Replacement
Alternatives are often argued not to be ‘the real thing’, but neither are live animal models. In the field of toxicity testing, the US National Academy of Sciences17 has put forward a vision of replacement using high-throughput in vitro screening assays, tests in ‘lower’ organisms, systems biology, functional genomics and transcriptomics as well as predictive in silico approaches. Practical moves towards replacement among regulatory authorities include the Organisation for Economic Co-operation and Development (OECD) guidelines18 accepting the use of artificial human skin as a replacement for living skin in the testing of chemical irritancy. Groups such as the European Centre for the Validation of Alternative Methods (http://ecvam.jrc.it/), the European Partnership for Alternative Approaches (http://ec.europa.eu/enterprise/epaa/), the Centre for Alternatives to Animal Testing – Europe (http://caat.jhsph.edu/about/_includes/index_eu.html) and the In Vitro Testing Industrial Platform (www.ivtip.org/) have risen to prominence in recent years as impetus (and funding) has increased the rate of discovery and application of alternatives to chemical and drug safety testing.
Reduction
When animals cannot be replaced, proper planning of experiments is required in order to produce reliable data with the fewest and most suitable animals. The application of statistical methods such as power analysis and blocking, and the use of inbred strains of animal to reduce variation have been advocated for many years19 with some success. Yet it remains frustrating that surveys of published data continue to show improper designs or a lack of uptake of these ideas20.
Refinement
Refinement can improve welfare by acting on both direct and contingent suffering. The search for refinement must be continual to take advantage of technological advances.
Academic research tends to be very focused into narrow areas. Scientists are strongly driven to do high-quality research in their field, but may lack similar drive when evaluating the influence of methodology on the scientific quality of their results or on the welfare of animals used. The implementation of the three Rs is seen almost as a separate subject area, whereas it would be better if seen as a normal part of the research package and integrated into it. Within the pharmaceutical sector, strong corporate drivers for consistency and harmonisation within global organisations can be used to bring about refinement (e.g. housing improvements) and in an increasingly tough external environment, a strong focus on corporate reputation can also bring useful leverage to welfare initiatives.
Some current examples of refinement include
- the almost universal application and continuous updating of anaesthesia and analgesia methods,
- a refined non-surgical technique involving trans-cervical instillation of genetically altered embryos into the uterus of surrogate recipients, potentially rendering laparotomies redundant for many thousands of mice21,
- clear evidence that the usual method of capturing and picking up mice (by the tail), results in anxiety compared with cupping, and may impinge on welfare22.
A key requirement for the three Rs is sharing accurate data. There remains a reluctance from scientists and publishers to use print space to report negative results or experimental ‘failures’, which, if overcome, would avoid needless repetition23. Sufficient detail on animal care for experiments to be reliably repeated without errors is often lacking24. The Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines are a welcome initiative designed to correct this deficiency25.
Prospective, ongoing and retrospective review: reflective practice and the refinement loop
Refinement is an iterative process, which begins with a critical evaluation of practice, leading to recognition and assessment of poor or suboptimal welfare, identification of the causes of this, selection of improvement strategies and implementation of these strategies. Any changes then have to be evaluated for their efficacy; thus the process begins again, forming the refinement loop (see Figure 2.2)26.
Critical evaluation of practice
Researchers have to look critically at what they do and identify whether there is a better way of conducting the research that will minimise welfare implications and maximise the scientific output, thus improving the harm/benefit balance and the justification for doing the work. It is particularly important that this is seen as an ongoing requirement: new developments in refinement may turn what was yesterday’s best practice into today’s outdated methodology.
Objective assessment of animal welfare and scientific quality
This requires first and foremost an understanding of well-being and what particular animals need. Only then is it possible to identify appropriate parameters to assess well-being and scientific quality in a meaningful manner. Sufficient resources have to be provided to perform the assessments effectively. This requires the researcher to schedule observations appropriately to maximise the likely detection of problems, to recognise where there is deviation from normal, taking into account species, strain and inter-animal differences and to be able to identify when there is room for improvement.
Evaluation of improvement strategies
Having implemented an improvement strategy it must be evaluated to determine whether there has been an improvement. It may be that the new method is found to be better, or that the current method is confirmed as being the best one available; either way, the information is valuable to others in the field. This information should then be disseminated to others working in the same area, ideally by publication in mainstream journals, but as a minimum it should be used for internal reference.
It is essential to coordinate the approach to refinement within an institution or organisation. It may be beneficial to identify someone with overall responsibility for this: a ‘refinement champion’ who is responsible for ensuring that refinements are actively implemented at the establishment. The institution needs to ensure that support is available for key people in developing a culture of care, and that the professional integrity of the experts in welfare assessment is recognised. The animal management team needs to communicate effectively with senior management, to make sure that adequate resources are provided to implement refinements appropriately. There should be a clear process for the implementation and reporting of problems, and the development of a culture of advice-seeking and support, not blame and isolation. Scientists need to recognise that there is a learning curve to all new methods, and accept that while inexperience may lead to new or increased problems in the short term, there will be longer-term benefits from perseverance. Refinements may be developed to enhance animal welfare, to improve scientific quality or sometimes simply as a defensive reaction to prevent criticism of old-fashioned methodologies. The underlying reason of why a procedure is done matters less than what is done, when, how and by whom.
Public Perceptions
The polling company Ipsos MORI has been asking the public in the UK about their views on animal research since 199927. Among their findings, as reported by the organisation Understanding Animal Research (www.understandinganimalresearch.org.uk/your_views), was that throughout this time more than 80% of respondents accepted the need for animal research provided that certain conditions were being met:
- that there is no unnecessary suffering,
- that the research is for serious medical or life-saving purposes,
- that there is no alternative.
Much of the existing regulatory process is built around a desire to satisfy these caveats. The Ipsos MORI poll showed that, since 2005, a majority of the surveyed population ‘expect that the rules in Britain on animal experimentation are well enforced’. A significant, and often vocal, minority of the population are opposed to any use of animals in research and campaigning organisations such as the British Union for the Abolition of Vivisection (BUAV) argue that ‘harming animals in the name of science is morally indefensible’ (www.buav.org/humane-science).
For the most part, society accepts that the use of animals is necessary for medical progress, provided there are assurances over the purpose for which the work is carried out and the degree of suffering inflicted. Surveys have shown that people will accept a greater degree of suffering to animals in the pursuit of cures for devastating illnesses such as childhood leukaemia than for minor problems or for toxicity testing28. However, there is a significant sector in society which believes that however high the anticipated benefit no animal should undergo more than transient suffering, which may be at odds with the interests of science and industry. A majority of people seem to support the use of mice in fundamental biomedical research if they come to no harm, but begin to show disapproval as soon as pain, surgery or illness became involved. If animal suffering cannot be ruled out it may be hard to convince the public of the value of fundamental biological research. However, much research of this type is relatively benign, and so might win public support if measures to limit suffering were implemented effectively and described in detail. It is up to the scientist therefore to fully explain the nature of the work being undertaken, and to put it in context, such that the public can understand the motives for the work and gain a greater understanding of research.
In contrast to the many examples in which animals suffer pointlessly (it could be argued; such as over-exploitation of sporting animals in competitions, cosmetic mutilations or organised dog fighting) at the hands of people, usage of laboratory animals in experimental procedures is purposeful and is ethically scrutinised in advance. However, this process leads to the harms that might occur being premeditated, which may lead to accusations of scientists being unemotional, inhumane or even abusive29. Although animal research has historically received public criticism similar to activities such as hunting, fishing and factory farming, the moral case for carefully controlled research using animals is actually much more defensible. And yet, an individual animal’s perception of pain and suffering is the same whatever the context or ‘reason’ for its life. A laboratory animal will not have the benefit of knowing that its harm is for a ‘good cause’; nor can it give permission. A system to compare life experiences of laboratory animals with farm, companion or wild animals has been proposed15.
Transparency and freedom of information
Modern society demands accountability in laboratory animal use. If this use is truly defensible and ethically robust, it should be more transparent. Labelling drugs and household substances to show whether animals were used during development could be part of this. This would build trust, assist those who do not wish to use products derived from experiments involving animals and increase uptake of the three Rs. However, some patients may refuse important treatment. Much of the information held in research institutes and by the funding agencies is now available under the UK Freedom of Information Act. This has caused some concern as researchers worry about the security implications of actions by animal rights protesters.
Campaigners in the UK have historically played a vital role in bringing about legislation to control animal research. Martin’s Act of 1822 against cattle cruelty, the Cruelty to Animals Act 1876 and the Animals (Scientific Procedures) Act 1986 all owed an enormous amount to campaigners bringing the issues into the public arena. Activism has directly influenced the research of some groups30 and different parts of the scientific community have either adopted greater public openness or been driven to regrettable but understandable secrecy. Animal cruelty has no doubt occurred in the history of research and anti-vivisectionists have rightly called attention to it. Establishment in 1999 of the local ERP owes much to the importance placed on animal welfare and the ethics of animal research. There is now a degree of peer pressure in many establishments to ensure that the welfare of animals is paramount, both for its own sake and for the management of wider reputational risks. The modern research community generally puts the ethics of animal experimentation at the heart of all its work, and the aim for the future must be not only to maintain this high standard but to continue openly to seek improvement.
During a 2-day conference in Basel in 2010, more than 80 life science researchers from Switzerland, Germany, Sweden, France and Great Britain addressed the problems of animal research and adopted the Basel Declaration (www.basel-declaration.org/). The Declaration marks an unprecedented effort of the scientific community towards more trust, transparency and communication on animal research. The signatories commit to accepting greater responsibility in animal experiments and to intensive cooperation with the public, and also with national and international decision makers. They are actively seeking to show that science and animal welfare are not diametrically opposed and to make a constructive contribution to the dialogue taking place in society.
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