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Aging and Environmental Exposure Are environmental agents robbing us of both life span and life expectancy, or are we approaching natural maximums of both? Should we concentrate our research effort less on the study of aging processes and more on living longer in the midst of the noxious substances in our environment? Should we devote more effort to the study of environmental induction of age-associated disease? By eliminating the causes of age-associated disease that are not inherently related to the aging processes, we can probably increase the quality of life in old age. If mechanisms of development of disease depend more on basic underlying processes of aging than on factors that can be eliminated from such processes, the piecemeal study of the diseases of old age will have only limited success. Our inability to separate the aging processes from environmental influences lies at the heart of the problem. Precisely how environmental agents affect aging processes is not known. The subject has not been adequately studied, and aging processes themselves have not been adequately described. However, it is reasonable to assume that environmental agents acting at critical periods of development can affect age-related phenomena later in life. For example, exposure to an agent that affects or interferes 10

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AGING AND ENVIRONMENTAL EXPOSURE 11 with the development of stem celb during the fetal stage, in in- fancy, or in early childhood might contribute to nervous system decline in later life. For instance, a depletion of precursors of the neurons of the substantia nigra might increase the probability of a comparatively early onset of Parkinson's disease. A change in the susceptibility to a great many other pathophysiologic accompani- ments of aging might have, in part, such an etiology. In addition, the elderly might be particularly vulnerable to the effects of many environmental agents because of normal age-related alterations in cellular structure and function and a general decrease in the abil- ity to maintain physiologic homeost~is, or because of alterations acquired as a result of environmental exposure. The classic studies of Nathan Shock (1977) suggest that there are almost linear declines in the functional capacity of many (if not all) physiologic systems in many but not all humans after age 30. The rate of decline varies among organ systems, from 2.5~o per decade in basal metabolic rate and nerve conduction velocity to logo per decade in renal and respiratory capacity. It follows that the homeostatic reserve of the organism, which is proportional to the dynamic range of the integrated functions of physiologic systems, declines with age. Clinical studies have revealed that a number of adaptive re- sponses are diminished in old people. For example, body tem- perature is influenced by increases in ambient temperature to a far greater extent in the old adult than in the young adult. This phenomenon is attributable largely to the slower onset of vasodi- latation and sweating that follows an increase in ambient temper- ature. Homeostatic responses are also blunted after an increase in blood glucose concentration, blood pressure, or heart rate. Young adults are protected from environmental stresses by their homeostatic reserves. Their deaths more often result from injuries or diseases that exceed their homeostatic capacity. Over 95~o of deaths in young adults can be associated with a pathologic state. However, in one study of deaths among people who were more than 85 years old, 26~o of the subjects had "no acceptable cause of deaths (Kohn, 1982~. They might have died of environ- mental stresses that would have caused no mortal complications in young people. Epidemiologic studies have shown that older patients admitted to hospitals are slower to return to good health: the duration of hospitalization and its associated mortality increase between the

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12 AGING IN TODAY'S ENVIRONMENT ages of 35 and 75 years. Bed rest itself can so Recondition an older person that the simple act of dressing after 2 weeks in bed can induce maximal heart rate in an 8~year-old. BASIS O1? THE SCIENTIFIC PROBLEM The scientific problem of distinguishing states of disease and impaired function that result only from an essential underlying process- aging from states that are caused by environmental exposures is complicatedly by the fact that aging and chronic envi- ronmental exposure are absolute concorn~tants. Even in the labm ratory, environmental influences can be only minimized, not elim- inated. The effects of diet and other essential components of the laboratory environment can be successfully reproduced and oh~- served as changes in structure, function, and disease states in inbred laboratory animals. However, the extent to which the characteristics of d~eterio- ration seen in animals that age in a controlled environment are predictive for anunals of the same species that age in another environment is limited, as is extrapolation to different animals whether they age in similar or dissimilar environments. Further- more, the specific effects of intrinsic agingthose produced solely by an essential, constitutive biologic process that would~ occur in an optimal and absolutely nonperturbing environment have not been identified. Gerontologists and toxicologists have assumed that interac- tions between aging and the laboratory environment constitute a process that can be accounted for in a "control" population. However, both groups have sought descriptors of structure, func- tion, or disease that are relevant only for independent underlying ~ ~ The two groups have termed these descriptors "biomarkers of agings and ~biomarkers of toxicity, respectively. Much effort is being expended in the search for biomarkers that best predict aging or their. r"~:nnn.c:" in an organism, but to date then- Art.. Hart Up mailer r~or+;=ll~r successful. - processes ot e~ther aging or toxic stress. . ~ ~ __= ~ ~ _^A -_ ^~^ ~ ~ ~~} e~A Us The failure to identify biomarkers as descriptors exclusively of aging or of toxicity might simply reflect our meager knowledge of the essential mechanisms that underlie these processes. Or it might reflect a basic interplay between aging and environment through homeostatic and compensatory mechanisms that make

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AGING AND ENVIRONMENTAL EXPOSURE 13 unlikely the identification of universal and exclusive biomarkers of aging or of a specific toxic process. If toxic agents are administered for short periods at high concentrations or if aging occurs in an artificially pristine environment, the two processes- might become; more clearly separable. But the separation is extremely difficult to discern in experiments relevant to human beings, who age for extended periods in environments that contain multiple agents at various concentrations. The difficulty of applying the results of experiments on ag- ing in laboratory animals to human beings is also related to extrapolation across wide dose ranges, from laboratory to real environment, and from laboratory animal to human being. Va- lidity depends on various biologic assumptions, for example, as to the shape of the dose-response curve, the interactions among many agents, and the biologic similarity of the laboratory animal to the human being. In the case of aging in a multiagent toxic environment, such assumptions are difficult to propose in exact terms or, once proposed, to defend rigorously. These problems complicate not only laboratory study of aging in a toxic environment, but also epidemiologic and demographic studies of the aging of human populations in various environments. The latter kinds of study are also confounded by our inability to distinguish between the contribution of intrinsic aging to the health status of the aged and the contribution of environmental factors. That inability confounds the determination of the type of old age we should expect in terms of life expectancy and disease prevalence. STRUCTURE OF TEE REPORT This report describes current knowledge about the relation- ship between chemicals and aging from two perspectives: the ef- fects of chemicals on the aging processes and the effects of aging on the body's ability to respond to environmental chemicals. It dis- cusses some specific needs for research in aging and toxicology, sug- gests the need for a data base on ~gerontotoxicology," and guides the development of such a data base. In separate chapters, it de- fines and describes the aged population (Chapter 2), reviews basic principles of gerontology and toxicology to identify relationships between aging processes and environmental exposures (Chapters 3 and 4), identifies candidate situations for environmental effects

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14 on aging processes (debater 5)) examines potable ~tuatlons far averse environment impacts on the elderly (Chapter 0~$ out- Une~ boa the use of model system can expand the knowledge bee in both toxicology ad gerontology (abater 7~, and presents the committee conclusions and reco~end~t~ns (Chapters 8 ad g).