GET AOP TRAINED
The Adverse Outcome Pathway (AOP) concept was developed to address a practical need in toxicology: to be able to use the latest in vitro (non-animal) tools to predict what exposure to a chemical might do to a whole animal or population. In order to design testing strategies that sufficiently address the breadth of potential adverse possibilities, it is important to understand the underlying biology as explicitly and with as much confidence as possible. Simply stated, an AOP is an explicit description of the biology that underlies a biological pathway that can be perturbed by an external force (such as chemical exposure) – of all of the steps that occur from the original perturbation at the molecular level, through changes at the cellular, tissue, organ, organ system, individual and even population levels (Figure 1).
The Organization for Economic Cooperation and Development (OECD) is coordinating the AOP framework: a tool that allows compilation, organization and evaluation of biological information in a formalized way in order to facilitate the use of molecular and cellular information in decision making – whether to support weight-of-evidence evaluations, identify information needs and direct further research, or to design testing strategies to answer questions about chemical safety. The AOP framework consists of guidance documents that aid in building and using AOPs, software for collecting and organizing the information, a program for formally assessing the information, and a training group that creates materials to train new AOP builders and users.
According to the OECD, 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). An 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) as a matter of practicality, a convention of AOP development is that each AOP is linear: one AOP consists of a mostly linear link from one MIE to one AO; (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).
Figure 1. Diagram of an AOP.
OECD is also coordinating the software necessary for collecting and evaluating AOP information, the AOP Knowledgebase (AOP-KB, Figure 2). 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 (OECD, 2018, 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.
Figure 2. The AOP Knowledge-Base and related projects
In addition to materials available from the OECD, we have developed presentations, a continuing education course lecture, and an online training course in the AOP wiki, all of which are free and linked below.
*An ongoing program, in the form of “AOPs 101” and “AOPs 201” sessions, were created Human Toxicology Project Consortium (HTPC) in partnership the Physicians Committee for Responsible Medicine (PCRM) to introduce scientists, regulators, and researchers to the OECD AOP program. The programs have been running several times a year since 2014. The HTPC has been reorganized into this AFSA Tox21 workstream and will continue the partnership with PCRM in AOP training going forward.
Introduction to AOPs
|Online AOP Wiki course||
Course 1: AOP History and Overview
Course 2: AOP Wiki Tutorial
Self exam: AOP Wiki Tutorial
|OECD AOP development program|
|OECD AOP handbook||
Guidance that describes how to use the AOP wiki, including nomenclature, conventions, a description of what information goes where, and how to evaluate the information in the KERs.
|OECD webinar program|
|The AOP Wiki||
Direct link to the wiki – please read guidance and/or take courses first!
|Latest AOPs 101 program(s)||
Indian AOP Training program
How to build an AOP(Dr Surat Parvatam, CCMB Centre for Predictive Human Model Systems)
AOP Hands-on Training: Building the Foundation for Predictive Toxicology
July 16, 2019: IUTOX (International Union of Toxicology) 15th International Congress of toxicology
Location: Honolulu, Hawaii
|Selected AOPs 101 & 201 lectures||
The AOP Concept, Creating and using an AOP, Evaluating the AOP evidence, and Hands-on activity
March 13, 2018: SOT (Society of Toxicology) 57th Annual Meeting
Location: San Antonio, USA