Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24–25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.

The Adverse Outcome Pathway (AOP) framework is increasingly used to integrate data based on traditional and emerging toxicity testing paradigms. As the number of AOP descriptions has increased, so has the need to define the AOP in computable terms. Herein, we present a comprehensive annotation of 172 AOPs housed in the AOP-Wiki as of December 4, 2016, using terms from existing biological ontologies. AOP Key Events (KEs) were assigned ontology terms using a concept called the Event Component, which consists of a Process, an Object, and an Action term, with each term originating from ontologies and other controlled vocabularies. Annotation of KEs with ontology classes from 14 ontologies and controlled vocabularies resulted in a total of 685 KEs being annotated with a total of 809 Event Components. A set of seven conventions resulted, defining the annotation of KEs via Event Components. This expanded annotation of AOPs allows computational reasoners to aid in both AOP development and applications. In addition, the incorporation of explicit biological objects will reduce the time required for converting a qualitative AOP description into a conceptual model that can support computational modeling. As high-throughput genomics becomes a more important part of the high-throughput toxicity testing landscape, the new approaches described here for annotating KEs will also promote the visualization and analysis of genomics data in an AOP context.

• Artificial Intelligence (AI) has potential to improve chemical risk assessment (CRA) and associated regulatory decisions. • AI could influence the scientific-technical evaluation process and the social aspects of the CRA decision making process. • Systematic Reviews are among the CRA processes that will profit most from the application of AI techniques. • Using AI as external objective monitor could make Weight of Evidence considerations less subjective and more trustable. • AI could identify pitfalls not observable by individuals participating in the CRA process.

Motivation: The field of toxicogenomics (the application of ‘-omics’ technologies to risk assessment of compound toxicities) has expanded in the last decade, partly driven by new legislation, aimed at reducing animal testing in chemical risk assessment but mainly as a result of a paradigm change in toxicology towards the use and integration of genome wide data. Many research groups worldwide have generated large amounts of such toxicogenomics data. However, there is no centralized repository for archiving and making these data and associated tools for their analysis easily available. Results: The Data Infrastructure for Chemical Safety Assessment (diXa) is a robust and sustainable infrastructure storing toxicogenomics data. A central data warehouse is connected to a portal with links to chemical information and molecular and phenotype data. diXa is publicly available through a user-friendly web interface. New data can be readily deposited into diXa using guidelines and templates available online. Analysis descriptions and tools for interrogating the data are available via the diXa portal. Availability and implementation:http://www.dixa-fp7.eu Contact:d.hendrickx@maastrichtuniversity.nl; info@dixa-fp7.eu Supplementary information: Supplementary data are available at Bioinformatics online.

Adverse Outcome Pathways (AOPs) describe the mechanistic interactions of biological entities with a stressor (chemical, nanomaterial, radiation, virus, etc.) that produce an adverse response. How these interactions and associations are catalogued contributes to our ability to understand mechanistic effects and apply this knowledge to New Approach Methods (NAMs) that have the potential to reduce animal testing in chemical, biological, and material safety assessments. Making AOP data align with FAIR (Findable, Accessible, Interoperable, and Reusable) metadata standards relies on technical tools that implement and process AOP data and related metadata, and the establishment of coordinated and consensus computational bioinformatic methods. Herein current efforts in addressing the FAIRification of AOP mechanistic data and metadata, as well as the international, collaborative efforts to document, and improve the (re)-use and reliability of AOP information will be described. These coordinated efforts contribute to the establishment of a directive for the processing and storing of standardized AOP mechanistic data in the AOP-Wiki repository, and application of these data to next generation risk assessment.

Adverse Outcome Pathways (AOP) provide structured frameworks for the systematic organization of research data and knowledge. The AOP framework follows a set of key principles that allow for broad application across diverse disciplines related to human health, including toxicology, pharmacology, virology and medical research. The COVID-19 pandemic engages a great number of scientists world-wide and data is increasing with exponential speed. Diligent data management strategies are employed but approaches for systematically organizing the data-derived information and knowledge are lacking. We believe AOPs can play an important role in improving interpretation and efficient application of scientific understanding of COVID-19. Here, we outline a newly initiated effort, the CIAO project (https://www.ciao-covid.net/), to streamline collaboration between scientists across the world toward development of AOPs for COVID-19, and describe the overarching aims of the effort, as well as the expected outcomes and research support that they will provide.