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.

Cancer Prevention and Therapy of Two Types of Gap Junctional Intercellular Communication–Deficient “Cancer Stem Cell”

“…Specific inherited mutations of specific connexin genes are also associated with various abnormal syndromes [61,62]. As will be demonstrated later, also, both endogenous and exogenous chemicals can modulate connexin gene expression or gap junction functions [63].…”

What Can Chemical Carcinogenesis Shed Light on the LNT Hypothesis in Radiation Carcinogenesis?

“…23 Some of the early observations of the formation of cancers has led to the operational concepts that carcinogenesis is a "multistep, multimechanism process," consisting of the "initiation" of a single cell in the body, followed by the amplification or "promotion" of that single "initiated" cell into a benign clone and the subsequent conversion of one of these cells into an invasive and metastatic malignant cancer cell, the "progression" step. [9][10][11]24 This evolutionary process requires very different underlying molecular, biochemical, cellular mechanisms, which includes mutagenic, cytotoxic, and "epigenetic" mechanisms, affecting a number of genes in the nuclear and mitochondrial genomes. 25 From the operational level of these 3 steps of carcinogenesis, it appears that all cancers are the result of being "initiated" from a single cell in the body (stem cell hypothesis).…”

“…79,80 Fifth, these promoting agents, while able to induce oxidative stress, 81 were not genomic DNA damaging or mutagenic agents. 24 Sixth, promotion can also be accomplished by stimulation of cell/tissue growth and inhibition of apoptosis 82,83 by cell death, cell loss, or cell compensatory hyperplasia. 84 This latter point needs to be explained.…”

Evolving Concepts of Food Safety: The Need for Understanding Mechanisms of Food Toxicology for Public Policy

“…Moreover, one cannot ignore the biological and cultural evolutionary roles that interact in food safety in both the biological effect of toxins/ toxicants [17,18]. For example, threshold levels that are needed to trigger mutagenic, cytotoxic and epigenetic changes during the acute or chronic levels of exposure; and the differential effects of these food toxins/toxicants have on stem cells, progenitor and terminally differentiated cells [19]. To say this in another manner, all life depends on a food source for individual and species survival.…”

“…For multiple reasons, this approach was shown to be a faulty assumption for testing mutations that might occur in human cells [35,36]. In addition, in vitro assays, designed to detect mutations in animal and human cells have also proven to be less than accurate in predicting the mutagenicity of chemicals [19].…”