Implications of multiple mechanisms of carcinogenesis for short‐term testing

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Abstract
The attempt has been made recently to categorize carcinogens into two mechanistic types based on their mechanism of action: genotoxic (capable of reacting with and damaging DNA) and epigenetic (unable to damage DNA to any detectable extent). By requiring that a given chemical fit into one or the other of these narrowly defined categories for regulatory purposes, we are probably oversimplifying potential biological effects. In fact, based on our limited understanding of carcinogenic mechanisms, this artificial distinction should probably be abandoned in favor of a more precise statement of each chemical's mechanism or relative potency of initiating and promoting effects. Since the standard short-term tests by which carcinogenicity of chemicals is screened were designed to detect certain chemical classes with active electrophilic intermediates, weak or specialized carcinogens may be missed and may be assumed erroneously to be nongenotoxic. The mechanisms of carcinogenicity for such carcinogens may include particulate deposition, active radical formation, liver toxicity, and hormonal interactions. Not all of these secondary mechanisms depend upon a detectable level of binding to DNA, damage to DNA, or modification of the DNA sequence, even though they may demonstrate other characteristics of a complete carcinogen (that is, irreversibility and lack of a threshold). Certain agents have been labeled as epigenetic. However, a consideration of the literature on sample agents (diethylstilbestrol, asbestos, and urethane) reveals that these are not epigenetic carcinogens despite their being labeled as such. Agents with irreversibility and no threshold have initiating potential and, as such, are genotoxic, whereas carcinogens that are classified as nongenotoxic are largely agents that promote the growth of liver tumors. Even promotion can be a mechanistically specialized phenomenon. For example, some promoters are cytotoxic to the liver, but not all liver toxins are liver tumor promoters or liver carcinogens. Further, the carcinogens commonly labeled as epigenetic might cause a unique specialized genotoxicity not detected by common screening tests routinely used for detecting genotoxicity. If we assume that this unrecognized but necessary initiating potential is mediated by some specialized genotoxicity, extra care must be taken to establish a genuine lack of genotoxicity before an agent can be classified (and regulated) as a promoter (lacking the ability to initiate tumor growth but still enhancing tumor development). There is no question that reversible effects with definite thresholds should be evaluated differently from thos that are irreversible and lack a threshold, but the distinction should be based on their effect and potncy, not on their (often unknown) mechanism of genotoxicity.

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