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.

ANSES French Agency for Food Environmental and Occupational Health and Safety Fougères Laboratory Toxicology of Contaminants Unit Fougères France

Department Experimental Toxicology and ZEBET German Centre for the Protection of Laboratory Animals and Department Food Safety BfR German Federal Institute for Risk Assessment Berlin Germany

Department of Chemistry RPTU Division of Food Chemistry and Toxicology Kaiserslautern Germany

Department of Genetic Toxicology and Cancer Biology NIB National Institute of Biology Ljubljana Slovenia

Department of Pharmacology and Toxicology School of Pharmacy and Nutrition UNAV University of Navarra Pamplona Spain

Health Effects Laboratory NILU The Climate and Environmental Research Institute Kjeller Norway

INRAE Toxalim INRAE INP ENVT INP EI Purpan Université de Toulouse 3 Paul Sabatier Toulouse France

INSERM INSERM UMR S 1124 T3S Université Paris Cité Paris France

IRFMN Istituto di Ricerche Farmacologiche Mario Negri IRCCS Milan Italy

Radiation Chemical and Environmental Hazards UKHSA UK Health Security Agency Chilton Oxfordshire United Kingdom

RECETOX RECETOX Faculty of Science Masaryk University Brno Czechia

RIVM National Institute for Public Health and the Environment Bilthoven Netherlands

UL LACDR Leiden Academic Centre for Drug Research Leiden University Leiden Netherlands

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