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The Alternatives Concept

(Originally published in the Animal Welfare Information Center Newsletter 2(2):1-2,8. April-June 1991)
Andrew Rowan, D.Phil.
Humane Society of the United States

The growth of scientific interest in the topic of alternatives has been marked by legislative initiatives and campaigns by animal advocates against animal testing. However, the topic is also marked by rhetoric that has served to confuse the public and others who have to deal with the subject because of legislative or regulatory mandate.

The public basically agrees with the argument that animal research is necessary [according to most polls, about 75 percent accept the practice (1)] but many are not entirely comfortable with the fact that their health is dependent on a practice that often causes death and possible distress of animals. Thus, the public comfortably supports the use of animals in research and medicine when there is a direct benefit for a human and little or no apparent distress caused to an animal. However, when there is apparently much distress and no immediate and obvious benefit to humans, public opposition is relatively easily mobilized.

Discomfort over the need to use animals in research and testing may also be observed among many who work in the laboratory (2,3). When I have specifically asked whether or not a scientist would use an animal if he or she did not need to, nearly all state that they would not. Current legislative mandates and organizational policy statements also imply this premise and urge scientists to use as few animals as possible and then only when necessary.

Some abolitionists believe that all animal research should stop today while others are willing to be more pragmatic. Most animal welfare supporters would like to see the end of animal use in research but do not perceive this to be a realistic or practical goal at the moment. Instead, they believe that the research establishment should devote more time and money to finding ways to eliminate animal pain and distress in research techniques (i.e., the three R's--Reduction, Refinement, and Replacement). While supporting the concept of alternatives in principle, the average scientist still seems to be confused over what should be done to develop and promote these techniques more aggressively, and over how they should meet the new regulatory requirement to search the information base for possible alternatives. Then, there are some scientists who mistakenly see the term "alternatives" as a plot by all animal activists to stop all animal research.

If we are to develop an effective debate on the public policy aspects of animal research and alternatives, we should focus not on the question of whether animals should be used at all (although this is a legitimate issue albeit supported by only a small proportion of the public), but on how we might reduce both animal distress and the number of animals used in the laboratory. The concept of alternatives to animal use and the appropriate level of government effort to develop and promote the concept are key elements in such a debate.

The concept of alternatives is relatively simple and was first enunciated in 1959 by two British scientists who argued that animal researchers should always follow the principle of the "Three R's"--Replacement, Reduction and Refinement (4).

Replacement refers to situations where non-animal techniques may be substituted for techniques using research animals. There are a number of examples of such replacement in the diagnosis of disease and in the testing and standardization of biological therapeutic agents. Rabbits are no longer used in pregnancy tests. Using mice to test the potency of batches of yellow-fever vaccine was long ago replaced by a cell culture test. We may be close to eliminating the use of mice in insulin-standardization procedures as a result of a variety of technical advances.

Reduction refers to cases where the number of animals required for a particular activity or project can be reduced. One example of recent progress comes from the field of acute toxicity testing. Most toxicologists now agree that it is not necessary to use from 60 to 200 rodents to generate the statistically precise lethal dose. One can obtain perfectly adequate lethal-dose data using no more than 10 to 20 animals (5,6).

Another spectacular example of a reduction in animal use comes from the National Cancer Institute's (NCI) drug research and development program. A few years ago, NCI was reportedly using as many as 4.5 million rodents a year to screen chemicals for anti-tumor activity. However, the standard animal model system was far from ideal. After much argument and debate, NCI switched to the use of cell culture screening systems using human cancer cell lines. The program now uses between 500,000 and 1 million mice, an 80- to 90-percent reduction in animal use. It should be noted that the decision to switch was made for scientific rather than animal welfare reasons, illustrating the point that the pursuit of alternatives is not, in and of itself, anti-science.

Refinement is a very neglected aspect of the alternatives concept. It refers to the modification of a technique to reduce the pain and distress experienced by research animals. For example, various jacket and tether systems have been developed to protect catheters inserted into research animals which then allow an investigator to administer doses of test chemicals and take blood samples from an animal without having to restrain it. Capture and restraint often cause significant distress to an animal, so the use of the jacket and tether constitutes a real refinement.

The reduction of pain and/or distress is a popular topic now because Institutional Animal Care and Use Committees (IACUC's) at research institutions are deciding how to respond to the new regulations from the U.S. Department of Agriculture (7) and the guidelines from the National Institutes of Health (8). Principle investigators are now required to minimize animal pain and distress in their research projects (7). In their discussions, the committees should recognize that alternatives are nothing more than new techniques that should help scientists do their job more efficiently and effectively.

Alternatives differ in a significant way from the usual scientific search for new techniques because they require that the use of animals or animal pain and distress be reduced as a result of their implementation. Given the current state of our knowledge, it would be ridiculous to argue that the present rate of advance in the development of biomedical knowledge could be maintained without animal research. But today's refinement may be replaced tomorrow by a new technique that uses no animals. And the development of new research techniques that have also allowed us to reduce the use of laboratory animals in research or the distress caused them has been an important element in the current success of biomedical research. For example, in the development of the polio vaccine, the Nobel prize was awarded to the authors of 1949 cell culture paper. Techniques of human and animal cell culture have been enormously improved since then, and the range of questions that can be investigated and answered in cell culture has expanded commensurately.

A powerful and convincing argument can be made that the development of new research techniques (e.g., paper chromatography, radioimmunoassay, monoclonal antibody production, genetic engineering, polymerase chain reaction, and positron emission tomography, to name a few) has been a critical factor behind rapid advances in biomedical knowledge. Since an alternative is nothing more than a new technique that also happens to lead to reduced animal use and/or distress, I find it hard to see how the pursuit of alternatives could be inimical to science. Toxicologists have begun to embrace the alternatives concept in the last few years, but many other branches of science avoid the issue as much as possible despite considerable public and congressional pressure to do something about "alternatives."

Part of the resistance to the issue of alternatives is the common misunderstanding that the term refers only to replacement. At a talk I gave, I was once introduced as an expert on alternatives. The moderator proceeded to define the term as referring to the three R's and then stated that, although there are a number of alternatives in toxicology, there are none available in cardiovascular or behavioral research. The moderator had fallen into the classic error of defining the term as the three R's and then thinking only in terms of one R, replacement. There are clearly opportunities to explore reduction and refinement in cardiovascular and behavioral research.

When principle investigators (PI) search for documentation that they have considered but rejected as alternatives, they should consider whether their use of new anesthesia and post-operative husbandry techniques may be identified as an alternative. IACUC's and PI's must incorporate not just replacement but also reduction and refinement into their planning and consideration of animal research protocols.

It is obvious to anyone who is able to step back from the laboratory bench and review the public's attitudes toward science that there is concern, not just about animal abuse, but also about any use of animals. In the 1960's, a scientist could feel like a public hero. Today, he or she may be made to feel like a criminal. In the last 10 years, the membership of animal protection groups has increased fivefold to tenfold. Symbols of public concern for animals are widespread throughout popular culture. Even Superman has been drawn into the animal research controversy. In a recent issue of the comic book, Lois Lane exposed a callous biomedical researcher, and Superman had to subdue the monstrous ape resulting from the research, if possible, without killing it!

The public wants alternatives developed and promoted. Scientists can satisfy these public concerns without compromising the quality of their research. To continue the polarized argument about whether or not animals are needed in research is unproductive. Scientists can show the public that they are greatly concerned about research animal use and distress by instituting and publicizing programs that actively seek ways to reduce animal use and distress, and increase the well-being of laboratory animals.

References

1. Rowan, A.N. 1991. "Animal experimentation and society: A case study of an uneasy interaction." In: Bioscience and Society, J. Wiley and Sons, New York (in press).

2. Arluke, A.B. 1988. "Sacrificial symbolism in animal experiments: Object or pet." Anthrozoos 2:98-117.

3. Arluke, A.B. 1990. "Uneasiness among laboratory technicians." Lab Animal 19(4):20-39.

4. Russell, W.M.S. and R.L. Burch. 1959. The Principles of Humane Experimental Technique. Methuen, London.

5. van den Heuvel, M.J., A.D. Dyan, and R.O. Shillaker. 1987. "Evaluation of the BTS approach to the testing of substances and preparations for their acute toxicity." Human Toxicology 5:151-157.

6. Bruce, R.D. 1985. "An up-and-down procedure for acute toxicity testing." Fundamental and Applied Toxicology 5:151-157.

7. Animal Welfare Regulations. 9 C.F.R. (Parts 1,2, and 3). Federal Register Parts 1 and 2, (August 31, 1989), Part 3, (February 15, 1991).

8. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. 1985. Guide for the Care and Use of Laboratory Animals, NIH Publication No. 85-23 Bethesda, MD.