Re: Hormesis? / DNA repair...

[Muckerheide <muckerheide@mediaone.net>]

Hi Bjorn,

Thanks for your response. But to a large extent it exemplifies the problem.
Great detail about irrelevant factors to the role of radiation in causing
cancer.

>> We know the mechanisms well enough to know that the concept of "damage" or
>> detriment at low doses is invalid. The idea that a ray/particle can
>> initiate a cancer is invalid.
> 
> This depends on the definition of initiation. One definition for the
> majority of mechanisms (for a mutation) being analyzed is that it involves
> one descreet event on a DNA level.

Agree. But radiation makes a minuscule contribution.  There's no unique
contribution from a damage from radiation. Even though the proportion of
DSBs has been considered to be higher for radiation, it is still trivial
compared to compared to other DSBs.  Radiation causes cancer at higher doses
because it overwhelms the repair system, leaving many unrepaired cells.
(Actually it is more correct to identify this situation as "error prone
repair" since it is likely that there is repair but it is not under the
routine control of the cell cycle check point arrest, which LDR enhances.)

> Then followed by more such events. Each one of these events typically knocks
> out a cell cycle control function, a DNA integrity mechanism, or a function
> that involves signal transduction (membrane receptor level or signal
> transduction inside the cell). Other subsequent promotional events may not
> involve DNA.
> ---

This is right, especially from cells-in-culture studies, but largely
irrelevant.  The likelihood that it was a rad-caused DNA event is
vanishingly small, with rad-caused effect on DNA no different than other
endogenous damage (and trivial compared to many other carcinogens.)

>> However, DNA "breakage" occurs from normal metabolic and heat processes >at
>> rates that are millions of times greater than the effect of >background
>> radiation (say 1 mSv/yr, ignoring the nonsense about radon >lung-dose
>> equivalence).
> 
> It is not clear yet what classes of DNA DSBs give rise to what fractions of
> misrepair and how this is related to the different repair mechanisms.

This isn't important since the "model" it presumes can't be valid.

> Much of the published kinetics cannot be used because it was based on DNA mass
> instead of DNA breaks.

But from conditions that don't apply to causing cancer; and mostly from
cells in cultures.  These are biological artifacts that help to understand
cell mechanics, but not consequences.

Also, what's not known is the number of endogenous DSBs, which are much
higher than had been previously estimated - remember the article in
Science(?) a few months ago showing data on electrons linking to one strand
that led to an energy event that caused a break to the other strand.  The
expectation was that the number of DSBs are likely much higher. (Again not
relevant to the rad-DNA-cancer connection.

> This includes essentially all data based on neutral filter elution (NFE) as
> well as essentially all uncalibrated so called FAR measurements for data
> based on pulsed field gel electrophoresis (PFGE). The comet assay is another
> weird area where data can't be subjected to meaningful interlaboratory
> comparisons because different labs run the equipment in different ways (same
> as in the PFGE business). There is a lot of confusion out there. The bottom
> line is that a lot of nice experimental data can't be used (yet - most of
> them can be reanalyzed) because they were not analyzed properly and
> misinterpreted.

Again, ok as details of cellular mechanics, but it isn't related to
radiation causing cancer.
  
> I have also seen what goes on when RNA and protein expression is studied.
> Some people analyze spots from gels in a semiquantitative manner - strange
> things happen when backgrounds are subtracted from spots with different
> areas (like diameters), photographic film saturation is not taken into
> account (a "nice" example can be found in Science for PFGE and DSB repair
> about 6-7 years ago - it was a DNA-PK study - most probably an extreme error
> that seems to be due to photographic saturation that must have escaped the
> reviewers' attention - wonder if anyone else noticed - to find it you must
> read another earlier paper by the same authors) and so on. I wrote one of
> the key authors but there seemed to be no interest in understanding the
> performance of the equipment they used.
> ---

Interesting physics, but the issues are in the biology of living cells in
immunologically "whole" organisms.

>> DNA repair half-times are in the order of 20-45 minutes.
> 
> For SSBs it may be minutes or less, for other damages it may be months (the
> cell may have to divide before certain damages are repaired). For
> lymphocytes the fraction of residual (unrepaired) DSBs after hours seems to
> be very high (more than 25 %).

Right. I should have said "mean" half times. The same is true for
radioactive decay - a lot right now, some tens of half lives later :-)

The turnover still leaves 30,000+  DNA lesions at any given time in a tissue
cell.  

> One should be cautious about a fast interpretation before we understand the
> damage signaling mechanisms as a function of cell cycle phase and tissue
> type. In addition, we need more DSB repair kinetics people who are truly
> interested in math rather than percentage surrogates that guarantees under-
> or overestimates of breaks. Before these two parts have been resolved
> properly comparisons with other endpoints (like epidemiological data) seem
> questionable or meaningless. There is probably a long way to go before cell
> & molecular biology data become consistent with cancer epidemiology and
> other ends points.

Knowing the math and physics won't help (although some biophysics in
Germany/Russia is making great strides - but certainly not following the
non-science "model" of radiation damage).

The biology is rather well known - and is what counts.  It is certain that
LDR up-regulates major functions that prevent/eliminate cancerous cells, and
even tumors - real tumors in real animals and humans; and the more recent
work of the last 15-20 years has elucidated the underlying molecular
immunological, enzymatic, hormonal and physiological response mechanisms
that clearly produce the macro organism effects (as provided in the limited
example references - which continue to be actively ignored and suppressed,
as usual).
 
I'd like your review of refs (as biology).   There are dozens/hundreds more.
But science can't get past the small closed NCRP/ICRP/UNSCEAR/BEIR IV/V/VI
gate-keeper cadre  -  and now BEIR VII has delaying its report to get the
next (useless) RERF update - to make "intelligent" rad protection
"decisions" from the largely unknown dosimetry of instantaneous
gamma-neutron exposures!? :-)

> My personal reflections only,
> 
> Bjorn Cedervall   bcradsafers@hotmail.com

And mine :-)

Regards, Jim
muckerheide@mediaone.net
===========================

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