Talking Pointpoint the Ethics of Animal Research

talkingtalking pointpoint The ethics of animal research

Talking Point on the use of animals in scientific research Simon Festing & Robin Wilkinson

nimal research has had a vital role assessed in terms of any harm to the ani- hanks to some extensive opinion in many scientific and medical mals. This involves detailed examination of polls by MORI (1999a, 2002, 2005), Aadvances of the past century and the particular procedures and experiments, Tand subsequent polls by YouGov continues to aid our understanding of vari- and the numbers and types of animal used. (2006) and ICM (2006), we now have a ous diseases. Throughout the world, peo- These are then weighed against the poten- good understanding of the public’s atti- ple enjoy a better quality of life because tial benefits of the project. This cost–benefit tudes towards animal research. Although of these advances, and the subsequent analysis is almost unique to UK animal society views animal research as an ethi- development of new medicines and treat- research legislation; only German law has cal dilemma, polls show that a high pro- ments—all made possible by animal a similar requirement. portion—84% in 1999, 90% in 2002 and research. However, the use of animals in 89% in 2005—is ready to accept the use of scientific and medical research has been The UK has gone further than animals in medical research if the research a subject of heated debate for many years is for serious medical purposes, suffering in the UK. Opponents to any kind of ani- any other country to write such is minimized and/or alternatives are fully mal research—including both animal- an ethical framework into law considered. When asked which factors rights extremists and anti-vivisectionist by implementing the Animals should be taken into account in the regu- groups—believe that animal experimenta- (Scientific Procedures) Act 1986 latory system, people chose those that— tion is cruel and unnecessary, regardless unknown to them—are already part of the of its purpose or benefit. There is no mid- UK legislation. In general, they feel that dle ground for these groups; they want the In addition, the UK government intro- animal welfare should be weighed against immediate and total abolition of all animal duced in 1998 further ’local’ controls—that health benefits, that cosmetic-testing research. If they succeed, it would have is, an Ethical Review Process at research should not be allowed, that there should enormous and severe consequences for institutions—which promote good animal be supervision to ensure high standards of scientific research. welfare and humane science by ensuring welfare, that animals should be used only No responsible scientist wants to use that the use of animals at the designated if there is no alternative, and that spot- animals or cause them unnecessary suf- establishment is justified. The aims of this checks should be carried out. It is clear fering if it can be avoided, and therefore additional review process are: to provide that the UK public would widely support scientists accept controls on the use of ani- independent ethical advice, particularly the existing regulatory system if they knew mals in research. More generally, the bio- with respect to applications for project more about it. science community accepts that animals licences, and standards of animal care and should be used for research only within an welfare; to provide support to licensees It is clear that the UK public ethical framework. regarding animal welfare and ethical issues; The UK has gone further than any other and to promote ethical ana lysis to increase would widely support the country to write such an ethical framework awareness of animal welfare issues and existing regulatory system if they into law by implementing the Animals to develop initiatives for the widest possi- knew more about it (Scientific Procedures) Act 1986. It exceeds ble application of the 3Rs—replacement, the requirements in the European Union’s reduction and refinement of the use of ani- Directive 86/609/EEC on the protection of mals in research (Russell & Burch, 1959). Unsurprisingly, medical general prac- animals used for experimental and other In practice, there has been concern that titioners (GPs) are even more aware of the scientific purposes, which is now under- the Ethical Review Process adds a level of contribution that animal research has made going revision (Matthiessen et al, 2003). bureaucracy that is not in proportion to its and continues to make to human health. The Act requires that proposals for research contribution to improving animal welfare In 2006, a survey by GP Net showed that involving the use of animals must be fully or furthering the 3Rs. 96% of GPs agreed that animal research

As a House of Lords Select Committee report in July 2002 stated, “The availabil- ity to the public of regularly updated, good quality information on what animal experiments are done and why, is vital to create an atmosphere in which the issue of animal experimentation can be discussed produc- tively” (House of Lords, 2002). Indeed, according to a report on public attitudes to the biological sciences and their oversight, “Having information and perceived hon- esty and openness are the two key consid- erations for the public in order for them to have trust in a system of controls and regulations about biological developments” (MORI, 1999b). In the past five years, there have been four major UK independent inquiries into the use of animals in biomedical research: a Select Committee in the House of Lords (2002); the Animal Procedures Committee (2003); the Nuffield Council on Bioethics (2005); and the Weatherall Committee (Weatherall et al, 2006), which specifi- cally examined the use of non-human primates in scientific and medical research. has made important contributions to many such as the research councils. The FOI Act is All committees included non-scientists medical advances (RDS News, 2006). The intended to promote openness and account- and examined evidence from both sides opinion poll also sought doctors’ views ability, and to facilitate better public under- of the debate. These rigorous independent about the safety testing of medicines. standing of how public authorities carry out inquiries all accepted the rationale for the Almost nine out of ten GPs (88%) agreed their duties, why and how they make deci- use of animals in research for the benefit of that new medicines should be tested on sions, and how they spend public money. human health, and concluded that animal animals before undergoing human trials. There are two ways in which information can research can be scientifically validated on GP Net also asked whether GPs agreed be made available to the public: some infor- a case-by-case basis. The Nuffield Council that “medical research data can be mis- mation will be automatically published and backed the 3Rs and the need for clear infor- leading”; 93% agreed. This result puts into some will be released in response to indi- mation to support a constructive debate, context the results from another poll of GPs vidual requests. The FOI Act is retro spective and further stated that violence and intimi- in 2004. Europeans for Medical Progress so it applies to all information, regardless of dation against researchers or their allies is (EMP; London, UK), an anti-vivisection when it was created. morally wrong. group, found that 82% had a “concern […] In response to the FOI Act, the Home that animal data can be misleading when Office now publishes overviews of all new Animal research has obviously applied to humans” (EMP, 2004). In fact, animal research projects, in the form of it seems that most GPs think that medical anonymous project licence summaries, on become a smaller proportion of research in general can be misleading; it a dedicated website. This means that the overall bioscience and medical is good scientific practice to maintain a UK now provides more public information R&D spending in the UK healthy degree of scepticism and avoid about animal research than any other coun- over-reliance on any one set of data or try. The Research Defence Society (RDS; research method. London, UK), an organization representing In addition, the Advertising Standards doctors and scientists in the debate on the Authority (ASA; London, UK) has investi- nother law, which enables people use of animals in research and testing, wel- gated and ruled on 38 complaints made to get more information, might also comes the greater openness that the FOI Act since 1992 about published literature— Ahelp to influence public attitudes brings to discussions about animal research. leaflets and brochures—regarding claims towards animal research. The UK Freedom With more and reliable information about about the validity or otherwise of animal of Information (FOI) Act came into full force how and why animals are used, people research and the scope of alternative meth- on 1 January 2005. Under the Act, anybody should be in a better position to debate the ods. In 34 out of 38 cases, they found can request information from a public body issues. However, there are concerns that against the anti-vivisectionist groups, either in England, Wales or Northern Ireland. extremist groups will try to obtain personal supporting complaints about anti-vivisec- Public bodies include government depart- details and information that can identify tionist literature, or rejecting the com- ments, universities and some funding bodies researchers, and use it to target individuals. plaints by anti-vivisectionists about the

literature from medical organizations. Only and incremental decreases in some types of complex physiological systems of whole four complaints against scientific/medical animal use over recent years, whilst novel living organisms—a challenge that will be research literature have been upheld, not medicines have continued to be produced. hard to meet. There has been some progress because the science was flawed but as This is an achievement of which the sci- recently imitating single organs such as the a result of either semantics or the ASA entific community can be rightly proud” liver, but these need further refinement to judging that the advertisement fell outside (Flint, 2005). make them suitable models for an entire the UK remit. After a period of significant reduction, organ and, even if validated, they can- the number of regulated animal proce- not represent a whole-body system. New Animal-rights groups also dures stabilized from 1995 until 2002. and promising techniques such as micro- Between 2002 and 2005, the use of geneti- dosing also have the potential to reduce the disagree with the 3Rs, since these cally modified animals—predominantly number of animals used in research, but principles still allow for the use of mice—led to a 1–2% annual increase in again cannot replace them entirely. animals in research; they are only the number of animals used (Home Office, Anti-vivisectionist groups do not accept interested in replacement 2005). However, between 1995 and 2005, this reality and are campaigning vigorously the growth in UK biomedical research far for the adoption of other methods with- outstripped this incremental increase: com- out reference to validation or acceptance However, seemingly respectable main- bined industry and government research of their limitations, or the consequences stream groups still peddle dangerously mis- and development (R&D) spending rose by for human health. Animal-rights groups leading and inaccurate information about 73% from £2,080 million to £3,605 million also disagree with the 3Rs, since these the use of animals in research. As previ- (ABPI, 2007; DTI, 2005). Animal research principles still allow for the use of ani- ously mentioned, EMP commissioned a has obviously become a smaller propor- mals in research; they are only interested survey of GPs that showed that the “major- tion of overall bioscience and medical in replacement. Such an approach would ity of GPs now question the scientific worth R&D spending in the UK. This shows the ignore the recommendations of the House of animal tests” (EMP, 2004). The raw data commitment of the scientific community of Lords Select Committee report, and is available on the website of EMP’s sister to the development and use of replace- would not deal with public concerns about group Americans For Medical Advancement ment and reduction techniques, such as animal welfare. Notwithstanding this, the (AFMA; Los Angeles, CA, USA; AFMA, computer modelling and human cell lines. development of alternatives—which invar- 2004), but their analysis is so far-fetched Nevertheless, animal research remains iably come from the scientific community, that the polling company, TNS Healthcare a small, but vital, part of biomedical rather than anti-vivisection groups—will (London, UK), distanced itself from the research—experts estimate it at about 10% necessitate the continued use of animals conclusions. In a statement to the Coalition of total biomedical R&D spending. during the research, development and for Medical Progress (London, UK)—a validation stages. group of organizations that support animal he principles of replacing, reduc- research—TNS Healthcare wrote, “The con- ing and refining the use of animals Society should push authorities clusions drawn from this research by AFMA in scientific research are central to T to quickly adopt successfully are wholly unsupported by TNS and any UK regulation. In fact, the government research findings or comment published established the National Centre for the validated techniques, while by AFMA is not TNS approved. TNS did not Replacement, Refinement and Reduction realizing that pushing for provide any interpretation of the data to the of Animals in Research (NC3Rs; London, adoption without full validation client. TNS did not give permission to the UK) in May 2004 to promote and develop could endanger human health client to publish our data. The data does high-quality research that takes the 3Rs into not support the interpretation made by the account. In support of this, then Science client (which in our opinion exaggerates Minister Lord Sainsbury announced in The scientific community, with par- anything that may be found from the data)” 2005 that the Centre would receive an ticular commitment shown by the pharma- (TNS Healthcare, 2004). Nonetheless, EMP additional £1.5 million in funding over the ceutical industry, has responded by has used its analysis to lobby government next three years. investing a large amount of money and ministers and misinform the public. The ultimate aim of the NC3Rs is to sub- effort in developing the science and tech- stitute a significant proportion of animal nology to replace animals wherever pos- pproximately 2.7 million regulated research by investigating the development sible. However, the development of direct animal procedures were conducted of alternative techniques, such as human replacement technologies for animals is a Ain 2003 in the UK—half the number studies, and in vitro and in silico studies. slow and difficult process. Even in regula- performed 30 years ago. The tight controls RDS supports this aim, but believes that tory toxicology, which might seem to be governing animal experimentation and the it is unrealistic to expect this to be pos- a relatively straightforward task, about widespread implementation of the 3Rs by sible in every area of scientific research in 20 different tests are required to assess the the scientific community is largely responsi- the immediate future. After all, if the tech- risk of any new substance. In addition, intro- ble for this downward trend, as recognized nology to develop these alternatives is not ducing a non-animal replacement tech- recently by then Home Office Minister, available or does not yet exist, progress is nique involves not only development of the Caroline Flint: “…new tech nologies in likely to be slow. The main obstacle is still method, but also its validation by national developing drugs [have led] to sustained the difficulty of accurately mimicking the and international regulatory authorities.

These authorities tend to be conservative Research (Harrogate, UK), funded research animal in some studies and has therefore and can take many years to write a new into the use of cell cultures to understand reduced the number of mice used (Double, technique into their guidelines. Even then, better the cellular mechanisms of prostate 2004). In neuroscience, techniques such some countries might insist that animal cancer—allowing researchers to investigate as cooling regions of the brain instead of tests are carried out if they have not been potential therapies using fewer animals. removing subsections, and magnetic reso- explicitly written out of the guidelines. Microdosing is an exciting new tech- nance imaging, have both helped to reduce Society should push authorities to quickly nique for measuring how very small doses the number of laboratory animals used adopt successfully validated techniques, of a compound move around the body. (Royal Society, 2004). while realizing that pushing for adoption In principle, it should be possible to use without full validation could endanger this method in humans and therefore to The benefits of animal research human health. reduce the number of animals needed to have been enormous and it study new compounds; however, it too has espite the inherent limitations of limitations. By its very nature, it cannot would have severe consequences some non-animal tests, they are predict toxicity or side effects that occur at for public health and medical Dstill useful for pre-screening com- higher therapeutic doses. It is an unrealistic research if it were abandoned pounds before the animal-testing stage, hope—and a false claim—that microdosing which would therefore reduce rather than can completely replace the use of animals replace the number of animals used. An in scientific research; “animal studies will Matching the number of animals gen- example of this is the Ames test, which still be required,” confirmed the Fund for erated from breeding programmes to the uses strains of the bacterium Salmonella the Replacement of Animals in Medical number of animals required for research has typhimurium to determine whether chemi- Experiments (FRAME; Nottingham, UK; also helped to reduce the number of surplus cals cause mutations in cellular DNA. FRAME, 2005). animals. For example, the cryopreservation of This and other tests are already widely However, as with many other advances sperm and oocytes has reduced the number used as pre-screens to partly replace in non-animal research, this was never clas- of genetically modified mice required for rodent testing for cancer-causing com- sified as ‘alternatives research’. In general, breeding programmes (Robinson et al, 2003); pounds. Unfortunately, the in vitro tests there is no separate field in biomedical mice lines do not have to be continuously can produce false results, and tend to be research known as ‘alternatives research’; it bred if they can be regenerated from frozen used more to understand the processes of is one of the highly desirable outcomes of cells when required. mutagenicity and carcinogenicity than to good scientific research. The claim by anti- replace animal assays. However, there are vivisection campaigners that research into lthough animals cannot yet be moves to replace the standard mouse car- replacements is neglected merely reflects completely replaced, it is impor- cinogenicity assay with other animal-based their ignorance. Atant that researchers maximize tests that cause less suffering because reduction and refinement. Sometimes this they use fewer animals and do not take ood science and good experimen- is achieved relatively easily by improving as long. This has already been achieved tal design also help to reduce the animal husbandry and housing, for exam- in tests for acute oral toxicity, where the Gnumber of animals used in research ple, by enriching their environment. These LD50—the median lethal dose of a sub- as they allow scientists to gather data using simple measures within the laboratory aim stance—has largely been replaced by the the minimum number of animals required. to satisfy the physiological and behavioural Fixed Dose Procedure, which was devel- However, good science also means that a needs of the animals and therefore maintain oped, validated and promoted between sufficient number must be used to enable their well-being. 1984 and 1989 by a worldwide collabo- precise statistical analysis and to generate Another important factor is refining ration, headed by scientists at the British significant results to prevent the repetition the experimental procedures themselves, Toxicological Society (Macclesfield, UK). of experiments and the consequent need to and refining the management of pain. An use more animals. In 1998, FRAME formed assessment of the method of administra- Although animals cannot yet a Reduction Committee, in part to publicize tion, the effects of the substance on the be completely replaced, it is effective reduction techniques. The data animal, and the amount of handling and collected by the Committee so far provides restraint required should all be consid- important that researchers information about the overall reduction in ered. Furthermore, careful handling of the maximize refinement and animal usage that has been brought about animals, and administration of appropri- reduction by the efforts of researchers worldwide ate anaesthetics and analgesics during the (FRAME Reduction Committee, 2005). experiment, can help to reduce any pain For example, screening potential anti- experienced by the animals. This culture of Furthermore, cell-culture based tests cancer drugs uses the so-called hollow-fibre care is achieved not only through strict reg- have considerably reduced the use of system, in which tumour cells are grown in ulations but also by ensuring that animal rodents in the initial screening of potential a tube-like polymer matrix that is implanted technicians and other workers understand new medicines, while speeding up the proc- into mice. Drugs are then administered, and adopt such regulations. Therefore, ade- ess so that 10–20 times the number of com- the tubes removed and the number of cells quate training is an important aspect of the pounds can be screened in the same period. determined. This system has increased the refinement of animal research, and should A leading cancer charity, Yorkshire Cancer amount of data that can be obtained per continually be reviewed and improved.

In conclusion, RDS considers that the Flint C (2005) Report by the Animal Procedures Royal Society (2004) The Use of Non-Human use of animals in research can be ethi- Committee—Review of Cost Benefit Assessment Animals in Research: A Guide for Scientists. in the Use of Animals in Research: Ministerial London, UK: The Royal Society cally and morally justified. The benefits of Response. London, UK: Home Office Russell WMS, Burch RL (1959) The Principles of animal research have been enormous and FRAME (2005) Human microdosing reduces the Humane Experimental Technique. London, UK: it would have severe consequences for number of animals required for pre-clinical Methuen public health and medical research if it pharmaceutical research. Altern Lab Anim TNS Healthcare (2004) Statement to the Director 33: 439 of Coalition for Medical Progress. London, UK: were abandoned. Nevertheless, the use of FRAME Reduction Committee (2005) Bibliography TNS Healthcare the 3Rs is crucial to continuously reduce of Training Materials on Experimental Design Weatherall D, Goodfellow P, Harris J, Hinde R, the number and suffering of animals in and Statistical Analysis. Nottingham, UK: Johnson L, Morris R, Ross N, Skehel J, Tickell C research. Furthermore, a good regulatory Fund for the Replacement of Animals in (2006) The Use of Non-Human Primates in Medical Experiments. www.frame.org.uk/ Research. London, UK: The Royal Society regime—as found in the UK—can help reductioncommittee/bibliointro.htm YouGov (2006) Animal Testing. Daily Telegraph to reduce further the number of animals Home Office (2005) Statistics of Scientific Survey Results. London, UK: YouGov. used. Therefore, we support a healthy and Procedures on Living Animals, Great Britain 2004. www.yougov.com continued debate on the use of animals London, UK: Home Office in research. We recognize that those who House of Lords (2002) Select Committee on Animals in Scientific Procedures, Volume I—Report. oppose animal experimentation should be London, UK: The Stationery Office free to voice their opinions democratically, ICM (2006) Vivisection survey, conducted on behalf and we look forward to constructive dis- of BBC Newsnight. London, UK: ICM Research. cussion in the future with organizations www.icmresearch.co.uk Matthiessen L, Lucaroni B, Sachez E (2003) Towards that share the middle ground with us. responsible animal research. EMBO Rep 4: 104–107 REFERENCES MORI (1999a) Animals in Medicine and Science. ABPI (2007) Facts & Statistics from the Research Study Conducted for the Medical Pharmaceutical Industry. London, UK: Research Council. London, UK: MORI. Association of the British Pharmaceutical www.ipsos-mori.com Industry. http://www.abpi.org.uk/statistics/ MORI (1999b) The Public Consultation on Simon Festing is Executive Director and section.asp?sect=3 Developments in the Biosciences. Executive Robin Wilkinson is Science Communications AFMA (2004) New Survey Among Doctors Summary. London, UK: MORI. Officer at the Research Defence Society Suggests Shift in Attitude Regarding Scientific www.ipsos-mori.com in London, UK. Worth of Animal Testing. Listed as EFMA Survey MORI (2002) The Use of Animals in Medical E-mail: [email protected] of 500 General Practitioners. Los Angeles, CA, Research. Research Study Conducted for the USA: Americans For Medical Advancement. Coalition for Medical Progress. London, UK: doi:10.1038/sj.embor.7400993 www.curedisease.com MORI. www.ipsos-mori.com Animal Procedures Committee (2003) Review MORI (2005) Use of Animals in Medical Research. of Cost–Benefit Assessment in the Use of Research Study Conducted for Coalition for Animals in Research. London, UK: Animal Medical Progress. London, UK: MORI. Procedures Committee. www.apc.gov.uk www.ipsos-mori.com Double JA (2004) A pharmacological approach Nuffield Council on Bioethics (2005) The Ethics for the selection of potential anticancer agents. of Research Involving Animals. London, UK: Altern Lab Anim 32: 41–48 Nuffield Council on Bioethics DTI (2005) Science Funding SET Statistics. RDS News (2006) GPs Back Animal Research. London, UK: Department of Trade and Industry. London, UK: Research Defence Society For more discussion on this topic, see also www.dti.gov.uk Robinson V et al (2003) Refinement and reduction Gannon F (2007) Animal rights, human wrongs? EMP (2004) Doctors Fear Animal Experiments in production of genetically modified mice: This issue p519. Endanger Patients. Press release. London, UK: Sixth report of BVAAWF/FRAME/RSPCA/UFAW Rollin BE (2007) Animal research: a moral Europeans for Medical Progress. Joint Working Group on Refinement. Lab Anim science. This issue p521. www.curedisease.net 37: 1–51