Recognition and Alleviation of Distress in Laboratory Animals (2008)

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Recognition and Alleviation of Distress in Laboratory Animals Committee on Recognition and Alleviation of Distress in Laboratory Animals Institute for Laboratory Animal Research Division on Earth and Life Studies THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu 

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, N.W.   Washington, DC 20001 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 com- petences and with regard for appropriate balance. This study was supported by the American Veterinary Medical Association; Aventis Pharma- ceuticals; the Bosack-Kruger Foundation; Bristol-Myers Squibb; GlaxoSmithKline; Humane Society of the United States; Scientists Center for Animal Welfare; Wyeth-Ayerst Pharmaceu- ticals; Department of Agriculture, Animal and Plant Health Inspection Service; and Depart- ment of Health and Human Services, National Institutes of Health through Contract Number N01-OD-4-2139 Task Order #161. Any opinions, findings, conclusions, or recommendations expressed in this publication 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 pub- lication 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 U.S. government. Library of Congress Cataloging-in-Publication Data Recognition and alleviation of distress in laboratory animals / Committee on Recognition and Alleviation of Distress in Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-0-309-10817-1 (pbk.) ISBN-10: 0-309-10817-9 (pbk.) 1. Laboratory animals—Health. 2. Laboratory animals—Effect of stress on. 3. Animal welfare. I. Institute for Laboratory Animal Research (U.S.). Committee for Recognition and Alleviation of Distress in Laboratory Animals. [DNLM: 1. Animal Welfare—standards. 2. Animals, Laboratory. 3. Laboratory Animal Science—ethics. QY 54 R307 2008] SF406R43 2008 636.088’5—dc22 2007052927 Additional copies of this report are available from The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2008 by the National Academy of Sciences. All rights reserved. Printed in the United States of America 

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. 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 e ­ ngineers. 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 M. Vest is presi- dent 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 



Committee on Recognition and Alleviation of Distress in Laboratory Animals Members Peter A. Ward (Chair), University of Michigan Medical School Robert Blanchard, University of Hawaii Valerie Bolivar, New York State Department of Health Marilyn J. Brown, Charles River Laboratories Fon Chang, AstraZeneca, Boston James P. Herman, University of Cincinnati Robert Hubrecht, Universities Federation for Animal Welfare David M. Lawson, Wayne State University School of Medicine (retired) Steven F. Maier, University of Colorado David Morton, University of Birmingham, United Kingdom (retired) Steven M. Niemi, Massachusetts General Hospital Melinda A. Novak, University of Massachusetts Stephen L. Zawistowski, American Society for the Prevention of Cruelty to Animals Staff Joanne Zurlo, Director Lida Anestidou, Study Director (from November 2006) Marsha Barrett, Former Project Assistant (to September 2006) Kathleen Beil, Administrative Coordinator Cameron Fletcher, Senior Editor (from June 2007) Rhonda Haycraft, Senior Project Assistant (from September 2006) Jennifer Obernier, Former Study Director (to August 2006) Susan Vaupel, Former Senior Editor (to June 2007) Shimere Williams, Mirzayan Fellow  

Institute for Laboratory Animal Research Council Members Stephen W. Barthold (Chair), University of California, Center for Comparative Medicine, Davis, California Kathryn A. Bayne, Association for Assessment and Accreditation of Laboratory Animal Care International, Waikoloa, Hawaii Myrtle A. Davis, Lilly Research Laboratories, Greenfield, Indiana Jeffrey I. Everitt, GlaxoSmithKline Research and Development, Comparative Medicine and Investigator Support, Research Triangle Park, North Carolina Michael F. Festing, Leicestershire, United Kingdom (to June 2006) James G. Fox, Massachusetts Institute of Technology, Division of Comparative Medicine, Cambridge, Massachusetts Nelson L. Garnett, Consultant, Laboratory Animal Care and Use Programs, Dickerson, Maryland Estelle B. Gauda, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland Coenraad F.M. Hendriksen, Netherlands Vaccine Institute, Bilthoven, The Netherlands Jon H. Kaas, Vanderbilt University, Nashville, Tennessee Joseph W. Kemnitz, University of Wisconsin, Primate Research Center, Madison, Wisconsin Judy A. MacArthur Clark, (formerly) Pfizer Global R&D, Groton, Connecticut Leticia V. Medina, Abbott Laboratories, Abbott Park, Illinois Bernard E. Rollin, Colorado State University, Department of Animal Sciences, Fort Collins, Colorado Abigail L. Smith, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania Stephen A. Smith, Virginia Polytechnic Institute and State University, Department of Biomedical Sciences and Pathobiology, Blacksburg, Virginia Peter Theran, Massachusetts Society for the Prevention of Cruelty to Animals, Boston, Massachusetts (to January 2007) James E. Womack, Texas A&M University, College Station, Texas Staff Joanne Zurlo, Director Lida Anestidou, Program Officer Kathleen Beil, Administrative Coordinator Cameron Fletcher, Managing Editor, ILAR Journal Rhonda Haycraft, Senior Project Assistant vi 

Institute for Laboratory Animal Research Publications 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) Occupational Health and Safety in the Care and Use of Research Animals (1997) Guide for the Care and Use of Laboratory Animals (1996) Guide for the Care and Use of Laboratory Animals—Korean Edition (1996) vii 

Guide for the Care and Use of Laboratory Animals—Chinese Version (1996) Guide for the Care and Use of Laboratory Animals—Spanish Version (1996) Guide for the Care and Use of Laboratory Animals—Russian Version (1996) Guide for the Care and Use of Laboratory Animals—French Version (1996) Guide for the Care and Use of Laboratory Animals—Taiwanese Edition (1996) Guide for the Care and Use of Laboratory Animals—Portuguese Edition (1996) Guide for the Care and Use of Laboratory Animals—Japanese Edition (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 viii 

Preface The impetus for this project was a letter from the New Jersey Associa- tion for Biomedical Research requesting that the National Academies’ Insti- tute for Laboratory Animal Research (ILAR) form a Committee to update its 1992 report Recognition and Alleviation of Pain and Distress in Laboratory Animals. More than a decade had passed since publication of the initial report, and many in the laboratory animal community felt that scientific progress in the areas of pain and distress warranted an update, as there was little guidance to assist investigators, laboratory animal veterinarians, animal care staff, and animal care and use committee (IACUC) members in assess- ing whether a proposed protocol would cause distress or whether an animal was experiencing distress. Current literature dealing with the development and recognition of stress and distress in other vertebrates, such as fish, is similarly very limited. Although there is reasonable consensus regarding the clinical signs of stress and distress, there are mixed views as to whether stress and distress develop independently of each other or whether the latter derives from the former. Much more information is still needed. The panel of experts that prepared this report has endeavored to present its best understanding of the diagnosis and treatment of stress and distress, based on peer-reviewed published literature. This report represents a consen- sus of experts who have described areas where there seems to be ­reasonable agreement as well as areas where there is inadequate knowledge, indicat- ing the need for future research. The Committee was challenged to adopt a consistent terminology and define the subjects of the report. In ­deference to extensive deliberations and varied interpretations of the available litera- ture, and in the name of achieved consensus, the Committee refrained from ix 

 PREFACE proposing any definitions. Moreover, due to inadequate relevant scientific information, the report references the Committee’s best professional judg- ment and expert opinion in areas where further research is needed. We believe that the outcome reflects a balanced exposition of where this field currently stands. The Committee hopes this report will be useful to all who are involved in the care and use of laboratory animals. The Committee acknowledges the individuals who provided assistance and valuable information for our deliberations. At the first meeting of the Committee, on April 10, 2006, a group of experts made presentations that addressed policy implications and covered numerous perspectives on the concept of laboratory animal distress. Specifically, the Committee thanks: Joseph Garner, Purdue University J.R. Haywood, Michigan State University, East Lansing Philip V. Holmes, University of Georgia Michael D. Oberdorfer, National Eye Institute, NIH Andrew N. Rowan, Humane Society of the United States Michael Scheeringa, Tulane University Two additional speakers addressed the Committee at its meeting on September 6, 2006, and the Committee thanks them as well: Roland Anderson, The Seattle Aquarium James D. Rose, University of Wyoming This report has been reviewed in draft form by individuals chosen for their diverse perspective and technical expertise, in accordance with proce- dures approved by the Report Review Committee of the National Research Council (NRC). 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 this report: Donald M. Broom, University of Cambridge Joy Cavagnaro, Access BIO Mary Dallman, University of California San Francisco Michael Festing, University of Leicester (retired) Monika Fleshner, University of Colorado Boulder Joseph P. Garner, Purdue University Barbara Hansen, University of South Florida 

PREFACE xi Randall J. Nelson, University of Tennessee Health Science Center Glen Otto, University of Texas at Austin Cynthia Pekow, VA Puget Sound Health Care System Jeremy Turner, Illinois College and Southern Illinois University The review of the report was overseen by: Hilton J. Klein, Merck Research Laboratories (retired) Harley W. Moon, Iowa State University (emeritus) Appointed by the NRC, these individuals were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring Committee and the institution. I also extend my deep appreciation to the Committee members and staff who devoted considerable time to this report. In particular I would like to acknowledge the assistance of Jennifer Obernier, who worked on the report until she left ILAR in August 2006, and of Lida Anestidou, who assumed this project upon her arrival at the National Academies in November 2006. Their work made this report possible. Peter A. Ward, Chair Committee on Recognition and Alleviation of Distress in Laboratory Animals 



Contents Summary 1 Scope of the Study, 1 Stress versus Distress, 2 Recognition and Assessment of Stress and Distress, 3 Avoiding, Minimizing, and Alleviating Distress, 5 Future Studies and Recommendations, 6 References, 8 1 Introduction 9 Regulations Governing Pain and Distress in Laboratory Animals, 9 Organization of the Report, 11 References, 12 2 Stress and Distress: Definitions 13 Introduction, 13 What Is Stress?, 14 What Is Distress?, 15 Implications for Animal Welfare, 17 Implications for Research, 21 Conclusions, 22 References, 22 xiii 

xiv CONTENTS 3 Recognition and Assessment of Stress and Distress 25 Introduction, 25 Behavioral Recognition of Stress and Distress, 26 Physiologic Measures of Stress and Distress, 36 Assessment of Distress, 42 References, 44 Additional References, 52 4 Avoiding, Minimizing, and Alleviating Distress 63 Introduction, 63 Avoiding or Minimizing Distress in Laboratory Animal Care, 64 Avoiding or Minimizing Distress in Laboratory Animal Use, 70 Alleviating Distress in Laboratory Animals, 75 Studying Distress, 79 References, 80 5 Topics for Further Investigation and Recommendations 87 Research Directions, 87 Recommendations, 90 References, 92 Appendix 95 Tools to Monitor and Assess Health Status and Well-Being in Stress and Distress, 95 About the Authors 113 Index 117