90 



After sublethal doses, the inhibition of citric acid synthesis in spleen 

 and thymus was reversible. After 200 r, citric acid formation in the spleen 

 showed an initial decrease to less than half the normal value. This was follow- 

 ed by a gradual return toward normal. At 14 days after 200 r, the ability of the 

 spleen to accumulate citric acid was the same as in normal animals. After 400 

 r, the same initial type of depression occurred but it was greater in amount and 

 the reversal took place at a slower rate. The results of these experiments and 

 similar findings on thymus glands are shown in Figure 2. In these studies we 



obtained a correlation between the X- 

 ray exposure and amount of inhibition. 

 A correlation between the exposure and 

 rate of reversal was also noted with the 

 higher dose requiring a longer time for 

 reversal. 



At this point, while we are talking 

 about low doses of X-rays, perhaps it 

 should be mentioned that we feel that 

 studies using sublethal amounts of radia- 

 tion are more valuable in searching for 

 the mechanism of acute radiation damage 

 in animals than is the lethal dose. This 

 viewpoint is one for which there is a 

 great deal of supporting evidence from 

 experiments with other toxic agents. The 

 arsenicals, for example, produce their 

 inhibitory effects on sulfhydryl enzymes 



DAYS AFTER X-RAY 



Figure 2. Durationof effects of single 

 doses of X-rays on the ability of rat tissues 

 to accumulate citric acid after fluoroa ce- 

 tate treatment. A. Spleen, 200 r. B. Thy- 

 mus, 200 r. C. Spleen, 400 r. D. Thymus, 

 400 r, E. Liver, 200 r. F. Liver, 400 r. 

 (This charthas been published in a paper 

 by K.P.DuBois, K.W. Cochran and J. DouU 

 in Proc. Soc. Exp. Biol. andMed. 76, 

 422-427 1951). 



at doses far below the lethal. The agents that have strong inhibitory action on 

 cholinesterase also are effective at doses that are far below lethal. We might 

 expect that any action that is of importance in connection with the primary bio- 

 chemical mechanism of radiation damage ought to occur at exposures that are 

 below the LD 50. High dose studies, e.g. , 800 r, are useful for exploratory 

 work. In studying the effect of radiation on enzymes, we are inclined to first 

 use large amounts of radiation to ascertain whether a particular reaction is af- 

 fected. If the reaction is unaffected it can be discarded from further considera- 

 tion, but if it is inhibited, then it seems advisable to conduct additional studies 

 using sublethal doses. By this method, I believe that we can screen out and 

 eliminate secondary biochemical effects. It seems probable that many of the 

 changes that have been reported in animals after 800, 1000 or 1200 r would not 

 be detectable after sublethal exposures. They may be secondary to bacterial in- 

 fection or they may actually be due to radiation but not essential for the lethal 

 action in animals. 



BARRON: Do you think there are two different problems? One being 

 the effect of lethal doses of X radiation and the other, to determine the initial 

 point of action of the radiation. The approach you propose is that of using small 

 amounts of radiation to find the initial point of damage, whereas when we are 

 working with lethal amounts of radiation, as you pointed out, death is produced 

 mostly by secondary infections. 



PATT: Not necessarily. I have some reservation about this philoso- 

 phy for screening biochemical effects that may be related to lethal action. 



BARRON: I am not against his philosophy. I am agreeing with him. 



PATT: I believe that DuBois implied that biochemical effects from low 

 doses, below the LD50, might mean. that these are probably intimately related to 



