Tanabe Shihori, Hirose Akihiko, Whelan Maurice, Yamada Takashi
Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences.
European Commission, Joint Research Centre (JRC).
Yakugaku Zasshi. 2020;140(4):485-489. doi: 10.1248/yakushi.19-00190-2.
The Organisation for Economic Co-operation and Development (OECD) has initiated the adverse outcome pathway (AOP) Development Program in which the concept of AOP is applied to evaluate the safety of molecules such as chemicals. This program aims to assist regulatory needs and construct a knowledge base by accumulating AOP case studies. AOP consists of a molecular initiating event (MIE) as the initiating event of the pathway; key events (KEs) as the events themselves, such as cellular-molecular interactions; and adverse outcome (AO), such as signaling transduction-induced toxicity, as adverse events. KEs are extracted as important events at various levels, such as the molecular, cellular, tissue, organ, individual, and species levels; measurement of KEs and key event relationships (KERs), including mechanisms, plausibility, species differences, and empirical support information, are gathered. The development status of the AOP relating to histone deacetylase inhibition-induced testicular toxicity, currently being reviewed by the OECD, has been introduced. The AOP describing malignancies by Wnt ligand stimulation and Wnt signaling activation using gene expression network analysis-based mechanisms in molecular pathway elucidation has been suggested.
经济合作与发展组织（OECD）启动了不良结局途径（AOP）开发项目，该项目将AOP概念应用于评估化学品等分子的安全性。该项目旨在满足监管需求，并通过积累AOP案例研究来构建知识库。AOP由作为途径起始事件的分子起始事件（MIE）、作为事件本身的关键事件（KEs）（如细胞-分子相互作用）以及作为不良事件的不良结局（AO）（如信号转导诱导的毒性）组成。KEs作为分子、细胞、组织、器官、个体和物种等不同层面的重要事件被提取出来；收集KEs的测量数据以及关键事件关系（KERs），包括机制、合理性、物种差异和实证支持信息。介绍了目前经合组织正在审查的与组蛋白脱乙酰酶抑制诱导的睾丸毒性相关的AOP的发展状况。有人提出了在分子途径阐释中利用基于基因表达网络分析的机制通过Wnt配体刺激和Wnt信号激活来描述恶性肿瘤的AOP。
