Re: FW: Mice and elephants

[JMUCKERHEIDE@delphi.com]

Dick King wrote: 

> > Date: Mon, 7 Jul 1997 10:06:34 -0400 (EDT)
> > From: Bernard L Cohen <blc+@pitt.edu>
> > Subject: Re: FW: Mice and elephants
> > 
> >       From my personal point of view, all that is required is answering
> > questions like the one I raised. Many thanks for your help on this.
> >       It still seems remarkable to me that, if cancers were caused by a
> > single hit on a single DNA molecule, the cancer risk would be roughly the
> > same for all animals even though the number of DNA molecules varies by
> > many orders of magnitude. It isn't impossible to understand, but it seems
> > like a remarkable coincidence.
> 
> It's worse than that, when you consider DNA molecule-years.
> 
> To a mouse, a mean time to first cancer of ten years is not that big a deal.
> If elephants routinely got cancer as Poisson events with a lambda of ten years
> that would be One Sorry Species.
> 
> 
> And never mind the fact that youth of any species get cancer less than their
> elders, even though the cells divide far more.
> 
> -dk

And to think there are still people who "believe" the "linear model", AND the
supposed "biological basis": stochastic DNA damage. Note that Bruce Ames with
Kenneth Beckman has written again recently (in press, J. of Biological
Chemistry) a "Minireview" on "Oxidative Decay of DNA". This even further
confirms the DNA damage processs that massively outstrip the damage of
background radiation. He notes that "Early on, radiation biologists discovered 
that radiolysis of water generates oxygen free radicals, which are responsible 
for many of the consequences of irradiating living things." This caused "a
surge of interest" in DNA oxidation per se, and the possibility of oxidative
damage from biological oxidants, and set out key questions: "how much
oxidative DNA damage is there?" and others. The paper notes that "a companion
minireview covers indepth the biochemistry of DNA oxidation". Then: "The
steady-state amount of DNA oxidation appears to be massive". After discussing
issues of measurement and associated artifactual problems, he uses as an
example of a measurement of a particular adduct which is one of 20 and is
estimated to be 5% of the total for which results in  "This estimate, about a
million oxidative adducts per rat cell..." and continues to discuss methods
that have confirmed this estimate, and continues into bases for comparisons to 
human cells, resulting in about 600,000 per human cell. He notes that a
contribution to confirmation of measurements/estimates include low variability 
in results and "dramatic patterns of appearance and disappearance of oxo-8-dG
following oxidant challenges, occurring in parallel with the induction of
oxo-8-dG repair activity..." 

They then address "the cloning and overexpression of repair enzymes ... which
recognize and excise oxidized pyrimidines and purines..". Note that radiation
effects research has dramatically established the role of radiation in causing 
significant expression of repair enzymes and stimulation of related repair
mechanisms far in excess of insignificant contributions of radiogenic DNA
damage in the vast sea of normal metabolic DNA damage (and massive repair). 

They report on measuring in humans "the daily flux of repaired adducts (that)
reflect the intracellular rate of DNA damage" leading to discussion of
mechanisms and location of DNA oxidation, with reference to sources of
oxidative DNA damage such as heat and exercise [let's see, 1 mSv produces the
DNA damage of a 1-mile jog? 100-yard dash? a cup of coffee? (which is noted
elsewhere as a high source of DNA damage :-)] This is followed by control of
oxidative mutatgenesis, leading to: "The removal of oxidative adducts in human 
cells appears to be very rapid. In lymphoblats, the half-lives of H2O2-induced 
adducts ranged from 8.5 to 62 min. In human respiratory tract epithelial
cells, repair of some H2O2-induced adducts is so rapid that a narrow window of 
opportunity (Approx 30 min) exists for their detection." 
  And "Hormesis, or the 'beneficial effect of a low-level exposure to an agent 
that is harmful at high levels", may be relevant for some oxidative stresses,
as it has been argued to tbe the case for low-level radiation exposure.
Hyperbaric oxygen therapy for humans (100% O2 at 2.5 atm), for instance,
induces significant oxidative DMA damage to peripheral blood cells on the
first day of therapy, but fails to cause damage on subsequent days; in fact,
it results in a lower baseline level of total and oxidative DNA damage.
Similarly, g-radiation of rats, which significantly elevates oxidative adducts 
in hepatic chromatin, results in a lower baseline level of some oxidative DNA
adducts 24 h after an acute exposure, and other observations of the lowering
of baseline oxidative damage by oxidants have appeared. These results are not
surprizing, since defense systems are often induced in response to oxidative
stress, a generalization which has recently been extended to oxo-8-dGua
glycosylase activity in E. coli and rats. This implies that there is a degree
of slack in oxidative defense and repair under 'normal' circumstances, and
that cells may ordinarily tolerate a burden of oxidative adducts that
contributes to the spontaneous rate of mutation." 

They then discuss "DNA oxidation and cancer", noting that it "is a major
contributor to human cancer thru: smoking, chronic inflammation, and
endogenous oxidants such as leakage from mitochondria. Cigarette smoking ..
NOx depletes the body's antioxidants, and phagocytic cells recruited to sites
of chronic infection abundantly generate reactive oxidants such as NOx and
HOCl." ... "Some studies have provided more than a simple association between
carcinogenic agents and oxidative DNA damage, by measuring the specific
induction of repair enzymes by oxidative carcinogens, and by demonstrating the 
suppression of carcinogenesis by administration of antioxidants. The latter
results are consistant with the strong correlation between a high intake of
fruits and vegetables, which are the principle sources of dietary
antioxidants, and reduction cancer risk by as much as half. We have reported
elevated oxidative damage to sperm in smokers and in men on low serum
antioxidants (vitamin C), and have hypothesized that oxidative damage to male
germ cells contributes to cancer and birth defects in the children of male
smokers, for example, the risks of acute lyphoblastic leukemia, lymphoma, and
brain tumors are increased 3 to 4 times." [Anyone up to revisit the
Marshall/Kinlen UK work that showed increased leukemia in the children of
workers in large-scale construction development areas, including nuclear
projects, in the UK?] 

Discussing age effects they note that frequency of adducts increases as much
as 2-fold, and "Therefore, it may be that an age-realted, persistent 5-100%
increase in the steady-state number of adducts is physiologically relevant,
representing an inability to prevent or repair oxidative damage." 

In "Conclusions": "A principal outstanding question is. 'what proportion of
carcinogenic and spontaneous mutations are caused by metabolic oxidants?'
Although there is evidence that specific oxidative injury, such as reperfusion 
injury, chronic infection, or smoking, may result in mutagenesis, it is less
clear that spontaneious mutations are oxidative." 

Suffice to say that it's hard for a knowledgeable biologist to take seriously
the simple-minded concept that "cancer is related to the probability that a
ray may hit a DNA molecule" predicted "by an equation of the first-degree" (as 
stated by Walinder, concluding that sticking to this fiction in the face of
massive, known, contradictory evidence, with specific actions to suppress that 
evidence, is "the greatest scientific scandal of the 21st century"). 

Note that they also report, "Transgenic mice have been established which
possess altered antioxidant activities, and which permit in vivo
quantification of mutagenesis. Combined with transgenic mice possessing
deleted or overexpressed oxidative repair endocucleases, they may provide
ideal models for studies in which analytical measurements of oxidative adducts 
are combined with direct measurements of mutagenesis." 

But again, radiation is a gallon of water in an olympic pool relative to the
risk of drowning. (But if it's boiling water, it would cause the evaporation
of more than a gallon to produce a net lowering of the level?! :-) But, note
that in Japan the stimulative effect of LLR has been used at levels generally
equivalent to 15 fractions of 10 rem to *cure* cancer, including success with
nasal carcinoma from half-body radiation of the trunk. 

Thanks.

Regards, Jim Muckerheide
jmuckerheide@delphi.com
Radiation, Science, and Health, Inc.