Special Report 19

Definitions

Adverse Outcome (AO)[1]: A specialised type of key event (KE), measured at a level of organisation that corresponds with an established protection goal and/or is functionally equivalent to an apical endpoint measured as part of an accepted guideline test. Generally at the organ level or higher. Anchors the “downstream” end of an adverse outcome pathway (AOP).

Adverse Outcome Pathway (AOP): A conceptual framework that organises existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organisation of regulatory relevance.1 AOPs are informed by, but independent of, the chemicals that may affect a pathway. An AOP is usually described as a linear sequence of key events, starting from a molecular initiating event, followed by various key intermediate events, as compensatory mechanisms and feedback loops are overcome, linked by defined key-event relationships, and ending with an adverse outcome. Thus, an AOP encompasses increasing levels of complexity from the molecular initiating event, via the biochemical, cellular, tissue and organ levels to the adverse outcome at the entire organism or population level (see Figure 1).

Apical Endpoint: Traditional, directly measured, adverse whole-organism outcomes of exposure in in vivo tests. In this context, generally death, reproductive failure, or developmental dysfunction.

Developmental Toxicity Ontology (DTO): This is an application ontology built for the specific purposes of organising existing information about modes of action of developmental toxicants and their relationships with adverse outcomes.

Integrated Approaches to Testing and Assessment (IATA): A structured approach that strategically integrates and weights all relevant data to inform regulatory decisions regarding potential hazard and/or risk and/or the need for further targeted testing and therefore optimising and potentially reducing the number of tests that need to be conducted.[2]

Key Event (KE)1: A measurable change in biological state that is essential, but not necessarily sufficient, for the progression from a defined biological perturbation toward a specific adverse outcome. KEs are represented as nodes in an AOP diagram or AOP network and provide verifiability to an AOP description.

Key Event Relationship (KER)1: A scientifically-based relationship between a pair of KEs, identifying one as upstream and the other as downstream. It facilitates inference or extrapolation of the state of the downstream KE from the known, measured or predicted, state of the upstream KE.

Molecular Initiating Event (MIE)1: A specialised type of KE, defined as the point where a chemical directly interacts with a biomolecule within an organism to create a perturbation that starts the AOP – as such, by definition, it occurs at the molecular level. Anchors the “upstream” end of an AOP.

Mode Of Action (MOA): A biologically plausible sequence of key events leading to an observed effect supported by robust experimental observations and mechanistic data. A mode of action describes key cytological and biochemical events—that is, those that are both measurable and necessary to the
observed effect—in a logical framework[3]. A mode of action starts with the molecular initiating event. Unlike AOP, it does not (usually) include consideration of exposure or effects at higher levels than the individual (see Figure 1).

Ontology: An ontology is an organised representation of a domain of knowledge consisting of concepts and information, generally referred to as classes, and relationships between classes. Ontologies are useful in organising information into a structure that makes the information more understandable and facilitates hypothesis generation.

Resource Description Framework (RDF): An infrastructure for storing information, usually in triplestore or RDF triple format. The relationships in an RDF are organised and described by an ontology. The ontologies themselves can be stored in an RDF.

Toxicity pathway: Perturbation of a normal biochemical pathway from the molecular initiating event to the cellular effect (see Figure 1).

Figure 1: Schematic representation of the concept of the Adverse Outcome Pathway showing relationship to Mode of Action and Toxicity Pathway. (adapted from OECD (2013a) Guidance Document on Developing and Assessing Adverse Outcome Pathways, ENV/JM/MONO(2013)6 )

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[1] Taken from Villeneuve et al. (2014a,b). Adverse Outcome Pathway (AOP) Development I: Strategies and Principles, Toxicological Sciences 142:312-320 and/or the OECD (2013b), Users’ Handbook Supplement to the Guidance Document for Developing and Assessing AOPs (ENV/JM/MONO(2013)6.

[2] Working definition taken from OECD (2015). Report of the workshop on a framework for the development and use of integrated approaches to testing and assessment Series on Testing and Assessment No. 215. ENV/JM/MONO(2015)22, 22 July 2015.

[3] Boobis AR, Cohen SM, Dellarco V, McGregor D, Meek ME, Vickers C, Willcocks D, Farland W (2006). IPCS framework for analyzing the relevance of a cancer mode of action for humans. Crit Rev Toxicol 36:781–792.

 

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