In order to be able to make decisions using this new type of information, we need to understand how changes at the molecular level in cells and tissues are related to the apical adverse outcomes (such as tumor development, changes in organ size or histology, or death) that toxicologists are more familiar with Fig. 1). The Organization of Economic Cooperation and Development (OECD) has created the Adverse Outcome Pathway framework to collect, organize and evaluate the biological information that links upstream molecular changes with downstream organ, organism and population changes (Fig. 1). According the OECD AOP handbook, AOPs “can be viewed as a sequence of events commencing with initial interactions of a stressor with a biomolecule in a target cell or tissue (i.e., molecular initiating event), progressing through a dependent series of intermediate events and culminating with an adverse outcome… AOPs are typically represented sequentially, moving from one key event to another, as compensatory mechanisms and feedback loops are overcome” (OECD 2018).
Every AOP consists of a variable number and arrangement of a few key elements: a molecular initiating event (MIE), the adverse outcome (AO) of regulatory relevance, any number of intermediate Key Events (KE) and the relationships between these elements (key event relationships or KERs). Five general principles are involved in AOP development: (1) AOPs are not chemical specific, (2) AOPs are modular (consisting of KEs and KERs) that can be shared between two or more pathways, (3) An individual AOP is a pragmatic unit of development and evaluation; (4) for most real-world applications, AOP networks are the functional unit of prediction, and (5) AOPs are living documents, and, as more information is discovered, will be continuously updated and never really finished (Villeneuve et al. 2014). OECD is coordinating the development of the software (the AOP knowledge-base or AOP-KB) as well as a number of guidance documents to facilitate the development, evaluation and use of AOPs. In addition, the Human Toxicology Project Consortium (which is coordinated by the Humane Society of the United States), in collaboration with OECD’s AOP program, has created a training course that is freely available to anyone. These documents are available from the OECD website, and the training course is available from the HTPC website or at https://aopwiki.org.Footnote 1
The main element of the AOP-KB is currently the AOP Wiki (https://aopwiki.org). The AOP wiki is designed to capture all of the information about AOP elements in text form, via standardized drop-down menus (to keep a standard format and consistent ontology) and free text fields (to accommodate data, explanations and references). As of this writing, there are more than 200 AOPs and more than 1000 KEs and KERs described in the wiki linked to 340 different stressors (metrics available on the AOP Wiki). As more pathways are described, connections between KEs that are common to different pathways are identified, and in this way, biological networks, which are the basis for predicting AOs from MIEs, are discovered.
The AOP Wiki also supports evaluation of the consistency, quantity and quality of the information supporting the KERs and AOP overall (Table 1). The criteria for evaluating KERs and AOPs, modified from the Bradford-Hill criteria for evaluating causal linkages are described in the OECD guidance and in Meek et al. 2014. AOPs that are published in the OECD program series are evaluated in two stages. The first review is by members of the OECD AOP program to make sure the information has been entered in compliance with OECD guidance. The second stage is an independent scientific review by a subject matter expert group that can be a combination of OECD and outside experts - this is similar to peer review of a scientific publication. Once the authors and reviewers are satisfied, a “snapshot” of the AOP at that time is published on the OECD website and is considered the current state of knowledge about that pathway.