Policy ForumANIMAL RESEARCH

Harmonization of Animal Care and Use Guidance

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Science  05 May 2006:
Vol. 312, Issue 5774, pp. 700-701
DOI: 10.1126/science.1124036

Societal expectations for improvements in the health of humans and animals require scientific studies involving the use of animals. At the same time, the public is concerned about the welfare of animals used in science. Animal welfare is also of importance because of the link between healthy, well-cared-for animals and sound science.

Most national oversight mechanisms emphasize basic principles of humane science, in particular the “three R's” tenet of replacement, reduction, and refinement of animal use (1).[HN1] However, the oversight of animal care and use occurs through a wide variety of local, national, and international mechanisms [HN2], some based on legislation [the European Union (EU); (2)][HN3], others on peer review or other forms of nonlegislated oversight (Canada [HN4]) and yet others on a combination of legislated and nonlegislated oversight (United States [HN5]). This patchwork of mechanisms can cause problems, given the global nature of science.

Different standards for animal care and use can complicate the comparison of results from animal-based studies and the reproducibility of such results and can also slow international scientific collaboration. For example, CO2 euthanasia is more commonly used for rodents in the United States than in the EU, and T-61 (a combination of three drugs—a local anesthetic, a general anesthetic, and a curariform drug) is available to animal users in Europe but not the United States. [HN6] There are also international trade implications: multinational companies face the challenge of having to work with research and testing sites operating within very different regulatory structures. Specific standards of animal care and use required by scientific journals [HN7] can also present a barrier to publication. The patchwork of mechanisms can be especially daunting for developing countries, in elaborating their own mechanisms and in international collaboration. Finally, there is concern that differences in animal care and use requirements may lead to the transfer of animal-based studies to countries with weaker requirements. As far back as 1985, the Committee of International Organizations of Medical Science (CIOMS), which works closely with the World Health Organization, said “The varying approaches in different countries to the use of animals for biomedical purposes, and the lack of relevant legislation or of formal self regulatory mechanisms in some, point to the need for international guiding principles elaborated as a result of international and interdisciplinary consultations” (3). [HN8]

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There are international efforts to use guidance that is based on performance standards [i.e., standards that define an outcome and provide criteria for assessing that outcome, but do not limit the methods by which that outcome may be achieved (4)], and to work on filling gaps in the science needed for sound animal welfare guidance. Examples of international collaboration include the CIOMS Principles, the Mutual Acceptance of Data Program of the Organisation for Economic Cooperation and Development (OECD) [HN9], and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [HN10]. These instances of collaboration have reduced unnecessary duplication of studies involving animals by developing internationally accepted common methods for chemical testing and drug development.

Guidance on the recognition of clinical signs as humane end points [HN11] is now being implemented by member nations of the OECD, in conjunction with the OECD test guidelines for safety evaluation, which means that regulatory agencies in these countries should no longer require death in extremis as an end point for safety tests (5). In countries that are not OECD members, death may still be commonly accepted as an end point.

The International Council for Laboratory Animal Science [HN12] [ICLAS (6)] has brought members of the international community together to identify and to recommend acceptance of guidance documents. ICLAS believes in the harmonization of animal care and use guidance as a reflection of the globalization of research. However, harmonization must be distinguished from standardization (one worldwide set of regulations); ICLAS believes that each country should be able to maintain an oversight mechanism for animals used in science that reflects its cultures, traditions, religions, laws, and regulations.

ICLAS first worked with the Canadian Council on Animal Care (CCAC) on best practices to minimize pain and distress for animals used in regulatory testing; these were agreed upon and published (7). [HN13] Two guidance documents on humane end points were recognized as effective refinement tools (5, 8).[HN14]

In November 2003, the Institute for Laboratory Animal Research (ILAR) organized an international workshop (9) to discuss harmonization. [HN15] During this workshop, many experts from around the world independently reported about a desire for and worldwide pressures to have international benchmarks for animal welfare. However, many participants pointed out that there are strong attachments to existing national guidance and gaps in the science needed as a basis for some of the regulations, standards, and guidelines.

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ICLAS held its First International Meeting for the Harmonization of Guidelines on the Use of Animals in Science in Nantes, France, on 13 and 14 June 2004 (10). An ICLAS Working Group on Harmonization of Guidelines, composed of representatives from major organizations producing and/or using guidelines for the use of animals in science, was created at the meeting (11). [HN16] The working group agreed on general principles for the establishment of humane end points that are based on the earlier documents from the OECD and CCAC (5, 8, 12). The working group encourages consultation of the extensive literature available on end points and recognizes the need for research to support performance-based standards. The current general principles for humane end points defined by the working group are described in the table above.

The working group also agreed on general principles for euthanasia and recommended two documents (13, 14) [HN17] as international references (15). Both documents provide general principles and guidance on ways to ensure that euthanasia methods meet the goal of assuring the humane death of animals. There are some areas of inconsistency between the two references. This is partly because the American Veterinary Medical Association document is designed for a more general audience (i.e., not only for animal use in science) and because of differing practices and traditions in the United States and Europe, but mostly it is due to insufficient knowledge about the best methods of euthanasia for various species at different life stages. The areas in which further research will be needed were identified as mass animal euthanasia, euthanasia of fetuses and neonates, euthanasia of cold-blooded animals, proper use of CO2 for various species, decapitation with or without prior anesthesia, cervical dislocation, and the use of N2 and/or argon gas. With more research in these areas, the working group felt that the discrepancies between the documents could be addressed and better guidance incorporated into future versions of the guidelines. The general principles for euthanasia defined by the working group are shown in the table above.

ICLAS will continue to work with its many partners around the world to identify solid, practical guidance that can easily be used by the international community to promote good animal welfare while conducting sound animal based science.

HyperNotes Related Resources on the World Wide Web

General Hypernotes

Web Collections and Resource Lists

The American College of Laboratory Animal Medicine offers links to Internet resources.

The Center for Animal Alternatives, University of California, Davis, provides links to Internet resources.

The Lab Animal Web site provides links to Internet resources.

Laboratory Animals Ltd. provides links to Internet resources.

The Scientists Center for Animal Welfare offers a collection of Internet links.

NetVet Veterinary Resources are maintained by K. Boschert, Division of Comparative Medicine, Washington University.

Online Texts and Organizational Resources

The Foundation for Biomedical Research provides educational resources about animal research.

IACUC.ORG is an information resource for members and staff of institutional animal care and use committees. A collection of links to international policies, guidelines, and other documents is included.

The Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International is an organization that promotes the humane treatment of animals in science through voluntary accreditation and assessment programs.

The Institute for Laboratory Animal Research (ILAR) is a program in the Division on Earth and Life Studies of the National Academy of Sciences. Links to Internet resources are provided.

The National Agricultural Library's Animal Welfare Information Center (AWIC) provides information for improved animal care and use in research, teaching, and testing.

The intramural Office of Animal Care and Use of the National Institutes of Health (NIH) offers regulations, guidelines, Internet links, and other resources. Online training courses for animal users are provided.

The Office of Laboratory Animal Welfare is part of the NIH Office of Extramural Research. A presentation on the Public Health Service (PHS) policy on humane care and use of laboratory animals is provided, as is a tutorial on the PHS policy.

The Department of Comparative Medicine, Stanford School of Medicine, offers a resource page on laboratory animal care.

General Reports and Articles

The Guide for the Care and Use of Laboratory Animals (1996) (4) is made available by the National Academies Press (NAP). Versions in languages other than English are also available.

Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003) is also available from NAP.

Essentials for Animal Research: A Primer for Research Personnel (1994) is provided by AWIC.

The NIH Office of Animal Welfare makes available in PDF format the Institutional Animal Care and Use Committee Guidebook (2002).

The European Commission Environment Division makes available in PDF format a 2005 report titled “Aspects of the biology and welfare of animals used for experimental and other scientific purposes.”

The Use of Non-Human Animals in Research: A Guide for Scientists (2004) is made available in PDF format by the Royal Society.

Johns Hopkins University's Center for Alternatives to Animal Testing makes available the 1994 book Animals and Alternatives in Testing: History, Science, and Ethics by J. Zurlo, D. Rudacille, and A. M. Goldberg.

The Nuffield Council on Bioethics makes available in PDF format a 2005 report titled The Ethics of Research Involving Animals.

Numbered Hypernotes

1. The 3Rs of humane science. The 3Rs are defined by RDS Online. FRAME (Fund for the Replacement of Animals in Medical Experiments) defines the 3Rs and provides presentations on refinement, reduction, and replacement, with links to Internet resources. The 1992 edition of The Principles of Humane Experimental Technique by W. M. S. Russell and R. L. Burch (1) is made available by AltWeb. The UK National Centre for the Replacement, Refinement and Reduction of Animals in Research is a resource on the promotion, development, and implementation of the 3Rs in animal research and testing. The vol. 43 supplement, 2002, of the ILAR Journal had an article by S. Sterling and A. Rispin titled “Incorporating the 3Rs into regulatory scientific practices.” Johns Hopkins University's Center for Alternatives to Animal Testing provides a collection of Internet links to organizations and agencies.

2. International variations in oversight mechanisms. AAALAC International offers a collection of links to international regulations and resources. FRAME provides links to Internet resources for legislation and regulation in various countries. The August 2005 issue of The Physiologist had a public affairs note titled “Transnational impacts of animal welfare regulations.”

3. European regulation. AAALAC International provides links related to European regulations. The European Commission Environment Division provides a resource page on laboratory animals with information about related legislation. Directive 86/609 seeks to ensure the well-being of laboratory animals throughout the countries of the European Union. The European Science Foundation makes available in PDF format an August 2001 Policy Briefing titled “Use of animals in research” (2). A resource page on animals in scientific research is provided by the UK Home Office Web site.

4. Canadian oversight. AAALAC International provides links related to regulation in Canada. The Canadian Council on Animal Care (CCAC) proves a statement of its mandate and makes available volumes 1 and 2 of the Guide to the Care and Use of Experimental Animals.

5. Links to relevant United States legislation, policies, guidelines, and codes of practice are provided by AWIC.

6. Euthanasia practices and agents. CCAC's Euthanasia of Experimental Animals Module includes a section on the classification of euthanasia agents. The American Veterinary Medical Association (AVMA) makes available in PDF format the 2000 Report of the AVMA Panel on Euthanasia (13). Euthanasia of Animals Used for Scientific Purposes is provided in PDF format by the Australian and New Zealand Council for the Care of Animals in Research and Teaching. The University of Iowa's Institutional Animal Care and Use Committee provides a resource page on euthanasia of research animals. The Department of Comparative Medicine, Stanford School of Medicine, makes available euthanasia recommendations. The 1993 Report of the AVMA Panel on Euthanasia, available from AWIC, has sections on carbon dioxide and T-61. The CCAC's Guide to the Care and Use of Experimental Animals includes information on T-61 in the chapter on euthanasia. An entry for T-61 is included in Health Canada's Drug Product Database.

7. Policies of scientific journals. Uniform Requirements for Manuscripts Submitted to Biomedical Journal, recommendations of the International Committee of Medical Journal Editors, include a section on the protection of human subjects and animals in research. The American Physiological Society provides information about its policies for research involving animals. The Society for Neuroscience provides information about its policies on the use of animals and humans in neuroscience research. The Royal Society outlines its journal policy on animal testing. Nature outlines its publication policy on animal research. Cell provides a statement of its policy on studies involving humans and animals. The FASEB Journal provides an editorial policy statement on the ethical use of humans and/or animals in research.

8. The Council for International Organizations of Medical Sciences makes available the 1985 guidelines titled “International guiding principles for biomedical research involving animals” (3).

9. OECD Mutual Acceptance of Data. The Organisation for Economic Co-operation and Development (OECD) provides information on the Mutual Acceptance of Data Program.

10. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) offers a presentation on the history of ICH.

11. Humane end points. OECD makes available a November 2000 publication titled “Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation” (5). Laboratory Animals Ltd. makes available in PDF format papers from the 1998 conference “Humane endpoints in animal experiments for biomedical research.” The vol. 41, no. 2, 2000, issue of the ILAR Journal was a special issue titled “Humane endpoints for animals used in biomedical research and testing.” AWIC offers a resource page on pain management and humane end points.

12. The International Council for Laboratory Animal Science (ICLAS) provides facts about ICLAS and links to its scientific members.

13. Published standards for regulatory testing. The vol. 43 supplement, 2002, of the ILAR Journal published the proceedings of the 2001 symposium on regulatory testing and animal welfare (7).

14. Two documents recognized by ICLAS as effective refinement tools. OECD makes available a November 2000 publication titled “Guidance document on the recognition, assessment, and use of clinical signs as humane endpoints for experimental animals used in safety evaluation” (5). CCAC makes available the CCAC guidelines Choosing an Appropriate Endpoint in Experiments Using Animals for Research, Teaching and Testing (8).

15. 2003 ILAR workshop on harmonization. The Development of Science-Based Guidelines for Laboratory Animal Care is the proceedings of the November 2003 International Workshop available from NAP (9).

16. ICLAS Working Group on Harmonization of Guidelines. ICLAS provides an introduction to the ICLAS Working Group on Harmonization of Guidelines on the Use of Animals in Science and the report (in Word format) of the First ICLAS Meeting for the Harmonization of Guidelines on the Use of Animals in Science (10). Laboratory Animals Ltd. makes available in PDF format the proceedings of the symposium titled “Internationalisation and harmonisation of laboratory animal care and use issues”; the ICLAS report appears in section 2.

17. ICLAS working group recommends two documents on euthanasia. The AVMA makes available in PDF format the 2000 Report of the AVMA Panel on Euthanasia (13). Laboratory Animals Ltd. makes available in PDF format the 1996 working party report (parts 1 and 2) titled “Recommendations for euthanasia of experimental animals” (14).

18. Gilles Demers is president of ICLAS, Quebec, Canada. Gilly Griffin and Marie Bédard are at the Canadian Council on Animal Care, Ottawa. Guy De Vroey is at Johnson & Johnson, Beerse, Belgium. Joseph R. Haywood is in the Department of Pharmacology and Toxicology, Michigan State University. Joanne Zurlo is at the Institute for Laboratory Animal Research, National Academy of Sciences.

Supporting Online Material

www.sciencemag.org/cgi/content/full/312/5774/700/DC1

All of the authors are members of the Working Group on Harmonization of Guidelines for ICLAS. G. Demers is the President of ICLAS, and G. De Vroey and J. R. Haywood are members of the ICLAS Governing Board; J. R. Haywood represents the International Union of Basic and Clinical Pharmacology. In addition, G. De Vroey was the chair of the subcommittee (of the ICLAS Working Group on Harmonization) on euthanasia and J. R. Haywood the chair of the subcommittee on endpoints.

References and Notes

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