Principles Of Humane Experimental Technique Research Articles

The Evolution of the Three Rs

Whilst the whole world is celebrating the bicentenary of the birth of Charles Darwin and the 150th anniversary of the publication of his renowned book, The Origin of Species, another anniversary should not be forgotten - the publication of The Principles of Humane Experimental Technique by W.M.S. Russell and R.L. Burch. The concomitance of the anniversaries of the two publications is not a coincidence, since, as reflected by the numerous quotes chosen by Russell from Darwin's masterpiece, numerous analogies can be found between the two works and the new ideas they describe. From a discrete birth, and after decades of struggle, the Three Rs concept can now celebrate its 50th anniversary, the result of its evolution through harsh selection and adaptation. The emergence of new types of techniques, in combination with the descent of modified old ones, testify to the undeniable change in our society toward a more efficient and more ethical science, through the progressive replacement of animal models. Both Darwin and Russell would no doubt have welcomed such progress, not only in terms of science, but also of moral values. One could also expect that, if Russell could have foreseen the incredible technological advances achieved 50 years later, where Replacement becomes a reality, as illustrated by some edifying examples, The Principles of Humane Experimental Technique would have probably been defined as the One R concept.

The Origins and Early Days of the Three Rs Concept

Some questions are answered concerning the origins of the Three Rs (Replacement, Reduction, Refinement) concept in relation to animal experimentation, expounded 50 years ago by Russell and Burch in The Principles of Humane Experimental Technique, by reference to some key publications and to correspondence in the W.M.S. and Claire Russell Archive, which is currently being established at the University of Nottingham. Some insight is also given into the relationship between Russell and Burch, the first use of "alternatives" in the Three Rs context, and the background to the publication of the book.

International Outcry Follows Attacks on Neuroscientist's Home

International Outcry Follows Attacks on Neuroscientist's Home

Toxicogenomics in Drug Safety Assessment

PharmacogenomicsVol. 9, No. 4 Conference SceneToxicogenomics in drug safety assessmentPhilip Hewitt & Alexandra WalijewPhilip Hewitt† Author for correspondenceeTox, Institute of Toxicology, Merck Serono Research, Frankfurterstrasse 250, 64293 Darmstadt, Germany. Search for more papers by this authorEmail the corresponding author at philip.hewitt@merck.de & Alexandra WalijeweTox, Institute of Toxicology, Merck Serono Research, Frankfurterstrasse 250, 64293 Darmstadt, Germany. Search for more papers by this authorEmail the corresponding author at philip.hewitt@merck.dePublished Online:2 Apr 2008https://doi.org/10.2217/14622416.9.4.379AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleBibliography1 MAQC consortium: The MicroArray Quality Control (MAQC) project shows inter- and intra-platform reproducibility of gene expression measurements. Nat. Biotechnol.24,1151–1161 (2006).Crossref, Medline, Google Scholar2 Pennie W, Pettit SD, Lord PG: Toxicogenomics in risk assessment: an overview of an HESI collaborative research program. Environ. Health Perspect.112,417–419 (2004). Crossref, Medline, Google Scholar3 Russell WMS, Burch RL: The principles of humane experimental technique. Methuen, London, UK (1959).Google Scholar4 Kruetzfeldt J, Rajewsky N, Braich R et al.: Silencing of microRNAs in vivo with ‘antagomirs’. Nature438(7068),685–689 (2005).Crossref, Medline, CAS, Google Scholar5 Thum T, Galuppo P, Wolf C et al.: MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation116(3),258–267 (2007).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByMetabolism Comparative Cytotoxicity Assay (MCCA) and Cytotoxic Metabolic Pathway Identification Assay (CMPIA) with cryopreserved human hepatocytes for the evaluation of metabolism-based cytotoxicity in vitro: Proof-of-concept study with aflatoxin B1Chemico-Biological Interactions, Vol. 179, No. 1 Vol. 9, No. 4 Follow us on social media for the latest updates Metrics Downloaded 235 times History Published online 2 April 2008 Published in print April 2008 Information© Future Medicine LtdAcknowledgementsI would like to thank Gregor Tuschl for his assistance during the meeting and for taking (more) detailed notes.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, royalties.No writing assistance was utilized in the production of this manuscript.PDF download

The ethics of the Three Rs principle: a reconsideration

AbstractIn the past decades the Three Rs concept, famously launched by Russell and Burch in their 1959 bookThe Principles of Humane Experimental Technique, has gained a prominent place in the landscape of societal and ethical concern about animal use. Important scientific and institutional initiatives have been taken in order to promote replacement, reduction and refinement. It appears, however, that conceptual and ethical thinking about the presuppositions and changing contexts of the Three Rs concept has lagged behind the scientific and practical efforts. In this paper, first, I argue that there is a threefold argument to make for the need to reconsider the moral basis of the Three Rs concept. Second, I outline a number of standard assumptions of the traditional approach to the Three Rs and question the tenability of these assumptions. Third, I propose some elements of a new framework for the Three Rs principle and connect this to a number of developments in science and society. I conclude with four remarks on the future of the ethics of the Three Rs principle.

Trends in Animal Use and Animal Alternatives

The Third World Congress (1999, Bologna) celebrated the fortieth anniversary of the publication of Russell & Burch's The Principles of Humane Experimental Technique. There was the general notion that the Three Rs offer a unifying concept that contributes to a progressive reduction and refinement in animal use without compromising the quality of research, human health or the protection of the environment. The Bologna Three Rs Declaration was accepted unanimously, calling upon all parties involved to incorporate the Three Rs into animal-based research. The question is raised, what progress has been made and, in particular, what are the developments in animal use and in the implementation of validated alternative methods. For the present contribution, we requested colleagues from European countries, Canada and the United States to provide information on the numbers of animals currently used for scientific purposes, on the development and implementation of alternative methods and on future perspectives about the issues. Based on the results of this survey, the conclusion is reached that legislative regulations are widely implemented and have become rather strict during the last decade. An exception here is the legislative regulation for rats, mice and birds in the USA. These species are not (yet) protected by the US Animal Welfare Act. The number of animals used has decreased considerably, and the review of protocols by animal ethics committees has become a significant trend. In all countries, there is growing support for the Three Rs concept.

Searching for information on replacements to the use of animals in research

Russell and Burch's ‘3Rs’ principles of humane experimental technique - replacement, reduction and refinement - have been accepted widely throughout the world. Researchers generally recognize the need for a thorough search for, and wherever possible use of, alternatives to using live animals. Evidence that such searches have been undertaken is expected by ethical committees responsible for judging applications for research, and is required by law in the UK and some other countries. As written in the UK Animals (Scientific Procedures) Act 1986, ‘the Secretary of State shall not grant a licence unless he is satisfied (a) that the purpose of the programme to be specified in the licence cannot be achieved by any other reasonably practical method not entailing the use of animals … ‘. There have been developments in many fields of science in finding alternatives to the use of animals and a great deal ofinformation has been published on the subject. However, this information is scattered widely in the scientific literature and because of this, and the relative scarcity of good reviews, searching for information on alternatives in particular fields can be difficult. The world wide web now provides the potential for obtaining information on almost any subject very rapidly but the value of this remarkable resource is, as all of us have come to discover, limited by the capacities of the available machinery for searching and finding. The ‘web’ is like a colossal encyclopaedia with entries of very variable quality and a misleading and fragmentary index. Considerable efforts are being made by a variety of organisations to develop improved methods for extracting reliable and complete information on 3Rs alternatives and this book published by FRAME (see below) is a very useful review.

The Three Rs and Biomedical Research

The authors are at the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), Johns Hopkins School of Public Health, 111 Market Place, Suite 840, Baltimore, MD 21202-6709, USA. E-mail: caat@caat.spharbor.jhu.edu In 1959, British scientists William M. S. Russell and Rex L. Burch wrote that scientific excellence and humane use of laboratory animals are inextricably linked. In The Principles of Humane Experimental Technique,* they described the “three Rs”—reduction, refinement, and replacement—of animal use in the life sciences, concepts now known as “alternatives.” Legislation mandating the incorporation of the three Rs into animal research and testing has been passed in the United States and Europe. Because some scientists view discussion of alternatives as driven exclusively by political and social forces rather than by scientific considerations, an international group of scientists prominent in the alternatives field met at a May 1995 workshop to reaffirm the scientific basis of the three Rs and to discuss how these concepts can best be disseminated to the scientific community.† Published surveys of the scientific literature have found inefficient use of animals due to poor experimental design or inappropriate statistical analysis of results or both. Reduction alternatives allow comparable amounts of data to be obtained from fewer animals or more information to be obtained from a given number of animals. The number of animals used should be the minimum necessary to test the experimental hypothesis and give statistically usable results. Refinement alternatives are methods that eliminate or minimize pain and distress or enhance animal well-being. Assessments of animal pain and distress are currently based on subjective evaluation of abnormal behavior and appearance. Because proper evaluation of pain relies largely on the ability to understand the behavior and needs of each species of laboratory animal, it is best for investigators to assume that a procedure that inflicts pain and distress on humans will inflict pain and distress on animals. Much pain and distress can be diminished or eliminated with the proper use of anesthetics and analgesics. Researchers can enhance animals9 well-being by using environmental enrichment techniques, such as proper handling, appropriately sized cages, and group housing of social species. Replacement alternatives are methods that use organisms with limited sentience or that do not use whole animals. They include improved information exchange to avoid unnecessary repetition of animal experiments; physicochemical techniques and structure-activity relations; mathematical and computer models; use of invertebrates, plants, and microorganisms; in vitro methods; and human studies, including the use of human volunteers, postmarketing surveys, and epidemiology. In the biomedical sciences, in vitro methods are increasingly being used, not because they provide precisely the same information as do animal studies but because they offer the best scientific approach. Such methods often use results from past animal studies as a basis for cellular and molecular investigations. Successful implementation of the three Rs requires that scientists and technicians be formally trained to scientifically and ethically evaluate the use of laboratory animals and to perform animal experiments that meet the highest scientific and animal welfare standards. Coursework should be included in graduate training programs and should focus on strengthening the principles of experimental design and teaching competence in animal handling, how to make ethical decisions about using animals in experiments, and how to find alternative methods. As the participants at the workshop concluded, present and future scientists should be encouraged to view the three Rs as an intellectual challenge and an opportunity to enhance the scientific, economic, and ethical value of their research.

Responsible Animal Research: A Riff of Rs

The Three Rs, reduction, refinement and replacement, were introduced in 1959 by Russell & Burch in their important publication The Principles of Humane Experimental Technique. These Three Rs are now collectively referred to as alternatives. Using the letter R, we have developed an expanded list of Rs not only to stimulate our own thinking, but to encourage others to examine the issue of alternatives in animal research.

Reduction in Animal Use 35 Years after Russell & Burch's Principles of Humane Experimental Technique

“Reduction” in animal use can be achieved by better experimental strategy and improved experimental design. In 1959, one strategy for discovering new drugs involved the random testing of thousands of chemicals in animal models of disease. This strategy was deplored by Russell & Burch in The Principles of Humane Experimental Technique (1959) as being inefficient and inhumane, and has now been almost completely superseded, following fundamental research resulting in an improved understanding of the mechanisms of drug action. Random screening is still done on a large scale, but by using in vitro methods. Good experimental design involves the control of variation. In 1959, it was not clear whether isogenic (inbred or F1 hybrid) strains of mice and rats were more uniform than outbred stocks and whether they should therefore be used preferentially in bioassays. It is now generally accepted that F1 hybrids and inbred strains tend to be more uniform, but, as precision also depends on sensitivity, which is unpredictable, there is no general rule for choosing the best strain for a bioassay. Choice should be based on pilot studies. However, the use of more-uniform, specific pathogen-free animals, which were only just becoming available in 1959, has certainly reduced the number of animals which are used. Other aspects of experimental design, such as the need to avoid bias, have a wide range of applicability; the importance of simplicity and the ability to calculate uncertainty are, apparently, not always appreciated by research scientists. The concept of “reduction” has been useful in focusing attention on the need for improved experimental design. In the long-run, animal welfare legislation and improved training for research scientists should lead to improvements, not only in the way in which animals are kept, but also in the way in which experiments are planned and analysed.

Book Review: The Principles of Humane Experimental Technique

Book Review: The Principles of Humane Experimental Technique

Use of animals in experimental research: a scientist's perspective.

The present article was written as an attempt to understand the position of animal rights groups, to stimulate scientists to define their own positions, and to encourage scientists to interpret their use of animals to the rest of society. The article attempts to generate a statement of practices that might be useful in experiments that utilize animals in research. The statement is an extension of the three R's originally proposed by Russell and Burch (W.M.S. Russell and R.L. Burch [1959]: Principles of Humane Experimental Technique, Springfield, IL, Charles C. Thomas) into four R's: refinement, reduction, replacement, and review.

Reviews

Vistas in Botany. Edited by W. B. Turrill Practical Botany for the Tropics. By W. O. Howarth and L. G. G. Warne Perspectives in Virology. Edited by M. Pollard Progress in Biochemistry since 1949. By F. Haurowitz Biochemistry of Antibiotics (Edited by K. H. Spitzy and R. Brunner), and Biochemistry of Morphogenesis (Edited by W. J. Nickerson) Cell, Organism and Milieu. (17th Symposium of the Society for the Study of Development and Growth, 1958.) Edited by D. Rudnick A Symposium on Molecular Biology, 1956–7. Edited by R. E. Zirkle Plant Nematology. Edited by J. F. Southey Plant Growth Substances. By L. J. AudusMüller, P. (general editor): DDT, the Insecticide Dichloro‐Diphenyltrichloroethane and its Significance. Vol. 1. Ed. by Paul MüllerMüller, P. (general editor): DDT, the Insecticide Dichloro‐Diphenyltrichloroethane and its Significance. Vol. 11. Ed. by S. W. Simmons Statistical Methods in Biology. By N. T. J. Bailey. Elementary Statistics, with Applications in Medicine and the Biological Sciences. By F. E. Croxton Subcellular Particles. (5th Annual Symposium publication of the Society of General Physiologists in America.) Edited by Teru Hayashi Comparative morphology of Vascular Plants. By Adriance S. Foster and Ernest M. Gifford, Jr., 555 Breeding Field Crops. By J. M. Poehlman Rice. By J. H. Grist (3rd edition) Principles of General Physiology. Vol. 1: The Physico‐Chemical Background. By L. E. Bayliss. Evolution of Nervous Control from Primitive Organisms to Man. Edited by Allan D. Bass The Principles of Humane Experimental Technique. By W. M. S. Russell and R. L. Burch Photoperiodism and Related Phenomena in Plants and Animals. Editor Robert B. Withrow The Scientific Principles of Crop Protection. By Hubert Martin British Parasitic Fungi. By W. C. Moore Blakeslee: the genus Datura. By A. G. Avery, S. Satina and J. Rietsema