Environment Industrial

How wonderful it would be for both the scientist and policy regulator if, in fact, cancers, in their full-blown form, were “caused” by a single exposure to an agent, which is currently called a “carcinogen”.  However, this is naïve, since current experimental cancer studies in rodents (Siaga et al., 1982), in vitro studies with human cells (McCormick and Maher, 1989), cancer-prone human syndromes (i.e., retinoblastoma)(Levine et al., 1991; Moolgavkar and Knudson, 1981), and epidemiological studies (Armitage and Doll, 1954), all point to multiple and discreetly unique steps involved in carcinogenesis.  Indeed, it is fairly well accepted by most that a variety of genetic factors can influence the ultimate appearance of a cancer, that the developmental stage and sex of the individual will influence the effect of the agent contributing to the process, that dietary habits, as well as exposure to a wide variety and class of chemicals and drugs, could modify the effluence of the agent thought to be the primary “carcinogen” (Trosko and Chang, 1978a).  This, then leads to our first conceptual problem; namely, “What is a ‘carcinogen’?”

To begin the process of trying to understand the carcinogenic process, introduction to several current hypotheses will be necessary; namely, the ‘initiation promotion-proression’ hypothesis (Pitot et al., 1981); the stem cell theory or the ‘disease of differentiation’ theory[“ontogeny as partially blocked ontogeny”] (Markert, 1968; Pierce, 1974; Potter,1988; Trosko and Chang, 1989a); the nature and nurture theory (Trosko and Chang,1978b); oncogenes and tumor suppressor gene theory (Bishop,1983; Sager, 1986); and the blocked intercellular communication hypothesis (Trosko et al., 1983a).  To some, to muse on the theoretical nature of carcinogenesis will get nowhere.  One only needs either to test the suspected cancer-causing agent in an animal system, short term assay designed presumably to test for a suspected mechanism in carcinogenesis or do epidemiological analyses on humans exposed to the agent.  There are all kinds of inherent problems with all of these approaches, as has been demonstrated with recent challenges to the current procedures to test for “cancer-causing” chemicals (Trosko, 1988; Trosko, 1989).  The basic nature of the problem seen by some is that the animal bioassay procedure, by not being designed with the multi-stage nature of carcinogenesis in mind, cannot provide information as to how the chemical could contribute to the multi-stage nature of carcinogenesis (i.e., Is the chemical a mutagen/initiator or is it a nitrogen/promoter?) (Ames and Gold, 1990b; Cohen and Ellwein, 1990).  On the other hand, because of so many fundamental artifacts and limitations of short-term tests (most assumed only to measure mutations (Trosko, 1988; Trosko,1989)), extrapolation of these results (positive or negative) from an artificial in vitro single cell system to an interacting multicellular rodent, let alone a human being, is truly stretching our current scientific knowledge.

To defend the necessity of trying to understand the mechanistic/theoretical bases of carcinogenesis, it seems that those who claim one needs only empirical animal and short-term tests fail to mention that these tests themselves are based on many implicit assumptions and hypotheses concerning the nature of carcinogenesis and “carcinogens”.  Therefore, in order for an epidemiologist to design a study to check if chemical x or radiation y, shown to induce a positive result in either a short term assay for mutagenesis or animal bioassay for tumor genesis, an understanding of how that particular agent contributes to the multi-stage, multimechanism carcinogenic process will be necessary for the reasons to be shown later.  In the same sense, any agent found by an epidemiologist to be associated with human cancers cannot automatically be assumed to be a mutagen/initiator of carcinogenesis as is implied with the concept, “carcinogen as mutagen” (Ames et al., 1973).

At this point, we have introduced several terms which need to be defined; namely, carcinogen; mutagen; initiator; and promoter.  In the process of defining these terms, the terms of mitogen, cytotoxicant, epigenetic and progressor will b=have to be defined.  Based on the fact that carcinogenesis ins a multi-stage, multi-mechanism process, the implied definition of a “carcinogen” is that it is an agent which “causes” cancer by interacting with a normal cell, transforming it through all the stages, via all of the different mechanisms, and altering all the required genetic factors needed to escape biological defense mechanisms against cancer.  The word, “carcinogen”, itself, creates the wrong impression in the minds of lay persons, risk assessors and scientists alike.  In other words, “carcinogen” does not reflect our current understanding of the multi-stage nature of carcinogenesis.  If, in fact, an agent is truly associated with the ultimate appearance of a cancer, the real question is “Which step in the multi-stage process of cancer did it influence and by what mechanism did it act?”  Possibly, we would do well if the word was banished from the language (Trosko et al., 1983b).

Now when an agent influences the carcinogenic process, it interacts with the organism/human ultimately at the cell level (after various routes fo entry and survival/chemical transformation via pharmokinetic action).  At this point, the biological consequence of the agent’s interaction at the molecular/biochemical level could be: mutagenesis; cell death; or epigenetic alteration (altered gene expression).