Re: Hormesis? / DNA repair...

["Harry Hinks" <harryhinks@hotmail.com>]

Dr. Cedervall,

It is so nice to read your objective emails.  It is refreshing to read your 
scientific views rather than the rampant political posturing.  Thank-you for 
taking the time to educate us.

Thanks,

Harry Hinks
harryhinks@hotmail.com



>From: "Bjorn Cedervall" <bcradsafers@hotmail.com>
>Reply-To: radsafe@romulus.ehs.uiuc.edu
>To: Multiple recipients of list <radsafe@romulus.ehs.uiuc.edu>
>Subject: Re: Hormesis? /  DNA repair...
>Date: Thu, 15 Feb 2001 16:17:18 -0600 (CST)
>
> >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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