Background: Advances in the science of cancer epidemiology and toxicology have provided opportunities for enhancing the inclusion of mechanistic information useful to the evaluation of carcinogenic hazards. The IARC Monographs programme has guided this change over >50 years of cancer hazard evaluations. In the past decade, several research institutions and agencies globally, including the IARC Monographs programme, have placed mechanistic evidence alongside evidence for cancer in humans and in experimental animals for the overall evaluation of cancer hazard. With growing confidence in the relevance and applications of mechanistic data, it is likely that cancer hazard identification in the future will increasingly rely on mechanistic information together with cancer studies in humans. The implementation into the Monographs evaluation of the key characteristics (KCs) of carcinogens framework has proven a useful and unbiased tool to organize and evaluate mechanistic data. The KCs framework has supported the carcinogenicity evaluation of approximately 120 agents, from chemicals, to complex mixtures, occupational exposures, biological agents, and more recently, pharmaceuticals and pesticides.
Objectives and methods: We will discuss the identification and interpretation of specific mechanistic endpoints for the KCs, by focusing on the relevance of these endpoints in relation to the test systems in which they are measured (i.e., exposed humans, experimental systems in vivo and in vitro, and application of omics data). With particular emphasis on the studies in exposed humans and documented molecular and disease-related endpoints for IARC Group 1 and Group 2A agents, we describe how mechanistic information is considered in the cancer hazard evaluation, and the associated challenges in its interpretation.
Results: Several factors have been critically important for the evaluation of strong mechanistic evidence, including endpoint identification and measurement across different test systems, especially in exposed humans (e.g., for welding fumes, styrene, styrene 7,8 oxide, and antimony); aspects of study design and informativeness (e.g., for occupational exposure as a firefighter, PFOA, and automotive gasoline); persistence of the effects (e.g., for talc, occupational exposure as a firefighter, and antimony); and specificity (e.g., for 2-bromopropane, voriconazole, and tacrolimus). Integration and consistency of the information across different streams of evidence are also critical, including considerations of endpoints associated with chronic cancer-related diseases, such as pneumoconiosis, fibrosis, keratosis, and metabolic alterations.
Conclusion, implications: Mechanistic information, including emerging data, supports the understanding of how carcinogenicity occurs and helps to identify specific molecular and cellular changes related to human tumour development. Well-conducted studies in exposed humans are especially informative. It is critically important that the incorporation of scientific advances is also supported by the furtherance of the methodologies used to evaluate them. It is expected that the integration of evidence across test systems, and the integration of emerging data also with findings associated with cancer-related diseases, will allow a more holistic understanding of cancer hazards, and will strengthen biological plausibility connecting environmental and/or occupational exposures with cancer.