Understanding mechanisms of human carcinogenesis.

What is it about?

A challenge to the new protocol to classify if chemicals can "cause" cancer was made. Human carcinogenesis is the complex evolution of a single normal cell to an invasive metastatic tumor or "cancer stem cell". There are three distinct mechanistic phases, namely, the irreversible "initiation" of a adult organ-specific stem cell by a mutagen event , caused by either an "error of DNA replication" or by an "error of DNA repair". That "initiated stem cell" now can no longer divide by asymmetric cell division to differentiate but can still divide by symmetrical cell division when stimulated by agents that can induce cell proliferation. (the "promotion" phase"). This promotion phase is the result of "epigenetic" mechanisms, that is, mechanis in the body that can alter the expression of genes. This promotion process requires (a) having exceeded "threshold" levels of action; (b) being exposed to the chemical ( endogenous, such as cytokines, hormones, growth factors; or exogenous, such as pollutants, drugs, dietary factors), and (c) that the "promoter" be present in the absence of anti-oxidants or anti-inflammatory factors. The problem using the proposed 10 IARC characteristics found in the literature is fundamentally because of two sources of misleadiung or false information concerning the action of chemicals shown to be invoklved in either in vitro, in vivo animal experiments and epidemiological associations, namely, (a) all the in vitro assays to detect mutagens have far too many false positives; (b) few chemical in vitro assays test for their "epigenetic" actions; (c) epidemiological studies ignore the fact that all human beings have "spontaneous: initiated or mutated stem cells in their organs.; (c) only UV light is a true "initiator" or point mutagen of skin stem cells, while all chemicals, even those metabolized into electrophiles , are never point mutagens of genomic DNA, especially in stem cells. Chemical exposures at threshold levels, in the absence of anti-promoters and for long interruptible periods of time , such as cigarette smoking or drinking alcohol, or having lodged asbestos fibers in the lung, can be "tumor promoters", not mutagens or "initiators" of carcinogenesis. Exposures to TCDD, alcohol , etc. for a short time, at sub-threshold levels or in the presence of anti-promoters will not be of any significant health risk.

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Why is it important?

Government agencies, pharmaceutical and chemical companies are now allowed to use chemicals that should not be used and as well as these agencies are not permitting the use of many chemicals that could be beneficial if they understood how these chemicals should be used. In effect, without the mechanistic understanding of the human carcinogenetic process or The mechanisms by which a chemical could INDUCE "toxicities" of mutagenesis, cytotoxicity or epigenetic alteration of gene expression, more confusion will creep into public policy of what chemicals can or cannot do to human health.

Perspectives