Clinical Ethics in Anesthesiology. A Case-Based Textbook

4. Research and publication

29. Animal subjects research Part II: Ethics of animal experimentation

Gail A. Van Norman

The Case

Fifty hemophilic mice are anesthetized with an intraperitoneal injection of ketamine (which kills six mice), followed by blunt force trauma to a knee joint in half of the survivors. Post-trauma analgesics are administered only on day 0 and 1 following knee trauma. Two days later, and every 2–4 days thereafter, all mice are placed on a rotating rod and forced to ambulate until they fall off. Blunt trauma is administered in the test group weekly, and the process repeated. After 4 weeks, all mice are killed to examine their joints. The authors conclude that joint trauma and hemarthrosis leads to problems with ambulation and hemophilic synovitis –“consistent with clinical experience.”1

The editors of the journal in which this experiment appeared commented that the manuscript “proved challenging on review,” citing obligations of journal editors to assure that investigators minimize animal pain and suffering. One reviewer points out that progressive joint functional limitation is well known in human patients with hemophilia, particularly following trauma associated with hemarthrosis. He also raises concerns about animal suffering, pointing out that, although they were given analgesia for a brief period following acute trauma, the mice were forced thereafter to ambulate on traumatized joints without analgesia.2 Mice in the test group lost weight, limped, and fell off the rotating rod more quickly, all of which might be signs of pain and suffering that went untreated.

Nonhuman animals are used as subjects in research experiments, as test subjects for industries, and as objects for dissection and instruction in science classrooms – a subject of intense moral dispute. Most reviews addressing the ethics of animal research describe this debate as a war of wills between scientists and animal rights activists. Extremism on both fronts garners media attention. Leading scientists, and even some ethicists to insist that there is “no consensus” about the appropriate use of, and treatment of animals in testing, education, and research. But this is a distorted and misleading perspective. Specific moral frameworks regarding the use of animals by humans are evolving; nevertheless, there is moral, scientific, and public consensus about animals in research. It is likely that this consensus will evolve as our understanding of nonhuman animals deepens – their experiences, intelligence, and capacities for suffering, pain, and enjoyment. But it is imperative that every physician and researcher who uses animals in teaching, testing, and/or experimentation understands that they have explicit ethical obligations to their animal subjects.

Moral justifications of animal research

At its heart, the debate over the use of animals in research is centered on a single moral question: are humans morally justified in using animals in this way? Ethical arguments favoring animal experimentation generally fall into two categories: (1) humans have higher moral standing than animals and have a right to use animals in experiments that better human lives, and (2) the benefits of animal experimentation outweigh the harms, and that animal experimentation is sometimes the only way in which science can answer important questions necessary to human well-being.

The moral standing of humans versus animals

Western culture is heavily imbued with Judeo-Christian traditions, in which animal interests are subordinate to those of humans. Earth and its contents were bequeathed by a Creator to humankind to benefit humans. This view is still prominent among conservative Judeo-Christian leaders:

“The animal rights movement can best be understood by viewing it as an attempt to undo the opening chapters of the biblical Book of Genesis.” 3

In the last 50 years, detrimental effects of human populations on the environment have begun to threaten global repercussions. The views of conservative Judeo-Christian philosophers toward man’s relationship with the planet and nonhuman animals have begun to shift in response, but still describe the ethical obligations of humans in the utilitarian framework of serving the ultimate interests of mankind – i.e., we should take care of the environment and animals because, if we don’t, it will lead to depletion of resources and jeopardize the future of human existence.

Many twentieth-century religious scholars were challenged to reconcile new scientific theories and evidence (e.g., the theory of evolution and the fossil record supporting it) with mainstream theology. Pierre Teilhard de Chardin, a Jesuit priest and paleontologist, argued that, in parallel with biological evolution, humans are a part of a continuum in a “spiritual evolution” that also includes plants and animals.*4 Breaking down bright theological lines between animals and humans begs the question of whether our relationship with animals should really be viewed only through a utilitarian glass. Are we allowed to treat animals in ways that only promote human interests? Or do they have legitimate “interests” of their own? (For more discussion of ethical arguments regarding animal interests and rights, seeChapter 28.)

Are humans and nonhuman animals fundamentally different?

Up until the mid-to-late twentieth century, Western biologists operated under a “Cartesian” paradigm that attributed minimal, if any, intelligence to nonhuman species. Reasoning, emotions, and suffering were believed to be uniquely human attributes – animals were merely pre-programmed, instinct-driven robots that did not have moral standing.

“They eat without pleasure, cry without pain, grow without knowing it; they desire nothing, fear nothing, know nothing.”5

Current research demonstrates unequivocally that, far from being simple bundles of instinctual programming, the intellectual abilities of animals parallel that of humans in many startling ways. The manufacture and use of tools, long held to be a uniquely human ability, is now well described in nonprimate and even nonmammalian species.6 Animals demonstrate “culture,” in which uniquely individual and adaptive behaviors are passed within social groups by observation and mimicry, and not by instinct or genetic programming.7 The great apes appear to be capable of learning and using symbolic language, an important marker of abstract thinking.8 Meadow voles demonstrate “episodic recall,” believed to be an important marker of sentience.9 Whales and dolphins understand symbolic representations and have self-awareness,10 which has also been demonstrated in primates, elephants,11 and magpies.12

Why have animal researchers been slow to acknowledge these critical similarities with humans? Zoologist Frans de Waal proposes that “Our culture and dominant religion have tied human dignity and self-worth to our separation from nature and distinctness from other animals.” This cultural bias, he argues, keeps scientists from recognizing how similar humans and other animals really are, and thereby weakening arguments of human moral superiority.13

Bioethicist Bernard Rollin suggests that scientists now have an “ideology” of their own, in which they assert that science is “objective” and not burdened by moral values. “The bottom line,” he says, is the belief that “science might provide society with the facts relevant to making moral decisions, but it steers clear of any ethical debate.”14 But if it were true that there is no moral dimension to scientific endeavor, then there would be no need to argue that animal experimentation is permissible, nor that cruel experimentation on human subjects must be disallowed because it violates moral principles. Almost any experiment that simply produced new information would be allowed under such an ideology, without regard for treatment of any of its subjects, human or animal. The idea that medical research is immune from moral consideration has long been discredited, as exemplified in the Doctor’s Trial at Nuremberg after World War II.

Most bioethicists concede that many animals have at least some moral standing, although which animals and how much moral standing are unclear. Deliberately causing an animal to suffer due to pain, fear, starvation, illness, or poor conditions of care constitutes a moral harm to be prevented or mitigated, and considered carefully against the benefits such conditions might produce. Apart from any consideration of animal “rights,” many ethicists propose that cruelty to animals should still be discouraged, because it is likely that those who are cruel to animals will be cruel to humans as well.

Assessing the benefits of animal research

There is no doubt that animal experimentation has contributed to advances in anesthesia, cardiovascular and orthopedic surgery, treatment of such diseases as diabetes and hemophilia, vaccines, antimicrobial agents, cancer therapy, treatment protocols for trauma and shock, and many other areas. Yet is it simply not sensible to assert that medical science would have come to a complete halt without animal experimentation. As Harold Hewitt, himself an animal researcher, points out:

‘It underrates the ingenuity of researchers to assert that medical progress would have been seriously impeded had animal experiments been illegal, although a different strategy would have been required. It is the skill of the scientist to find a way around the intellectual, technical and ethical limits to investigation. No one complains, surely that we have been denied the benefit of potential advances by prohibiting experiments on unsuspecting patients, criminals or idiots.15

The contributions of animal experimentation to human medicine may also be greatly over-estimated. Critical analysis of the quality of animal experimentation leads to disturbing conclusions. A systematic review of animal experiments in fluid resuscitation, for example, found that many studies were fraught with poor design, were statistically underpowered, showed evidence of publication bias, and were seldom subjected to cross-species analysis or meta-analysis to determine if the results were even applicable to humans.16 Animal trials have been frequently conducted simultaneously with human trials, and were thus superfluous. They often set out to answer questions that had already been answered or could have been answered by a systematic review of existing studies.17 Historically, animal experimentation has, at times, been frankly misleading. It probably actually impeded such endeavors as developing the polio vaccine; understanding the role of asbestos exposure and lung disease; understanding the connections between tobacco smoke and lung cancer; and in developing other cancer treatments.18

An analysis of 76 animal studies cited in seven prominent scientific journals found that almost half were never subsequently tested in human trials. Of those that had been tested in humans, 18% were contradicted in the humans. Only 37% were eventually confirmed in human studies. Almost two-thirds of animal studies were not confirmed by testing in humans, and did not result in any human benefit.19Another review of 221 experiments involving over 7000 animals found that results were in agreement with human studies in only 50% of cases. The authors found that basic methodological errors, such as lack of randomization and blinding, poor sample size, and publication bias probably contributed to poor concordance with human studies.20 In the words of physician R. Burns, “As physicians, researchers, and educators, we must take a long-overdue objective look at how and why we use animals in research and education. A great deal of animal-based research adds very little to our understanding of the diagnosis and treatment of our patients.”21

How many animals are used in research and testing laboratories? According to the United States Department of Agriculture (USDA), the use of “reportable” animals in research has declined steadily, from over 2 million animals in 1992, to just over 1 million in 2007.22 Because a 2002 amendment to the Animal Welfare Act (AWA) exempted laboratories from reporting research on birds, rats, and mice, USDA statistics only reflect the use of cats, dogs, hamsters, rabbits, guinea pigs, primates, and farm animals. Rats and mice are estimated to comprise approximately 95% of laboratory animals in research, and it is estimated that over 20 million animals are actually experimented on every year in the US.23 In 2007, about half of the reported experiments produced pain in the subjects, and almost 80 000 animals were subjected to pain without analgesia. An accurate number regarding how many “exempted” animals are subjected to untreated pain during research protocols is unavailable, but presumed to be in the millions.

According to the Home Office of Great Britain, approximately 3.7 million procedures were done on animals – including all vertebrates and one species of octopus – in research in the UK in 2008 that was deemed “likely to cause pain, suffering, distress, or lasting harm.” In only about 35% of procedures was some form of anesthesia or analgesia used.24

Public perceptions and public consensus

Scientists rightfully point out that research based solely on tissue cultures and cell lines may not accurately mimic conditions found in a human being. Many tests felt to be essential to human health, such as testing drugs and chemicals for teratogenic potential, do not currently have reasonable alternatives to animal testing and pose too high a risk for human testing. Would we be willing to give up important health protections for human beings in order to eliminate animal research entirely?

A 2008 US poll found that public concern about treatment of animals is significant; all but 3% believe that animals require protection, and a startling 25% believed that animals should have the exact same rights as humans to be free from harm and exploitation. A significant portion of respondents (35%) would ban all medical research on animals, and 39% would ban all product testing on animals.25 In a 2007 poll, 37% rated medical testing on animals as “morally wrong.”26 A 1994 comparison of public opinion regarding animal research across 15 nations indicates that opposition to any research that causes pain or injury to animal subjects is common globally – ranging from about 35% in Portugal to almost 70% in France.27

The three Rs

In 1954 William Russell, a zoologist and classical scholar, and Rex Burch, a microbiologist, were appointed by the Universities Federation for Animal Welfare in the UK to systematically study the ethical aspects of laboratory research. The result was the seminal publication of The Principles of Humane Experimental Technique in 1959.28 They stated that “the humanest possible treatment of experimental animals, far from being an obstacle, is actually a prerequisite for successful animal experimentation.” In fact, as J. Edward Gates from the University of Maryland observes, “Pain and stress adds an uncontrollable variable into an experiment, and so it is in the interest of good science to control pain and distress whenever possible.”29

Russell and Burch introduced the “3 Rs” of humane experimentation. These principles were: (1) replacement of animal subjects whenever possible with other methodologies, human volunteers, or computer modeling; (2) reduction of animal use by using fewer animals or obtaining more information from the same number of animals; and (3) refinement by improving scientific procedures and husbandry to minimize actual or potential pain, suffering, distress, or lasting harm, and increase animal welfare when animal use is unavoidable. These principles now form the bedrock of ethical animal use in laboratory research.

Current issues

Most Western nations now have laws regulating the treatment of animals in research and industry testing. In the US, federal legislation includes the AWA, initially passed in 1966. The Health Extension Act in 1985 and amendments to the AWA required the establishment of Institutional Animal Care and Use Committees (IACUCs), to oversee conditions of laboratory animals, review and approve animal research protocols, and educate and train investigators in ethical issues and aspects of animal handling such as anesthesia, analgesia, and euthanasia. In Great Britain, the Animals (Scientific Procedures) Act of 1986 (ASPA) regulates experimentation that might cause “pain, distress, suffering or lasting harm” to any vertebrate animal (and one species of octopus).30 In 1999, the UK introduced ethical review of scientific research involving living animals through local ethical review committees. In the European Union (EU), agreement on the protection of animals in research was codified in the 1986 European convention for the Protection of Animals used for Experimental and Other Scientific Purposes.*31 Laws and regulations of the US, UK, EU, and others have recognized the “3Rs” as foundational to ethical animal experimentation, and explicitly call for the replacement of animals in scientific research whenever possible.

‘A research institution that receives money and support from the public is responsible for conducting research according to the limits set by society…the use of animals in research is a privilege, and not a right. The consensus at this time in the United States is that animals should be treated humanely and that pain and distress should be minimized when animals are used for research or teaching purposes.’29

A number of national and international scientific organizations provide information for researchers seeking alternatives to animal experimentation and testing, as well as the use of live animals in education. Several resources may be found in “Further reading” at the end of this chapter.

IACUCs in the US, and ethical review committees in the UK can play a significant role in enforcing the 3Rs, by refusing to approve studies that are poorly designed; are not anticipated to significantly alter existing knowledge; could have been conducted in humans or alternative models; do not use the bare minimum number of animals; and do not provide adequate management of pain and distress. However, there is considerable resistance among IACUC’s to becoming reviewers of “scientific merit” rather than simply overseeing animal care.32 In addition, it is clear that many IACUC members do not have adequate education in ethical issues in animal research and ethical decision-making to perform well as ethics reviewers.33

Because publication is an important determinant of research funding, professional promotion, and academic prestige, peer-review journal editors and reviewers have significant power to impact researcher behavior. Yet evidence points to a systematic lack of competent peer-review in animal studies. In an analysis of 271 published animal research studies,34 only 59% stated the hypothesis they were testing, over 85% did not use randomization or blinding to reduce bias, and 30% did not identify the statistical methods used in analysis. In many, basic information was omitted, such as the total number of animals, and the strain, sex, age, and weights of the animals used – all factors that clearly can affect experimental results.

A study of journal editorial policies among 236 randomly selected English language peer-review journals that publish animal research found that 53% did not have a relevant editorial policy. Of 111 journals that did have policies, only one explicitly mentioned adherence to the 3Rs, and only one had a statement that adherence to their policy was a prerequisite for publication.35

Subjecting animal studies to the same strict level of review afforded human subjects studies, and requiring adherence to ethical guidelines as a prerequisite for publication may be important ways to encourage more rigorous research design, and conformation to the principles of replace, reduce, and refine.

Key points

• Mainstream scientific study has now challenged long-held beliefs that animals are fundamentally different than humans in many morally relevant ways.

• Public opinion, scientific communities, and biomedical ethicists agree that researchers have moral obligations to reduce or eliminate animal suffering in research, and to strive to eliminate animal experimentation altogether.

• The 3Rs of animal research ethics: replace, reduce, and refine have been adopted internationally in legislation and regulations regarding animal research.

• Animal researchers have ethical obligations to seek alternative models whenever possible, to design research protocols that use the fewest numbers of animals for meaningful results, and to offer humane care that reduces pain, distress and harm when using animals in research.

• IACUCs have regulatory obligations to review research protocols to assure that redundant, insignificant, or poorly designed research is not allowed.

• Biomedical journals should have established policies regarding publication of animal research, including emphasis on the 3Rs, and pledges not to publish studies that do not meet editorial or humane guidelines.

References

1 Mejia-Carvajal, C.Hakobyan, N.Enockson, C., and Valentino, L.A. (2008). The impact of joint bleeding and synovitis on physical ability and joint function in a murine model of haemophilic synovitis. Haemophilia15, 119–26.

2 Berntorp, E. (2008). Protecting the joints of mice and men. Haemophilia14, 117–18.

3 Environmental stewardship in the Judeo-Christian tradition: Jewish, Catholic, and Protestant Wisdom on the Environment. Barkey MB, edit. (2009). The Interfaith Council on Environmental Stewardship. Action Institute, Grand Rapids MI. http://www.acton.org/ppolicy/environment/ppolicy_environment_theology_monograph.php.

4* Teilhard De Chardin, P. (1959). The Human Phenomenon. New York, NY: Harper and Row

5 Philosopher Nichoas Malebranche, 1638–1715.

6 Taylor, A.H.Hunt, G. R.Holtzhalder, C., and Gray, R.D. (2007). Spontaneous metatool use by New Caledonian crows. Curr Biol 17(17), 1504–7.

7 Byrne, R.W.Barnard, P.J.Davidson, I.et al. (2004). Understanding culture across species. Trends in Cognitive Sciences8(8), 341–6; Madden, J.R. (2008). Do bowerbirds exhibit culture? Anim Cogn,11(1), 1–12.

8 Tanner, J.E.Patterson, F.G., and Byrne, R.W. (2006). The development of spontaneous gestures in zoo-living gorillas and sign-taught gorillas: from action and location to object representation. J Devel Process1, 69–102.

9 Ferkin, M.H.Combs, A.delBarco-Trillo, J.et al. (2007). Meadow voles, microtus pennsylvaicus, have the capacity to recall the “what”, “where”, and “when” of a past single event. Anim Cogn11(1),147–59.

10 Marino, L.Connor, R.C.Fordyce, E.et al. (2007). Cetaceans have complex brains for complex cognition. PLoS Biol5(5), e139.

11 Plotnik, J.M., de Waal, F.B., and Reiss, D. (2006). Self-recognition in an Asian elephant. Proc Natl Acad Sci USA103(45), 17053–7.

12 Prior, H.Schwarz, A., and Gunturkun, O. (2008). Mirror-induced behavior in the magpie (Pica pica): evidence of self-recognition. PLoS Biol6(8), e202.

13* De Waal, F. (2001). The Ape and the Sushi Master; Reflections of a Primatologist. New York, NY: Basic Books.

14 Rollin, B.E. (2007). Animal research: a moral science. EMBO Rep8(6), 521–5.

15 Hewitt, H. (1990). Benefits of animal research and the doctor’s responsibility. BMJ300, 811.

16 Roberts, I.Kwan, I.Evans, P.et al. (2002). Does animal experimentation inform human healthcare? Observations from a systematic review of international animal experiematns on fluid resuscitation.BMJ324, 474.

17* Pound, P.Ebrahim, S.Sandercock, P.et al. (2004). Where is the evidence that animal research benefits humans? BMJ328, 514–17.

18 Dennis, C. (2006). Cancer: Off by a whisker. Nature442, 739–41.

19 Hackam, D.G. and Redelmeier, D.A. (2006). Translation of research evidence from animals to humans. JAMA296, 1731–2.

20 Perel, P.Roberts, I.Sena, E.et al. (2007). Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ334, 197–203.

21 Burns, R. (1989). Animals in research. Acad Med62, 780.

22 Animal care annual report of activities, fiscal year 2007. United States Department of Agriculture, August 2008.http://www.aphis.usda.gov/publications/animal_welfare/content/printable_version/2007_AC_Report.pdf

23 Trull, F.L. and Rich, B.A. (1999). More regulation of rodents. Science284, 1463.

24 Statistics of scientific procedures on living animals: Great Britain 2008. Home Office. Ordered by the House of Commons to be printed. London. July, 2009.http://www.homeoffice.gov.uk/rds/pdfs09/spanimals08.pdf.

25 Post Derby tragedy, 38% support banning animal racing. The Gallup Organization. May 15, 2008. http://www.gallup.com/poll/107293/PostDerby-Tragedy-38-Support-Banning-Animal-Racing.aspx.

26 Americans rate the morality of 16 social issues. The Gallup Organization. June 4, 2007. http://www.gallup.com/poll/27757/Americans-Rate-Morality-Social-Issues.aspx.

27* Pifer, L.Shimizu, K., and Pifer, R. (1994). Public attitudes toward animal research: some international comparisons. Soc Animals2(2), 95–113.

28* Russell, W. and Burch, R. (1959). The Principles of Humane Experimental Technique. London: Methuen and Co. Ltd.

29 Gates, J.E. Committee Chair, Appalachian Laboratory, University of Maryland Center for Environmental Science (Lecture: Insitutional Animal Care and Use Committee, General Information).

30 Animal (Scientific Proceures) Act 1986. Great Britain. http://www.archive.official-documents.co.uk/document/hoc/321/321.htm

31* European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes. Strasbourg, 18.III.1986 (amended Dec 2, 2005 to reflect formation of the European Union). http://conventions.coe.int/treaty/en/treaties/html/123.htm

32 Rowan, A.N. (1990). Animals, science, and ethics – section IV. Ethical review and the animal care and use committee. Hastings Cent Rep20(3), s19–24.

33 Houde, L.Dumas, C. and Leroux, T. (2009). Ethics: views from IACUC members. Altern Lab Anim37(3), 291–6.

34* Kilkenny, C.Parsons, N.Kadyszewski, E.et al. (2009). Survey of the quality of experimental design, statistical analysis and reporting of research using animals. PLoS One4(11), e7824.

35* Osborne, N.J.Payne, D., and Newman, M.L. (2009). Journal editoral policies, animal welfare, and the 3Rs. Am J Bioeth9(12), 55–9.

Further reading

Cavalieri, P. (2009). The ruses of reason strategies of exclusion. Logos8(1).

Fund for the Replacement of Animals in Medical Experiments (FRAME)http://www.frame.org.uk/page.php?pg_id=152.

Gaul, G.M. (2008). In US, few alternatives to testing on animals. The Washington Post. April 12.

Harrison, P. (1992). Descartes on animals. Philos Quart42(167), 219–27.

Hastings Center Report Special Supplement. (1990). Animals, Science and EthicsDonnelley, S., and Nolan, K. eds. 20(3), s1–32.

Hobson-West, P. (2010). The role of ‘public opinion’ in the UK animal research debate. J Med Ethics36, 46–9.

The Humane Society of the United States. Biomedical Research. http://www.humanesociety.org/issues/biomedical_research/Accessed March 1, 2010.

The Johns Hopkins Center for Alternatives to Animal Testinghttp://caat.jhsph.edu/contact/index.htm.

Kilkenny, C.Parsons, N.Kadyszewski, E.et al. (2009). Survey of the quality of experimental design, statistical analysis and reporting of research using animals. PLoS One4(11), e7824.

Langley, G. (2009). The validity of animal experiments in medical research. Revue Semestrielle de Droit Animalier1, 161–8.

NC3Rs. National Center for Replacement, Refinement, and Reduction. http://www.nc3rs.org.uk/.

The Royal Society for Prevention of Cruelty to Animals. Research Animal Science. http://www.rspca.org.uk/sciencegroup/researchanimals Accessed March 1, 2010.

Universities Federation for Animal Welfare. http://www.ufaw.org.uk/.