THE DEVELOPMENT OF SCIENCE-BASED GUIDELINES FOR LABORATORY ANIMAL CARE

Proceedings of the November 2003 International Workshop

Institute for Laboratory Animal Research

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop THE DEVELOPMENT OF SCIENCE-BASED GUIDELINES FOR LABORATORY ANIMAL CARE Proceedings of the November 2003 International Workshop Institute for Laboratory Animal Research Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop 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 competences and with regard for appropriate balance. This study was supported by Grant No. RR0118801-01 and Contract No. N01-OD-4-2139, TO 72 between the National Academy of Sciences and the National Institutes of Health. Other contributors were the Association for Assessment and Accreditation of Laboratory Animal Care International, Canadian Council on Animal Care, Centre for Best Practice for Animals in Research (Medical Research Council, UK), Federation of European Laboratory Animal Science Associations, International Council for Laboratory Animal Science, Laboratory Animals, Ltd., and the U.S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number 0-309-09302-3 (Book) International Standard Book Number 0-309-54532-3 (PDF) Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, D.C. 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu Copyright 2004 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and 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. 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. Wm. A. Wulf 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 education. Dr. Harvey V. Fineberg 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. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop INTERNATIONAL WORKSHOP ON THE DEVELOPMENT OF SCIENCE-BASED GUIDELINES FOR LABORATORY ANIMAL CARE PROGRAM COMMITTEE Hilton J. Klein, VMD (Chair), Merck Research Laboratories, West Point, Pennsylvania Stephen W. Barthold, DVM, PhD, University of California, Davis Coenraad F.M. Hendriksen, DVM, PhD, Netherlands Vaccine Institute, Bilthoven, Netherlands William Morton, VMD, National Primate Research Center, University of Washington, Seattle, Washington Randall J. Nelson, PhD, University of Tennessee Health Science Center, Memphis, Tennessee Emilie F. Rissman, PhD, University of Virginia Medical School, Charlottesville, Virginia William S. Stokes, DVM, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina Staff Joanne Zurlo, PhD, Director, Institute for Laboratory Animal Research Marsha Barrett, Senior Project Assistant Kathleen Beil, Administrative Assistant Jennifer Obernier, Program Officer Susan Vaupel, Editor

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL Peter A. Ward (Chair), Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan Stephen W. Barthold, Center for Comparative Medicine, University of California, Davis, California William C. Campbell, Drew University, Madison, New Jersey Rosemary W. Elliott, Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York Michael F. Festing, MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom Janet C. Gonder, Pinehurst, North Carolina Coenraad F.M. Hendriksen, Netherlands Vaccine Institute, Bilthoven, Netherlands Jay R. Kaplan, Department of Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina Hilton J. Klein, Department of Laboratory Animal Resources, Merck Research Laboratories, West Point, Pennsylvania William Morton, National Primate Research Center, University of Washington, Seattle, Washington Randall J. Nelson, Department of Anatomy and Neurobiology, University of Tennessee, Memphis, Tennessee Emilie F. Rissman, Department of Biochemistry and Molecular Genetics, University of Virginia Medical School, Charlottesville, Virginia William S. Stokes, Environmental Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina Michael K. Stoskopf, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina Thomas Wolfle, Cambridge, Maryland Staff Joanne Zurlo, Director Marsha Barrett, Senior Project Assistant Kathleen Beil, Administrative Assistant Jennifer Obernier, Program Officer Susan Vaupel, Managing Editor, ILAR Journal

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Preface Each country or group of countries addresses the regulation of laboratory animal care in its own way, and even within a single country, there may be different agencies exerting separate regulations or guidelines (e.g., the US has regulations through the Animal Welfare Act administered through the Department of Agriculture and through the Health Extension Act administered through the Department of Health and Human Services as Public Health Service Policy). In Europe, the member nations of the European Union (EU) are governed by Directive 86/609 on the protection of animals used for experimental and other scientific purposes which provides a minimum standard of care for animals in these countries. Each country, in turn, can add more stringent regulations for its own research community, and this has been done. The Council of Europe (CoE), which has 45 member states, adopted the European Convention ETS 123 for the protection of vertebrate animals in 1986. Since the CoE is not a regulatory body, Conventions do not have the force of law, but they do exert a considerable moral pressure, especially in CoE countries for which the Convention is the only pan-European agreement. Nevertheless, once a Member State ratifies a Convention, it becomes a “party” and is bound to be implemented as national law. The standards of housing and care for laboratory animals outlined in Appendix A of ETS 123 served as the basis for these standards in the EU Directive 86/609. These standards are very similar to those specified in the 1996 revision of the Guide for the Care and

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Use of Laboratory Animals, which was written by an ILAR committee and which serves as the basis of Public Health Service Policy. The Council of Europe is currently revising Appendix A of ETS 123 during the process known as a Multilateral Consultation, whose participants include representatives from member nations as well as “observers.” Nations that are “parties” to the Convention (i.e. have ratified it) play the largest role in acceptance or rejection of the proposed changes recommended by appointed expert working groups for each species or group of species. Observers represent non-member countries, including the US, Canada, and Japan, and non-governmental organizations (NGO), such as the Federation of European Laboratory Animal Science Associations (FELASA), the Eurogroup for Animal Welfare, the European Federation of Pharmaceutical Industries and Associations (EFPIA), and Institute for Laboratory Animal Research (ILAR) of the National Academies (as the authoring body for the Guide). The proposed revision of ETS 123 includes changes that may result in substantial differences in recommended housing and care conditions for laboratory animals between Europe and the US. Consequently, many discussions have focused on whether these differences will impact the interchange of research results among countries, and have questioned the value and/or need for harmonization of guidelines among countries. Arguments may be made for and against harmonization of guidelines for laboratory animal care throughout the world. Intuitively, one might assume that results from studies on animals kept under identical conditions would be more comparable and that harmonization of standards would lead to more collaboration among countries. However, some research has shown that this is not necessarily the case. It is generally agreed that guidelines that incorporate the newest scientific evidence for the best conditions for laboratory animals should also ensure that the data generated are the most reliable. However, if the standards proposed in one country or group of countries are not scientifically based, they are not likely to be freely adopted globally. Financial constraints associated with making major changes could seriously impede the ability to perform animal research at current levels. There is also a concern that in order to avoid making costly changes, institutions may choose to “export” their animal research to countries that have more questionable standards of laboratory animal care, thus generating genuine animal welfare concerns. There is widespread agreement in the laboratory animal community that these issues need to be continually examined on an international basis. Since ILAR is one of the few organizations with the international reputation and credibility to bring together experts and interested parties from around the world, it was logical that ILAR should host a meeting to discuss these issues. Consequently, an international workshop was held

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop in Washington, DC, in November 2003 to bring together experts from around the world to discuss the available knowledge that can positively influence current and pending guidelines for laboratory animal care, identify gaps in that knowledge in order to encourage future research endeavors, and discuss the scientific evidence that can be used to assess the benefits and costs of various regulatory approaches affecting facilities, research, and animal welfare. This workshop brought together experts from 15 countries over three days to share information, discuss future endeavors, and consider the question of whether or not to harmonize standards. Many fruitful discussions took place during the workshop and the outcome was a better understanding of the cultural influences that serve as a backdrop to regulation and guideline development. The proceedings from this workshop are reported in the pages of this publication. ILAR wishes to acknowledge and thank the following sponsors of this workshop: the National Institutes of Health (National Center for Research Resources and Office of Laboratory Animal Welfare), Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), Canadian Council on Animal Care, Centre for Best Practice for Animals in Research (Medical Research Council, UK), Federation of European Laboratory Animal Science Associations, International Council for Laboratory Animal Science, and Laboratory Animals, Ltd.

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Contents INTRODUCTION   1     Building the Case for Science-based Guidelines—Introductory Remarks Hilton J. Klein   3 PLENARY LECTURE   7     Genes, Environments, and Mouse Behavior John C. Crabbe   9 SESSION 1:   CURRENT STATUS: IDENTIFYING THE ISSUES   15     AAALAC International Perspective John G. Miller   17     The Council of Europe: What Is It? Wim deLeeuw   23     ICLAS and the International Community Gilles Demers   30     Role of the National Institutes of Health Office of Laboratory Animal Welfare and the Public Health Service Policy on Humane Care and Use of Laboratory Animals Nelson L. Garnett   36     Regulatory Authority of the US Department of Agriculture Animal and Plant Health Inspection Service Chester A. Gipson   41

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop     A Review and Comparison of Processes to Change Regulatory Guidelines: A European Perspective Jonathan Richmond   46     Japanese Regulations on Animal Experiments: Current Status and Perspectives Naoko Kagiyama and Tatsuji Nomura   50     Process for Change—Development and Implementation of Standards for Animal Care and Use in Canada Clément Gauthier   57     Building Credible Science from Quality, Animal-Based Information Paul Gilman   60 SESSION 2:   ASSESSMENT OF ANIMAL HOUSING NEEDS IN THE RESEARCH SETTING—PEER-REVIEWED LITERATURE APPROACH   63     Disruption of Laboratory Experiments Due to Leaching of Bisphenol A from Polycarbonate Cages and Bottles and Uncontrolled Variability in Components of Animal Feed Frederick S. vom Saal, Catherine A. Richter, Rachel R. Ruhlen, Susan C. Nagel, and Wade V. Welshons   65     Assessment of Animal Housing Needs in the Research Setting Using a Peer-Reviewed Literature Approach: Dogs and Cats Graham Moore   70     Housing for Captive Nonhuman Primates: The Balancing Act Melinda Novak   79     Assessment of Animal Housing Standards for Rabbits in a Research Setting Markus Stauffacher and Vera Baumans   86 SESSION 3:   APPROACHES TO CURRENT GUIDELINES—US AND EUROPE   91     Housing Standards: Development of Guidelines and the Process for Change William J. White   93     Revision of Appendix A to the European Convention ETS 123: The Participants, the Process, and the Outcome Derek Forbes   100

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop     Breakout Session: Rats and Mice   103     Effects of Housing Density and Cage Type on Young Adult C57BL/6J Mice   107     New Housing Standards for Rats and Mice Developed with Focus on the Needs of the Animals   114     Breakout Session: Approaches for Implementing Current US and European Guidelines for Housing Standards for Dogs and Cats   120     Breakout Session: Nonhuman Primates   124     Breakout Session: Rabbit Housing   128 SESSION 4:   ENVIRONMENTAL CONTROL FOR ANIMAL HOUSING   131     Environmental Controls (US Guidance) Bernard Blazewicz and Dan Frasier   133     European Guidelines for Environmental Control in Laboratory Animal Facilities Harry J. M. Blom   140     Breakout Session: Lighting   147     Breakout Session: Effects of Sound on Research Animals   153     Breakout Session: Environmental Control for Animal Housing—Impact on Metabolism and Immunology   156     Breakout Session: Environmental Controls/Engineering Issues   164 DINNER SPEAKER: KAY E. HOLEKAMP   167     A View from the Field: What the Lives of Wild Animals Can Teach Us About Care of Laboratory Animals Kay E. Holekamp   169 SESSION 5:  ENVIRONMENTAL ENRICHMENT ISSUES   175     Enriching the Housing of the Laboratory Rodent: How Might It Affect Research Outcomes? William T. Greenough and Ann Benefiel   177     Search for Optimal Enrichment Timo Nevalainen   184     Breakout Session: Environmental Enrichment Issues: Mice/Rats/Rabbits   189     Breakout Session: Environmental Enrichment for Dogs and Cats   191     Breakout Session: Assessment of Nonhuman Primate Enrichment—Science Versus Welfare Concerns   193

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop POINT/COUNTERPOINT: THE CASES FOR AND AGAINST HARMONIZATION   199     Point/Counterpoint: The Cases For and Against Harmonization William S. Stokes   201 APPENDIX A:   International Workshop on Development of Science-based Guidelines for Laboratory Animal Care   227 APPENDIX B:   Workshop Faculty   232 APPENDIX C:   Committee Bios   238 APPENDIX D:   International Guiding Principles for Biomedical Research Involving Animals (1985)   240