In this next section, I'm going to introduce you to the OECD AOP framework. With that introduction to the AOP concept, we are now ready to learn about the formal OECD AOP framework. The AOP framework is being developed and coordinated through the OECD. The OECD is the Organization for Economic Cooperation and Development, an organization of 36 or so of the countries with the largest economies. OECD creates guidance for things that are traded, including chemicals and their guidance documents and test guidelines are followed by all member countries. Central to the OECD AOP framework, is the AOP knowledge base. It's an information hub designed to collect, organize, and evaluate AOP information. The AOP-KB is a global collaboration with the primary contributors being the OECD, the European Commission's Joint Research Center, the US EPA, and the US Army Corps. There is also an international ad-hoc committee, called the Society for Advancement of AOPs, that helps administer the AOP Wiki. The knowledge-base consists of several software packages, each package being developed by a different lead organization. The most developed element of the knowledge base is the AOP Wiki. In the next few slides, I'll be focusing on this element of the AOP-KB. The AOP Wiki is a database for capturing and organizing all information and supporting document, for the key events and key event relationships of AOPs. As the name indicates, the AOP Wiki is a wiki based, and like Wikipedia, is meant to be crowd sourced, and developed by as many people as possible around the world. The AOP Wiki captures and organizes all information about the AOP elements. It's supported by extensive documentation, tutorials, and an online course. It's designed to enable rigorous evaluation and scientific review. It's been publicly available since 2014. The current version is a AOP Wiki 2.2, and it's available at the URL here, aopwiki.org. The AOP Wiki supports the five fundamental principles of AOP development. Number one, the AOPs are not chemical specific. Number two, AOPs are modular, and composed of reusable components, notably the key events and key event relationships. Number three, as a pragmatic construct, an individual AOP is composed of a single sequence of key events and key event relationships, leading to a single adverse outcome. Number four, networks will emerge as AOPs are constructed and common key events and key event relationships are shared between AOPs. Networks are likely to be the functional unit of prediction for most real-world scenarios. Number five, AOPs are living documents that will evolve over time as new knowledge is generated. In this slide, I'd like to emphasize how biological networks emerge as more AOPs are developed. It becomes evident that different pathways share common elements, key events, or key event relationships. This diagram shows three related AOPs. ER antagonism, aromatase inhibition, and androgen receptor agonism, that share several key events and several key event relationships. As the key events and key event relationships are used in two or more AOPs, biological networks emerge. As the networks emerge, the AOP system begins to resemble biology. Let's take a look at the AOP Wiki homepage. Reading through the homepage gives you an overview and links to important documents like guidance documents and online training materials. You can also search the Wiki by every kind of AOP element. You can search by AOPs, you can search by key events, or key event relationships, you can even search by stressors that can initiate the AOPs. Anyone can go online and search and read about any AOP or any field in the Wiki. It's a public resource. However, if you want to enter information into the Wiki, you will need to register to be able to leave comments or for write access, so that the edit can be tracked. This is similar to Wikipedia. Here's what a typical search looks like. In this case, the search was for liver fibrosis. This search pulls up any AOP with a term in the title or in any key event. The entry at the top is an AOP with liver fibrosis in the title, protein alkylation leading to liver fibrosis. The list below is any AOP that mentions liver fibrosis in any element anywhere in the AOP. This slide shows an overview of the organization of the AOP Wiki. The top page is the AOP page. The AOP page has links to pages that cover each element of the AOP. Each AOP page has a link to key event pages that can be added for each key events, and it has unique pages for specialized key events like molecular initiating events or adverse outcomes. The OECD has developed extensive guidance for developers to assist with filling in each one of these fields, and the current version of the Wiki has drop-down menus and ontology tags, combined with a number of different ontologies to aid in consistency of labeling for each key event and each key event relationship. Note that the key event relationship pages also have fields for evaluation of the information. This is an evaluation of the quality and consistency of the information for each KER. It helps with the overall evaluation of the quality of the AOP. I'll talk more about this in the next section. This is an overview of the AOP creation and OECD evaluation process. If you'd like to begin entering an AOP, first you need to sign up for an account, and apply for write access. You can do this either through the OECD website or, less formally, through the Society for the Advancement of a AOPs website. As information is entered, members of the SAAOP monitor the entries to make sure the authors are following the instructions and the guidance, and to shepherd the authors a bit. If and when the authors are ready, they can enter the OECD process by filling out an AOP project form. Again, when the authors are ready, they can signal the OECD that they would like to begin the formal review process. The first review is just to make sure that the fields are filled out correctly, and follow the AOPs convention. Once the reviewer and authors are satisfied with the content format, the authors can go forward to the technical review by a panel of subject experts. During this review, the review organizers solicit subject matter experts with a deep knowledge about the biology, to review and comment back to the authors, who can then revise the AOP elements as needed. Once all parties are satisfied that the AOP represents the current state of knowledge, the AOP review process is reviewed, and possibly endorsed by the OECD. Note that what is reviewed is a static representation of the AOP or a snapshot taken on a specific date. If the AOP is endorsed, it is published on the OECD website, in the list of endorsed a AOPs. Development of the AOP can continue after the formal review. All entries in the Wiki are timestamped so changes can be followed. There are currently five AOPs that have been through the entire evaluation process. The low number reflects the fact that this is a relatively new project, and that the review process is quite labor intensive and time consuming. This slide summarizes this current state of knowledge in the AOP Wiki. There are currently 230 AOPs comprised of more than 1000 key events and key event relationships. On the left is a diagrammatic representation of the biological space covered in the Wiki. This was created by Dan Villeneuve in 2017. The sphere represents all of biology. The size of the spots indicate how many times the element is used. In other words, how highly networked it is. You can see that very little biological space is best far accounted for in the Wiki, and that there are some hotspots that are highly networked. A recent survey of the Wiki found the most common endpoints addressed are: eco toxicology, reproductive toxicology, neuro toxicology, carcinogenicity, and endocrine activity. Ideally, we'd like to get to a place where the dots are scattered throughout the sphere. We need to cover enough biological space to make sure we can predict which adverse outcome might occur, given a particular perturbation, and that we won't miss any potential effects. To do that, we need as many people contributing information as possible.
