animal research study with ethical issues

Physiology News Magazine

• Autumn 2012 - Issue Number 88

Current ethical issues in animal research

The use of animals in research is a matter of substantial public interest and can generate impassioned debate which includes the ethics of using animals for experimentation. dominic wells reviews specific ethical issues in the scientific use of animals and puts the debate into context..

Dominic Wells Royal Veterinary College, UK

https://doi.org/10.36866/pn.88.18

Ethics can be defined as a framework in which moral decisions (what is right or wrong) can be made. There are two main schools of thought: Consequential (utilitarian) or Deontological (intrinsic).

Within the animal rights movement two of the best-known philosophers are examples of these different schools of thought. Peter Singer is a utilitarian ethicist who argues that there is no valid reason for separating man from all the other animals, which he calls a speciesist view with close similarities to racism and sexism. Consequently animals have rights in a similar way to man. His seminal book, Animal Liberation , was published in 1975 (1) and he is regarded by many as the founding father of the animal rights movement. However, while animals have similar rights to man, the rights of the individual can in some cases be subsumed for the greater good, although this requires a very clear cost–benefit analysis. In contrast, Tom Reagan is a deontological ethicist who argues animals have intrinsic worth and rejects the concept that the ends can justify the means. Consequently animals have intrinsic value as do humans: for example, this argument is presented in (2). Thus, in this school of thought, the use of animals in research can never be justified.

Interestingly, the earliest clear statement on the ethics of animal experimentation occurred at the time of the debate about the rights of man. In his 1789 Introduction to the Principles of Morals and Legislation (3), the utilitarian philosopher Jeremy Bentham queried the use and abuse of animals. He wrote: “The question is not, Can they reason? nor, Can they talk? but, Can they suffer?”. It should be noted that Bentham had no fundamental objection to animal experiments provided that the goal was of benefit to humanity and that there was a reasonable prospect of achieving that goal.

In Animal Liberation (1), Singer codified the concept of animal rights in the context of human rights as: “Animal rights means that animals deserve certain kinds of consideration – consideration of what is in their own best interests regardless of whether they are cute, useful to humans, or an endangered species and regardless of whether any human cares about them at all (just as a mentally-challenged human has rights even if he or she is not cute or useful or even if everyone dislikes him or her). It means recognizing that animals are not ours to use – for food, clothing, entertainment, or experimentation”.

How do we relate these ethical views to the use of animals in research? Our attitude to ethical questions in animal research stems from the relationship of human society with all animals. Animals are used for food, transport and entertainment as well as research. In many societies ill-treatment of animals is not accepted, although this is by no means universal. Thus, in general we take a modified utilitarian attitude – ‘the end can justify the means’ or ‘the greatest good of the greatest number’, but crucially with humans given a greater worth than any other species – the speciesist view disparaged by Singer.

We seek to minimise the cost of the means to justify the end by minimising pain, suffering, distress and lasting harm in experimental animals. Thus, we aim to reduce the number of animals used in experiments to a minimum. We strive to refine the way experiments are carried out, to make sure animals suffer as little as possible. And we replace animal experiments with non-animal techniques wherever possible. These key tenets of humane experimental use of animals, often referred to as the 3Rs, were developed by Russell and Burch in their highly influential 1959 publication The Principles of Humane Experimental Technique .

The current Animals (Scientific Procedures) Act 1986 (4) relies on this modified utilitarian ethical judgement. The revised version that will come into force in January 2013, which incorporates changes associated with Directive 2010/63/EU, will continue the same approach. Each project must be assessed on a cost–benefit basis, by asking the question of whether the ends justify the means. Experimental design should aim to reduce the costs (by application of the 3Rs) and critically evaluate the likely benefits. A strong case needs to be made that the studies are necessary and that the experimental aims are well defined and are likely to yield clear answers. The benefits may be for humans and/or other animals but there is a clear hierarchy, with no protection for invertebrate animals other than octopus and with cats, dogs, horses and primates being given special status of greater protection compared with other non-human mammals.

Genetically modified (GM) mice raise additional ethical questions. GM animals are the most rapidly growing element of animal use with more than 1.6 million GM animals and harmful mutants bred in the UK without other manipulations in 2011 (5) and this trend appears likely to continue to increase. It has been argued that GM violates the integrity of the organism’s genome. This is of course unacceptable in the deontological and questionable from the strict utilitarian view. However, the modified utilitarian view would argue that, in the absence of a harmful phenotype, there is no difference from wild-type in terms of the welfare of the animals, i.e. the animal is unaware that its genome has been modified.

Other human uses of animal

It is reasonable to ask why there is so much focus on animal experiments. Much of this may be due to the lack of public understanding of other uses of animals. The use of shock tactics of antivivisectionists and the ‘Yuk factor’ of some of the images used are partly responsible for the exaggerated emphasis on animal experimentation. There are many non-experimental uses of animals, for example, as food, clothing, transport, pets, sport and exhibition. The numbers used in non-experimental activities are huge. The UK uses 3.6 million animals in research annually (78% rodents, 15% fish) but UK meat and fish eaters consume 2.5 billion animals every year (6). This is nearly 700 times the numbers used in research yet it could be argued that consumption of fish and meat is not essential for human wellbeing, whereas at least some of the animal research is essential. Both utilitarian and intrinsic ethical arguments would suggest this use of animals for meat is the more important problem that should be tackled ahead of the use of animals in research. This disparity between animals used for food and research is even greater when considered on a world-wide basis. It has been estimated that 140 billion animals are killed for food every year (3000 times the number estimated for use in research worldwide). While the slaughter of domestic mammals and birds may in many cases be reasonably humane, that cannot be said of most of the 90 billion fish killed worldwide each year, where suffocation is the most common cause of death.

Recreational uses of animals should also be considered in comparison with the use of animals in research. Fishing for game or coarse fish is a very popular pastime in the UK but, although it gives pleasure to many, it does not have major consequences in terms of human health. There is little doubt that fish feel pain and respond to it and so recreational fishing is less ethically justified than the use of fish in research. Sport involving animals often has a high attrition rate. As mentioned previously, horses receive special protection under ASPA legislation yet almost 50% of thoroughbred foals do not reach flat race training in the UK (7), as many suffer tendon injuries and fractures that impair their ability to perform. Again, the utilitarian argument would suggest that horse racing was ethically less acceptable than the use of horses in experimental research. Very large numbers of animals are kept as pets and this is not without ethical consequences. For example, based on a survey of over 600 cat owners (7) it can be estimated that cats kill over 220 million vertebrate wild animals per year in the UK, the majority of them being small mammals. This is 60 times the number used in research. So decreasing the cat population, or keeping them indoors on a permanent basis, would have a greater impact on the loss of life than reducing the numbers of animals used in research, but is keeping a cat indoors for life infringing its rights?

What is the ethical way forward? Both Singer and Regan argue that we should not eat meat or fish or use animals in any way that cause them harm. So we should all be vegetarian and limit our harmful interactions with animals. That is philosophically an entirely reasonable approach. However, given our current modified utilitarian (speciesist) use of animals in non-research areas, much of the ethical debate about the use of animals in research is redundant.

• Peter Singer (2001) . Animal Liberation , 1975. 3rd edition. Harper Collins.
• Tom Regan (2004) . The Case for Animal Rights , 1983. 3rd Edition. University of California Press, Berkley, Los Angeles.
• Jeremy Bentham (1789) . Introduction to the Principles of Morals and Legislation , 1789. Reprinted by General Books LLC, 2010.
• Animals (Scientific Procedures) Act 1986 . Available online at: http://www.archive.official-documents.co.uk/document/hoc/321/321-xa.htm
• Statistics of Scientific Procedures on Living Animals, Great Britain 2011 . Available online from: http://www.homeoffice.gov.uk/publications/science-research-statistics/research-statisticsother-science-research/spanimals11/
• http://www.understandinganimalresearch.org.uk/the-animals/animals-and-society/
• Wilsher S, Allen WR & Wood JL (2006) . Factors associated with failure of thoroughbred horses to train and race. Equine Vet J 38 (2), 113–118.
• Woods M, McDonald RA & Harris S (2003) . Predation of wildlife by domestic cats Felis catus in Great Britain. Mammal Rev 33, 174–188.

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The ethics of animal research

Animal use has been a hotly contested moral issue for hundreds of years. In the 17th century René Descartes, a French philosopher, argued that animals were no more than automata and could not feel pain. This was rejected by Jeremy Bentham in the 18th Century who extended his utilitarian conception of rights to animals due to their capability to suffer. This was expanded by Peter Singer, in 1975, who wrote in Animal Liberation that arbitrarily treating humans above animals – particularly in marginal cases where animals may be as intelligent as young children or severely cognitively-impaired adults – was not justified. Animal rights philosophy is distinct from proponents of animal welfare who argue that we must provide adequate conditions for animals in our care – a position held by the RSPCA among others. The scientific community has often been the driving force for these improvements, arguing that better conditions for animals was conducive to better, more replicable, scientific results.

Animal Liberation (Peter Singer) was an immensely influential book which discussed the ethics of animal use (including animal research). It is often considered the forerunner to the animal liberation movement. This is, perhaps, the core piece of literature on  animal rights philosophy.  - Singer, P., 1995. Animal Liberation. 2nd Ed. London: Pimlico. Do Animals Have Rights? (Alison Hills) is an objective assessment of the case for whether animals should have rights and what rights those should be. Hills discusses their ability of mind, whether all animals should be regarded as equal, and what that means. Hills concludes with a graded scale of animals rights.  - Hills, A., 2005. Do Animals Have Rights? Cambridge: Icon Books. The Case for Animal Rights (Tom Reagan) is another major piece of philosophical writing which argues for animal rights on the basis of their similar cognitive abilities.  - Reagan, T., 1983. The Case for Animal Rights. Berkeley: University of California Press. A Rat is a Pig is a Dog is a Boy (Wesley J Smith) takes its title from a quote from PETA president, Ingrid Newkirk. It is a useful book covering many issues of animal rights activism and philosophy. In Chapter 18, Smith creates his argument in favour of animal research on the basis of human rights and duties.  - Smith, W.J., 2009. A rat is a pig is a dog is a boy. New York: Encounter Books. The Human Use of Animals: Case Studies in Ethical Choice (Beauchamp et al.) investigates a number of difficult issues regarding the use of animals in society. Through 16 case studies, and plenty of ethical theory, the authors attempt to navigate the moral minefields involved.  - Beauchamp, T.L., Orlans, F.B., & Dresser, R. Morton D. and Gluck J. 2008.  The Human Use of Animals: Case Studies in Ethical Choice. 2nd ed. New York: Oxford University Press. An Odyssey with Animals (Adrian Morrison) investigates the relationship between humans and animals, and explains why efforts to halt animal research would be damaging to human health.  - Morrison, A., 2009.  An Odyssey with Animals. New York: Oxford University Press

Online resources

Ethics (Pro-Test) looks at the question of whether animals have rights, concluding that their lack of understanding does not allow them to participate in the system of rights and duties.  - Pro-Test.  Ethics. [online]Available at:  http://pro-test.org.uk/facts.php?lt=a The ethics of research involving animals (Nuffield Council on Bioethics) is an independent report on the use of animals for medical science. Although it looks at the whole issue, it pays particular attention to the ethics, specifically in chapter three.  - Nuffield Council on Bioethics, 2006. The ethics of research involving animals. [online] London: Nuffield Council on Bioethics. Available at:

https://nuffieldbioethics.org/wp-content/uploads/The-ethics-of-research-involving-animals-full-report.pdf

Animal Rights Beliefs (SR) provides a polemic disagreeing with Bentham’s basis of animal rights. It also investigates the question of whether animals should be considered “innocent”.  - Speaking of Research. Animal Rights Beliefs. [online] Available at:  http://speakingofresearch.com/extremism-undone/ar-beliefs/ The Ethics of Animal Research (Simon Festing and Robin Wilkinson) provides an insight into the ethics of animal research, including a look at public opinion and the animal welfare regulations. It also has a useful and extensive references list.  - Festing S. and Wilkinson R., 2007. The Ethics of Animal Research. EMBO reports. Available at: www.nature.com/embor/journal/v8/n6/full/7400993.html The moral relevance of human intelligence (Dario Ringach) – this blog post by Prof. Ringach discusses the arguments made by animal rights activists about marginal cases – how do we compare the moral value of a baby, or brain damaged person to a mouse or monkey.  - Ringach, D., 2012. The moral relevance of human intelligence.  Speaking of Research. [blog] 12 Sept, Available at:  http://speakingofresearch.com/2012/09/12/the-moral-relevance-of-human-intelligence/ Click on one of the links below to see other topics on animal research

• History of animal research
• Ethics of animal experiments
• Costs and benefits of research
• Regulatory systems and the 3Rs
• Animal rights activism and extremism
• General Websites

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• Research article
• Open access
• Published: 29 March 2016

The ethics of animal research: a survey of the public and scientists in North America

• Ari R. Joffe 1 , 2 , 5 ,
• Meredith Bara 3 ,
• Natalie Anton 1 &
• Nathan Nobis 4  

BMC Medical Ethics volume  17 , Article number:  17 ( 2016 ) Cite this article

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Metrics details

To determine whether the public and scientists consider common arguments (and counterarguments) in support (or not) of animal research (AR) convincing.

After validation, the survey was sent to samples of public (Sampling Survey International (SSI; Canadian), Amazon Mechanical Turk (AMT; US), a Canadian city festival and children’s hospital), medical students (two second-year classes), and scientists (corresponding authors, and academic pediatricians). We presented questions about common arguments (with their counterarguments) to justify the moral permissibility (or not) of AR. Responses were compared using Chi-square with Bonferonni correction.

There were 1220 public [SSI, n  = 586; AMT, n  = 439; Festival, n  = 195; Hospital n  = 107], 194/331 (59 %) medical student, and 19/319 (6 %) scientist [too few to report] responses. Most public respondents were <45 years (65 %), had some College/University education (83 %), and had never done AR (92 %). Most public and medical student respondents considered ‘benefits arguments’ sufficient to justify AR; however, most acknowledged that counterarguments suggesting alternative research methods may be available, or that it is unclear why the same ‘benefits arguments’ do not apply to using humans in research, significantly weakened ‘benefits arguments’. Almost all were not convinced of the moral permissibility of AR by ‘characteristics of non-human-animals arguments’, including that non-human-animals are not sentient, or are property. Most were not convinced of the moral permissibility of AR by ‘human exceptionalism’ arguments, including that humans have more advanced mental abilities, are of a special ‘kind’, can enter social contracts, or face a ‘lifeboat situation’. Counterarguments explained much of this, including that not all humans have these more advanced abilities [‘argument from species overlap’], and that the notion of ‘kind’ is arbitrary [e.g., why are we not of the ‘kind’ ‘sentient-animal’ or ‘subject-of-a-life’?]. Medical students were more supportive (80 %) of AR at the end of the survey ( p  < 0.05).

Conclusions

Responses suggest that support for AR may not be based on cogent philosophical rationales, and more open debate is warranted.

Peer Review reports

Given the massive public funding of animal research (AR) in democratic societies, it might be expected that the arguments for and against AR are well settled [ 1 , 2 ]. However, the details of standard ethical arguments and counterarguments for AR are not often publically discussed, and it is likely that most people are not aware of the details of the debate. This is also true in the peer-reviewed medical literature, where open debate including details of all the arguments is uncommon. Nevertheless, AR is an ethical issue because animals are harmed in experimentation from such things as confinement, fear, pain, and early death [ 3 , 4 ]. In this study, we refer to AR which is harmful (detrimental to some significant interest the being has, such as the interest in maintaining life and bodily integrity, and avoiding pain and frustration), non-therapeutic (does not aim at restoring the health of a research subject with prior injury/disease), and non-consensual (conducted with subjects who have not voluntarily agreed to participate), and thus would be unethical if done in a non-research setting [ 4 ].

The question to debate is this: is any or all AR that involves seriously harming animals morally permissible? The moral justification is usually given by one of three types of arguments [ 5 – 7 ]. “Benefits arguments” claim that AR benefits humans greatly, is necessary for human benefit, or that there are no alternatives for human benefit; these are the most common justifications given by pro-AR groups [ 8 – 10 ]. “Characteristics of non-human-animals (NHA) arguments” claim that animals are property, are not sentient, or that animals harm other animals; these arguments led to the initial development of AR and its legal regulation [ 11 ]. “Human exceptionalism arguments” claim that humans have more advanced abilities, are of a special ‘kind’, can enter into contracts, or must sacrifice NHAs in their lifeboat [ 12 – 15 ]. Importantly, the first two types of arguments actually rely on human exceptionalism arguments: to justify using animals [as necessary] for human benefits, or as property, requires an argument for why humans cannot be used in the same way [ 12 ]. Previous surveys have generally asked only whether people support AR for human benefit, and have not asked people to evaluate their reasons for supporting (or not) AR [ 16 – 20 ]. When we presented common arguments and counterarguments to a small sample of pediatric health care workers at our children’s hospital, we found that most were not convinced of the moral permissibility of AR [ 21 ]. Here, we survey a large sample of the public, medical students, academic pediatricians, and scientists to determine their considered opinions regarding the moral permissibility of AR. We aimed to determine not simply whether the public, medical students, academic pediatricians, and scientists support AR, but whether they think the usual arguments (and counterarguments) in support (or not) of AR are convincing. Our objective in this exploratory research was to determine how strong commitment was to each argument in favor of animal research, in the face of the counterarguments presented.

Questionnaire development

The development and reporting of the questionnaire followed published recommendations [ 22 ]. As described elsewhere, this included a literature search, content and construct validation by non-author experts using a clinical sensibility tool and tables of specifications ( n  = 4 experts), face and content validation by pilot testing using a clinical sensibility tool and informal semi-structured interviews (to ensure clarity, realism, validity, and ease of completion) ( n  = 14 individuals) [ 21 ]. Not all of the authors, or the experts and public validators were in favor of AR. The study was approved by the health research ethics board of the University of Alberta (Pro00039590), and return of the survey was considered consent to participate.

Questionnaire administration

We surveyed the public (4 groups), adults with biomedical science training (2 groups), and animal researchers (2 groups), the details of which are as follows:

1. Public: we chose 4 groups that represented a range of situations that were conveniently accessible for survey distribution: i) A convenience sample of adults approached while in various line-ups at the Heritage Festival in Edmonton, Alberta, Canada in August 2013 ( n  = 195). These adults were asked if they would fill out a paper survey about AR in return for $5 food ticket as an incentive. We did not track the number of people asked to participate, but our impression was that most adults approached completed the survey. ii) A random sample of Canadian adults accessed using the marketing firm Survey Sampling International (SSI) in November 2014 ( n  = 586). The sample “was selected to be reflective of the Canadian population over age 18 years with at least a high school education, by age, gender, race/ethnicity, income, and geographic region.” Of those invited to participate, 1 terminated, 85 submitted partial responses, and 501 submitted complete responses. iii) A sample of US adults using Amazon Mechanical Turk (AMT) in February 2015 ( n  = 439). For this sample, we limited potential responders to those living in the US, with a Human Intelligence Task approval rate >90 %, and we paid $1.60 on completion. The survey was on the AMT site for <4.5 h, and the average time spent per survey was 31 min. Crowdsourcing on AMT has found results to be psychometrically valid, with high test-retest reliability, attentiveness, and truthfulness, even on complex cognitive and decision-making tasks [ 23 – 27 ]. We included two attention checks with excellent results (one-third of the way in: “please tell us whether you agree with this equation: 2 + 2 = 4”; 407/18 (97 %) agree; and toward the end of the survey: “to show you have read the instructions, please check ‘none of these’ as your answer to this question”; 413/415 (99.5 %) ‘none of these’). iv) A convenience sample of adult visitors on the pediatric wards of the Stollery Children’s Hospital, Edmonton, Alberta, Canada in May 2015 ( n  = 107). We did not track the number of people asked to participate, but our impression was that most of those approached completed the paper survey.

2. Adults with biomedical science training: i) The second year University of Alberta Medical School in September 2013, and ii) The next second year class in November 2014. Non-respondents were sent three reminders at about 2–3 week intervals.

3. Animal researchers: i) The corresponding authors of AR papers published during the 6 months from October 2012 to March 2013 in the high impact journals Nature, Science, and Critical Care Medicine (i.e., representing leaders in their field of AR); and ii) All academic faculty pediatricians at The Hospital for Sick Children in Toronto, Ontario, Canada, as listed by email on the University of Toronto website. We assumed these pediatricians would have many ties to research activities, including knowledge of, if not participation in, AR. Non-responders were sent three reminders at about 2–3 week intervals.

The surveys were done using the web-based tool REDCap, which allows anonymous survey responses to be collected or entered, and later downloaded into statistical software for analysis [ 28 ]. The paper surveys done at the local festival and the children’s hospital were entered by hand, whereas all other groups entered data directly into the REDCap surveys after invitation by email or using the SSI and AMT platforms.

Questionnaire content

The background section stated “In this survey, ‘animals’ means: mammals, such as mice, rats, dogs, and cats. It has been estimated that over 100 million animals are used in the world for research each year. There are many good reasons to justify animal research, which is the topic of this survey. Nevertheless, some people argue that these animals are harmed in experimentation, because their welfare is worsened. In this survey, ‘harmful’ means such things as: pain, suffering (disease/injury, boredom, fear, confinement), and early death. We value your opinion on the very important issue of the ethical dimension of animal research.” We chose mammals to represent a group of sentient animals that are thus capable of being harmed.

We presented demographic questions, 3 questions about support for AR, and 12 arguments with their counterarguments to consider. The survey stated: “a) First, we give you an argument to justify harmful animal research, and we ask if you agree with that argument; b) Then we give some responses to the argument, and we ask if you think each response would make it harder for someone to justify harmful animal research using the initial argument (i.e., would make the initial argument less convincing). All the arguments and responses in this survey are those commonly made in the literature on animal research.” When each argument was presented, it was followed with the question “Is this a good enough reason to justify using animals in medical research?” When the responses to an argument were presented, they were followed with the question: “Do any of the following responses make it harder for someone to justify animal research using Argument x (i.e., make Argument x much less convincing)?”

We used REDCap as our web-based survey management tool, allowing anonymous survey responses to be collected, and later downloaded into an SPSS database for analysis [ 28 ]. Responses are described using proportions (percentages). Pre-specified subgroup analyses included exploratory comparisons on all responses for: the 4 public groups; the two medical school classes; and the two animal researcher groups. If results were not statistically and clinically significantly different within each of these groups, we planned to compare the groups to each-other. These comparisons were done using the Chi-square statistic, with P  < 0.05 after Bonferroni correction for multiple comparisons considered statistically significant. Prior to statistical analysis, we defined a clinically significant difference between groups as one where the comparison is statistically significant, in addition to having a clear majority (at least 60 %) on different sides of the yes/no response option. This was done because we are interested in whether the groups have opinions that could result in different practical consequences both for the animals, and for the researchers involved. For example, if many respondents have very different opinions about the moral permissibility of AR, this might lead to very different levels of support of AR, and thus have different implications for the actual practice of AR.

Public responses

Demographics.

There were 195 respondents from the local festival, 586 from SSI, 439 from AMT, and 107 from the children’s hospital samples. Most respondents were under 45 years old, had at least some college or university training, and the vast majority had never done AR (in Additional file 1 : Table E-1).

Benefits arguments and counterarguments

Responses are shown in Table  1 , and (see Additional file 1 : Table E-2). About half of respondents accepted the benefits arguments that “AR benefits humans greatly” (55 %), “Animal experimentation is necessary for human benefit” (50 %); and “There are no alternatives to animal experimentation” (41 %) as good enough to justify AR. Far fewer accepted the argument that “Humans naturally need to seek knowledge” (24 %). Many found the counterarguments convincing, including those who initially responded that the argument was enough to justify AR. Most were convinced by counterarguments suggesting that there are alternative experimental methods (84 %), or that more effort must be devoted to developing alternative methods (79 %). About half found counterarguments convincing that pointed out that if AR [is necessary] for great benefits to humans, this should also justify using humans in the same experiments. There were few statistically significant differences among the public samples, with none being clinically significant.

Characteristics of NHA arguments and counterarguments

Responses are shown in Table  2 and (see Additional file 1 : Table E-3). Almost all respondents were not convinced by these arguments, and each counterargument explained this for about half of respondents. The statistically significant differences in some responses were only clinically significant for one (more respondents on AMT were convinced by the counterargument that “this would mean that a pet cat or dog is simply a living machine, without any feelings”).

Human exceptionalism arguments and counterarguments

Responses are shown in Table  3 and (see Additional file 1 : Table E-4). Only a minority of respondents accepted these arguments as good enough to justify AR (18–36 %). For most respondents, the stated counterarguments explained this lack of acceptance of the initial arguments. For example, the counter-arguments from species overlap [“not all humans have these abilities”], that animals are “subjects of a life” [“of the ‘kind’ able to have experiences, memories, and preferences”], and that similar arguments of prejudice were used in the past [“it is unclear why caring more about someone justifies harming those we care less about. For example, in the past this argument was used to justify prejudice (for example, slavery) against those we cared less about, who were considered not of our own kind”] were convincing for most (60 %, 55 %, and 58 % respectively). The few statistically significant differences between the public groups were clinically significant for one (more respondents on AMT were convinced by the counterargument that “this would mean we have no direct moral duties to humans who cannot enter into this contract. For example, babies, and severely brain-damaged people”).

General questions

Reponses are shown in Table  4 and (see Additional file 1 : Table E-5). At the beginning and again at the end of the survey we asked if “in order to achieve human benefits, research that results in harm to animals should be supported”; 44 % and 41 % responded “yes” respectively. Finally, when asked “what is it about vulnerable humans that makes it wrong to use them in experiments”, the most common response was “they are still human” (49 %). The responses to these questions were statistically significantly different, although not clinically significant.

Adults with biomedical science training (Medical School Classes)

The response rate was 112/164 (68 %) and 82/167 (49 %) in the two medical school classes. Most respondents were under 35 years, and 60–62 % had never done AR (in Additional file 1 : Table E-1). There were no statistically significant differences between the two medical classes in the responses to any question, and results from both are presented together below. Given only 2 clinically significant differences among the public survey groups for responses to arguments, we pooled the public responses for comparison to medical students.

Responses are shown in Table  2 . Similar to the public, most respondents accepted the ‘benefits arguments’ and were convinced by counterarguments suggesting that there are alternative experimental methods. Eleven of these 13 questions had statistically significant differences between the public and medical student responses; although not meeting our clinically significant criterion, consistently, medical students were more convinced by benefits arguments, and less convinced by their counterarguments compared to the public. For example, only a minority found counterarguments convincing that pointed out that if AR [is necessary] for great benefits to humans, this should also justify using humans in the same experiments (26–34 %).

Responses are shown in Table  3 . Almost all respondents were not convinced by these arguments, and the counterarguments explained this for most of respondents. There were two statistically significant differences from the public responses, but these were not clinically significant.

Responses are shown in Table  4 . Similar to the public, only a minority of respondents accepted these arguments as good enough to justify AR, and the stated counterarguments explained this lack of acceptance of the initial arguments. The four statistically significant differences between the public and medical students were not clinically significant; however, consistently, the medical students were more convinced by several of the counterarguments.

Responses are shown in Table  4 . When asked at the beginning and again at the end of the survey if “in order to achieve human benefits, research that results in harm to animals should be supported”; 80 % and 80 % responded “yes” respectively. Compared to the public, this high level of support for AR was statistically and clinically significant. Finally, when asked “what is it about vulnerable humans that makes it wrong to use them in experiments”, the most common response was “they are still human” (60 %), statistically more often than for the public.

Animal researchers

Corresponding authors ( n  = 178) were invited to participate by e-mail. The response rate was 5/178 (3 %) after 4 mailings; therefore, no useful results can be reported here. Academic pediatricians at the Hospital for Sick Children ( n  = 141) were invited to participate by e-mail. The response rate to the demographics questions was 18/141 (13 %); however, before all the benefits arguments were presented the response rate dropped to only 14/141 (10 %), and therefore no useful results can be reported here. The difference in response rates between medical students and animal researchers was statistically significant (Chi-square p  < 0.001).

There are several important findings from this survey. First, the public (44 %) and medical students (80 %) are supportive of AR. Second, ‘benefits arguments’ were usually thought sufficient to justify AR. However, when confronted with counterarguments pointing out that alternative research methods may be available, most were not as convinced of the initial argument. In addition, counterarguments suggesting that it is unclear why the same ‘benefits arguments’ do not apply to using humans in the same medical experiments were convincing for about half of the public and one third of medical students. Third, almost all respondents were not convinced by “characteristics of NHA arguments”, including that NHA may not be sentient or are simply property. Fourth, most respondents were not convinced by ‘human exceptionalism’ arguments; these are the arguments that justify AR due to benefits but claim the same benefits do not justify human research. These include arguments that humans have more advanced mental abilities than NHAs, are of a special ‘kind’, can enter into social contracts, or face a lifeboat situation where human interests trump NHA interests. Fifth, common counterarguments explained much of the respondents’ lack of acceptance of ‘human exceptionalism’ arguments: the ‘argument from species overlap’ (pointing out that not all humans have these more advanced abilities, while some animals do) [ 29 – 31 ]; the notion that ‘kind’ is vague (why are we not of the kind ‘sentient animal’ or ‘subject-of-a-life’?) [ 32 ]; and the notion of ‘kind’ has been used in the past to justify prejudice against those society cared less about [ 33 ]. Sixth, there were several differences between the public and medical school student responses; however, most were not clinically significant, although medical students seemed consistently more convinced by benefits arguments and less convinced by their counterarguments. Medical students were much more supportive of AR, even at the end of the survey (80 %). Finally, animal researchers did not agree to engage with this survey, with too few responses to report any data.

Previous surveys of the public and scientists have generally asked only whether people support AR for human benefit, and not asked people to evaluate their reasons for supporting (or not) AR (Table  5 ) [ 16 – 20 , 34 ]. The few surveys that have asked for some elaboration on reasons for supporting AR did not ask for the amount of detail, or explore response to counterarguments, as in our survey (Table  5 ) [ 35 , 36 ]. These prior surveys do suggest that people believe there are no alternatives to AR to achieve great human benefits, and that the moral justification for using NHA and not humans is not clear. Our survey supports and expands on these prior findings, with several suggested implications. First, the findings for ‘benefits arguments’ and ‘human exceptionalism’ arguments and their counterarguments suggest that public and medical student support for AR may not be based on cogent philosophical rationales. We suggest that the support may be based on group membership effects, with commitment to a current ‘Kuhnian’ scientific research paradigm of AR, without knowledge of or serious engagement with the detailed arguments [ 37 ]. Similarly, the Oxford Animal Ethics Center has called this institutionalization of the practice of AR “normalizing the unthinkable.” [ 38 ] Second, the findings for the ‘characteristics of NHA arguments’ and their counterarguments suggest that current AR animal protection practices may not be in line with the public and medical student beliefs about NHAs. For example, legal protections of NHAs are based on the assertion that these NHAs are property [ 39 ], and belief that NHAs are sentient is the basis for the counterarguments that question the moral permissibility of AR (e.g., argument from species overlap). Third, counterarguments suggesting that “researchers have not looked hard enough for alternatives to animal experimentation” and “if more effort was devoted to developing alternative research methods that do not use animals, animal experimentation may not be necessary anymore” were convincing for most respondents. Thus, a focus on return on investment from AR and alternative research methods may help people in considering the ethics of AR [ 2 , 40 , 41 ]. The translation rate into human benefit (i.e., accuracy of research models) is very low for AR, on the order of 0–8 % in all fields it has been examined in, far short of reliably providing ‘great human benefit’ [ 8 , 42 – 48 ]. Fourth, that animal researchers are reluctant to engage in this survey, described as an academic study from the University of Alberta and approved by our health research ethics board, is disappointing. More open discussion regarding the ethics of AR is surely warranted. Finally, that many were supportive of AR even after considering all the arguments/counterarguments, particularly for medical students, suggests that social science research is needed to determine why philosophical argumentation does not translate into practical behavior change.

This study has several limitations. Response rates for medical school classes were 68 % and 49 %; thus we cannot rule out biased participation in the survey. In addition, we do not know the true response rate for our public festival, hospital wards, and AMT samples. Nevertheless, we estimate that most people approached for the paper surveys agreed to participate, the AMT surveys were completed in a very short period of time (<4.5 h on-line), and the SSI surveys were fully completed by 501/587 of those invited (85 %). Arguments and counterarguments presented needed to be short and concise, and this may have left out important details that would have influenced the understanding and response to the text. We did not ask about specific subtypes of AR and thus do not know if opinions will vary by whether research is on toxicology or efficacy, cancer or sepsis, etc. Nevertheless, the questions were framed assuming great benefit to humans from AR, and thus we believe the opinions are reflective of beliefs for types of AR that have such great benefit. We did not involve animal researchers in the development of the survey, and this may have biased the wording of the questions. Finally, our description of AR as harmful may have biased the responses. However, the survey was meant to apply to AR that is harmful to the animals; AR is a moral issue precisely because it is harmful to the animals; and, that AR is said by advocates to be done as ‘humanely’ as possible, with suffering minimized, entails that it is harmful to the animals.

Strengths of this study include the rigorous survey development process (including review by moral philosophers), and the inclusion of the most common and accepted arguments/counterarguments in the literature. This is the first survey we are aware of that asks the public and medical students to consider not just whether they support AR, but rather to consider the most common arguments in the literature in favor of and against AR. Another strength is the large sample size of the public, obtained from 4 different samples, with strikingly similar responses, enhancing the generalizability of our results. The similarity of findings to our previous sample of pediatric health care workers also enhances the generalizability of the results [ 21 ].

When presented with common arguments to justify AR, most respondents accepted ‘benefits’ arguments, and only a minority found the ‘characteristics of NHA arguments’ and ‘human exceptionalism’ arguments convincing. Most found the argument to justify AR significantly weakened by common counterarguments, including those who initially found the ‘benefits’ arguments convincing. These responses to all the common arguments/counterarguments on offer in the literature regarding the moral permissibility of AR suggest that the public may want to re-consider whether public funds ought to support AR. Engagement with and serious discussion of the arguments on both sides of the AR debate by the public and scientists (including animal researchers); and deliberate extensive investigation of alternative research methods, and the return on investment from using them (as compared to the poor track record of AR [ 8 , 38 , 42 – 48 ]) are potential ways forward in the debate about the moral permissibility of AR.

Ethics approval and consent to participate

The study was approved by the health research ethics board of the University of Alberta (Pro00039590), and return of the survey was considered consent to participate.

Consent for publication

Not applicable.

Availability of data and materials

The survey instrument, and all aggregated data is reported in the manuscript. The database can be made available on request to the authors.

Abbreviations

amazon mechanical turk

animal research

non-human animals

survey sampling international

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MB was supported for this research by a summer studentship from Alberta Innovates- Health Solutions; the funding agency had no role in the design and conduct of the study; collection, management, analysis or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

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ARJ contributed to conception and design, acquisition, analysis and interpretation of data, and drafted the paper, and had final approval of the version to be published. MB contributed to design, acquisition and interpretation of data, and revising the manuscript critically for intellectual content, and had final approval of the version to be published. NA contributed to design, and interpretation of data, and revising the manuscript critically for intellectual content, and had final approval of the version to be published. NN contributed to design, and interpretation of data, and revising the manuscript critically for intellectual content, and had final approval of the version to be published. ARJ had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.

Additional file

Additional file 1:.

E-Tables describing respondent demographics, and the details of responses in the 4 different public groups surveyed. Table E-1 . Demographics of survey respondents. Table E-2 . Public survey results for questions about “Benefits Arguments” to morally justify animal research. Table E-3 : Public survey results for questions about “Characteristics of non-human-animals arguments” to morally justify animal research. Table E-4 . Public survey results for questions about “Human exceptionalism arguments” to morally justify animal research. Table E-5 . Public survey results for general questions about support for animal research. (PDF 165 kb)

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Joffe, A.R., Bara, M., Anton, N. et al. The ethics of animal research: a survey of the public and scientists in North America. BMC Med Ethics 17 , 17 (2016). https://doi.org/10.1186/s12910-016-0100-x

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The use of animals in research, teaching and testing is a controversial ethical and political issue. Much of the discussion about this issue revolves around the relative value, often referred to as 'moral value', of humans and animals. When the needs of animals and humans come into conflict, which takes precedence? Today there exists a wide spectrum of views on this subject, ranging from those concerned with animal 'rights' to those who view animals only as a resource to be exploited. All of these viewpoints have contributed to the development of ethical principles of animal use. These in turn have shaped animal use regulations promulgated by the USDA and the Public Health Service, and reinforced by organizations such as AAALAC , AALAS and the AVMA .

Current legislation also recognizes that there are diverse viewpoints about the moral value of animals. Thus, all live animal use in research, teaching or testing must be reviewed by a committee (the IACUC) with diverse membership. This evaluation includes an emphasis on minimizing the overall use of animals.

Proposals for animal use are reviewed based on the potential for learning new information, or for teaching skills or concepts that cannot be obtained using an alternative. There are provisions for ensuring that animal use is performed in as humane a manner as possible, minimizing pain, distress or discomfort. These provisions include a requirement for a veterinarian to be employed at each institution, so that the needs of the animals are looked after by someone trained in, and sympathetic toward animals' needs. It is also required that all personnel with animal contact be trained in appropriate handling techniques and that they be skilled in any experimental procedures that will be performed. Finally, basic husbandry requirements are specified, ensuring that an animal's food, water and shelter will be provided for in an optimal manner. Deviations from the numerous requirements are granted by the IACUC only if adequate scientific justification is given that the proposed experiment is scientifically and socially important, and that any methods to alleviate pain or distress would frustrate the experimental objectives.

Animals have been used throughout history for anatomical and physiological research as well as for testing new medications and toxic substances. Many medical advances, including vaccines for polio and rabies, the development of certain antibiotics, cancer treating agents and transplant medicines, have been developed thanks to the use of animals in research.

The use of animals in research is a privilege and not a right. A research institution that receives money and support from the public is responsible for conducting research humanely and responsibly according to the limits set by society and regulatory bodies.  

Animal Welfare Act

The Animal Welfare Act (AWA) was passed in 1966. This act licenses dealers, exhibitors and breeders of animals, regulates research facilities that use animals, sets standards for the humane care and treatment of animals, and regulates the transportation of animals. The Act has been amended multiple times adding further protections for animals covered by the Act. The AWA specifically exempts birds, mice, rats, amphibians and reptiles used in research as well as agricultural animals that are used for agricultural production.

The United States Department of Agriculture is the government agency that is responsible for the enforcement of this act. Facilities must submit an annual report to the USDA. The USDA conducts unannounced inspections of research facilities at least once a year. If violations of the Act are found, fines can be imposed or research activities can be stopped.

Public Health Service Policy

The Public Health Service (PHS) Policy on the Humane Care and Use of Laboratory Animals is based on the United States Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training. This policy covers all research that is funded by the National Institutes of Health (NIH) using vertebrate species of animals including birds, mice, and rats.

Institutions covered by this policy must follow the Guide for the Care and Use of Laboratory Animals (see below) and annually submit a written document called an Animal Welfare Assurance to NIH, which documents how the institution is complying with all the regulations covering animals used in research. The Office of Laboratory Animal Welfare (OLAW) at NIH is the agency that is responsible for enforcement of the PHS policy.

Guide for the Care and Use of Laboratory Animals

The Guide for the Care and Use of Laboratory Animals ("The Guide"), first developed in 1963, is a manual for research facilities receiving public funding for research using animals. The latest (2011) version of the Guide , sets specific standards for the care and use of laboratory animals. It addresses institutional responsibilities, husbandry and housing standards, veterinary care and physical plant specifications. It is written by experts in laboratory animal care and is published by the National Research Council.

AAALAC stands for the Association for the Assessment and Accreditation of Laboratory Animal Care. This is an independent (non-government) and voluntary accreditation organization. AAALAC accredits laboratory animal facilities through a process of intensive inspections (every 3 years) and reports (yearly). AAALAC follows the high standards put forth in the Guide. Accreditation, while voluntary, represents commitment to excellence in animal care and is an important factor to many funding agencies.

University of Minnesota Policy

The Regents Policy on Animal Care and Use addresses the use of all animals in research, teaching or display at the University of Minnesota. This policy follows from the federal and other laws and regulations. It addresses the roles and responsibilities of the Institutional Official, the Institutional Animal Care and Use Committee (IACUC), Research Animal Resources, and the University Community.

The Institutional Official (IO) is appointed by the University President and reports directly to him/her as well as to the federal authorities regarding compliance with all laws and regulations governing the use of laboratory animals in research and teaching. The President has formally delegated responsibility to appoint IACUC members to the Institutional Official.

The IACUC, which is a committee mandated by the AWA and the PHS policy, reviews and approves all activities involving animals at the University of Minnesota. The AWA and PHS policy have specific membership requirements for the committee. There must be at least:

• one veterinarian (with laboratory animal background and programmatic responsibility at the institution),
• one member of the community (non-affiliated member to represent the public interest),
• one scientist who uses animals in research, and
• one non-scientist member.

University policy states that the committee should have at least 5 members, but the committee has many members, including several student members and ex-officio representatives from Occupational Health & Safety and the Department of Environmental Health and Safety.

The committee reviews all animal care and use protocols to ensure:

• that the use of animals is necessary to achieve the stated objectives,
• that pain and distress is minimized, and
• that all the laws and policies for the use of animals are followed.

The committee also ensures the humane care of animals through the inspection of animal housing and use facilities twice a year and by investigating any complaints made regarding animal use. The committee is also responsible for reporting any instances of non-compliance and recommending corrective action.

Research Animal Resources (RAR) is designated by University policy as the program that provides the housing and husbandry as well as the veterinary care for the laboratory animals on the Twin Cities campus. They are also designated to serve as a consultation resource for the care and use of animals in research and teaching.

University policy also lists the roles and responsibilities of the University community. The University researchers and staff are to be appropriately trained and qualified to conduct activities with animals and are to abide by the decisions of the University and the IACUC.  

For serious questions or concerns about animal welfare, the process of review, or about committee decisions, contact:

Shashank Priya Institutional Official (612) 624-5054 [email protected]

Joanne Billings Deputy Institutional Official (612) 624-0999 [email protected]

You may also report animal welfare concerns or policy violations via the University of Minnesota's reporting system.  The UReport provides a way for University community members to report violations of rules, regulations and policies. The report can be made anonymously.

Note that, by federal law, no facility employee, Committee member, or laboratory personnel shall be discriminated against or be subject to any reprisal for reporting violations of any regulation or standards.  

Agricultural

The Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching is a text published by the Federation of Animal Sciences Societies. This Guide addresses standards for agricultural animal husbandry, housing and veterinary care. It does not apply to agricultural animals used for biomedical type research or teaching.

The standards are slightly different than those listed in the Guide for the Care and Use of Laboratory Animals. For example, cage space requirements may differ slightly between the two texts. Although this text is not regulatory, the University uses its provisions and principles as the basis for its care and use programs involving animals used for production or agricultural research.

There are several references available for the use of fish , amphibians and mammals in wildlife research . Again, these documents are not regulatory documents but are excellent references for the care and handling of these animals.  

Pain & Distress

The AWA defines a painful procedure in an animal as: "any procedure that would reasonably be expected to cause more than slight or momentary pain or distress in a human being to which that procedure was applied, that is, pain in excess of that caused by injections or other minor procedures." Pain can be acute, short lived - or chronic, lasting a long time. The signs manifesting acute or chronic pain may differ and may be different in different species. Prey species of animals can be adept at hiding signs of pain or illness and may be more difficult to assess discomfort.

Signs of Acute Pain in Animals

• vocalization
• attempts to escape the stimulus
• aggressive responses
• increased heart and respiratory rates
• anorexia or shaking

Signs of Chronic Pain

• weight loss
• poor or unkempt hair coats
• depression or lethargy
• general debilitation

Distress is currently defined as "a state in which an animal cannot escape from or adapt to the external or internal stressors or conditions it experiences resulting in negative effects upon its well being…" Distress differs from stress, which is a physiological reaction that can lead to an adaptive response.

Principle IV of the US Government Principles states that unless the contrary is established, the assumption must be made that a procedure that causes pain or distress in a human being will cause pain and distress in an animal.

Alternatives

Current regulations stress the need to search for and utilize alternatives to procedures on animals that cause more than momentary pain or distress. The concept of the three "R"s has been used when thinking about alternatives to animal use. This concept was developed in 1959 by Russell and Burch in their book: The Principles of Humane Animal Experimental Techniques.

The three "R"s are Replacement, Reduction, and Refinement. Investigators at the University of Minnesota, who use animals that may undergo more than momentary pain or distress, should consider the three “R”s when conducting procedures which may be painful or distressful.

Replacement of animals with other systems may be an option. Computer modeling or in vitro testing may be a substitute for animal models. "Lower" or non-vertebrate animals, such as the fruit fly may be used in some situations rather than a higher order animal.

Reduction of the number of animals used for research is also an important concept. This is done mostly through experimental design and the use of statistics. The use of too few animals could result in statistically invalid results, which could necessitate the use of even more animals in subsequent experiments. Pilot studies to help determine statistical parameters can sometimes assist in determination of group sizes. Reduction of pain and distress may also actually require the use of more animals so that repeated procedures are not conducted on the same animal.

Refinement refers to methods that decrease the amount of pain and distress experienced by the animals that are actually needed to perform an experiment. This is not only done through the use of pain relieving measures such as anesthetics and analgesics whenever possible, but also through environmental enrichment.

The use of early endpoints can also be a form of refinement. For instance if an animal were to suffer from an early indicator of disease or a tumor reaches a certain measurable size, this could be used as the endpoint. The animals should be humanely euthanized at this point rather than waiting until the death of the animal.

For more examples of replacement/reduction/refinement and searches for alternatives, see IACUC's web page, “Finding Models and Alternatives”.

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Mankind has been using animals already for a long time for food, for transport and as companion. The use of animals in experimental research parallels the development of medicine, which had its roots in ancient Greece (Aristotle, Hippocrate). With the Cartesian philosophy in the 17th century, experiments on animals could be performed without great moral problems. The discovery of anaesthetics and Darwin's publication on the Origin of Species, defending the biological similarities between man and animal, contributed to the increase of animal experimentation. The increasing demand for high standard animal models together with a critical view on the use of animals led to the development of Laboratory Animal Science in the 1950s with Russell and Burch's three R's of Replacement, Reduction and Refinement as guiding principles, a field that can be defined as a multidisciplinary branch of science, contributing to the quality of animal experiments and to the welfare of laboratory animals. The increased interest in and concern about animal welfare issues led to legislative regulations in many countries and the establishment of animal ethics committees.

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Russell WMS, Burch RL . The Principles of Humane Experimental Technique . Methuen: London, 1959, Reprinted by UFAW, 1992: 8 Hamilton Close, South Mimms, Potters Bar, Herts EN6 3QD England.

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Baumans, V. Use of animals in experimental research: an ethical dilemma?. Gene Ther 11 (Suppl 1), S64–S66 (2004). https://doi.org/10.1038/sj.gt.3302371

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Article Contents

Introduction, ethics and animal research, pain in animals: general ethical principles, animal pain research: ethical dilemma and paradox, ethical guidelines for iacucs, ethical guidelines in current laws and regulations, ethical guidelines of professional groups, iasp ethical guidelines, conclusion: the work ahead.

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Ethics and Pain Research in Animals

Jerrold Tannenbaum, J.D., was in the Department of Environmental and Population Health, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts, when he wrote this article. He is currently a Professor in the Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California.

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Jerrold Tannenbaum, Ethics and Pain Research in Animals, ILAR Journal , Volume 40, Issue 3, 1999, Pages 97–110, https://doi.org/10.1093/ilar.40.3.97

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Pain research in animals raises distinctive and sometimes difficult ethical issues for institutional animal care and use committees (IACUCs 1 ), attending veterinarians, and investigators. In this paper, I explore and defend a number of widely accepted ethical principles regarding animal pain. I develop from these principles guidelines for use by IACUCs in assessing the humaneness of pain research in animals. Relevant ethical standards in current US laws and regulations and in policy statements of professional research associations are also examined.

Attention to ethics is an essential part of the work of IACUCs, veterinarians, animal researchers, and all who affect the lives of research animals. The entire enterprise of animal research is motivated by an ethical principle--the belief that it is not only appropriate but morally obligatory to try to understand, alleviate, and prevent conditions that harm and kill so many. It would be incongruous and inconsistent to engage in animal research for this ethical reason and deny the importance of dealing ethically with the animals essential to this research. Moreover, virtually everyone accepts the principle that we have a fundamental ethical obligation to treat properly animals we use for our own benefit. Many scientists and veterinarians believe that it is a privilege to use animals in research ( Dubner 1983 ). Regarding animal use as a privilege involves treating research animals with appreciation, gratitude, respect, and a genuine concern for their needs and welfare.

Legal Recognition of the Importance of Ethics in Animal Research

Congress and agencies that regulate animal research have recognized the importance of ethics by articulating a number of ethical rules IACUCs and others involved in animal research are expected to follow. The Preamble to the federal Animal Welfare Act (AWA 1 ) declares that the entire statute and its regulatory structure are intended “to insure that animals intended for use in research facilities or for exhibition purposes or for use as pets are provided humane care and treatment” (7 USC 2131(1)). The terms “humane care and treatment” and treating animals “humanely” are used by most people, and clearly by the AWA, as synonyms for ethical care and treatment and treating animals as we are ethically obligated to do ( Tannenbaum 1995 , p 120-121,419-420). The statute and its regulations contain many ethical obligations made legally enforceable, such as the requirements that procedures “will avoid or minimize discomfort, distress, and pain to the animals” (9 CRR 2.31 (d)(1)(i)) and that “animals' living conditions will be appropriate for their species and contribute to their health and comfort” (2.31(d)(1)(vi)).

Public Health Service (PHS 1 ) policies also contain ethical standards, many of which are set forth in the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training ( PHS 1996 ). For example, “procedures involving animals should be designed and performed with due consideration of the relevance to human or animal health, the advancement of knowledge, or the good of society” ( PHS 1996 , p i). This principle requires that what is done to animals in research be justified by practical or theoretical results. The first sentence of the Guide for the Care and Use of Laboratory Animals (Guide 1 ), which institutions covered by PHS rules must consult, proclaims an ethical principle intended to underlie the Guide's recommendations: “all who care for or use animals in research, teaching, or testing must assume responsibility for their well-being” ( NRC 1996 , p 1).

Attention to the ethical treatment of animals in research is not just morally obligatory. It is required by law.

In discussing ethical considerations relating to pain research in animals, it is important to begin with general ethical principles. An essential part of ethical deliberation involves giving reasons for ethical beliefs, which involves appealing to underlying principles. If the soundness of these principles can be maintained independently of particular applications, the principles can then be applied confidently to these applications. In the area of pain research, there is a special reason to begin with general ethical principles. Although laws and regulations contain ethical rules for IACUCs and investigators regarding animal pain, these rules do not specifically address the intentional causation of pain that is characteristic of much pain research in animals. The rules instead invoke general and widely held ethical standards relating to animal pain. Application of these governmental ethical rules to pain research in animals requires an understanding of the underlying ethical standards that give these rules meaning and specificity.

Centrality of Animal Pain in Our Ethical Framework

People apply many different ethical principles to their interactions with animals. One significant recent development in animal ethics is growing acceptance by the public and members of the biomedical research community of the view that animals used in research should be provided enriched environments and positive psychological experiences ( Rollin 1995 , p 3-26). However, this view is recent and is not yet universally extended to all species. For at least the past 100 yr, most people in Western societies have believed their primary ethical obligation to all animals is not to cause them unnecessary or unjustifiable pain ( Tannenbaum 1995 , p 120-122). Most laws relating to animal use (such as cruelty-to-animals statutes, humane slaughter laws, and most laws and regulations governing animal research) require that animals used for legitimate purposes not be caused pain if possible and not be caused unnecessary pain if some pain is unavoidable. The view that the capacity of animals to feel pain is the primary source of our ethical obligations to them was argued by the 18th century English philosopher Jeremy Bentham, who maintained that the important question regarding animals is not “Can they reason? nor Can they talk? but Can they suffer?” (1948, p 311, emphases in original). Bentham also argued that there is no ethical issue whatsoever if an animal raised or used in research does not feel pain, distress, or discomfort. This position is accepted widely (but by no means universally) by the general public and biomedical scientists today.

Reality of Animal Pain

The principle that our primary obligation to animals is not to cause them unjustifiable pain presupposes that animals can experience pain. It may seem obvious that animals feel pain. Moreover, using animals in pain research as a model for human pain clearly presupposes that animals feel pain; if they did not, the model would be pointless. Nevertheless, there still exist among some scientists remnants of behaviorist notions that animals do not feel pain, or that feelings of pain in animals are of no practical significance because they are incapable of expression in the language of chemistry or physics ( Rollin 1987, 1997 ). Many IACUC members have encountered investigators who, when asked whether their work might cause animals pain, respond that one cannot really know what animals feel or be certain that they feel pain at all. They might look scruffy, depressed, or agitated, it is sometimes said, but who can know what they feel if they feel anything? Such statements recognize the ethical relevance of causing pain but attempt to lessen or negate ethical issues by questioning the reality of animal pain. Although doubts about animal pain are less likely among pain researchers who use animal models for human pain than among investigators whose work may secondarily cause animals pain, questioning whether animals feel pain, or feel pain “as we do,” can be a tempting neutralizer of unsettling ethical aggravations.

Pain As a Fundamental Evil

Pain is not only an evil--something that is bad or a harm--but is an evil in itself. Pain is an evil simply because of the way pain feels and not for some other reason (although pain can have additional bad effects and for these reasons be evil). Pain is sometimes beneficial in signaling the presence of some problem such as injury or disease. However, the experience of pain is bad in and of itself, which is why humans and animals generally avoid it. We do not ask why pain is bad, not just because we know that it is bad but because we cannot say anything more about it than that it is pain. If someone asked you to explain why feeling pain is a bad thing, and if you took the question seriously, you would respond that it is bad because it feels the way it does--that pain is bad because it is pain. In other words, it is self-evident that pain is evil in and of itself.

Equality Principle

If the essential character of pain and suffering themselves make them evil--evil not for their consequences but in their intrinsic natures--then it follows that given magnitudes of pain and suffering are equally evil in themselves whenever and wherever they occur. An intense toothache is an evil in a young person or an old person, a man or a woman, a Caucasian or a Negro, a human being or a lion. A skeptic might deny that a toothache hurts a lion as much as it does a human being, but once one concedes that lion pain and human pain are equally pain--in the same sense and the same degree--then one cannot deny that they are equally evils in themselves. All this follows necessarily from the view that pain as such is an intrinsic evil, and not evil only because it tends to produce bad effects of other kinds ( Feinberg 1980 , p 194).

If animals of a “lower” species experience less pain than those of a “higher” species under certain circumstances, this fact could be relevant to determining whether a pain research experiment is justified on them, because it causes them insignificant pain, or is better done on them than on animals of a species that would experience more pain. However, one cannot regard an experience of pain as less a harm or evil, and therefore raising a less serious ethical issue, because that experience would occur in rats, for example, rather than in cats or primates.

Justification Principle

…condemn and conscientiously avoid inflicting unnecessary pain and suffering on other human beings simply because we regard pain and suffering as an intrinsic evil. That is, we judge pain and suffering to be evil simply because they are pain and suffering. In the case of human beings, at least, we never ask for any further reason that a given condition is evil and therefore to be avoided or corrected after we learn that it is a painful condition. The question “What's wrong with pain anyway?” is never allowed to arise ( Feinberg 1980 , p 194, emphases in original).

It is a basic ethical wrong--perhaps the most basic ethical wrong of all--to harm another being without justification. Because pain is an evil, we act wrongly if we cause any animal we use for our own benefit or for the benefit of other animals unnecessary or unjustifiable pain. It is difficult to state generally how strong a justification must be given for the infliction of pain. It can, however, be said that causing any pain is not a trivial matter and requires not trivial but substantial justification.

Value Principle

From the Justification Principle and the fact that pain is an evil to animals follows a critically important ethical principle that is often invoked by IACUCs when they consider research likely to cause animals pain. Because pain is an evil, more or more severe pain is a greater evil than less or less severe pain. Therefore, the more pain an experiment will cause animals, the greater must be the justification. Expressed another way by what I call the “Value Principle,” the more pain an experiment or test will cause, the greater must be its value. Saying that the value of an experiment must justify the level or kind of pain the experiment causes is of course just to begin ethical deliberation. People disagree about whether certain kinds of animal uses are sufficiently valuable to justify a certain level of animal pain. Some people, for example, believe that testing cosmetics is of sufficient value to justify animal pain; others disagree. Some people believe that animal pain can never be justified by basic research that does not promise practical benefits for people or other animals; others disagree. It is possible to argue not only about whether such goals are sufficiently valuable to justify a certain level of animal pain, but also about the relative ranking of these goals. Thus, one can maintain that although basic knowledge may be valuable, it is not as valuable as practical knowledge in the sense that it justifies causing animals pain and cannot justify as much animal pain as would applied medical research.

There are other difficult issues in assessing and comparing the value of medical research relative to justification of animal pain ( Tannenbaum 1995 , p 485-486). For example, although research that could bring relief from suffering to many people may often seem of greater value than research that would benefit only a few, if those few suffer grievously and lack means of relief, the urgency and value of research to help them may be greater. However we decide to characterize the value of research, because pain is an evil to animals and because more pain is a greater evil to them than less pain, the value of research causing that pain must be greater when the pain for the animals is worse.

Components of Value in Research

There are two components of the kind of value that is needed to justify animal pain caused by research: the value of the aims of the research and the level of its scientific soundness. Research that causes animals pain to test a new and potentially more effective pain-killing drug for cancer patients will likely have an aim that is sufficiently valuable to justify the infliction of some animal pain. A project that would cause animals pain simply to amuse a “researcher” who enjoys watching animals suffer has no value and would not justify the infliction of any pain. However, good aims are not enough for the value that is required to justify animal pain. Ethically acceptable research must also have some level of scientific soundness (sometimes termed “scientific merit”). Although the results of research are often unpredictable, research that will cause animals pain must be based on accurate scientific knowledge, involve scientifically defensible hypotheses, and use scientifically appropriate techniques. An investigator who wants to find better ways of alleviating pain in cancer patients (a valuable aim) is no more justified causing pain to animals than one who has a foolish aim if the proposed research of the former investigator is scientifically inept. The infliction of pain on the animals will still be pointless, and unjustified. Performing scientific experiments that are sufficiently valuable to justify animal pain includes being competent to do the scientific work. Bad science cannot be good ethics, certainly when it involves causing animals pain.

Minimization Principle

From the Justification Principle follows the ethical principle that is employed most frequently in current laws and regulations governing animal research. What I call the “Minimization Principle” holds that we should minimize pain experienced by research animals. Assuming one is justified in doing harm, doing less harm to a being is always better than doing more harm. Less pain is less a harm or evil than greater pain. Therefore, one can never justify causing more pain to an animal than one needs to cause. The Minimization Principle is best considered after the Value Principle because whether a certain amount or kind of pain is deemed necessary and therefore justified will depend on whether the infliction of any pain on an animal is justified by proposed research. Once causing some pain is justified, the Minimization Principle requires that it be minimized, but this minimized level or amount of pain must also be justified by the value of the research. The Minimization Principle requires that no pain be caused if this is possible under the circumstances because no pain is the ultimate minimization of pain.

Conceptual Problems of Minimization

Although the Minimization Principle is persuasive, it will sometimes be difficult or impossible to apply it confidently to pain research in animals. This difficulty stems from the fact that experiences of pain have a number of different possible components, including duration and severity, and a variety of different characteristics, such as sharp, dull, piercing, throbbing, and burning. Given a specified severity and kind of pain (such as intense and sharp pain), we can say with confidence that such pain experienced for 1 min is less than such pain experienced for 10 min. Given a specified duration of pain, the Minimization Principle requires causing this duration of dull pain rather than sharp and burning pain, because we characterize the former as less pain. The principle is difficult to apply, however, when we compare different durations with different intensities and kinds of pain. For example, is 1 min of sharp and intense pain “less” pain than 10 min of dull pain? Is dull pain more or less pain than throbbing pain? Does it become more after a certain intensity or time? When we add to the mix different numbers of animals, the task of comparing and minimizing can become even more difficult. For example, how many cats experiencing sharp and burning pain for 10 min will constitute more pain than 50 cats experiencing dull pain for several hours? When we attempt to make such comparisons across species (to determine, for example, whether pain would be minimized by doing an experiment on rats rather than cats), the problems are magnified further because it may not be clear how to compare pain felt by different species even when we know that they feel pain.

Application of the Minimization Principle presupposes that we can determine whether a given use of animals involves more or less pain than another. However, we cannot always clearly say that some animals experience more pain than others because it is not clear that the term “pain” (even when properly applied) always refers to the same entity of which the relative amounts can be compared and then “lessened” or “minimized.” It is not clear what it means to say that 10 min of dull pain is the same amount of pain or is more or less than 1 min of excruciating pain, except that we think it is better —or more accurately, less bad —to experience the former duration and type. It is not clear that the 1 min of excruciating pain and the 10 min of dull pain are the same thing or can be converted into amounts of the same thing and compared for quantity.

When it seems difficult to determine whether one approach minimizes pain because it is difficult to compare the amount of one kind of pain experience with another kind, we must fall back on intuitive judgments and reliable behavioral evidence regarding what appears better or worse for an animal or human to experience. Because the underlying motivation of the Minimization Principle is to assure that animals feel no worse than necessary, this approach seems reasonable.

Fairness to Individual Animals

The Minimization Principle must be qualified by another important ethical principle. Talk of pain “minimization” may lead some people to think that the real ethical concern is the total amount of pain experienced and that our moral obligation is to minimize this total. The following example illustrates why this view is incorrect. Suppose a pain experiment could achieve satisfactory results either by causing excruciating pain in five animals for 1 hr or moderate and well-tolerated pain in 20 animals for 1 day. It might be correct in such circumstances to say that more total pain would be caused by using the 20 animals. However, I would argue that using the 20 animals would be ethically preferable, because each individual animal will be harmed less. The ethical problem in causing animals pain arises not from causing total amounts of pain but from causing individual animals pain. There is no such thing as a totality of pain that exists in the world. Individuals feel pain, and what makes pain evil is that it is an evil to the individual experiencing it. Therefore, in determining whether the infliction of animal pain is justified, we must ask whether what we are doing is fair to the individual animals we use. Sometimes considerations of fairness to these individuals will mean that we demand too much of each animal by subjecting it to a great amount of pain if we can accomplish the same end by having each animal used suffer less.

The important ethical principle of fairness to individuals is embodied in the provision of the AWA regulations that “no animal will be used in more than one major operative procedure from which it is allowed to recover” (9 CFR 2.3 l(d)(1)(x)) in the absence of scientific justification. This prohibition recognizes that although the total amount of pain or distress, and indeed the total number of animals, may be lessened if fewer animals are subjected repeatedly to major procedures, it can be unfair to each individual animal used to do this. In pain as in other kinds of research, fairness to individual animals may sometimes require using more rather than fewer animals, extending rather than shortening the duration of an experiment, and not minimizing total pain and distress.

Associated Negative Feelings

In considering ethical responsibilities relating to causing animals pain, it is important to take into account unpleasant mental states that typically accompany pain. Some of these states (such as distress) may occur so frequently with feelings of pain that they may sometimes properly be described as part of the pain experience itself. Others (like discomfort, fear, or anxiety) may sometimes be easier to separate phenomenologically from pain or be better viewed as reactions to pain. What is ethically important about pain--what makes it an evil to animals as well as to humans--is that it feels bad. Other unpleasant feelings such as distress or discomfort also feel bad, and the same ethical principles apply to causing them in animals as apply to causing pain. Therefore, in determining whether causing animal pain in an experiment is ethically justifiable, we must include in our deliberations other unpleasant or negative animal experiences. The presence of such feelings is likely to increase the total evil an animal will be caused and thus increase the required minimum level of justification and value of a proposed experiment. The Minimization Principle requires pain researchers to minimize these associated negative feelings (while still causing necessary pain) if minimization of such associated feelings is possible given justified experimental aims.

The need to include negative feelings associated with pain in ethical assessment of pain research causes no small conceptual, scientific, and practical problems. If there is disagreement among philosophers and scientists about the meaning of the term “pain” in animals and lack of knowledge about its nature and causes, there is even greater disagreement about the meaning and causes of psychological states in animals such as distress, discomfort, fear, or anxiety ( Tannenbaum 1995 , p 416-418). Nevertheless, such disagreements and lack of knowledge do not diminish the strength of the ethical principle that bad or unpleasant feelings inflicted on animals must be justified and minimized. Indeed this ethical principle requires us to learn as much as possible about negative mental states associated with pain so that they too can be minimized in research.

Imprecision in Ethical Deliberation Relating to Animal Pain

Aristotle warned that different kinds of investigations require different levels or degrees of precision and that ethical discussions are unreliable if they seek more precision than the subject allows ( Aristotle 1952 , Book I, p 339). The ethical principles relating to pain discussed above are widely accepted and seem eminently reasonable. Their acceptance, however, does not mean that they can always be applied precisely. For example, sometimes knowing how to minimize pain is easy: If an animal is fully anesthetized, its pain is minimized during the time of anesthesia. But when animals feel pain--a situation common in pain research--it is often impossible to know whether they are being caused absolutely the minimum amount of pain necessary even when comparisons of amounts of pain seem possible. There is still much to be discovered about what behavioral and physiological signs indicate the presence of pain in various species. Pain behavior (and presumably pain perception) varies significantly among different individuals within species ( Soma 1987 ). Much remains to be learned about what kinds of chemical and environmental interventions can lessen animal pain. However, the most serious problem for precisely estimating and then minimizing animal pain results from the fact that animals cannot talk about their pain. Adult humans can usually describe precisely when pain begins and ends, where it is located, and how it feels. We estimate the severity of human pain in terms of more intense versus less intense, sharp versus dull, piercing versus diffuse, throbbing versus steady, and with many other kinds of descriptions. All such information can be critical to determining whether pain is being lessened or minimized. Perhaps many of these discriminations will some day be applied to animals based on similarities between their physiological states or behavior and those of humans when we make these discriminations. In light of the inherent inability of animals to describe their pain, it seems unlikely that we will ever be able to make such determinations with anything approaching the precision we make them regarding pain in humans.

Ethical consideration of animal pain in pain research, like the research itself, must often settle for imprecise or gross estimates of how much and what kind of pain and associated negative feelings animals experience. It is therefore more accurate to say that one' s ethical obligation regarding animal pain is not to minimize it but to try to minimize it in light of best knowledge and practice. Moreover, because pain is a fundamental evil to animals as it is to humans, the following ethical principle seems appropriate: If there is reasonable scientific question about whether animals under certain circumstances are or are not feeling pain or are feeling more or less pain, we should err on the side of judging that they feel this pain or that they are feeling the worst or largest amount of reasonably attributable pain. By assuming the presence of such pain and requiring sufficient justification for it, we may be able to assure that the research is ethically justified whether or not it actually results in this pain.

…in 1988 112 million Americans (45 percent) experienced acute pain requiring medical care caused by 40 million injuries, 2 million bums, 5 million dental disorders, 10 million nontraumatic musculoskeletal diseases, 3 million childbirths, 15 million with acute pain in the postoperative period, and 37 million cases of visceral disease. Among this group 59 million, or 25 percent of the total population, experienced pain that was moderate to severe or excruciating and required major therapy in the form of opioids and other therapeutic modalities ( Bonica 1992 , p 2).

… pain is the most common reason individuals seek medical care, with millions of medical visits annually; costing the American public more than $100 billion each year in health care, compensation and litigation …. Pain-related disability presents a significant and costly liability to workers, employers and society. In the workplace, a significant proportion of employees, about 14%, take time off from their jobs due to pain conditions. In hospitalized patients, pain has been associated with increased length of stay, longer recovery time, and poorer patient outcomes, all of which have health care quality and cost implications ( NINDS and others 1998 ).

It is also clear that progress in understanding and alleviating pain in humans and animals requires the use of animals. Only live animals feel pain and behave in ways that are similar to humans' behavior when experiencing pain. Pain research in animals has been essential in improved understanding of the neural basis of pain and the “development of better narcotic and nonnarcotic analgesic drugs, the introduction of pain-relief procedures using electrical stimulation of peripheral nerves, sensory pathways or neural centers in the brain, and the recognition and exploitation of endogenous pain-suppressing chemicals such as enkephalines in the brain” ( Sessle 1987 , p 75-76). Improved understanding of and ability to deal with pain require continued research on animals ( Bonica 1992 ; Dubner 1983, 1987 ; Sessle 1987 ; Sternbach 1976 ; Zimmermann 1986 ).

Unfortunately, it is often impossible to do pain research on animals without the animals experiencing pain. Some important knowledge regarding pain mechanisms and modulation has been gained from studies on animals that cannot feel pain because they have been anesthetized or rendered unconscious by decerebration or decortication. However, much of what needs to be known requires awake and conscious animals, especially in research on pain neurophysiology at levels above the spinal cord ( Dubner 1987 ; Sessle 1987 ; Zimmermann 1986 ). Although some pain studies can allow animals to escape or to avoid painful stimuli when they presumably become too uncomfortable, several areas of pain research require unavoidable painful experiences. Some research into pain-suppressing pathways and mechanisms requires activation of painful and nonpainful stresses, including inescapable noxious stimuli. Studies of chronic pain often require experiences of pain and can involve such techniques as intermittent or continuous electrical stimulation of nerves or tissues; manipulation of nerves and tissues to produce chronic pain such as induction of neuromas or intradermal inoculation of bacterial toxins; and changes in sensory pathways by such methods as peripheral nerve deafferentiation, production of lesions, or injection of convulsive drugs, toxins, and chemicals resulting in neural hyperexcitability ( Dubner 1987 ; Sessle 1987 ; Zimmermann 1986 ). Animal models that can involve unrelieved pain include some for amputation pain ( Blumberg and Janig 1982 ; Wall and Gutnick 1974 ), arthritis pain ( Coderre and Wall 1987 ; Colpaert 1987 ; DeCastro Costa and others 1981-1987 ), cardiac pain ( Uchida and Murao 1974 ), chronic pain ( Sweet 1981 ), deafferentiation pain ( Brinkus and Zimmerman 1983 ; Wiesenfeld and Lindblom 1980 ), muscle pain ( Mense and Schmidt 1974 ), neuropathic pain ( Bennett and Xie 1988 ), stress-induced analgesia ( Lewis and others 1980 ), trigeminal neuralgia ( Black 1974 ), and visceral pain ( DeLeo and others 1992 ).

Pain research thus places us between horns of a troublesome ethical dilemma ( Dubner 1983 ; Zimmermann 1986 ). We appear obligated to do something--pain research on animals--that will sometimes involve doing something else--causing pain--that we are generally obligated not to do. To do great good we must sometimes cause great harm. And although causing such harm may often be justified, the nature of the needed justification sometimes makes the ethical dilemma more troublesome: As the problem of pain for humans and animals becomes greater, the pain we can justify causing animals when they are used in valuable pain research increases. Moreover, although the Minimization Principle applies even when pain is justifiably inflicted on animals, in pain research this principle may often fail to accomplish its ultimate goal, which is to spare animals significant or substantial pain.

None of this means that it is inherently wrong to cause animals pain in pain research. However, as Feinberg (1980 , p 194) observes, although causing “some pain does more good on balance, what follows is that justifiable pain is a necessary evil, not that some pain is good in itself.” That causing animals pain, even when justified, is a necessary evil explains why we should be unhappy about the need to do it and why we should feel unsettled by it (which is not the same as saying we should feel guilty about doing it). That causing animals pain in pain research may sometimes be a necessary evil also implies that IACUC members and investigators must pay special attention to their ethical obligations of minimizing harm to animals.

In the following enumerated recommendations, I use the general ethical principles defended above to propose ethical standards for IACUC members in their consideration of pain research. These recommendations are provided to assist committees and scientists in developing their own approaches. Although intended specifically for use by committees as required by laws and regulations in the United States, the recommendations, like the general ethical principles on which they rest, are universally applicable. I assume, however, as a given that the interests of research animals and of the general public in assuring the appropriate use of animals require that animal research proposals be reviewed for humaneness by local institutional committees.

1. The IACUC should apply to the consideration of any pain research proposal the fullest and most complete consideration available under its operating procedures. Because the deliberate infliction of animal pain is the infliction of a fundamental harm and evil, an IACUC should take all reasonable steps to assure that any pain research on animals performed at the institution is ethically appropriate, without question. There should not be expedited review of such research, nor review by a delegated member, committee, or subgroup of the IACUC. So that the best scientific, technical,-and ethical questions can be asked, all members of the IACUC should attend the review of pain research proposals. It is especially important for all nonaffiliated members to be present. The principle that animals should not be caused unnecessary pain is a deeply held ethical standard of the public, and pain research is typically justified on the grounds that it benefits the public. The community representatives on the IACUC should be available to apply this ethical standard and consider the sufficiency of this justification. Unaffiliated and certainly nonscientist members are also likely to insist on descriptions of any pain the animals may experience in lay terms that not only are understandable to them but also reflect the public's concern about what animals might actually feel. If necessary, an expert consultant should be invited to assist the committee if members require additional knowledge regarding pain research or mechanisms of pain avoidance, alleviation, or minimization. In light of the ethical significance of deliberately causing animals pain, any animal pain research must receive meticulous review by a committee, even if the research is not covered by federal laws and regulations because the institution does not receive PHS funds and the work is done on species currently not subject to US Department of Agriculture regulation.

2. Any proposal of pain research in animals should contain clear and convincing statements of the justification and value of the research, including the relevance of the work to practical benefits or important theoretical knowledge, the soundness of the science, and the competence and ability of research and animal care personnel to monitor and minimize animal pain. The greater the pain experienced by the animals, the greater must be the justification and value of the research. Because of the obvious general need for pain research, some investigators and IACUCs may be tempted to settle for quick, boilerplate justifications of experiments that assert in the most abstract terms the importance of pain and pain research. However, such statements are unacceptable. An investigator should explain to the IACUC what kind or kinds of pain are being investigated, why such pain is in great need of understanding or alleviation, and how it is hoped that the proposed research will contribute to this process. Because of the clear ethical cost of inflicting pain, investigators must be prepared to demonstrate knowledge of any experiments or tests that are similar or related to their proposed experiments and to show that their work is designed to verify or contribute relevant and important knowledge.

There is disagreement among IACUCs and commentators about whether committees can and should consider the scientific soundness of research proposals ( Prentice and others 1992 ; Tannenbaum 1995 , p 495,501). In my view, it is obvious that an IACUC must assure itself to at least some extent of the scientific soundness of research that will cause animals pain. It is difficult to imagine an IACUC responding to an experiment that would cause a large number of animals considerable and long-lasting pain with the statement that “we know there will be great pain here but we must leave it completely to a study section (initial review group) to decide whether there is any scientific or practical reason to do this work,” or “we know that there will be great pain here but we cannot express any position on whether there is a good scientific reason to cause this pain.” I believe that such responses are as unacceptable as they would be unusual. US laws require IACUCs (and not someone else) to determine whether proposed animal experiments are humane (that is, ethical). Infliction of pain cannot be ethical unless it is justified, and an IACUC that is unwilling to undertake any consideration of the scientific or practical reasons for inflicting pain simply cannot determine whether that pain is justified.

In assuring that proposed research is likely to be sufficiently sound to justify infliction of pain, an IACUC may ask the principal investigator to demonstrate familiarity with pain research. Students, research associates, and less experienced investigators who propose or work on animal pain research experiments should either demonstrate sufficient knowledge of pain research and the value of a proposed experiment that will cause animals pain or be closely supervised by a scientist with such knowledge. The IACUC should assure that the investigator and other personnel who work on an experiment that will cause pain are knowledgeable regarding methods of assessing and alleviating pain; otherwise, even the most justifiable experiment could result in unnecessary pain.

3. IACUCs should encourage investigators to demonstrate in experiments that will cause animals pain or distress a level of justification and value that is as high as possible. Estimating animal pain is and will likely always be imprecise. Moreover, it is sometimes difficult to estimate the potential theoretical and practical benefits of scientific experimentation. Some experiments fail, and much basic research has brought practical results that could not have been predicted at the time it was done ( Comroe and Dripps 1976 ). There are significant conceptual issues regarding how to define such states as pain, distress, discomfort, and anxiety in animals ( Tannenbaum 1995 , p 416-418; Wall 1992 ). People disagree on ethical grounds whether certain kinds of research justify animal pain or some degree of animal pain.

In light of these uncertainties and controversies, the higher the level of justification and value of the research an investigator can demonstrate, the easier it will be for the IACUC to feel confident in the ethical appropriateness of the work---because the uncertainties and controversies become less likely to affect the final decision whether a piece of research is ethically justified. An experiment that is part of a general research program that has already led to medically significant improvements in treating pain and is proposed by a scientist with demonstrated expertise and success in the area will likely overcome issues regarding precisely how much pain is being produced, whether the animals are feeling some distress as well as pain, or whether the negative feelings experienced by the animals will be absolutely minimized. If the research has great value, what the animals experience will probably be viewed as justified, provided that all reasonable steps are taken to try to minimize their pain and distress.

4. Investigators should characterize and estimate the likely pain and associated negative feelings that will be experienced by the animals as completely and accurately as reasonably possible. Investigators and IACUCs should consider a wide range of evidence, including inferences from similar pain experiences in humans and the best available scientific data regarding behavioral and physiological signs of animal pain. To determine that the research is justified, the IACUC must try to determine when the pain will start and end, how intense it is likely to be, and any other information about its phenomenological character. Investigators should assure the IACUC that they know how to assess and characterize pain in animals. Investigators should be familiar with normal behavior patterns in species in which they cause pain and with the kinds of deviations from such behaviors thought to be associated with pain ( Morton and Griffiths 1985 ; Sanford 1992 ; Sanford and others 1986 ; Soma 1987 ; Spinelli 1987 ; Spinelli and Markowitz 1987 ; Wright and others 1985 ). As a number of prominent animal pain researchers and specialists argue, one should not reject all anthropomorphism in describing the pain of animal subjects ( Dubner 1987 ; Soma 1987 ; Zimmermann 1986 ). The purpose of most pain research is to understand pain in humans, and it is often scientifically reasonable to assume that what the animals feel is similar to what humans feel.

Numerous schemes for scoring various levels or severity of animal pain have been proposed to assist IACUCs and investigators in estimating and minimizing pain. Some of these ( Orlans 1993 , p 87-88; SCAW 1987 ; Swedish Classification for Research Techniques 1984 ) were devised in an attempt to correlate levels of pain with standard kinds of surgical or experimental procedures. Others ( DeLeo and others 1992 ; Morton and Griffiths 1985 ) specify kinds of animal behavior that are presumed reflective of levels of pain. They direct investigators to locate what animals feel in an appropriate pain level category on the basis of observed behavior.

Investigators should also consider the possibility that pain in animals may sometimes be worse for them than pain in humans experienced under similar circumstances. Because animals may not know (or be able to know) why they are suffering pain or that the pain will end, pain may so completely dominate the animal's psychology that it may sometimes be appropriate to view its entire life for some period of time as a painful experience--as Rollin (1989 , p 60) aptly puts it, to view the animal as its pain. Analogizing from human experience may sometimes increase the estimate of expected harm to animals and thereby increase the level of required value of an experiment. For example, people who experience relatively low levels of pain for extended periods of time can become annoyed, depressed, and unhappy--they can suffer --because of the seemingly unending pain. The total negative experience can be worse than if one considered just the intensity and duration of the pain itself. Although one must be careful imputing to animals sophisticated emotional reactions to pain, neither should one preclude the possibility of such reactions.

The International Association for the Study of Pain (IASP 1 ) recommends that in pain research on conscious animals for “most non-invasive stimuli causing acute pain,” the investigator “should try the pain stimulus on himself” ( Zimmermann 1983 , p 109). As a nonscientist, I cannot assess the general validity of such an approach in estimating animal pain, but I can report an incident in which several members of an IACUC asked to receive an electric shock (not part of a pain study) that an investigator proposed to give to rabbits. They found the stimulus, when repeated several times as would have occurred in the experiment, so distressing that they asked the investigator to convincingly demonstrate the value of the research. (The investigator withdrew the proposal.) Perhaps IACUC members as well as investigators can try certain proposed painful stimuli on themselves if knowledge about the species and individuals used does not cast doubt on extrapolation of human reactions to what may be experienced by the animals. It might also be helpful for IACUC members to view animals that are subjected to painful procedures either before approving a proposal if possible or afterwards so that members can assure themselves that pain experienced by the animals is justified.

The IASP also recommends that pain studies “in animals paralyzed with a neuromuscular blocking agent should not be performed without a general anesthetic or an appropriate surgical procedure that eliminates sensory awareness” ( Zimmermann 1983 , p 110). This recommendation is supported by one of its authors on the grounds that because such animals “can be considered to be under stress in the condition of neuromuscular paralysis,” any results obtained “would be of no scientific value” ( Zimmermann 1986 , p 231). Additionally, paralysis removes overt signs of pain and distress and therefore removes one of the major ways to determine the severity, duration, and character of the animals' pain and distress. Because it is difficult if not impossible to characterize what paralyzed animals feel, one cannot determine whether what they feel is justified, whether their pain and distress is being minimized relative to the aims of the experiment, and whether their pain and distress have become so severe that the experiment must at some point be terminated.

5. Investigators should assure the IACUC that they are attempting to minimize pain in the design and performance of the research. Investigators should bear the burden of demonstrating to the IACUC why pain-relieving tools such as analgesia, pain avoidance, and environmental enrichment cannot be used, consistent with justified experimental aims. The veterinary and animal care staff must assure that procedures for pain minimization approved or required by the committee are followed. As Dubner (1987) explains, there is a range of techniques in animal pain research that are associated with different amounts or degrees of pain. Experiments on completely anesthetized animals, which have yielded some significant knowledge, cause no pain and do not raise ethical issues relating to whether pain is justified. Procedures on awake animals that have been given analgesic agents cause minimal pain or distress and can be relevant to certain kinds of information on, for example, neural processes minimally affected by such agents. Some animal pain research involves causing pain to animals that is not relieved but that can be escaped by avoidance behavior (such as tail-flicking or avoiding a painful stimulus) or administration of pain relief by the animal. Experiments involving physical restraint of animals can be quite stressful. The level of stress can sometimes be reduced by training the animals to perform pain detection and pain discrimination tests by, for example, having the animals decide when to initiate the test and when to withdraw from the experiment by ceasing to initiate trials. Experiments in which animals experience unrelieved pain include induction of acute pain of varying levels of severity as well as chronic pain of varying levels of severity and duration.

The Minimization Principle requires investigators to try to design research as far toward the pain-free end of this range of techniques as possible, consistent with justified experimental aims. IACUCs should therefore ask investigators to provide scientific reasons why the research cannot be of a sort that might cause less pain. Even when an experiment is appropriately designed, the investigator should assure the IACUC that all reasonable attempts will be made to minimize pain. Thus, in acute or chronic pain studies, the pain should not last longer than is required and should be alleviated with analgesics whenever or as soon as doing so is consistent with experimental aims. Animals should be allowed to avoid, self-treat, or escape pain when consistent with justified experimental aims. Environmental enrichment and opportunities for species behavior associated with stress reduction can lessen stress and discomfort experienced by the animals ( Mench 1998 ; Zimmermann 1986 ). Zimmermann (1986 , p 230-231) recommends that “animals in a chronic pain state should not be left alone. Wherever possible they should live in a rich environment providing social interaction with members of their own species, and much attention and handling by the scientist and his associates. There are indications that animals in pain suffer less when socially rewarded.”

Zimmermann (1986 , p 225-226) illustrates how applying the Minimization Principle can offer both possibilities and uncertainties. The leading model for amputation pain involves production of neuromas in rats and cats. After a peripheral nerve is transected under general anesthesia, the nerve fibers in the proximal stump begin to regenerate. This regeneration can cause severe pain, classified in humans as neuropathic pain. Rats and monkeys on which this procedure is done scratch and bite the denervated limb; the degree of self-mutilation is viewed by some scientists as a measure of the degree of pain. However, when a small nerve is lesioned, there is no self-mutilation, which appears to support the conclusion that there is no or minimal pain even though the neuropathophysiology has fully developed. Thus, there may be a way of doing this research that does not involve substantial pain. Nevertheless, because there is evidence that self-mutilation seen after nerve lesions is not always a sign of pain in animals, more work is needed to determine reliable criteria of pain so that we can accurately estimate the ethical costs of this kind of pain research.

Procedures that allow animals to escape pain have provided important data and would ordinarily be preferable to those that inflict unrelieved pain. However, it is not the case that, as suggested by Sessle (1987 , p 76), such techniques raise no ethical issue, because ethical guidelines governing pain research in humans approve of painful stimuli that human subjects can avoid or terminate at will ( Charlton 1995 ). Animals do not have the same kind of appreciation of what they are experiencing that can render it less stressful; they do not choose to be subjected to pain; and they cannot tell us that once they avoid or terminate a stimulus, their pain has ended. Although procedures that allow animals to escape or terminate pain may usually be less ethically problematic than those involving unrelieved or continuous pain, the infliction of even temporary pain is still the infliction of pain and must have sufficient ethical justification.

The Justification Principle requires anyone who causes animals pain to provide justification for doing so. The burden of providing sufficient justification should therefore be on the investigator and not the IACUC. Moreover, the likelihood of minimizing animal pain will probably be increased if, as a general policy, an IACUC asks investigators who cause animals pain to show why there is not some means of causing less pain consistent with justified research. Such a policy puts investigators on notice that they are always expected to try to minimize pain.

The Minimization Principle must be applied beyond consideration of research proposals by the IACUC. Pain can be minimized only if veterinary and animal care staff conscientiously and competently assure that the minimization procedures approved or required by the IACUC are followed.

6. In balancing pain and distress caused to animals against the value of the research, and in monitoring pain research in progress, the IACUC should consider whether pain has become so severe that individual animals should be removed from the research or the research itself should be terminated. At some point, the scientific reasons for a study may simply not justify the pain experienced by some or all of the animals.

7. Pain in “lower” species may not be considered less harmful or in need of less justification than pain in “higher” species. The Equality Principle permits differences in species to be taken into account only when relevant to the amount or intensity of pain or the likely presence of other negative experiences or emotions such as distress, fear, depression, or anxiety, which can accompany pain in humans.

8. Investigators and IACUCs should focus on what is fair to individual animals, which may sometimes require lengthening rather than shortening the duration of pain, using more rather than fewer animals, or causing more rather than less total pain. The IASP recommends that “the duration of the experiment must be as short as possible and the number of animals involved kept to a minimum” ( Zimmermann 1983 , p 110). Minimizing duration and numbers may often lessen the burdens experienced by individual animals used in pain research. However, fairness to individual animals may sometimes obligate investigators and IACUCs to consider alterations in experimental design that may increase or not lessen duration of pain or numbers of animals.

9. IACUCs should attempt to adhere to government ethical rules and should consult relevant professional association ethical guidelines but should view all general rules and guidelines as calling for, and ultimately subject to, independent ethical deliberation. Aside from having the force of law, government ethical rules relating to pain in animal research reflect society's most fundamental ethical views regarding animals. Ethical policies of professional research associations can provide unique perspectives of working scientists. However, laws often set forth minimal standards for behavior, which one may sometimes be ethically obligated to exceed. Both laws and professional association guidelines tend to be general and to fall back on general standards such as the Justification, Value, and Minimization principles. Therefore, to assure the humaneness of pain research in animals, IACUCs and investigators must engage in independent ethical assessment of research. They must apply to particular research situations general ethical principles such as those defended in this article.

US federal laws, regulations, and policies governing animal research contain many ethical guidelines applicable to pain research in animals. The AWA requires that regulations be effected that assure “animal pain and distress are minimized, including adequate veterinary care with the appropriate use of anesthetic, analgesic, tranquilizing drugs, or euthanasia” (7 USC 2143(a)(3)(A)); that “the principal investigator considers alternatives to any procedure likely to produce pain to or distress in an experimental animal” (7 USC 2143(a)(3)(B)); that “in any practice which could cause pain to animals,” a veterinarian be consulted in the planning of such procedures (7 USC 2143(a)(3)(C)(i)) and that these procedures provide for “the use of tranquilizers, analgesics, and anesthetics” (7 USC 2143(a)(3)(C)(ii)); and that “the withholding of tranquilizers, anesthesia, analgesia, or euthanasia when scientifically necessary shall continue for only the necessary period of time” (7 USC 2143(a)(3)(C)(v)). These provisions, all of which express the Minimization Principle, are elaborated in regulations that reiterate and sometimes apply this principle more concretely with, for example, the requirements that “procedures involving animals will avoid or minimize discomfort, distress, and pain to the animals” (9 CFR 2.31 (d)(1)(i)); that investigators provide the IACUC a written narrative showing that they have considered “alternatives to procedures that may cause more than momentary or slight pain to the animals” (9 CFR 2.31(d)(1)(ii)); and that an animal research proposal contain a “description of the procedures designed to assure that discomfort and pain to the animals will be limited to that which is unavoidable for the conduct of scientifically valuable research, including provision for the use of analgesic, anesthetic, and tranquilizing drugs where indicated and appropriate to minimize discomfort and pain to the animals” (9 CFR 2.31(d)(1)(x)). Other provisions of the AWA or regulations, which appear to have been intended at least in part to avoid unnecessary pain, include the prohibition of the use of paralytics without anesthesia (7 USC 2143(a)(3)(C)(iv), 9 CFR 2.3 l(d)(1)(iv)); the requirement that animals “that would otherwise experience severe or chronic pain or distress that cannot be relieved will be painlessly euthanized at the end of the procedure, or, if appropriate, during the procedure” (9 CFR 2.31 (d)(1)(v)); the requirement that activities involving surgery include “appropriate provision for pre-operative and post-operative care of the animals in accordance with established veterinary medical and nursing practices” (9 CFR 2.3 l (d)(1)(ix)); and the directive that methods of euthanasia involve no pain or distress (9 CFR 2.31(d)(l)(xi), 9 CFR 1.1. “Euthanasia”). The AWA describes the purpose of the IACUC's mandatory semiannual inspection in terms of minimizing pain. Although the statute requires that an inspection uncover all deficiencies, the only matters specifically mentioned are inspection of “practices involving pain to animals” and “the condition of animals, to ensure compliance with the provisions of this chapter to minimize pain and distress to animals” (7 USC 2143(a)(7)A)). The primary purpose of the AWA and regulations to minimize animal pain, distress, and discomfort is underscored by the requirement that all institutions file the annual report, which must contain not only an assurance that the facility has adhered to all standards and regulations under the Act, but also a statement that there has been “appropriate use of anesthetic, analgesic, and tranquilizing drugs, prior to, during, and following actual research…” (9 CFR 2.36(b)(1)) and that “each principal investigator has considered alternatives to painful procedures” (9 CFR 2.36(b)(2)). The main feature of the report is the specification of numbers of animals with respect to experiences of pain. The Minimization Principle lies squarely behind inclusion in the report of the category of animals that experience “pain or distress … for which the use of appropriate anesthetic, analgesic, or tranquilizing drugs would have adversely affected the procedures, results, or interpretations” of research projects, and the requirement that a statement explaining why such drugs were not used be attached to the report (9 CFR 2.36(b)(7)).

PHS ethical guidelines for animal research also focus on the minimization of pain and distress. These policies incorporate the requirements of the AWA regulations and state explicitly that “procedures with animals will avoid or minimize discomfort, distress, and pain to the animals, consistent with sound research design”; that “procedures that may cause more than momentary or slight pain or distress to the animals will be performed with appropriate sedation, analgesia, or anesthesia, unless the procedure is justified for scientific reasons in writing by the investigator”; and that “animals that would otherwise experience severe or chronic pain or distress that cannot be relieved will be painlessly killed at the end of the procedure or, if appropriate, during the procedure” ( PHS 1996 , p 9). The US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training declare that (1) “proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals”; (2) “procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia. Surgical or other painful procedures should not be performed on unanesthetized animals paralyzed by chemical agents”; and (3) “animals that would otherwise suffer severe or chronic pain or distress that cannot be relieved should be painlessly killed at the end of the procedure or, if appropriate, during the procedure” ( PHS 1996 , p i). The Minimization Principle also appears to underlie the statement of the Guide that “an integral component of veterinary medical care is prevention or alleviation of pain … The proper use of anesthetics and analgesics in research animals is an ethical and scientific imperative” ( NRC 1996 , p 64).

Pain Research in the Laws and Regulations

The frequent invocation of the Minimization Principle in AWA regulations and PHS policies reflects the centrality of this principle in society's ethical framework relating to animals. However, although federal ethical guidelines emphasize minimization of pain, they contain no standards or suggestions relating specifically to pain research in animals. Even the policy statement of the Animal and Plant Health Inspection Service that addresses painful or distressful procedures in research does not include pain research in its examples of painful or potentially painful procedures ( APHIS 1998 ).

The absence in US laws and regulations of specific ethical guidelines relating to animal pain research means that investigators and IACUCs must apply to pain experimentation on animals more general ethical principles that relate to animal pain. Some of these general principles are enunciated in the laws and regulations relating to animal research. Ethical guidance in evaluating the humaneness of animal pain research also requires use of normative principles of the kind developed in this article. Another important source of ethical guidance are policies of professional scientific groups. Such policies reflect the experience and focused interests of scientists who sometimes deal with animal pain in distinctive investigational contexts.

IACUCs and investigators should be aware of ethical guidelines applicable to pain research issued by professional research associations. Many of these documents explicitly incorporate or refer to US government laws and regulations. For example, the American Association for Laboratory Animal Science Policy on the Humane Care and Use of Laboratory Animals ( AALAS 1997 ) is identical to the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing Research and Training (US Principles 1 ). The American Physiological Society Guiding Principles for the Care and Use of Animals provide that all US laws and regulations be followed and specify that postoperative care of animals “shall be such as to minimize discomfort and pain” and that “all measures to minimize pain and distress that would not compromise experimental results may be employed” ( APS 1996 , p 1). The constituent societies of the Federation of American Societies for Experimental Biology have adopted a Statement of Principles for the Use of Animals in Research and Education. These guidelines state that “sound scientific practice and humane considerations require that animals receive sedation, analgesia or anesthesia when appropriate. Animals should not be permitted to suffer severe or chronic pain or distress unnecessarily; such animals should be euthanized” ( FASEB 1994 , p 2). This document also requires conformance with all applicable laws and, like the US Principles, states that “all work with animals shall be designed and performed in consideration of its relevance to the improvement of human or animal health and the advancement of knowledge for the good of society” ( FASEB 1994 , p 1). The Society for Neuroscience Policy on the Use of Animals in Neuroscience Research recommends and is based on the PHS Policies and the Guide, and it repeats or paraphrases the requirements of the US Government Principles: “the avoidance or minimization of discomfort, distress, and pain,” including use of sedation, analgesia or anesthesia in procedures “that may cause more than momentary or slight pain or distress” ( SFN 1997 , p 2).

Research should be undertaken with a clear scientific purpose. There should be a reasonable expectation that the research will a) increase knowledge of the processes underlying the evolution, development, maintenance, alteration, control, or biological significance of behavior; b) determine the replicability and generality of prior research; c) increase understanding of the species under study; or d) provide results that benefit the health or welfare of humans or other animals ( APA 1992 , p 2);

The scientific purpose of the research should be of sufficient potential significance to justify the use of animals ( APA 1992 , p 2).

In 1980, the Committee for Research and Ethical Issues of the IASP issued a set of ethical standards for use of animals in experimental pain research ( Covino and others 1980 ). These guidelines were revised in 1983 ( Zimmermann 1983 ). The preface to the current guidelines state that investigators “should make every effort to minimize pain” and should “accept a general attitude in which the animal is regarded not as an object for exploitation, but as a living individual” ( Zimmermann 1983 , p 109).

The 1983 IASP guidelines are contained in Table 1 . Several of the guidelines have already been discussed in this paper. The first guideline endorses the Justification and Value principles and appears to allow ethical evaluation of even scientifically sound research. The IASP guidelines require that investigators demonstrate likely practical benefits of experiments by showing their relevance to pain therapy. I have suggested that a stronger showing of the importance of a piece of basic research must be made when that work would cause pain or discomfort to animals than when research shows prospects of providing medical benefits ( Tannenbaum 1995 , p 472). However, I have not built this principle or the requirement that pain research causing animal pain must promise practical benefits into my recommendations to IACUCs. There has been very little consideration in the literature of the ethics of causing animal pain in basic research, and our understanding of this issue could benefit from additional discussion. The 1980 IASP guidelines contained the statement that “the investigator should choose a species which is as low as possible in the phylogenic order, compatible with the aim of the investigation. This recommendation infers that the degree of suffering is smaller in lower than in higher animals although this assumption cannot be taken as proven” ( Covino and others 1980 , p 142). The 1983 guidelines wisely deleted this statement. Although the Equality Principle is consistent with using “lower” species if they do experience less pain or suffer less, allowing investigators to proceed on the basis of an unproved assumption could reinforce the notion that the experience of pain in “lower” animals is less real or less ethically relevant.

Table 1 Ethical Guidelines for Investigations of Experimental Pain in Conscious Animals of the Committee for Research and Ethical Issues of the International Association for the Study of Pain a

Reprinted from Pain, Vol. 16, M. Zimmermann, “Ethical guidelines for investigations of experimental pain in conscious animals,” p 109-110, 1983, with permission from Elsevier Science.

To an animal, it does not matter whether its pain or distress is part of research designed to understand and treat pain. Moreover, because pain research is but one kind of biomedical research, animals that feel pain as a result of pain research surely represent a small fraction of research animals that feel pain or distress. Pain research, however, can lead the way in our general approach to ethical issues relating to pain in research animals. IACUCs and investigators cannot avoid confronting the reality of animal pain in experiments that intentionally cause such pain. They must engage in ethical deliberation in which animal and human interests are carefully balanced. They are ethically and legally obligated to find and implement techniques of lessening animal pain. Such ethical deliberation and such techniques for pain minimization will surely be applicable to animal pain associated with other kinds of research.

To help the countless people and animals that suffer pain, we need more pain research. The ethical paradox of pain research--that the evil of pain must sometimes be caused to ultimately understand and alleviate it--is for now inescapable. We owe it to the animals to approach the ethics of pain research as seriously as we approach the science.

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Animal Cell Culture: Principles and Practice pp 305–316 Cite as

Ethical Issues in Animal Cell Culture

• Divya Jindal 5 ,
• Vaishanavi 5 &
• Manisha Singh 5  
• First Online: 01 February 2023

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Part of the book series: Techniques in Life Science and Biomedicine for the Non-Expert ((TLSBNE))

For a long time, animals have been employed in research and studies. Even in affluent countries with Judeo-Christian ethical foundations, unambiguous ethical principles and relevant legislation were only enacted in the last several decades. We address the fundamentals of animal research ethics, ethical review and compliance criteria for animal experiments around the world, “our” fundamentals of institutional animal research ethics instruction and emerging alternatives to animal research in a concise manner. This book was painstakingly put together for scientists who are interested in or participating in animal research. We will go over some of the most important animal ethics ideas in this chapter. Even though ethical review and compliance guidelines for animal experiments are similar across industrialized nations, ethical review and compliance guidelines for animal experimentation vary.

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Jindal, D., Vaishanavi, Singh, M. (2023). Ethical Issues in Animal Cell Culture. In: Animal Cell Culture: Principles and Practice. Techniques in Life Science and Biomedicine for the Non-Expert. Springer, Cham. https://doi.org/10.1007/978-3-031-19485-6_20

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Ethical Guidelines for the Use of Animals in Research

Given by the National Committee for Research Ethics in Science and Technology (NENT), 2018.

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About the guidelines

These guidelines have been prepared by the National Committee for Research Ethics in Science and Technology (NENT). Their purpose is to provide ethical guidelines for researchers and other people who are considering experiments on animals. The guidelines will be useful when planning projects, assessing them, and when reporting and publishing findings and results. They are also intended to contribute to reflection on research ethics and the use of animals in research in both research communities and in the public debate.

The overarching framework for these guidelines is provided by the  Guidelines for Research Ethics in Science and Technology  (2016), particularly guidelines 12 and 13. A consultation process and a subsequent workshop organised by NENT in the autumn of 2016 found that relevant players see a need for a set of guidelines that can systematise and elaborate on the ethical responsibility inherent in the use of animals in research. This is the background for the current guidelines. 

In Norway, the use of laboratory animals is governed by the Regulations Relating to the Use of Animals in Research, which follow from the Animal Welfare Act. The EEA Agreement obliges Norway to implement EU Directive 2010/63/EU on the Protection of Animals used for Scientific Purposes. These rules provide a zero vision for research using animals. In Norway, the Gene Technology Act provides the legal framework for research on such organisms.

Many of the ethical obligations stipulated in these guidelines are also laid down in applicable legislation. Researchers who violate the guidelines can face legal sanctions. In that case, it is because they have broken the law, not primarily because they have violated the guidelines for research ethics. NENT does not have access to any sanctions of its own. NENT's role in following up the guidelines is to provide advice and recommendations, help increase awareness of animal welfare, and to stimulate continued discussion about research that involves animals. 

Ethics and Experiments on Animals

The ethical assessments related to the use of animals in research are wide-ranging. It is generally thought that it may be necessary to use laboratory animals in some cases in order to create improvements for people, animals or the environment. At the same time, the general opinion is that animals have a moral status, and that our treatment of them should be subject to ethical considerations. Such views are reflected in the following positions:

(i) Animals have an intrinsic value which must be respected.

(ii) Animals are sentient creatures with the capacity to feel pain, and the interests of animals must therefore be taken into consideration.

(iii) Our treatment of animals, including the use of animals in research, is an expression of our attitudes and influences us as moral actors.

The guidelines reflect all these positions, and stipulate principles and considerations that can be used as tools when balancing between harm and benefit. The three Rs (Replace, Reduce, Refine) are established principles that are also enshrined in legislation. These principles can establish absolute limits for experiments on animals, even when there are great benefits. These principles also state what can reasonably be considered harm and benefit, and the principles thus facilitate good assessments. Assessments of harm and benefit associated with experiments on animals are particularly demanding, because experiments may result in researchers intentionally causing actual harm to animals, while the future benefits are often uncertain.

The guidelines are dynamic and must be reviewed in line with technological developments and the appearance of new ethical issues. New gene  technology methods create new opportunities for the use of genetically modified animals in research, which is a growing trend. Genetically modifying laboratory animals, i.e. changing the genetic material of laboratory animals using gene technology, gives rise to a special responsibility in that this method entails a double intervention: first, intervention in the animal's genetic material and second, use of the animal as a research object. This practice has the potential to change our view of humans and our attitudes towards generating or eliminating genetic characteristics in ourselves. 

These guidelines provide a framework that also covers ethical questions associated with the use of genetically modified animals in research. 

Definitions

In these guidelines, the term «research» must be understood broadly, and include planning, execution and dissemination. The guidelines primarily address the «researcher» but apply to any person involved when animals are used for research, including funding and approval bodies, which are also responsible for making ethical assessments of projects involving experiments on animals. 

The guidelines cover «laboratory animals», as defined in the Regulations Relating to the Use of Animals in Research, but also cover all animals that are otherwise impacted by research activities.

1. Respect for animals' dignity

Researchers must have respect for animals' worth, regardless of their utility value, and for animals' interests as living, sentient creatures. Researchers must be respectful when choosing their topic and methods, and when disseminating their research. Researchers must provide care that is adapted to the needs of each laboratory animal.

2. Responsibility for considering options ( Replace )

Researchers are responsible for studying whether there are alternatives to experiments on animals. Alternative options must be prioritised if the same knowledge can be acquired without using laboratory animals. If no good options are available, researchers should consider whether the research can be postponed until alternative methods have been developed. When justifying experiments on animals, researchers therefore must be able to account for the absence of options and the need to acquire knowledge immediately.

3. The principle of proportionality: responsibility for considering and balancing suffering and benefit

Researchers must consider the risk that laboratory animals experience pain and other suffering (see guideline 5) and assess them in relation to the value of the research for animals, people or the environment. Researchers are responsible for considering whether the experiment may result in improvements for animals, people or the environment. The possible benefits of the study must be considered, substantiated and specified in both the short and the long term. The responsibility also entails an obligation to consider the scientific quality of the experiments and whether the experiments will have relevant scientific benefits. 

Suffering can only be caused to animals if this is counterbalanced by a substantial and probable benefit for animals, people or the environment. 

There are many different methods for analysing harm and benefit. Research institutions should provide training on suitable models, and researchers are responsible for using such methods of analysis when planning experiments on animals.

4. Responsibility for considering reducing the number of animals ( Reduce )

Researchers are responsible for considering whether it is possible to reduce the number of animals the experiment plans to use and must only include the number necessary to maintain the scientific quality of the experiments and the relevance of the results. This means, among other things, that researchers must conduct literature studies, consider alternative experiment designs and perform design calculations before beginning experiments. 

5. Responsibility for minimising the risk of suffering and improving animal welfare ( Refine )

Researchers are responsible for assessing the expected effect on laboratory animals. Researchers must minimise the risk of suffering and provide good animal welfare. Suffering includes pain, hunger, thirst, malnutrition, abnormal cold or heat, fear, stress, injury, illness and restrictions on the ability to behave normally/naturally. 

A researcher's assessment of what is considered acceptable suffering should be based on the animals that suffer the most. If there are any doubts regarding perceived suffering, consideration of the animals must be the deciding factor. 

Researchers must not only consider the direct suffering that may be endured during the experiment itself, but also the risk of suffering before and after the experiment, including trapping, labelling, anaesthetising, breeding, transportation, stabling and euthanising. This means that researchers must also take account of the need for periods of adaptation before and after the experiment.

6. Responsibility for maintaining biological diversity 

Researchers are responsible for ensuring that the use of laboratory animals does not endanger biological diversity. This means that researchers must consider the consequences to the stock and to the ecosystem as a whole. The use of endangered and vulnerable species must be reduced to an absolute minimum. When there is credible, but uncertain, knowledge that the inclusion of animals in research or the use of certain methods may have ethically unacceptable consequences for the stock and the ecosystem as a whole, researchers must observe the precautionary principle.[ 1 ]

7. Responsibility when intervening in a habitat

Researchers are responsible for reducing disruption and any impact on the natural behaviour of individual animals, including those that are not direct subjects of research, as well as of populations and their surroundings. Certain research and technology-related projects, like those regarding environmental technology and environmental surveillance, may impact on animals and their living conditions, for example as a result of installing radar masts, antennas or other measurement instruments. In such cases,  researchers must seek to observe the principle of proportionality (see guideline 3) and minimise the possible negative impact.

8. Responsibility for openness and sharing of data and material

Researchers are responsible for ensuring that there is transparency about research findings and facilitating the sharing of data and material from experiments on animals. Such transparency and sharing are important in order to avoid unnecessary repetition of experiments. Transparency is also important in order to ensure that the public are informed and is part of researchers' responsibility for dissemination. 

In general, the negative results of experiments on animals should be public knowledge. Disclosing negative results may give other researchers information about which experiments are not worth pursuing, shine a light on unfortunate research design, and help reduce the use of animals in research.

9. Requirement of expertise on animals

Researchers and other parties who handle live animals must have adequately updated and documented expertise on animals. This includes specific knowledge about the biology of the animal species in question, and a willingness and ability to take care of animals properly. 

10. Requirement of due care

There are national laws and rules and international conventions and agreements regarding the use of laboratory animals, and both researchers and research managers must comply with these. Any person who plans to use animals in experiments must familiarise themselves with the current rules.

References and useful resources

[ 1 ] The Norwegian National Committee for Research Ethics in Science and Technology (NENT). Guidelines for research ethics in science and technology (2007) 2016. Oslo.

Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes.  https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32010L0063

Regulation on the capture and collection of wild animals for scientific or other special purposes (Forskrift om innfanging og innsamling av vilt for vitenskapelige eller andre særlige formål). 2003. https://lovdata.no/dokument/LTI/forskrift/2003-03-14-349

Regulation on Animal Experimentation (Forskrift om bruk av dyr i forsøk). 2015.  https://lovdata.no/dokument/SF/forskrift/2015-06-18-761

Act of 2 April 1993 No. 38 Relating to the Production and Use of Genetically Modified Organisms, etc. (Gene Technology Act) (Lov om framstilling og bruk av genmodifiserte organismer m.m. 1993).  https://www.regjeringen.no/en/ dokumenter/gene-technology-act/id173031/

The Animal Welfare Act. 2009.  https://www.regjeringen.no/en/dokumenter/animal-welfare-act/id571188/

The ARRIVE Guidelines (Animal Research: Reporting of In Vivo Experiments). 2010.  https://www.nc3rs.org.uk/sites/default/files/documents/Guidelines/NC3Rs%20ARRIVE%20Guidelines%202013.pdf

The Norwegian Food Safety Authority's instructions on the management of the Regulation on Animal Experimentation (Mattilsynets instruks om forvaltningen av Forsøksdyrforskriften):  https://www.mattilsynet.no/dyr_og_dyrehold/dyrevelferd/forsoksdyr/ instruks_om_mattilsynets_forvaltning_av_forsoksdyrforskriften.21015/binary/Instruks%20om%20Mattilsynets%20forvaltning%20av%20forsøksdyrforskriften

PREPARE (Planning Research and Experimental Procedures on Animals: Recommendations for Excellence) guidelines. 2017.  https://norecopa.no/prepare

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Animal Experiments in Biomedical Research: A Historical Perspective

Simple summary.

This article reviews the use of non-human animals in biomedical research from a historical viewpoint, providing an insight into the most relevant social and moral issues on this topic across time, as well as to how the current paradigm for ethically and publically acceptable use of animals in biomedicine has been achieved.

The use of non-human animals in biomedical research has given important contributions to the medical progress achieved in our day, but it has also been a cause of heated public, scientific and philosophical discussion for hundreds of years. This review, with a mainly European outlook, addresses the history of animal use in biomedical research, some of its main protagonists and antagonists, and its effect on society from Antiquity to the present day, while providing a historical context with which to understand how we have arrived at the current paradigm regarding the ethical treatment of animals in research.

1. Introduction

Animal experimentation has played a central role in biomedical research throughout history. For centuries, however, it has also been an issue of heated public and philosophical discussion. While there are numerous historical overviews of animal research in certain fields or time periods, and some on its ethical controversy, there is presently no comprehensive review article on animal research, the social controversy surrounding it, and the emergence of different moral perspectives on animals within a historical context. This perspective of animal use in the life sciences and its moral and social implications from a historical viewpoint is important to gauge the key issues at stake and to evaluate present principles and practices in animal research.

This review aims to provide a starting point for students and scholars—either in the life sciences or the humanities—with an interest in animal research, animal ethics, and the history of science and medicine. The reader interested in a more in-depth analysis on some of the topics reviewed is referred to the reference list for suggestions of further reading.

2. From Antiquity to the Renaissance

Humans have been using other vertebrate animal species (referred to henceforth as animals) as models of their anatomy and physiology since the dawn of medicine. Because of the taboos regarding the dissection of humans, physicians in ancient Greece dissected animals for anatomical studies [ 1 ]. Prominent physicians from this period who performed “vivisections” ( stricto sensu the exploratory surgery of live animals, and historically used lato sensu as a depreciative way of referring to animal experiments) include Alcmaeon of Croton (6th–5th century BCE) [ 2 , 3 ], Aristotle, Diocles, Praxagoras (4th century BCE), Erasistratus, and Herophilus (4th–3rd century BCE) [ 1 , 3 , 4 ]. The latter two were Hellenic Alexandrians who disregarded the established taboos and went on to perform dissection and vivisection on convicted criminals, benefiting from the favorable intellectual and scientific environment in Alexandria at the time [ 1 ]. All of these authors had a great influence on Galen of Pergamon (2nd–3rd century CE), the prolific Roman physician of Greek ethnicity who developed, to an unprecedented level, the techniques for dissection and vivisection of animals [ 3 , 5 ] and on which he based his many treatises of medicine. These remained canonical, authoritative, and undisputed until the Renaissance [ 1 , 6 ].

For most ancient Greeks, using live animals in experiments did not raise any relevant moral questions. The supposed likeliness of humans to their anthropomorphic deities granted them a higher ranking in the scala naturae (“the chain of being”), a strict hierarchy where all living and non-living natural things—from minerals to the gods—were ranked according to their proximity to the divine. This view of humans as superior would later influence and underline the Judeo-Christian perspective of human dominion over all nature, as represented by texts by Augustine of Hippo (IV century) and Thomas Aquinas (XIII Century), the most influential Christian theologians of the Middle Ages. For Augustine, animals were part of a natural world created to serve humans (as much as the “earth, water and sky”) and humankind did not have any obligations to them. For Thomas Aquinas, the mistreatment of another person’s animal would be sinful, not for the sake of the animal in itself, but because it is someone else’s property. Cruelty to animals was nevertheless condemned by Aquinas, as it could lead humans to develop feelings and actions of cruelty towards other humans. Also, for this theologian, one could love irrational creatures for the sake of charity, the love of God and the benefit of fellow humans (for selected texts, see reference [ 7 ]).

The belief amongst ancient Greek physicians that nature could be understood by means of exploration and experiment—and the medical knowledge thus obtained to be of clinical relevance in practice—would be replaced by other schools of medical thought. Most notably, the Empiric school (3rd century BCE–4th century) would reject the study of anatomy and physiology by dissection of cadavers or by vivisection, not only on the grounds of cruelty and the established taboos, but also for its uselessness. Empiricists believed pain and death would distort the normal appearance of internal organs and criticized the speculative nature of the conclusions drawn from experiments. Indeed, and despite taking an experimental approach to understand the human body and illness, the interpretations of physiological processes made by ancient Greeks who performed vivisections were often inaccurate. The theoretical frameworks by which physicians interpreted their experiments more often than not led them to misguided conclusions. Observations would be understood in light of such paradigms as the Hippocratic theory of the four humors or the Pythagorean theory of the four elements, along with others of natural or supernatural basis, and to which they added their own theoretical conceptions and observational errors [ 1 , 4 , 6 , 8 , 9 ]. The study of human or animal anatomy and physiology was hence deemed irrelevant for clinical practice. Beginning with the decline of the Roman Empire and continuing throughout the Middle Ages, physiological experiments—along with scientific activity in general—would fall almost entirely into disuse and medical knowledge would become dogmatic. In an increasingly Christianized Europe, there was little motivation to pursue scientific advancement of medical knowledge, as people became more concerned with eternal life than with worldly life, and returned to Pre-Hippocratic beliefs in supernatural causes for disease and in the healing power of faith and superstition. Therefore, and despite medieval physicians’ reverence for Galen and his predecessors, the experimental approach used by these classical authors had been sentenced to oblivion [ 3 , 8 , 9 , 10 , 11 ].

The use of animal experiments to satisfy scientific enquiry would only re-emerge in the Renaissance. Flemish anatomist Vesalius (1514–1564), through the course of his work as a physician and surgeon, realized that many anatomical structures thought to exist in humans—on account of them being present in other animals—were in fact absent [ 6 ]. This led him to break the established civil and religious rules and dissect illegally obtained human cadavers, and publish very accurate descriptions of the human anatomy, which challenged the authority of the classical authors. As Herophilus did centuries before (but not carried on by his successors) [ 1 ] Vesalius would also examine the similarities and differences between the internal structure of humans and other animals, thus setting the foundations of modern comparative anatomy.

Alongside the progress in anatomical knowledge made possible by experimenters defying the Catholic Church’s opposition to the dissection of human bodies, the Renaissance period also witnessed the resurgence of vivisection as a heuristic method for the understanding of animal physiology. Vesalius would again recognize the value of physiological experiments on animals as both a learning and teaching resource—he would vivisect animals for medical students as the finishing touch at the end of his courses—a view shared by his contemporary, and presumable student and rival, Realdo Colombo (1516–1559) [ 3 ]. Later, Francis Bacon (1561–1626), considered by many the founder of modern scientific methodology, would also approve of the scientific relevance of vivisection, stating that “the inhumanity of anatomia vivorum was by Celsus justly reproved; yet in regard of the great use of this observation, the inquiry needed (…) might have been well diverted upon the dissection of beasts alive, which notwithstanding the dissimilitude of their parts may sufficiently satisfy this inquiry” [ 12 ].

3. Seventeenth Century and the Dawn of the Enlightenment

Physiological experiments on animals carried on throughout the seventeenth century, in the period favorable to scientific progress now known as the Age of Enlightenment. René Descartes’s (1596–1650) description of animals as “machine-like” [ 13 ] was heavily criticized by many of his contemporaries, but nevertheless provided scientists a way to justify what would now be considered extremely gruesome experiments [ 3 , 14 , 15 , 16 ] in a time when anesthesia, for humans and animals alike, was not available. It has been argued, however, that Descartes’s views on animals were misinterpreted [ 17 , 18 ]—misconstructions that may not always have been free from malice, either by his contemporaries [ 19 ] or present-day critics [ 20 ]—as he did not explicitly state that animals were incapable of feeling pain and indeed recognized them to be able to do so insofar as it depends on a bodily organ, and even admitted animals to be capable of such sentiments as fear, anger, hope or joy [ 13 ]. Nonetheless, regardless of it being misinterpreted or not (for a discussion see [ 21 ]), Cartesian machinism would be recurrently evoked in defense of vivisection in the 17th and 18th centuries [ 14 , 15 , 16 ]. Malebranche, following his interpretation of Descartes, would explicitly justify vivisection on the grounds of it only being “apparently harmful” to animals [ 3 , 15 , 22 ]. Also, as someone deeply interested in physiology and medicine [ 23 , 24 ], and a “man of his time,” Descartes performed vivisections himself [ 15 , 16 , 21 ], an activity for which his—perhaps more apologetic than wholehearted—view of animals as soulless, senseless automata “absolved man from the suspicion of crime” [ 25 ].

As for other contemporary philosophers, Baruch Spinoza (1632–1677) did not deny animals’ ability to feel, but considered we should nevertheless “use them as we please, treating them in a way which best suits us; for their nature is not like ours” [ 26 ], whereas John Locke (1632–1704) fully recognized that animals could feel and stated that children should be brought up to abhor the killing or torturing of any living thing in order to prevent them from later becoming capable of cruel actions to fellow humans [ 27 ]. Immanuel Kant (1724–1804) would reject Cartesian mechanistic views, thus acknowledging sentience to other animals. However, Kant would not extend his concept of human intrinsic and inalienable dignity to other species. In his Of Duties to Animals and Spirits , and mirroring Thomas Aquinas’s views on the subject, he observed that “all animals exist only as means, and not for their own sakes, in that they have no self-consciousness, whereas man is the end (…) it follows that we have no immediate duties to animals; our duties towards them are indirect duties to humanity” [ 28 ]. Kant believed his anthropocentric philosophy provided the moral tradition and contemporary thought of his society; it was a philosophical underpinning, rather than an abstraction distant from the thoughts and feelings of the ordinary man [ 29 ]. Indeed, his argument that cruelty against animals would lead to cruelty to humans was—as it continues to be—popular amongst the public and scholars (e.g., [ 30 ]). In Duties to Animals, Kant would refer to William Hogarth’s (1697–1764) popular series “The Four Stages of Cruelty” ( Figure 1 ), a set of four engravings that depicted how cruel actions against animals could lead to moral degradation and crime. Regarding animal use in research, Kant would state that “Vivisectionists, who use living animals for their experiments, certainly act cruelly, although their aim is praiseworthy, and they can justify their cruelty, since animals must be regarded as man’s instruments; but any such cruelty for sport cannot be justified” [ 28 ]. While he believed actions that offended human intrinsic dignity were unacceptable—no matter how laudable their ultimate purpose should be—when it came to animals it would not be the actions themselves, but rather their justification that defined the acceptability of those actions. While the Enlightenment marked the beginning of the departure from Christian theocentrism, in the new anthropocentric view, animals continued to have no moral standing on their own. In perspective, it should be noted this was a time in which the slave market thrived and women were seen as inferior. However, the recognition of animals’ sentience in the new philosophical thought would later be instrumental for new ethical perspectives to arise on the moral status of animals.

“First Stage of Cruelty” by William Hogarth (1750), the first plate from “The Four Stages of Cruelty” series, which describes the escalating violent behavior that follows childhood cruelty to animals to an adulthood of criminal life. In this scene, two boys plunge an arrow into the rectum of a dog, while another boy, most likely the pet’s owner, pleads with them to stop. Meanwhile, some boys are burning the eye of a bird, while others tie bones to a dog’s tail. Also, some boys play “cock-throwing” (a popular sport in eighteenth-century England, consisting of throwing stones or bottles at a cockerel tied to a stake) while others hang fighting cats, and others even throw animals from windows. Source: © Victoria and Albert Museum, London.

Amidst the list of notable Western seventeenth-century physiologists using animals, the most noteworthy was undoubtedly William Harvey (1578–1657), physician to kings James I and Charles I, and one of the founders of modern science. In 1628, his groundbreaking Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (“An Anatomical Exercise on the Motion of the Heart and Blood in Living Beings”) was published, in which he provided the most accurate description of blood circulation and heart function of his time [ 31 , 32 , 33 , 34 ]. Using the results of meticulously planned experiments on live animals, as well as their interpretation through mathematics and physics, in this treatise, Harvey disproved many of Galen’s fifteen-hundred-year-old ideas [ 35 , 36 ]. In the tradition of his own academic lineage (he studied in Parma with the renowned anatomist Fabricius, a pupil of Colombo), Harvey was also a prolific and skilled comparative anatomist, whose studies on the anatomy of animals included species of several taxa, including mammals, fish, amphibians, reptiles and even insects [ 37 ].

Harvey’s De Motu Cordis was highly criticized, since his experimental observations did not fit the prevalent theories of Western natural philosophy of his time (for an insight on the social, scientific and academic context surrounding Harvey see [ 33 , 37 , 38 ]), still heavily grounded on Galenic principles. Harvey’s findings would challenge firmly established beliefs, such as blood being continuously produced in the liver and transported through the veins to be consumed by other organs, while arteries were thought to be filled with air; the heart was believed to have a heating—rather than pumping—function, and blood was thought to flow between the ventricles across a permeable septum; the vascular system as a whole was thought to be open; the arterial and venous bloods were believed not to mix; and the mere concept of blood circulation was virtually unknown (however, his teacher Fabricius might already have envisaged the concept of blood circulation [ 34 ]. Also, blood circulation was already known in Chinese medicine sixteen centuries before Harvey [ 39 ]). From an epistemological point of view, such opposition also reflected a dispute between the empiricist and the rationalist approach to the understanding of nature, for Harvey professed “to learn and teach anatomy not from books but from dissection, not from the tenets of Philosophers but from the fabric of Nature” (from De Motus Cordi , cited in [ 32 ]). Not surprisingly, Descartes—although a researcher himself—disagreed emphatically with most of Harvey’s findings, since he believed that theories forged through philosophical reflection on metaphysics were superior to those resulting from experimental observation, thus considering experiments or interpretations that did not confirm his own natural philosophy as flawed [ 40 , 41 ]. He nevertheless praised Harvey’s discovery of circulation and the method of experiment and observation that had led to it, a support that would actually help to turn the tide amidst scholars in favor of Harvey’s observation-over-doctrine ideas and methodological approach on experimental physiology, thereby setting the ground for further developments in physiological knowledge [ 38 ].

Further advancements in physiology would be prompted by questions left unsolved by Harvey, many of them addressed by an ensemble of his colleagues and followers at Oxford who applied Harvey’s principle that life should be interpreted in light of new findings in physics in their physiological experiments on animals [ 42 , 43 , 44 , 45 ]. The Oxford Group included polymaths like Robert Hooke (1635–1703), John Locke (1632–1704), John Mayou (1640–1679), Richard Lower (1631–1691), Thomas Willis (1621–1675), Robert Boyle (1627–1691) and Christopher Wren (1632–1723), amidst several others. Most physiologists did not expect direct therapeutic applications to result from their experiments [ 45 ]. There were, however, a few exceptions, such as Lower’s attempts at intra and inter-species blood transfusions having in mind their medical application, or Johann Wepfer’s (1620–1695) use of animals as a proxy to humans to infer the toxicity of several substances [ 3 ], a practice that is still carried out to this day. Seventeenth-century physiology would mark the dawn of modern scientific inquiry in the life sciences. Animal experiments were now proving to be more informative and relevant for obtaining scientifically sound knowledge on basic biological processes than ever before. These advancements would eventually diminish the importance of Galenic dogmatic medicine—although some of its principles would still endure for many years—and ultimately pave the way for today’s evidence-based medicine.

The seventeenth century would also witness the advent of skepticism towards experiments on animals on scientific grounds. Physicians like Jean Riolan, Jr. (1580–1657) and Edmund O’Meara (1614–1681) began to question the validity of physiological experiments carried out on animals in such an extremely altered state as one endured under vivisection, although their hidden agenda was to restore the credibility of Galenic medicine [ 3 , 46 , 47 ]. This dispute between critics and advocates of the informative value of animal models of human physiology still echoes today, e.g., [ 48 ].

The moral acceptability of inducing suffering in animals on the physiologist’s workbench would also become an issue raised in opposition of vivisection before the end of the seventeenth century [ 3 ]. However, the acceptance of the animal-machine paradigm by many physiologists reassured them that their scientific undertakings were not cruel. Furthermore, even the many who acknowledged that animals suffered a great deal with experiments, nevertheless defended themselves against the accusation of cruelty by alleging that the suffering inflicted was not unjustified, but rather for the sake of humankind, in the same line of reasoning by which today animal research is still justified. Nevertheless, these scientists were often overwhelmed by the extreme ill treatment they forced themselves to carry out on fully conscious animals [ 3 , 45 , 49 ]. One such investigator was Robert Boyle, whose infamous experiments on live animals on an air pump (conceived by him and developed by Robert Hooke) consisted in registering how animals responded to increasingly rarefied air. While only two animal experiments in Boyle’s “pneumatic chamber” are described in his New Experiments Physico-Mechanical Touching the Spring of the Air and its Effects (1660)—he would nevertheless go on to publish further animal studies on physiology [ 50 , 51 ]. Public demonstrations of this experiment would become very popular in the eighteenth century, although it bore more of an entertaining, rather than educational, nature ( Figure 2 ).

“An Experiment on a Bird in an air pump”, by Joseph Wright of Derby (detail) (1768). In this brilliant artwork, the artist captures the multiple reactions elicited by the use of live animals as experimental subjects in eighteenth-century Britain, for which we can find a parallel in present day’s diverse attitudes on this topic, including shock, sadness, appreciation, curiosity and indifference. Currently in The National Gallery , London. Source: Wikimedia Commons .

4. Eighteenth Century and the Rise of Moral Consideration for Animals

Amongst the many remarkable physiologists of the eighteenth century, polymaths Stephen Hales (1677–1761) and Albrecht von Haller (1708–1777) stood out. Hales was responsible for the first measurement of pressure in the blood vessels, and for other important insights into cardiovascular and respiratory physiology [ 52 , 53 , 54 ]. He also gave landmark contributions to public health and other medical breakthroughs, including the invention of forceps. Von Haller was arguably the most prolific physiologist of his time, better known for his groundbreaking work on inflammation, neurophysiology, heart function, and hemodynamics [ 55 , 56 , 57 , 58 , 59 , 60 ]. Both researchers were disgusted by the gruesomeness of their own experiments and were concerned about their moral justification, but nevertheless carried on, certain of the need for the use of live animals for the comprehension of many basic physiological processes, which were yet far from being understood [ 3 , 49 , 61 , 62 ]. Other relevant landmarks of eighteenth-century biomedical science based on animal studies included the foundation of experimental pharmacology [ 63 ], electrophysiology [ 64 , 65 ], and modern embryology [ 66 ]. Despite these advancements in biological knowledge, the clinical relevance of animal studies continued to be challenged [ 3 , 61 , 62 ] and, indeed, direct benefits to human health from animal experiments would remain elusive throughout the eighteenth century [ 45 , 55 ] and well into the following century.

Opposition to vivisection had raised its tone since the beginning of the eighteenth century, prompted by the popularization of public displays of experiments on live animals—in particular the notorious demonstrations of Boyle’s notorious air pump experiments [ 3 , 61 , 62 ], which were seen as purposeless, and thus inherently cruel—but became more prominent in the second half of the century, particularly in northern Europe [ 3 , 61 , 62 , 67 ]. Anthropocentric views on human duties to animals began to become increasingly challenged by philosophers, from Voltaire’s (1694–1778) criticism of Cartesian machinism and the gruesomeness of animal experiments [ 68 ] to Jean-Jacques Rousseau’s (1712–1778), Jeremy Bentham’s (1748–1832) and Arthur Schopenhauer’s (1788–1860) criticism of those who viewed animals as mere “means to an end.” By referring to sentience rather than intelligence to grant animals inherent worth, these philosophers proposed a shift from an anthropocentric justification for our duties of kindness to animals, to human obligations towards other animals for the sake of the animals themselves [ 69 , 70 , 71 ]. Rousseau proposed that despite animals being unable to understand the concept of natural law or rights, they should nonetheless, as a “consequence of the sensibility with which they are endowed (…) partake of natural right.” While Bentham found the concept of natural right “nonsense” [ 72 ], he sanctioned the idea of granting animals moral standing for the sake of their sentience. As he would famously state: “The question is not, Can they reason? Nor, Can they talk? But, Can they suffer?” [ 71 ]. From his utilitarian philosophy standpoint ( i.e. , that a moral action is that which results in the highest overall wellbeing for all stakeholders), he deemed animal research acceptable, provided the experiment had “a determinate object, beneficial to mankind, accompanied with a fair prospect of the accomplishment of it,” thus admitting that humans had precedence over other animals, limited by the due consideration for their suffering [ 73 ]. Bentham’s utilitarianism continues to exert a great deal of influence in today’s debate on animal use in the life sciences.

Among philosophers and physiologists alike, the issue of discussion was now not if animals could feel or not and to what extent, but rather whether vivisection was justifiable based on the benefit for human beings derived from it. Thus, even when researchers had strong misgivings about the inflicted suffering of animals, benefit to humans remained a valid justification for them to pursue their scientific goals through vivisection [ 61 ]. While knowledge of bodily functions and pathology was still incipient at that time, eighteen-century physiologists differed from their seventeenth-century predecessors, as they believed that medical improvements could one day be achieved through advancing knowledge by the means of animal experimentation [ 62 ]. The same rationale—that human interests took precedence over animal suffering—would also be used by nineteenth-century physicians as an ethical justification for the use of animals.

5. The Nineteenth-Century Medical Revolution and the Upsurge of the Antivivisection Societies

By the beginning of the nineteenth century, medicine was undergoing a major revolution. The organization of medical practice was changing, with the construction of hospitals, the university training of medical doctors, and the invention of new instruments and methods for the medical profession [ 74 ]. There was also a growing acknowledgement by the medical community that most medical practice, up to that period, was based on unproven traditions and beliefs and that most therapies were not only ineffective but often worsened the patient’s condition. As a result, medical practice increasingly began to focus more on understanding pathology and disease progression, pursuing more accurate diagnosis and prognosis, and thus providing reliable and useful information to patients and families, as they realized this was often the best they could do at the time. This paradigm shift would help give more credit and recognition to medical doctors and scientists, who, at that time, were often viewed with disdain and suspicion by the general public. This gain in medical knowledge would, however, sometimes be at the expense of unapproved trials, invasive procedures, and no respect for what we would now call patients’ rights [ 75 , 76 , 77 ].

Another kind of medical revolution was taking place in the laboratories, one that would ultimately provide the consistent basic science on which twentieth-century modern medicine would set its foundations. This scientific revolution began with a political one. The French Revolution of the late eighteenth century would later, in the first-half of nineteenth century, set the grounds for the establishment of the Académie Royale de Médecine , a thriving academic environment where science—and physiology, chemistry, and pharmacy, in particular—would finally be incorporated into medicine. The acknowledgment of the great knowledge gap in physiology and pathology, and the openness to positivist views on scientific knowledge, led to the definitive abandonment of the quasi-esoteric and, up to that time, dominant vitalistic theories in physiology, which stated that a vital principle, the “soul”, was the main source of living functions in organisms, rather than biochemical reactions. This led to a generalization of the understanding of all bodily processes as an expression of physical and chemical factors, and to a greater relevance given to animal experiments for answering scientific questions ( Figure 3 ). At the Académie , animal experiments were being increasingly prompted by existing clinical problems, and carried out with the ultimate goal of developing new therapeutic approaches to tackle these issues. Importantly, the integration of veterinarians in the Académie was deemed valuable for their insight on such experiments [ 57 , 78 , 79 ]. Amidst many other prominent scientists, two physician–physiologists stood out for their contributions to experimental physiology, François Magendie (1783–1855) and, most notably, Magendie’s disciple, Claude Bernard (1813–1878) [ 67 , 80 , 81 , 82 , 83 , 84 ]. Bernard’s experimental epistemology, unlike his tutor’s more exploratory approach, advocated that only properly controlled and rigorously conducted animal experiments could provide reliable information on physiology and pathology of medical relevance, setting the landmark of experimental medicine [ 85 , 86 , 87 , 88 ]. Conciliating Descartes’s rationalism with Harvey’s empiricism, Bernard acknowledged the importance of ideas and theories for the formulation of hypotheses, safeguarding, however, that these were only useful if testable and only credible if substantiated through experimentation [ 80 , 89 ]. He seemed to have been aware of how important and groundbreaking his approach to medical knowledge would become, when in his opening remarks to medical students in his very first lecture he quoted himself from his seminal “Introduction to the Study of Experimental Medicine,” stating: The scientific medicine that I’m responsible to teach does not yet exist. We can only prepare the materials for future generations by founding and developing the experimental physiology which will form the basis of experimental medicine” [ 89 ].

“A physiological demonstration with vivisection of a dog,” by Émile-Édouard Mouchy. This 1832 oil painting—the only secular painting known of the artist—illustrates how French scholars valued physiological experimentation in service of scientific progress [ 90 ]. Notice how the struggling of the animal does not seem to affect the physiologist or his observers. Currently part of the Wellcome Gallery collection, London. Source: Wellcome Library .

From the 1830s and throughout the second half of the century, the concept of scientific medicine would also flourish amidst a distinct group of German/Prussian physiologists. Following the rationale that biology could be understood through the means of chemistry and physics, and through their pivotal animal experiments and the use of microscopy, these scientists vastly contributed to the development of anatomy, histology, pathology, embryology, neurophysiology, physiology and physics. The setting for this scientific and epistemological progress was the Anatomisches Museum in Berlin, where anatomist, zoologist, and physiologist Johannes Müller (1801–1858) offered workspace and supervision to brilliant students whose independent research he wished to encourage. Although lacking the money, space, and instruments available in the great German laboratories founded after 1850, the museum provided these young scientists—notably Theodor Schwann (1810–1882), Robert Remak (1815–1865), and Friedrich Henle (1809–1885) in the 1830s, and Carl Ludwig (1816–1895), Emil du Bois-Reymond (1818–1896), Ernst Brücke (1819–1892), Hermann von Helmholtz (1821–1894), and Rudolph Virchow (1821–1902) in the 1840s—a singular intellectual atmosphere for research. Henle and Virchow would become leaders of the 1840s’ medical revolution in Germany, promoting the reform of medicine by providing it with a scientific basis, while Brücke, Helmholtz, and Bois-Raymond’s focused on the development of physiology as an autonomous science [ 83 , 91 , 92 , 93 , 94 , 95 ]. Their contributions to medical knowledge through the nineteenth century, along with Magendie’s and Bernard’s pivotal works, would deeply influence their counterparts across the Western world in the latter decades of the nineteenth century. Thousands of students flocked to attend medical schools in Germanic universities (and French institutes, although to a lesser extent), many of them from across the Atlantic [ 85 , 88 , 91 , 96 , 97 ]. This, in turn, would lead to an unprecedented rise in animal research-based advancement in biological and medical knowledge in the late nineteenth century—with important consequences for public health and quality of life—as further discussed later in this text.

While the second half of the nineteenth century marked the beginning of scientifically meaningful and medically relevant animal research, this period also saw opposition to vivisection becoming a more widespread idea in Europe, especially in Britain. Although animal experiments were not yet regulated in the first half of the century, the development of British physiology research in the Victorian Era was losing pace to Germany and France, where unprecedented progress in medical knowledge was taking place. The openly antivivisectionist positions of influential jurists, politicians, literary figures, clergymen, distinguished members of the medical community, and even Queen Victoria, contributed to an unfriendly environment for animal-based medical research [ 90 , 91 ]. There was, however, also a matter of divergence of opinion between British anatomists and French physiologists on which was the best approach for obtaining medical knowledge. Taking advantage of the rising antivivisection trend, British anatomists explored the (undoubted) gruesomeness of Magendie’s experiments, along with some nationalistic partisanship and xenophobic feelings against France, in their defense of anatomical observation as the primary method for advancing physiology, to the detriment of experiment through vivisection. However, they seldom disclosed their own positive (or at least ambivalent) views on animal experiments as a means to corroborate findings achieved through anatomical exploration [ 90 , 98 , 99 ]. Magendie would become the arch-villain of the antivivisection movement. Despite the broad recognition of his contributions to science by most peers, he was also amongst the most infamous of his time for the disdain he held for his experimental subjects. This contestation was louder outside of France, where many of his fellow scientists, even those who approved of animal experimentation, described him as an exceptionally cruel person who submitted animals to needless torture [ 85 , 90 , 100 ]. His public presentations became the most notorious, particularly one he performed in England when he dissected a dog’s facial nerves while the animal was nailed down by each paw, and was left overnight for further dissection the following day [ 82 ]. A description of Magendie’s classes to medical students by an American physician added further to the widespread disgust directed towards his work:

This surgeon’s spring course of experimental physiology commenced in the beginning of April. I seldom fail of “assisting” at his murders. At his first lecture, a basketful of live rabbits, 8 glass receivers full of frogs, two pigeons, an owl, several tortoises and a pup were the victims ready to lay down their lives for the good of science! His discourse was to explain the function of the fifth pair of nerves. The facility was very striking with which the professor could cut the nerve at its origin, by introducing a sharp instrument through the cranium, immediately behind and below the eye. M. Magendie drew the attention of the class to several rabbits in which the fifth pair of nerves had been divided several days before. They were all blind of one eye, a deposition of lymph having taken place in the comes, from inflammation of the eye always following the operation alluded to, although the eye is by this section deprived of all its sensibility. Monsieur M. has not only lost all feeling for the victims he tortures, but he really likes his business. When the animal squeaks a little, the operator grins; when loud screams are uttered, he sometimes laughs outright. The professor has a most mild, gentle and amiable expression of countenance, and is in the habit of smoothing, fondling and patting his victim whilst occupied with preliminary remarks, and the rabbit either looks him in the face or ‘licks the hand just raised to shed his blood. During another lecture, in demonstrating the functions of the motive and sensitive fibers of the spinal nerves, he laid bare the spinal cord in a young pup, and cut one bundle after another of nerves. (…) Living dissection is as effectual a mode of teaching as it is revolting, and in many cases the experiments are unnecessarily cruel and too frequently reiterated; but so long as the thing is going on, I shall not fail to profit by it, although I never wish to see such experiments repeated. cit in Olmsted, 1944 [ 101 ]

All of Magendie’s experiments were carried out without anesthesia or analgesia (and animals would be left in agony for hours, or for students’ “hands-on” anatomical studies. While, in fairness, it should be recognized that anesthetics had not yet been discovered when Magendie performed the bulk of his work, even after this technique had become available, he and nearly all of his students continued to forgo anesthesia in their experiments [ 102 ]. Moreover, animal studies on the effects of anesthetics themselves (Bernard was responsible for significant contributions to the understanding of the physiology of anesthesia: for an overview, see references [ 103 , 104 ]) were performed, as well as anatomical studies that could well have been conducted with cadavers, with no need for animals to be exposed to such prolonged suffering. Magendie was so ill famed in Britain that his experiments were referenced in the House of Commons by Richard Martin (1754–1834) when he presented a bill for the abolition of bear-baiting and that would become the “Cruel Treatment of Cattle Act” of 1822, one of the first animal protection laws. He would be again evoked in the report favoring the regulation of animal experiments that led to the “Cruelty to Animals Act” of 1876, the first piece of legislation ever to regulate animal experiments. By that time, Magendie had been dead for over twenty years [ 82 , 90 , 100 ].

After Magendie’s death, the focus of antivivisectionists’ attention moved to Bernard’s works, which included cutting open conscious animals under the paralyzing effects of curare , or slowly “cooking” animals in ovens for his studies on thermoregulation [ 105 ]. Bernard’s line of work would eventually have a heavy personal cost. Tired of her husband’s atrocious experiments, his wife would divorce him—taking with her his two daughters, who grew up to hate him—and, joining the antivivisectionists’ ranks, set up rescue shelters for dogs. Even Bernard’s cause of death is attributed to years of work in a humid, cramped, and poorly ventilated laboratory. He would, however, die a national hero, being given the first state funeral ever to be granted to a scientist in France. In his later years, he would collect the highest academic and political honors, including a seat in the French senate [ 88 , 102 , 106 , 107 ].

Despite their utter disregard for animal suffering, Magendie and Bernard did not see themselves as the immoral senseless villains portrayed by their detractors, but rather as humanists. Indeed, their view that animals did not deserve the same moral consideration as humans made them condemn experiments in humans without previous work on animals, the general principle on which the use of animal models in biomedical science is still grounded. In a time when proper dosage, administration, and monitoring of anesthesia were still largely unknown, often leading to serious side effects and accidental deaths, Magendie would state, on the use of anesthetics in humans without previous and thorough tests on animals: “That is what I do not find moral, since we do not have the right to experiment on our fellows” [ 5 , 108 , 109 ]. The amorality of human experiments prior to animal testing in animals was also an ethical argument raised in favor of vivisection by Bernard [ 89 ], who wrote:

No hesitation is possible, the science of life can be established only by experiment, and we can save living beings from death only by sacrificing others. Experiments must be made either on man or on animals. Now I think physicians already make too many dangerous experiments on man, before carefully studying them on animals. I do not admit that it is moral to try more or less dangerous or active remedies on patients, without first experimenting with them on dogs; for I shall prove, further on, that results obtained on animals may all be conclusive for man when we know how to experiment properly. If it is immoral, then, to make an experiment on man when it is dangerous to him, even though the result may be useful to others, it is essentially moral to do experiments on an animal, even though painful and dangerous to him, if they may be useful to man.

British physiologists often refrained from experimenting on mammals, mostly on account of the public’s opposition to the gruesomeness of continental physiologists’ experiments. However, with the publication of Bernard’s book (1868) and John Burdon-Sanderson’s Handbook for the Physiological Laboratory (1873), the scientific relevance of animal experiments became increasingly acknowledged, providing a utilitarian justification for vivisection, despite the harm endured by animals, eventually resulting in the rise in animal studies in medical schools in Britain in the 1870s [ 5 , 88 , 99 ]. Furthermore, by this time, anesthetics were already available and used by British physiologists, leading RSPCA secretary John Colam to state that “laboratory practices in England were very different indeed from [those] of foreign physiologists.” While the usefulness of anesthetics to chemically restrain animals was certainly advantageous for researchers, pain relief was most likely the major reason behind their ready adoption by many physiologists in Britain, as the paralyzing properties of curare were already known and used for this purpose. In fact, even before the solidifying of the antivivisectionist struggle, British physiologists had set themselves guidelines for responsible research [ 110 , 111 ]. Nevertheless, many researchers still found the analgesic and anesthetic effect of these volatile agents to be a source of undesired variability, thus avoiding their use altogether [ 99 , 105 ].

The upsurge of animal research in Britain was accompanied by an intensification of the antivivisectionist struggle. In 1875, the first animal protection society with the specific aim of abolishing animal experiments was founded: the Victoria Street Society for the Protection of Animals Liable to Vivisection (later known as the National Anti-Vivisection Society), led by Irish feminist, suffragist, and animal advocate Frances Power Cobbe (1822–1904). Vivisection became a matter of public debate, only matched in Great Britain that century by the controversy around the 1859 publication of Charles Darwin’s (1809–1882) On the Origin of Species , in which he presented a strong scientific rationale for the acknowledgement of our close kinship with the rest of the animal world, giving both physiologists and antivivisectionists a strong argument for their cause, depending on the perspective.

As the original argument of antivivisectionists that animal research was inacceptable because it did not provide useful medical knowledge began to lose strength (however, it remained a recurrent accusation against animal research, see, for instance, [ 112 ]), the discussion shifted towards preventing unnecessary harm, rather than questioning the scientific value of animal experiments [ 99 ]. On the other hand, the use of anesthetics now allowed British scientists to argue that most physiological experiments involved little, if any, pain [ 105 , 110 , 113 ]. While this made some antivivisectionists ponder about their own standing on the use of animals in research—namely those who opposed vivisection on the grounds that the intense and prolonged suffering endured by animals on the physiologist table was intolerable—many others felt that the most relevant value at stake was the preservation of each animal life in itself, questioning if human benefit was sufficient reason for sacrificing animals [ 99 , 110 ]. Moreover, the claim that animals were rendered senseless to pain gave carte blanche to many physiologists to use as many animals as they pleased for research, teaching, and demonstrations, despite anesthesia often being improperly administered, thus failing to prevent suffering for more than the brief initial moments. A famous quote by George Hoggan (a former vivisectionist who was appalled to witness Bernard’s experiments and who would later co-found the Victoria Street Society ) illustrates the relevance of the new ethical issues that emerged: “I am inclined to look upon anaesthetics as the greatest curse to vivisectible animals” [ 5 , 99 ].

In the last decades of the nineteenth century, all of today’s most relevant arguments on the debate surrounding the use of animals for scientific purposes were already in place, as well as most of the rhetoric and means of action in defense of each position. These views included outright abolitionism and, on the opposite pole, scientists demanding to be allowed to work without restrictions; non-scientists accusing researchers to be self-biased and unable to think ethically about their work and, on the other side of the barricade, researchers disdaining the authority of non-scientists to criticize their work; the benefit for humankind argument vs . the questioning of the scientific and medical value of animal research on scientific grounds; public demand for stronger regulation vs . researchers’ appeals for more autonomy, freedom, and public trust; advocates of the justifiability of only applied research (but not basic research) vs. apologists of the value of all scientific knowledge, see [ 105 , 112 , 113 ].

Just like today, there were also those who valued both animal protection and scientific progress and, recognizing that each side had both relevant and fallacious arguments, found themselves in the middle-ground, where they sought ways for compromise and progress. Amongst these, the most notable was Charles Darwin, known for his affection to animals and abhorrence for any kind of cruelty, but also for his commitment to scientific reasoning and progress [ 111 , 114 , 115 ]. Additionally, Joseph Lister (1827–1912), one of the most influential physicians of his time, would decline a request by Queen Victoria in 1875 for him to speak out against vivisection. Lister was one of the few British surgeons that carried out vivisection, albeit only occasionally, and was acquainted with some of the most eminent continental physiologists. In his response letter to the Queen, he pointed out the importance of animal experiments for the advancement of medical knowledge, stressed that anesthetics should be used at all times, and also denounced the ill treatment of animals in sports, cruel training methods, and artificial fattening of animals for human consumption as being more cruel than their use in research [ 116 ].

With the controversy assuming growing complexity and relevance, two opposing bills were presented to the British parliament in 1875: the “Henniker bill,” named after its sponsor Lord Henniker and promoted by Frances Cobbe, and the “Playfair bill,” named after scientist and Member of Parliament, Lyon Playfair, and promoted by Charles Darwin himself, along with fellow scientists and friends. Despite coming from opposite ends , both bills proposed reasonable regulation of animal experiments, rather than demanding severe restriction or granting scientists unlimited rights to use animals. Somewhat surprisingly, the Playfair bill drafted by researchers was, in some aspects, more restrictive than Henniker’s by proposing, for instance, that animal experiments should only be performed for the advancement of physiology and not for teaching purposes. The crucial difference was that the Henniker bill called for all researchers and all kinds of experiments to be properly licensed and supervised, as it is today in Great Britain, while the Playfair bill proposed that the law should only be applied to painful experiments. In the absence of parliamentary consensus for either one or the other bill, a Royal Commission—properly balanced to include members of the RSPCA and a few eminent scientists, including T.H. Huxley—was appointed that same year to address this issue, which would result in the 1876 amendment of the 1835 Cruelty to Animals Act in order to regulate the use of animals for scientific purposes, being the first case of this kind of legislation in the world [ 99 , 111 , 117 , 118 ]. This bill would endure for 110 years, until the enactment of the 1986 Animals (Scientific Procedures) Act, and remain the only known legislation to regulate animal experiments for nearly 50 years, despite some attempts to pass similar bills in other Western countries, where antivivisectionism was growing, particularly in Germany, Switzerland, Sweden, and North America [ 14 , 119 ].

The recrudescence and spread of antivivisection feelings in the late nineteenth century was coincidental with the long-awaited beginning of direct clinical and public health benefit from animal research. Before the end of the century, the germ theory of infectious diseases— i.e. , that pathogenic microbes were the causative agent of such diseases, rather than internal causes, “miasmas” in the air or water, or even more esoteric explanations—would gain broad recognition by the medical community, mostly on account of the work of Louis Pasteur (1822–1895) and his German counterpart, Robert Koch (1843–1910), which was largely based on animal experimentation. This knowledge would have an immediate, profound, and enduring effect on public health, surgery and medicine. Although it had been earlier proposed by Ignaz P. Semmelweis (1818–1865) that puerperal fever was caused by infections resulting from poor hygiene of physicians [ 120 ], only after Joseph Lister’s paper On the Antiseptic Principle of the Practice of Surgery (1867)—prompted by Pasteur’s findings—was the importance of hand-washing and instrument sterilization before surgical procedures and child delivery finally acknowledged, leading to a drastic drop in deaths from puerperal fever and post-surgical sepsis. Until then, previous efforts to make hand-washing a standard procedure had been ridiculed by the medical class.

Pasteur, a professor of chemistry with a doctoral thesis on crystallography, would turn his attention to biology in 1848 [ 121 ]. He began by unraveling the biological nature of fermentation (the inhibiting effect of oxygen on fermentation is still called the “Pasteur effect”), moving on to devise solutions of great economic value by tackling wine and beer spoiling, as well as silkworm disease, all of which he properly identified as being caused by microbes. Together with Claude Bernard, a close friend, he would later develop the process of pasteurization to destroy microorganisms in food. Pasteur began hypothesizing that microbes could also be the causative agents of many diseases affecting humans and other animals. Together with his disciples, most notably Emile Roux (1853–1933), he would go on to identify Staphylococcus , Streptococcus , the “septic vibrio” (now Clostridium septicum ), the causative agents of anthrax ( Bacillus anthracis ) and chicken cholera ( Pasteurella multocida ), being the first to develop vaccines for these zoonotic diseases, as well as for Swine Erypselas, thus setting the foundations of modern immunology [ 122 ]. However, it would be Pasteur’s successful use of a therapeutic vaccine against rabies in humans that would grant him international celebrity status [ 107 , 122 , 123 , 124 ].

Pasteur’s work required the experimental infection of numerous animals, as well as inflicting surgical wounds to test antiseptic techniques and disinfectant products, which made him a prime target of antivivisectionists. Either by genuine conviction or pragmatic convenience, amongst the ranks of Pasteur’s critics for his use of animals, one could easily find opponents of vaccination and the germ theory. Pasteur would frequently receive hate letters and threats, mostly for his infection studies on dogs, although he also used chickens, rabbits, rodents, pigs, cows, sheep, and non-human primates ( Figure 4 ). Pasteur was, however, more sensitive to animal suffering than most of his French counterparts. Not only was he uneasy with the experiments conducted—although sure of their necessity—he would also always insist animals be anesthetized whenever possible to prevent unnecessary suffering. He would even use what we now call “humane endpoints” (for a definition, see [ 125 ]): in a detailed description of his method for the prophylactic treatment of rabies (from 1884), the protocol for infecting rabbits with the rabies virus (for ulterior extraction of the spinal cord to produce a vaccine), he stated that: “The rabbit should begin to show symptoms on the sixth or seventh day, and die on the ninth or tenth. Usually the rabbit is not allowed to die, but is chloroformed on the last day in order to avoid terminal infections and unnecessary suffering” [ 126 ]. Furthermore, he would become directly responsible for saving countless animals from the burden of disease and subsequent culling [ 5 , 107 , 113 , 127 , 128 ].

This full-page illustration of Pasteur in his animal facility was published in Harper’s Weekly in the United States, on 21 June 1884. At this time, there was moderate curiosity on Pasteur’s work in the US, which would intensify after his first successful human trials of a therapeutic vaccine for rabies in 1885. In the article, the reader is reassured that the use of dogs is both humane and justified in the interest of mankind. The use of other species, however, is barely mentioned [ 5 ]. Source: Images from the History of Medicine , U.S. National Library of Science.

Robert Koch, a practicing rural physician, would follow the tradition of the great German/Prussian physiologists of his time (and indeed was a student to many of them), providing invaluable contributions to medical knowledge through animal research, mainly in the field of bacteriology and pathology. His famous “Koch postulates” would play an important role in microbiology Along with his associates, Koch developed from scratch methods that are still used today, such as microphotography of organisms, solid medium culture, and staining or microbe quantification. They would go on to identify the causative agents of tuberculosis ( Micobacterium tuberculosis , also known as the “Koch bacillus”), cholera ( Vibrio cholera , albeit 30 years after Filippo Pacini, 1812–1883 [ 129 ]), and anthrax. The overlapping interest of Pasteur and Koch on anthrax would trigger a bitter rivalry between the two, fuelled by their different approaches to microbiology, as well as chauvinistic Germany–France rivalry [ 130 , 131 ]. Koch’s own school of microbiology housed many of the leading late-nineteenth, early-twentieth-century medical researchers. This included Emil von Behring (1854–1917) and Paul Ehrlich (1854–1915), both responsible for the first antitoxin for treatment of diphtheria—developed from horse serum—for which von Behring received the Nobel Prize in 1901. Von Behring would also develop an antitoxin for immunization against tetanus, along with Shibasaburo Kitasato (1853–1931), who had also studied under Koch. In 1908, Ehrlich would also be awarded the Nobel Prize for contributions to immunology, and would yet again be nominated for his contributions to chemotherapy and the development of Salvasaran (an effective treatment against syphilis), in particular [ 132 , 133 , 134 , 135 ]. The development and production of vaccines and antitoxins led to a dramatic increase in the number of animals used in research. The number of animals used by physiologists in the nineteenth century would be negligible in comparison with the several hundred used by Pasteur to develop, test, and produce vaccines, the thousands of mice used by Paul Ehrlich for the production of Salvasaran—his syphilis drug—and the millions of primates that would be used to produce Polio vaccines in the 1950s [ 5 ].

6. The Twentieth-Century Triumph of Science-Based Medicine

By the end of the nineteenth and beginning of the twentieth century, the pharmacopeia had effective, scientifically tested drugs, a landmark that allowed for an increasing number of people to understand the importance and validity of scientifically sound medical knowledge and, with it, the relevance of animal-based research (see [ 113 , 136 , 137 , 138 ]). One could still find as far as the end of the nineteenth century, however, physicians who disregarded the ideals of scientific medicine and vigorously stood by their traditional epistemological view of medicine and clinical practice, which they saw as more of a form of art than as a science. Many such physicians also opposed experiments on live animals and were members of antivivisection societies [ 77 , 139 , 140 , 141 ]. Nonetheless, the medical profession, medicine itself, and human health had now been irreversibly changed by science, and would continue to be pushed forward throughout the twentieth century to now.

The twentieth century would witness astonishing advances in medical knowledge and the treatment of disease. The discovery of vitamins, hormones, antibiotics, safe blood transfusion, new and safer vaccines, insulin, hemodialysis, chemo and radiotherapy for cancer, the eradication of small pox (and the near eradication of poliomyelitis), advanced means of diagnostic and new surgical techniques are but a very few examples of twentieth century’s medical achievements that have not only saved millions of lives—human and non-human—but also allowed countless humans and animals to live a “life worth living,” by the relief of disease-induced suffering. The advances of biomedical research to human health since the dawn of the past century are countless, with animal research playing a role in a number of important discoveries (for an overview, see [ 142 ]). Of the 103 Nobel Prizes in physiology or medicine given since 1901, on 83 occasions work conducted on vertebrate species (other than human) was awarded, while in another four instances, research relied heavily on results obtained from animal experiments in vertebrates conducted by other groups [ 143 ]. Another indirect measure of the impact that biomedical progress had on the twentieth century was the increase in life expectancy, which in some developed countries doubled between 1900 and 2000, and is still on the rise today [ 144 , 145 , 146 ].

By the 1910–1920s, antivivisection groups were fighting an increasingly difficult war for the public’s support. The argument that no medical progress could be obtained through animal research was becoming increasingly difficult to uphold and, as researchers pledged to avoid animal suffering whenever possible, criticism of animal experiments on the grounds of cruelty toned down. However, not all scientists had sufficient, if any, consideration for animal suffering, and research would continue to be unregulated in most countries. Nevertheless, the exaggerated claims, radical abolitionist views, and scientific denialism by more inflexible antivivisectionists would make them lose support from the general public and more moderate animal protection groups, leading to a decline—albeit not an end—to the antivivisection movement, until its resurgence in the 1970s. Confronted with a general lack of support, moreover in a period that would witness two great world wars and a serious economic recession—which would push the interests of animals further to the background—the line of action of antivivisectionists through most of the twentieth century focused on banning the use of dogs and other companion animals [ 5 , 147 , 148 , 149 , 150 ].

The toning down of the opposition to animal use in the life sciences had also something to do with the emergence of rodent species as a recurrent animal model in research. Unlike dogs or horses, rodents like mice and rats were seen as despicable creatures by most of the public, and therefore less worthy of moral consideration, which in turn deemed their use in research more acceptable [ 147 ]. While this came as an advantage to researchers, it is hard to say, however, if the actual weight of the public’s misgivings about the use of domestic animals was a relevant contributing factor for the ready adoption of rodent models, especially when considering their other numerous advantages as experimental animals when compared to other species. Firstly, they are small, easy to handle, and relatively cheap to house. Secondly, they are highly resistant to successive inbreeding and have a short lifespan and rapid reproduction rate [ 151 , 152 ].

Domesticated rats ( Rattus norvegicus ) were the first rodent species to be used for scientific purposes. Their use in physiological research dates to as early as 1828, but only in the first decades of the twentieth century did they become a preferred tool in research, after the development in 1909 of the first standard rat strain, the Wistar Rat , from which half of all rats used in laboratories today are estimated to have descended (for a historical perspective, see [ 153 , 154 ]) ( Figure 5 ). The mouse ( Mus musculus ) had also been used in the nineteenth century, famously by Gregor Mendel in his 1850s studies on heredity of coat color, until the local bishop censored mouse rearing as inappropriate for a priest, which made him turn to using peas instead [ 155 ]. The mouse would be again picked up in the beginning of the nineteenth century by Lucien Cuénot (1866–1951) to demonstrate that mammals also possessed “genes” (a vague concept at the time) that followed the laws of Mendelian inheritance, and would since then become a privileged model in the study of genetics, a field that would grow exponentially after the discovery of the DNA structure in 1953 by James Watson (born 1928) and Francis Crick (1916–2004). In 1980 John Gordon and Franck Ruddle developed the first transgenic mouse [ 156 ], and in 1988, the first gene knockout model was produced, which granted Mario R. Capecchi (born 1937), Martin J. Evans (born 1941), and Oliver Smithies (born 1925) the 2007 Nobel Prize. In 2002, the mouse became the second mammal, after humans, to have its whole genome sequenced. These, along with other technologies, have opened unlimited possibilities for the understanding of gene function and their influence in several genetic and non-genetic diseases, and have made the mouse the most commonly used animal model in our day (for a historical overview of the use of the mouse model in research, see [ 157 , 158 ]), with prospects being that it will continue to have a central role in biomedicine in the foreseeable future.

Two outbred laboratory rats, of the Lister Hooded (Long–Evans) strain. Rodents are the most commonly used laboratory animals, making up nearly 80% of the total of animals used in the European Union, followed by cold-blooded animals (fish, amphibian and reptiles, making up a total of 9.6%) and birds (6.3%) [ 159 ] Photo: Francis Brosseron, reproduced with permission.

7. Animal Liberation and the Pathway for a More Humane Science

Opposition to animal experiments resurged in the second half of the twentieth century, in particular after the 1975 publication of Animal Liberation by Australian philosopher Peter Singer (born 1946) [ 160 ]. Singer offered a strong philosophical grounding for the animal rights movement, by arguing that the use of animals in research—as well as for food, clothing or any other purpose—is mostly based on the principle of speciesism (coined by Richard Ryder in 1970 [ 161 ]), under which animals are attributed a lower moral value on the sole basis of belonging to a different species [ 162 ], which he considers to be no less justifiable than racism or sexism. His argument, however, does not stem from the premise that animals have intrinsic rights. As a preference utilitarian—and unlike hedonistic utilitarians like Bentham and Mill who argued we should act in order to maximize net happiness—Singer proposed that our actions should aim to do what on balance “furthers the interests of those affected” [ 163 ]. Holding that the interest of all sentient beings to both avoid pain and have positive experiences deserves equal consideration, he thus argues that it is difficult to justify animal research, since it generally does not hold to Bentham’s “ Each to count for one and none for more than one ” postulate. Furthermore, it is usually unfeasible to prospectively quantify how many may benefit directly from a given animal experiment. According to Singer, by using the principle of equal consideration of interests, one should give priority to relieving the greater suffering. Singer does not propose we should assume different species suffer similarly under the same conditions but, on the contrary, that care should be taken when comparing the interests of different species as, for instance, a human cancer patient, for his higher cognitive skills, can suffer a great deal more than a mouse with the same disease [ 164 ]. For this reason, he does not consider animal research to always be morally wrong in principle, and even admits that in certain occasions it may be justifiable, albeit these situations are, in his view, exceptional [ 165 ].

The animal rights movement would, however, receive from American philosopher Tom Regan (born 1938) a more uncompromising view of our duties to animals than Singer’s utilitarianism, one that would question the use of animals in research—or in any other way—altogether, regardless of the purpose of research. In Regan’s book The Case for Animal Rights (1983), he proposed we should extend the Kantian concept of intrinsic value to all sentient beings. This perspective inherently affords vertebrates rights, despite their incapacity to understand or demand such rights, as it is also the case—Regan argues—of small infants and the severely mentally handicapped. Hence, the respect for the life and wellbeing of sentient animals should be taken as absolute moral values, which can only be violated in very specific and extreme cases—such as self-defense. Regan’s moral philosophy hence only allows for an abolitionist view on animal research—since no “ends” can justify the “evil means” of sacrificing an animal in the face of the inviolable dignity of sentient beings [ 166 ]—and has become the main theoretical reference for the animal rights movement.

From the impact of Singer’s and Regan’s works in society and the academic world, “animal ethics” would emerge as a whole new field of philosophical and bioethical studies, and, with it, new and diverse ethical views on animals—including on animal research—and of our duties towards them. However, despite the diversity of philosophical views on the use of animals, the public debate on animal research would become polarized between animal rights activists and animal research advocates. While the first would uphold an uncompromising abolitionist stand, one could also find on the opposite side several persons who did not regard animal research as a moral issue at all [ 167 ]. Furthermore, and despite the debate in the philosophical ground remained civilized—even between diametrically opposed perspectives, see, for example, [ 168 ]—in the “real world” the antagonism began to build up. In the 1970s, animal rights extremist groups began resorting to terrorist actions, thus becoming a serious problem for researchers and authorities in several Western countries still today. These actions more often consist of trespassing, raiding animal facilities and laboratories, damage to property, harassment and death threats to researchers, their families and neighbors. It has also sometimes escalated into kidnapping, car and mail bombings, arson of homes and research facilities, mailing of AIDS-contaminated razorblades, and violence against scientists and their family members [ 169 , 170 ]. These actions, which have been classified as unjustifiable and damaging to the animal rights cause by Tom Regan himself [ 171 ], made researchers close themselves within their community and avoid speaking publicly about their work [ 172 , 173 , 174 ], which in turn left pro-research advocacy to emotion-appealing campaigns, of the likes of the Foundation for Biomedical Research’s “Will I be alright, Doctor?” film [ 175 ], or the advertisement depicted in Figure 6 .

A large advertisement published in the 13 May 1991 edition of The Hour (p. 9), and part of a campaign in defense of animal research, sponsored by the United States Surgical Corporation. While the value of Pasteur’s work is undeniable, there is, however, no scientific grounding for the claim that only by experimenting on dogs would a vaccine for rabies have been developed, or that other animal models or even non-animal methods could not have been used to achieve this in over a century. These dramatic and biased portraits of animal research are now more uncommon, as an increasing number of scientists acknowledge the need to be more candid and open to objective discussion over the possibilities and limitations of animal research, and of the scientific process altogether.

In spite of the emergence of the animal rights movement, animal research for biomedical purposes was—as it continues to be—seen as morally acceptable by the majority of the public [ 176 , 177 ]. It became, however, increasingly evident that animal suffering was morally and socially relevant, and that an ethical balance between the benefits brought about by biomedical progress and the due consideration to animal wellbeing should be sought. However, whilst antivivisection movements would only re-emerge in the late 1970s [ 5 , 178 ], the need for a more humane science had already been acknowledged and addressed within the scientific community as early as the 1950s.

Following the first edition of the Universities Federation for Animal Welfare’s Handbook on the Care and Management of Laboratory Animals (1954), the organization’s founder Charles Hume commissioned that same year a general study on humane techniques in animal experimentation to zoologist and classicist (and overall polymath) William Russell (1925–2006) and microbiologist Rex Burch (1926–1996), under a project chaired by immunologist Peter Medawar (1915–1987), Nobel Prize laureate in 1960 [ 179 , 180 , 181 ]. From this work, Russell and Burch would develop the tenet of the “Three Rs”— Replacement, Reduction, Refinement —principles that would be extensively developed in their seminal book, The Principles of Humane Experimental Technique [ 182 ]. In this book, the authors argued “humane science” to be “best science,” going so far as to state that “If we are to use a criterion for choosing experiments to perform, the criterion of humanity is the best we could possibly invent.” Replacement was defined as “any scientific method employing non-sentient material [to] replace methods which use conscious living vertebrates”; Reduction as the lowering of “the number of animals used to obtain information of a given amount and precision”; and Refinement as the set of measures undertaken to “decrease in the incidence or severity of […] procedures applied to those animals which have to be used,” later including also the full optimization of the wellbeing of laboratory animals, also seen as a basic requirement for the quality of science [ 179 ]. They also challenged the commonly held belief that vertebrate animals—and mammals in particular—are always the most suitable models in biomedical research, a reasoning they called the high-fidelity fallacy . Despite receiving a warm welcome, Russell and Burch’s work would remain largely ignored well into the 1970s. In 1978, physiologist David Henry Smyth (1908–1979) would again bring the Three Rs to the light of day and encompass them under the concept of alternatives [ 67 , 183 ], which he defined as “all procedures which can completely replace the need for animal experiments, reduce the numbers of animals required, or diminish the amount of pain or distress suffered by animals in meeting the essential needs of man and other animals” [ 184 ]. More than a restatement of the Three Rs, this definition had the added value of placing onto researchers the burden of providing convincing evidence for the necessity of using animals [ 183 ], a particularly important statement from the then-president of the UK’s Research Defence Society.

The Three Rs approach would provide an ethically and scientifically sound framework on which a reformist approach to the use of animals in biomedicine could be grounded. It would also set the stage for a more moderate advocacy of animal rights to appear: while remaining incompatible with an abolitionist animal rights perspective, this paradigm grants animals something like a right to protection from suffering, or at least certain suffering beyond a defined threshold [ 185 ], preserving the central idea that there are absolute and non-negotiable limits to what can be done to animals. This welfarist perspective stems from a utilitarian view that animals can be used as means to an end as long as their interests—as far as they can be ascertained—are taken into account, but also accepting that the lives and wellbeing of human beings must be granted greater consideration than animals’. Utilitarian philosopher Raymond G. Frey (1925–2012) offered a philosophical view compatible with the current paradigm, by acknowledging that what we do to animals matters morally, since animals’ sentience and ability to control their lives grants them moral standing and a rightful place in the “moral community.” However, when weighing the interests of humans against animals’ interests (or between animals, or humans), he held that the main question should not lie on one who has moral standing or not, or to which degree, but rather on whose life may be more valuable. In Frey’s view, the value of life “is a function of its quality, its quality of its richness, and its richness of its capacities and scope for enrichment.” Hence, as a result of their higher cognitive capabilities, human lives are typically richer than animal lives, being therefore generally more valuable [ 186 ].

A “welfarist–reformist” approach has been accepted as a compromise by some prominent animal rights advocates who, while maintaining the long-term goal of a full end to all animal experiments, believe that it is by successive short-term improvements of the status quo that their goal can be achieved; see [ 178 , 187 , 188 ]. This position—also endorsed by influential animal advocacy groups like the Humane Society of the United States, or the UK’s FRAME—has, however, been highly criticized by less compromising animal rights advocates, like Regan and Gary Francione (born 1954), who believe reformist attitudes validate and perpetuate the exploitation of animals [ 171 , 189 , 190 ].

The 1980s and the 1990s would witness considerable progress in the development and acknowledgment of the Three Rs, to the satisfaction of William Russell and Rex Burch, who lived to see the “rediscovery” of their principles and the emergence of a whole new field of research inspired by their groundbreaking work [ 179 , 191 ]. As Peter Medawar had predicted in the 1960s, the number of animals used in research would peak in the 1970s and start to decline thereafter, although the number of biomedical papers has since then more than doubled [ 181 , 192 , 193 , 194 , 195 , 196 ]. This data is, however, limited to the Western world, as statistics on animal use in emerging countries such as India and China are unavailable [ 197 ], and there is no way to assess if (and, if so, to what extent) the decline in numbers of animals used in Western countries may be attributed to the outsourcing of animal experiments to these emerging countries. In recent years, the rise in the use of genetically modified animals has led to the stabilization of what would otherwise be a continuously downward trend [ 198 , 199 ] ( Figure 7 ).

This schematic illustration (adapted with permission from an original by Professor Bert van Zupthen) attempts to describe trends in the use of animals for scientific purposes in the Western world across time. It depicts the emergence of the first vivisection studies by classical Greek physicians, the absence of animal-based research—along with most medical and scientific research—across the Middle Ages, its resurgence in the Renaissance onwards, and the rapid increase in animal studies following the rise of science-based physiology and medicine in the nineteenth century. The curves represented are nevertheless conjectural, as there are no reliable statistics on animal use for most of the period covered. Even nowadays it is hard to estimate trends in animal research, as data from several developed countries is insufficient (for instance, in the United States, rodents, fish and birds are not accounted for in the statistics). The available data, however, suggest that the number of animals used in research and testing in the Western world peaked in the 1970s, and decreased until the late 1990s, or early 2000s, to about half the number of 30 years earlier, and stabilizing in recent years. While many, if not most, researchers do not foresee an end to animal experiments in biomedicine, the European Commission has nevertheless set full replacement of animal experiments as an ultimate goal [ 204 ], and the Humane Society of the United States has the optimistic goal of full replacement by the year 2050 [ 192 ].

In 1999, the Declaration of Bologna, signed in the 3rd World Congress on Alternatives and Animal Use in the Life Sciences, would reaffirm that “ humane science is a prerequisite for good science, and is best achieved in relation to laboratory animal procedures by the vigorous promotion and application of the Three Rs ” [ 200 ]. The Three Rs would also become the overarching principle of several legislative documents regulating animal use in science since the 1980s (including the latest European legislation [ 201 ]). Most recently, biomedical researchers in both industry and academia have also acknowledged the central importance of the Three Rs and the need for more transparency regarding animal use in biomedical research through the Basel Declaration [ 202 , 203 ]. More important, there are currently thousands of scientists devoted to the progress of animal welfare and development of alternatives to animal use in the life sciences.

8. Conclusion

The historical controversy surrounding animal research is far from being settled. While the key arguments in this debate have not differed significantly since the rise of antivivisectionism in nineteenth-century England—and even before—we have since then moved a long way forward in regards to the protection of animals used in research and transparency regarding such use. While animal experiments have played a vital role in scientific and biomedical progress and are likely to continue to do so in the foreseeable future, it is nonetheless important to keep focusing on the continuous improvement of the wellbeing of laboratory animals, as well as further development of replacement alternatives for animal experiments.

Acknowledgments

The author thanks Francis Brosseron ( Lycée Français du Porto ) for the photograph in Figure 5 , Bert van Zutphen (Emeritus Professor, Utrecht University) for the original picture that has been adapted for Figure 7 , and I. Anna S. Olsson, Manuel Sant’Ana (IBMC, University of Porto) and four anonymous referees for their valuable comments on this manuscript.

Conflict of Interest

The author declares no conflict of interest.

References and Notes

Ethical issues associated with the use of animal experimentation in behavioral neuroscience research

Affiliation.

• 1 Department Animals in Science & Society, Faculty of Veterinary Medicine, University Utrecht, Yalelaan 2, PO Box 80.166, 3508 TD, Utrecht, The Netherlands, [email protected].
• PMID: 25023419
• DOI: 10.1007/7854_2014_328

This chapter briefly explores whether there are distinct characteristics in the field of Behavioral Neuroscience that demand specific ethical reflection. We argue that although the ethical issues in animal-based Behavioral Neuroscience are not necessarily distinct from those in other research disciplines using animal experimentation, this field of endeavor makes a number of specific, ethically relevant, questions more explicit and, as a result, may expose to discussion a series of ethical issues that have relevance beyond this field of science. We suggest that innovative research, by its very definition, demands out-of-the-box thinking. At the same time, standardization of animal models and test procedures for the sake of comparability across experiments inhibits the potential and willingness to leave well-established tracks of thinking, and leaves us wondering how open minded research is and whether it is the researcher's established perspective that drives the research rather than the research that drives the researcher's perspective. The chapter finishes by introducing subsequent chapters of this book volume on Ethical Issues in Behavioral Neuroscience.

Publication types

• Animal Experimentation / ethics*
• Behavioral Research / ethics*
• Models, Animal*
• Neurosciences / ethics*

Elan Abrell's talk "The Ethical and Methodological Challenges of Animal-Centered Ethnography"

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