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

Alice Krebs, Barbara M A van Vugt-Lussenburg, Tanja Waldmann, Wiebke Albrecht, Jan Boei, Bas Ter Braak, Maja Brajnik, Thomas Braunbeck, Tim Brecklinghaus, Francois Busquet, Andras Dinnyes, Joh Dokler, Xenia Dolde, Thomas E Exner, Ciarán Fisher, David Fluri, Anna Forsby, Jan G Hengstler, Anna-Katharina Holzer, Zofia JanstovaPaul Jennings, Jaffar Kisitu, Julianna Kobolak, Manoj Kumar, Alice Limonciel, Jessica Lundqvist, Balázs Mihalik, Wolfgang Moritz, Giorgia Pallocca, Andrea Paola Cediel Ulloa, Manuel Pastor, Costanza Rovida, Ugis Sarkans, Johannes P Schimming, Bela Z Schmidt, Regina Stöber, Tobias Strassfeld, Bob van de Water, Anja Wilmes, Bart van der Burg, Catherine M Verfaillie, Rebecca von Hellfeld, Harry Vrieling, Nanette G Vrijenhoek, Marcel Leist*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)2435-2461
Number of pages27
JournalArchives of Toxicology
Issue number7
Early online date6 Jul 2020
Publication statusPublished - Jul 2020


Open Access funding provided by Projekt DEAL. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 681002. The work was also supported by the Doerenkamp-Zbinden foundation, the Konstanz Research School Chemical Biology (KoRS CB), the Bundesministerium für Bildung und Forschung (BMBF) and the InViTe graduate school. We are indebted to many coworkers in the many contributing laboratories for technical help, experience, discussions and some of the test method setups. We are grateful to Daniel Bachler and Ody Mbegbu from EdelweissConncect who took care of the ToxData explorer. The EU-ToxRisk project profited from the above and other research initiatives in further defining the requirements for collaborative testing. The consortium of 39 partners from academia, industry and regulatory authorities is funded by the European Commission with the goal to establish new animal-free strategies of hazard evaluation. These new concepts comprise in vitro methods, based exclusively on human cells, as well as in silico methods like read-across and quantitative structure–activity relationship (QSAR) (Daneshian et al. ; Delp et al. ; Graepel et al. ; Nyffeler et al. ).

FundersFunder number
Doerenkamp-Zbinden foundation
Konstanz Research School Chemical Biology
Horizon 2020 Framework Programme681002
European Commission
Bundesministerium für Bildung und Forschung


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