Refine and Strengthen SAR-Based Read-Across by Considering Bioactivation and Modes of Action

Structure–activity relationship (SAR)-based read-across is an important and effective method to establish the safety of a data-poor target chemical (structure of interest (SOI)) using hazard data from structurally similar source chemicals (analogues). Many methods use quantitative similarity scores to evaluate the structural similarity for searching and selecting analogues as well as for evaluating analogue suitability. However, studies suggest that read-across based purely on structural similarity cannot accurately predict the toxicity of an SOI. As mechanistic data become available, we gain a greater understanding of the mode of action (MOA), the relationship between structures and metabolism/bioactivation pathways, and the existence of “activity cliffs” in chemical chain length, which can improve the analogue rating process. For this purpose, the current work identifies a series of classes of chemicals where a small change at a key position can result in a significant change in metabolism and bioactivation pathways and may eventually result in significant changes in chemical toxicity that have a big impact on the suitability of analogues for read-across. Additionally, a series of SAR-based read-across case studies are presented, which cover a variety of chemical classes that commonly link to different toxic endpoints. The case study results indicate that SAR-based read-across can be refined and strengthened by considering MOAs or proposed reactive metabolite formation pathways, which can improve the overall accuracy, consistency, transparency, and confidence in evaluating analogue suitability.基于构效关系 (Structure–activity relationship, SAR) 的交叉参照 (read-across) 是利用结构相似源化学品（类似物）的危害数据，为数据匮乏的目标化学品（目标感兴趣结构 (structure of interest, SOI)）确立安全性的重要且有效的方法。诸多方法通过定量相似性评分来评估结构相似性，以用于检索、筛选类似物并评价类似物的适用性。然而研究表明，仅基于结构相似性的交叉参照无法准确预测目标感兴趣结构的毒性。随着机制数据逐步可获取，我们对作用模式 (mode of action, MOA)、结构与代谢/生物活化途径 (metabolism/bioactivation pathways) 的关联，以及化学碳链长度中“活性悬崖 (activity cliffs)”的存在有了更为深入的理解，这些均可优化类似物的评级流程。为此，本研究明确了一系列化学品类别：在关键位置发生微小变化即可显著改变代谢与生物活化途径，并最终引发化学品毒性的显著改变，进而对交叉参照所用类似物的适用性产生重大影响。此外，本文还呈现了一系列基于构效关系的交叉参照案例研究，涵盖了通常与不同毒性终点 (toxic endpoints) 相关的各类化学品类别。案例研究结果表明，通过考虑作用模式或拟议的活性代谢物生成途径，可以优化并强化基于构效关系的交叉参照方法，从而提升类似物适用性评价的整体准确性、一致性、透明度与可信度。