to the lung, liver, cardiovascular and nervous system, with extensively defined KEs and key event relationships (KERs), could be utilized to develop AOPs that are relevant for NMs. However, the majority of the studies included in our literature review were of poor quality, particularly in reporting NM physicochemical characteristics, and NM-relevant mitochondrial MIEs were rarely reported. This study highlights the potential role of NM-induced mitochondrial toxicity in human-relevant adverse outcomes and identifies useful AOPs in the AOP-Wiki for the development of AOPs for NMs.
不良结局途径 (AOP) 框架在毒性测试向新方法学的开发和应用的范式转变中起着至关重要的作用。针对化学物质开发的 AOP 在理论上可适用于纳米材料 (NMs)。然而，仅初步努力将关于 NM 诱导毒性的信息整合到现有的 AOP 中。在之前的研究中，我们在 AOP-Wiki 中确定了与科学文献中报道的 NM 引起的毒性相关的 AOP，这些 AOP 与分子起始事件 (MIE) 和关键事件 (KE) 相关。在下一步中，我们分析了这些 AOP，发现线粒体毒性在其中几个 AOP 中在分子和细胞水平上起着重要作用。在这项研究中，我们旨在生成与 NM 诱导的线粒体毒性相关的基于假设的 AOP。这是通过将 NM 诱导的线粒体毒性知识整合到 AOP-Wiki 中所有现有的 AOP 中实现的，这些 AOP 已经将线粒体毒性作为 MIE/KE 包括在内。AOP-Wiki 中与肺、肝、心血管和神经系统相关的几个 AOP 具有广泛定义的 KEs 和关键事件关系 (KER)，可用于开发与 NMs 相关的 AOP。然而，我们文献综述中包含的大多数研究质量较差，特别是在报告 NM 物理化学特性方面，很少有报道与 NM 相关的线粒体 MIE。本研究强调了 NM 诱导的线粒体毒性在人类相关不良结局中的潜在作用，并确定了 AOP-Wiki 中用于开发 NM 的 AOP 的有用 AOP。
