Re: Contributions to the historical record

[Jim Muckerheide <jmuckerheide@delphi.com>]

Bjorn,

Bjorn Cedervall wrote:
> 
> Jim, I don't mind the references you are giving 

That's a great relief. Have you read them? I don't see their hisorical context
having a relationship to your "but" below:

>but there are also some
> papers that point at higher relative effects at lower doses. This area is
> indeed very complex. 

Complex, but not confusing. The underlying mechanics are still being
developed, but the results are unambiguous.

>Check out for instance the papers by Ehrenberg et al.
> from the early 1960:ies (mutation rates in plants) or P. Lambin, M. Joiner
> and others from around 1992 and on (and cell survival for some human cell
> lines). 

See the ref to Joiner, Lambin, et al by Skov 1999 below!

Of course, some research is not directly relevant because cell lines in
culture do not respond as "immunologically whole" organisms. Researchers learn
about underlying biological processes to contribute to understanding the whole
organism, if they don't have a fully functional immune system, etc. etc. they
do not reflect biological dose-response. (ICRP/NCRP know this, but use
straight lines from cell lines to misrepresent current knowledge from whole
organisms.) 

Also, some endpoints are not relevant or misrepresented (e.g., chromosome
aberrations, the 'bystander effect' claiming that it supports linear response
at low dose instead of showing that a single hit stimulates
tissue/organ/organism-level responses that contribute to the demonstrable
stimulation that controls immunological, enzymatic, apoptotic, and related
responses as a net beenfit to the organism, as with other stressors, from
exercise to anti-oxidants, etc. that "make you stronger" while we deliberately
ignore the fundamentals of biology to allow a "biophysics" rationale to
misrepresent effects, or simply a lack of knowledge by most that are being
misled.)

>These papers seem convincing from a statistical point.

See the abstract below. If you get a chance to review this (in addition to the
historical papers) I would be very interested in your conclusions.

> It would be nice to see a theory emerge where findings on a cell and
> molecular level are consistent with epidemiology.

A start?:
 
Mutat Res 1999 Dec 6;430(2):241-53
 Radioresponsiveness at low doses: hyper-radiosensitivity and increased
radioresistance in mammalian cells. 
 Skov KA 
The rationale for and importance of research on effects after radiation at
"low doses" are outlined. Such basic radiobiological studies on induction of
repair enzymes, protective mechanisms, priming, and hypersensitivity are
certainly all relevant to treatment of cancer (see Section 1, Studies at low
doses - relevance to cancer treatment). Included are examples from many
groups, using various endpoints to address the possibility of an induced
resistance, which has been compared to the adaptive response [M.C. Joiner, P.
Lambin, E.P. Malaise, T. Robson, J.E. Arrand, K.A. Skov, B. Marples,
Hypersensitivity to very low single radiation doses: its relationship to the
adaptive response and induced radioresistance, Mutat. Res. 358 (1996)
171-183.]. This is not intended to be an exhaustive review--rather a
re-introduction of concepts such as priming and a short survey of molecular
approaches to understanding induced resistance. New data on the response of
HT29 cells after treatment (priming) with co-cultured activated neutrophils
are included, with protection against X-rays (S1). Analysis of previously
published results in various cells lines in terms of increased radioresistance
(IRR)/intrinsic sensitivity are presented which complement a study on human
tumour lines [P. Lambin, E.P. Malaise, M.C. Joiner, Might intrinsic
radioresistance of human tumour cells be induced by radiation?, Int. Radiat.
Biol. 69 (1996) 279-290].It is not feasible to extrapolate to low doses from
studies at high doses. The biological responses probably vary with dose, LET,
and have variable time frames. The above approaches may lead to new types of
treatment, or additional means to assess radioresponsiveness of tumours.
Studies in many areas of biology would benefit from considerations of
different dose regions, as the biological responses vary with dose. There may
also be some implications in the fields of radiation protection and
carcinogenesis, and the extensions of concepts of hyper-radiosensitivity
(HRS)/IRR extended to radiation exposure are considered in Section 2, Possible
relevance of IRR concepts to radiation exposure (space). More knowledge on
inducible responses could open new approaches for protection and means to
assess genetic predisposition. Many endpoints are used currently--clonogenic
survival, mutagenesis, chromosome aberrations and more
direct--proteins/genes/functions/repair/signals, as well as different
biological systems. Because of scant knowledge of the relevant aspects at low
doses, such as inducible/protective mechanisms, threshold, priming, dose-rate
effects, LET within one system, it is still too early to draw conclusions in
the area of radiation exposure. Technological advances may permit much needed
studies at low doses in the areas of both treatment and protection.

> Bjorn Cedervall   bcradsafers@hotmail.com
> http://www.geocities.com/bjorn_cedervall/

Regards, Jim
muckerheide@mediaone.net
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