THE THREE Rs DECLARATION OF BOLOGNA

Reduction, Refinement and Replacement
Alternatives and Laboratory Animal Procedures

Adopted by the 3rd World Congress on Alternatives and Animal Use in the Life Sciences, Bologna, Italy, on 31 August 1999

The "Three Rs" of Russell and Burch, reduction, refinement and replacement, had their origin in a project initiated in 1954 by the Universities Federation for Animal Welfare (UFAW), which led to the publication in 1959 of The Principles of Humane Experimental Technique, by W.M.S. Russell and R.L. Burch (1). In 1978, David Smyth used the word alternatives to define the Three Rs (2).

In their book, Russell and Burch stated that "The greatest scientific achievements have always been the most humane and the most aesthetically attractive, conveying that sense of beauty and elegance which is the essence of science at its most successful". They defined:

Reduction alternatives as methods for obtaining comparable levels of information from the use of fewer animals in scientific procedures, or for obtaining more information from the same number of animals.

Refinement alternatives as methods which alleviate or minimise potential pain, suffering and distress, and which enhance animal well-being.

Replacement alternatives as methods which permit a given purpose to be achieved without conducting experiments or other scientific procedures on animals.

  1. Russell, W.M.S. and Burch, R.L. (1959). The Principles of Humane Experimental Technique. 239pp. London, UK: Methuen.
  2. Smyth, D. (1978). Alternatives to Animal Experiments. 218pp. London, UK: Scolar Press.

The participants in the 3rd World Congress on Alternatives and Animal Use in the Life Sciences strongly endorse and reaffirm the principles put forward by Russell and Burch in 1959. Humane science is a prerequisite for good science, and is best achieved in relation to laboratory animal procedures by the vigorous promotion and application of the Three RS The "Three Rs" should serve as a unifying concept, a challenge, and an opportunity for reaping benefits of every kind -- scientific, economic and humanitarian.

Background to the Three Rs Declaration of Bologna, as adopted by the 3rd World Congress on Alternatives and Animal Use in the Life Sciences, Bologna, Italy, on 31 August 1999

Prepared by the Executive Committee of the Congress

Introduction

Laboratory animal procedures have made significant contributions to biomedical research in the past, as well as to the safety and efficacy evaluation of chemicals and products of various kinds. Some such use of vertebrate animals will continue for the foreseeable future, in the interests of human beings and other animals.

 

The origins of the Three Rs concept

What are now known as the Three Rs of Russell and Burch, namely, reduction, refinement and replacement, had their origin in a project initiated in 1954 by the Universities Federation for Animal Welfare (UFAW), which led to the publication in 1959 of The Principles of Humane Experimental Technique, by W.M.S. Russell and R.L. Burch [1].

Russell and Burch defined reduction as a means of lowering "the number of animals used to obtain information of a given amount and precision", refinement as any development leading to a "decrease in the incidence or severity of inhumane procedures applied to those animals which have to be used", and replacement as "any scientific method employing non-sentient material which may in the history of animal experimentation replace methods which use conscious living vertebrates". They summed up their main message, as follows:

"If we are to use a criterion for choosing experiments to perform, the criterion of humanity is the best we could possibly invent.

"The greatest scientific achievements have always been the most humane and the most aesthetically attractive, conveying that sense of beauty and elegance which is the essence of science at its most successful."

 

The acceptance of the Three Rs concept

Relatively little attention was paid to the Three Rs concept during the 1960s, but a number of significant developments took place during the 1970s, including the publication of a survey of Alternatives to Animal Experiments, conducted for the Research Defence Society by Professor David Smyth, in which he provided a Three RS definition of alternatives [2]:

"All procedures which can completely replace the need for animal experiments, reduce the number of animals required, or diminish the amount of pain or distress suffered by animals in meeting the essential needs of man and other animals."

The 1980s saw the introduction of a number of national and international laws and conventions with a Three RS basis, notably, in Europe, the Council of Europe Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes [3] and Council Directive 86/609/EEC of 24 November 1986 on the Approximation of Laws, Regulations and Administrative Provisions of the Member States Regarding the Protection of Animals Used for Experimental and Other Scientific Purposes [4].

Also in 1986, a report by the US Congress Office of Technology Assessment on Alternatives to Animal Use in Research, Testing and Education [5] provided detailed evidence of the broad scope and potential value of the Three RS concept of alternatives, while in 1985, the Council of International Organisations in the Medical Sciences (CIOMS) published a set of International Guiding Principles for Biomedical Research Involving Animals [6].

 

The Three Rs concept today

By the end of the 1980s, new laws and guidelines were in place in various parts of the world, which not only recognised Russell and Burch's concept, but placed legal and moral obligations on all concerned, to seek to reduce, refine and/or replace laboratory animal procedures wherever possible.

Much will have been achieved by the end of the 1990s, but, for some time to come, securing the universal implementation of the Three Rs concept will remain a major challenge confronting all those who are in any way involved in the use of laboratory animals in research, testing and education.

The 1st and 2nd World Congresses on Alternatives and Animal Use in the Life Sciences were held in Baltimore, USA, in 1993, and in Utrecht, The Netherlands, in 1996. The Executive Committee for the 3rd World Congress will put this Declaration before participants in the Congress, in Bologna, Italy, on 31 August 1999, in a year which marked the fortieth anniversary of the publication of The Principles of Humane Experimental Technique. The Declaration is based on the conclusions and recommendations of The Three Rs: The Way Forward, a workshop held in Sheringham, UK, on 30 May to 3 June 1995, under the auspices of the European Centre for the Validation of Alternative Methods (ECVAM) and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) [7].

 

Main conclusions and recommendations of the Sheringham Workshop

Legal controls, and scientific and ethical justification

  1. All countries should have a legal framework which actively incorporates the Three Rs into all animal-based research, testing and education.
  2. There should be formal and informal mechanisms for the education and training of all scientists and officials involved in any way in animal experimentation, to ensure compliance with the spirit and letter of laboratory animal protection legislation, guidelines and regulations.
  3. Any proposed experiments should be subjected to prior and effective expert and independent review, for both scientific and animal welfare considerations.
  4. It should be recognised that the assessment and weighing of the likely benefit and likely animal suffering involved in a proposed programme of work are essential parts of the review process whereby permission for the work to proceed is/is not granted.
  5. There should be international agreement on levels of animal suffering which should not be permitted in any circumstances, regardless of any potential or likely benefits.
  6. It should be regarded as unacceptable for scientific work involving laboratory animals to be exported to other countries, as a means of avoiding scientifically realistic, but more stringent, controls on laboratory animal studies.

Reduction alternatives

  1. The term reduction alternatives describes methods for obtaining comparable levels of information from the use of fewer animals in scientific procedures, or for obtaining more information from the same number of animals.
  2. In cases where a choice between species is possible, there is generally no scientific justification for using more of the smaller species than of the larger one.
  3. The design of regulatory testing procedures, including the sample sizes required, should be reviewed regularly, as part of a continuous international harmonisation process.
  4. All research workers should have adequate training in experimental design and in the proper use of statistical methods.

Refinement alternatives

  1. Refinement alternatives encompass those methods which alleviate or minimise potential pain and distress, and which enhance animal well-being. Pain results from potential or actual tissue damage, such as that caused by injury, surgery or disease, and can lead to distress. Distress is an aversive state, in which an animal is unable to adapt completely to stressors and the resulting stress. Suffering is a generic term for "undergoing, experiencing or being subject to pain, distress and/or lasting harm".
  2. There should be internationally agreed guidelines for the categorisation of animal pain, distress and other adverse effects, including agreement on physiological and behavioural signs for the recognition of adverse effects and for their measurement.
  3. Individuals and institutions should be responsible to their national authorities for prospective and retrospective assessments of the nature and levels of adverse effects likely to be experienced and actually experienced by the animals used in each programme of work.
  4. Research on refinement and animal welfare should be encouraged and funded, including studies on the effects of procedures aimed at minimising pain and distress on the quality of data produced.

Replacement alternatives

  1. Replacement alternatives are methods which permit a given purpose to be achieved without conducting experiments or other scientific procedures on animals.
  2. The range of replacement alternative approaches includes:
    • the improved storage, exchange and use of information from animal experiments already carried out, so that unnecessary repetition can be avoided;
    • the use of physical and chemical techniques, and of predictions based on the physical and chemical properties of molecules;
    • the use of mathematical and computer modelling, including modelling of structure-activity relationships, molecular modelling and the use of computer graphics, and modelling of biochemical, pharmacological, physiological, toxicological and behavioural processes;
    • the use of "lower" organisms with limited sentience (for example, invertebrate animals, plants and microorganisms);
    • the use of early developmental stages of vertebrates, before they reach the point at which their use for experimental and other scientific purposes is controlled;
    • the use of in vitro methods, including the short-term maintenance of perfused organs, tissue slices and cell suspensions, and cell and tissue culture proper. For most in vitro studies, human cells and tissues should be used in preference to those isolated from laboratory animals, provided that the unavoidable ethical, legal and safety considerations have been fully satisfied; and
    • human studies, including epidemiology, post-marketing surveillance, and the ethically approved use of human volunteers.
  3. In the case of regulatory efficacy, safety and toxicity testing, research specifically aimed at providing validated replacement alternative procedures should be encouraged and funded.
  4. Ideally, the development of replacement alternative methods should be based on a sufficient understanding of the molecular and cellular mechanistic basis of the phenomenon being measured or studied.
  5. Since it is likely that, in many circumstances, an animal test could not be replaced by a single replacement alternative method, the development, evaluation and optimisation of stepwise testing strategies and integrated testing schemes should be encouraged.
  6. The acceptance and use of a satisfactorily validated replacement alternative method, and the cessation of use of the equivalent animal procedure, should not be seen as options, but as requirements.

Education and training

  1. A clear distinction should be made between education, which aims to contribute to the development of proper attitudes toward the use of animals and alternatives, and training, which aims to contribute to the proper care and use of animals and to ensuring that experiments are of the highest quality.
  2. The responsible authorities should require all those with any practical involvement in laboratory animal work to take accredited courses, with emphasis on the Three Rs and on the legal obligation to use replacement alternative methods wherever possible.
  3. School, college and undergraduate university students should not be forced to conduct regulated procedures, but should be provided with alternative options.

 

Concluding statement

The participants in the 3rd World Congress on Alternatives and Animal Use in the Life Sciences will be invited to endorse the principles put forward by Russell and Burch in 1959 [1], and thereby to reaffirm that only humane science is good science, which is best achieved by vigorous promotion and application of the Three Rs (reduction, refinement and replacement alternatives).

The only acceptable animal experiment is one which has been approved by an ethical review committee, uses the smallest possible number of animals, and causes the least possible suffering which is consistent with the achievement of its scientific purpose.

The Three Rs should be seen as a unifying concept, and as a challenge and an opportunity for reaping benefits of every kind -- scientific, economic and humanitarian.

 

References

  1. Russell WMS, Burch RL. The Principles of Humane Experimental Technique. London: Methuen, 1959, 238 pp.
  2. Smyth D. Alternatives to Animal Experiments. London: Scolar Press, 1978, 218 pp.
  3. Council of Europe. European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes. Strasbourg. France: Council of Europe, 1986.
  4. EEC. Council Directive of 24 November 1986 on the Approximation of Laws, Regulations and Administrative Provisions of the Member States Regarding the Protection of Animals Used for Experimental and Other Scientific Purposes. Official Joumal of the European Communities 1986;L358:1-29.
  5. US Congress. Alternatives to Animal Use in Research,Testing and Education. Washington, DC: US Congress Office of Technology Assessment, 1986.

 

 


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