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,~ - - - ~ es _F~ Committee on Rodents Institute of Laboratory Animal Resources Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1996

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National Academy Press 2101 Constitution Avenue, N.W. Washington, 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, National Academy of Engineering, and 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, National Academy of Engineering, and Institute of Medicine. This study was supported by the U.S. Department of Health and Human Services (DHHS) through contract number NO1-CM-07316 with the Division of Cancer Treatment, National Cancer Institute; the Animal Welfare Information Center, National Agricultural Library, U.S. Department of Agriculture (USDA), through grant number 5932U4-8-59; and Howard Hughes Medical Institute through grant number 70209-500104. Additional support was provided by Charles River Laboratories, Wilmington, Massachusetts; Harlan Sprague Dawley, Indianapo- lis, Indiana; and the following members of the Pharmaceutical Manufacturers Association: Abbott Laboratories, Abbott Park, Illinois; Amgen, Inc., Thousand Oaks, California; Berlex Laboratories, Inc., Cedar Knolls,~New Jersey; Bristol-Myers Squibb Co., New York, New York; Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey; Burroughs Wellcome Co., Research Triangle Park, North Carolina;' Ciba-Geigy, Summit, New Jersey; Dupont Merck Research & Development, Wilmington, Delaware; Johnson & Johnson, New Brunswick, New Jersey; Marion Merrell Dow Inc., Kansas City, Missouri; Pfizer Inc., Groton, Connecticut; Sandoz Research Institute, East Hanover, New Jersey; Schering-Plough Research, Bloomfield, New Jersey; SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylva- nia; Syntex Discovery Research, Palo Alto, California; 3M Corporation, St. Paul, Minnesota; and Wyeth-Ayerst Research, Philadelphia, Pennsylvania. Core support is provided to the Institute of Laboratory Animal Resources by the Com- parative Medicine Program, National Center for Research Resources, National Institutes of Health, through grant SP40RR0137; the National Science Foundation through grant BIR-9024967; the U.S. Army Medical Research and Development Command, which serves as the lead agency for combined U.S. Department of Defense funding also received from the Human Systems Division of the U.S. Air Force Systems Command, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, and U.S. Naval Medical Research and Development Command, through grant DAMD17-93-J-3016; and research project grant RC-1-34 from the American Cancer Society. Any opinions. findings, and conclusions or recommendations expressed in this publica- tion are those of the committee and do not necessarily reflect the views of DHHS, USDA, or other sponsors, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. government or other sponsors. Library of Congress Cataloging-in-Publication Data Rodents / Committee on Rodents, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council. p. cm. (Laboratory animal management series) 'February 1996." Includes bibliographical references and index. ISBN 0-309-04936-9 1. Rodents as laboratory animals. I. Institue of laboratory Animal Resources (U.S.). Committee on Rodents.' II. Series. SF407.R6R62 1996 619' .93 dc20 96-4532 Copyright 1996 by the National Academy of Sciences. All rights reserved.

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COMMITTEE ON RODENTS Bonnie J. Mills (Chairman), Biotech Group, Immunotherapy Division, Baxter Healthcare Corp., Irvine, California Anton M. Allen, Laboratory Animal Health Services Division, Micro- biological Associates, Inc., Rockville, Maryland Lauretta W. Gerrity, Animal Resource Program, University of Alabama at Birmingham, Birmingham, Alabama Joseph J. Knapka, Veterinary Resources Program, National Center for Research Resources, National Institutes of Health, Bethesda, Maryland Arthur A. Like, Department of Pathology, University of Massachusetts, Worcester, Massachusetts Frank Lilly, Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York George M. Martin, Department of Pathology, University of Washington, Seattle, Washington Gwendolyn Y. McCormick, Laboratory Animal Resources, Searle, Skokie, Illinois Larry E. Mobraeten, The Jackson Laboratory, Bar Harbor, Maine William J. White, Professional Services, Charles River Laboratories, Wilmington, Massachusetts Norman S. Wolf, Department of Pathology, University of Washington, Seattle, Washington CONTRIBUTORS Wallace D. Dawson, Department of Biological Sciences, University of South Carolina, Columbia, South Carolina Edward H. Letter, The Jackson Laboratory, Bar Harbor, Maine Barbara McKnight, Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington Glenn M. Monastersky, Transgenics, Charles River Laboratories, Wilmington, Massachusetts Richard J. Traystman, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Hospital, Baltimore, Maryland Stay Dorothy D. Greenhouse, Senior Program Officer Amanda E. Hull, Program Assistant Norman Grossblatt, Editor . . .

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INSTITUTE OF LABORATORY ANIMAL RESOURCES COUNCIL John L. VandeBerg (Chairman), Southwest Foundation for Biomedical Research, San Antonio, Texas Christian R. Abee, University of South Alabama, Mobile, Alabama I. Derrell Clark, University of Georgia, College of Veterinary Medicine, Athens, Georgia Muriel T. Davisson, The Jackson Laboratory, Bar Harbor, Maine Bennett Dyke, Southwest Foundation for Biomedical Research, San Antonio, Texas Neal L. First, University of Wisconsin, Madison, Wisconsin flames W. Glosser, Massillon, Ohio John P. Hearn, Wisconsin Regional Primate Research Center, Madison. Wisconsin Margaret Landi, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania Charles R. McCarthy, Kennedy Institute of Ethics, Georgetown Univer sity, Washington, D.C. Roberta. Russell, Harlan Sprague Dawley, Inc., Frederick, Maryland Richard C. Van Slayters, University of California, School of Optometry, Berkeley, California Peter A. Ward, University of Michigan School of Medicine, Ann Arbor, Michigan Thomas D. Pollard, The Johns Hopkins University School of Medicine, Baltimore, Maryland (ex officio member) Stay Eric A. Fischer, Director Thomas L. Wolfle, Program Director Mara L. Glenshaw, Research Assistant Carol M. Rozmiarek, Project Assistant The Institute of Laboratory Animal Resources (ILAR) was founded in 1952 under the auspices of the National Research Council. A component of the Commission on Life Sciences, ILAR develops guidelines and positions and disseminates information on the scientific, technological, and ethical use of laboratory animals and related biological resources. ILAR promotes high-quality, humane care of laboratory animals and the appropriate use of laboratory animals and alternatives in research, testing, and education. ILAR serves as an advisor to the federal government, the biomedical research community, and the public. IV

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COMMISSION ON LIFE SCIENCES Thomas D. Pollard (Chairman), The Johns Hopkins University School of Medicine, Baltimore, Maryland Frederick R. Anderson, Cadwalader, Wickersharn & Taft, Washington, D.C. John C. Bailar, III, McGill University, Montreal, Canada John E. Burris, Marine Biological Laboratory, Woods Hole, Massachusetts Michael T. Clegg, University of California, Riverside, California Glenn A. Crosby, Washington State University, Pullman, Washington Ursula W. Goodenough, Washington University, St. Louis, Missouri Susan E. Leeman, Boston University School of Medicine, Boston, Massachusetts Richard E. Lenski, Michigan State University, East Lansing, Michigan Thomas E. Lovejoy, Smithsonian Institution, Washington, D.C. Donald R. Mattison, University of Pittsburgh, Pittsburgh, Pennsylvania Joseph E. Murray, Wellesley Hills, Massachusetts Edward E. Penhoet, Chiron Corporation, Emeryville, California Emil A. Pfitzer, Research Institute for Fragrance Materials, Inc., Hackensack, New Jersey Malcolm C. Pike, University of Southern California School of Medicine, Los Angeles, California Henry C. Pitot, III, McArdle Laboratory for Cancer Research, Madison, Wisconsin Jonathan M. Samet, The Johns Hopkins University, Baltimore, Maryland Harold M. Schmeck, Jr., North Chatham, Massachusetts Carla J. Shatz, University of California, Berkeley, California John L. VandeBerg, Southwest Foundation for Biomedical Research, San Antonio, Texas Stay Paul Gilman, Executive Director v

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The National Academy of Sciences is a private, nonprofit, 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. Bruce M. Alberts 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. Harold Liebowitz 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 Academv of Sciences bY its congressional charter to be an adviser to the O federal government and upon its own initiative to identify issues- of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. The National Research Council was established by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's pur- poses of furthering knowledge and advising the federal government. Functioning in accor- dance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and National Academy of Engi- neering in the conduct of their 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. Bruce M. Alberts and Dr. Harold Liebowitz are chairman and vice- chairman, respectively, of the National Research Council. Vl

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Preface Biomedical and behavioral research, product testing, and many aspects of science education rely heavily on the use of animals. Quality care of these animals is essential, not only for the animals' welfare, but also for obtaining valid data. Environmental and biologic factors can influence experimental results by exerting subtle influences on an animal's physi- ologic characteristics, behavior, or both. Although there is a tendency to feel more concern for species to which humans develop an attachment (e.g., dogs and cats) and species that are biologically "closer" to humans (nonhu- man primates), the same attention to environmental control for and good care of every laboratory species is necessary to ensure the high quality of both science and ethical practice. Rodents are, by far, the largest group of animals used in research and testing. In 1986, the Office of Technology Assessment estimated that 17-22 million animals were being used each year in the United States, of which about 13.2-16.2 million were rodents (Alternatives to Animal Use in Re- search, Testing, and Education; Pub. No. OTA-BA-273; U.S. Congress Of- fice of Technology Assessment; Washington, D.C.; 1986~. In the 15 years since the last Institute of Laboratory Animal Resources report on the gen- eral management of rodents was published, important advances in biomedi- cal research and increased public awareness have created a new environ- ment for animal research. Modern technology- such as insertion of functional genes from other species into mice or rats, elimination of a single selected . . V11

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. . . V111 PREFACE gene or function in mice, and the re-creation of elements of the human immune system in mice has greatly expanded the usefulness of rodents in drug development and as models of human diseases. The technologic re- quirements of such advanced systems have led to improved understanding and implementation of environmental requirements for the care and use of rodents in research. The intent of this report is to provide current information to laboratory animal scientists (including both animal-care technicians and veterinarians), investigators, research technicians, and administrators on general elements of rodent care and use that should be considered both for optimal design and conduct of research and to meet current standards of care and use. We emphasize that this report provides guidelines and should not be used as a substitute for good professional judgment, which is essential in the applica- tion of the guidelines. Where possible, we refer to other documents that provide more detail on specific aspects of rodent care and use. Bonnie J. Mills, Chairman Committee on Rodents

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Contents 1 LABORATORY ANIMALS AND PUBLIC PERSPECTIVE Regulatory Issues 1 Ethical Considerations 3 References 4 2 RESPONSIBILITIES OF ANIMAL CARE AND USE COMMITTEES Program Oversight 6 Protocol Review 7 Personnel Qualifications and Training Occupational Health and Safety 12 Use of Hazardous Agents 14 References 1 5 3 CRITERIA FOR SELECTING EXPERIMENTAL ANIMALS Species and Stocks 16 Standardized Nomenclature 21 Quality 27 Selected Aspects of Experimental Design 31 References 33 6 16 4 GENETIC MANAGEMENT OF BREEDING COLONIES 35 Genetically Defined Stocks 35 Nongenetically Defined Stocks 39 IX

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x Cryopreservation 40 Record-Keeping 42 References 43 HUSBANDRY Housing 44 Environment 49 Food 58 Water 64 Bedding 65 Sanitation 66 Identification and Records 71 Rodents Other Than Rats and Mice 72 References 76 6 VETERINARY CARE Preventive Medicine 85 Surveillance, Diagnosis, Treatment, and Control of Diseases 190 Emergency, Weekend, and Holiday Care 97 Minimization of Pain and Distress 98 Survival Surgery and Postsurgical Care 100 Euthanasia 105 References 107 7 FACILITIES Location and Design 115 Construction and Architectural Finishes 1 18 Monitoring 1 18 Special Requirements 1 19 Security 1 19 References 1 20 8 RODENTS THAT REQUIRE SPECIAL CONSIDERATION Immunodeficient Rodents 123 Wild Rodents 128 Aging Cohorts 131 Rodent Models of Insulin-Dependent Diabetes Mellitus 141 Transgenic Mice 148 References 1 54 APPENDIX: SOURCES OF INFORMATION ON IMPORTING RODENTS INDEX CONTENTS 44 85 114 159 161

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