Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.
Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.
Chem Res Toxicol. 2021 Feb 15;34(2):452-459. doi: 10.1021/acs.chemrestox.0c00313. Epub 2020 Dec 30.
Recently, we reported an toxicogenomics comparison approach to categorize chemical substances according to similarities in their proposed toxicological modes of action. Use of such an approach for regulatory purposes requires, among others, insight into the extent of biological concordance between and findings. To that end, we applied the comparison approach to transcriptomics data from the Open TG-GATEs database for 137 substances with diverging modes of action and evaluated the outcomes obtained for rat primary hepatocytes and for rat liver. The results showed that a relatively small number of matches observed were also observed , whereas quite a large number of matches between substances were found to be relevant solely or . The latter could not be explained by physicochemical properties, leading to insufficient bioavailability or poor water solubility. Nevertheless, pathway analyses indicated that for relevant matches the mechanisms perturbed are consistent with those perturbed . These findings support the utility of the comparison approach as tool in mechanism-based risk assessment.
最近，我们报告了一种毒理基因组学比较方法，根据其提议的毒理学作用模式相似性对化学物质进行分类。为了监管目的而使用这种方法，除其他外，需要了解 和 研究结果之间的生物学一致性程度。为此，我们将比较方法应用于来自 Open TG-GATEs 数据库的 137 种具有不同作用模式的物质的转录组学数据，并评估了在大鼠原代肝细胞和大鼠肝脏中获得的结果。结果表明，观察到的相对较少的匹配项 也存在于 中，而在物质之间发现的相当多的匹配项仅在 或 中是相关的。后者不能用物理化学性质来解释，导致生物利用度不足或水溶性差。然而，途径分析表明，对于相关的匹配项，受干扰的机制 与受干扰的机制 一致。这些发现支持将比较方法作为基于机制的风险评估工具的实用性。
