Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis

Abstract

Background: A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens.

Objectives and methods: IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens.

Discussion: These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply.

Conclusion: We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program.

Citation: Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.

Figure 1

Literature flow diagram, illustrating the systematic identification and categorization process for benzene mechanistic studies. Using appropriate MeSH terms and key words, targeted literature searches were conducted for the 10 key characteristics using online tools available from the HAWC Project (https://hawcproject.org/). Section 4 refers to the location of the discussion of mechanistic data within the IARC Monograph structure (http://monographs.iarc.fr/ENG/Preamble/currentb4studiesother0706.php). All inclusion categories were expanded to document the number of studies attributed to each, down to the individual key characteristic level, which were expanded to illustrate human information when > 100 total studies were identified. Less frequently encountered key characteristic categories (blue-shaded circles) were left unexpanded for clarity. “Human” refers to both humans exposed in vivo and human cells exposed in vitro.

Figure 2

An overview of how benzene induces eight of the key characteristics in a probable mechanism of carcinogenicity. A full review of these mechanistic data is given by McHale et al. (2012), from which this figure was adapted.

Figure 3

An overview of how polychlorinated biphenyls (PCBs) may induce seven key characteristics in their carcinogenicity (Lauby-Secretan et al. 2013). Highly chlorinated PCBs act as ligands for the aryl hydrocarbon receptor (AhR) and other receptors activating a large number of genes in a tissue- and cell-specific manner that can lead to cell proliferation, apoptosis, and other effects that influence cancer risk. Less chlorinated PCBs can be activated to electrophilic metabolites, such as arene oxides and quinones, which can cause genotoxic effects and induce oxidative stress. Receptor binding to CAR (constitutive androstane receptor) and AhR (a key characteristic) leads to xenobiotic metabolism induction (not a key characteristic; brown box) that in turn leads to genotoxicity and other key characteristics.