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PROGRAM OF WSEARCH ON AGING SPONSORED BY THE ATOMIC ENERGY COMMISSION IN 1972 As part of a broad-based effort to in sure the radiological safety of nuclear energy activities,the Atomic Energy Commission has for many years sponsored a comprehensive program of biomedical and environmental research to assess hazards associated with man-nnde radiation and naturally occurring radioactive materials used by man. A major goal of the biomedical research is to define human radio sensitivity in quant it a - tive terms, develop a capability for estimating the biological costs of nuclear energy, and devise means of reducing the severity of radiation injury in man. Of particular interest at the present time isthe study of long-term somatic and genetic effects of ionizing radiation in living systems, such as may arise as a consequence of exposure to radiation from an external source or from internally deposited radio nuclides. This report will deal primarily with those investigations that are concerned with biological aging as it relates to, or isa component of, late somatic manifestations of radiation injury. The late somatic effects represent a delayed expression.of latent, unrepaired radiation damage in living tissue. irreversible effects is gained from animal experimentation, epidemiological surveys of irradiated human populations, and studies(usually retrospective) of occupational and medical exposures. the main types of late somatic effects are known. They are expressed as specific diseases in particular organs, functional impairment o r other abnormalities in particular organs, a generalized deterioration i n * all organs, and life shortening. The diseases and lesions that develop as apart of the late somatic response are not unique to radiation stress; that is, they are qualitatively similar to manifestations of biological deterioration that arise spontaneously in un irradiated populat ions from natural aging or other causes. Because of this lack of uniqueness, the causal relationship between radiation stress and late somatic effects is generally obscure, particularly so i n view of the protracted period of latency that typically separates the two. lishment of a cause-and-effect relationship can be accomplished only a t the population level ' by the use of statistical methods. Thus, the late effects are identified and studied as statistical deviations frcm the a prospective basis,require years for their completion. mation on the late somatic effects accumulates slowly. Information on these From past studies, Studies of this sort,especially when conducted on Important insights have emerged from long-term studies in animals. late somatic effects are not unique, the causes of death in sub lethally ir radi aced populations are essen tia € lythe same as those seen i n aging populations under normal circumstances. However, in irradiated pop"- lat ions there occurs an increase in the absolute incidence of certain
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diseases, an advancement in the time of appearance of many disea and ther degenerative lesions commonly associated with senescence, and a decrease i n life span, all roughly in proportion to the magnitude of the radiation dose. Neoplasms (cancer and leukemias) have been identified as the main cause of radiation-induced life shortening. The reduction in life span as a result of nonneoplastic lesions is generally small by comparison and is associated with the early onset of a variety of common diseases and, therefore, with non specific mortality. understood, but it has been postulated that the underlying came may be a generalized,sub clinical deterioration occurring in all tissues as a consequence of radiation damage. This non specific type of response is not yet fully On the basis of the limited data available,it appears.that the late somatic response i n man resembles that described i n animal species. non specific life shortening has not yet been unequivocally demonstrated i n sub lethally irradiated human populations. Because sub lethally irradiated anitnals (and possibly humans as well)die prematurely from degenerative deseases closely resembling those associated with senescence, it has been suspected that radiation may cause life shortening by accelerating tne natural aging process. shortening and the early onset of common diseases, as seen in irradiated animals, are thought t o be particularly suggestive of accelerated aging. However, as data have accumulated, more and more differences between irradiated and aging animals have been noted. Therefore, the concept of radiation-accelerates aging remains an unproved hypothesis that requires Current research is directed toward the goal of obtaining a better understanding of the late somatic effects,including their relationship to the degenerative processes responsible for senescence. reasons, the major research effort is concerned with the collection of informatLon on the wanner i n which factors such as genetic makeup, age a t time of exposure, superimposed stress, and various radiological parameters influence.the qualitative and quantitative expression of late somatic effects. Information of this sort is essential to the formulation of radiation protection guides and the.estimation of biological costs of nuclear energy activities. Data obtained may also contribute toward the more effective use of radiation in the therapy. It should be emphasized that lifetime studies of late sonlatic effects, even when conducted primarily for radio biological information, frequently provide useful longitudinal data on the aging process in un irradiated control populations. Data on the clinical and epidemiological aspects of aging are valuable,in turn, as part of the total body of knowledge needed t o understand the consequences i n man of chronic, low-level radiation stress, such as m y occur in certain Longitudinal data on norrral patterns of disease
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and mortalit? i n workers contributes toward a better understanding by helping to resolve the question of whether chronic radiation stress, when superimposed on natural aging, accelerates spontaneous degenerative processes or contributes to biological deterioration in some other way. Other ongoing studies seek to define in greater detail the degenerative changes associated with radiation-induced life shortening and natural aging and to elucidate their underlying causes. Only by achieving a better understanding atthe mechanistic level will it be possible to determine the extent to which these two phenomena share a common importance inasmuch as only by elucidating the mechanisms underlying later ad ' ation effects may it, become possible to predict with conf i - . dence the hazards t o man posed by small radiation doses. These studies are also of potential practical These two lines of research entail a spectrum of activities ranging from the cellular and molecular levels. areas i s summarized below. a long-term nature and will continue i n 1973. tive changes inthe program are expected in Fiscal Year 1973, buta modest reduction in the level of effort is anticipated. Year 1973, an increasing trend in effort and support i s planned. epidemiological studies in humans t o fundamental research at The present status of work in these Virtually all of the ongoing studies are of Ro significant qua lita - Long-term studies of late radiation effects in human populations are essential to an understanding of man's sensitivity to ionizing radiation. Four major efforts of this sort are now i n progress. The oldest of the human studies is a prospective epidemiological inves - tiga tion conducted by the Atomic Bomb Casualty Commission ( a cooperative research agency of the United States National Academy of Sciences and the Japanese National Institute of Health) to evaluate delayed radiation effects in survivors of the atomic explosions that occurred a t Hiroshima and Nagasaki i n August 1945. In this unique study, which began inthe late 1940 ' s , approximately 112,000 Japanese nationals are being observed to evaluate changes i n body function and chemistry and to collect epi - demiological data on morbidity, mortality, and life shortening. Among the wealth of longitudinal information accumulating from the study are invaluable data on late somatic effects,including non specific life shortening ; data compiled through 1970 show no definitive evidence of non specific life shortening. on various aspects of natural aging and on morbidity and mortality in the control (unexposed) population. Illustrative of the interest i n aging i s a study now i n progress i n which a chemical index of aging is being used t o search for evidence of accelerated aging inthe most heavily exposed Important in form tion is also being obtained This study entails the quantitative measurement of components
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of connective tissue in samples of skin and aorta removed a t autopsy. connection with the study of aging, a Symposium on Problems of Measurement of Aging inthe Human Population was held in Hiroshima on May 29-30, 1972. A similar but much smaller study is being conducted by members of the staff at the Brookhavea National Laboratory to evaluate biological sequelae inthe people of the Phr shall Islands who, by accident,received acute exposures (both externally and internally) fram radioactive fallout released by a thermonuclear device during atest conducted i n March 1954. Approximately 200 exposed individuals and alike number of unexposed controls are examined annually by a medical survey team. chemical parameters, as well as pathology, morbidity, and mortality are monitored during each visit. and control groups, late radiation effects of a subtle nature are not malities has been clearly identified as the most prominent delayed manife station in the exposed Marshallese population, members of which received large internal radiation doses tothe thyroid from fallout radio iodine. In all cases,thyroid al pathology has been satisfactorily managed by surgery or thyroid hormone therapy. aging criteria have been noted between the exposed and control groups. Because of the small size of the exposed 5 A substantial elevation in the incidence of thyroid al abnorNo differences in a battery ot The largest of the long-term human studies is a retrospective-prospective epidemiological survey of occupational groups se1ecte.d from AEC and AECcontractor employees. This effort, which i s conducted jointly by investi gators at the University of Pittsburgh,contractors at several AECowned facilities, and a group at the Social Security Administration, was initiated in 1964 t o determine if.any unusual patterns of morbidity o r mortality are associated with employment in the nuclear energy industry. At the present time, employment, exposure, health, and (where appropriate) mortality records are being collected on approximately 176,000 present and former workers, along with analogous data on an appropriate control la tion will eventually be obtained through the United States Transuranium Registry, which i s operated by t h e Hanford Environmental Health Foundation. Radiobiological and occupational information are of primary interest in this study. Postmortem data on some individuals in the exposed pop"- A long-term study of radium radio toxicity in hurnans, which has been i n progress for over twenty years at several different locations,has ROW been fully consolidated at the Argonne National Laboratory. tiga tion is documenting patterns of radium metaboliskn, including tissue retention, and late somatic effects in individuals who accumulated body burdens of radium-226 from occupational or medical exposures before the hazards of this material were fully realized. and dead) are estimated t o have accumulated significant radium burdens in this country. Of these,3000 have been identified, 2000 have been
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located, and approximately 800 are under study atthe Argonne facility. Incidences of late effects,particularly in bone, are being correlated with the magnitude of body burdens and tissue doses. The Argonne radium study i s of interest in the context of aging because of the possibility that internal alpha radiation may affect degenerative processes related to normal senescence. LONG-TERM STUDIES IN DOGS Since few populations of irradiated humans are available ?or study, knowledge about the late somatic effects mt is t be supplemented by controlled experiments with laboratory animals. Over twenty years ago, the beagle dog was selected as a principal animal model for use in radio biological research because of its intermediate size and life span, as well as Since that time,nearly 5000 dogs have lived out their full span of years in lifetime experiments and approximately 3000 dogs are currently assigned t o such studies. Long-term studies with dogs are i n progress atthe Argonne National Laboratory, the Pacific Northwest Taboratory, the University of California a t Davis, the University of Utah, the University of Rochester, and the b ve lace Foundation, detailed characterization of delayed responses (primarily those manifeste d as late somatic effects)to external or internal radiation, as well as a n understanding of the bases of the observed responses. present,the major effort is directed toward the study of delayed e f - fects induced by internally deposited radionuclides, both man-made and naturally occurring. Doses and dose rates inthe lower range are also in both exposed and control animals throughout the 1ifespaG. aspect of these studies is the fact that they serve to evaluate the useful - ness of the dog as a model of the human system. These investigations are conducted to obtain a I n each study, multiple biological parameters are monitored An abundance of data on aging in the beagle has accumulated over a period of years,particularly from the Davis, Rochester, Argonne, and Utah longevity and causes of death. Information is now accumulating on changes i n body function and chemistry as the beagle ages. Aging aspects are sr;ressed to varying degrees at different laboratories.. of an active effort is that at the Davis location where investigators are seeking to quant it ate.age - related changes inthe beagle. endocrine function,the cell -mediated immune response, autoantibody production, cellular bio synthetic capacity, rhythms in cell proliferation, and adaptation to the rmi stress are among the parameters selected for antioxidants as possible modifiers of the aging process. Detailed longitudinal data on patterns of diseases and hfsto - are available for mo.st major organ systems, as are data OII Tentative plans have also been developed €or a study of nutrient
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LONG-TERM STUDIES OF LATE SOMATIC EFFECTS IN OTmR SPECIES OF ANIMALS Rodents - Because of their small size, ready availability, and short life span, rodents 2re ideally suited for use in large - scale,lifetime studies. The availability of a number of inbred strains(particularly in the case of the mouse) is another advantage inthe study or' late somatic effects. Extrapolations t o man are generally considered more tenuous when observat ions are made in rodents than when they are made inthe dog. this limitation,rodents have proved very valuable in the development of conceptual and theoretical insights into late radiation effects of the somatic type. Moreover, data collected from rodent experiments serve as a valuable guide inthe design of long-term studies in dogs and humans. ,Long-term radiation studies in mice, which have been in progress for many In each laboratory,studies are comprehensive i n scope and seek both phenomenological and mechanistic in form tion on late somatic effects induced by external, whole-body radiation. Both efforts are supported by strong programs of basic research on aging and emphasize conceptual aspects of the two related areas of interest. atthe Argonne and Oak Ridge National Laboratories. Inthe -4rgonne study, mice are exposed t o gamma radiation or to neutrons from the JANUS research reactor. The study of basic cellular and tissue mechanisms i s included in the research protocol and information on natural aging processes in control populations is collected as the research progresses. In a related study, comparative aspects of late somatic effects are being investigated in a …
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