Reflections on the use of 10 IARC carcinogenic characteristics for an objective approach to identifying and organizing results from certain mechanistic studies

Abstract

To find a scientifically based method for evaluating mechanistic data related to risks to human beings, a new protocol for identifying, organizing, and summarizing mechanistic data for decision-making on cancer hazard identification was proposed by the International Agency for Research on Cancer and by an international working group of multidisciplinary experts. This Commentary examined the 10 key carcinogens’ characteristics proposed in the context of several paradigms assumed in the using of these 10 characteristics. These characteristics were assumed to represent a “carcinogen’s” mechanism of action but what was ignored were characteristics of the mechanisms of the “initiation,” “promotion,” and “progression” carcinogenic process. Challenges were made to the interpretation of genotoxicity data as well as from concepts and findings related to the promotion phase and the role of adult human stem cells. Reliance of interpretation of “genotoxicity” data (molecular-DNA lesions in DNA; induction of free radicals/oxidative stress markers; phenotypic surrogates of gene mutations), as well as from lesions in genomic versus mitochondrial DNA, or in the target cells for the carcinogenic process in either in vitro cultures or in vivo tissues, makes this “objective” use of the data questionable. A challenge to the “dedifferentiation” hypothesis of cancer was made. Because of an agent being misclassified as “genotoxic”—rather than an “epigenetic”—agent (which works by threshold levels; can be blocked; and must be present at critical times during development and at regular, sustained chronic exposures) could lead to unwise policy decisions.