Knowledge infrastructure for integrated data management and analysis supporting new approach methods in predictive toxicology and risk assessment.

The EU-ToxRisk project (2016-2021) was a large European project working towards shifting toxicological testing away from animal tests, towards a toxicological assessment based on comprehensive mechanistic understanding of cause-consequence relationships of chemical adverse effects. More than 40 partners from scientific institutions, industry and regulators coordinated their work towards this goal in a six-year long programme. The breadth and variety of data and knowledge generated, presented a challenging data management landscape. Here, we describe our approach to data management as developed under EU-ToxRisk. The main building blocks of the data infrastructure are: 1) An easy-to-use, extensible data and metadata format; 2) A flexible system with protocols for data capture and sharing from the entire consortium; 3) A methods database for describing and reviewing data generation and processing protocols; 4) Data archiving using a sustainable resource; 5) Data transformation from the archive to the system that provides granular access; 6) Application Programming Interface (API) for access to individual data points; 7) Data exploration and analysis modules, based on a «web notebook¼ approach to executable data processing documentation; and 8) Knowledge portal that ties together all of the above and provides a collaboration space for information exchange across the consortium. This knowledge infrastructure is being extended and refined for the support of follow-up projects (RISK-HUNT3R, ASPIS cluster, European Open Science Cloud (2021-2026)).

The EU-ToxRisk method documentation, data processing and chemical testing pipeline for the regulatory use of new approach methods.

Hazard assessment, based on new approach methods (NAM), requires the use of batteries of assays, where individual tests may be contributed by different laboratories. A unified strategy for such collaborative testing is presented. It details all procedures required to allow test information to be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. The EU-ToxRisk project developed a strategy to provide regulatorily valid data, and exemplified this using a panel of > 20 assays (with > 50 individual endpoints), each exposed to 19 well-known test compounds (e.g. rotenone, colchicine, mercury, paracetamol, rifampicine, paraquat, taxol). Examples of strategy implementation are provided for all aspects required to ensure data validity: (i) documentation of test methods in a publicly accessible database; (ii) deposition of standard operating procedures (SOP) at the European Union DB-ALM repository; (iii) test readiness scoring accoding to defined criteria; (iv) disclosure of the pipeline for data processing; (v) link of uncertainty measures and metadata to the data; (vi) definition of test chemicals, their handling and their behavior in test media; (vii) specification of the test purpose and overall evaluation plans. Moreover, data generation was exemplified by providing results from 25 reporter assays. A complete evaluation of the entire test battery will be described elsewhere. A major learning from the retrospective analysis of this large testing project was the need for thorough definitions of the above strategy aspects, ideally in form of a study pre-registration, to allow adequate interpretation of the data and to ensure overall scientific/toxicological validity.