In order to ascertain whether there might be a scientific basis for determining practical “thresholds” for “carcinogens,” the concepts of thresholds and carcinogens were examined in the context of some current ideas on cardnogenesis. The observation that cardnogenesis seems to involve the donal expansion of a pre-malignant cell through a series of pheno-typic changes was explained by the initiation/promotion model of cardnogenesis. Unrepaired DNA lesions, acting as substrates for mutations in dividing cells, were speculated to play a role in the initiation phase of cardnogenesis (and indirectly to the promotion phase if the lesions lead to significant cell killing, forcing “compensatory hyperplasia”). Inhibition of intercellular communication, either by cell removal, cell death, growth factors or chemical promoters, was speculated to allow the donal expansion of initiated cells to reach a “critical mass.” During that donal expansion of initiated cells, additional phenotypic changes were speculated to occur during cell replication by mutational and/or epigenetic events. Therefore, it was concluded, on the basis of this model, that conditions which prevented the inhibition of intercellular communication between normal cells and the initiated cell(s) contributed to the rate limiting step of cardnogenesis.
Assuming the initiation and promotion model of cardnogenesis, the classical concepts of “thresholds” and “carcinogens” were viewed as grossly inadequate because they did not symbolically represent the known determinants of the complex carcinogenic process. Unless genetic, developmental stage, tissue, nutritional, stress, life style, as well as concurrent antagonists and/or synergists, factors are known, extrapolation about the potential carcinogenicity of a given chemical from molecular, in vitro or even in vivo experiments or epidemiological data would be extremely risky. It was concluded that, at this stage of our understanding of the mech-anism(s) of carcinogenesis, attempts to determine “thresholds” for “carcinogens” naively assume “carcinogens” are the single determinants for carcinogenesis, and that all chemicals which might influence the appearance of tumors act the same way.
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