New approach methodologies to facilitate and improve the hazard assessment of non-genotoxic carcinogens—a PARC project

Frontiers in Toxicology

Toxicology

Ludovic Le Hégarat¹  Kevin Hogeveen¹  Mariam Saleh¹  Ann-Sophie Assmann²  Michael Oelgeschläger²  Norman Ertych²  Tanja Burgdorf²  Verena Fetz²  Albert Braeuning²  Jörg Fahrer³  Lea Thibol³  Martina Stampar⁴  Bojana Zegura⁴  Amaya Azqueta⁵  Ariane Vettorazzi⁵  Adela López de Cerain⁵  Maria Dusinska⁶  Elise Rundén-Pran⁶  Naouale El Yamani⁶  Cynthia Recoules⁷  Marc Audebert⁷  Kloé Debizet⁸  Sylvie Bortoli⁸  Céline Tomkiewicz⁸  Xavier Coumoul⁸  Giuseppa Raitano⁹  Emilio Benfenati⁹  Pavel Babica^1,10  Iva Sovadinová^1,10  Harm J. Heusinkveld^1,11  Mirjam Luijten^1,11  Miriam N. Jacobs^1,12  Bob Van de Water^1,13  Peter Bouwman^1,13 

[1] 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 (Bf3R) 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;RECETOX: RECETOX, Faculty of Science, Masaryk University, Brno, Czechia;RIVM: National Institute for Public Health and the Environment, Bilthoven, Netherlands;Radiation, Chemical and Environmental Hazards, UKHSA: UK Health Security Agency, Chilton, Oxfordshire, United Kingdom;UL-LACDR: Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands;

关键词: non-genotoxic carcinogens;    NGTxC;    new approach methodologies;    NAM;    PARC;   

DOI  :  10.3389/ftox.2023.1220998

 received in 2023-05-11, accepted in 2023-06-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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Copyright © 2023 Audebert, Assmann, Azqueta, Babica, Benfenati, Bortoli, Bouwman, Braeuning, Burgdorf, Coumoul, Debizet, Dusinska, Ertych, Fahrer, Fetz, Le Hégarat, López de Cerain, Heusinkveld, Hogeveen, Jacobs, Luijten, Raitano, Recoules, Rundén-Pran, Saleh, Sovadinová, Stampar, Thibol, Tomkiewicz, Vettorazzi, Van de Water, El Yamani, Zegura and Oelgeschläger.