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

• Published in: Frontiers in toxicology 2023-07, Vol.5, p.1220998-1220998
• Main Authors: Audebert, Marc, Assmann, Ann-Sophie, Azqueta, Amaya, Babica, Pavel, Benfenati, Emilio, Bortoli, Sylvie, Bouwman, Peter, Braeuning, Albert, Burgdorf, Tanja, Coumoul, Xavier, Debizet, Kloé, Dusinska, Maria, Ertych, Norman, Fahrer, Jörg, Fetz, Verena, Le Hégarat, Ludovic, López de Cerain, Adela, Heusinkveld, Harm J, Hogeveen, Kevin, Jacobs, Miriam N, Luijten, Mirjam, Raitano, Giuseppa, Recoules, Cynthia, Rundén-Pran, Elise, Saleh, Mariam, Sovadinová, Iva, Stampar, Martina, Thibol, Lea, Tomkiewicz, Céline, Vettorazzi, Ariane, Van de Water, Bob, El Yamani, Naouale, Zegura, Bojana, Oelgeschläger, Michael
• Format: Article
• Language: English
• Subjects: Life Sciences; NAM; new approach methodologies; NGTxC; non-genotoxic carcinogens; PARC; Toxicology
• ISSN: 2673-3080; 2673-3080
• DOI: 10.3389/ftox.2023.1220998

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 and 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 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 assays and 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.