Myden Alun, Stalford Susanne A, Fowkes Adrian, White Emma, Hirose Akihiko, Yamada Takashi
Lhasa Limited, Granary Wharf House, 2 Canal Wharf, Leeds LS11 5PS, United Kingdom.
Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki 210-9501, Japan.
Curr Res Toxicol. 2023 Sep 15;5:100124. doi: 10.1016/j.crtox.2023.100124. eCollection 2023.
Integrated approaches to testing and assessments (IATAs) have been proposed as a method to organise new approach methodologies in order to replace traditional animal testing for chemical safety assessments. To capture the mechanistic aspects of toxicity assessments, IATAs can be framed around the adverse outcome pathway (AOP) concept. To utilise AOPs fully in this context, a sufficient number of pathways need to be present to develop fit for purpose IATAs. approaches can support IATA through the provision of predictive models and also through data integration to derive conclusions using a weight-of-evidence approach. To examine the maturity of a developmental and reproductive toxicity (DART) AOP network derived from the literature, an assessment of its coverage was performed against a novel toxicity dataset. A dataset of diverse compounds, with data from studies performed according to OECD test guidelines TG-421 and TG-422, was curated to test the performance of an model based on the AOP network - allowing for the identification of knowledge gaps within the network. One such gap in the knowledge was filled through the development of an AOP stemming from the molecular initiating event 'glutathione reaction with an electrophile' leading to male fertility toxicity. The creation of the AOP provided the mechanistic rationale for the curation of pre-existing structural alerts to relevant key events. Integrating this new knowledge and associated alerts into the DART AOP network will improve its coverage of DART-relevant chemical space. In addition, broadening the coverage of AOPs for a particular regulatory endpoint may facilitate the development of, and confidence in, robust IATAs.
已经提出了测试和评估的综合方法（IATA），作为一种组织新方法学的手段，以取代用于化学安全评估的传统动物试验。为了捕捉毒性评估的机制方面，IATA可以围绕不良结局途径（AOP）概念构建。为了在这种情况下充分利用AOP，需要有足够数量的途径来开发适用于特定目的的IATA。相关方法可以通过提供预测模型以及通过数据整合以采用证据权重法得出结论来支持IATA。为了检查从文献中得出的发育和生殖毒性（DART）AOP网络的成熟度，针对一个新的毒性数据集对其覆盖范围进行了评估。精心策划了一个包含各种化合物的数据集，其数据来自根据经合组织测试指南TG-421和TG-422进行的研究，以测试基于AOP网络的模型的性能——从而能够识别网络中的知识空白。通过开发一条源自分子起始事件“谷胱甘肽与亲电试剂反应”并导致雄性生育毒性的AOP，填补了其中一个知识空白。该AOP的创建为整理与相关关键事件的现有结构警报提供了机制依据。将这一新知识和相关警报整合到DART AOP网络中将提高其对与DART相关的化学空间的覆盖范围。此外，扩大针对特定监管终点的AOP的覆盖范围可能有助于开发稳健的IATA并增强对其的信心。
