Pathway-based Toxicology – Emerging Science & Policy

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Pathway-Based Toxicology

Emerging Science & Policy

Last updated: July 1, 2014

The Organization for Economic Cooperation and Development (OECD) AOP Project

The OECD held a Workshop on Using Mechanistic Information in Forming Chemical Categories in 2010, one of the first workshops to gather scientific expertise to guide further AOP development (OECD, 2011). The 2010 workshop focused on the use of AOPs in building chemical categories for read-across, how AOPs might be used in Approaches to Integrated Testing and Assessment (IATA) and in identifying Key Events. For the purposes of the Workshop, an AOP was defined as “a narrative which delineates the documented, plausible, and testable processes by which a chemical induces molecular perturbations and the associated biological responses which describe how the molecular perturbations cause effects at the subcellular, cellular, tissue, organ, whole animal and (if required) population levels of observation” (Table 1; OECD, 2011).  Based on discussion of several case studies, AOPs were further defined as being based on a single, defined MIE that is linked to a specific in vivo hazard outcome. The workshop also discussed development of a template that would summarized all of the information supporting the AOP, including “1) the level of qualitative understanding of the AOP; 2) consistency of the experimental data; 3) confidence in the AOP, and 4) level of quantitative understanding of the AOP” (OECD, 2011).

Since the 2010 workshop, OECD has published guidance and a template for development that is currently undergoing further revision (OECD, 2013). The published Guidance includes a description of the elements and uses of AOPs, a glossary of terms, and a template for developing an AOP. The goals of this guidance are to provide consistency in structure and facilitate harmonized use of AOPs.

According to the OECD Guidance, an AOP consists of three main elements: one molecular initiating event (Anchor 1), one Adverse Outcome (Anchor 2), and any number of intermediate events. While in reality an MIE can be associated with a number of adverse effects, and similarly an adverse effect can result from a number of different MIE, to streamline the development and use of AOPs, OECD has defined an AOP as being a linear pathway from one MIE to one adverse outcome. A full description of an MIE should include cellular/tissue location – as immediately elicited intermediate events may be similar in two different AOPs, but differ in cell-type or tissue location (for example, metabolic transformation of a chemical to an electrophilic species may occur in both skin sensitization and liver fibrosis – only in keratinocytes for the former and hepatocytes for the latter). In order for an intermediate event to be identified as a “key event,” it must be able to be evaluated experimentally and causally linked to the adverse outcome. A key event may be shared between two or more AOPs. The Guidance describes the process for evaluating weight-of-evidence for each step in development of an AOP.

Similar to the IPCS MoA frameworks described above, the OECD guidance suggests evaluation following the Bradford-Hill principles. In addition, the guidance recommends evaluating the confidence in each element of the AOP, specifically to address the following: how well characterized are the MIE, adverse outcome, and each intermediate or key event? What are the limitations of the evidence used to support the AOP? What are the specific parameters of the AOP (e.g., life stage, tissue, etc.)? To what degree are the AOP elements conserved across species?

AOPs have a number of potential uses, including 1) supporting chemical category formation and “read-across” (predicting the toxicity of one chemical based on results from a related chemical), 2) priority setting for further testing, 3) hazard identification 4) classification and labeling, and 5) risk assessment. As use progresses from 1–5, a corresponding increase in the level of evidence and certainty is necessary for adequate confidence. An AOP can also form the basis for an integrated approach to testing and assessment (IATA) or an integrated testing strategy (ITS) that would be designed to increase the certainty of any decision made regarding a particular substance (OECD, 2013).

There are currently more than 20 AOP projects in the OECD work plan, including pathways and case studies (an AOP that is related to one specific chemical). In addition, OECD is collaborating with the European Commission Joint Research Centre and the US EPA to develop the AOP Knowledge base (AOP KB; described in more detail in the next section).

The AOP Knowledge Base and related projects

To develop a system of AOPs that covers the broad spectrum of biological pathways that are likely to be involved in human health and ecological risk assessment, it is necessary to create a unified knowledge base for AOPs and their supporting evidence that integrates information from all scientific sectors, including toxicology, drug development, disease, medicine and research. An Adverse Outcome Pathway Knowledge Base (AOP KB) is currently being developed by the OECD Extended Advisory Group on Molecular Screening and Toxicogenomics (EAG MST) and is being implemented by the European Commission’s Joint Research Centre (JRC) and the US Environmental Protection Agency (US-EPA).  The AOP KB is an IT system to capture, manage and share AOP information and will consist of three modules: 1) AOP-WIKI, a text-based tool allowing the management of AOP-related knowledge (AOPs, Key Events, relationships between them) in a Wikipedia-like environment, 2) a graphical tool implementing quantitative models depicting the relationship between two events in an AOP (Effectopedia) and 3) an Intermediate Effects Database (AOP Network tool) to manage information about intermediate effects triggered by chemicals.

The first available module, the AOP Wiki, leads AOP developers through the steps necessary to capture the scientific information needed to document an AOP – following and implementing OECD guidance on how to describe AOPs. The Wiki also provides a collaborative space for groups to develop AOPs independent of geography or organizational boundaries. Currently a beta version of the AOP Wiki is available only for OECD AOP development teams but the goal is to eventually make this publicly accessible with registration.

Catherine E. Willett, PhD
Humane Society of the United States