Abstract：
The aim of this study is to define chemical categories that can be applied to regulatory read-across assessments for repeated-dose toxicity, by classifying toxic substances based on their structures and mechanism of actions (MoAs). Hemolytic anemia, which often appears primarily, was examined as an example. An integrated database was constructed by collecting publicly available datasets on repeated-dose toxicity, in which 423 out of a total of 1518 chemicals were identified as capable of inducing hemolytic anemia. Subsequently, by grouping these chemicals based on their chemical structures and plausible MoAs on hemolytic substances, we identified the following categories: (i) anilines, (ii) nitrobenzenes, (iii) nitroanilines, (iv) dinitroanilines, (v) ethylene glycol alkyl ethers, (vi) hydroquinones, (vii) oximes, and (viii) hydrazines. In these categories, the toxicant and the measurable key events leading to hematotoxicity were identified, thereby allowing us to justify the categories and to discriminate the category substances. Moreover, toxicokinetics seems to critically affect the hemolytic levels of the category substances. Overall, the categories were validated through a comprehensive analysis of the collected information, while the utility was demonstrated by conducting a case study on the selected category. Further endeavors with this approach would attain categories for other organ toxicity endpoints.
摘要：
本研究的目的是定义可用于重复剂量毒性评估的化学类别，通过根据有毒物质的结构和作用机理（MoAs）对其进行分类。溶血性贫血,通常主要出现，作为一个例子。通过收集有关重复剂量毒性的公开数据集，构建了一个综合数据库，在总共1518种化学物质中，有423种被鉴定为能够诱导溶血性贫血。随后，通过根据这些化学物质的化学结构和溶血物质上合理的MoAs进行分组，我们确定了以下类别：(I)苯胺，(ii)硝基苯，(iii)硝基苯胺，(iv)二硝基苯胺，(v)乙二醇烷基醚，(vi)氢醌，(vii)肟，和(viii)肼。在这些类别中,确定了导致血液毒性的毒物和可测量的关键事件，从而使我们能够证明类别和区分类别物质。此外，毒物动力学似乎严重影响类别物质的溶血水平。总的来说,通过对收集的信息进行全面分析，验证了这些类别，而实用性是通过对所选类别进行案例研究来证明的。这种方法的进一步努力将获得其他器官毒性终点的类别。
