Welfare of Animals used in Research, Testing and Education 實驗用動物、教學用動物的動物福利

1. Welfare of Animals used in Research, Testing and Education實驗用動物、教學用動物的動物福利 Module 22 模組 22

2. This module will enable you to本模組將使您能夠 • Describe the present and likely future uses of animals in research, testing and education 闡明實驗用動物、教學用動物的現況與未來的使用。 • Explain arguments for and against the use of animals in experimentation 了解實驗用動物的贊成/反對論證 • Describe the main welfare issues of animals in laboratories 闡明實驗用動物的主要動物福利議題 • Describe the ‘3 Rs’ 闡明3R的概念 • Describe the types of legislation in force around the world on animal use in research, testing and education闡明全世界實驗用動物、教育用動物的法令

3. How many and what sort ?數量及種類? • Estimated 100 million worldwide全世界估計約1億 • Mice and rats are commonest老鼠、玄鼠最常見 • Species chosen on basis of:選擇特定物種，基於 • Convenience便利性 • Cost成本考量 • Handling & husbandry管理與飼養 • Availability取得性 • Refinement精緻 • Scientific suitability/ ‘Krogh Principle’科學上的實證性/霍科原則

4. Uses of laboratory animals 1實驗動物之利用1 • Fundamental research: Increasing knowledge without immediate practical applications 基礎(純)研究：增進知識無立即應用性 • Physiology (usually invasive)生理學(通常有侵入性) • Research into animal behaviour (could be invasive or non-invasive)動物行為的研究(可能具侵入性或否)

5. Uses of laboratory animals 2實驗動物之利用2 • Applied research (human medicine) e.g.應用研究(人類藥物) 如: • Animal models of human disease 人類疾病的動物實驗 • Drug testing 藥物測試 • Distinction between applied and fundamental research not clear 應用研究與基礎研究的分隔不明顯 • Applied research (veterinary medicine) 應用研究(獸醫用藥物) Investigation of animal disease and production of veterinary drugs 動物生病與藥物生產的調查

6. Uses of laboratory animals 3實驗動物之利用3 • Production and quality control of human and veterinary medicines 人類藥物及獸醫用藥物之生產及品質管理 • Biologicals: medicines made from living organisms or their products e.g. 生物學: 從活的有機體或其產品所製 造的藥物，如: • vaccines 疫苗 • blood and plasma products e.g. antibody production in rabbits 血液及血漿製品，如:兔子所產生的抗體

7. Uses of laboratory animals 4實驗動物之利用4 • Toxicology: Product testing of substances for human safety毒理學:人類使用安全的產品測試 • New drugs 新藥物 • Household products居家用品 • Cosmetics 化妝品

8. Cosmetics testing: Draize test化妝品測試:德萊茲試驗

9. Uses of laboratory animals 4實驗動物之利用4 • Diagnosis of disease – about 2% 疾病診斷用-約2% • Education and training – about 2-3% of laboratory animals are used in dissections, undergraduate wet labs and research 教育及訓練用-約2-3%的實驗動物被用於解剖、大學生物實驗及研究

10. Alternative models in education教學用實驗動物的替代方案

11. Ethics of animal experimentation 1 Arguments for動物試驗倫理學1:贊成使用實驗動物之論述 • ‘Speciesism’ is morally right 物種主義是道德正確 • Utilitarianism: Benefits (to humans) outweigh costs (to animals) 效益主義:(人類)的福祉勝過(動物的)犧牲

12. Ethics of animal experimentation 2 Arguments against動物試驗倫理學2: 反對動物試驗之論述 • Animal suffering is not worth the (alleged) benefits to humans 動物的受苦與人類(聲稱)的利益不能相提並論 • Role of animal research exaggerated 實驗動物的效果被誇大 • Ignores role of improvements in public health (diet, sanitation) 忽視公共衛生(飲食,衛生條件)的改善 • Role of clinical research 臨床研究的角色 • Animal experiments are misleading 動物實驗的誤導

13. Ethics of animal experimentation 2 Arguments against (cont’d)動物試驗倫理學2: 反對動物試驗之論述(續) • Adverse effects of animal testing on human health immoral 動物試驗的不良作用造成不道德的健康後果 • Money better spent elsewhere? 錢應該花到哪兒?

14. Case study: Polio vaccination病例研究：小兒麻痺症疫苗 • Viral disease that paralyses children, sometimes fatal使兒童癱瘓的病毒型疾病(可能導致死亡) • Vaccine research used 1 million Rhesus monkeys, mostly from India 疫苗的研發使用了一百萬隻印度恆河猴 • Results from clinical research may have changed course of vaccine development臨床的研究結果可能顛覆疫苗的發展

15. Welfare issues 1: Sources of animals福利議題1:動物來源 • Animals bred specifically for research 為了研究而飼養動物 • Wild-caught animals 野外捕捉隻動物 • Use of stray animals from pounds or animal shelters 使用繫留所或收容所裡的流浪動物

16. Welfare issues 2: Housing of animals福利議題2:動物舍 • Animals spend most time in housing, not procedures 實驗動物大部份時間都是在動物舍，而非實驗室。 • Often provided with physical needs – food, water and disease prevention 通常提供生理需求物資-食物、水、疾病預防

17. Welfare issues 2: Housing of animals (cont’d)福利議題2:動物舍(續) • Barren environments?空洞的環境? • ‘Environmental enrichment’: 環境豐富化 • Provision of a stimulating environment which improves the animal’s welfare提供動物更多的刺激性來提升動物福利

18. Welfare issues 3: Procedures福利議題3:試驗過程 • Pain in laboratory animals historically poorly recognised and treated有史以來實驗動物的痛人類從不處理。 • Different species show different behaviours – animals are not little humans不同的物種有不同的行為-動物並非人的縮小物 • Analgesia and anaesthesia can reduce pain止痛與麻醉可降低痛苦 • Pain scores can help to measure pain痛計數可幫助測量痛。

19. Welfare issues 3: Procedures(cont’d)福利議題3:試驗過程(續) • Not all procedures are painful並非所有的程序都痛苦 • For example, minor procedures or anaesthetization例如:不嚴重的過程或麻醉 • However, some painful procedures may be seen as ‘minor’ as they are simple or common許多過程被視為不嚴重的原因，只是因為司空見慣，或容易操作

20. Welfare issues 4: Euthanasia福利議題4:安樂死 • Euthanasia because: humane endpoint, end of trial, or integral to experiment安樂死的原因:人道終點、測試或實驗整體的結束。 • Ideal: 理想條件: • Non-painful沒有痛 • Time to unconsciousness and death short快速完成 • Reliable and non-reversible方法要正確, 且非可逆性 • Minimal psychological stress to animals最低的心理壓力 • Safe for operator操作者必須安全 • Death must be confirmed要確認已經死亡 • Methods: Injection, inhalation, physical方法:注射,吸入,物理

21. Primates: A special case?靈長類: 屬於特例嗎? • Primates used in research are mostly marmosets and macaques用於研究之非人猿靈長類主要是狷猴與獼猴 • They enjoy rich social lives and complex mental abilities - greater potential for suffering in laboratory?豐富的社會生活與複雜的心智能力是否在試驗時更會受苦 • Great Apes have even greater mental abilities大猿類有更卓越的心智能力 • Use of Great Apes banned in UK英國禁止使用大猿類試驗

22. New frontiers: Genetic engineering新前鋒: 基因工程 • Number of genetically engineered animals growing fast in scientific research 科學研究下的基因工程動物數量快速成長 • Includes manipulating genes within or between species to produce ‘transgenic animals’ 包含操控物種的基因來產生“基因轉殖動物” • Increasing number of possible commercial applications in animals可增加商業應用

23. Animal applications of genetic engineering基因工程用在動物 • ‘Bio reactors’: Production of therapeutic proteins in milk 「生物反應者」：奶中生產治療用蛋白質 • Livestock/agriculture家畜/農業 • Transgenic animals as models of human diseases基因轉殖動物用於人類疾病研究的模型 • Xenotransplantation(異種移植): Production of compatible organs for transplantation into humansu移植相容的器官到人身上

24. Animal applications of genetic engineering (cont’d)基因工程用在動物(續) • Xenotransplantation: Use of live cells, tissues, and organs from a non-human animal source, transplanted or implanted into humans or used for clinical ex-vivo perfusion異種移植:使用來自非人類動物之活細胞、組織與器官，移植/植入人體或臨床之體外灌注。 • Significant animal welfare problems嚴重關切動物的福利議題 • Significant human health concerns嚴重關切人的健康 • Animal viruses may cross over to humans動物病毒可能轉入人體

25. Alternatives: the 3 Rs其它選項: 3Rs • Experiments as ‘necessary evil’動物試驗是不可避免的惡 • ‘The Principles of Humane Experimental Technique’ Russell and Burch, 1959世界名著:「人道實驗動物技術原則」，1959年 • 3Rs: Replacement, Reduction and Refinement取代、減量、精緻 • Research without animals covers almost every scientific discipline 各學門皆不作動物試驗 William Russell (left) and Rex Burch

26. Research without animals不用動物做研究 • Cell, tissue and organ cultures 細胞培養, 組織培養, 或器官培養 • Biotechnological research 用人類來源的基因做生物技術 • Computer and mathematical models 電腦與數學模型

27. Research without animals 2不用動物做研究 2 • Epidemiological studies流行病學研究 • Clinical research臨床研究 • Human volunteer studies用人類志工做研究

28. Replacement取代 • The replacement of sentient animals with non-living or non-sentient alternatives (Russell and Burch, 1992)用沒有生命或沒有感覺的來取代有感覺的(Russell and Burch, 1992) • Broadening definition to include ‘any approach in scientific research, product testing, and other technical procedures in which no animals are used’ 廣義包含 “任何科學研究、產品測試及操作程序都不使用動物”

29. Reduction減量 • The reduction in the numbers of animals used to an absolute minimum 動物數目降至最低 • Pooling resources收集各項資源 • Appropriate statistics應符合統計原則 • Avoid repetition避免重複試驗 • Questions to ask before embarking on project using animals使用動物的計畫在進行前之問題

30. Refinement精緻 • The reduction of suffering in laboratory animals降低實驗動物受苦 • Suffering includes pain but also other adverse experiences動物受苦包括痛，也有其他負面經驗 • Importance of housing conditions動物舍條件的重要性 • Good welfare = Good science好的福利=好的科學 • Use of anaesthesia and analgesia使用麻醉劑與止痛劑 • Humane endpoints人道終點

31. Legal control of experimentation 1: Centralised inspection合法實驗管理1：中央監督 • Example: UK Animals (Scientific Procedures Act) administered by Home Office例如在英國動物事務(科學程序法) 由內政部主管 • Covers all vertebrates and octopuses掌管所有脊椎動物與八足類 • Licences for researchers, projects and institutions研究員證照，計畫與機構 • Inspectors consider licence applications, inspect institutions to enforce act and give expert advice督察員要察考執照申請、監督機構確實執法並提供建議 • Ethical review committees倫理審查委員會

32. Legal control of experimentation 2: Enforced self-regulation合法實驗管理2：強制自我規範 • Example: Australia例如:澳洲 • has no federal legislation; only state laws against cruelty沒有聯邦立法, 只有防虐之州法 • ‘Code of practice for Care and Use of Animals for Scientific Purposes’ 「動物科學應用之照顧與使用法」 • Code incorporates 3Rs包含3R之法規 • Local committees, containing qualified and lay staff, enforce code地區性委員會包含合格與執法義工

33. Legal control of experimentation 3: Self-regulation合法實驗管理3：自我規範 • Example: USA例如:美國 • Federal Animal Welfare Act excludes birds, rats, mice and farm animals聯邦動物福利法剔除鳥、 鼠、小白鼠、農場動物 • Institutional Animal Care and Use Committees operate locally各機構之動物照顧與使用委員會是地區性運作 • Big funders of animal research have own regulations動物研究之大型財團有自己之規定 • Voluntary accreditation to private organisations非營利認證給私立機構

34. Summary 總結 • Laboratory animals are used for a variety of purposes, from education to drug development實驗動物被應用於各方面，從教育到藥物研發 • Discussion about the ethics of these uses is more than 100 years old 有關的倫理討論已經超過一百年 • Welfare issues of laboratory animals include sourcing, housing, procedures and euthanasia實驗動物的福利益提包含:來源、屋舍、過程與安樂死 • The use of primates in laboratories may offer some special welfare and ethical problems實驗用的靈長類動物有特殊的福利及倫理議題

35. Summary 總結 • Implementation of 3Rs has broad acceptance as a pragmatic way of addressing welfare and ethical issues of laboratory animals 有關實驗動物福利、倫理議題的處理，3R的概念被廣泛接受且確實有用 • More funding and efforts should be put into development, validation and implementation of non-animal replacement alternatives 應投入資金與人力於研發、證實及進行非動物試驗的替代方案 • Genetic engineering creates another set of welfare and ethical problems 基因工程產生新的福利及倫理議題 • There are different laws in force around the world, for the protection of laboratory animals全世界的實驗動物保護法規都不盡相同 • Some laws are stronger than others有些較強，有些較弱

36. Further Reading • Anon (1995) Poor model man; experimenting on chimpanzees. Proceedings of Pace’s Conference on the Use of Chimpanzees in Biomedical Research. Alternatives to Laboratory Animals 23: 571-651 • Anon 2005 Commission of the European Communities. Commission Staff Working Document Annex to the Report on the Statistics on the Number of Animals used for Experimental and other Scientific Purposes in the Member States of the European Union in the year 2002 {COM(2005)7 final}. Brussels. • Alternatives to Animal Use in Research, Testing and Education, U.S. Congress Office of Technology Assessment, Washington, D.C.:Government Printing Office, 1986, p. 64. • Balcombe J 2000 The Use of Animals in Higher Education: Problems, Alternatives, and Recommendations. Humane Society Press, Washington • Balcombe J, Barnard N, Sandusky C 2004. Laboratory routines cause animal stress. Contemporary Topics in Laboratory Animal Science 43(6):42-51.

37. Further Reading • Bhogal N and Combes R (2006) TGN1412: time to change the paradigm for the testing of new pharmaceuticals. Alternatives to Laboratory Animals 34:225–229. • British Union Against Vivsection undercover investigation into monkey farms in Vietnam: http://www.buav.org/campaigns/primates/monkeybusiness/flashindex.html • Brown M, Carbone L, Conlee KM, Dawkins MS, Duncan IJ, Fraser D, Griffin G, Hampshire VA, Lambert LA, Mench JA, Morton D, Richmond J, Rollin BE, Rowan AN, Stephens ML, Wurbel H 2006. Report of the Working Group on Animal Distress in the Laboratory. Lab Anim (NY) 35(8):26-30. • Cavalieri P & Singer P (Eds.) 1994. The Great Ape Project: Equality Beyond Humanity. St. Martins Press • Crawford, L 2004. More compounds failing Phase I. The Scientist 06.08.04

38. Further Reading • De Boo J and Hendriksen C 2005 Reduction Strategies in Animal Research: A Review of Scientific Approaches at the Intra-experimental, Supra-experimental and Extra-experimental Levels. Alt. Lab An. 33: 369-377 • EMEA (1997) Committee for Proprietary Medicinal Products. Note for Guidance on Preclinical and Toxicological Testing of Vaccines. European Medicines Agency (EMEA). Available from: http://www.emea.eu.int/pdfs/human/swp/046595en.pdf • European Union ‘Council Directive 86/609/EEC on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes’ (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31986L0609:EN:HTML

39. Further Reading • Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. (2005) Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 365: 475-481. • Hendriksen C F M, Van der Gun J W , Marsman F R and Kreeftenberg J G 1987 The effects of reductions in the numbers of animal used for the potency assay of the diphtheria and tetanus components of adsorbed vaccines by the methods of the European Pharmacopoeia. Journal of Biological Standardization 15: 353-362. • Knight A, Bailey J, Balcombe J 2006 Animal carcinogenicity studies: 1 poor human predictivity. Alternatives to Laboratory Animals 34(1):19-27. • LaFollette, H and Shanks, N (1994) Animal Experimentation: the legacy of Claude Bernard. International studies in the philosophy of science 8(3): 195-210. • Smith & Boyd (Eds.) 2002. The Use of Non-human Primates in Research and Testing. The Boyd Group, Published by the British Psychological Society.

40. Further Reading • Lazarou J, Pomeranz, B H and Corey, P N (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279:1200-1205. • Physicians Committee for Responsible Medicine News Release July 14 2005:Doctors Sue Merck Over Vioxx Animal Tests. Available from: http://www.pcrm.org/cgi-bin/lists/mail.cgi?flavor=archive&list=news&id=20050714093909 (accessed December 2006 • Rollin, B 1998. The Unheeded Cry: Animal Consciousness, Animal Pain and Science. Iowa State University Press • Statistics of Scientific Procedures on Living Animals Great Britain 2004: http://www.official-documents.gov.uk/document/cm67/6713/6713.pdf (accessed December 2006) • US Food and Drug Administration Press Release September 30 2004. Available at: http://www.fda.gov/bbs/topics/news/2004/NEW01122.html

41. Further Reading • Bailey J 2005. Man or Mouse: Genetically modified animals in medical research – a critical review. Animal Aid, Tonbridge, Kent, UK. www.animalaid.org.uk/images/pdf/manmouse.pdf (accessed December 2006) • De Simone F & Serratosa J 2005. Biotechnology, animal health and animal welfare within the framework of European Union legislation. Rev. sci. tech. Off. int. Epiz. 24(1): 89-99. (www.oie.int/eng/publicat/rt/2401/24-1%20pdfs/08-simone89-100.pdf accessed December 2006) • Group of Advisers to the European Commission on the Ethical Implications of Biotechnology (GAIEB) 1996. Ethical aspects of genetic modification of animals. Opinion No. 7, 21 May 1996. • Kaiser M 2005. Assessing ethics and animal welfare in animal biotechnology for farm production. Rev. sci. tech. Off. int. Epiz. 24(1): 75-87. (www.oie.int/eng/publicat/RT/2401/24-1%20pdfs/07-kaiser75-88.pdf) • Lundstrom, K 2006. Structural genomics: the ultimate approach for rational drug design. Mol. Biotechnol. 34(2): 205-212. • Focus on Alternatives http://www.focusonalternatives.org.uk/PDFs/5th%20World%20Congress%20Poster.pdf (accessed December 2006)

42. Further Reading • Russell WMS and Burch RL 1959 (reprinted 1992). The Principles of Humane Experimental Technique. Universities Federation for Animal Welfare: Wheathampstead, UK • Taylor M 2005. Overview of the NAS report Animal biotechnology: science-based concerns. In: Exploring the Regulatory and Commercialization Issues related to Genetically Engineerd Animals. Pew initiative on food and biotechnology • Worth, A & Balls, M (Eds.) 2002. Alternative (Non-animal) Methods for Chemicals Testing: Current Status and Future Prospects. A Report prepared by ECVAM and the ECVAM Working Group on Chemicals. European Centre for the Validation of Alternative Methods, Institute for Health & Consumer Protection, European Commission Joint Research Centre, 21020 Ispra (VA), Italy • Zucco MF, Botti C, Stammati A, Vitale A, Pollo S, Hendriksen C, De Boo J, Vorstenbosch J, Buchanan-Smith HM, Rennie A (2005). Alternative methods in animal experimentation: evaluating scientific, ethical and social issues in the 3Rs context. Final Report and Recommendations. www.inemm.cnr.it/animalsee/Finalresult.html

43. Further Reading • Nevalainen T, Blom HJM, Guaitani A, Hardy P, Howard BR and Vergara P 2002. FELASA recommendations for the accreditation of laboratory animal science education and training. Laboratory Animals 36: 373-377. (www.felasa.org/Documents/Workinggroups/final_reports/Accreditation_LAS_EdU_TRNG.pdf accessed December 2006) • Gartner K, Buttner D, Dohler K, Friedel R, Lindena J, Trautschold I 1980. Stress response of rats to handling and experimental procedures. Lab Anim. 14(3):267-74. • Home Office UK. Legislation Animals in Scientific Procedures: http://scienceandresearch.homeoffice.gov.uk/animal-research/legislation/ (accessed December 2006) • UK centre for alternatives NC3R: www.nc3rs.org.uk/default.asp?id=1 • Plous & Herzog 2001. Animal Research, Reliability of Protocol Reviews for Animal Research. Science 27 July 2001.

44. Further reading • Animal Welfare Information Center. USDA. Available at: http://awic.nal.usda.gov/nal_display/index.php?info_center=3&tax_level=1) • Barnett, S.W. (Ed.) “Introduction to Animal Technology (2nd Edition)” and “Manual of Animal Technology”. Blackwell Publishing. www.iat.org.uk • INGLIS, B., 1983: Diseases of Civilisation.Granada Publishing, • GREEK, C.R. & GREEK, J.S., 2002: Sacred Cows and Golden Geese: The Human Cost of Experiments on Animals.Continuum International • MCKEOWN, T., 1979: The Role of Medicine. Blackwell Publishing • MELVILLE, A. & JOHNSON, C., 1982: Cured to Death: The Effects of Prescription Drugs. Harper & Collins

45. Further reading • NAVS & LDF, 2002: Monkeys and Men: An assessment of the use of primates and non-animal techniques in neuroscience research. National Anti-Vivisection Society and Lord Dowding Fund for Humane Research/www.navs.org.uk • REINHARDT V, REINHARDT A (Eds). Comfortable Quarters for Laboratory Animals. Animal Welfare Institute, Washington, 2002. Available from:http://www.awionline.org/pubs/cq02/cqindex.html • RUSSELL WMS, BURCH RL 1959 (reprinted 1992) The Principles of Humane Experimental Technique. Universities Federation for Animal Welfare: Wheathampstead, UK • Weatherall, Sir D (Chair) 2006. The use of non-human primates in research. www.acmedsci.ac.uk/images/project/nhpdownl.pdf • Wolfensohn, S & Lloyd, M 1998.Handbook of Laboratory Animal Management and Welfare. Blackwell Science.

46. Websites for alternatives for animals in education • www.interniche.org • www.eurca.org • http://oslovet.veths.no/NORINA • www.HumaneLearning.info • www.avar.org • www.pcrm.org • www.navs.org/site/PageServer?pagename=index • www.hsus.org/animals_in_research/ • www.animalearn.org

47. Websites about the 3 Rs • UK centre for alternatives NC3R: www.nc3rs.org.uk/default.asp?id=1 • Fund for the Replacement of Animals in Medical Experiments: www.frame.org.uk/index.htm • Netherlands Centre Alternatives to Animal use (NCA): www.nca-nl.org/ • John Hopkins University Center for Alternatives to Animal Testing (CAAT): http://caat.jhsph.edu/ • ZEBET – Centre for Documentation and Evaluation of Alternatives to Animal Experiments: www.bfr.bund.de/cd/1591 • Centre for Alternative and Complementary Methods to Animal Testing (ZET): www.zet.or.at/ • European Centre for the Validation of Alternative Methods (ECVAM): http://ecvam.jrc.it/index.htm • The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM): http://iccvam.niehs.nih.gov/ • Japanese Society of Alternatives to Animal Experiments (JSAAE): http://wwwsoc.nii.ac.jp/jsaae/index-e.html • Australian Association for Humane Research (AAHR): www.aahr.asn.au/ • Alternatives Research & Development Foundation (ARDF): www.ardf-online.org/ • AltWeb: http://altweb.jhsph.edu/