IARC Workshop on the Key Characteristics of Carcinogens: Assessment of End Points for Evaluating Mechanistic Evidence of Carcinogenic Hazards

Abstract

Background: The 10 key characteristics (KCs) of carcinogens form the basis of a framework to identify, organize, and evaluate mechanistic evidence relevant to carcinogenic hazard identification. The 10 KCs are related to mechanisms by which carcinogens cause cancer. The International Agency for Research on Cancer (IARC) Monographs programme has successfully applied the KCs framework for the mechanistic evaluation of different types of exposures, including chemicals, metals, and complex exposures, such as environmental, occupational, or dietary exposures. The use of this framework has significantly enhanced the identification and organization of relevant mechanistic data, minimized bias in evaluations, and enriched the knowledge base regarding the mechanisms of known and suspected carcinogens.

Objectives: We sought to report the main outcomes of an IARC Scientific Workshop convened by the IARC to establish appropriate, transparent, and uniform application of the KCs in future IARC Monographs evaluations.

Methods: A group of experts from different disciplines reviewed the IARC Monographs experience with the KCs of carcinogens, discussing three main themes: a) the interpretation of end points forming the evidence base for the KCs, b) the incorporation of data from novel assays on the KCs, and c) the integration of the mechanistic evidence as part of cancer hazard identification. The workshop participants assessed the relevance and the informativeness of multiple KCs-associated end points for the evaluation of mechanistic evidence in studies of exposed humans and experimental systems.

Discussion: Consensus was reached on how to enhance the use of in silico, molecular, and cellular high-output and high-throughput data. In addition, approaches to integrate evidence across the KCs and opportunities to improve methodologies of mechanistic evaluation of cancer hazards were explored. The findings described herein and in a forthcoming IARC technical report will support future working groups of experts in reporting and interpreting results under the KCs framework within the IARC Monographs or in other contexts. https://doi.org/10.1289/EHP15389.

Figure 1.

Comprehensive analysis of the key characteristics of carcinogens for agents with strong mechanistic evidence evaluated since IARC Monographs volume 112. (A) Average number of KCs with consistent and coherent evidence per agent (X represents the mean, and whiskers the range). (B) Percentage of agents with consistent and coherent evidence per KC. (C) Agents with strong mechanistic evidence. According to the current IARC Monographs Preamble, the mechanistic evidence is considered strong if results in several different experimental systems are consistent and the overall mechanistic database is coherent. Each column represents one agent evaluated with strong mechanistic evidence. Each line represents the test system of the mechanistic evidence evaluated as consistent and coherent. (D) Percentage of agents with consistent and coherent evidence per test system. Agents with consistent and coherent mechanistic evidence in exposed humans or mechanistic evidence likely to be operative in humans: dark blue background. Agents with mechanistic evidence in human primary cells or tissues: orange pattern background. Agents with consistent and coherent mechanistic evidence in experimental systems (e.g., human cell line, nonhuman mammalian systems in vivo, nonhuman mammalian cells in vitro, in silico): gray background. Data are reported in Excel Tables S1–S4. Note: IARC, International Agency for Research on Cancer; KC, key characteristic of carcinogens.