S4: Enriching Key Events in Adverse Outcome Pathways

Enriching Key Events in Adverse Outcome Pathways with links to biomolecular databases to allow experimental data analysis for regulatory risk assessment

S4: Enriching Key Events in Adverse Outcome Pathways, OpenTox Euro 2017

Marvin Martens


BiGCaT at Maastricht University


PhD Student


Marvin Martens, Chris Evelo, Egon Willighagen


Regulatory risk assessment of chemical compounds is facilitated by the concept of Adverse Outcome Pathways (AOPs). These AOPs are simplified, mostly linear sequences of general building blocks representing stand-alone biological events. These include the Molecular Initiating Event, Key Events, and Adverse Outcomes. The Horizon 2020 toxicology project EU-ToxRisk tries to improve risk assessment strategies. It develops AOPs based on literature, and expert knowledge complemented with data that is generated within the project.
Biological assays can be used to detect if a Key Event happens, and this can indicate the activation of the AOP. In this way such biological assays can become useful for risk assessment.  This requires the availability or development of biological assays that measure biomarkers occurring in Key Events. Since such assays can include omics methods that assess many things in parallel it is helpful to link the Key Events to the entities measured in these bio assays. To allow such a data linkage we typically describe the biological pathways that represent the Key Events with links to databases that describe their nature. Databases such as UniProt and CheBI can for instance be used for this purpose. Since data linkage methods for the analysis of such biomolecular pathways do already exist and are often used in other types of genomics and metabolomics based research the main challenge is to get such pathways related to the Key Events in AOPs and to make these available to the toxicology community to allow data analysis that will support risk analysis for possibly toxic compounds.
Interestingly the same approach can be used to evaluate and predict the kinetic behavior of such compounds. When the biokinetic routes and enzymes involved are known these too can be described as biological pathways, and generic biotransformation pathways are already available. Such targeted biotransformation pathways can then be combined with measurements of enzymes, their activities or their RNA precursors to evaluate the activity of such pathways, and that information can subsequently be used to estimate or calculate the bioavailability. Because much information is available from various existing resources and tools, we only need them to be linked to KEs to cover all elements of importance for using the AOP as a tool in risk assessment. This talk will cover, step by step, the databases and tools that we can use as input to create a complete description of KEs, including ontology terms for all elements, within the AOP so that it can serve as guidance in regulatory risk assessment.