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Animals as Sentinels of Environmental Health Hazards Committee on Animals as Monitors of Environmental Hazards Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1991

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NAT1ONALACADEMY PRESS 2101 Constitution Am, N.W. W~4 D.C 20418 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 competencies 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, non-profit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the further- ance 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 presi- dent 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 autono- mous in its administration and in the selection of its members, sharing with the National Acade- my 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 responsibility 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 educa- tion. 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 Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Research Council. The project was supported by the Agency for Toxic Substances and Disease Registry through cooperative agreement No. USO/ATU 300009-01. Library of Congress Catalog Card No. 91~1734 International Standard Book Number ~309 0404~9 Additional copies of this report are available from the National Academy Press, 2101 Constitu- tion Avenue, N.W., Washington, D.C. 20418 S37~7 Printed in the United States of America

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Committee onAnimals as Monitors of Environmental Hazards LAWRENCE T. GLICKMAN (Chairman), Purdue University, West Lafayette, IN ANNE FAIRBROTHER, (mice chair), Environmental Protection Agency, Cor- vallis, OR ANTHONY M. GUARINO, (mice chair), Food and Drug Administration, Dau- phin Island, AL HAROLD L. BERGMAN, University of Wyoming, Laramie WILLIAM B. BUCK, University of Illinois, Urbana LINDA COLLINS CORK, Johns Hopkins University, Baltimore HOWARD M. HAYES, National Cancer Institute, Rockville, MD MARVIN S. LEGATOR, University of Texas Medical Branch, Galveston ERNEST E. MCCONNELL, Raleigh, NC DAVID N. MCNELIS, University of Nevada, Las Vegas STANLEY A. TEMPLE, University of Wisconsin, Madison Consultants IAN NISBET, Lincoln, MA JOHN REIF, Colorado State University Staff LEE R PAULSON, Project Director CAROLYN FULCO, Staff Officer (until June 1990) NOR~L\N GROSSBLATT, Editor RUTH CROSSGROVE, Copy Editor BERNIDEAN WILLIAMS, Information Specialist SHELLEY NURSE, Project Assistant Sponsor Agency for Toxic Substances and Disease Registry ... Flu

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Board on Environmental Studies and Toxicology GILBERT S. OMENN (ChainnanJ, University of Washington, Seattle FREDERICK R ANDERSON, Washington School of Law, American University, Washington, D.C. JOHN C. BAILAR, McGill University School of Medicine, Montreal LAWRENCE W. BARN~OUSE, Oak Ridge National Laboratory, Oak Ridge CARRY D. BREWER, Yale University, New Haven, CI JOANNA BURGER, Nelson Laboratory, Rutgers University, Piscataway, NJ YORAM COHEN, University of California, Los Angeles JOHN L. EMMERSON, Lilly Research Laboratories, Greenfield, IN ROBERT L. HARNESS, Monsanto Agricultural Company, St. Louis ALFRED G. KNUDSON, Fox Chase Cancer Center, Philadelphia GENE E. LIKENS, The New York Botanical Garden, Millbrook PAUL J. LIOY, UMDNJ-Robert Wood Johnson Medical School, Piscataway JANE LUBCHENCO, Oregon State University, Conallis DONALD MADISON, University of Pittsburgh, Pittsburgh NATHANIEL REED, Hobe Sound, FL F. SHERWOOD ROWLAND, University of California, Irvine MILTON RUSSELL, University of Tennessee, Knoxville MARGARET M. SEMINARIO, AFL/CID, Washington, DC I. GLENN SIPES, University of Arizona, Tucson WALTER J. WEBER, JR., University of Michigan, Ann Arbor Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Program Director for Applied Ecology and Natural Resources ROBERT B. SMYTHE, Program Director for Exposure Assessment and Risk Reduction RICHARD D. THOMAS, Program Director for Human Toxicology and Risk Assessment LEE R. PAULSON, Manager, Toxicology Information Center n,

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C· ~ r or ommlsslon on t`'Je Sciences BRUCE M. ALBERTS (ChairmanJ, University of California, San Francisco BRUCE N. AMES, University of California, Berkeley FRANCISCO J. AVAIL, University of California, Irvine J. MICHAEL BISHOP, Hooper Research Foundation, University of California Medical Center, San Francisco MICHAEL T. CLEGG, University of California, Riverside GLENN A. CROSBY, Washington State University, Pullman FREEMAN J. DYSON, Princeton University, NJ LEROY E. HOOD, California Institute of Technology, Pasadena DONALD F. HORNIG, Harvard School of Public Health, Boston MARIAN E. KOSHI^ND, University of California, Berkeley RICHARD E. LENSKI, University of California, Irvine STEVEN P. PAKES, Southwestern Medical School, Dallas EMIL A. PF1TZER, Hoffman-LaRoche, Inc., Nutley, NJ THOMAS D. POLLARD, Johns Hopkins Medical School, Baltimore JOSEPH E. RALL, National Institutes of Health, Bethesda, MD RICHARD D. REMINGTON, University of Iowa, Iowa City PAUL G. RISSER, University of New Mexico, Albuquerque HAROLD M. SCHMECK, JR., Armonk, NY RICHARD B. SETLOW, Brookhaven National Laboratory, Upton, NY CARLA J. SHATZ, Stanford University School of Medicine, Stanford TORSTEN N. WIESEL, Rockefeller University, NY JOHN E. BURRIS, Executive Director

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Preface As part of its health-related responsibilities pertaining to hazardous waste sites and emergency chemical releases, the Agency for Toxic Substances and Dis- ease Registry (ATSDR) requested that the National Academy of Sciences (NAS) gather an NRC committee to review and evaluate the usefulness of animal epidemiologic studies for human risk assessment and recommend the types of data that should be collected. In response, the Committee on Ani- mals as Monitors of Environmental Hazards was formed in the NRCis Board on Environmental Studies and Toxicology in the Commission on Life Sciences. In formulating its report, the committee asked the following questions: · Can we develop interdisciplinary approaches to risk assessment using animal populations and that span epidemiology, toxicology, ecology, and veter- inary medicine? · Have opportunities to integrate environmental effects on animals health into the risk assessment process been missed or underused? · How can the effects of toxic substances on ecosystems and animals health be monitored and evaluated using existing programs and resources? · How can current animal-health monitoring programs be improved and coordinated for use in risk assessment? · What species of animals are most suitable for detecting environmental hazards, and will this information be predictive of risk to humans? · Is the use of animals as sentinels of environmental health hazards a humane alternative to experiments with laboratory animals, or can it reduce our dependence on the latter? With these specific questions in mind, the committee attempted to deter- mine how animals could be used for ecological and human health risk deter- mination as well as to provide an early-warning system for risk assessment and management. vat

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PREFACE The committee reviewed relevant literature, unpublished information, and available data bases. It also held a 2-day workshop in May 1988 to obtain information on programs that collect animal sentinel data from a panel of experts in epidemiology, wildlife population biology, environmental health, toxicology, and veterinary medicine. This committee was not the first NRC group to evaluate the potential for using animals as sentinels for environmental hazards. In 1979, the NRC published proceedings entitled, Symposium on Pathobiology of Environmental Pollutants: Animal Models and Midlife as Monitors. This symposium focused on research approaches, methods, and techniques using wildlife, but specific application to risk assessment was not addressed. The committee used the 1979 NAS report as the starting point and expand- ed the scope of animal sentinels to include fish and other wildlife, companion animals, and food animals. An attempt was made to synthesize and present information so as to be of use to individuals or agencies that are designing animal sentinel systems or those using data from such systems for ecological or human health risk assessment. Our basic philosophy was based on a 1981 recommendation from the Task Force on Environmental Cancer and Heart and Lung Disease that "one should use experiments of nature which involve not only humans but other species, such as animal pets, food-producing ani- mals, controlled wildlife, and aquatic animals." No report on the use of animals in biomedical research would be complete without careful consideration of the welfare of the species used. The commit- tee weighed any potential harm to animals against the potential benefits that might accrue for both animal and human health. We concluded that most sentinel systems use naturally occurring exposures and diseases, and when experimental studies are performed, existing federal animal welfare laws and guidelines regulate their performance and can adequately protect the animals used. This conclusion is similar to ones reached by the NRC Committee on the Use of Laboratory Animals in Biomedical and Behavioral Research in 1988, which states that "in cases in which research with animals is the best available method, . . . animals should be used. We also believe that scientists are ethically obliged to ensure the well-being of animals in research and to minimize their pain and suffering." Furthermore, our committee feels that in some instances, animal sentinel studies could complement or even replace traditional toxicologic studies in the risk assessment process, thereby reducing the number of laboratory animals that are used. The work of this NRC committee was truly a team effort across many scientific disciplines and institutions. The committee recognizes the valuable contribution of invited speakers at the 1988 workshop. NRC staff members, including Dr. Devra Davis, organized the committee's efforts, providing admin-

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PREFACE LO istrative assistance, acting as a sounding board, and making sure that the "ship" was headed in the right direction. Dr. James Reisa, director of the Board on Environmental Studies and Toxicology, acted as our adviser. Advice on risk assessment and extrapolation of animal data to humans was received from Dr. Curtis Travis of Oak Ridge National Laboratory. Drs. Karen Hulebak and Robert Smythe served as program directors, and Lee Paulson as project director. Carolyn Fulco served as project director until June 1990. Shelley Nurse produced draft after draft in her role as project assistant, and Norman Grossblatt and Ruth Crossgrove had the unenviable task of editing the report. Although every committee member contributed to this report in some way, two members served well beyond the call of duty: Drs. Anthony Guarino and Anne Fairbrother not only wrote considerable portions of the report, but also provided guidance and ideas to other committee members. Similar contribu- tions were received from consultants to the committee, Drs. John Reif and Ian Nisbet. On behalf of the committee, I thank all who assisted in completing this report. Larry Glickman, Chainnan Committee on Animals as Monitors of Environmental Hazards 14 May 1991

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Contents EXECUTIVE SUMMARY 1 INTRODUCTION Overview, 19 Purpose of the Study, 19 Historical Use of Animal Sentinels, 21 Current Use of Animal Sentinels in Risk Assessment, 21 Structure of the Report, 30 2 CONCEPTS AND DEFINITIONS Characteristics of Animal Sentinel Systems, 33 Objectives of Monitoring Animals Sentinels, 40 Animal Sentinel Systems in Observational Epidemiologic Studies, 45 Animal Sentinel Systems in Experimental Epidemiologic Studies, 48 Advantages and Limitations of Animal Sentinel Systems, 48 FOOD ANIMALS AS SENTINELS Descriptive Epidemiologic Studies, 54 Analytic Epidemiologic Studies, 64 Summary, 65 4 COMPANION ANIMALS AS SENTINELS Descriptive Epidemiologic Studies, 70 Analytic Epidemiologic Studies, 71 Summary, 80 FISH AND OTHER WILDLIFE AS SENTINELS Descriptive Epidemiologic Studies, 81 1 19 33 53 69 81

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mu CONTENTS Analytic Epidemiologic Studies, 93 In Situ Studies, 99 Summary, 101 6 ANIMAL SENTINELS IN RISK ASSESSMENT Use of Animal Sentinel Systems in Exposure Assessment, 105 Use of Animal Sentinel Systems in Hazard Identification, 109 Use of Animal Sentinel Systems in Dose-Response Assessment, 111 Use of Animal Sentinel Systems in Risk Characterization, 111 Use of Animal Sentinel Systems in Risk Management, 116 Summary, 118 103 7 SELECTION AND APPLICATION OF ANIMAL SENTINEL SYSTEMS IN RISK ASSESSMENT 121 System Design, 123 Implementation, 126 Validation, 128 Program Integration, 129 8 CONCLUSIONS AND RECOMMENDATIONS REFERENCES 131 137 APPENDIX: MAY 1988 WORKSHOP PARTICIPANTS 159