GUIDE FOR THE CARE AND USE OF LABORATORY ANIMALS

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GUIDE FOR THE CARE AND USE OF LABORATORY ANIMALS Eighth Edition Committee for the Update of the Guide for the Care and Use of Laboratory Animals Institute for Laboratory Animal Research Division on Earth and Life Studies

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Govern- ing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineer- ing, 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 study was supported by the Office of Extramural Research, Office of the Direc- tor, National Institutes of Health/Department of Health and Human Services under Contract Number N01-OD-4-2139 Task Order #188; the Office of Research Integrity, Department of Health and Human Services; the Animal and Plant Health Inspection Service, U.S. Department of Agriculture; Association for Assessment and Accreditation of Laboratory Animal Care International; American Association for Laboratory Animal Science; Abbott Fund; Pfizer; American College of Laboratory Animal Medicine; Ameri- can Society of Laboratory Animal Practitioners; Association of Primate Veternarians. Any opinions, findings, conclusions, or recommendations expressed in this pub- lication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for the project. The content of this publication does not necessarily reflect the views or policies of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. International Standard Book Number-13: 978-0-309-15400-0 (Book) International Standard Book Number-10: 0-309-15400-6 (Book) International Standard Book Number-13: 978-0-309-15401-7 (PDF) International Standard Book Number-10: 0-309-15401-4 (PDF) Library of Congress Control Number: 2010940400 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); http://www.nap.edu. Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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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 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 Acad- emy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone 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 engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles Vest 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 Insti- tute 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 education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences 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. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE FOR THE UPDATE OF THE GUIDE FOR THE CARE AND USE OF LAbORATORy ANIMALS Members Janet C. Garber (Chair), Garber Consulting R. Wayne barbee, Virginia Commonwealth University Joseph T. bielitzki, University of Central Florida Leigh Ann Clayton, National Aquarium, Baltimore John C. Donovan, BioResources, Inc. Coenraad F. M. Hendriksen, Netherlands Vaccine Institute, Bilthoven, The Netherlands (until March 2009) Dennis F. Kohn, Columbia University (retired) Neil S. Lipman, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College Paul A. Locke, Johns Hopkins Bloomberg School of Public Health John Melcher, U.S. Senate (retired) Fred W. Quimby, Rockefeller University (retired) Patricia V. Turner, University of Guelph, Canada Geoffrey A. Wood, University of Guelph, Canada Hanno Würbel, Justus Liebig University of Giessen, Germany Staff Lida Anestidou, Study Director Frances Sharples, Acting Director Kathleen beil, Administrative Coordinator Administrative Cameron H. Fletcher, Senior Editor Ruth Crossgrove, Senior Editor Radiah Rose, Manager of Editorial Projects Rhonda Haycraft, Senior Project Assistant Senior Joanne Zurlo, Director (until April 2010) 

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INSTITUTE FOR LAbORATORy ANIMAL RESEARCH COUNCIL Members Stephen W. barthold (Chair), Center for Comparative Medicine, University of California-Davis Kathryn A. bayne, Association for Assessment and Accreditation of Laboratory Animal Care International, Frederick, Maryland Myrtle A. Davis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Jeffrey I. Everitt, Comparative Medicine and Investigator Support, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina (until June 2010) James G. Fox, Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge Nelson L. Garnett, Laboratory Animal Care and Use Programs, Dickerson, MD Estelle b. Gauda, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland (until June 2010) Joseph W. Kemnitz, Institute for Clinical and Translational Research and Department of Physiology, University of Wisconsin-Madison Judy A. MacArthur Clark, Animals in Scientific Procedures Inspectorate, Home Office, London, United Kingdom Martha K. McClintock, Institute for Mind and Biology, University of Chicago, Illinois Leticia V. Medina, Animal Welfare and Compliance, Abbott Laboratories, Abbott Park, Illinois Timo Olavi Nevalainen, National Laboratory Animal Center, University of Eastern Finland, Kuopio, Finland bernard E. Rollin, Department of Animal Sciences, Colorado State University, Fort Collins Abigail L. Smith, School of Veterinary Medicine, University of Pennsylvania, Philadelphia (until June 2010) Stephen A. Smith, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University, Blacksburg James E. Womack, Department of Veterinary Pathology, Texas A&M University, College Station (until June 2010) i

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Staff Frances Sharples, Acting Director Lida Anestidou, Senior Program Officer Kathleen beil, Administrative Coordinator Administrative Cameron H. Fletcher, Managing Editor, ILAR Journal Rhonda Haycraft, Program Associate Program Joanne Zurlo, Director (until April 2010) ii

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INSTITUTE FOR LAbORATORy ANIMAL RESEARCH PUbLICATIONS Recognition and Alleviation of Pain in Laboratory Animals (2009) Scientific and Humane Issues in the Use of Random Source Dogs and Cats for Research (2009) Recognition and Alleviation of Distress in Laboratory Animals (2008) Toxicity Testing in the 21st Century: A Vision and a Strategy (2007) Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models (2006) Guidelines for the Humane Transportation of Research Animals (2006) Science, Medicine, and Animals: Teacher’s Guide (2005) Animal Care and Management at the National Zoo: Final Report (2005) Science, Medicine, and Animals (2004) The Development of Science-based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop (2004) Animal Care and Management at the National Zoo: Interim Report (2004) National Need and Priorities for Veterinarians in Biomedical Research (2004) Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003) International Perspectives: The Future of Nonhuman Primate Resources, Proceedings of the Workshop Held April 17-19, 2002 (2003) Occupational Health and Safety in the Care and Use of Nonhuman Primates (2003) Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 (2000) Strategies That Influence Cost Containment in Animal Research Facilities (2000) Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1999 US/Japan Conference (2000) Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference (1999) Monoclonal Antibody Production (1999) The Psychological Well-Being of Nonhuman Primates (1998) Biomedical Models and Resources: Current Needs and Future Opportunities (1998) Approaches to Cost Recovery for Animal Research: Implications for Science, Animals, Research Competitiveness and Regulatory Compliance (1998) Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use (1997) iii

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Occupational Health and Safety in the Care and Use of Research Animals (1997) Guide for the Care and Use of Laboratory Animals (1996) Rodents (1996) Nutrient Requirements of Laboratory Animals, Fourth Revised Edition (1995) Laboratory Animal Management: Dogs (1994) Recognition and Alleviation of Pain and Distress in Laboratory Animals (1992) Education and Training in the Care and Use of Laboratory Animals: A Guide for Developing Institutional Programs (1991) Companion Guide to Infectious Diseases of Mice and Rats (1991) Infectious Diseases of Mice and Rats (1991) Immunodeficient Rodents: A Guide to Their Immunobiology, Husbandry, and Use (1989) Use of Laboratory Animals in Biomedical and Behavioral Research (1988) Animals for Research: A Directory of Sources, Tenth Edition and Supplement (1979) Amphibians: Guidelines for the Breeding, Care and Management of Laboratory Animals (1974) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu ix

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Reviewers T his eighth edition of the Guide for the Care and Use of Laboratory Animals has been reviewed in draft form by individuals chosen for their diverse perspectives and expertise, in accordance with proce- dures approved by the Report Review Committee of the National Research Council. The purpose of this independent review is to provide candid and critical comments that will assist the Committee in making its published report as sound as possible, and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberation process. The Committee thanks the follow- ing individuals for their review of the draft report: Michael B. Ballinger, Amgen Philippe J.R. Baneux, PreLabs Stephen W. Barthold, University of California-Davis Linda C. Cork, Stanford University Jann Hau, University of Copenhagen, Denmark Michael J. Huerkamp, Emory University Michael D. Kastello, sanofi-aventis Arthur L. Lage, Harvard Medical School Christian Lawrence, Children’s Hospital Boston Randall J. Nelson, University of Tennessee College of Medicine- Memphis Steven M. Niemi, Massachusetts General Hospital Melinda A. Novak, University of Massachusetts-Amherst xi

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Overview T his eighth edition of the Guide is divided into five chapters and four appendices. Chapter 1 presents the goals and intended audiences of the Guide as well as key concepts and terminology essential to its premise and use. Incorporating some of the material from the Introduction to the last edition, the chapter highlights a commitment to the concepts of the Three Rs—Replacement, Reduction, and Refinement—and provides an enhanced discussion of the ethics of animal use and investigator/institu- tional obligations. Chapter 2 focuses on the overall institutional animal care and use program (Program), in addition to many of the topics previously covered in Chapter 1 of the seventh edition. It defines the evolved concept of Program and provides a framework for its intra-institutional integration, taking into account institutional policies and responsibilities, regulatory considerations, Program and personnel management (including training and occupational health and safety), and Program oversight. Discussions of the latter include institutional animal care and use committee (IACUC) functions, protocol and Program review, postapproval monitoring (a new section), and consid- erations such as humane endpoints and multiple survival surgical proce- dures. The Committee endorses the American College of Laboratory Animal Medicine’s “Guidelines for Adequate Veterinary Care.” Chapter 3 focuses on the animals themselves and, unlike previous edi- tions, addresses terrestrial and aquatic species in separate sections, reflect- xii

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xiii OVERVIEW ing the growing role of aquatic animals in biomedical research. The chapter provides recommendations for housing and environment, discusses the importance of social housing, and includes enhanced sections on environ- mental enrichment, animal well-being, and scientific validity. Space recommendations were nominally expanded based on the Com- mittee’s professional and expert opinion and on current housing methods. Cage sizes have historically been interpreted as minimum space needs by users of the Guide, and were labeled as such (“recommended minimum space”) in this edition. The use of the word “minimum” does not further restrict users of the Guide because, although the space requirements are numbers (i.e., engineering standards), they are used in a performance stan- dards framework. The Committee recommends minimum space for female rodents with litter and an increase of the cage height for rabbits to 16”. Further, in light of many comments submitted to the Committee requesting more information on performance goals and how to achieve them, rodent breeding recommendations are accompanied by substantial guidance. With respect to nonhuman primates (NHPs), the Committee endorses social housing as the default and has provided some species-specific guid- ance. An additional group has been added for monkeys, and chimpanzees are separated in a new category. These changes were motivated by the Committee’s recognition (affirmed in comments solicited from NHP experts) that these animals need more floor and vertical space, at least in some groups, to exercise their natural habits. Chapter 4 discusses veterinary care and the responsibilities of the attending veterinarian. It introduces the concept of animal biosecurity and upholds its central role in ensuring the health of laboratory animals. The chapter includes recommendations relative to animal procurement, trans- portation, and preventive medicine, and expands the sections on clinical care and management, surgery (with a new section on intraoperative moni- toring), pain and distress, and euthanasia. Chapter 5 discusses physical plant–related topics and includes updated and new material on vibration control; physical security and access con- trol; hazardous agent containment; and special facilities for imaging and whole body irradiation, barrier housing, behavioral studies, and aquatic spe- cies housing. The chapter provides detailed discussion of centralized versus decentralized animal facilities and introduces the concept of variable-volume HVAC systems with a nod toward energy conservation and efficiency. Appendix A is the updated bibliography; Appendix B presents the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training; Appendix C presents the Statement

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xix OVERVIEW of Task; and Appendix D provides the biographical sketches of the Com- mittee members. In accordance with the Statement of Task (“In addition to the published report, the updated Guide will be posted on the Internet in a pdf or equiva- lent format such that users will be able to search the entire document at one time”), the Guide is available in searchable pdf format on the National Academies Press website, www.nap.edu.

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Contents 1 KEy CONCEPTS 1 Applicability and Goals, 2 Intended Audiences and Uses of the Guide, 3 Ethics and Animal Use, 4 The Three Rs, 4 Key Terms Used in the Guide, 5 Humane Care, 6 Animal Care and Use Program, 6 Engineering, Performance, and Practice Standards, 6 Policies, Principles, and Procedures, 7 Must, Should, and May, 8 References, 8 2 ANIMAL CARE AND USE PROGRAM 11 Regulations, Policies, and Principles, 12 Program Management, 13 Program Management Responsibility, 13 The Institutional Official, 13 The Attending Veterinarian, 14 The Institutional Animal Care and Use Committee, 14 Collaborations, 15 Personnel Management, 15 Training and Education, 15 Occupational Health and Safety of Personnel, 17 xxi

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xxii CONTENTS Personnel Security, 23 Investigating and Reporting Animal Welfare Concerns, 23 Program Oversight, 24 The Role of the IACUC, 24 IACUC Constitution and Function, 24 Protocol Review, 25 Special Considerations for IACUC Review, 27 Postapproval Monitoring, 33 Disaster Planning and Emergency Preparedness, 35 References, 35 3 ENVIRONMENT, HOUSING, AND MANAGEMENT 41 Terrestrial Animals, 42 Terrestrial Environment, 42 Microenvironment and Macroenvironment, 42 Temperature and Humidity, 43 Ventilation and Air Quality, 45 Illumination, 47 Noise and Vibration, 49 Terrestrial Housing, 50 Microenvironment (Primary Enclosure), 50 Environmental Enrichment, 52 Sheltered or Outdoor Housing, 54 Naturalistic Environments, 55 Space, 55 Terrestrial Management, 63 Behavioral and Social Management, 63 Husbandry, 65 Population Management, 75 Aquatic Animals, 77 Aquatic Environment, 77 Microenvironment and Macroenvironment, 77 Water Quality, 78 Life Support System, 79 Temperature, Humidity, and Ventilation, 80 Illumination, 81 Noise and Vibration, 81 Aquatic Housing, 82 Microenvironment (Primary Enclosure), 82 Environmental Enrichment and Social Housing, 82 Sheltered, Outdoor, and Naturalistic Housing, 83 Space, 83

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xxiii CONTENTS Aquatic Management, 84 Behavior and Social Management, 84 Husbandry, 84 Population Management, 87 References, 88 4 VETERINARy CARE 105 Animal Procurement and Transportation, 106 Animal Procurement, 106 Transportation of Animals, 107 Preventive Medicine, 109 Animal Biosecurity, 109 Quarantine and Stabilization, 110 Separation by Health Status and Species, 111 Surveillance, Diagnosis, Treatment, and Control of Disease, 112 Clinical Care and Management, 113 Medical Management, 114 Emergency Care, 114 Recordkeeping, 115 Surgery, 115 Training, 115 Presurgical Planning, 116 Surgical Facilities, 116 Surgical Procedures, 117 Aseptic Technique, 118 Intraoperative Monitoring, 119 Postoperative Care, 119 Pain and Distress, 120 Anesthesia and Analgesia, 121 Euthanasia, 123 References, 124 5 PHySICAL PLANT 133 General Considerations, 133 Location, 134 Centralization Versus Decentralization, 134 Functional Areas, 135 Construction Guidelines, 136 Corridors, 136 Animal Room Doors, 137 Exterior Windows, 137 Floors, 137

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xxi CONTENTS Drainage, 138 Walls and Ceilings, 138 Heating, Ventilation, and Air Conditioning (HVAC), 139 Power and Lighting, 141 Storage Areas, 141 Noise Control, 142 Vibration Control, 142 Facilities for Sanitizing Materials, 143 Environmental Monitoring, 143 Special Facilities, 144 Surgery, 144 Barrier Facilities, 145 Imaging, 146 Whole Body Irradiation, 147 Hazardous Agent Containment, 148 Behavioral Studies, 149 Aquatic Species Housing, 150 Security and Access Control, 151 References, 151 ADDENDUM 155 APPENDICES A ADDITIONAL SELECTED REFERENCES 161 Subject Matter, 161 Use of Laboratory Animals, 162 Alternatives, 162 Ethics and Welfare, 163 Experimental Design and Statistics, 164 Research and Testing Methodology, 165 Program Management, 167 General References, 167 Laws, Regulations, and Policies, 168 Education, 169 Monitoring the Care and Use of Animals, 169 Occupational Health and Safety, 170 Environment, Housing, and Management, 172 General References, 172 Environmental Enrichment, 173 Genetics and Genetically Modified Animals, 175

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xx CONTENTS Species-Specific References—Environment, Housing, and Management, 176 Agricultural Animals, 176 Amphibians, Reptiles, and Fish, 178 Birds, 179 Cats and Dogs, 180 Exotic, Wild, and Zoo Animals, 181 Nonhuman Primates, 182 Rodents and Rabbits, 184 Other Animals, 187 Veterinary Care, 188 Transportation, 188 Anesthesia, Pain, and Surgery, 188 Disease Surveillance, Diagnosis, and Treatment, 190 Pathology, Clinical Pathology, and Parasitology, 190 Species-Specific References—Veterinary Care, 191 Agricultural Animals, 191 Amphibians, Reptiles, and Fish, 192 Birds, 193 Cats and Dogs, 193 Exotic, Wild, and Zoo Animals, 193 Nonhuman Primates, 194 Rodents and Rabbits, 194 Design and Construction of Animal Facilities, 196 b U.S. GOVERNMENT PRINCIPLES FOR THE UTILIZATION AND CARE OF VERTEbRATE ANIMALS USED IN TESTING, RESEARCH, AND TRAINING 199 C STATEMENT OF TASK 201 D AbOUT THE AUTHORS 203 INDEx 209

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