Abstract Carcinogenic chemicals, or their metabolites, can be classified as genotoxic or non-genotoxic carcinogens (NGTxCs). Genotoxic compounds induce DNA damage, which can be detected by an established in vitro and in vivo battery of genotoxicity assays. For NGTxCs, DNA is not the primary target, and the possible modes of action (MoA) of NGTxCs are much more diverse than those of genotoxic compounds, and there is no specific in vitro assay for detecting NGTxCs. Therefore, the evaluation of the carcinogenic potential is still dependent on long-term studies in rodents. This 2-year bioassay, mainly applied for testing agrochemicals and pharmaceuticals, is time-consuming, costly and requires very high numbers of animals. More importantly, its relevance for human risk assessment is questionable due to the limited predictivity for human cancer risk, especially with regard to NGTxCs. Thus, there is an urgent need for a transition to new approach methodologies (NAMs), integrating human-relevant in vitro assays and in silico tools that better exploit the current knowledge of the multiple processes involved in carcinogenesis into a modern safety assessment toolbox. Here, we describe an integrative project that aims to use a variety of novel approaches to detect the carcinogenic potential of NGTxCs based on different mechanisms and pathways involved in carcinogenesis. The aim of this project is to contribute suitable assays for the safety assessment toolbox for an efficient and improved, internationally recognized hazard assessment of NGTxCs, and ultimately to contribute to reliable mechanism-based next-generation risk assessment for chemical carcinogens. Keywords: non-genotoxic carcinogens, NGTxC, new approach methodologies, NAM, PARC
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Marc Audebert, Ann-Sophie Assmann, Amaya Azqueta et al.. New approach methodologies to facilitate and improve the hazard assessment of non-genotoxic carcinogens—a PARC project. Frontiers in Toxicology. (2023). https://doi.org/10.3389/ftox.2023.1220998 Marc Audebert, Ann-Sophie Assmann, Amaya Azqueta, Pavel Babica, Emilio Benfenati, Sylvie Bortoli, Peter Bouwman, Albert Braeuning, Tanja Burgdorf, Xavier Coumoul, Kloé Debizet, Maria Dusinska, Norman Ertych, Jörg Fahrer, Verena Fetz, Ludovic Le Hégarat, Adela López de Cerain, Harm J Heusinkveld, Kevin Hogeveen, Miriam N Jacobs, Mirjam Luijten, Giuseppa Raitano, Cynthia Recoules, Elise Rundén-Pran, Mariam Saleh, Iva Sovadinová, Martina Stampar, Lea Thibol, Céline Tomkiewicz, Ariane Vettorazzi, Bob Van de Water, Naouale El Yamani, Bojana Zegura, Michael Oelgeschläger
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INRAE: Toxalim, INRAE, INP-ENVT, INP-EI-Purpan, Université de Toulouse 3 Paul Sabatier, Toulouse, France 2
Department Experimental Toxicology and ZEBET, German Centre for the Protection of Laboratory Animals (Bf3R) and Department Food Safety, BfR: German Federal Institute for Risk Assessment, Berlin, Germany 3
Department of Pharmacology and Toxicology, School of Pharmacy and Nutrition, UNAV: University of Navarra, Pamplona, Spain 4
RECETOX: RECETOX, Faculty of Science, Masaryk University, Brno, Czechia 5
IRFMN: Istituto di Ricerche Farmacologiche Mario Negri—IRCCS, Milan, Italy 6
INSERM: INSERM UMR-S 1124 T3S—Université Paris Cité, Paris, France 7
UL-LACDR: Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands 8
Health Effects Laboratory, NILU: The Climate and Environmental Research Institute, Kjeller, Norway 9
Department of Chemistry, RPTU: Division of Food Chemistry and Toxicology, Kaiserslautern, Germany 10
ANSES: French Agency for Food, Environmental and Occupational Health and Safety, Fougères Laboratory, Toxicology of Contaminants Unit, Fougères, France 11
RIVM: National Institute for Public Health and the Environment, Bilthoven, Netherlands 12
Radiation, Chemical and Environmental Hazards, UKHSA: UK Health Security Agency, Chilton, Oxfordshire, United Kingdom 13
Department of Genetic Toxicology and Cancer Biology, NIB: National Institute of Biology, Ljubljana, Slovenia 