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LettersRadiation Carcinogenesis

A number of difficulties lie in the wayof accepting Blum's thesis [Science 130,1545 (1959)] that his data on ultra-violet carcinogenesis in mice and hismathematical deductions therefrom areevidence for the concept that there isno threshold dose for radiation carcino-genesis. It is not simply that he is argu-ing not from data but from projectionsof that data into unstudied areas, orthat this was done even though directobservation was possible. There is alsothe fact that other data from his seriesof studies point rather directly to theopposite conclusion. They not only de-scribe a threshold phenomenon but offersome clues as to quantitation.As to the first objection, Blum in his

Fig. I presents the incidence data forvarying doses of radiation. Accordingto his figure, halving the radiation dosemeans that 0.15 is added on to the logof the time necessary for tumor devel-opment. According to the chart thisrelation holds for each halving of dosedown to 1/32 of the dose required formost rapid carcinogenesis. The chart isdescribed as being based on experimentsdescribed in his recent monograph (1).Unfortunately, neither the monographor the original papers I could find dealwith doses corresponding to his twolowest curves, and the third dose levelis described as treated partly by extra-polation (2). Hence it would appearthat the dose ranges on which the ques-tion of threshold is based are quitenarrow, more so than the diagramswould suggest.

If such information were all thatwere available to us, there would besome justification for making projec-tions therefrom, even though the tenta-tive nature of the projections wouldhave to be emphasized. Actually this isnot the case. Blum makes the point thatthere is a practical limit on the dosesof carcinogenic radiation that can betested because, with low doses, the timefor cancer development will be longerthan the life span of the animal. Ofcourse, if the first cancers are not toappear until after all animals are dead,we have a practical threshold if not abiologic one. But further than this, ourinformation need not be as limited asBlum claims. He does not spell it out inhis article, but all his figures on dose-time relations are concerned with thetime within which cancers appear visibleto the unaided eye. Nowhere in his workcould I find reference to the power ofthe microscope to detect cancers muchearlier in their course. Given his figuresfor cell size and rate of growth, a can-cer should have a cross section of 100

cells visible under the microscope afteran interval one-third that necessary fora gross lesion to develop. This meansthat doses of irradiation supposedlyleading to far more slowly growingtumors than have presently been studiedare quite accessible to experimental in-vestigation, so that abstract speculationis neither needed nor appropriate.

But beyond these caveats, there isevidence on threshold existence in otherwork of Blum himself: his studies onthe effect of interruption of irradiationand its resumption after a 30-day restperiod (3). (The figures for 30-percenttumor incidence are the most conven-ient to analyze because there was a sec-ond interruption of radiation in someseries before the 50-percent incidencetime was reached.) According to thesefigures, with uninterrupted radiation ittook 95 doses of 2 X 107 ergs/cm2 toproduce visible cancer in 30 percent ofthe animals. Interruption late in thecourse of treatment, after 53 doses,meant that only 85 doses were neededfor tumor production; the tumors ap-parently grew during the rest period.This, however, was not the case whenthe interruption occurred earlier in thecourse of treatment. When the restperiod was given after 33 treatments,there was no progression, and the sametotal of 95 treatments was needed forcancer production as had been true forthe controls. By contrast, when the restperiod was introduced still earlier, therewas recovery from the first course andmore radiation was needed than if therehad been no interruption. With thebreak after 23 treatments, an additional81 treatments for a total of 104 wereneeded. And if only three or four treat-ments were given (the actual numberis not clear), more radiation (100doses) was needed after the rest periodthan if both the rest period and the firstdoses of radiation had been omitted.

It seems to me that this evidence forreversibility of the effects of smallamounts of radiation bears directly onthe question of a threshold. For if thereis a dose of radiation low enough sothat the exposed tissues recover or be-come even less than normally sensitiveto subsequent radiation, this must bea subthreshold dose by definition. Itappears that only above a certain doselevel are the effects of radiation irre-versible and hence inexorably carcino-genic. Hence, from both negative andpositive aspects I find myself unable toaccept Blum's thesis that no radiationthreshold exists for carcinogenesis.

Extrapolation of this work to carcino-genesis by ionizing radiation presentsother problems. It is reasonable to thinkthat there might be parallel quantita-tive patterns. At least it is hard to imag-ine that there is no correlation between

(Contitnued otn page 866)

SCIENCE, VOL. 131

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