RADIOBIOLOGICAL MIXIHAXISM Al THE CELLULAR LEVEL 



These lines of evidence appear to constitute firm grounds for an attempt 

 to trace the actual sequence of changes which connects the initiating event — 

 be it ionization, excitation, or an attack by a free radical — and the observed 

 chromatid lesion. No corresponding evidence exists as yet in the case of 

 mitochondrial damage. 



Carcinogenesis 



Transformation to malignancy is an inherently detectable type of change, 

 and the rate of growth of most malignant cells is such that if this change 

 occurred in a single cell early in the life of a mouse, the fact of the occurrence 

 would be declared clinically. A rough calculation of the number of basal 

 layer cells in the skin of a mouse shows that if the probability of conversion 

 from the normal to the fully malignant state in one step were even as low 

 as 10^^",rad, half the population of mice exposed to 100 rad would develop 

 epitheliomas. As this is not observed, we must conclude either that the 

 probability of transformation is lower than 10~^*^/rad, or that the trans- 

 formation to malignancy is not a one step process. Independent evidence 

 strongly favours tlie latter alternative. A single application ot one of the 

 more active chemical carcinogens will give rise to skin cancer in mice if 

 followed by repeated applications of a 'promoting' agent such as croton oil. 

 If croton oil is applied repeatedly to irradiated mouse skin, tumours appear 

 after ^-ray doses down to 700 r^, and possibly down to 300 r (Schubick — 

 personal communication) . When small areas of mouse or rat skin were exposed 

 to j8 radiation only^, no tumours were produced unless the dose was such 

 (12,000 rad in a single exposure, or 4,600 rad in two fractions 2 months apart) 

 as to produce actual tissue breakdown. The appearance of malignant cells 

 was regarded as an end product of repeated cycles of tissue breakdown and 

 repair. On this view the role of irradiation is unspecific. It may be, however, 

 that when radiation is used alone as a carcinogen, it has both to initiate 

 specific cellular transformation and also to serve as a 'promoter', and that, 

 in the case of skin cancer, promotion is achieved by way of regenerative 

 hyperplasia. Similarly, in the case of the induction of lymphomas, ovarian 

 tumours, and pituitary tumours, it may be that the important roles played 

 by hormonal imbalance, or by haemopoietic insufficiency, are concerned 

 with promotion. If this view is correct, then the characteristics of any specific 

 transformation which may be involved might be more readily revealed by 

 experiments in which tissue which had been exposed to moderate doses of 

 radiation was then subjected to the action of an independent 'promoting' 

 agent. 



Stimulation of Visual Receptors 

 Perhaps the most immediate indication of molecular disturbances induced by 

 ionizing radiation known to us at present is provided by the retinal response 

 in mammals and amphibia, and related response in lower organisms. The 

 subject has been reviewed by Lipetz, who himself contributed many of the 

 important original observations'-^. The X-ray threshold for stimulation of 

 the frog retina is of the order of 1 rad delivered, for example, as a 5 sec 

 exposure to 0-2 rad/sec. This is estimated to correspond to between 0-5 and 

 150 times as much energy absorbed by the visual purple as the minimum for 

 visible light stimulation. Baylor and Smith'*, have examined the response of a 



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