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Microbial and Phenotypic Definition of Rats and Mice Proceedings of the 1998 US/Japan Conference International Committee of the Institute for Laboratory Animal Research National Research Council NATIONAL ACADEMY PRESS Washington, D.C.
NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NW Washington, DC 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 competences and with regard for appropriate balance. This study was supported by Grant No. P40-RR-11611 between the National Academy of Sciences and the National Institutes of Health. Any opinions, findings, conclusions, or recommenda- tions 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 0-309-06591-7 Copyright 1999 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.
INTERNATIONAL COMMITTEE OF THE INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL Christian R. Abee (Chair), Department of Comparative Medicine, University of South Alabama, Mobile, AL Hilton J. Klein, Department of Laboratory Animal Resources, Merck Research Laboratories, West Point, PA William Morton, Regional Primate Research Center, University of Washington, Seattle, WA Robert J. Russell, Harlan Sprague Dawley, Inc., Indianapolis, IN William S. Stokes, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC John L. VandeBerg, Southwest Foundation for Biomedical Research, San Antonio, TX Peter A. Ward, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI Staff Ralph B. Dell, Director Kathleen A. Beil, Administrative Assistant Susan S. Vaupel, Managing Editor, ILAR Journal Marsha K. Williams, Project Assistant iii
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distin- guished 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 Na- tional 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. William 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. Kenneth I. Shine 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 Academyâs 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. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council. iv
Preface US-Japan meetings on laboratory animal science have been held virtually every year since 1980 under the US-Japan Cooperative Program on Science and Technology. Over the years these meetings have resulted in a number of impor- tant documents including the Manual of Microbiologic Monitoring of Laboratory Animals published in 1994 and the article Establishment and Preservation of Reference Inbred Strains of Rats for General Purposes published in 1991. In addition to these publications, these meetings have been instrumental in increas- ing awareness of the need for microbiologic monitoring of laboratory rodents and the need for genetic definition and monitoring of mice and rats. In cooperation with the Comparative Medicine section of NCRR/NIH, ILAR Council and staff are pleased to become the host for this important annual meeting and look forward to participating in future meetings. The support and sponsor- ship of NCRR (P40 RR 11611) in the United States and the Central Institute for Experimental Animals in Japan are gratefully acknowledged. These meetings have increased understanding of American and Japanese approaches to labora- tory animal science and should continue to strengthen efforts to harmonize ap- proaches aimed at resolving common challenges in the use of animal models for biomedical research and testing. This effort to improve understanding and coop- eration between Japan and the United States should also be useful in developing similar interaction with other regions of the world including Europe, Australia, and Southeast Asia. Christian R. Abee, Chair International Committee of the Institute for Laboratory Animal Research v
Contents Opening Remarks 1 Shin-ichi Ota Historical Overview, 1 Expectations, 2 References, 2 Opening Remarks 3 Judith L. Vaitukaitis The Need for Defined Rats and Mice in Biomedical Research: Problems, Issues, and the Current State of Affairs 5 Tatsuji Nomura Introduction, 5 Participants and Format, 5 Standardization and Quality, 6 Questions and Answers, 6 The Need for Defined Rats and Mice in Biomedical Research: Problems, Issues, and the Current State of Affairs 7 Norikazu Tamaoki Global Health Issue and the Necessity of Laboratory Animals, 7 Importance of Laboratory Animals for Human Health, 7 Laboratory Animal Models in Major Disease Categories, 8 Aspects of Future Laboratory Animal Use, 10 Questions and Answers, 10 References, 11 vii
viii CONTENTS The Biological Integrity of Laboratory Rodents 12 Robert O. Jacoby References, 14 Quality Testing System for SPF Animals in Japan and Problems in the Management of Such Systems 15 Toshio Itoh Role of the ICLAS Monitoring Center in the Quality Control System of Laboratory Animals, 15 Microbiological Monitoring System of the ICLAS Monitoring Center, 16 Microbiological Contamination of Laboratory Animals in Japan, 17 Conclusion, 22 References, 23 Definition of Microbiological Status of Rats and Mice / The Need for Methods of Defining Flora / International Standards for Terminology 24 Kazuaki Mannen Current Status of Microbiological Quality of Laboratory Animals in University Animal Centers in Japan, 24 Importance of Identifying Contamination, 25 Development of Rodent Pathogen Profiles and Adequacy of Detection Technology 28 Steven H. Weisbroth Problematic Issues, 36 References, 38 Current Status of Pathogen Status in Mice and Rats 39 J. Russell Lindsey Past Progress toward Reducing Pathogens, 39 Pathogens Still Pose Pervasive Risks in the United States, 40 Pathogen Status Gets Lost in the Terminology Morass, 40 Principles of Pathogen Status Are Being Compromised, 41 Scientists Have Little Appreciation of Pathogen Status, 41 References, 42 Genetic Background and Phenotypes in Animal Models of Human Diseases 44 Kuzuo Moriwaki Development of Experimental Mouse Strains, 44 Transgenic and Knockout Mice, 45 Recombinant Inbred Strains, 45 Common Disease Models, 46 Conclusion, 46 References, 47
CONTENTS ix Genetic and Phenotypic Definition of Laboratory Mice and Rats / What Constitutes an Acceptable Genetic-Phenotypic Definition 48 Hideki Katoh Genetic Studies on Closed Colonies of the Rat, 48 Human Ancestry, 48 Laboratory Animals, 51 Demonstration of the Existence of Closed Colonies Using Genetic Monitoring, 52 Summary and Discussion, 54 References, 57 Phenotype Assessment Requires More Than a Casual Observation 58 Philip A. Wood Primary Level Assessment: Find Abnormalities, 59 Secondary Level Assessment: Evaluate and Quantify Abnormalities, 59 Environmental Influences, 61 Examples, 61 References, 62 Genetic and Phenotypic Definition of Laboratory Mice and Rats / What Constitutes an Acceptable Genetic-Phenotypic Definition 63 Muriel T. Davisson Genetically Defined Mice, 63 Genetic Standardization, 63 Genetic Nomenclature, 64 Definition and Value of Different Kinds of Strains, 65 Genetic Monitoring, 67 Genetic Databases, 68 Training Scientists to Use Genetically Defined Mice, 70 References, 70 Genetic and Phenotypic Definition of Laboratory Mice and Rats / What Constitutes an Acceptable Genetic-Phenotypic Definition 71 Joseph DeGeorge Necessity for Globally Standardized Outbred Rats for Carcinogenicity Bioassay, 71 Change in Laboratory Animal Science, 71 Globalization of Drug Development, 72 Segmentation of Toxicology Testing, 72 Need for Integrated Findings, 74 Managing Changes Over Time, 74
x CONTENTS CIEA/NCRR/NIH Genetic and Microbiological Monitoring of Mouse and Rat Resources: Directions for the Future 76 Tatsuji Nomura Differences Between Countries, 76 Questions and Answers, 77 CIEA/NCRR/NIH Genetic and Microbiological Monitoring of Mouse and Rat Resources: Directions for the Future 78 Neal West NIH Structure, 78 NCRRâs Mission, 78 Database Recommendation, 80 Questions and Answers, 80 Learning from Each Other, 81 Policy Setting, 81 Reference, 82 Closing Comments / Summary of Presentations 83 Thomas J. Gill III Introduction, 83 Need for Genetically Defined Animals, 83 Development of Genetically Engineered Animals, 84 Importance of Disease Models, 86 Standardization and Monitoring, 87 Rat Repository Workshop, 87 National Rat Genetics Resources Center, 88 Recommendations, 89 Summary of Presentations 90 Steven P. Pakes Current Status of Laboratory Animal Science, 90 Revitalization of Original Focus, 90 Future Cooperation, 91 Summary of Presentations 92 Tatsuji Nomura Laboratory Animal Science: 1950s to 1990s, 92 Genetically Engineered Animals, 93 Conclusion, 94 Appendix A: US/Japan Meeting Agenda 95 Appendix B: Meeting Participants 98