In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114-134, 2020. © 2019 Wiley Periodicals, Inc.

中文翻译：

---

不良后果途径框架在遗传毒性作用模式中的应用。

2017年5月，健康与环境科学研究所的遗传毒理学技术委员会主持了一个研讨会，讨论是否可以通过应用不良结果途径（AOP）框架来增强行动模式（MOA）调查。由于AOP是遗传毒理学中一个相对较新的方法，因此本报告介绍了如何利用五个示例案例研究来利用AOP来推进对遗传毒性途径的MOA分析。建议进一步开发的这些遗传毒理学AOP均包括相关的分子引发事件，关键事件和不良后果（AO），鉴定和/或进一步开发将试剂与这些事件联系起来的适当测定方法，以及有关生物学的讨论拟议AOP的合理性。这些提议的遗传毒理学AOP与传统AOP之间的主要区别在于，与生物体或种群的不利状态相比，AO是在风险表征中具有潜在重要意义的遗传毒理学终点。前两个详细的案例研究描述了抑制Aurora激酶和微管蛋白结合的临时AOP，导致非整倍性的常见AO。其余三个案例研究重点介绍了通过间接DNA相互作用（抑制拓扑异构酶II，产生细胞活性氧和抑制DNA合成）导致染色体断裂或突变的临时AOP。这些案例研究是遗传毒性AOP的起点，遗传毒性AOP最终会被更广泛的毒理学界发布和使用，并说明了将此类AOP正式化所需的实际考虑因素和证据，以便可以将其应用于遗传毒性评估方案。环境。大声笑 诱变剂。2020年61：114-134。©2019 Wiley Periodicals，Inc.