James Stanley Smith, Jr., Ph.D. jssmith at oak-creek.net
Fri Apr 30 07:53:37 EST 1999

"c. miller" wrote:

> I agree with you James. There should be an EQUAL and RATIONAL treatment for
> all chemicals. I think we need some molecular biology/epidemiology studies
> for agents that require significant cytotoxicity to cause cancers. If a
> common set of specific mutations in specific genes are found in hepatic
> cancers caused by generally "non-genotoxic" agents like acetaminophen,
> dichloromethane, etc., then it would support a model in which the outgrowth
> of previosly initiated cells is facilitated by cytotoxicity. Such molecular
> biomarkers could reveal the actual initiating event and perhaps the
> agent(s) that caused the tumor--or at least rule out some possibilities.
> Without cell death (a promotion/progression factor) and clonal expansion of
> the initiated cells, there would be no chance to form a tumor if these
> "carcinogens" have no initiating activity of their own.
> Chuck

I agree.  The problem, however, becomes more complicated with "threshold"
carcinogens because they have little measurable effect on DNA (not known to
cause mutation).  These epigenetic genetic carcinogens include compounds like
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) which the US EPA claims is
one of the most potent carcinogens known to man.  TCDD is not known to cause
mutation in several bacterial, yeast or mammalian test systems and is thought
to act to promote previously initiated cells (always present) through receptor
mediated pathways to form tumors.

Would you suggest another set of biological markers of "threshold" based events
that can be said to be "promotional" in nature as useful markers of epigenetic
carcinogen action?  Such a proposal would have to encompass the fact that
chemicals known to promote cancer progression can be dependent on not only the
dose applied, but also to the time and frequency of application as well as
route and tissue specificity.


James S. Smith, Jr., Ph.D.
President & Toxicologist

Toxicology & Risk Assessment Consulting
     RR 3  Box 246B
     Route 22
     Gorham, Maine  04038-9428

     Voice      : 207.929.6375
     Facsimile: 207.929.6474
     E-mail     : jssmith at oak-creek.net
     WWW    : http://www.oak-creek.net

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