me= slope of straight line for control mice (Fig. 1) M= slope of straight line for man (Fig. 2,A) and = time in days. mice are nearly the same. It may be possible to get some guidance by considering the physiologic implications. In our analysis we are really postulating that there is some agent (of unknown nature) that is responsible for spontaneous aging in mouse and man. The agent need Since the difference in the slopes was found not be the same in both cases, but its po above to be 20-fold mc M= 20 tency is expressible in some unit "r," equivalent to one roentgen. Since sX has the unit of dose ("r"/dayXdays), assuming a constant k for man and mouse implies that Now, it was found that for the control mice a certain dose of this hypothetical agent Hence, by taking 0.64 "r"/day as the fictitious dose rate corresponding to spontaneous aging in man, we have assumed that k is the same for mouse and man. All we know for sure is the value of M (for man). If the analysis of the mouse data of Lorenz et al. is reasonably correct, we also know m. and k for mice. On the same basis there should be a k and a fictitious dose rate s for man. Denoting these quantities for man by kм and SM we have where s and k represent the values for mice already found. It is evident that the values of sм and kм may vary widely so long as their product equals 4.45X10-3. Therefore, in order to determine the fictitious dose rate SM for man it is necessary to know whether kuk or, if it does not, how it differs from k. A preliminary analysis of experiments on rats similar to Lorenz et al.'s experiments on mice conducted by Dowdy, Boche and Bishop and reported by Boche2 indicates that k is very nearly the same for rats. This, however, may be an accidental coincidence and in any case not much weight can be given to it in the extrapolation to man, since the life spans of rats and produces the same change in mortality rate in both mouse and man. On this basis the agent is equally effective in producing aging in both man and mouse. Since the time required to do this in the case of man is 20 times longer than in the mouse case, the fictitious dose rate for man must be 1/20 of that for mouse. On the other hand, we may get the same result by assuming that the spontaneous aging agent has the same dose rate (12.8 "r"/day) for both man and mouse, but it is 20 times less effective in producing aging in man than in the mouse. This would imply that the biologic system of man is 20 times more stable, vis-à-vis the hypothetical aging agent, than that of the mouse. At the moment no choice can be made between the two alternatives. (As pointed out earlier, these are not the only two possible alternatives). Since the comparison between man and mouse is usually made on the basis of life span; that is, by changing the age scale in the ratios of the life spans, Curves B and C of Figure 2 have been determined on a similar basis but using the factor of 20, which applies to the respective Gompertz straight lines.* Therefore, in Figure 2 the fictitious dose rate for spontaneous aging in man (Curve A) is 0.64 "r"/day. The corresponding dose rates for Curves B and C are 0.1 r/day and 0.5 The ratios of life spans are usually taken as 30 to 36. Our ratio of 20 is considerably smaller than this, but comes out directly from the slopes of the two straight lines. As pointed out earlier, the slope of the line for the control mice is not known accurately. On the other hand, it should not be assumed that the two slopes should be in the ratio of the life spans, since the variation of mortality rate with time is very different for man and mouse before middle age. =r/day, respectively. If it is assumed that the fictitious dose rate for man is the same as that for mouse; Curve A corresponds to a dose rate of 12.8 "r"/day and Curves B and C to 2 r/day and 10 r/day respectively. We may now estimate the life shortening in man to be expected from chronic wholebody exposure to roentgen rays of high penetrating power. The simple method worked out for mice will be used and, therefore, only the spontaneous aging Curve A in Figure 2 and the fictitious dose rate applicable to that curve are needed. The curve was extended down to age twenty in order to consider cases of occupational exposure that may begin at that age.* If exposure is at an average rate of 0.1 r/day for 40 years, the accumulated dose at age 60 will be 1,460 r. Taking the fictitious dose rate for man as 0.64 "r"/day or 234 "r"/year, the increase in physiologic age will be 1,460 /234 6.25 years. Therefore, at age sixty the individual would have the physiologic age of a nonexposed individual 66.25 years old. The life expectancy of United States white males (as of 1950) is sixteen years at age sixty and twelve at age 66.25. Therefore, the life shortening is four years or Obviously, if the fictitious dose rate for man is 12.8 "r"/day, the life shortening will be approximately 1/20 of a day per r. Therefore, life shortening determined on the basis of a fictitious dose rate of 0.64 "r" /day may be considered to give a reasonable upper limit. There are, of course, some variations in the life shortening per r when the above calculation is made for other ages, because the life expectancy is not a linear function of age, but the maximum is approximately 1.5 days per r. Considering the inherent uncertainties involved, an average value of 1 day per r is a close enough estimate. These calculations have been made for a daily dose of 0.1 r because Curve B of Fig In this country the minimum legal age for work with radiation is actually 18. ure 2 is for o.1 r/day on the basis of 0.64 "r"/day for Curve A, and the age difference can be read directly from the curves. As pointed out earlier in the case of the mice, so long as the exposure is chronic and the dose rate not too high, the dose accumulated up to the age of interest is all that is needed to determine the approximate life shortening. Thus, in the case of the radiologists in Shields Warren's survey, if we take 500 r for the average dose accumulated up to age sixty, the age difference is The data of the experiment of Lorenz et al. on chronic irradiation of mice with radium gamma rays have been analyzed in terms of the Gompertz function in such a way that the resulting curves are internally consistent. The straight line for the controls (on a semilog plot) represents the increase in mortality rate with age of the animals. It is customarily assumed that, at least beyond a certain age, the increase is due to the aging process, whatever it may be. The slope of the straight lines for the chronically irradiated mice is greater than for the controls. Therefore, chronic whole body irradiation causes an acceleration of aging in these mice. Irrespective of the mechanism by which radiation causes aging, the effect is additive to the spontaneous one. From the relative positions of the straight lines (Fig. 1) it is then simple to calculate a fictitious dose rate of radiation that would produce the same aging as occurs spontaneously. This turns out to be 12.8 "r" per day. Adding this fictitious dose rate to the actual gamma-ray dose rates used in the experiment makes the total accumulated dose at the time when the groups of mice have equal mortality rates the same, irrespective of the dose rate (within the limits of the experiment, o-8.8 r per day). This is as it should be if the effects of the spontaneous aging process and aging by irradiation are additive. For man the Gompertz curve is known accurately, but varies from country to country and to some extent with the year when the statistical data were compiled. The one given in Figure 2 applies to the white population of the United States. It is not known how this population would respond to chronic irradiation and, therefore, it is impossible to determine directly the fictitious dose rate that would produce aging equivalent to spontaneous aging. However, a value may be obtained by comparing the Gompertz straight lines for the control and chronically irradiated mice (Fig. 1) with the straight line portion of the Gompertz curve for man (Fig. 2A). It is found that the slope of the straight line for the nonirradiated mice is 20 times greater than the slope of the straight line for man, when the same time scale is used. This means that the mice used in the experiment of Lorenz et al. age 20 times faster than man. It is reasonable to assume then that the fictitious dose rate for man is 1/20 of that for these mice. Obviously, if the life span of mouse is shorter than that of man, either the aging agent (whatever it may be) is more powerful in mouse than in man, or the biologic system of man is more stable than that of mouse. Be that as it may, the time rate of aging differs by a factor of 20. If we use this factor to determine the fictitious dose rate for man we find that it is 0.64 "r" per day. On the same basis the aging produced in mice by 1 r per day should be produced in man by 1 r in twenty days; that is, by 0.05 r per day. This makes possible the estimation of the life shortening in man to be expected from chronic exposure at any given dose rate (not in excess of 8.8/20=0.44 r per day, 8.8 r per day be ing the highest dose rate used by Lorenz et al.). A simple method for doing this is described in the text. The most widely quoted estimate of the life shortening to be exepcted in man from exposure to radiation is one made by Hardin B. Jones, which is fifteen days per roentgen. The value derived by us is ap proximately one day per roentgen of accumulated dose for chronic exposure at a dose rate not in excess of 0.5 r per day. The National Committee on Radiation Protection has recommended a maximum permissible accumulated dose of 50 r in ten years for individuals occupationally exposed to roentgen or gamma rays. This amounts to 210 r in forty-two years (age eighteen to sixty). According to our method of estimation, the life shortening attributable to this accumulated dose is about two-thirds of a year. On the same basis the life shortening to be expected in radiologists who in the past (when the dangers of exposure to radiation were not well known) may have accumulated whole-body doses of 500 r is 1.5 years. It should be noted that the method of extrapolation from animal to man developed by us has only one new feature the assignment of a fictitious dose rate to spontaneous aging. This is really a necessary consequence of the application of the Gompertz function to the mortality of chronically irradiated animals. Therefore, if this is justified, the extrapolation according to our method is correct in principle. How ever, owing to the small numbers of ani mals used in chronic exposure experiments the derived numerical values for man may have a considerable error, but this woul not be so large as to make the life shorten ing in man equal to anything like fiftee days per roentgen. It is well to point ou explicitly that the present discussion ap plies only to chronic exposure at low dos rates not to the effect of a large dose re ceived in a short time. G. Failla, Sc. D. 630 West 168th Street New York 32, New York REFERENCES 1. BERLIN, N. I., and DIMAGGIO, F. L. A Survey of Theories and Experiments on the Shortening of Life Span by Ionizing Radiation. AFSWP608, June 28, 1956. 2. BOCHE, R. D. In: Zirkle, R. E., Editor. Biological Effects of External Radiation; National Nuclear Energy Series VI-2. McGraw-Hill Book Company, New York, 1954, pp. 222-236. 3. DUBLIN, L. I., and SPIEGELMAN, M. Mortality of medical specialists, 1938-1942. J.A.M.A., 1948, 137, 1519-1524. 4. JONES, H. B. Factors in longevity. Kaiser Found. M. Bull., 1956, 4, 329–341. 5. LEWIS, E. B. Leukemia and ionizing radiation. Science, 1957, 125, 965–972. 6. LORENZ, E., and others. In: Zirkle, R. E., Editor. Biological Effects of External X and Gamma Radiation; National Nuclear Energy Series IV22B. McGraw-Hill Book Company, New York, 1954, pp. 24-148. 7. WARREN, S. Longevity and causes of death from irradiation in physicians. J.A.M.A., 1956, 162, 464. 58454 0-60-15 Representative HOLIFIELD. Our next witness will be Dr. James Crow, professor of genetics and zoology, University of Wisconsin. STATEMENT OF DR. JAMES CROW,1 PROFESSOR OF GENETICS AND ZOOLOGY, UNIVERSITY OF WISCONSIN Dr. CROW. Thank you, sir. Representative HOLIFIELD. It is nice to have you with us again, sir. Dr. CROW. Thank you. I should like, Mr. Chairman, to join those others who have commented favorably on the careful, detailed, unbiased, and conscientious efforts of the Special Subcommittee on Radiation and its chairman and staff. The large amount of material assembled from diverse sources and made available to the public has been and will continue to be invaluable. The work of this committee, the NCRP, the ICRP, the National Academy committees, the United Nations committees, the Federal Radiation Council, and others insure that we are moving into the nuclear age with careful consideration of the health problems. This has not always been true of new technical developments. There has been criticism that too much attention has been given to radiation effects, and that chemical industry has developed with much less public discussion of toxicity levels and health hazards. This may be true, and to the extent that trained manpower that is in short supply is taken from more urgent or more basic problems to work on radiation protection, the attention to the hazard becomes itself a hazard. But I believe that the thought, the discussion, and the detailed work done on this question are far better than the haphazard way in which many other health risks have grown. In some respects knowledge of radiation effects is very deep. Measuring instruments have a sensitivity such that extremely minute amounts can be detected. The physical knowledge of different kinds of radiation is solid. The qualitative effects of radiation on plants and animals are known in great detail, and extrapolation to man is fairly secure. It is when we come to the quantitative effects of low doses that the great uncertainty appears. As has been brought out repeatedly before this committee and elsewhere, the genetic effects of radiation seem to have no threshold and the best evidence is that, at the low doses to which the public is likely to be exposed in peacetime, the genetic risk is, to a first approximation at least, simply proportional to the total dose prior to reproduction. Russell's work on mice, confirmed for Drosophilla in Muller's laboratory, shows that in the early germ cell stages chronic irradiation is less effective than acute. This and other complications make the quantitative assessment of genetic risks seem even more uncertain than they did a few years ago. But none of these complications are such as to necessitate a revision of the previous conclusion that there is no threshold below which the risk is zero. 1 Born Phoenixville, Pa., Jan. 18, 1916 A.B., Friends University (Wichita, Kans.), 1937; Ph. D., University of Texas, 1941. Instructor and assistant professor, Dartmouth College and Dartmouth Medical School, 1941-48; assistant professor of genetics and zoology, University of Wisconsin, 1948-50; associate professor, 1950-54; professor, 1954 to present. Present position: Chairman, Department of Medical Genetics. President, Genetics Society of America; associate managing editor, Genetics, 1951-56; member of NAS Commission on Effects of Atomic Radiations; Genetics Study Section, National Institutes of Health; National Committee on Radiation Protection; editorial board, American Naturalist. |