Chapter 7: Dissecting Modes of Action of Non-genotoxic Carcinogens

In safety assessments of chemicals, genotoxic and carcinogenic potential is considered one of the basic requirements. Overall, regulatory guidelines for carcinogenicity testing focus on genotoxic potential, because the majority of carcinogens induce tumors by inflicting irreversible DNA damage in critical genes. However, there is a group of carcinogens that induce cancer via non-genotoxic mechanisms. Apart from the carcinogenicity bioassay, suitable assays to detect these chemicals hardly exist. This is mainly due to the diversity in mode of action of non-genotoxic carcinogens. We employed toxicogenomics in primary mouse hepatocytes to categorize non-genotoxic carcinogens according to their overlap in transcriptional profile. This approach, based on a limited set of significantly regulated genes, may be further improved by using a concentration range instead of a single concentration per chemical. We explored this by performing a case study using cyclosporine A and tacrolimus. Testing multiple concentrations strongly enhanced our approach to detect modes of actions of non-genotoxic carcinogens. We therefore propose to include a concentration range when using in vitro toxicogenomics approaches to detect non-genotoxic carcinogens. This approach is a promising tool for future safety assessments, since its applicability is not necessarily limited to carcinogens, but may comprise environmental and pharmaceutical chemicals in general.