EU Commission Joint Research Centre (JRC), Ispra, Italy.
ALTEX. 2019;36(1):39-64. doi: 10.14573/altex.1805181. Epub 2018 Jul 12.
The replacement of animals in acute systemic toxicity testing remains a considerable challenge. Only animal data are currently accepted by regulators, including data generated by reduction and refinement methods. The development of Integrated Approaches to Testing and Assessment (IATA) is hampered by an insufficient understanding of the numerous toxicity pathways that lead to acute systemic toxicity. Therefore, central to our work has been the collection and evaluation of the mechanistic information on eight organs identified as relevant for acute systemic toxicity (nervous system, cardiovascular system, liver, kidney, lung, blood, gastrointestinal system and immune system). While the nervous and cardiovascular systems are the most frequent targets, no clear relationship emerged between specific mechanisms of target organ toxicity and the level (category) of toxicity. From a list of 114 chemicals with acute oral in vivo and in vitro data, 98 were identified with target organ specific effects, of which 93% were predicted as acutely toxic by the 3T3 neutral red uptake cytotoxicity assay and 6% as non-toxic. This analysis will help to prioritise the development of adverse outcome pathways for acute oral toxicity, which will support the assessment of chemicals using mechanistically informed IATA.
在急性全身毒性测试中替代动物仍然是一个相当大的挑战。目前监管机构只接受动物数据，包括通过减少和改进方法生成的数据。由于对导致急性全身毒性的众多毒性途径的理解不足，综合测试和评估方法（IATA）的发展受到阻碍。因此，我们的工作重点是收集和评估与急性全身毒性相关的八个器官（神经系统、心血管系统、肝脏、肾脏、肺、血液、胃肠道系统和免疫系统）的机制信息。虽然神经系统和心血管系统是最常见的靶器官，但靶器官毒性的特定机制与毒性水平（类别）之间没有明显的关系。从具有急性口服体内和体外数据的 114 种化学物质列表中，确定了 98 种具有靶器官特异性效应的化学物质，其中 93%的化学物质被 3T3 中性红摄取细胞毒性测定预测为急性毒性，6%的化学物质为非毒性。该分析将有助于确定急性口服毒性的不良结局途径的优先级，这将支持使用基于机制的 IATA 对化学物质进行评估。
