The First Forty Years of the Alternatives Approach: 8CHAPTER Refining, Reducing, and Replacing the Use of Laboratory Animals An updated version of “Looking Back Thirty-three Years to Russell and Burch: The Development of the Concept of the Three Rs (Alternatives)” (Rowan 1994) Martin L. Stephens, Alan M. Goldberg, and Andrew N. Rowan Introduction he concept of the Three Rs— were established during the ’90s. By proved unpersuasive (French 1975; reduction, refinement, and 2000 the use of animals in research Turner 1980). Activism in the United Treplacement of animal use in had fallen by up to fifty percent from States over animal research waned biomedical experimentation—stems its high in the 1970s. after World War I and remained at a from a project launched in 1954 by low level until after World War II, a British organization, the Universi- when a new dimension in the animal ties Federation for Animal Welfare The Alternatives research controversy emerged. (UFAW). UFAW commissioned William Spurred in part by advances in Russell and Rex Burch to analyze the Approach in technological methods, animal pro- status of humane experimental tech- tectionists began advocating for niques involving animals. In 1959 the Context alternatives to laboratory animal use, these scientists published a book that of the Animal not simply advocating against animal set out the principles of the Three Rs, use or otherwise criticizing the sta- which came to be known as alterna- tus quo. These alternatives make up Research Issue the Three Rs: methods that could tive methods. Initially, Russell and Animals have been used as experi- replace or reduce laboratory animal Burch’s book was largely ignored, but mental subjects in biomedical re- use in specific procedures or refine their ideas were gradually picked up search, testing, and education during such use so that animals experience by the animal protection community the last 150 to 200 years, but the less suffering. Sympathetic scientists in the 1960s and early ’70s. In the practice began to burgeon in nine- joined in this more constructive ’80s, spurred by public pressure, the teenth century Europe. Alarmed by approach; indeed, scientists them- alternatives approach was incorporat- this increase, early critics of animal selves were the ones who first formu- ed into national legislation through- research challenged it from several lated the Three Rs concept. At the out the developed countries and perspectives. They argued variously dawn of the twenty-first century, this embraced by industry in Europe and that animal research was cruel and approach is proving to be a powerful America. Government centers devot- inhumane; unethical; and medically force in decreasing the use and dis- ed to the validation and regulatory unproductive, unnecessary, or even tress of animals in experimental biol- acceptance of alternative methods misleading. Their criticism largely ogy and medicine. 121 Table 1 Alternatives Chronology: 1876–1959 1876 Cruelty to Animals Act—the first law to specifically 1954 Universities Federation for Animal Welfare (UFAW) regulate animal experimentation—is enacted in establishes a committee to study humane techniques Great Britain. used in laboratory animal experiments. 1927 The LD50 Test is introduced to standardize the 1957 UFAW holds a symposium, “Humane Techniques in potency of digitalis extract. the Laboratory,” at which William Russell presents a paper, marking the first time the Three Rs of 1938 The Federal Food, Drug, and Cosmetic Act is enacted, replacement, reduction, and refinement are discussed marking the first time a U.S. government agency in public. is given the power to regulate consumer products. 1959 Russell and Burch’s study is published as The Principles 1944 Eye irritancy testing is standardized as the of Humane Experimental Technique, which develops Draize Test. the Three Rs approach at length. Estimates of the numbers of re- British experimental physiologist dur- emerge from the work of UFAW. search animals used annually in the ing the first half of the nineteenth UFAW published a handbook on the United States and worldwide are high- century, proposed five principles for care and management of laboratory ly speculative. The last official esti- animal experimentation that would animals (Worden 1947) that was well mate for the United States was 17 to eliminate unnecessary and repetitive received. This gave UFAW the confi- 22 million animals (U.S. Office of procedures and minimize suffering dence to address the more con- Technology Assessment 1986), but (Manuel 1987). Hall also recommend- tentious topic of experimental tech- that study was conducted more than ed the use of phylogenetically “lower,” niques involving animals (as distinct fifteen years ago. There is some evi- less sentient, animals and praised the from animal care). Accordingly, in dence that this estimate was made findings of a colleague who demon- 1954 Major Charles Hume (the during a period of declining animal strated that an animal that had just founder of UFAW and its director at use that began in the 1960s and been killed could be substituted for a the time) established a committee to continued into the ’90s (Rowan et living one, thereby eliminating pain. initiate a systematic examination of al. 1995). Consequently, the current figure could be lower. Worldwide Fifty years after Hall set out his the progress of humane technique in animal use was estimated to be five principles, a short-lived research the laboratory. Hume served as the between 60 and 85 million animals foundation—the Leigh Brown Trust— committee’s secretary, but it is note- in the early 1990s (Rowan 1995), was established to promote and worthy that the committee was but more conservative estimates of encourage scientific research without chaired by Peter Medawar, a well- rodent use suggest a total of 40 mil- inflicting pain on experimental ani- respected immunologist, and also lion animals worldwide (D. Kawahara, mals (French 1975). Although the included among its members William personal communication with A. Trust commissioned several publica- Lane-Petter, secretary of the Research Goldberg 1998). tions in the 1890s, it never succeeded Defence Society, an organization in developing a research program established to defend animal research. that convinced a significant propor- The committee employed William The 1950s: tion of the research community to Russell (a zoologist) and Rex Burch (a adopt its principles. From 1900 to microbiologist) to carry out the pro- The Three 1950, those who opposed the use of ject (Hume 1962). animals lost much of their political The exact origin of the Three Rs Rs Approach influence and were relegated to the concept is not entirely clear (Russell fringes of political activity. As a 1995). In a 1959 talk, Hume indicat- Launched result, little attention was paid to the ed that Russell was the originator The British scientists William Russell ethical questions posed by the use of of the “Three Rs” concept (Hume and Rex Burch formally launched the animals in research. 1962), while Russell (1995), in a ret- Three Rs with their book The Princi- After World War II, interest in the rospective paper entitled “The Devel- ples of Humane Experimental Tech- animal research issue began to grow opment of the Three Rs Concept,” nique (Russell and Burch 1959). How- again. In the United States, newly ever, hints of Russell and Burch’s credited Hume as our “inspiration and formed animal protection groups guide throughout.” In that paper Rus- ideas had appeared in earlier discus- began to criticize animal research sell recalled that the Three Rs concept sions about the appropriate use of practices. In England the Three Rs evolved sometime between the sum- animals in research. Marshall Hall, a concept of alternatives began to 122 The State of the Animals: 2001 Table 2 Alternatives Chronology: 1960 –1969 1962 Lawson Tait Trust (UK) is established—the first 1967 United Action for Animals is formed in the research fund to support the scientific development United States and later campaigns specifically of alternatives. for replacement alternatives. 1963 The first edition of The Guide for the Care and Use of 1969 The Fund for the Replacement of Animals in Laboratory Animals, written by the National Academy Medical Experiments (FRAME) is formed in the of Sciences, is published by the National Institutes United Kingdom to promote to the scientific of Health. community the idea of alternatives. 1965 Littlewood Committee Report (UK) concludes that 1969 Lord Dowding Fund (UK) is established to support little would be gained by paying special attention alternatives research. to alternatives. Sir Peter Medawar correctly predicts the subsequent worldwide decline in animal use. mer of 1955 and May 1957. The first examples of the lukewarm reaction to of animal research to medical ad- recorded mention of the Three Rs was the book within the scientific commu- vance and mentioned Russell and on May 7, 1957, at a meeting, nity. In Nature, a leading international Burch and the concept of the Three “Humane Technique in the Laborato- science journal based in England, Rs only once, in a final chapter. He ry,” organized by UFAW and chaired by Weatherall (1959) commented: noted that distinguished scientists at Medawar. Russell (1957) gave a pre- [It] is useful to have a résumé a UFAW meeting sentation at this meeting in which he of ways which have already been discussed, among other things, described the Three Rs. A brief pro- adopted to make experimentation how the numbers of laboratory ceedings (Anonymous 1957) was pub- as humane as possible…[but the animals used, and the numbers of lished later that year by the Laborato- book] is not sufficiently informa- experiments done on them, could ry Animals Bureau of the Medical tive to be used as guide either to be reduced, how their welfare details of experimental design or could be improved, how the tech- Research Council.