毒理学风险评估对于评估和授权不同类别的化学物质至关重要。遗传毒性和致突变性测试是最优先的,并且依赖于已建立的细菌和哺乳动物细胞体外系统,有时使用啮齿动物动物模型进行体内测试。转录组学方法最近也显示了它们确定遗传毒性特异性转录物特征的价值。这里,我们研究了转录组数据,结合人类细胞的体外测试,可用于鉴定受试化合物的遗传毒性。为此,我们使用了28天口服毒性研究的大鼠肝脏样本与杀虫活性物质伊玛唑,噻虫啉,和clothianidin,一种新烟碱类杀虫剂,在其他人中,已知的肝毒性。对转录组结果进行了生物信息学评估,并指出了噻虫胺的遗传毒性潜力。人HepaRG肝癌细胞的体外彗星和γH2AX测定,辅以诱变性的计算机模拟分析,作为后续实验进行,以检查转录组学研究的遗传毒性警报是否与一系列指南遗传毒性研究的结果一致。我们的结果说明了毒物基因组学的联合使用,经典毒理学数据和风险评估中的新方法。通过证据权重的决定,我们得出的结论是,噻虫胺很可能不会对人类造成遗传毒性风险。
Toxicological risk assessment is essential in the evaluation and authorization of different classes of chemical substances. Genotoxicity and mutagenicity testing are of highest priority and rely on established in vitro systems with bacterial and mammalian cells, sometimes followed by in vivo testing using rodent animal models. Transcriptomic approaches have recently also shown their value to determine transcript signatures specific for genotoxicity. Here, we studied how transcriptomic data, in combination with in vitro tests with human cells, can be used for the identification of genotoxic properties of test compounds. To this end, we used liver samples from a 28-day oral toxicity study in rats with the pesticidal active substances imazalil, thiacloprid, and clothianidin, a neonicotinoid-type insecticide with, amongst others, known hepatotoxic properties. Transcriptomic results were bioinformatically evaluated and pointed towards a genotoxic potential of clothianidin. In vitro Comet and γH2AX assays in human HepaRG hepatoma cells, complemented by in silico analyses of mutagenicity, were conducted as follow-up experiments to check if the genotoxicity alert from the transcriptomic study is in line with results from a battery of guideline genotoxicity studies. Our results illustrate the combined use of toxicogenomics, classic toxicological data and new approach methods in risk assessment. By means of a weight-of-evidence decision, we conclude that clothianidin does most likely not pose genotoxic risks to humans.