PDF(Pubmed)
Abstract：
Adverse outcome pathways (AOPs) synthesize toxicological information to convey and weigh evidence in an accessible format. AOPs are constructed in modules that include key events (KEs) and key event relationships (KERs). This modular structure facilitates AOP expansion and network development. AOP development requires finding relevant information to evaluate the weight of evidence supporting each KER. To do this, the use of transparent/reproducible search methods, such as systematic review (SR), have been proposed. Applying SR to AOP development in a data-rich area is difficult as SR requires screening each article returned from a search. Here we describe a case study to integrate a single new KE into an existing AOP. We explored the use of SR concepts and software to conduct a transparent and documented literature search to identify empirical data supporting the incorporation of a new KE, increase in cellular reactive oxygen species (ROS), upstream of an existing AOP: \"Oxidative DNA Damage Leading to Chromosomal Aberrations and Mutations\". Connecting this KE to the AOP is supported by the development of five new KERs, the most important being the first adjacent KER (increase in ROS leading to oxidative DNA damage). We initially searched for evidence of all five KERs and screened 100 papers to develop a preliminary evidence map. After removing papers not containing relevant data based on our Population, Exposure, Comparator and Outcome statement, 39 articles supported one or more KERs; these primarily addressed temporal or dose concordance of the non-adjacent KERs with limited evidence supporting the first adjacent KER. We thus conducted a second focused set of searches using search terms for specific methodologies to measure these first two KEs. After screening, 12 articles were identified that contained quantitative evidence supporting the first adjacent KER. Given that integrating a new KE into an existing AOP requires the development of multiple KERs, this approach of building a preliminary evidence map, focusing evidence gathering on the first adjacent KER, and applying reproducible search strategies using specific methodologies for the first adjacent KER, enabled us to prioritize studies to support expansion of this data-rich AOP.
摘要：
不良结果途径（AOPs）合成毒理学信息，以可访问的格式传达和衡量证据。AOP在包括关键事件(KE)和关键事件关系(KER)的模块中构建。这种模块化结构有利于AOP扩展和网络开发。AOP开发需要找到相关信息来评估支持每个KER的证据的权重。要做到这一点，使用透明/可重复的搜索方法，如系统审查(SR)，已被提议。在数据丰富的区域中将SR应用于AOP开发是困难的，因为SR需要筛选从搜索返回的每篇文章。在这里，我们描述了一个案例研究，将单个新的KE集成到现有的AOP中。我们探索了SR概念和软件的使用，以进行透明和有案可查的文献检索，以确定支持新KE合并的经验数据，细胞活性氧（ROS）的增加，现有AOP的上游：“导致染色体畸变和突变的氧化性DNA损伤”。将此KE连接到AOP是由五个新的KER的开发支持的，最重要的是第一个相邻的KER（ROS增加导致氧化性DNA损伤）。我们最初搜索了所有五个KER的证据，并筛选了100篇论文以开发初步的证据图。在删除不包含基于我国人口的相关数据的论文后，曝光,比较器和结果声明，39篇文章支持一个或多个KER；这些主要解决了不相邻KER的时间或剂量一致性，支持第一个相邻KER的证据有限。因此，我们使用特定方法的搜索词进行了第二组重点搜索，以测量前两个KEs。筛选后,确定了12篇文章，其中包含支持第一个相邻KER的定量证据。鉴于将新的KE集成到现有的AOP中需要开发多个KER，这种建立初步证据地图的方法，将证据收集集中在第一个相邻的KER上，并使用特定的方法对第一个相邻的KER应用可重复的搜索策略，使我们能够优先考虑研究，以支持这种数据丰富的AOP的扩展。
