DOSE RATES AND RAD. EFFECTS

[GOODEN@VMS.OCOM.OKSTATE.EDU]

	I am pleased with John Moulder's response to a recent RadSafe 
question regarding dose rate effects on radiation induced immunosuppression 
in mice (John's response is shown in its entirety at the end of my 
comments).  I wonder what some of the rest of you think?  

	I agree with John that immunosuppression will be different (lower) 
for 500 rads delivered at 8 rads per minute when compared to 500 rads 
delivered at 70 rads per minute.  In fact, the "effect" may go to zero as 
the dose rates get smaller and smaller.  Some in our community even believe 
that the immune system is "stimulated" by low dose rate radiation. 

	Dose rate effects are well known for most (all?) biological end 
points.  We see the effect all the time in radiation therapy for cancer in 
humans.  There seems to be universal acceptance among informed scientists 
that the effects also exist for radiation induced cancer in humans.  Today 
it is a common practice to attempt to account for the inadequacies of the 
NLT model to describe radiation induced cancer with dose rate effects 
factor (DREFs).  But is a value of 2, or even 10, reasonable as the dose 
rates get smaller and smaller?  Is it scientifically reasonable and 
defensible to expect radiation related human cancer induction to go to zero 
(DREF equal to infinity) as the dose rate gets smaller and smaller?  

	This is, of course, one part of the question raging within 
scientific circles today regarding the scientific soundness of using the 
linear, no-threshold model to describe radiogenic cancer in humans.  Dose
rate effects are something we all should think about as we contribute to 
the knowledge pool regarding the effects of radiation on humans.  
Consideration of do(>>~5ose rate effects are important since ng and 
proposed regulatory annual radiation limits translate to public exposures 
to only a few microrem per hour.  

	Such limits can be incredibly expensive to meet and could 
compromise the financial stability of even the strongest industry or
nation.  We must consider whether or not our limited dollars for health and 
safety are well spent by trying to achieve these limits.  Dose rate issues 
may be paramount in these considerations.  


David S. Gooden, Ph.D., J.D. 
Director, Biomedical Physics 
Saint Francis Hospital 
Tulsa, OK  74136 
(918) 494-1444  phone 
(918) 494-1452  FAX 


From:	IN%"radsafe@romulus.ehs.uiuc.edu" 28-AUG-1996 10:23:46.34
To:	IN%"radsafe@romulus.ehs.uiuc.edu"  "Multiple recipients of list"
CC:	
Subj:	RE: Mice Irradiation Questions


Date: Wed, 28 Aug 1996 10:20:21 -0500
From: John Moulder <jmoulder@post.its.mcw.edu>
Subject: RE: Mice Irradiation Questions


> A researcher here at Montana State University has proposed to irradiate 
> a few dozen mice to 500 rads each.  The purpose of this exercise is 
> to enhance post-irradiation implanted tumor growth... 
>  
> Most of the literature that we are looking at does not describe the 
> dose rate used in preparing mice for tumor implantation.  Nearly 
> all indicate a dose of 500 rads, although one article suggests a dose 
> of 150 rads given at a dose rate 70 rads/min. 

The dose rate matters very little as long as it is above about 50 rad/minute, 
and is delivered continuously.

> How critical is the "acuteness" of the dose given to the mice (in order 
> to achieve the desired effect).  Given target uniformity 
> considerations, the highest dose rate I can produce with our 
> "irradiator" (naval radiac calibrator AN/UDM-1A) is a little over 8 
> rads/minute. 

This dose rate is low enough that you will see a dose rate effect.  That is, 
the 500 rad will not be as "effective" as the above cited paper that used 70 
rad/min.

> Obviously, before we proceed we want to be reasonably confident that 
> we'll obtain positive results.  For those who have experience in this 
> area, will our system work (or will the dose rate limitation 
> compromise this undertaking)? 

It should work, but you may have to adjust the total dose to get the desired 
effect.  The solution is for the investigator to define what the endpoint is, 
then do a dose-response curve at the highest dose rate you can get.

If you are trying to reproduce what someone else has done, then you have a 
problem because 8 rad/min is just not biologically equivalent to 70 rad/min.


> One more question: 
>  
> There are mice available that have been bred to express 
> immunodepression (apparently there are some transgenic lines available 
> as well).  However, despite the phenotype, these mice do not sustain 
> and promote implanted tumor growth as well as mice that have 
> received significant doses of radiation. 
> Not having explored this realm of radiation biology much, what 
> "other radiation induced factors" are at play here? 

This depends a lot on the type of tumor and its relationship to the host.  
When a tumor arises in an inbred strain of animals, it can generally be freely 
transplanted to any other animal in that strain, and pre-irradiation of the 
host will make little difference (this is a nonimmunogenic tumor model).  
However, then a tumor is transplanted to another strain, there will usually 
(always?) be an immune response, and pre-irradiation will enhance tumor growth 
(this would be an immunogenic tumor model).

Note that the best current data is that human tumors are non-immunogenic, and 
hence that immunogenic animal tumor models have little relevance to human 
tumor therapy.

If the mice are sufficiently genetically immune incompetent, then you can grow 
just about any tumor in them, even a human tumor.  Athymic nude mice, are 
immunocompromised, they will allow many tumors to grow, but irradiating the 
host helps.  SCID mice, however, will grow just about any type of tumor, and I 
don't think preirradiation makes much difference.


John Moulder (jmoulder@its.mcw.edu)
Radiation Biology Group
Medical College of Wisconsin