Animal Subjects

Summary

Author: Michael Kalichman, 2001
Contributors: P.D. Magnus, Dena Plemmons
Updates: Michael Kalichman, 2016

Fundamental Questions
Humans have often used non-human animals for basic and biomedical research, but also for companionship, supporting those with disabilities or suffering from stress, protection, sources of medicine and clothing, entertainment, transportation, and food. Although the focus of this discussion is the use of animals in research, two fundamental questions are relevant to any use of animals:
  1. Is the use beneficial?
  2. Even if beneficial, are some uses of animals unacceptable?

Nominal Guidelines
Opinions among scientists, philosophers, and the general public about how to answer these questions are widely divergent. However, as a minimum, scientists should always take the question of animal use seriously:

Background

Without the use of animals and human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans, but also among animals.
Albert Sabin, Developer of Polio Vaccine (Sabin, 1992)

Virtually every major medical advance for both humans and animals has been achieved through biomedical research using animal models to study and find a cure for disease, and through animal testing, to prove the safety and efficacy of a new treatment.
C. Everett Koop, U.S. Surgeon General, 1982-1989 (UCSD, 2001)



Is Animal Research Useful?

The merits of animal research are widely accepted by scientists and largely appreciated by the general public:

That said, the recognition of benefits of animal research will depend greatly on precisely what question is being asked:

It would appear that people’s attitudes toward experiments involving animals are likely to change depending on the beneficiary, purpose or necessity of the research.
(Ormandy et al., 2014)


For example, it is likely that someone who expresses general misgivings about animal research, but perceives the value of vaccines, will prefer that those vaccines be first tested for safety before being used in their children.

Is Animal Research Conducted Responsibly?

Foundations of Responsible Research

Animal research has tremendous utility because an understanding of the complex interactions of molecular, biochemical, and physiological mechanisms ultimately depends on studies in intact, living organisms.

Failures of Responsible Research

While researchers typically recognize the need for responsible use of animals, poorly trained or inexperienced investigators may, for example:

Although these lapses may occur rarely, they are never acceptable.

It is hoped that the conduct of most researchers is principled and responsible, but this is not always the case. One of the most important early experimental scientists was Claude Bernard. Despite his fundamental and important contributions to science, his words suggest someone who did not recognize the suffering of the subjects of his research:

To translate and paraphrase Bernard*,
The physiologist is not a worldly man. He is a scientist seized and absorbed by scientific inquiry. He no longer hears the cries of the animals. He no longer sees the flow of the blood. He only sees his idea and the systems that conceal from him the questions he seeks to answer.
(Bernard, 1865)


In this context, it is noteworthy that some instances of animal abuse have been far worse than inadequate care or feeding.

In 1984, head injury studies conducted with baboons at the University of Pennsylvania were found to exemplify the worst fears of those opposed to animal research. In studies with restrained baboons, researchers were testing the effects of rapid, traumatic head injury. Some of those researchers made comments suggestive of a callous, if not sadistic, attitude toward the experimental subjects. Videotapes documenting these abuses were obtained by an animal rights organization and were aired on national television.



Despite the potential importance of what might be learned, such incidents reflect badly not just on one group of researchers, but on all of research.

Investigators who are irresponsible risk not just their own research project, but also the research of others at the same institution. Potentially, they also risk the public's willingness to support or allow any research with animal subjects.

Opposition to Animal Research

The support for biomedical research is tempered in part by widespread misunderstanding about the general nature of research, and research with animals in particular, but also an impassioned opposition, by some groups, to any use of animals.

Arguments against the use of animals in research can broadly be divided into those that focus on the rights of animals and those that emphasize a utilitarian calcluation to balance net benefits and harms.

Rights
Some in the animal rights movement rely on carefully reasoned, philosophical arguments that humans do not have the right to use animals for experiments (e.g., Regan, 1983), even if such studies might contribute important new knowledge about physiology or the mechanisms of disease in both humans and animals.


Utilitarian
Other opponents of animal research focus more on balancing benefits and harms (e.g., Singer, 1975). The focus in this case is on claims that:

While compelling arguments have been made to diminish the case made by Singer (Russell and Nicoll, 1996), it is important to remember that the principle of "the greatest good," is of paramount importance to Singer, who has even gone on record as saying studies in non-human primates for the purpose of Parkinson's Disease research could be defensible (Crowley, 2006). This is clearly contrary to the typical Rights argument.

Scientific Community Concerns about Animal Research

Singer is not the only one to have questioned the unmitigated value of animal research.

Frances Collins, director of the National Institutes of Health since 2009, noted:

The use of animal models for therapeutic development and target validation is time consuming, costly, and may not accurately predict efficacy in humans
(Collins, 2011)



John Ioannidis, a widely respected Stanford Professor of Statistics, Medicine, and Health Research and Policy, concluded from systematic reviews of the animal research literature that (Ioannidis, 2012):

Limited concordance exists between treatment effects in preclinical animal experiments and clinical trials in human subjects.

[It is] nearly impossible to rely on most animal data to predict whether or not an intervention will have a favorable clinical benefit-risk ratio on human subjects



This is consistent with an increasing body of literature noting a dismaying lack of reproducibility of published research (Prinz et al., 2011; Begley and Ellis, 2012). However, this doesn't necessarily mean that animal models per se are the problem.

First, not all uses of animals in research are the same:

Animal models vary in their capacity for predicting efficacy or safety in humans (Greaves et al., 2004). Just as there are cases in which correlations are strong (e.g., lethal doses for anticancer drugs in mice with maximum tolerated dose in humans or that dogs can be better predictors "of human adverse effects than rodents or, surprisingly, monkeys"), there are others which have little correlation (e.g., rodents appear to be poor predictors of subjective adverse neurological reactions in humans).



Further, as pointed out by Ioannidis (2012), there are at least two reasons that research with animals might not be reliable:

Potential explanations for the failure of animal models to capture treatment effects in humans can be placed into two categories: First, both the human and animal results are accurate, but human physiology and disease are not adequately captured by animal models. Second, the animal literature is susceptible to biases in the study design, to reporting biases that distort the published evidence, or both. Indeed, although the scientific literature related to human clinical trials suffers from biases.





*Bernard C (1865): Le physio­logiste n'est pas un homme du monde, c'est un savant, c'est un homme qui est saisi et absorbé par une idée scientifique qu'il poursuit : il n'entend plus les cris des animaux, il ne voit plus le sang qui coule, il ne voit que son idée et n'aperçoit que des organismes qui lui cachent des problèmes qu'il veut décou­vrir.

Regulations and Guidelines

Enhancing the quality of animal studies will directly improve a quarter of the biomedical literature and may also benefit much of the other three-quarters that have an interface with animal research. Efforts are needed to minimize publication and other selective-reporting biases. Study design, conduct, and reporting can be improved—for example, by using the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guidelines [Kilkenny et al., 2010]
(Ioannidis, 2012)



Roots of Regulation

Except for a set of guidelines for animal use recommended by the National Institutes of Health (NIH) in 1935, animal research in the United States was conducted with little public attention and virtually no oversight until the 1960s.

This changed with a report titled "Concentration Camps for Dogs", published in Life magazine in 1966, documenting brutal conditions and lack of care by suppliers of dogs to research laboratories (Cosgrove, 2014):

Regulations

The use of animal subjects is covered by numerous regulations.

Although many federal agencies have relevant regulatory controls, the two most important for biomedical research are the Public Health Service (PHS) and United States Department of Agriculture (USDA). Institutions are charged with implementing federal regulations primarily through the Institutional Animal Care and Use Committee (IACUC):

Guidelines

There is no presumption that animals may be sacrificed for research. Use of animals should only be considered if there is a legitimate scientific advantage to doing so, and even then the harm should be as little as possible.

Replacement, Reduction, and Refinement

Russell and Burch (1959) proposed three specific strategies for minimizing the pain and distress to animal subjects:


These strategies have an ethical basis, but they also have practical advantages. Research with animal subjects is expensive. If experiments can be conducted, for example, with mice rather than monkeys, with fewer animals, or without animals altogether, then the cost of those studies will generally be reduced.

ARRIVE Guidelinens

Even if a case can be made that research is consistent with the principles of reduction, replacement, and refinement, the research cannot be considered ethical if it doesn't also adhere to minimal precautions to favor research that will be reproducible. A widely accepted set of such guidelines are those noted above for Animals in Research: Reporting In Vivo Experiments (Kilkenny et al., 2010).

Discussion

Discussion Questions
  1. Discuss the benefits of using animals in biomedical research and list at least three different studies that could be accomplished only with the use of animal subjects.
  2. To what extent does your field of work depend on the use of animal subjects? To what extent is your work intended to benefit both humans and other animals?
  3. Describe at least one instance in which abuse of animals in research resulted in public concern about the use of animals in research. Identify federal regulations that were apparently direct responses to such abuses.
  4. Define the terms replacement, reduction, and refinement in the context of research with animal subjects.
  5. What are the responsibilities of an IACUC?
  6. In your institution, what minimal changes (e.g., increase in number of animals) to your protocol require review and approval of the IACUC? What changes are of a magnitude to require submission, review, and approval of a new protocol?
  7. If you observed another investigator abusing the privilege of animal use, who should be notified?
  8. Describe your criteria for the acceptable use of animals. Consider the importance and likelihood of benefits to be obtained, the nature of the species to be used (e.g., invertebrates versus vertebrates, primates versus non-primates, dogs or cats versus rats or mice), the number of animals to be used, and the extent of likely pain or suffering.
  9. What forums are available in your institution to examine the ethical and/or legal ramifications of animal use? What, if anything, can you do to promote such discussion?
Case Studies



Resources

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