Re: Hormesis? / DNA repair...

["Bjorn Cedervall" <bcradsafers@hotmail.com>]

>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. 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.
---

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

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.

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.
---

>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 %).

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.

My personal reflections only,

Bjorn Cedervall   bcradsafers@hotmail.com

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