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

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.

Finding a Direct method for a Dynamic process: the DD (Direct and Dynamic) Cell-Tox method

“…Innovative methods for testing carcinogenic cells continue to be a focus of research and development in oncology and cancer biology [37,38]. Cancer treatments aim to preserve the function of healthy cells by maintaining homeostasis, while inducing cell death of cancer cells to control the disease [39].…”

Finding a Direct Method for a Dynamic Process: The DD (Direct and Dynamic) Cell-Tox Method

“…Innovative methods for testing carcinogenic cells continue to be a focus of research and development in oncology and cancer biology [45,46]. Cancer treatments aim to preserve the function of healthy cells by maintaining homeostasis while inducing the cell death of cancer cells to control the disease [47].…”

A modular strategy for the testing and assessment of non-genotoxic carcinogens

“…Parallel activities and dynamic exchanges are needed, and this is being considered in for instance EU-funded projects such as PARC (Audebert et al 2023;Marx-Stoelting et al 2023), where, going forward, test method developers and regulators have the opportunity to work closely together. Robust comparative and combinatorial analyses of carcinogenicity computational tools are not new, they have been conducted for over 20 years, e.g.…”