Defining Molecular Initiating Events in the Adverse Outcome Pathway Framework for Risk Assessment
Defining Molecular Initiating Events in the Adverse Outcome Pathway Framework for Risk Assessment
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DOI：
10.1021/tx500345j
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发表时间：
2014-12-01
影响因子：
4.1
通讯作者：
Russell, Paul J.
中科院分区：
文献类型：
--
作者：
Allen, Timothy E. H.;Goodman, Jonathan M.;Russell, Paul J.
消费者和环境安全决策基于暴露和危害数据，并使用风险评估方法进行解释。不良后果途径（AOP）概念框架已被提出为生物系统中事件或过程的逻辑序列，可用于理解不良影响并改进生态毒理学中当前的风险评估实践。这一框架也可以应用于人类毒理学，并在研究化合物的分子起始事件（MIEs）的基础上进行了探索。MIE的精确定义尚未得到普遍接受。在这项工作中，我们提出了一个统一的MIE定义：MIE是分子与生物分子或生物系统之间的初始相互作用，可以通过途径因果联系到结果。介绍了案例研究，并讨论了当前定义的问题。随着统一的MIE定义的发展，该领域可以期望定义、分类和描述更多的MIE，并使用这些过程的化学知识来帮助AOP研究和毒性风险评估。我们还介绍了MIE研究在体外和硅毒理学发展中的作用，并建议如何通过使用生物和化学方法的结合，尽管缺乏详细的报告，即使对于一些毒理学中研究最多的分子，也可以识别和表征MIEs。
Consumer and environmental safety decisions are based on exposure and hazard data, interpreted using risk assessment approaches. The adverse outcome pathway (AOP) conceptual framework has been presented as a logical sequence of events or processes within biological systems which can be used to understand adverse effects and refine current risk assessment practices in ecotoxicology. This framework can also be applied to human toxicology and is explored on the basis of investigating the molecular initiating events (MIEs) of compounds. The precise definition of the MIE has yet to reach general acceptance. In this work we present a unified MIE definition: an MIE is the initial interaction between a molecule and a biomolecule or biosystem that can be causally linked to an outcome via a pathway. Case studies are presented, and issues with current definitions are addressed. With the development of a unified MIE definition, the field can look toward defining, classifying, and characterizing more MIEs and using knowledge of the chemistry of these processes to aid AOP research and toxicity risk assessment. We also present the role of MIE research in the development of in vitro and in silico toxicology and suggest how, by using a combination of biological and chemical approaches, MIEs can be identified and characterized despite a lack of detailed reports, even for some of the most studied molecules in toxicology.