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ILAR Journal V32(4) 1990
Issues for Institutional Animal Care and Use Committees (IACUCs)

Important Laboratory Animal Resources: Selection Criteria and Funding Mechanisms for Their Preservation

Committee on Preservation of Laboratory Animal Resources
Institute of Laboratory Animal Resources
Commission on Life Sciences
National Research Council

Reprinted from ILAR News, Volume 32, Number 4, 1990

NATIONAL ACADEMY PRESS
Washington, D.C. 1991

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 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, the National Academy of Engineering, and the Institute of Medicine.

The National Academy of Sciences is a private. non-profit, 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. Frank Press 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. Robert M. White 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. Samuel 0. Thier 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 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 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. Frank Press and Dr. Robert M. White are chairman and vice-chairman, respectively, of the National Research Council.

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 serves as a coordinating agency and a national and international resource for compiling and disseminating information on laboratory animals, promoting education, planning and conducting conferences and symposia, surveying existing and required facilities and resources, upgrading laboratory animal resources, and promoting high-quality, humane care of laboratory animals in the United States.

This study has been supported by the National Research Council Fund, a pool of private, discretionary, nonfederal funds that is used to support a program of Academy-initiated studies of national issues in which science and technology figure significantly. The NRC Fund consists of contributions from a consortium of private foundations, including the Carnegie Corporation of New York, the Charles E. Culpeper Foundation, the William and Flora Hewlett Foundation, the John D. and Catherine T. MacArthur Foundation, the Andrew W. Mellon Foundation, the Rockefeller Foundation, and the Alfred P. Sloan Foundation; the Academy Industry Program, which seeks annual contributions from companies that are concerned with the health of U.S. science and technology and with public policy issues with technological content; and the National Academy of Sciences and the National Academy of Engineering endowments.

Available from

Institute of Laboratory Animal Resources
2101 Constitution Avenue, NW
Washington, DC 20418

******************

This report is fondly dedicated to the memory of

DOROTHEA BENNETT

December 1929-August 1990

Her contributions to science and her humanity will not be forgotten.

*******************

Committee on Preservation of Laboratory Animal Resources

Dorothea Bennett (Chairman), Department of Zoology, University of Texas, Austin (Deceased)
Linda C: Cork, Division of Comparative Medicine, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Thomas J. Gill III. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Jon W. Gordon, Department of Obstetrics and Gynecology, Mt. Sinai School of Medicine, New York, New York
Andrew G. Hendrickx, California Primate Research Center, University of California, Davis
Larry E. Mobraaten, The Jackson Laboratory, Bar Harbor, Maine
John L. VandeBerg, Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas

Staff
Dorothy D. Greenhouse, Senior Program Officer

Institute of Laboratory Animal Resources Council
Steven P. Pakes (Chairman), The University of Texas Southwestern Medical Center, Dallas
June R. Aprille, Tufts University, Medford, Massachusetts
Melvin W. Balk, Charles River Laboratories, Inc., Wilmington, Massachusetts
Douglas M. Bowden, University of Washington, Seattle
Lester M. Crawford, U.S. Department of Agriculture, Washington, D.C.
Thomas J. Gill III, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Alan M. Goldberg, The Johns Hopkins University, Baltimore, Maryland
Jon W. Gordon, Mt. Sinai School of Medicine, New York, New York
Margaret Z. Jones, Michigan State University, East Lansing
Michael D. Kastello, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey
Robert H. Purcell, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
Fred W. Quimby, New York State College of Veterinary Medicine, Cornell University, Ithaca
J. Wesley Robb, School of Medicine, University of Southern California, Los Angeles
John L. VandeBerg, Southwest Foundation for Biomedical Research, San Antonio, Texas

Staff
Thomas L. Wolfle, Director

Commission on Life Sciences

Bruce M. Alberts (Chairman), University of California, San Francisco
Bruce N. Ames, University of California, Berkeley
Francisco J. Ayala, University of California, Irvine
J. Michael Bishop, University of California Medical Center, San Francisco
Michael T. Clegg, University of California, Riverside Glenn A. Crosby, Washington State University, Pullman
Freeman J. Dyson, The Institute for Advanced Study, Princeton, New Jersey
Leroy E. Hood, California Institute of Technology, Pasadena
Donald F. Hornig, Harvard University School of Public Health, Boston, Massachusetts
Marian E. Koshland, University of California, Berkeley
Richard E. Lenski, University of California, Irvine
Steven P. Pakes, The University of Texas Southwestern Medical Center, Dallas
Emil A. Pfitzer, Hoffmann-LaRoche, Inc., Nutley, New Jersey
Thomas D. Pollard, The Johns Hopkins University, Baltimore, Maryland
Joseph E. Rall, National Institutes of Health, Bethesda, Maryland
Richard D. Remington, University of Iowa, Iowa City
Paul G. Risser, University of New Mexico, Albuquerque
Harold M. Schmeck, Jr., Armonk, New York
Richard B. Setlow, Brookhaven National Laboratory, Upton, New York
Carla J. Shatz, Stanford University School of Medicine, Stanford, California
Torsten N. Wiesel, Rockefeller University, New York, New York

Staff
John E. Burris, Executive Director

Preface

The Committee on Preservation of Laboratory Animal Resources was formed in response to the perception that some genetically unique animal models have been lost or are at risk, partly because of financial problems but also for other reasons such as the death or retirement of scientists responsible for specific stocks. The committee was organized in the Institute of Laboratory Animal Resources of the National Research Council's Commission on Life Sciences and was charged with documenting animal models and resources lost as a result of inadequate funding or for other reasons, evaluating the long-term effects of such losses on the biomedical research effort, assessing existing animal resources and the current mechanisms for maintaining them, and recommending procedures by which genetic stocks might be preserved cost-effectively. The charge did not include consideration of the genetically unique colonies maintained for U.S. Department of Agriculture-sponsored work on farm production animals. The committee was composed of scientists who have the expertise required to develop a rational system for evaluating animal models and resources worthy of retention. Furthermore, all members maintain animal resource colonies.

We on the committee investigated the types and extent of animal model losses in the past, but we found few hard facts and little documentation to guide us in assessing the magnitude or importance of these losses. Accordingly, to establish a base of information in this area, we used our own professional experience supplemented by interviews with scientists knowledgeable about animal models, including investigators who had either lost animal colonies or considered their current resources to be at risk, scientists at several federal agencies and private organizations that fund research with animals; and a scientist employed by a commercial animal supplier. We obtained clear evidence that some unique animal colonies have been lost, but the data were insufficient to allow a retrospective determination of the impact of these previous losses on the overall scientific effort. We did, however, identify significant inadequacies in the current system of animal model preservation. An obvious deficiency is the lack of a national oversight body that is responsible for assessing the relative value of animal models and resources or for preserving models of true importance. Thus, there exists a substantial risk that valuable resources will be lost. With the ever-increasing need for well-characterized animal models in biomedical research, and in consideration of the time and labor required to develop such models, it is essential to protect against future losses. Furthermore, the committee concluded that the dramatic changes in biological research resulting from the use of the powerful tools of molecular biology make it even more critical to refine and to strengthen the management of animal models; in many instances the results of molecular biological research are valuable only in relation to well-defined genetic and physiologic characteristics of the organisms from which the DNA was obtained.

To reduce the risk of losing valuable animal models, a long-term, stable, centralized program for safeguarding our national laboratory animal resources is necessary. Because the funds for scientific research are limited, our goal has been to devise an approach that depends in part on the more cost-effective use of existing financial resources. We also recognize that the simple allocation of funds, without sufficient attention to organizational aspects. is not likely to be effective.

Our proposal includes the identification and implementation of criteria for selecting the most desirable animal resources for preservation, procedures for assessing and supporting investigator-maintained animal resources, centralization of some facilities for preserving animal resources, and establishment of national advisory panels to monitor these functions. It behooves us to seek all innovative and practical means to ensure retention of stocks that might prove invaluable to future generations of scientists. Thus, special consideration was given to the use of new techniques, such as frozen embryo storage, for the preservation of animal models. It is also of the utmost importance that the quality of long-term maintenance be sufficient to guarantee that preserved stocks exhibit, both with continuity and predictability, the characteristics that make them important as research tools. Elements of our proposal are intended to accomplish this objective.

The committee expresses its thanks to the people who appeared before the committee or provided information on specific animal colonies that can be found in the appendixes to this report. The committee, however, is responsible for all views and statements of fact in the report.

The committee also acknowledges the assistance of the professional and administrative staff of the Institute of Laboratory Animal Resources and the Commission on Life Sciences.

Dorothea Bennett, Chairman
Committee on Preservation of Laboratory Animal Resources

Contents

Introduction

Animal Resources Recommendations Summary References

Appendix I: Biographical Sketches of Committee Members
Appendix II: Scientists Who Formally Addressed the Committee
Appendix III: Examples of Animal Resources That Have Been Lost
Appendix IV: Examples of Animal Resources That Are at Risk
Appendix V: Annual Cost in 1989 Dollars and Cost-Effectiveness of Existing Animal Resources

Tables

Introduction

Animal models play an important role in scientists' efforts to conquer disease and to understand the basic processes of life. Animal models with specific genetic characteristics have been developed to study many important biological processes, including basic mechanisms of physiology and heredity, pathogenesis of disease, environmental effects on health, and efficacy of drugs and their mechanisms of action. Such experiments often cannot be done with human subjects; thus, the knowledge gained from animal studies provides the primary basis for understanding similar processes in humans. Extensive effort has been expended over many years to identify, develop, and make available the most effective animal models for intended areas of study. Nevertheless, some of these animal resources are at risk or are being lost.

In this report the Institute of Laboratory Animal Resources (ILAR) Committee on Preservation of Laboratory Animal Resources provides a set of basic criteria for assessing the value of an animal model and a framework for a system to maintain particularly valuable animal resources.

SOURCES OF INFORMATION

The committee encountered great difficulty in obtaining accurate and detailed information about the number and types of animals used in research and the kinds of research in which they are used. The problem is a general one that faces anyone who attempts to enumerate or classify animal use. Animals are used for research, testing, and teaching in academic, government, and industrial settings. Regular surveys of animal use, facilities, and resources have been conducted by ILAR for many years, most recently in 1978 (ILAR, 1980), and by other organizations, but the comprehensiveness of these surveys has been questioned (OTA, 1986). The Animal and Plant Health Inspection Service (APHIS) of the U.S. Department of Agriculture regulates the laboratory use of most warm-blooded animal species and maintains a data file on the numbers of those animals used. However, APHIS does not regulate the care and use of rats and mice, the most commonly used research animals, and reporting of numbers of these animals used is voluntary.

Table 1 presents estimates of animals used in the United States as determined by surveys conducted by ILAR and Health Designs, Inc., Rochester, New York, and by data collected by APHIS for fiscal years 1978 through 1989. The numbers provide a general idea of the extent of animal use, but they do not provide insight into the topic of specific interest to the committee, that is, how many of these animals are part of genetically unique animal colonies. The most complete listing of such colonies, to the committee's knowledge, is that compiled by ILAR in its Animal Models and Genetic Stocks Information Program database. The data in Table 2 are derived from the ILAR database and provide information on the number of sites at which breeding colonies of mice and rats are kept. It must be understood that many strains might be held at a particular site; for example, the one private, nonprofit site has hundreds of strains. Further analysis of the database yields the information presented in Table 3, which shows the number of rodent strains so unique that they are held by only one or two scientists or institutions in the country. However. the database did not arise from a comprehensive survey of rodent colonies in the United States; therefore, the numbers in Tables 2 and 3 might be lower than the actual numbers.

The important points of information that are not fully documented are as follows:

The ILAR Committee on National Survey of Animal Use, Facilities, and Resources, which was formed in 1985 to prepare a survey instrument for use by the National Institutes of Health (NIH), was asked to consider whether it would be possible to obtain such information. This committee concluded that collecting these detailed data would be costly in terms of money, resources, and time and might still result in incomplete data (D. D. Greenhouse, ILAR staff, personal communication).

In the absence of any comprehensive data on animal use in general, much less on the use of genetically unique animals, the committee members relied in part on their own experience, which includes research with mice, rats, rabbits, dogs, cats, marsupials, and nonhuman primates. One member is responsible for the largest mouse embryo-freezing facility in the United States. (See Appendix I for a biographical sketch of each committee member.)

In addition, the committee drew on the experience of ILAR staff and information from other working scientists with expertise in maintaining animal resource colonies, representatives from government agencies and private organizations, and a representative of a commercial animal supplier. The scientists who made formal presentations to the committee, along with their areas of expertise, are listed in Appendix II. Other scientists, who provided information by mail or telephone, are listed in Appendixes III and IV. The committee thanks these people for sharing their knowledge, experience. and wisdom. The conclusions reached and recommendations made in this report, however, are solely the responsibility of the committee.

TABLE 1 Various Estimates of the Numbers of Animals Used in the United States

ILAR, FY 1978a
APHIS FY 1982b
Health Designs (est.), 1983c
APHIS, FY 1984b
APHIS, FY 1986b
APHIS, FY 1989b
Animal
Mice
13,413,813
-
8,500,000
-
-
-
Rats
4,358,766
-
3,700,000
-
-
-
Hamsters
368,934
337,790
454,479
437,123
370,655
389,042
Guinea pigs
426,665
459,246
521,237
561,184
462,699
481,712
Other rodents
79,993
-
-
-
-
-
Rabbits
439,986
453,506
509,052
529,101
521,773
471,037
Cats
54,908
49,923
55,346
56,910
54,125
50,812
Dogs
183,063
161,396
182,245
201,936
176,141
156,443
Other carnivores
4,990
-
-
-
-
-
Ungulates
144,595
-
-
-
-
-
Nonhuman primates
30,323
46,388
59,336
55,338
48,540
51,688
Birds
450,352
-
100,000d
-
-
-
Amphibians
-
-
500,000d
-
-
-
Fish
-
-
4,000,000d
-
-
-
Wild animals
-
69,043
-
232,541
144,470
153,722
Total
19,956,388
1,576,556e
18,581,875
2,074,133e
1,778,403e
1,754,456e

APHIS, Animal and Plant Health Inspection Service; ILAR, Institute of Laboratory Animal Resources.

aFrom National Research Council. 1980. P. 32 in National Survey of Laboratory Animal Facilities and Resources: Fiscal Year 1978. A report of the Institute of Laboratory Animal Resources Committee an Laboratory Animal Facilities and Resources. NIH Pub. No. 80-2091. Washington, D.C.: U.S. Department of Health and Human Services.
bFrom Animal and Plant Health Inspection Service. 1983-1990. Animal Welfare Enforcement. Fiscal Years 1982, 1984, 1986, 1989. Reports made by the Secretary of Agriculture to the President of the Senate and the Speaker of the House of Representatives. Washington, D.C.: U.S. Department of Agriculture. Reporting of mice and rats is voluntary. and data on these animals are not included in the annual reports.
cFrom the Office of Technology Assessment (OTA). 1986. P. 60 in Alternatives to Animal Use in Research, Testing. and Education. Pub. No. OTA-BA-273. Washington, D.C.: U.S. Congress. Data we estimates from a 1984 report entitled Survey and Estimates of Laboratory Animal Use in the United States, which was prepared by Health Designs. Inc., Rochester. New York for OTA.
dEstimates are the highest of a rough range.
eTotal does not include numbers for mice and rats.

TABLE 2 Number of Sites at Which Colonies of Mice and Rats Are Held in the United Statesa
HolderMouse ColoniesRat Colonies
Commercial
17
8
Individual
134
39
Government
3
3
Private nonprofit
1
-
Total
155
50

aNumerous individual strains may be held at a site.

TABLE 3 Number of Strains of Mice and Rats in the United States Held by Only One or Two Scientists or Institutions
MiceRats
HoldersOneTwoOneTwo
Inbred strains
101
19
47
15
Recombinant inbred strains
226a
-
-
-
Congenic strains
322
46
28
-
Mutants
207
121
22
5

aAll these strains are held by a total of six holders.

Animal Resources

LOSSES OF ANIMAL MODELS AND RESOURCES

Data do not exist to permit construction of a comprehensive list of past losses of animal resources. Numerous examples, however, were brought to the attention of the committee. They included the loss of inbred and congenic strains of mice, rats, guinea pigs, hamsters, rabbits, and swine, as well as several colonies of mutant cats and dogs (see Appendix III).

In one example, Dr. John Neefe, then at Georgetown University, and Dr. Bruce Mauer, then at Litton Bionetics Laboratory, Kensington, Maryland, accumulated after several years of breeding and selection several rhesus families that had been typed for the rhesus major histocompatibility complex (MHC). These families were unique in that they had been defined as having an array of specific haplotypes for the Class I and Class II MHC antigens. In 1979 the Neefe-Mauer laboratory was disbanded. Personal attempts by Dr. W. H. Stone, then at the University of Wisconsin, to obtain funds from NIH to transfer the rhesus families to Wisconsin were unsuccessful. The monkeys were utilized in other projects and thus were lost to research on the MHC. The rhesus MHC was being intensively investigated by only one other laboratory, headed by Dr. H. Bainer in the Netherlands, and that laboratory also terminated work in this area a few years later. Although MHC-characterized rhesus monkeys would have been valuable for a variety of research purposes, the significance of their loss is highlighted by the advent of the acquired immune deficiency syndrome (AIDS) and its rhesus model, simian acquired immune deficiency syndrome (SAIDS). Research on how genetic variation of the MHC affects susceptibility to SAIDS and the course of this disease might well have increased our understanding of immune mechanisms in relation to AIDS.

Although some of the animal resources listed in Appendix III might have been very useful had they continued to exist, the committee could not retroactively assess the impact of these losses on biomedical research. It is clear, however, that the loss of these stocks took place in the absence of a mechanism to assess their value and without a system for preserving those colonies that warranted preservation.

The committee also is concerned that some existing animal resource colonies are threatened with termination (see Appendix IV) without rigorous evaluation using standardized criteria.

ASSESSMENT OF EXISTING ANIMAL RESOURCES

Maintenance and Preservation of Laboratory Animal Resources

Laboratory animal resources are usually preserved as breeding colonies of animals. However, the strategies for maintaining resources actively used in research are quite different from those for the long-term preservation of potentially valuable resources that are not currently in use. In the former instance, the objective is to make available to the scientific community in a cost-effective manner adequate numbers of animals of an assured genetic integrity.

The long-term preservation of resources for future use is a distinct goal that requires a different approach from the production of animals for current research. Traditionally, animals have been preserved for future use by painstaking maintenance of small breeding colonies. Animal stocks of many species, including mice, rats, rabbits, sheep, goats, and cows, can now be preserved by freezing of embryos, and cryopreservation programs for inbred strains of mice are already well established. However, maintaining minimal numbers of breeding animals is the only practical approach for preserving stocks of such species as dogs, domestic cats, swine, and nonhuman primates, for which cryopreservation methods have not yet been perfected. Freezing of sperm is practical for only a few species and has limited utility. Specific genotypes can be preserved in this manner, but an inbred strain cannot be reconstituted from a haploid gamete. Oocyte freezing is not now practical.

Cryopreservation methods, where applicable, can be a significant, cost-effective means of long-term preservation. The methodology is still under development, and because the principles of cryobiology are becoming better understood, it is likely that this technology will become feasible for additional animal resources.

General Problems Associated with Preserving Laboratory Animal Resources

The committee identified several general problems associated with preserving laboratory animal resources. Some of these result from the absence of a framework for decision-making and management. Others are related to financial issues. These include the following:


The committee recognizes that although the problems listed above are general ones, shared by all investigators who depend on animal resources in their research, the relative importance of each problem differs markedly depending on the species used.

CURRENT MECHANISMS FOR MAINTAINING ANIMAL RESOURCES

We on the committee examined the spectrum of organizations that have a programmatic interest in preserving animal resources to determine how these involved entities might play a role in any solution we recommend.

Investigator-Managed Colonies

Many laboratory animal resources are in investigator-managed colonies, which are supported primarily by investigator-initiated research grants or contracts. Thus, an essential component of any system developed for preserving laboratory animal resources is the support of these specialized animal models for specific research problems. Each investigator either has acquired wild animals for developing the stock, has developed the stock from existing laboratory animals by a specifically devised breeding program, or has used a combination of these two strategies. In so doing, the investigator has developed highly specialized expertise in the production and genetic management of the stock and in its experimental manipulation. As such stocks become known in the broader scientific community, it is common for other investigators to wish to obtain experimental animals or breeding nuclei of that stock, to obtain advice on its maintenance or experimental use, or to conduct experiments at the developer's laboratory, where specific animal needs (e.g., mothers with newborns) are more easily met and where expertise for specific manipulations (e.g., anesthesia and surgery) is readily available. Over a period of years, the nationwide value of such a resource to research in a variety of disciplines commonly transcends the value of the stock to the investigator who developed it for a single experimental purpose.

Federal Agencies

NIH Extramural Program

The NIH is the primary source of support to individual investigators for developing and maintaining laboratory animal (i.e., investigator-managed animal resources). Although NIH grant and contract support is substantial, it is generally targeted toward the research and not toward the animal resource that makes the research possible. Thus, such support seldom provides the stability required for the long-term preservation of many resources. Furthermore, the responsibility for preserving laboratory animal resources has not been assigned to a specific NIH institute or to the National Center for Research Resources (NCRR),1 Extramural Research Resources (ERR). Nonetheless, ERR has continued to support the development of animal models and has provided limited funding for maintaining selected animal resources, despite an increasingly restricted budget. Generally, ERR funds the development of animal models with the expectation that once established the model will become self-supporting or be supported by another NIH institute.

NIH Intramural Program

Intramural Research Resources (IRR), Veterinary Resources Program (VRP) maintains a variety of animal species primarily for intramural use. It is not intended to serve as a repository for stocks from outside investigators. Decisions regarding which new stocks to acquire and retain are largely determined by NIH needs. The IRR does supply breeding nuclei of rodents to outside laboratories and, in this sense, serves as a national resource. However, its usefulness to the general scientific community is limited because IRR/VRP is primarily responsive to intramural needs. With the merging of intramural and extramural research resources, and the enhanced liaison between the intramural program and the scientific community afforded by it, it is hoped that IRR will come to know the needs of the extramural community. Through this mechanism the unique resources of IRR/VRP will become increasingly valuable to the extramural community.

National Science Foundation

The National Science Foundation (NSF) has a Biological Research Resources Program whose budget includes funds for Living Organism Stock Centers. About $1.5 million is spent annually on such stock centers for organisms from bacteria and algae to mice and primates. The intention of NSF is to maintain these stocks in as stable a manner as possible, but only if the center is used primarily to distribute organisms to investigators funded by NSF. Thus, although this is a valuable program, total funding is small and of limited availability.

Other Organizations

Academic and Research Institutions

Limited financial support may be provided by an investigator's institution. However, this support usually covers only a small fraction of the cost of maintaining an animal colony and almost invariably terminates when an investigator leaves or retires. In addition, if an institution contributes significantly to supporting a resource, it generally does so with the mission of facilitating research at that institution and not with the goal of providing a national resource for the general scientific community. The most realistic role for these institutions in maintaining national animal resources is in conjunction with federal, and possibly private, support.

Nonprofit Granting Organizations

Of the private, nonprofit granting organizations, the American Cancer Society (ACS) is a potential source of support for stocks that have particular relevance to cancer or to growth-related or developmental phenomena. In addition to its regular grants system, the ACS has a special Research Development Program, which has an average application-to-funding time of 55 days. However, the program only supports projects for 12-18 months, and applications for resource support must compete with research proposals aimed more directly at answering specific questions pertaining to cancer.

Commercial Organizations

Private companies can provide support for stocks where potential exists for developing a stock into a commercially successful enterprise or where large numbers of a stock or species are required for testing drugs or other products. Companies can produce specific stocks for sale to investigators and occasionally provide support to investigator-managed laboratory animal resources. Only a limited number of stocks or investigator-managed laboratory animal resources, however, have commercial potential. Often, volume demand is low, even when the scientific value of a stock is high. This form of support is inherently unstable, because it is driven by market forces, not by scientific priorities.

1The NCRR was formed on February 15, 1989, by merging the NIH's extramural Division of Research Resources (now called Extramural Research Resources) and intramural Division of Research Services (now called Intramural Research Resources). The mission of NCRR combines the missions of its predecessor organizations: It administers, fosters, and supports research on, and development and support of. multi-categorical research resources needed on an institutional, regional, national, or international basis for health-related research."

Recommendations

The committee recommends that a long-term, stable, integrated program for safeguarding our national animal resources be established. The program should include mechanisms for identifying valuable animal resources, maintaining and preserving these resources, and providing for their financial support. The features of this program are described below.

CRITERIA FOR IDENTIFICATION OF VALUABLE ANIMAL RESOURCES

The committee emphasizes that not every animal model or colony should be designated for preservation. The program for preserving animal resources should be a rational one. Every animal model or colony that is considered for preservation should be rigorously evaluated on the basis of established criteria.

The committee recommends the following criteria for identifying valuable laboratory animal resources:

MECHANISMS FOR SUPPORTING LABORATORY ANIMAL RESOURCES

Having established criteria for evaluating animal models, the committee proposes that resources be preserved by implementation of two major new programs. The first is the initiation of a system of dual review of research grants that specifically includes consideration of investigator-managed animal colonies, which constitute the most important source of valuable animal models. The second is the establishment of a National Center for Laboratory Animal Resources that can serve as a stable repository for certain key animal models.

DUAL REVIEW OF REQUESTS FOR SUPPORT OF RESEARCH INVOLVING INVESTIGATOR-MANAGED ANIMAL RESOURCES

Funds should be allocated specifically for developing and preserving important laboratory animal resources that a maintained in investigator-managed facilities. Such funds should be administered through a competitive grants program reviewed by an appropriately constituted review group (see below). In the case of NIH, these funds should be administered conjointly by all the institutes in order to provide a single focus of responsibility for federally funded research that requires animal resources.

A Review Group for Laboratory Animal Preservation should be established to evaluate grant proposals that request funds to support investigator-managed resources. The group should be composed primarily of scientists who use animals in their own research. These scientists should represent a broad range of disciplines, including the study of pathogenesis of disease, basic physiologic processes, and fundamental genetics. In addition, there should be at least one geneticist who is capable of evaluating the genetic quality of the animals in a resource and at least one laboratory animal scientist who is capable of evaluating the health of the animals and the husbandry procedures for maintaining them. It will be the responsibility of this group to apply uniformly the Criteria for Evaluating Animal Resources described previously. In addition to reviewing the merits of a resource application, the Review Group for Laboratory Animal Preservation could, if deemed preferable, recommend that the proposed resource be maintained at some other established facility. Funding for any species or stock developed by an individual investigator could be requested on the basis of its punitive value as a national animal resource.

Applications for support of an investigator-managed animal resource, whether or not they are submitted in conjunction with an application for associated research, should be reviewed by the proposed new review group. Applications seeking support for both research and resource components would also be reviewed by the appropriate study section. Applicants preparing proposals with a resource component should describe and document the resource according to the criteria outlined above. In order to provide stability to NIH-supported resource colonies, grants should generally be made for a period of 5 years between competing renewals, irrespective of the duration of funding for the research component.

Although the review group would be organized at NIH, other federal agencies such as NSF and the Department of Energy might use this panel or a similarly constituted panel or consultants for the review of applications containing requests for support of animal resources.

While recognizing that many worthwhile goals in biomedical research exist and that financial resources are limited, the committee recommends that adequate financial support be designated specifically for the maintenance of investigator-managed animal resources because of the unique nature of many of these resources and their value to the advance of research.

The committee recommends the establishment of a Review Group for Laboratory Animal Preservation that will evaluate requests for support from the funds designated for investigator-managed resources.

NATIONAL CENTER FOR LABORATORY ANIMAL RESOURCES

A large number of inbred, congenic, and recombinant inbred strains and some unique stocks are essential for genetic studies, the development of animal models of diseases, and the study of normal physiologic functions. Many of these animals are not used consistently in large numbers, so commercial breeders do not maintain them. They also might not be used continuously enough by any one investigator to warrant maintaining them as an investigator-managed resource. It is in such situations that a national center would fulfill a major need.

A National Center for Laboratory Animal Resources would provide a source of genetically defined and appropriately monitored animals to ensure quality control and cost-effective maintenance. It could also hold duplicates of valuable animal resources so that if individual colonies housing such animals were lost, the resource would still survive. The center could distribute these animals for experimental purposes or as breeding nuclei.

In addition to distributing animals, the center would be a source of information about the various strains and stocks and would work actively to develop new and useful animal resources and unique methods of preserving them (e.g., cryopreservation). The center could form the core of a network of resource colonies, both commercial and investigator based, to provide extensive national coordination of laboratory animal resources.

A logical place to establish a National Center for Laboratory Animal Resources is the NIH because it is the major source of funding for biomedical research. Although NCRR has certain programs that contribute to preservation of selected animal resources, it does not fulfill the mission of the proposed new center. Not all of the resources need be kept at NIH; some of them could be maintained by contract with individual laboratories and research centers, as is presently the case for the Regional Primate Research Centers. Since the national center would be a resource for the entire biomedical research community, funding could be drawn from each of the institutes of NIH, as well as from other government funding agencies.

The committee recommends the establishment of a National Center for Laboratory Animal Resources. Because NIH has a prominent role in the conduct of research involving animals and in the funding of such research, it is recommended that the national center be located at NIH and perform the following functions:

Advisory Committee for the National Center for Laboratory Animal Resources

A critical part of the structure of the national center should be an advisory committee to set policy and make decisions about which species and which strains and stocks within a species should be maintained and what new animal resources should be developed. This advisory committee should be distinct from the Review Group for Laboratory Animal Preservation, although it should be composed of scientists with a similar scope of expertise. A committee with such a composition is critical to the success of the National Center for Laboratory Animal Resources. This advisory committee will represent the scientific community and will ensure appropriate oversight of the hard decisions that are essential in allocating limited resources.

The committee recommends the establishment of an advisory committee for the National Center for Laboratory Animal Resources. The advisory committee should set policy and make decisions for the national center in fulfilling the functions described above. This committee should be composed primarily of scientists who use animals in their own research. The qualifications of the members should be the same as those suggested for the members of the Review Group for Laboratory Animal Resources.

COST-EFFECTIVENESS OF RECOMMENDATIONS

The system recommended in this report should not greatly increase the overall amount spent for animal resources since the present system is inefficient and has large hidden costs that result in duplication of support for maintaining animal models and animal colonies. An important cost-effective aspect of the system proposed by the committee is that only animal resources that merit support, as determined by an appropriate group using objective criteria, will receive such support.

It is the consensus of the committee members that these recommendations are realistic and cost-effective and can provide the basis for many research initiatives. We believe the necessary investment, including the costs of operating the committees suggested in this report, will be offset in part by savings of funds currently committed. For example:

Some examples of costs associated with maintaining particular animal resources are provided in Appendix V, along with some comments about the cost-effectiveness of those resources.

SUMMARY

The task of the ILAR Committee on Preservation of Laboratory Resources was to determine whether there are problems associated with the identification and preservation of animal models as resources and, if so, to define the scope of the problems and recommend solutions. The committee found that substantial problems exist and that specific models and particular genetic stocks have been lost. The importance of these losses to the nations biomedical research effort could not be assessed retroactively. The most important problem recognized by the committee was the lack of adequate mechanisms for providing cost-effective and stable support, ensuring quality control, and distributing animals among investigators, even for very important models of broad interest to the scientific community.

The committee has recommended a framework (Figure1) for decision making that it believes to be a cost-effective means for the preservation of unique and valuable resources for the performance of biomedical research.

The committee's primary recommendations are summarized as follows.

COMMITTEE RECOMMENDATIONS

1. The committee recommends the following criteria for identifying valuable laboratory animal resources:


2. While recognizing that many worthwhile goals in biomedical research exist and that financial resources are limited, the committee recommends that adequate financial support be designated specifically for the maintenance of investigator-managed animal resources because of the unique nature of many of these resources and their value to the advance of research.

3. The committee recommends the establishment of a Review Group for Laboratory Animal Preservation that will evaluate requests for support of investigator-managed resources.

4. The committee recommends the establishment of a National Center for Laboratory Animal Resources. Because NIH has a prominent role in the performance of research involving animals and in the funding of such research, it is recommended that the national center be located at NIH and perform the following functions:
5. The committee recommends the establishment of an advisory committee for the National Center for Laboratory Animal Resources. The advisory committee should set policy and make decisions for the national center in fulfilling the functions described above. This committee should be composed primarily of scientists who use animals in their own research. The qualifications of the members should be the same as those suggested for the members of the Review Group for Laboratory Animal Resources.

REFERENCES


Figure 3

Appendix I
Biographical Sketches of Committee Members

DOROTHEA BENNETT, PH.D., CHAIRMAN
Dr. Bennett received her Ph.D. in Zoology/Genetics from Columbia University, New York, in 1956 and was chairman of the Department of Zoology at the University of Texas, Austin, at the time of her death on August 16, 1990. She authored numerous scientific publications and served on the editorial boards of many journals. Her research focused on the genetics of mouse chromosome 17. She maintained a large mouse colony containing a variety of embryonic 'lethal mutations' for more than 30 years.

LINDA C. CORK, D.V.M., PH.D.
Dr. Cork received her D.V.M. degree from Texas A&M University in 1970, received her Ph.D. from Washington State University in 1974, and became a diplomate of the American College of Veterinary Pathologists in 1975. She is a professor at the Johns Hopkins School of Medicine, Division of Comparative Medicine, and Department of Pathology, Baltimore, Maryland. Her research interests focus on animal models of human diseases, particularly neurological diseases. She has identified, established, and maintained feline, canine, and nonhuman primate colonies for study of human neurological diseases.

THOMAS J. GILL III, M.D.
Dr. Gill received his M.D. degree from Harvard Medical School in 1957 and has authored or coauthored over 200 scientific articles in the past 30 years. He is Menten Professor of Experimental Pathology and professor of human genetics at the University of Pittsburgh. His major interest is in immunogenetics, particularly the structure and function of the major histocompatibility complex and the application of knowledge about the major histocompatibility complex to the fields of tissue transplantation and reproductive immunology. He maintains approximately 46 strains of rats for his research program.

JON W. GORDON, PH.D., M.D.
Dr. Gordon received his Ph.D. in biology from Yale in 1978 and his M.D. from the same institution in 1980. His present position is at Mt. Sinai School of Medicine, New York. He has worked for a number of years in the area of mouse genetics. He has produced a number of allophenic mice and developed the technique of transgenic mouse production as a postdoctoral fellow at Yale University (1980-1982). He maintains a large animal colony with more than 30 lines of transgenic mice, and his research involves molecular cloning of insertional mutants and studies of gene regulation.

ANDREW G. HENDRICKX, PH.D.
Dr. Hendrickx received his Ph.D. degree from Kansas State University in 1963. He was first associated with the Southwest Foundation for Research and Education (now the Southwest Foundation for Biomedical Research), San Antonio, Texas, and is now at the University of California, Davis, where he is director of the California Primate Research Center. He has published numerous scientific articles on reproductive and developmental biology of nonhuman primates and served as an officer of several scientific societies.

LARRY E. MOBRAATEN, PH.D.
Dr. Mobraaten was educated at the University of California, Berkeley and the University of Maine, where he received a Ph.D. in zoology in 1972. He is a staff scientist at the Jackson Laboratory, Bar Harbor, Maine, where he is responsible for the largest mouse embryo-freezing facility in the United States. His research interests include cryopreservation of murine germplasm and transplantation genetics.

JOHN L. VANDEBERG, PH.D.
Dr. VandeBerg was educated at the University of Wisconsin and at Macquarie University in Sydney, Australia, where he received his Ph.D. in genetics in 1975. He has been chairman of the Department of Genetics at the Southwest Foundation for Biomedical Research, San Antonio, Texas, since 1982 and is also a professor of pathology and of cellular and structural biology at the University of Texas Health Science Center, San Antonio. His current research interests are focused on the interaction of genetic and environmental factors in determining the physiological characteristics of individuals in healthy or pathological states. He has extensive experience in developing and maintaining several species of marsupials and nonhuman primates as animal resources for these and other research initiatives. He also maintains several strains of mice and rats.

Appendix II
Scientists Who Formally Addressed the Committee

Christian R. Abee, D.V.M., is at the University of South Alabama College of Medicine and has one of three primate breeding and resource grants funded by the National Center for Research Resources (NCRR), National Institutes of Health (NIH). He is studying ways to enhance the reproduction of squirrel monkeys in captivity.

Alan Attie, Ph.D., is at the University of Wisconsin, where he is studying genetic factors involved in coronary artery disease using a swine model with a variety of alleles of apolipoprotein B, which is the primary protein constituent of low-density lipoproteins.

Melvin Balk, D.V.M., Charles River Breeding Laboratories, is familiar with the commercial aspects of animal production.

James L. Edwards, Ph.D., National Science Foundation (NSF), is in charge of resource colony funding.

Gordon M. Harrington, Ph.D., University of Northern Iowa, has developed a colony of rat strains used primarily in behavioral research.

John Holman, D.V.M., Ph.D., was a program officer at the Animal Resources Branch, DRR, NIH, and was familiar with funding policies of DRR.

William Jurgelski, M.D., Ph.D., was at the National Institute of Environmental Health Sciences, where he maintained a resource colony of opossums and attempted to develop a national center for marsupial research.

Stanley Leibo, Ph.D., was at Rio Vista Laboratories, San Antonio, Texas, and is an expert in embryo freezing.

Stephen Potkay, V.M.D., and Carl T. Hansen, Ph.D., Veterinary Resources Program, NCRR, NIH, management the NIH Genetic Resource.

Frank J. Rauscher, Jr., Ph.D., American Cancer Society, heads the society's Research Development Program.

James D. Willett, Ph.D., was at DRR, NIH, and was a leader in developing criteria for evaluating models for biomedical research supported by NIH.

Others who participated in the committee deliberations were Fred H. Bergmann, Ph.D., National Institute of General Medical Sciences; Dale B. Boyle, D.V.M., William Cole, D.V.M., and Judith Davis, D.V.M., U.S. Army Medical Research and Development Command; Fann Harding, Ph.D., and Nanci Parsons, B.A., National Heart. Lung, and Blood Institute: Joseph G. Mayo, D.V.M., and Clarence R. Reeder, B.S., National Cancer Institute; Kenneth Surrey, Ph.D., National Institute of Neurological and Communicative Disorders and Stroke; and Bruce L. Umminger, Ph.D., National Science Foundation.

Appendix III
Examples of Animal Resources That Have Been Lost

The examples included in this appendix were selected to represent the diversity of animal resources that have been lost and the diversity of research applications for which they were used. The committee did not attempt to judge the value of these resources at the time of their loss or to predict what value they might have had to biomedical research if they had been preserved. The primary concerns of the committee were that none of these resources had been evaluated according to a consistent set of criteria or by a panel of individuals experienced in assessing the scientific value of animal resources prior to their loss, nor were well-defined funding mechanisms available for enabling the preservation of those resources deemed to be of high scientific value in relation to cost.

SEWALL WRIGHT'S GUINEA PIGS
(information provided by Dr. W. H. Stone, Trinity University, San Antonio, Texas)

Dr. Sewall Wright began working with guinea pigs (Cavia porcellus) as a graduate student at Harvard in 1912. He had inherited a colony from Dr. Detlefsen at the University of Illinois and added numerous stocks and varieties from fanciers and other scientists. His brilliant studies on the inheritance of coat color yielded insight into the physiology of gene action. He continued these studies even after he moved to the University of Chicago in 1925. When he retired from the University of Chicago in 1954 and moved to the University of Wisconsin as an emeritus professor, the guinea pig colony was disbanded for lack of funding. Two strains (#2 and #13) are still available from commercial suppliers, but the extensive information that had accrued for many other strains and stocks became limited in value for future research initiatives. Much of Dr. Wright's research with guinea pigs is summarized in his biography:

Provine, W. B. 1986. Sewall Wright and Evolutionary Biology. Chicago: University of Chicago Press. 545 pp.

M. R. IRWIN'S PIGEONS AND DOVES
(information provided by Dr. W. H. Stone, Trinity University, San Antonio, Texas)

Dr. M. R. Irwin was a pioneer in the field of immunogenetics for some 50 years at the University of Wisconsin. During this half-century, he painstakingly established an extensive colony of pigeons and doves of various species. To study the inheritance of erythrocyte antigens, he produced numerous species hybrids and backcross hybrids. His research helped establish the field of immunogenetics and defined such phenomena as genetic interactions that produce hybrid substances and species-specific antigens. When Professor Irwin retired in 1967, he attempted to continue the maintenance of this resource, but adequate funding was not available. He tried to find other scientists who would maintain some of the rare hybrids and backcross hybrids, but to no avail. The colony was disbanded in the mid-1970s. The results of research with this colony are reviewed in the following papers:

Irwin, M. R., and Miller, W. J. 1961. Interrelationships and evolutionary patterns of cellular antigens in Columbidae. Evolution 15:30-43.
Irwin, M. R. 1966. Interaction of nonallelic genes on cellular antigens in species hybrids of Columbidae, III: Further identification of interacting genes. Proc. Natl. Acad. Sci. 56:93-98.

RHESUS MONKEY (Macaca mulatta) FAMILIES FOR STUDIES OF THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
(information provided by Dr. W. H. Stone, Trinity University, San Antonio, Texas)

After several years of breeding and selection, Dr. John Neefe, then at Georgetown University, and Dr. Bruce Mauer, then at Litton Bionetics Laboratory in Kensington, Maryland, accumulated several rhesus families that had been typed for the rhesus major histocompatibility complex (MHC). These families were unique in that they had been defined as having an array of specific haplotypes for the Class I and Class II MHC antigens. In 1979 the Neefe-Mauer laboratory was disbanded. Personal attempts by Dr. W. H. Stone, then at the University of Wisconsin, to obtain funds from NIH to transfer the rhesus families to Wisconsin were unsuccessful. The monkeys were utilized in other projects and thus lost to the research on MHC. The rhesus MHC was being intensively studied by only one other laboratory, headed by Dr. H. Balner in the Netherlands, and that laboratory also terminated work in this area a few years later. Although MHC-characterized rhesus monkeys would have been valuable for a variety of research purposes, the significance of their loss is highlighted by the advent of AIDS and its rhesus model, SAIDS. Research on how genetic variation of the MHC affects susceptibility to SAIDS and the course of this disease might well have increased an understanding of immune mechanisms in relation to AIDS. Two references to the research on these rhesus families are as follows:

Maurer, B. A., J. A. ]ones, and J. R. Neefe. 1978. Definition of 17 rhesus monkey histocompatibility antigens, including one new antigen. Tissue Antigens 11:1-19.
Neefe, J. R., Jr., L. Vaal, C. C. Darrow II, and G. N. Rogentine, Jr. 1973. Mixed lymphocyte reactivity in rhesus sibships. Transplantation 15:507-510.

RECOMBINANT INBRED MICE AT TEXAS A&M UNIVERSITY
(information provided by Dr. James E. Womack)

Dr. James E. Womack developed a panel of recombinant inbred (RI) strains from the C57BL/6N and C3H/N strains of mice. The original cross was made by Dr. David W. Nebert, and Dr. Womack received stock from him before they had become fully inbred as RI strains. Because limited funding was available to Dr. Womack, the RI strains were maintained in a single animal room rather than held as duplicates in two locations as is common practice for irreplaceable animal resources. Seven of the nine strains were lost due to a thermostat failure in the animal room. Because the gene mapping data from RI strains are cumulative, such that each gene mapped further enhances the value of the panel of strains, the loss of these strains was a major scientific loss in terms of the years of effort required to create them and to develop the cumulative data set that was available. The remaining two strains are of limited value by themselves.

CANINE MODEL OF HEREDITARY ATAXIA
(information provided by Dr. L. C. Cork, committee member)

Beginning in 1979, Dr. Linda Cork developed a small colony of dogs with hereditary ataxia. She defined the mode of inheritance, clinical features, light and electron microscopic features, changes in neurotransmitters, and she checked for a variety of metabolic problems in collaboration with physicians who were trying to understand human cerebellar degenerations. Funding was sought from NIH three times. In 1981, Dr. Cork was funded for 2 years, so she submitted a competing renewal application in 1982. This application was funded for 1 year, and she submitted another competing renewal application in 1983. The priority score on this occasion was not in a fundable range, so the dogs were killed. There are almost 60 inherited cerebellar degenerations in humans, and their neurobiological basis is unknown. References to the research conducted with this dog model are as follows:

Cork, L. C., J. C. Troncoso, and D. L. Price. 1981. Canine inherited ataxia. Ann. Neurol. 9:492-499.
Steinberg, H. S., J. C. Troncoso, L. C. Cork, and D. L. Price. 1981. Clinical features of inherited cerebellar degeneration in Gordon Setters. J. Am. Vet. Med. Assoc. 179:886-890.
Tiemeyer, M. J., H. S. Singer, J. C. Troncoso, L. C. Cork, J. T. Coyle, and D. L. Price. 1984. Synaptic neurochemical alterations associated with neuronal degeneration in an inherited cerebellar ataxia of Gordon Setters. J. Neuropathol. Exp. Neurol. 43:580-591.
Troncoso, J. C., L. C. Cork, and D. L. Price. 1985. Canine inherited ataxia: Ultrastructural observations. J. Neuropathol. Exp. Neurol. 44:165-175.

CANINE MODEL OF NEUROAXONAL DYSTROPHY
(information provided by Dr. L. C. Cork, committee member)

Beginning in 1981, Dr. Linda Cork developed a model colony of dogs with neuroaxonal dystrophy and developed preliminary information on the genetics, clinical features and pathogenesis, and light and electron microscopic alterations associated with this disease of the brain and spinal chord. Funding to support the resource was sought from NIH on two occasions. On the first occasion, 1 year of funding was provided. The priority score on the second proposal was not in the fundable range, so the dogs were killed in 1985. References to the research conducted with this model are as follows:

Chrisman, C. L., L. C. Cork, and D. A. Gamble. 1994. Neuroaxonal dystrophy of Rottweiler dogs. J. Am. Vet. Med. Assoc. 185:464-467.
Cork, L. C., J. C. Troncoso, D. L. Price, E. F. Stanley, and J. W. Griffin. 1983. Canine neuroaxonal dystrophy. J. Neuropathol. Exp. Neurol. 42:286-296.

JACKSON LABORATORY RABBITS
(information provided by Dr. R. R. Fox, The Jackson Laboratory)

Dr. W. E. Castle, a pioneer in the development of genetics as a science began developing genetically standardized stocks of rabbits in the 1920s. This work was expanded by Drs. P. B. Sawin, B. Cohen, and C. K. Chai, culminating in the development of inbred strains of rabbits. By 1975, 19 well-characterized inbred or partially inbred strains were maintained at the Jackson Laboratory. In addition, mutant genes that caused 15 different diseases were maintained in the colony, these diseases included lymphosarcoma, osteoporosis, spina bifida, epilepsy, and hemolytic anemia. During a 3-year sample period (1972-1975), 540 rabbits were distributed to 49 different investigators. Eventually, funding constraints forced the Jackson Laboratory to disband the rabbit resource in 1982, except for strain III/J, which continued to be maintained as a barrier-reared, Pasteurella-free colony. In 1986 this strain also was eliminated for lack of funding. Most of the strains and stocks are no longer available from any source. An overview of the scientific value of these rabbits is provided in the following reference:

Fox, R. R. 1984. The rabbit as a research subject. Physiologist 27:373-402.

PBB/Ld OBESE, DIABETIC MICE
(information provided by Dr. J. R. Lindsey, University of Alabama at Birmingham)

In the early 1970s, Dr. Charles E. Hunt developed the PBB/Ld mouse as a model of obesity and diabetes. The data he obtained indicated that susceptibility to disease was influenced by more than one gene, as is the case for human obesity and diabetes. When Dr. Hunt moved to another institution, the colony remained at the institution where it had been developed. As a consequence of insufficient funding, the colony was destroyed in 1980, and PBB/Ld mice are no longer available. Research with this strain is summarized in the following reference:

Walkley, S. U., C. E. Hunt, R. S. Clements, and J. R. Lindsey. 1978. Description of obesity in the PBB/Ld mouse. J. Lipid Res. 19:335-341.

KIRSCHBAUM MEMORIAL MOUSE COLONY
(information provided by Dr. A. G. Liebelt, National Cancer Institute)

This colony was a source of research and control animals from many strains of mice for a period of 30 years (1952-1982). The strains included some with high or low incidence of mammary cancer, some with high incidence of leukemia, and some resistant to all types of spontaneous tumor development. Some strains were available only from this colony. Insufficient funding forced the colony to be disbanded in 1982, at which time it was located at the Northeastern Ohio Universities College of Medicine in Rootstown, Ohio. At that time, breeding stock from 17 of the inbred strains was provided to Dr. Masaki Ohmori at the Kagawa Medical School in Japan. The rest of the mice were killed. The following are examples of the many publications describing research conducted with mice from this colony:

Bresnick, E., E. D. Mayfield, Jr., A. G. Liebelt, and R. A. Liebelt. 1971. Enzyme patterns in a group of transplantable mouse hepatomas of different growth rates. Cancer Res. 31:743-751.
Burki, K.. A. G. Liebelt, and E. Bresnick. 1973. Induction of aryl hydrocarbon hydroxylase in mouse tissues from a high and low cancer strain and their F1 hybrids. J. Natl. Cancer Inst. 50(2):369-380.
Liebelt, A. G. 1978. CBA/Ki vs. CBA/St/Ki: Fifteen years of observations. Pp. 475-479 in Origins of Inbred Mice, H. C. Morse III, ed. Proceedings of a workshop held February 14-16, 1978, at the National Institutes of Health, Bethesda, Maryland. New York: Academic Press.
Liebelt, A. G., and R. A. Liebelt 1967. Transplantation of tumors. Pp. 143-242 in Methods in Cancer Research, vol. 1, H. Busch, ed. New York: Academic Press.
Liebelt, A. G., and R. A. Liebelt. 1967. Chemical factors in mammary tumorigenesis. Pp. 315-345 in Carcinogenesis, A Broad Critique. Twentieth Annual Symposium on Fundamental Cancer Research, held in 1966 at the University of Texas, M.D. Anderson Hospital and Tumor Institute, Houston, Texas. Baltimore: Williams and Wilkins.
Liebelt, R. A., A. G. Liebelt, A. D. Gulledge, and J. Calvert. 1968. Autoregulation-normal organ and tumor homeostatis. Pp. 733-768 in The Proliferation and Spread of Neoplastic Cells. Twenty-first Annual Symposium on Fundamental Cancer Research, held in 1967 at the University of Texas. M.D. Anderson Hospital and Tumor Institute, Houston, Texas. Baltimore: Williams and Wilkins.
Liebelt, A. G., R. A. Liebelt, and L. Dmochowski. 1971. Cytoplasmic inclusion bodies in primary and transplanted hepatomas of mice of different strains. J. Natl. Cancer Inst. 47(2):413-427.

PITTSBURGH RAT (Rattus norvegicus) COLONY
(information provided by Dr. Heinz Kunz, University of Pittsburgh)

One of the largest inbred rat resources in the world is maintained by Dr. T. J. Gill III and his associates at the University of Pittsburgh, where they are used in research on immunogenetics and transplantation. Thousands of rats have been provided to investigators at other laboratories. Nonetheless, financial limitations have forced the termination of 36 strains over the years. One of the strains was VMA, which was initiated in 1909 and was discarded in 1988 after 237 generations of inbreeding. That strain possessed a rare haplotype of the major histocompatibility complex (MHC). Another strain that was discontinued is BI. These rats had several natural recombinants within the MHC and were used for experimental transplantation research. A review of some of the research conducted with these strains is provided in the following reference:

Gill, T. J., III, H. W. Kunz, D. N. Misra, and A. L. C. Hassett. 1987. The major histocompatibility complex of the rat. Transplantation 43:773-785.

BALB/cWm AND C58/Wm MICE
(information supplied by Dr. W. H. Murphy, University of Michigan)

The BALB/cWm and C58/Wm strains of mice had been inbred for over 250 generations by brother x sister mating. The C58/Wm strain was discontinued in 1985 as a consequence of inadequate funding. The BALB/cWm strain was transferred to Dr. Michael Potter at the National Institutes of Health. The BALB/cWm strain had been especially well characterized with respect to experimental microbial infection and immunologic response to tumors, and it was an exceptionally docile substrain. Its characteristics are summarized in the following reference:

Murphy, W. H., and G. L. Bolgos. 1988. Characteristics of the wm substrain of BALB/c mice. Curr. Top. Microbiol. Immunol. 122:3842.

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) DOG COLONY
(information provided by Dr. R. S. Schwartz, Tufts New England Medical Center, Boston, Massachusetts, and Drs. R. M. Lewis and F. W. Quimby, Cornell University, Ithaca, New York)

Beginning in the mid-1960s, an inbred colony of dogs derived from spontaneous cases of canine SLE was maintained at the Tufts New England Medical Center and was supported in part by NIH. This was the only animal model of SLE, except for the NZB mouse. It was especially valuable because the large size of the dogs enabled many types of investigations not possible with mice. Also, canine SLE is identical to human SLE in its genetic characteristics and in its response to environmental and therapeutic manipulations. The resource was utilized by at least six different research groups, but in the mid-1970s sufficient financial support could not be obtained to maintain the resource despite repeated resubmissions of grant applications and negotiations with NIH. Consequently, the colony was disbanded in the late 1970s. Some key references to work conducted with these dogs are as follows:

Lewis, R. M., and R. S. Schwartz. 1971. Canine systemic lupus erythematosus: Genetic analysis of an established breeding colony. J. Exp. Med. 134:417-437.
Lewis, R. M., J. Andre-Schwartz, G. S. Harris, M. S. Hirsch, P. H. Black, and R. S. Schwartz. 1973. Canine systemic lupus erythematosus: Transmission of serologic abnormalities by cell-free filtrates. J. Clin. Invest. 52:1893-1907.
Quimby, F. W., R. Jebert, S. Datta, J. Andre-Schwartz, W. J. Tannenberg, R. M. Lewis, I. B. Weinstein, and R. S. Schwartz. 1978. Characterization of a retrovirus that cross-reacts serologically with canine and human systemic lupus erythematosus. Clin. Immunol. Immunopathol. 9:194-210.
Quimby, F. W., R. S. Schwartz, T. Poskitt, and R. M. Lewis. 1979. A disorder in dogs resembling Sjogren's syndrome. Clin. Immunol. Immunopathol. 12:471-476.
Schwartz, R. S., F. W. Quimby, and J. Andre-Schwartz. 1978. Canine systemic lupus erythematosus: Phenotypic expression of autoimmunity in a closed colony. Pp. 287-294 in Genetic Control of Autoimmune Disease, N. R. Rose, P. E. Bigazzi, and N. L. Warner, eds. New York: Elsevier/North Holland.

SPECIFIC PATHOGEN-FREE INBRED MOUSE STRAINS AT THE UNIVERSITY OF CONNECTICUT
(information provided by Drs. Stephen Maxson and Benson Ginsburg, University of Connecticut, Storrs)

A set of specialized inbred strains of mice has been maintained in a pathogen-free colony at the University of Connecticut since the 1960s. In the mid-1980s the university reduced its support for animal care. Grant applications were submitted to the Connecticut Research Foundation, the Whitehall Foundation, NSF, and NIH in attempts to obtain support, but without success. As a consequence, the following strains were discontinued during the years 1984-1989: DN/Bg, which carries a mutation for deafness and was widely used in acoustic and behavioral research; HAS/Bg, which was susceptible to audiogenic seizures and was used in research on hippocampal morphology, hearing loss, and effects of early experience; C57BL/10Bg-at, which carried a mutation for increased susceptibility to audiogenic seizures and a black and tan coat color mutation; DBA/1-asr, which carried a mutation that blocked genetic but not acoustically primed susceptibility to audiogenic seizures and was coisogenic with DBA/1Bg; C57BL/10Bg-sps, which carried a mutation for spontaneous, eventually lethal seizures and was a model for grand mal and petite mal epilepsy; and nine strains of Y-chromosome congenic strains of mice that were at the 10th to 15th generation of backcrossing and used to study effects of the Y chromosome on aggression and copulation. In addition to these strains that have been lost, eight remaining inbred and five congenic strains have been saved temporarily by contributions from Professor Maxson's salary for their support and by care provided by him and his students without recompense. Some key references to the strains that already have been lost are as follows:

Ginsburg, B. E. 1967. Genetic parameters in behavioral research. Pp. 135-153 in Behavior-Genetic Analysis, J. Hirsch, ed. New York: McGraw-Hill.

Maxson, S. C., J. S. Cowen, and P. Y. Sze. 1977. Pharmacogenetic differences in audiogenic seizure priming of C57BL/6Bg and DBA/lBg-asr mice. Pharmacol. Biochem. Behav. 7:221-226.

Maxson, S. C., B. E. Ginsburg, and A. Trattner. 1979. Interaction of Y-chromosomal and autosomal gene(s) in the development of intermale aggression in mice. Behav. Genet. 9:219-226.

Maxson, S. C., M. Fine, B. E. Ginsburg, and D. L. Koneicki. 1983. A mutant for spontaneous seizures in C57BL/10Bg mice. Epilepsia 24:14-24.

Shrenker, P., and S. C. Maxson. 1983. The Y chromosomes of DBA/lBg and DBA/2Bg compared for effects on intermale aggression. Behav. Genet. 12:429-434.

Willott, J. F. 1983. The Auditory Psychobiology of the Mouse. Springfield, Ill.: Charles C Thomas.

Appendix IV
Examples of Animal Resources That Are at Risk

The examples included in this appendix were selected to represent the diverse types of animal resources that are at risk and the diverse research programs for which they are used. The committee did not attempt to judge the value or potential value of these resources, but the examples serve to illustrate the types of resources that ought to be evaluated according to a consistent set of criteria by a panel of qualified and experienced individuals. Some of these resources might be judged by such a panel not to warrant federal support, but any that are judged to have high scientific value relative to their cost should be supported by a well-defined funding mechanism such as the one recommended in this report.

GRAY SHORT-TAILED OPOSSUMS (Monodelphis domestics)
(information provided by Dr. J. L. VandeBerg, committee member)

This species was developed as a model marsupial particularly suited for research on early developmental processes as a consequence of the "fetal" state of newborn marsupials. The development of the primary colony of this species, and of methods for its husbandry and experimental manipulation, was supported by an institutional grant from the American Cancer Society during 1979-1980 and by a grant from the NIH Division of Research Resources (DRR) during 1982-1988 (with an unfunded extension of the grant to 1989). After it was apparent that the species was highly successful as a laboratory animal, DRR instigated a phaseout of funding beginning in 1985. The fully pedigreed resource colony, maintained at the Southwest Foundation for Biomedical Research in San Antonio, is the exclusive source of foundation breeding stock and experimental animals for investigators in North America and Europe, and it is used frequently by visiting scientists for on-site short-term research projects. The number of publications involving this species has approximately doubled each year from 1984 through 1987 (the most recent year for which complete data are available). Although the colony produces approximately 2,000 animals per year and has partially inbred strains at the F10 generation, volume demand is not nearly large enough to make the species commercially viable. The history of the resource and current uses of the species in research have been summarized by VandeBerg (1983, 1990). No other marsupial species is readily available as a laboratory animal.

VandeBerg, J. L. 1983. The gray short-tailed opossum: A new laboratory animal. ILAR News 26(3):9-12.

VandeBerg. J. L. 1990. The gray short-tailed opossum (Monodelphis domestics) as a model Didelphid species for genetic research. Aust. J. Zool. 37:235-247.

BABOONS (Papio hamadryas)
(information provided by Dr. T. M. Butler, Southwest Foundation for Biomedical Research, San Antonio, Texas)

In 1978 the DRR funded the development of a baboon breeding colony at the Southwest Foundation for Biomedical Research as a national resource that supplied approximately 150 colony-born animals per year to researchers throughout the country. Olive (P. h. anubis), yellow (P. h. cynocephalus), red (P. h. papio), and sacred (P. h. hamadryas) baboons were established and maintained in separate genetically characterized breeding colonies. Even though the colony met its goals and requests for colony-born baboons continued, DRR decided in 1985 to phase out support over a 5-year period. As a consequence, the colonies of yellow and sacred baboons were disbanded, and the colony of red baboons is now supported by an National Heart, Lung, and Blood Institute research grant and is not generally accessible to other research programs. The olive baboon breeding colony has been supported for the last 3 years by partial funding from DRR and income from sales, but the preservation of this resource beyond the termination of DRR (now NCRR) funding (June 30, 1990) is in jeopardy. No other source of substantial numbers of colony-reared baboons is available, and many research projects that require baboons of known age, medical history, and health status will not be possible if the resource is lost. If exportation of baboons from Africa is banned (as has occurred for short periods of time in the past), then even baboons of unknown age, history, and health status will become extremely limited in availability for biomedical research. The baboon resource is described in the following reference:

Goodwin, W. I., and A. M. Coelho, Jr. 1982. Development of a large scale baboon breeding program. Lab. Anim. Sci. 32(6):672-676.

SPONTANEOUSLY HYPERCHOLESTEROLEMIC PIGS
(information provided by Dr. Alan Attie, University of Wisconsin, Madison)

A colony of spontaneously hypercholesterolemic pigs was developed during the past 2 decades at the University of Wisconsin by Dr. J. Rapacz. Sixteen different stocks were developed, each carrying unique alleles for apolipoprotein-B (apoB), the major protein of low-density lipoproteins (LDLs). The alleles of apoB determine the level of LDL-cholesterol and susceptibility to atherosclerosis in each stock. The animals serve as unique models for familial combined hypercholesterolemia and familial defect in apo-B, both common human disorders. After repeated unsuccessful attempts to obtain sufficient funding, a large portion of the colony was killed, thereby imperiling the long-term preservation of the resource. The remaining stock is currently supported by an NIH research grant to Dr. Alan Attie and by institutional funds. A prominent reference to the research conducted with this colony is as follows:

Rapacz, J., J. Hasler-Rapacz, K. M. Taylor, W. J. Checovich, and A. D. Attie. 1986. Lipoprotein mutations in pigs are associated with elevated plasma cholesterol and atherosclerosis. Science 234:1573-1577.

DR. GORDON HARRINGTON'S RAT (Rattus norvegicus) COLONY
(information provided by Dr. Harrington, University of Northern Iowa, Cedar Falls)

Beginning in 1962, Dr. Gordon Harrington established a series of inbred rat strains for use in behavior research and collected extensive data on 12 of them. The strains were neurobehaviorally and genetically defined. Many attempts were made in the mid-1980s to obtain sufficient funding from federal, institutional, and private sources, but ultimately Dr. Harrington had to relinquish the colony for financial reasons and lack of institutional interest in resource activities. The colony has been relocated to the laboratory of a collaborator at another institution, and efforts to obtain funding are continuing. A reference that describes the strains and their characteristics is as follows:

Harrington, G. M. 1981. The Har strains of rats: Origins and characteristics. Behav. Genet. 11:445-468.

VIRGINIA OPOSSUM (Didelphis virginiana) MODEL FOR RESEARCH IN DEVELOPMENTAL BIOLOGY
(information provided by W. Jurgelski, Jr., formerly of the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, and J. L. VandeBerg, committee member)

A breeding colony of between 500 and 1,000 Virginia opossums was established at the National Institute of Environmental Health Sciences (NIEHS) in the late 1960s and early 1970s for the purposes of exploiting the unique characteristics of marsupials in research on early developmental processes. One of the uses of the colony was to investigate carcinogenesis. Some of this research is summarized in a cover article in Science in 1976 (Jurgelski et al., 1976). In the course of its existence, animals of the colony were used in collaborative studies with a number of investigators at NIEHS, where the colony was maintained, and with groups at the Armed Forces Institute of Pathology, the Johns Hopkins University, and research groups in Belgium, Germany, England and India. The colony was disbanded in the mid 1970s as a consequence of inadequate funding.

Prior to its abandonment, blood samples sent to Dr. John VandeBerg at another institution revealed a rare X-linked variant of glucose-6-phosphate dehydrogenase with potential value for research on X-chromosome inactivation. After two unfunded applications to NSF for funds to exploit this variant, Dr. VandeBerg received NSF funding in 1986 after a third application. Because the NIEHS colony had been disbanded, a search for the X-linked variant was initiated in wild populations from various geographical areas. Over 1,600 individuals were surveyed at substantial expense to NSF and to Dr. VandeBerg's institution, leading to the eventual acquisition for breeding purposes of 11 individuals carrying the variant gene. A pedigreed colony has been established, and after 3 years of NSF support, is now supported by an NIH grant. On completion of the funded work in 1992, the colony will no longer be needed by the current investigators, so current plans are to disband the colony at that time. The probability seems quite high that other investigators will require a breeding colony of this species, and perhaps the rare G6PD variant, at some time during the next decade, but the disposition of this colony will require additional funding to develop a new colony from scratch and to solve again in another laboratory the many husbandry and health problems associated with wild-caught Didelphis virginiana. Some key references are as follows:

Jurgelski, W., Jr. 1979. The marsupial as a laboratory animal. ILAR News 22(3):18-21.

Jurgelski, W., Jr., P. M. Hudson, H. L. Falk, and P. Kotin. 1976. Embryonal neoplasms in the opossum: A new model for solid tumors of infancy and childhood. Science 193:328-332.

Samollow, P. B., A. L. Ford, and J. L. VandeBerg. 1997. X-Chromosome dosage compensation in the Virginia opossum: Differential expression of the paternally derived Gpd and Pgk-A loci. Genetics 115:185-195.


NIH-SUPPORTED RHESUS MONKEY (Macaca mulatto) AND CHIMPANZEE (Pan troglodytes) RESOURCES
(information from Dr. L. A. Whitehair, National Center for Research Resources, NIH)

Until the mid-1970s. large numbers of feral rhesus monkeys were readily available at a modest cost from India, and very few captive breeding programs (other than those in the Regional Primate Research Centers) existed in the U.S. biomedical research community. Animals were imported from India primarily for the development of the polio vaccines during the mid-1950s. Subsequently, Indian rhesus monkeys continued to be imported and used for polio vaccine neurovirulence testing, as well as for other types of biomedical research during the 1960s and 1970s. By the mid-1970s it was apparent that feral rhesus monkeys would no longer be available and that captive breeding programs must be established for domestic biomedical needs. The NIH and the Food and Drug Administration committed significant funding for this effort, and several large rhesus breeding colonies were established to provide this resource for Public Health Service (PHS)-sponsored research and testing requirements. In the 1980s it became evident that specific pathogen-free (SPF) rhesus breeding colonies should be established to provide biomedical researchers with well-defined, quality animals. The Comparative Medicine Program, NCRR, NIH committed funds to develop an SPF rhesus breeding and research program that is primarily dedicated to AIDS research requirements. However, other PHS-sponsored research needs for SPF rhesus monkeys are not excluded. These colonies represent that "next generation of rhesus monkey that will better serve the biomedical community and ensure the availability of well-defined, high-quality research animals. These colonies are designed to provide substantial numbers of animals within the next several years. This effort, combined with other sources of SPF nonhuman primates from breeding colonies in Indonesia, should provide the biomedical community with an adequate supply of quality animals.

Approximately 1,400 chimpanzees are currently held in breeding and research colonies within the U.S. biomedical community. During the 1970s the largest single biomedical research use of chimpanzees was for the development and testing of hepatitis vaccines. Since future requirements for this species were evident for viral research, biomedical institutions began to seek methods to properly breed, maintain, and use these animals. When a critical need for chimpanzees in AIDS research developed in the mid-1980s, animals were available, but substantial funding was required from federal sources to properly house, maintain and develop breeding colonies. These colonies are currently producing about 50 offspring per year and priority needs dictate that federal funding continue to be maintained for the appropriate development of vaccines and therapeutic measures for the AIDS-related complex, as well as for other serious viral diseases. If currently unknown, devastating viral diseases should develop 10 or 20 years from now, it is very probable that high-quality, well-defined chimpanzees will be needed for research and testing. An adequate supply of chimpanzees must be available for PHS research and testing needs if such public health problems do arise. Four of the many references concerning the use of the chimpanzees in human viral disease research are as follows:

April, M., and E. Tabor. 1981. 1989. Experimental Non-A, Non-B Hepatitis in Chimpanzees. Animal Models of Human Diseases, Fascicles 10 and 17. Wash-ington, D.C.: Armed Forces Institute of Pathology.

Desrosiers, R. C., and N. L. Letvin. 1987. Animal mod-els for acquired immunodeficiency syndrome. Rev. Infect. Diseases 9:438-446.

Fultz, P. N. 1989. Nonhuman primates and the acquired immunodeficiency syndrome: A union of necessity. J. Med. Primatol. 18:73-83.

Tabor, E., and R. J. Gerety. 1978. Transmission of non-A, non-B hepatitis from man to chimpanzee. Lancet 1:463-466.

CANINE MODELS OF BASIC MECHANISMS OF HEMOSTASIS AND THROMBOSIS
(information provided by Dr. Jean Dodds, Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York)

Dr. Dodds established this colony in 1965 with a small number of dogs brought into this country from a colony at the Ontario Veterinary College, Guelph, Ontario, Canada. A nationwide communications network was developed with public and professional input to assist in locating and acquiring animal models. The colony is maintained for genetic, biochemical, and physiological studies; production of reagents for coagulation tests; and evaluation of hemostasis. This colony of dogs with inherited coagulation and platelet function defects includes dogs with hemophilia A, hemophilia B, von Willebrand's disease (vWD), factor VII deficiency, thrombasthenia, and thrombopathia. Studies with these naturally occurring animal models examine basic mechanisms of hemostasis and thrombosis in comparison to analogous human diseases.

The colonies of animals with hereditary hemostatic defects are unique. They include many animal models of human coagulation and platelet defects not available elsewhere and the largest collection of mutant strains of such defects as canine hemophilia A, Christmas disease, and vWD. A close analogy between the animal models and their human counterparts has been repeatedly demonstrated, making their use especially relevant to human diseases.

Because of the existence of the colonies, this laboratory receives many referrals of bleeding animals from throughout North America, affording an opportunity to discover and characterize defects not yet recognized in animals. A recent example is equine vWD. Discovery of animals with new defects provides additional models for comparative investigations, a standard source of deficient substrates for coagulation assays, and reagents for comparative immunologic and genetic studies. The laboratory supplies many investigators with them and other reagents, for example, anti von Willebrand factor (vWF) serum.

In collaboration with Cedars Sinai Hospital and Dr. Alan Rubinstein, the safety and efficacy of heat-treated human Factor VIII and Factor IX concentrates was established in hemophilia A and B dogs. The work resulted in the patenting and commercial licensing of methods for heat treating clotting factor concentrates. These techniques destroy hepatitis and HIV classes of viruses and directly benefit hemophiliacs who receive transfusions of concentrated blood derivatives to control or prevent bleeding episodes.

Lack of long-term funding places the existence of these colonies at risk. Only the most recent of more than 180 published papers concerning these colonies are listed below:

Brooks, M. B., and W. J. Dodds. 1989. Factor IX deficiency (hemophilia B) in two male domestic short-hair cats. J. Am. Anim. Hosp. Assoc. 25:153-155.

Catalfamo, J. L., and W. J. Dodds. 1989. Isolation of platelets from laboratory animals. Methods Enzymol. 169:27-36.

Catalfamo, J. L., S. L. Raymond, S. Taiman, and W. J. Dodds. In press. Evaluation of canine platelet function in whole blood. Am. J. Vet. Res.

Dodds, W. J. 1989. Hemostasis. Pp. 274-3 15 in Clinical Biochemistry of Domestic Animals, 4th ed., J. J. Kaneko, ed. New York: Academic Press.

Giger, U., and W. J. Dodds. 1989. Effect of desmopressin in normal dogs and dogs with von Willebrand's disease. Vet. Clin. Pathol. 18:39-42.

Raymond, S. L, D. W. Jones, M. B. Brooks, and W. J. Dodds. In press. Severe bleeding in Shetland sheepdogs associated with von Willebrand's disease (vWD). J. Am. Vet. Med. Assoc.

Appendix V
Annual Cost in 1989 Dollars and Cost-Effectiveness of Existing Animal Resources

INTRODUCTION

The examples chosen for inclusion in this appendix are based on firsthand experience of committee members. The costs are estimates of all funds required to maintain existing colonies during the calendar year 1989, including federal and institutional funds that are specifically designated for the resources as well as hidden costs that may not be as obvious. It is recognized that actual costs might vary by region and by institution because of differences in such factors as building costs, energy costs, salary levels, fringe benefits provided to employees, and the manner in which indirect costs are assessed. Therefore, these cost estimates are intended to serve only as rough guides.

GRAY SHORT-TAILED OPOSSUMS (Monodelphis Domestica)

Colony Structure

This budget estimate is based on a colony of Monodelphis domestica maintained at the Southwest Foundation for Biomedical Research (SFBR), San Antonio, Texas. The animals weigh 80-150 g at adulthood and are maintained in polycarbonate or polypropylene cages designed for rodents. Costs are scaled to a colony that maintains a steady-state size of 1,000 adults and postweaning juveniles and produces approximately 2,000 progeny per year.

Comments

A total cost of $260,000 for maintaining 1,000 animals reduces to $260 per animal-year or $0.71 per animal-day ($0.39 direct costs + $0.32 indirect costs). This is the cost of not simply maintaining the animals, but also of managing an active breeding and experimental colony that is fully pedigreed and has a computerized records system.

Alternatively, one can consider the cost of producing each of the 2,000 animals weaned in the colony each year to be $130 ($72 direct costs + $58 indirect costs). This figure is higher than the amount that would actually be required to produce 2,000 animals in a strictly production colony, because many pregnant and prime breeding-age animals at this colony are used for research purposes, as are many infants prior to weaning.

Some of the 2,000 animals produced are used to replace breeders that are retired or used experimentally; however, even many retired breeders are assigned to experimental purposes or distributed to other investigators. So, because the incidence of spontaneous death is very low, nearly 2,000 animals are killed annually for research. Many are used in research projects at SFBR, but 375 retired breeders, breeders, juveniles, and timed pregnant females were distributed to 30 different investigators at 24 other institutions during the period of July 1, 1989 to July 1. 1990. In many instances, age-matched animals of a single sex were required. In addition, 162 neonates were provided to nine investigators at other institutions, and blood and ear pinna samples from large pedigreed families were provided to one investigator for genetic analyses.

If each of the outside investigators were required to develop a colony to provide for his or her needs, the cost would be severalfold, because most investigators have specialized needs that require only a select subset of the animals that would be produced in any colony. Furthermore, the economy that accrues from the scale of the breeding operation and experience in efficient management of a breeding colony argues strongly in favor of a single centralized colony for a species such as Monodelphis domestics that is used in relatively small numbers.

Budget: Gray Short-Tailed Opossums

Personnel costs
Colony manager, 0.1 Full-Time Equivalent (FTE)
$10,000
Veterinarian, 0.1 FTE
10,000
Data management director, 0.05 FTE
5,000
Computer programmer, 0.2 FTE
5,000
Data management assistant, 03 FTE
6,000
Animal caretakers, 4 FTEs
61,000
Supplies
Feed and bedding
8,000
Cage replacement
30,000
Other
5,000
Pathology and microbiology support
3,000
Direct costs
$143,000
Indirect costs at 81.5% (e.g., building depreciation. heating electricity, administration, maintenance)
$117,000
Total costs (direct + indirect)
$260,000

TRANSGENIC MICE

Colony Structure

The cost of a transgenic mouse colony is highly variable depending on the size of the colony and the kinds of animals maintained. For example, to ensure survival, larger numbers of mice must be maintained if the mice are developmentally or reproductively compromised because of insertional mutations than if the mice are homozygous for a transgene, the expression of which is not harmful to the animal. Because the size of a colony may vary, the number of ancillary personnel such as veterinarians and maintenance workers is also variable, as are computer, diagnostic, and security facilities. Another important variable is the level of protection accorded the animals. A barrier facility is far more expensive than a conventional one.

Budget

In the transgenic mouse colony maintained by Dr. Jon Gordon at Mt. Sinai School of Medicine, New York, approximately 2,000 mice are maintained by conventional methods. The per diem charges are $0.12 per mouse. The per them charges cover approximately 70% of the cost of the animals. The remainder is supplied either from grants to the animal facility or from the institution. The annual cost of maintaining the colony is therefore:

$0.12 x 2,000 mice x 365 days + 0.7 = $125,143 per year.

DOGS (Canis familiaris)

Colony Structure

Dog colonies are typically maintained because they have a specific trait or disease that is inherited in a Mendelian fashion. Because of the high costs involved, most dog colonies of this type are small and are limited to producing only the numbers of dogs needed for study and to providing replacement breeding stock.

Several factors affect the size of a dog production colony: the mode of inheritance of the trait, whether affected individuals (either homozygous recessive or heterozygous dominant) are fertile, and how long pups must be kept before their genotype is manifested or before they can be used for experimental studies. For example, if there are biochemical tests that can determine the genotype of affected individuals at birth, the remainder of the litter (except for replacement breeding stock) can be culled accordingly. On the other hand, if the onset of disease is not until the dog is more than 6 months of age. the colony will have to retain dogs to identify affected individuals, and production costs will be higher.

Two examples are given. In the first, affected dogs are fertile and can be bred to produce affected progeny; in the second, the trait is recessive, and homozygous individuals are infertile. In the latter case, heterozygous individuals must be used for breeding, and only 25% of the progeny are affected and can be used for experimental studies. For brevity, an intermediate example in which homozygotes and heterozygotes can be bred to produce 50% affected progeny will not be shown, but the costs can be calculated and would be midway between the two examples illustrated.

Cost Structure

The examples include only direct costs. Depending on the institution, indirect costs ranging up to 100% of direct costs might also be included.

The biggest single line item is the per diem cost, and this is typical of that encountered in a major, urban, centrally managed research facility. The per diem cost estimate does not take into consideration any of the proposed changes in animal welfare regulations that might require more space or personnel costs associated with providing exercise. Per diem cost includes food, water, and cleaning of runs/cages by a caretaker. Dogs are housed either in social groups or individually in runs or cages that meet federal