Ethics of Research involving animals
Barriers to developing Replacements and how these could be overcome
11.19 There are some general principles regarding the constraints on the development of Replacements. These are well documented in the case of toxicity testing required by regulation14 but many of the same principles apply to biomedical research. We now consider some general features of scientific and non-scientific barriers to developing Replacements. In Chapter 15 (paragraphs 15.61–15.67) we set out recommendations about how they might be overcome.
Scientific barriers
11.20 There are scientific obstacles to developing relevant and reliable non-animal methods that can mimic the complex integrated physiological systems of humans and others animals. It is extremely difficult, using computational or in vitro systems, to take account of factors such as:
- The diversity of different tissues and cell types that make up a living organism; hundreds of different cell types at various stages of development may function and respond in different ways, or to different degrees.
- The ways in which cells and tissues interact, both locally and via the bloodstream and nervous system; immune reactions, germ cell development, metabolism and many other normal and disease-related processes involve extensive interaction between cells of different types and in various locations in the body.
- The influence of tissue organisation on the cellular environment; oxygen levels, rate of nutrient supply, intercellular communication and barrier formation all affect how cells behave and respond to external stimuli.
11.21 In research involving human volunteers, the scientific constraints are quite different, and usually secondary to ethical considerations. They include problems caused by variability (genetic and lifestyle) in the human population, the difficulty of controlling environmental variables such as diet and health over long periods, and the slow rate of human reproduction. Although human variability is an intrinsic facet of the very subject of medical research, there are occasions when it makes the design of conclusive scientific studies on humans impossible (see paragraph 10.33).
11.22 Scientific barriers to Replacement are likely to be more difficult to overcome in some areas of research than in others, and need to be considered on a case by case basis. To make further progress, there is an obvious need for scientific research to find ways of overcoming obstacles, and to develop non-animal techniques capable of addressing scientific questions about how biological systems work, how they are altered in disease, and how they are affected by chemicals and medicinal products.
Non-scientific barriers
11.23 Scientific obstacles are not the only limiting factors in replacing animal research. There are other possible constraints that may impede the implementation of Replacements. They include: regulatory inertia, insufficient funding, non-availability of human tissue, lack of incentives to explore the potential of Replacements, lack in the availability of information about suitable Replacements, insufficient integration of in vitro and in vivo research, and the possibility that tradition and conservatism may mean that researchers are reluctant to explore the potential of Replacements.
Regulatory inertia
11.24 Regulatory agencies have the crucial role of ensuring the safe use of products such as industrial chemicals, pharmaceuticals or vaccines. A very complex and intensely bureaucratic regulatory system has evolved to achieve adequate protection of humans, animals and the environment. The introduction of Replacements for established animal tests is therefore not straightforward. Regulatory authorities can be reluctant to depart from methods which they have traditionally relied upon for safety and liability requirements. The international regulatory authorities also need to be convinced that the alternative methods which are available and accepted in particular countries provide an adequate assessment of risk. Intensive efforts are needed to facilitate and accelerate the validation and regulatory acceptance of Replacements through bodies such as the OECD and ICH, as well as ECVAM and the European Commission (see paragraphs 11.32 and 15.84–15.87).
Funding
11.25 It is difficult to estimate accurately the amount of funding that is spent on research into Replacements. This is partly because funds are more commonly made available for all Three Rs rather than specifically for Replacement. Research is often directed towards developing specific techniques that, although they may have potential as Replacements, are envisaged as advanced methods rather than targeted specifically at replacing animals. There is a small number of charities such as FRAME, the Dr Hadwen Trust, the Lord Dowding Fund and the Humane Research Trust (see Boxes 2.3 and 2.4) that are dedicated to funding research on Replacements, but their budgets are limited.15 More recently, major research funding bodies, such as the MRC, the Biotechnology and Biological Sciences Research Council (BBSRC), and the newly established NC3Rs, have offered limited funds for research specifically dedicated to the development of Replacements (see Box 11.3). The pharmaceutical and chemical industries have already invested comparatively large sums in research on Replacements, particularly in toxicology, and seem likely to increase that investment.16 An initiative has also been established by the cosmetics and chemical industries, which seeks to fund development of Replacements in a limited number of specific regulatory tests.17
Availability of human tissue
11.26 Controversy surrounding issues of informed consent have highlighted ethical constraints on obtaining human tissue for research. In the UK, concerns about the unauthorised retention of human tissue and organs at a number of hospitals led to the drafting on new legislation to regulate their use.18 The draft provisions of the Human Tissue Bill were criticised by a range of stakeholders who feared that difficulties in both recruiting volunteers and gaining access to human tissue for use in non-animal research would be increased.19 However, revisions made in light of the ensuing discussion appear to have met most of these.
Incentives
11.27 Biomedical researchers are usually under pressure to achieve results and solve problems quickly. A number of factors are likely to influence this pressure: these include a genuine urgency to understand and alleviate human or animal suffering and a competitive environment that frequently makes research grants dependent on publication activity. In either case, researchers may be reluctant to spend time on developing non-animal alternative methods when it appears that an available animal method will give publishable results. In addition, the development of alternative methods may be perceived as having a lesser status than research. We consider ways of improving the recognition of the development of Replacements from within the academic research community in paragraph 15.61.
Availability of information
11.28 Fundamental to identifying alternative approaches is the availability of adequate information on past and current research in specific fields (see paragraph 11.34). Accessing information about suitable Replacements or alternative approaches to particular scientific questions can be difficult as such information is not always published. Even if it is published, the information is not usually indexed so as to highlight any of the Three Rs (see paragraph 15.58).
Integration of in vitro and in vivo research
11.29 In vitro toxicology, as distinct from in vivo toxicology, has become a science in its own right and there may be a risk that the primary goal of replacing animals can be overlooked. Some commentators are concerned that there is insufficient communication between scientists working in vivo and in vitro. They fear that in vitro toxicologists are becoming overly focused on methodological issues and the development and application of new techniques, gradually losing contact with the mainstream in vivo research in their original field. Such a shift could mean that valuable information on alternative techniques is not available to those who could apply them, because it is not published in journals relevant to their research interests or presented at the meetings that they attend. Others counter that it is problematic to make generalising statements in this area, asserting that, for example, in the pharmaceutical industry, there is a high degree of coordination and exchange of information.
Tradition and conservatism
11.30 Most scientists whose work involves animals are comfortable with the concept of Reduction and Refinement, although members of the Working Party also reported from personal experience that knowledge about the potential for Refinement varied. They had sometimes experienced hesitancy from other scientists in entering into serious discussion about the potential for replacing animals in their own field of research. If researchers have always used animals and are working in a field that has historically relied substantially on animal research, a change in methodology may not be straightforward, as it is common for scientists to frame research objectives in light of the means available. The creation of opportunities for appropriate lateral thinking is likely to require more than ‘better training’, and it may be useful to explore ways of achieving structural and institutional change which allow researchers to reconsider ways in which specific research questions can be answered by non-animal methods (see paragraph 15.60). This approach could be especially relevant to research fields such as experimental physiology and experimental biology, which have always depended very substantially on the use of whole, living animals and where the only alternative may be not to do the experiment. Questioning the justification for an entire research programme is, understandably, not something that comes easily to most researchers. This is particularly so in a climate where technological advances such as biotelemetry are continually pushing the boundaries of what is possible in fundamental physiology, and scientists are under increasing pressure to fully exploit these techniques. Hence, the concept of Replacements might be regarded by some researchers as either completely irrelevant or as a direct attack on their life’s work.
Footnotes15 See FRAME website, available at: http://www.frame.org.uk. Accessed on 29 Apr 2005; Dr Hadwen Trust website, available
at: http://www.crueltyfreeshop.com/drhadwen/about.htm. Accessed on 29 Apr 2005; The Lord Dowding Fund for Humane Research website, available at: http://www.navs.org.uk/research/about/ldf.htm. Accessed on 29 Apr 2005.
16 The ABPI estimates that the UK-based pharmaceutical industry spends in excess of £300 million annually on the development of non-animal methods, see Association of the British Pharmaceutical Industry (2003) Alternatives to the use of animals in medicines research, available at: http://www.abpi.org.uk/press/media_briefings_03/2003/Brief_%20Ani.pdf.
Accessed on 29 Apr 2005.
17 Major companies of the chemical, pharmaceutical and cosmetic industry are in the process of establishing an International
Partnership for Alternatives to Animal Testing (IPAAT). So far, there are three Working Groups focusing on developing Replacements for tests which are currently used in lung (inhalation) toxicity, repeat-dose toxicity/toxicokinetics and risk assessment strategies. The companies directly involved in these Working Groups are BASF, Cognis, DuPont, Henkel, L’Oreal,
Novozymes, Pfizer, P&G, TNO and Unilever. In the field of respiratory (immuno)toxicity a first joint project is expected to commence in late 2005. Personal communication Dr Erwin Roggen (Novozymes AS), 27 April 2005.
18 NHS Retained Organs Commission (2002) Retention and use of human tissue and organs (London: DoH); see also Furness P
and Sullivan R (2004)The Human Tissue Bill BMJ 328:533-4
19 See also Home Office (2004) Human Tissue Act 2004, available at:
http://www.legislation.hmso.gov.uk/acts/acts2004/20040030.htm. Accessed on: 29 Apr 2005; Nuffield Council on Bioethics
(2004) Human tissue: ethical and legal issues – Response from the Nuffield Council on Bioethics to the Human Tissue Bill,
available at: http://www.nuffieldbioethics.org/fileLibrary/pdf/ncob_response_-_ht_bill.pdf; European Commission (2004)
Directive 2004/23/EC of the European Parliament and of the Council on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells, available at:
http://europa.eu.int/comm/health/ph_threats/human_substance/tissues_en.htm. Accessed on: 29 Apr 2005.