Key messages

• Non-genotoxic carcinogens can contribute to cancer development without directly damaging DNA, making them challenging to identify with current tests;
• The project evaluates innovative animal-free testing approaches, combining advanced laboratory models, omics technologies, imaging methods, and computational tools;
• The project aims to improve cancer risk assessment, support chemical safety regulations, and help identify potentially harmful substances more effectively without relying on animal testing.

Overview

Most chemical carcinogens induce DNA damage and can be detected by the standard in vitro or in vivo genotoxicity tests. Some substances can however induce cancer without being detectable in those tests, namely nongenotoxic carcinogens (NGTxCs). Instead of directly damaging DNA, they may trigger processes linked to cancer development, such as oxidative stress, inflammation, changes in metabolism, altered cell signaling, epigenetic changes, epithelial-mesenchymal transition (EMT), or increased cell growth.

This project is a follow-up of a previous PARC project focused on studying those processes using advanced laboratory models, including 2D and 3D models of liver, breast, and colon tissue, as well as zebrafish models, including modern technologies such as transcriptomics, high-content imaging, cell painting, epigenetic analysis, high-throughput reporter systems, and computer-based testing methods.

It aims to evaluate how well these new methods work in practice by testing selected chemicals from The European Partnership for Alternative Approaches to Animal Testing ↗ (EPAA) and the European Food Safety Agency (EFSA) NGTxC databases. The work supports the growing use of New Approach Methodologies (NAMs) to reduce and replace animal testing, in line with European Chemical’s Agency (ECHA) and PARC priorities. The project will also contribute to developing Integrated Approaches to Testing and Assessment (IATA) for carcinogenicity within PARC.

Some methods will undergo transferability studies to confirm they can be reliably used in other laboratories and later validated for regulatory use. New Quantitative Structure–Activity Relationship (QSAR ↗) computer models for identifying NGTxCs will also be developed.

Overall, the project aims to improve cancer risk assessment, support chemical safety regulations, and help identify potentially harmful substances more effectively without relying on animal testing.

Policy relevance

The project will support regulatory decision-making (depending on the outcome) in different ways: by providing mechanistic information, facilitating analogy approaches like read across or prioritizing chemicals for further testing.

The latter might be particularly interesting for industrial chemicals registered under Regulation on the registration, evaluation, authorisation and restriction of chemicals (REACH ↗), whereas the data from these models or testing batteries can also support Weight of Evidence (WoE ↗), a methodology used for chemical risk assessment that combines relevance, quality, reliability, and consistency of data to strengthen a body of evidence, for pesticides or biocides. Finally, the project could also support the Safe and sustainable by design (SSbD) framework. Some more advanced methods should reach an OECD Guidelines for the Testing of Chemicals ↗.