The animal experimentation debate: a brief reviewBy Amelia Cornish (The World Society for the Protection of Animals)April 2012AbstractFor decades the many moral, ethical and welfare concerns of animal experimentation have been heavily debated. These concerns raise questions to what extent can we subject animals to experiments causing pain and distress in the name of bettering human knowledge and human medical therapies? Animals are used in a range of experiments from military defence weapon testing to human medical testing. The focus of this paper is on animal testing for scientific and medical purposes. To truly understand animal experimentation one must weigh up the benefits to humans against the cost to animals, taking into account any alternatives that may be available. The costs involve adverse effects to the animals such as pain, distress and possible death. The benefits include the acquisition of new knowledge, new medical therapies and potential benefits for human health and welfare. Undertaking this cost-benefit analysis should provide guidance and supporting information on whether animal experimentation is warranted, however much uncertainty remains. This paper aims to shed some light on the issue by exploring the animal welfare implications of animal experimentation, what current legislation governs animal experimentation and whether this falls short of what many would see as our obligation to protect and to ensure the welfare of animals. The validity concerns of the animal model and the available alternative models are also discussed. In conclusion, a focus on alternative models is suggested, as it is seemingly possible to invest in alternative models without negatively affecting scientific enhancement and improvements to human health.Animal experimentation in an animal welfare contextThe debate regarding the ethical, welfare and scientific validity of animal experimentation is not a straightforward debate and much uncertainty still remains. The costs to the animals can be discussed in an animal welfare context, as animal welfare underpins these arguments. Human concern for animals is not new, nor dwindling. The first specific laws on animal welfare were in the UK and were the 1822 Act to Prevent the Cruel and Improper Treatment of Cattle (Rickards, 1822) and the succeeding 1876 UK Cruelty to Animals Act. Current animal welfare and animal sentience studies have proven animals are capable of suffering and worthy of protection (Duncan, 2006). Animal welfare also now concerns an animal’s qualit y of life. Quality of life is a positive approach to how animals engage with their environment and live their lives (Wemelsfelder, 2007). It concerns the promotion of a positive welfare state for animals, not the mere alleviation of pain and suffering (Wemelsfelder, 2007).In 1959, “The Principles of Humane Experimental Technique” (Russell & Burch, 1959) was published. In this publication the authors advocated that all experiments using animals should ensure every effort is made to replace them with non-sentient alternatives, to reduce the number of animals used to the minimum, and to refine animal experiments so that they cause minimal pain and distress to the animals (Flecknell, 2002). This is what has become known as The Three R’s; Replacement, Refinement and Reduction, which have been instrumental in the development of muchnew legislation worldwide. The EU Directive 2010/63/EU which refers directly to the Three R’s is but one example of their global implementation. The implementation of the Three R’s ai ms to ensure a high level of animal welfare is achieved in all scientific research involving animals, although they cannot achieve this in isolation and many other means are also needed to ensure adequate animal welfare is achieved.The Three R’s concept considers replacement as the use of non-sentient beings instead of sentient animals in experiments (Flecknell, 2002). This is thought to minimise suffering, as it is only sentient animals that are thought capable of suffering pain and distress. However this raises concerns regarding animal sentience and what criteria we use to define sentient and non-sentient beings. One major concern is that in one country it would be sufficient to replace a rat with an invertebrate, as legislation does not deem that invertebrate to be sentient. As our knowledge of animal sentience increases, more animals are found to be sentient and capable of suffering, including many invertebrates (Mather, 2011). As scientific knowledge of sentience increases, it will become clear that many more animals are suffering in laboratories. It will also mean sentience knowledge is out-dating legislation. Given the time lags in the implementation of new legislation this could have huge animal welfare implications. Reduction involves reducing the number of animals involved in experiments (Flecknell, 2002). It can be achieved by experimental design, by reusing animals, or by collaborating more within the scientific community and ensuring full publication of experimental procedures and results (Flecknell, 2002). Collaboration between colleagues could ensure experiments are not needlessly repeated and full publication could ensure lessons-learned are shared within the scientific community.Finally the refinement component of the Three R’s purpose i s to lessen the severity of the adverse effects on the animal and to ensure reliable and valid data is gathered through the refinement of the scientific procedure (Flecknell, 2002). The refinement consideration should always involve an assessment of whether a less severe procedure could be used to still obtain scientifically valid data.The United Kingdom Animal Procedures Committee (2002) reviewed the use of primates in scientific procedures from 1990 to 2000 and gave recommendations to reduce primate use. The committee emphasises the use of primates in scientific procedures as a complex issue, however the committee states that the industry could be improved. They advocate for the development and implementation of non-animal alternatives to replace animals in scientific procedures in the future.The effects on laboratory animalsThere are a number of welfare concerns regarding the laboratory animals used in scientific experiments, beginning from where the animals come from, to how their life is ended. There has been much public attention to the use of wild-caught animals in scientific experiments and Article 9 of the EU Directive 2010/63/EU stated that wild-caught animals will not be used in procedures, however there are clear exemptions also stated in the Directive. Wild-caught animals are often captured and transported to breeding centres or laboratories in distant countries, requiring lengthy transportation periods, which are extremely stressful and can lead to injuries (Knight, 2011). Another concern, which is less frequently discussed, is the effect of isolation and removal from a family or social grouping (Knight, 2011). This can cause additional stress to the wild-caught animal and results in increased susceptibility to disease and other physiological effects (Broom, 1993). Both of which can affect the scientific validity of the results.The housing environment and the routine procedures in the laboratory are also of concern. Animal welfare incorporates an animal’s physical and mental wellbeing but also an animal’s ability to engage in natural behaviours, such as nest building for mice (Knight, 2011). The cage environment can often inhibit natural behaviours and leave an animal isolated from con-specifics, with minimal environmental enrichment. Most often the laboratory environment does not satisfy the needs of an animal and usually results in behaviours such as stereotypies (Broom, 1993). Mason & Latham (2004) analysed stereotypies in zoo and laboratory animals and found they were linked with poor welfare. Mason (1991) found stereotypes represent poor past or present welfare due to chronic under-stimulation.Most laboratory animals experience routine procedures such as human handling, cage movements, cage cleaning, injections, blood sampling and weighing (Knight, 2011). A study by Balcombe, et al. (2004) reported routine human handling of laboratory animals causes severe stress. Balcombe et al. (2004) also found laboratory animals did not habituate to these routine procedures.Finally in terms of the welfare concerns for laboratory animals, the one that gains the most public attention and concern is the use of invasive procedures on animals during experimentation and testing (Knight, 2011). Animal sentience studies, and the presence of sensory systems and nerves in many animals (Boyle, 2009), confirm that animals are capable of suffering from the invasive procedures and experiments they are subjected to in the laboratory. A study by Richardson & Flecknell (2005) reviewed how commonly analgesics were administered to laboratory rodents, and assessed the anaesthesia procedures used. The study found from 1992 to 2002 there was an increase in the reported prevalence of analgesic administration to laboratory rodents from 2.7 per cent to 19.8 per cent, although the use of post-operative pain relief for laboratory rodents was quite low.A brief look at current European legislation governing animal experimentationLegislation governing animal experimentation aims to focus on the control of adverse effects such as pain and distress induced during the scientific use of animals. The greatest concern with legislation involves effective enforcement and monitoring.A brief history of legislation governing animal use for experimental or scientific purpose includes the November 24, 1986 Directive 86/609/EEC that was introduced to eliminate disparities between existing laws and regulations of the Members States regarding required animal welfare and protection. However, further disparities between Member States seemed to emerge. Certain States within the EU used the Directive to improve animal welfare and enact high standards, while others applied the minimum requirements of the legislation, and therefore animal welfare remained fairly poor. These disparities between Members States had an effect on the trade within the EU of certain products and substances that involved animal testing. It became quite apparent that the Directive needed clarification to ensure efficient and effective internal trade. The legislation that now governs animals used for experimental or other scientific purpose within the European Union (EU) involves the EU Directive 2010/63/EU that came into effect 22 September 2010. This Directive now includes cyclostomes such ashagfishes, and cephalopods such as squids and octopuses. Invertebrates are now being recognised as sentient beings, based on scientific evidence proving that they are able to suffer. Governments are taking the scientific evidence of sentience in cephalopods seriously, and the UK (UK Home Office, 1993) and New Zealand (New Zealand Government, 1999)Directive 76/768/EEC governs animal testing for cosmetics. In 2004 a testing ban on finished cosmetic products was applied with the testing ban on ingredients or combination of ingredients to come into effect March 2009. In addition, the marketing ban was also applied in 2009 with the exception of repeated-dose toxicity, reproductive toxicity and toxicokinetics. These were omitted as it was thought they would take longer to be replaced with non-animal alternatives. For these specific tests the marketing ban will apply step by step. However the cut-off date is March 2013, where no cosmetic product containing an ingredient that has been tested for the purposes of the Directive using animals will be allowed for sale in Europe, irrespective of whether or not an alternative test is available.Furthermore animal testing for household products has been banned in the UK since 2011, as outlined in the EU Directive 2010/63/EU law. However this ban applies to‘finished products’ and not the chemical ingredients within the product (Home Office, 2011), hence the ban can easily be circumvented.Legislation and appropriate enforcements is the key to ensuring animal welfare improves within the realms of experiments and toxicity testing involving animals. However if legislation becomes too stringent in the EU or UK one real concern is it will simply move these experiments to countries with less stringent, or worse, no legislation governing animal welfare and inadvertently make things worse for animals. The key must be collaboration between legislators and enforces and the corporates, such as Pharmaceuticals and research bodies, such as Medical research institutes, that rely on animals for experimental purpose, to work together for a better outcome for animals, not to the detriment of scientific advancements or worse, human health.A brief look at legislation governing animal experimentation outside of the European UnionMany countries have legislation, regulations or have established animal ethics committees to govern the use of animals in scientific procedures (Baumans, 2004), however effective enforcement is the biggest concern. For example, the USA has the Health Research Extension Act of 1985 (Office of Laboratory Animal Welfare, 2004) and the Animal Welfare Act (Crawford, 2012), which governs animals used in experimentation. While in 1968 the Canadian Council of Medical Research established the Canadian Council on Animal Care that aims to provide guidelines for animal experimentation (Canadian Council on Animal Care, 1993). New Zealand has a National Animal Ethics Advisory Committee (NAEAC) that was established in 1984 under the Animal Welfare Act to provide independent advice to the Minister for Primary Industries about issues regarding animal research, teaching and testing. There is also the Australian and New Zealand Council for the Care of Animal in Research and Teaching (ANZCCART), which aims to govern and provide guidance for those involves in the use of animals in research, teaching and testing (Dandie, 2007). Additionally in Australia the use of animals in experimentation is governed by the Codes of Practice for the Care and Use of Animals for Scientific Purpose (Australia Environment Act, 2000) and also many institutional Animals Ethics Committees.Species difference: a critical look at the validity of the animal model Evolutionary theories state that we all share a common ancestor and evolutionary pressures have lead to subtle but significant changes between species (Darwin, 1859). Due to the differences between animals, species selection is critical in animal experimentation for both ethical and scientific reasons. The scientific validity and effectiveness of animal testing for human drugs and diseases is constantly under question, often regarding the effectiveness of the animal model for human health and diseases. Harding (2004) found attrition rate of drugs entering human clinical trials after passing animal testing to be 92 per cent. A study by Lazarou, et al (1998) found the incidence of adverse drug reactions in hospitalised patients in the US was 6.7 per cent, this meant it was “between the fourth and sixth leading cause of death” (Lazarou, et al., 1998, p.1200) for US hospitalised patients. Similarly a UK based study by Pirmohamed, et al. (2004) stated that adverse drug reactions are a huge burden on the UK National Health Service (NHS) and account for a large proportion of morbidity, mortality and extra costs, which could be avoided.There are many drug examples that have lead to the 92 per cent attrition rate of drugs at human clinical trial. These drugs not only fail upon human clinical trials but also sometimes cause severe health risks and even human deaths. One well-publicised example is the arthritic drug Vioxx, which was successful in animal trials and made it to human clinical trials and onto the US market, but was withdrawn in 2004 after causing 140,000 heart attacks and strokes, and estimated 27,000–60,000 patient deaths between 2000 and 2004 (Lyon, 2007).There is overwhelming evidence that many anomalies seen in animal experiments are due to the differing biology of the species being experimented on (Perel, et al, 2007) and the stress of constant human handling and the environment that the laboratory provides (Balcombe et al., 2004). The stress of human handling, confinement and isolation has been known to alter an animal’s physiology and to increase an animal’s susceptibility to infectious diseases (Balcombe, et al., 2004). It could be argued that animal experimentation lacks efficiency, as it is merely the behaviour of stressed animals, how they process drugs and how they interact with one another that is being tested.Perel et al., (2007) reviewed the treatment effects between clinical trials and animal experiments. They reviewed six interventions for which there were treatment effects in clinical trials, and then they reviewed the corresponding animal experimentation results. The six areas reviewed were: corticosteroids in traumatic head injury, antifibrinolytics in haemorrhage, thrombolysis in acute ischaemic stroke, tirilazad in acute ischaemic stroke, antenatal corticosteroids to prevent neonatal respiratory distress syndrome, and bisphosphonates to prevent and treat osteoporosis. Among the six interventions three had similar outcomes between clinical trials and animal studies and three did not. Perel et al., (2007) stated many animal studies showed very poor methodology and the “lack of concordance between animal experime nts and clinical trials may be due to bias, random error, or the failure of animal models to adequately represent human disease” (Perel, et al., 2007, p. 5).Non-human primates used in animal experimentationWhile there is a wide range of animals used for experimentation and testing purposes, non-human primates deserve particular attention due to the controversy their use hasgenerated throughout animal testing history, which mainly arose due to their genetic closeness to humans. Non-human primates make up a very small fraction of the animals used in experimentation. According to a European Union commissioned report in 2010 (as cited in Knight, 2011) non-human primates account for 0.08 per cent of laboratory animals used in the 27 EU Member States in 2008.A study by Carlsson, et al (2004) reported nonhuman primates were primarily used in research areas in which they appear to be the most appropriate models for humans. The most common areas of research were microbiology (including HIV/AIDS (26%)), neuroscience (19%), and biochemistry/chemistry (12%) (Carlsson, et al., 2004). Carlsson et al., (2004) also found the majority of publications using primates during 2001 were conducted in North America, Europe, and Japan.It is commonly argued in scientific literature, that non-human primates shouldn’t be used not on ethical grounds but on the basis of validity concerns. There are many physiological differences between human and non-human primate species (Bailey, 2005). They suffer from different diseases and respond in different ways to infectious agents (Bailey, 2005). Anzai, et al., (2003) studied human and chimpanzee responses to HIV and SIV (the ‘related’ simian immunodeficiency virus) and found the chimpanzee’s immune system detects and responds to HIV and SIV viruses very differently to humans. Anzai, et al., (2003) also found species-specific effects of other viral infection such as hepatitis B and C. In 2007 decades of AIDS vaccine research suffered disappointment when clinical trials of the new vaccine V520, involving 3000 people in 15 cities, failed to prevent or even suppress current viral loads (Watkins, et al., 2008). Furthermore, a study by Cáceres, et al. (2003) compared the human gene expression for the cerebral cortex to chimpanzees and rhesus macaques, and found many differences, mainly that the human brain involved up-regulation, which means genes were much more highly expressed in humans.Recently in 2011, the Institute of Medicine and National Research Council published in their report titled ‘Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity’ (p.16), that “recent advances in alternate research tools have rendered chimpanzees largely unnecessary as research subjects”. Bailey (2005) argues the validity of the animal model to test human concerns is increasingly coming under question. Such statements and reports such as the one from the Institute of Medicine and National Research Council, if taken seriously by the scientific community will be a much needed driving force for change away from the use of animals, especially non-human primates in research, and towards alternatives.A brief discussion of the alternative to animal modelsAs the validity of animal models continues to come under question, there needs to be a positive shift in focus towards alternative methods, such as in vitro, computer software, and attention to existing databases. Research facilities and organisations, such as the Johns Hopkins Centre for Alternatives to Animal Testing (CAAT) in the U.S. and Europe, and the Fund for the Replacement of Animals in Medical Experiments (FRAME) in the UK, are just some of the key organisations that are dedicated to finding more alternatives to animal testing on a global scale.Some of the alternatives being explored include in-vitro, epidemiological studies, clinical intervention trials, astute clinical observation aided by laboratory testing, humantissue and cell cultures, autopsy studies, endoscopic examinations and biopsy, as well as new imaging methods.In-vitro testing, which uses whole, living animals, is often employed for toxicology testing to determine the hazardous nature of a product (Murthy, 2007). In-vitro, which uses components of a whole animal such as cells, provides a positive alternative to in-vivo and highly invasive testing (Murthy, 2007).Piersma (2006) reports that there are currently three validated alternatives in developmental toxicology testing. The embryonic stem cell test, the limb bud micromass, and the rat post implantation whole embryo culture (Piersma, 2006). Piersma (2006) states these three tests are validated however their application is still under discussion.Furthermore, Computer Models can be used to simulate diseases and to help scientists understand different substances and their effects. The models are based on existing information and data, and can help researchers with information specifically relating to humans. Rosenkranz (1988) reports on Computer-Automated Structure Evaluation System (CASE) and states CASE can correctly predict carcinogenicity. Attention has also been given to the consideration of existing data and how such data can be better utilised and shared to avoid unnecessary future experimentations. It is often found that pharmaceutical and chemical compani es’ exclude from the public domain their data from experiments as a means of market competitiveness. Exclusion of such data leads to repetition of animal experiments and slower product development.In 2006 the EU finalised new legislation on the control of hazardous chemicals. The new regulation termed REACH (Registration, Evaluation and Authorisation of Chemicals) is the new system for controlling chemicals in Europe, which became law in the UK on 1 June 2007. It aims to better protect people and animals from dangerous chemicals (Health and Safety Executive, 2010). The regulation includes mandatory sharing of animal test data, which means companies registering the same chemicals are obliged to share their data, and if animal testing is required by REACH, only one of the registrants will be allowed to conduct such experiments. In addition the regulation heavily promotes the use of alternatives to animal models.Summary and conclusionThere remain many unanswered questions regarding the ethics and validity of animal experimentation. The welfare implications are clear and we know animals are suffering in laboratories, however we do not know if this is justified by the scientific findings. Animal sentience confirms an animal’s ability to suffer. However anima l sentience is poorly understood across the taxa.Currently only unequivocal scientific acceptance of sentience exists for vertebrate species and some invertebrates.Directive 2010/63/EU protects the welfare of animals used for experimental or other scientific purpose within the European Union, and this Directive includes cyclostomes and cephalopods, which is a great advancement for animal welfare. However as discussed previously we need to ensure legislation remains within working limits for the research bodies and scientific organisations reliant on animals for experimental purpose, as the risk of overly stringent legislation can do more harm than good. Ifdeemed unworkable it may simply mean these experiments are moved to countries with less stringent, or worse, no legislation governing animal welfare inadvertently making conditions worse for animals.Scientific evidence is demonstrating poor validity of the animal models and reports such as the Institute of Medicine and National Research Council 2011 report which questions the validity of the primate model for testing, corroborates this. As the validity continues to be questioned, there needs to be a positive shift in focus towards alternative methods, some of which were briefly discussed above. In conclusion it is seemingly possible for a future of scientific advancement and improvements to human heath and welfare, without compromising animal welfare.ReferencesAnzai, T., Shiina, T., Kimura, N., Yanagiya, K., Kohara, S., Shigenari, A.,… Inoko, H. (2003). 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