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AGING In Today's Environment Committee on Chemical Toxicity and Aging Board on Environmental Studies and Toxicology it_ . . ~ . ,- . - . commission on . Ate Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1987

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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Frank Press is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Robert M. White is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the reponsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Samuel O. Thier is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Frank Prep and Dr. Robert M. White are chairman and vice-chairman, respectively, of the National Research Council. This study was prepared under Grant No. CR-812961-01-0. The content of this publication does not necessarily reflect the views or policies of the U.S. Environmental Protection Agency or the U.S. Department of Health and Human Services, and an official endorsement should not be inferred. Available from: Committee on Chemical Toxicity and Aging National Research Council 2101 Constitution Avenue, N.W Washington, DC 20418 Printed in the United States of America

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COMMITT1:E: ON CHEMICAL TOXICITY AND AGING ROBERT N. BUTLER, Department of Geriatrics and Adult Development, Mt. Sinai Medical Center, New York, New York, Co-Chairman EMIL A. PFITZER, Department of Toxicology and Pathology, Hoffmann-La Roche Inc., Nutley, New Jersey, Co-Chairman PATRICIA BUFFLER, Epidemiology Research Unit, University of Texas Health Science Center, School of Public Health, Houston, Texas FREDERICK DE SERRES, Research Triangle Institute, Research Triangle Park, North Carolina BARBARA GILCHREST, Department of Dermatology, Boston University Hospital, Boston, Massachussetts RONALD HART, National Center for Toxicological Research, Jefferson, Arkansas THOMAS JOHNSON, Department of Molecular Biology and Biochemistry, University of California, Irvine, California CARL KUPFER, National Eye Institute, Bethesda, Maryland GEORGE MARTIN, Department of Pathology, University of Washington, Seattle EDWARD MASORO, Department of Physiology, University of Texas Health Sciences Center, San Antonio, Texas DAVID PRESCOTT, Department of Cellular and Developmental Biology, University of Colorado, Boulder PETER SPENCER, Institute of Neurotoxicity, Albert Einstein College of Medicine, New York, New York ELIOT VESELL, Department of Pharmacology, Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania ROBERT VESTAI,, Veterans Administration Medical Center Boise, Idaho MARK WEKSLER, Division of Geriatrics and Gerontology, Cornell University Medical College, New York, New York JERRY WILLIAMS, Johns Hopkins University Medical Center Baltimore, Maryland 111

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Natlon~ Resewn Call Stag ANDREW a. POPE, Pant D~- JEANN~ RICHARDS, Research Assistant NORMAN G-SSBL^~ Edna O~ COLDSBO-) Pant Sag

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY DONALD F. HORNIG, School of Public Health, Harvard University, Boston, Massachusetts, Chairman ALVIN L. ALM, Alliance Technologies Corporation, Bedford, Massachussetts RICHARD N. L. ANDREWS, UNC Institute for Environmental Studies, University of North Carolina, Chapel Hill, North Carolina DAVID BATES, Department of Medicine, UBC Health Science Center Hospital, Vancouver, B.C. RICHARD A. CONWAY, Engineering Department, Union Carbide Corporation, South Charleston, West Virginia WILLIAM E. COOPER, Department of Zoology, Michigan State University, East Lansing, Michigan BENJAMIN G. FERRIS, Department of Environmental Science and Physiology, Harvard School of Public Health, Boston, Ma~a~chussetts SHELDON K. FRIEDLANDER, Department of Chemical Engineering, University of California, Los Angeles, California BERNARD GOLDSTEIN, Department of Environrr~ental and Community Medicine, UMDN]- Robert Wood Johnson Medical School, Piscataway, New Jersey DONALD MATTISON, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas PHILIP A. PALMER, Engineering Department, E.~. DuPont de Nemours & Co., Wilmington, Delaware DUNCAN T. PATTEN, Center for Environmental Studies, Arizona State University, Tempe, Arizona EMIL PFITZER, Department of Toxicology and Pathology, Ho~mann-I`a Roche Inc., Nutley, New Jersey PAUL PORTNEY, Resources for the Future, Washington, D.C. PAUL RISSER, University of New Mexico, Alberquerque, New Mexico WILLIAM H. RODGERS, School of Law, University of Washington, Seattle, Washington F. SHERWOOD ROWLAND, Department of Chemistry, University of California, Irvine, California

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LIANE B. RUSSELL, Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee ELLEN SILBERGELD, Toxics Program, Environmental Defense Fund, Washington, D.C. GLENN I. SIPES, Department of Toxicology and Pharmacology, University of Arizona School of Medicine, Tucson, Arizona National Research Council Staff DEVRA DAVIS, Director, BEST JACQUELINE PRINCE, Staff Associate V1

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Preface ~ 1985, the Environmental Protection Agency (EPA) and the National Institute of Environmental Health Sciences (NIEHS) asked the National Academy of Sciences to evaluate current in- formation about the effects of environmental chemicals on aging processes and the aged population and to recommend research strategies in this area. In response to this request, the National Research Council's Board on Environmental Studies and Toxicol- ogy established the Committee on Chemical Toxicity and Aging. The formation of the committee constituted one of the country's first organized efforts to bring together experts in the fields of gerontology and toxicology to consider the interface between the two scientific disciplines. For many topics, the government has seen fit over the years to organize interagency groups to ensure information exchange and coordination or to speed the implementation of specific steps to a goal. Examples include the Nutrition Coordinating Com- rn~ttee, the Biotechnology Coordinating Committee, and groups concerned with such topics as radiation and regulatory matters. These groups have a mixed record of effectiveness. Often they are created by one administration but then fall into disuse and disappear with the next. Still, for those subject areas that are of interest and concern to many different agencies and that can ~ V.11

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benefit from a forum for discussion and coordination, the idea of forming such a committee Is attractive. Aging is such an area. The responsibility for research and policy formation for aging ~ found in several agencies: The major focus of basic research and training is at the National Institute on Aging (which includes the Interagency Committee on Aging Research), a major clinical training function is carried out by the Veterans' Adm~n~tration, and there are several policy eoord~nat- ing groups at the level of the Assistant Secretary for Health at the Department of Health and Human Services. Although it was beyond the scope of this committee's task to evaluate government programs on aging, the need was apparent to this committee for an increased effort in coordinating and conducting research on aging that would include toxicology. This report, which is the result of the committee's delibera- tions, reviews the important environmental factors that influence the aging processes and the aged, and it recommends research that needs to be done to improve our understanding of aging in today's environment and the health and weD-being of the aged population. On behalf of the committee, we would like to express our am preciation to the National Research Council staff and others who facilitated this committee's deliberations and work in preparing this document. We specifically thank Andrew Pope for his skill- ful writing, editing, and facilitation of committee process, Jeanne Richards for her enthusiastic contributions in literature research and drafting of materials, Edna Paulson for her tireless dedication to accuracy in reference verification, Devra Davis for her valuable guidance and creative oversight, Alvin Lazen for his sound direc- tion and sage advice, and Norman Grossblatt for his professional judgment and logic in editing the report. We are also grateful to the sponsors, EPA and NIEHS, and to the project officers from those agencies: Scott Baker for his vi- sionary planning, initiation, and continued support of this project, and Linda Birnbaum for her enthusiastic technical guidance and assistance. Robert N. Butler Emil A. Pfitzer Chairmen - ~ van

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Contents EXECUTIVE SUMMARY 1 AGING AND ENVIRONMENTAL EXPOSURE. Basis of the Scientific Problem, 12 Structure of the Report, 13 2 THE AGING POPULATION AND THE PSYCHOSOCIAL IMPLICATIONS OF AGING 15 Demographic Considerations of an Aging Population, 15 Psychosocial Environment, 26 3 PRINCIPLES OF GERONTOLOGY Conceptual Context of Gerontology, 28 Theories of Aging, 32 Deterministic Theories, 33 Stochastic Theories, 33 Biomarkers of Age or Aging, 39 Altered Susceptibility of the Aged, 42 4 PRINCIPLES OF TOXICOLOGY IN THE CONTEXT OF AGING 46 Chemical Fate and Effect, 49 Absorption, 51 Distribution, 52 ......... 10 28 L'C

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Metabolism and Elimination, 53 Mechanisms of Toxicity at the Molecular, Cellular, and Tissue Level, 58 Molecular Action, 59 Cellular Effects, 60 Effects at the Tissue Level, 61 Pharmacogenetics, 61 Biologic Markers, 67 Toxicity Testing, 69 5 CHARACTERISTICS OF THE ENVIRONMENT, AGING, AND THE AGED ~ 72 Nutrition, 75 Effects of Nutrition on Toxicity, 76 Nutrition and Cancer, 78 Nutrition and Aging, 80 Special Dietary Requirements of the Aged, 90 Pharmaceuticals, 94 Demographic Considerations, 94 Patterns of Drug Use and Drug Prescribing, 95 Medication Compliance in the Elderly, 98 Adverse Drug Reactions, 99 Life-Style, 101 Deliberate Chemical Exposure, 101 Learned Helplessness, 102 Atrophy of Disuse, 102 Indoor Pollutants, 103 6 ENVIRONMENTAL EFFECTS ON AG~ASSOCLATED DISEASES AND CHANGES IN ORGAN FUNCTION ..109 Demographics of Age-Associated Diseases, 110 Skin, 121 Vision, 124 Cataracts, 124 Glaucoma, 126 Diabetic Retinopathy, 127 Aging-Related Macular Degeneration, 127 Hearing, 128 Nervous System, 128 Changes Associated with Aging, 128 Induced Disorders and Diseases, 130 Neurotoxicants, 131 x

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Respiratory System, 135 Cardiovascular System, 136 Renal System, 139 Immune System, 140 Sexuality, 142 Role of Environment in Bone Metabolism and Vitamin D Nutrition, 143 7 MODEL SYSTEMS FOR THE EVALUATION OF TOXIC AGENTS AFFECTING AGING OR AG~RELATED DISEASES 145 Considerations In Choosing and Designing Mode} Systems, 146 Examples of Model Systems, 149 In Vitro Modem, 149 Nonmammalian Animal Models, 152 Mammalian Models, 156 Epidemiologic Models, 159 Life-Span Modulation by Drug Treatment, 160 8 CONCLUSIONS 9 RECOMMENDATIONS. Research, 165 Education, 168 Funtling and Resources, 169 REFERENCES - 162 .165 171 APPENDIX: Resources for Studying Aging 209 COMMITTEE BIOGRAPHIES ............................... X1 213

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Tables and Figures TABLES Table 2-1 Dependence of Civilian Noninstitutionalized Popula- tion in Activities of Daily Living, United States, 1979, 24 Table 2-2 Dependence of Nurs~ng-Home Residents in Activities of Daily Living, United States, 1977, 24 Table 2-3 Life Expectancy at Birth for Females and Males in Selected Countries, 25 Table (1 Monogenic Metabolic Pharmacogenetic Conditions and Putative Aberrant Enzymes, 65 Table ~1 Action of Food Restriction on Age-Associated Physio- logic Changes, 83 Table ~2 Action of Food Restriction on Age-Associated Disease Processes, 84 Table 6-1 Examples of Age-Associated Changes in Organ Struc- ture and Function and Possible Related Agents, Medi- cal Conditions, or I,ife-Styles, 110 Table 6-2 Death Rates for the 10 I,eading Causes of Death for Ages 65 and Over, by Age, 1976, 119 Table 6-3 Prevalence of Selected Impairments by Age and Sex, United States, 1981, 120 X11

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FIGURES Figure 2-1 Life expectancy at birth by race and sex, United States, 195~1983, 17 Figure 2-2 Death rates by age and sex, United States, 195~1984, 18 Figure 2-3 Average expectation of life at specified ages in selected years, l9C~L1982,19 Figure 2-4 Percent of cohort of white females surviving to specific ages, according to current life tables for United States, 198CL2050,20 Figure 2-5 Percentage increase in older population, by decade, 190~2050, 22 Figure 2-6 Percentage of population with severe activity limita- tion, 1982, 25 Figure 3-1 Estimates of cros~sectional versus longitudinal difl3er- ences with age in performance on a test of cognitive function (the verbal meaning test) by human subjects of various ages, 32 Figure 4-1 Schematic depiction of established or suspected envi- ronmental factors that can alter genetically controlled rates of drug elimination, 63 Figure ~1 Ag - specific incidence rates for female breast cancer in four population groups, 111 Figure ~2 Ag~adjusted death rates for persons 65 years of age and over, according to leading causes of death: United States, 195CL1979, 113 Figure ~3 Age-adjusted death rates for persons 65 years of age and over, according to sex: United States, 194~1978, 114 Figure 6-4 Age-adjusted cancer death rates for selected sites, males: United States, 193~1978, 115 Figure ~5 Age-adjusted cancer death rates for selected sites, fe- m~es: United States, 193C~1978, 116 Figure ~6 Major cardiovascular diseases: age-specific mortality rates versus all causes of mortality, 117 Figure ~7 All sites: age-specific cancer incidence and mortality rates versus all causes of mortality, 118 .. }C111