Abstract IA13: Key characteristics of carcinogens

Abstract

Abstract The key characteristics (KCs) of human carcinogens were recently introduced as the basis of a uniform approach for searching, organizing, and evaluating mechanistic evidence to support cancer hazard identification (Smith et al., 2016; Guyton et al., 2018). The KCs comprise the properties of known human carcinogens, including their ability to be genotoxic, be immunosuppressive, or modulate receptor-mediated effects. Established human carcinogens commonly exhibit one or more of these characteristics, and therefore, data on these characteristics can provide independent evidence of carcinogenicity when human data are lacking. Such data can also help in interpreting the relevance and importance of findings of cancer in animals and in humans. In its 2017 report, “Using 21st Century Science to Improve Risk-Related Evaluations,” the NRC recently opined that the KCs approach “avoids a narrow focus on specific pathways and hypotheses and provides for a broad, holistic consideration of the mechanistic evidence.” They further suggested that key characteristics be developed for other endpoints, such as endocrine disruption and reproductive toxicity, and efforts in this regard are approaching completion and publication. The KC approach therefore holds great potential to improve hazard identification and risk assessment but still needs to be further developed, especially in regard to its integration with the hallmarks of cancer and its potential for helping analyze the toxic effects of untested chemicals and chemical mixtures in cell culture and experimental animals. Unfortunately, the current Tox21 and Toxcast repertoire of assays is mostly lacking in relevance to the KCs, as are most clinical biomarkers. Approaches to developing a new set of high-throughput tests and biomarkers (a CarciCAST) will be described along with a discussion of the use of the key characteristics approach in hazard identification and risk assessment instead of, or as well as, the current MOA/AOP approach. References Guyton KZ, Rusyn I, Chiu WA, Corpet DE, van den Berg M, Ross MK, et al. Application of the key characteristics of carcinogens in cancer hazard identification. Carcinogenesis 2018;39:614-22; doi:10.1093/carcin/bgy031. Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, et al. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 2016;124:713-21; doi:10.1289/ehp.1509912. Citation Format: Martyn T. Smith. Key characteristics of carcinogens [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA13.