Animal Testing Alternatives; Animals; Artificial Intelligence; Computer Simulation; European Union; Gene Ontology; Humans; In Vitro Techniques; Risk Assessment; Toxicity Tests; 3Rs; Artificial intelligence; European project; In silico; In vitro; ONTOX; Ontology; Systemic toxicity
Abstract :
[en] The 3Rs concept, calling for replacement, reduction and refinement of animal experimentation, is receiving increasing attention around the world, and has found its way to legislation, in particular in the European Union. This is aligned by continuing high-level efforts of the European Commission to support development and implementation of 3Rs methods. In this respect, the European project called "ONTOX: ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment" was recently initiated with the goal to provide a functional and sustainable solution for advancing human risk assessment of chemicals without the use of animals in line with the principles of 21(st) century toxicity testing and next generation risk assessment. ONTOX will deliver a generic strategy to create new approach methodologies (NAMs) in order to predict systemic repeated dose toxicity effects that, upon combination with tailored exposure assessment, will enable human risk assessment. For proof-of-concept purposes, focus is put on NAMs addressing adversities in the liver, kidneys and developing brain induced by a variety of chemicals. The NAMs each consist of a computational system based on artificial intelligence and are fed by biological, toxicological, chemical and kinetic data. Data are consecutively integrated in physiological maps, quantitative adverse outcome pathway networks and ontology frameworks. Supported by artificial intelligence, data gaps are identified and are filled by targeted in vitro and in silico testing. ONTOX is anticipated to have a deep and long-lasting impact at many levels, in particular by consolidating Europe's world-leading position regarding the development, exploitation, regulation and application of animal-free methods for human risk assessment of chemicals.
Disciplines :
Engineering, computing & technology: Multidisciplinary, general & others
Author, co-author :
Vinken, Mathieu; Research Group of In VitroToxicology and Dermato-Cosmetology, Department of
Benfenati, Emilio; Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche
Busquet, François; Altertox, Brussels, Belgium.
Castell, José; Department of Biochemistry and Molecular Biology, University of Valencia-Spain,
Dent, M., Teixeira Amaral, R., Da Silva Amores, P., Ansell, J., Boisleve, F., Hatao, M., Hirose, A., Kasai, Y., Kern, P., Kreiling, R., Milstein, S., Montemayor, B., Oliveira, J., Richarz, A., Taalman, R., Vaillancourt, E., Verma, R., Cabral, Vieira O.’Reilly, Posada, N., Weiss, C., Kojima, H., Principles underpinning the use of new methodologies in the risk assessment of cosmetic ingredients. Comput. Toxicol. 7 (2018), 20–26, 10.1016/j.comtox.2018.06.001.
Desprez, M., Birk, B., Blaauboer, B., Boobis, A., Carmichael, P., Cronin, M.T.D., Curie, R., Daston, G., Hubesch, B., Jennings, P., Klaric, M., Kroese, D., Mahony, C., Ouédraogo, G., Piersma, A., Richarz, A.N., Schwarz, M., van Benthem, J., van de Water, B., Vinken, M., A mode-of-action ontology model for safety evaluation of chemicals: outcome of a series of workshops on repeated dose toxicity. Toxicol. In Vitro 59 (2019), 44–50, 10.1016/j.tiv.2019.04.005.
ECHA, Guidance on Information Requirements and Chemical Safety Assessment Chapter R.6: QSARs and Grouping of Chemicals. 2008, 1–74.
EU, Special Eurobarometer 442: Attitudes of Europeans Towards Animal Welfare. 2016, 1–86.
EU, Special Eurobarometer 456: Chemical Safety. 2017, 1–105.
EU, Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions: chemicals strategy for sustainability towards a toxic-free environment. COM(2020), 2020 667 final.
EURL ECVAM, Status Report on the Development, Validation and Regulatory Acceptance of Alternative Methods and Approaches (2019)., 2020, Publications Office of the European Union, Luxembourg, 1–152.
Hartung, T., Making big sense from big data in toxicology by read-across. ALTEX 33 (2016), 83–93, 10.14573/altex.1603091.
Knapen, D., Angrish, M.M., Fortin, M.C., Katsiadaki, I., Leonard, M., Margiotta-Casaluci, L., Munn, S., O'Brien, J.M., Pollesch, N., Smith, L.C., Zhang, X., Villeneuve, D.L., Adverse outcome pathway networks I: development and applications. Environ. Toxicol. Chem. 37 (2018), 1723–1733, 10.1002/etc.4125.
Luechtefeld, T., Hartung, T., Computational approaches to chemical hazard assessment. Altex 34 (2017), 459–478, 10.14573/altex.1710141.
Luechtefeld, T., Rowlands, C., Hartung, T., Big data and machine learning to revamp computational toxicology and its use in risk assessment. Toxicol. Res. 7 (2018), 732–744, 10.1039/c8tx00051d.
Mahony, C., Ashton, R.S., Birk, B., Boobis, A.R., Cull, T., Daston, G.P., Ewart, L., Knudsen, T.B., Manou, I., Maurer-Stroh, S., Margiotta-Casaluci, L., Müller, B.P., Nordlund, P., Roberts, R.A., Steger-Hartmann, T., Vandenbossche, E., Viant, M.R., Vinken, M., Whelan, M., Zvonimir, Z., Cronin, M.T.D., New ideas for non-animal approaches to predict repeated-dose systemic toxicity: report from an EPAA blue sky workshop. Regul. Toxicol. Pharmacol., 114, 2020, 104668, 10.1016/j.yrtph.2020.104668.
NRC, Toxicity Testing in the 21st Century: a Vision and a Strategy. 2007, The National Academies Press, Washington, DC.
OECD, Guidance document on good in vitro method practices (GIVIMP). OECD Series on Testing and Assessment 286 (2018), 1–264.
Piersma, A.H., van Benthem, J., Ezendam, J., Staal, Y.C.M., Kienhuis, A.S., The virtual human in chemical safety assessment. Curr. Opin. Toxicol. 15 (2019), 26–32, 10.1016/j.cotox.2019.03.009.
