Application of the key characteristics of carcinogens in cancer hazard identification

Abstract

Smith et al. (Env. Health Perspect. 124: 713, 2016) identified 10 key characteristics (KCs), one or more of which are commonly exhibited by established human carcinogens. The KCs reflect the properties of a cancer-causing agent, such as 'is genotoxic,' 'is immunosuppressive' or 'modulates receptor-mediated effects,' and are distinct from the hallmarks of cancer, which are the properties of tumors. To assess feasibility and limitations of applying the KCs to diverse agents, methods and results of mechanistic data evaluations were compiled from eight recent IARC Monograph meetings. A systematic search, screening and evaluation procedure identified a broad literature encompassing multiple KCs for most (12/16) IARC Group 1 or 2A carcinogens identified in these meetings. Five carcinogens are genotoxic and induce oxidative stress, of which pentachlorophenol, hydrazine and malathion also showed additional KCs. Four others, including welding fumes, are immunosuppressive. The overall evaluation was upgraded to Group 2A based on mechanistic data for only two agents, tetrabromobisphenol A and tetrachloroazobenzene. Both carcinogens modulate receptor-mediated effects in combination with other KCs. Fewer studies were identified for Group 2B or 3 agents, with the vast majority (17/18) showing only one or no KCs. Thus, an objective approach to identify and evaluate mechanistic studies pertinent to cancer revealed strong evidence for multiple KCs for most Group 1 or 2A carcinogens but also identified opportunities for improvement. Further development and mapping of toxicological and biomarker endpoints and pathways relevant to the KCs can advance the systematic search and evaluation of mechanistic data in carcinogen hazard identification.

Figure 1.

Results of the search, screening and organization of the published scientific literature, according to the KCs and other topics relevant to mechanistic data evaluation for PCP (Group 1, IARC Monograph Meeting 117). Of note, more than one exclusion criteria may apply to each excluded study, and more than one category may apply to included studies (e.g. if more than one KC, endpoint, species, etc. was evaluated).

Figure 2.

Results of the search, screening and organization of the published scientific literature, according to the KCs and other topics relevant to mechanistic data evaluation for 2,4,6-trichlorophenol (Group 2B, IARC Monograph Meeting 117). Of note, more than one exclusion criteria may apply to each excluded study, and more than one category may apply to included studies (e.g. if more than one KC, endpoint, species, etc. was evaluated).

Figure 3.

KCs of carcinogens with strong evidence across multiple evaluations. The number of Group 1/2A and Group 2B carcinogens with strong evidence for each characteristic is indicated, of 34 agents evaluated. All but one of the Group 2B carcinogens (1-bromopropane, see Table 3) had strong evidence for only one KC. No agent had strong evidence for three KCs (alters DNA repair or causes genomic instability; induces epigenetic alterations and causes immortalization).