Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Neurotoxicology Research Group, Toxicology and Pharmacology Division, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands.
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Food Chem Toxicol. 2018 Nov;121:115-123. doi: 10.1016/j.fct.2018.08.007. Epub 2018 Aug 8.
Mode of action information is one of the key components for chemical risk assessment as mechanistic insight leads to better understanding of potential adverse health effects of a chemical. This insight greatly facilitates assessment of human relevance and enhances the use of non-animal methods for risk assessment, as it ultimately enables extrapolation from initiating events to adverse effects. Recently, we reported an in vitro toxicogenomics comparison approach to categorize (non-)genotoxic carcinogens according to similarities in their proposed modes of action. The present study aimed to make this comparison approach generally applicable, allowing comparison of outcomes across different studies. The resulting further developed comparison approach was evaluated through application to toxicogenomics data on 18 liver toxicants in human and rat primary hepatocytes from the Open TG-GATEs database. The results showed sensible matches between compounds with (partial) overlap in mode of action, whilst matches for compounds with different modes of action were absent. Comparison of the results across species revealed pronounced and relevant differences between primary rat and human hepatocytes, underpinning that information on mode of action enhances assessment of human relevance. Thus, we demonstrate that the comparison approach now is generally applicable, facilitating its use as tool in mechanism-based risk assessment.
作用模式信息是化学风险评估的关键组成部分之一，因为机制理解有助于更好地了解化学物质潜在的不良健康影响。这种理解极大地促进了对人类相关性的评估，并增强了对非动物方法在风险评估中的使用，因为它最终能够从引发事件推断出不良反应。最近，我们报告了一种体外毒理学基因组学比较方法，根据其提议的作用模式的相似性对（非）遗传毒性致癌物进行分类。本研究旨在使这种比较方法具有普遍适用性，允许跨不同研究比较结果。通过将进一步开发的比较方法应用于来自 Open TG-GATEs 数据库的人类和大鼠原代肝细胞中 18 种肝毒物的毒理学基因组学数据，对其进行了评估。结果表明，作用模式部分重叠的化合物之间存在合理的匹配，而作用模式不同的化合物之间则没有匹配。对跨物种的结果进行比较表明，大鼠和人原代肝细胞之间存在明显且相关的差异，这表明作用模式信息增强了对人类相关性的评估。因此，我们证明该比较方法现在具有普遍适用性，可作为基于机制的风险评估的工具。
