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

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.

Automated summary

Carcinogenic chemicals can be classified as genotoxic or non-genotoxic carcinogens. Genotoxic compounds cause DNA damage and can be detected through genotoxicity assays, while non-genotoxic compounds have diverse modes of action and do not have specific assays for detection. Evaluation of the carcinogenic potential of non-genotoxic compounds still relies on long-term studies in rodents, which are time-consuming, costly, and limited in their predictivity for human risk assessment. Therefore, there is an urgent need for new approach methodologies that integrate human-relevant in vitro assays and in silico tools to improve hazard assessment and risk assessment for chemical carcinogens.