Frontiers in Toxicology (Jul 2023)
New approach methodologies to facilitate and improve the hazard assessment of non-genotoxic carcinogens—a PARC project
- 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
Affiliations
- Marc Audebert
- INRAE: Toxalim, INRAE, INP-ENVT, INP-EI-Purpan, Université de Toulouse 3 Paul Sabatier, Toulouse, France
- Ann-Sophie Assmann
- 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
- Amaya Azqueta
- Department of Pharmacology and Toxicology, School of Pharmacy and Nutrition, UNAV: University of Navarra, Pamplona, Spain
- Pavel Babica
- RECETOX: RECETOX, Faculty of Science, Masaryk University, Brno, Czechia
- Emilio Benfenati
- IRFMN: Istituto di Ricerche Farmacologiche Mario Negri—IRCCS, Milan, Italy
- Sylvie Bortoli
- INSERM: INSERM UMR-S 1124 T3S—Université Paris Cité, Paris, France
- Peter Bouwman
- UL-LACDR: Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
- Albert Braeuning
- 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
- Tanja Burgdorf
- 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
- Xavier Coumoul
- INSERM: INSERM UMR-S 1124 T3S—Université Paris Cité, Paris, France
- Kloé Debizet
- INSERM: INSERM UMR-S 1124 T3S—Université Paris Cité, Paris, France
- Maria Dusinska
- Health Effects Laboratory, NILU: The Climate and Environmental Research Institute, Kjeller, Norway
- Norman Ertych
- 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
- Jörg Fahrer
- Department of Chemistry, RPTU: Division of Food Chemistry and Toxicology, Kaiserslautern, Germany
- Verena Fetz
- 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
- Ludovic Le Hégarat
- 0ANSES: French Agency for Food, Environmental and Occupational Health and Safety, Fougères Laboratory, Toxicology of Contaminants Unit, Fougères, France
- Adela López de Cerain
- Department of Pharmacology and Toxicology, School of Pharmacy and Nutrition, UNAV: University of Navarra, Pamplona, Spain
- Harm J. Heusinkveld
- 1RIVM: National Institute for Public Health and the Environment, Bilthoven, Netherlands
- Kevin Hogeveen
- 0ANSES: French Agency for Food, Environmental and Occupational Health and Safety, Fougères Laboratory, Toxicology of Contaminants Unit, Fougères, France
- Miriam N. Jacobs
- 2Radiation, Chemical and Environmental Hazards, UKHSA: UK Health Security Agency, Chilton, Oxfordshire, United Kingdom
- Mirjam Luijten
- 1RIVM: National Institute for Public Health and the Environment, Bilthoven, Netherlands
- Giuseppa Raitano
- IRFMN: Istituto di Ricerche Farmacologiche Mario Negri—IRCCS, Milan, Italy
- Cynthia Recoules
- INRAE: Toxalim, INRAE, INP-ENVT, INP-EI-Purpan, Université de Toulouse 3 Paul Sabatier, Toulouse, France
- Elise Rundén-Pran
- Health Effects Laboratory, NILU: The Climate and Environmental Research Institute, Kjeller, Norway
- Mariam Saleh
- 0ANSES: French Agency for Food, Environmental and Occupational Health and Safety, Fougères Laboratory, Toxicology of Contaminants Unit, Fougères, France
- Iva Sovadinová
- RECETOX: RECETOX, Faculty of Science, Masaryk University, Brno, Czechia
- Martina Stampar
- 3Department of Genetic Toxicology and Cancer Biology, NIB: National Institute of Biology, Ljubljana, Slovenia
- Lea Thibol
- Department of Chemistry, RPTU: Division of Food Chemistry and Toxicology, Kaiserslautern, Germany
- Céline Tomkiewicz
- INSERM: INSERM UMR-S 1124 T3S—Université Paris Cité, Paris, France
- Ariane Vettorazzi
- Department of Pharmacology and Toxicology, School of Pharmacy and Nutrition, UNAV: University of Navarra, Pamplona, Spain
- Bob Van de Water
- UL-LACDR: Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
- Naouale El Yamani
- Health Effects Laboratory, NILU: The Climate and Environmental Research Institute, Kjeller, Norway
- Bojana Zegura
- 3Department of Genetic Toxicology and Cancer Biology, NIB: National Institute of Biology, Ljubljana, Slovenia
- Michael Oelgeschläger
- 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
- DOI
- https://doi.org/10.3389/ftox.2023.1220998
- Journal volume & issue
-
Vol. 5
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.
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