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Developments on the implementation of the Three Rs in research and education
Toxicology in Vitro 15 (2001) 591–595 www.elsevier.com/locate/toxinvit
Developments on the implementation of the Three Rs in research and education L.F.M. van Zutphena,*, J.B.F. van der Valkb a Department of Laboratory Animal Science, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands Netherlands Centre for Alternatives to Animal Use, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
b
Abstract More than 40 years ago, Russell and Burch published their views on the implementation of the ‘Three Rs’ in animal experimentation. Since then, much has been achieved in this area. Recently, the European Science Foundation (ESF) has made a further step forward. In a position paper on the use of animals, ESF has formulated what it sees as prerequisites for the humane use of animals in research, testing and education. In this paper, we briefly report on these ESF guidelines. Also, an overview is presented on European legislative regulations for the (ethical) review of research protocols and for the education and training of persons involved in animal experiments. The great diversity between countries is illustrated with some examples and the need for harmonization is emphasised. The paper ends by highlighting the special role that editorial boards of journals can play in the further implementation of the Three Rs. # 2001 Elsevier Science Ltd. All rights reserved. Keywords: European Science Foundation (ESF); ESF guidelines; Animal ethics committees; Education
1. Introduction It is now generally accepted that animal alternatives are defined by the Three Rs, as elaborated by Russell and Burch (1959) in their book The Principles of Humane Experimental Technique. They have outlined the conditions that must be met when an experiment on live animals is considered and wrote in the Introduction: ‘‘We cannot do more than pick up a few trails for others to follow.’’ Their trails proved to be attractive and many have followed the signs and have explored new trails, using the Three Rs as their guide. During the last decades, much has been achieved in the fields of replacement, reduction and refinement of animal experiments, but nevertheless, there is still a long way to go. The further development and validation of Three Rs alternatives require input from many different disciplines. Their acceptance and implementation also depends heavily on the attitude of the persons involved in animal experimentation. In this paper, we describe some of the initiatives and developments that are relevant for the implementation of alternatives in Europe. * Corresponding author. Tel.: +31-30-253-2033; fax +31-30-2537997. E-mail address: [email protected] (L.F.M. van Zutphen).
We will focus on the position paper on the use of animals in research that has recently been prepared by the European Science Foundation and on developments regarding animal ethics committees, education and the policies of scientific journals. All three could have a major impact on the implementation of the Three Rs.
2. European Science Foundation (ESF) guidelines on animal use ESF is the European association of national organisations responsible for the support of scientific research. ESF is an influencing organisation, comprising 67 leading national science-funding agencies (e.g. research councils, academies of science) in 23 European countries. In 1999, the board of ESF established the ‘‘Expert Group on Biology and Society’’. One of the tasks of this Expert Group was to prepare for ESF a position paper on the use of animals in research. This document has recently been published (ESF, 2000; see also http:// www.esf.org). It contains guidelines and recommendations for the ethical use of animals in research. The main aspects covered by the guidelines of the position paper are the following:
0887-2333/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0887-2333(01)00065-0
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. ESF recognises that laboratory animals not only have an instrumental value, but also an intrinsic value (value in themselves) which must be respected; . While accepting the need of animal use for the advancement of scientific knowledge, and for promoting human and animal health and their wellbeing, ESF strongly endorses the principles of the Three Rs; . Research aiming at improving the welfare of animals should be encouraged and actively supported by ESF Member Organisations; . Prior to the performance of a programme of research, animal use should be subjected to independent expert review, for both scientific and animal welfare considerations. The assessment and weighing of the likely benefit and likely animal suffering should be an essential part of the review process; . Investigators should assume that procedures that would cause pain in humans also cause pain in other vertebrates, unless there is evidence to the contrary; . Investigators and other personnel involved in the design and performance of animal-based experiments should be adequately educated and trained. ESF Member Organisations should encourage the development and organisation of accredited courses on laboratory animal science, including information on animal alternatives, welfare and ethics; . ESF encourages the editorial board of journals publishing the results of animal-based research to include in the ‘‘instructions to authors’’ a statement on the ethical use of animals. The contents of this document clearly illustrate that the leading science organisations in Europe have chosen to endorse fully the Three Rs and to give high priority to aspects concerning animal welfare. The ESF guidelines can be considered, at least in part, as a reinforcement of developments, which have already been started in several countries but did not always receive full support of the scientific community. For the implementation of the Three Rs alternatives, the evaluation of protocols by animal ethics committees and the education and training in laboratory animal science are of particular importance. In the following paragraphs information on the requirements and the developments on these issues in Europe will be presented. Also, the Three Rs policy of journals publishing animal-based results will briefly be discussed.
3. Animal ethics committees In Section 12.1 of the ‘‘Council Directive on the protection of animals used for experimental and other scientific
purposes’’ (Directive 86/609/EEC, European Commission, 1986) it is indicated that ‘‘Member States shall establish procedures whereby experiments (. . .) shall be notified in advance to the authority’’. Section 12.2 states that ‘‘Where it is planned to subject an animal to an experiment in which it will, or may, experience severe pain which is likely to be prolonged, that experiment must be specifically declared and justified to, or specifically authorised by, the authority. The authority shall take appropriate judicial or administrative action if it is not satisfied that the experiment is of sufficient importance for meeting the essential needs of man or animal’’. These provisions have been the impetus for some EU member states to include into their national law the requirement that animal experiment protocols must be evaluated by a competent authority, usually an animal ethics committee, prior to the conduct of the experiment. de Greeve and de Leeuw (1999) have recently reviewed the situation on the implementation of the above-mentioned provisions in the Directive 86/609/ EEC. They concluded that in Sweden, Germany and the Netherlands, an experiment cannot begin unless there is a positive advice from a local or regional animal ethics committee. These committees evaluate research protocols on ethical and animal welfare bases. An experiment cannot be performed if, according to the judgement of the committee, the potential benefit does not outweigh the likely suffering of the animal(s) involved. In Finland, local committees on animal experimentation have the task of deciding on the degree of suffering involved in the experiment. If it is estimated that the experiments might cause severe suffering, the committee is not allowed to give it a licence, but must send the application to the Provincial State Office, that has the authority to grant a licence for such experiments. In Switzerland, any experiment with animals is subject to authorization by the cantonal authorities. Each canton appoints a committee of specialists for animal experiments that examines the proposal and offers advice to the authority entitled to authorise the experiment. The advice covers the supervision of the housing of the experimental animals as well as the conduct of the experiments. In the UK, licenses are granted by the Home Office. The Secretary of State requires that all designated scientific procedure establishments have a local ethical review process in place. There is no specific section in the law requiring that a protocol must be submitted to a (local) animal ethics committee. This is also not the case in several other European countries, for example, France, Italy and Norway, but this does not mean that in those countries there is no ethical evaluation prior to the conduct of the experiment. In the UK, there are over 250 designated establishments with some form of ethical review. In France many institutions have set up their own committees.
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Apart from the legal requirements, some granting bodies also require the advice of an animal ethics committee when a proposal, entailing the use of experimental animals, is submitted. Animal ethics committees often have an explicit role in stimulating the implementation of the Three Rs. Section 7.2 of Directive 86/609/EEC (European Commission, 1986) deals with replacement where it states that ‘‘An experiment should not be performed if another scientifically satisfactory method of obtaining the result sought, not entailing the use of an animal, is reasonably and practically available’’. In Section 7.3, requirements for the implementation of reduction and refinement procedures are covered: ‘‘When an experiment has to be performed, the choice of the species shall be carefully considered and, where necessary, explained to the authority. In a choice between experiments, those which use the minimum number of animals, involve animals with the lowest degree of neuro-physiological sensitivity, cause the least pain, suffering, distress or lasting harm and which are most likely to provide satisfactory results shall be selected’’. Protocols submitted to animal ethics committees should not only contain the information needed for weighing the potential benefit versus the animal’s suffering, but also for evaluating the question on how the requirements of Sections 7.2 and 7.3 have been addressed. This implies that the ethical evaluation is performed at the level of projects rather than programmes, and is thus preferably performed by local (or regional) committees, rather than by a national committee. In order to promote the implementation of the Three Rs through the ethical review of protocols, it is a prerequisite that the committee members are unbiased and competent. Most animal ethics committees are composed of persons with different expertise with respect to animal experimentation. Often laypersons or persons from outside the research institute are also members of the committee. Several authors have emphasised the importance of organizing training courses for members of animal ethics committees (de Cock Buning, 1997; Johnston and Rusche, 1997; de Greeve and de Leeuw, 1999). It might be of interest to give some details here on how in the Netherlands the ethical evaluation of animal experiments is organised. In most institutions where animal experiments are performed, an animal ethics committee was established more than 15 years ago. However, a legal basis for these committees was not provided until 1997, as a revision of the Dutch Experiments on Animals Act. Section 10 now states that: ‘‘No experiment on animals may be conducted unless (....) a recommendation has been made by an ethical review committee (....)’’. The committee must assess ‘‘whether the benefit of the experiment outweighs the animal’s suffering’’ and ‘‘whether or not the results can be achieved by means other than an animal experiment, or
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by means of an experiment using fewer animals or entailing less distress than described in the proposed protocol’’. Other aspects that must be assessed by the members of the committee are the competence of the persons involved in the experiment, the origin of the animals, and their housing and care. The animal ethics committee consists of at least seven members, with experts in the field of animal experiments, animal alternatives, animal welfare and ethics. At least two of these experts must not be involved in the conduct of animal experiments. Furthermore, the chairperson and two members must not be employed by the institute applying the protocol for review. There are now 29 committees, working for a total of 86 institutes (licence holders). Once per year, a 1-day training course is organised for members of these committees. Each year the committee must report to the Minister of Public Health.
4. Education, training and competence Persons involved in the design and conduct of animal experiments must be specifically educated and adequately trained. This is essential, both for the quality of experiments and for the welfare of animals (Balls et al., 1995). There are several sections dealing with competence in Directive 86/609/EEC: . Experiments shall be performed solely by competent authorised persons, or under the direct responsibility of such a person (Article 7.1); . Persons who carry out experiments or take part in them, and persons who take care of animals used for experiments, including duties of supervisory nature, shall have appropriate education and training. In particular, persons carrying out or supervising the conduct of experiments shall have received instruction in a scientific discipline relevant to the experimental work being undertaken and be capable of handling and taking care of laboratory animals; they shall also have satisfied the authority that they have attained a level of training sufficient for carrying out their tasks (Article 14); . In each user establishment sufficient trained staff shall be provided. A veterinarian or other competent person shall be charged with advisory duties in relation to the well being of the animals (Article 19 b, d).
The provisions on education and training in national laws of EU member states must be in line with the Directive 86/609/EEC. There is, however, a problem here. Although the objectives of the provisions on competence, as formulated in the Directive, are clear, there is still much room for interpretation when it comes to a
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practical implementation. In an attempt to harmonise the requirements on education and training at the European level, the Council of Europe (CoE, 1994), in collaboration with the Federation of European Laboratory Animal Science Associations (FELASA, 1995), has worked out the provisions in more detail. Four categories of persons, where appropriate education and training is considered essential, are distinguished: A. Persons taking care of animals Programmes in this category should include basic instruction in ethics and legal aspects of the care of laboratory animals; animal handling and husbandry; recognition of health and disease; recognition of pain, suffering and distress; (local) practices for security, administration, transport, receipt of animals and supplies; and the disposal of animals. Programmes should also include training for tasks supporting performance of specific experimental procedures. B. Persons carrying out procedures Programmes in this category should include all aspects in Category A and, in addition, some detailed knowledge of the anatomy, physiology and behaviour of animal species, breeds and strains; implications of the microbiological status of animals; practical aspects of health monitoring; experimental techniques and surgical procedures; anaesthesia, analgesia and euthanasia (including application of ‘humane end-points’); and appreciation of elements of experimental design, including replacement, reduction and refinement. Training for Category A and B persons must have a large practical component, which will usually be achieved by working under the supervision of someone with extensive relevant experience. C. Persons responsible for directing or designing animal experiments In addition to completion of a graduate study (bachelor’s or master’s degree) in a biomedical discipline, a person in this category also requires a basic course in laboratory animal science. This should include ethical and legal aspects; biology and husbandry of laboratory animals; microbiology and disease; design of animal experiments; anaesthesia, analgesia and experimental procedures; alternatives to animal use; and analysis of relevant scientific literature. It should take at least 80 h or the equivalent. D. Laboratory animal specialists Training should include the Category C items, but more in-depth and specialised knowledge and experience
should be achieved by training in areas such as microbiology of relevant species, quality control, health monitoring, pathology, disease prevention and treatment, ethical aspects and legislation, techniques of humane killing of animals and post-procedural pain relief and nursing care. These outlines provide guidance for the design of education and training courses that are organised in order to meet the requirements on competence, as demanded by the European Commission (Directive 86/ 609/EEC, European Commission, 1986) and by the Council of Europe (European Convention, ETS 123, 1986). In most EU countries, national laws on animal experimentation now contain a section on competence. Despite the programme outlines as recommended by CoE (1994) and FELASA (1995), specific requirements still differ between countries. For example, for the persons belonging to Category C, most countries require an academic degree in biology, medicine or veterinary medicine, but in some countries (e.g. UK, Portugal, Ireland and Denmark) the degree is not specified. Also, the recommended basic course in laboratory animal science of at least 80 h has not yet been implemented in all EU member states. In Sweden, Denmark, Finland, France, the Netherlands and the UK, a course has been made mandatory, but the length of the course varies (1– 3 weeks). In other countries, like Belgium, Spain and Germany, courses are organised at several universities, although such a course has not been made mandatory (for details on the differences in legal requirements, see: Van Zutphen, 1997). There is a need for harmonization in this respect, not only because the diversity that presently exists hampers the free exchange of scientists between member states, but also because harmonisation with respect to the Council of Europe and FELASA guidelines, will have a positive effect on the welfare of laboratory animals. In the Netherlands, a course on laboratory animal science was made compulsory in 1985. According to Dutch law, all scientists who intend to perform experiments that (may) involve the use of live animals, must have completed a graduate study in one of the biomedical disciplines and, in addition, must have taken a 3-week course in laboratory animal science. In designing the course, it was recognised that the content must not only contribute to the quality of research, but also to the welfare of the animals. Because of the crucial role of scientists in the implementation of the Three Rs in animal research, considerable emphasis is placed on personal responsibility and the adoption of an attitude of respect towards animals. The design of the course and the didactic approach have previously been published in some detail (Van Zutphen, 1995, 1997; Van Zutphen and Van der Valk, 1995; Van Zutphen and Blom, 2000).
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5. Three Rs policy of editorial boards Further to the ethical review of protocols and to the education of persons involved in animal experimentation, editorial boards of journals, publishing animalbased research, can play an important role in the implementation of the Three Rs. To this end, editorial boards should develop a policy on the ethical aspects of animal use and should formulate the prerequisite standard as for considering review and subsequent publication of any submitted animal research manuscript. Preferably, the journal’s policy should be explained in the ‘‘Instructions to Authors’’, or a reference can be made to a separate document. Several journals have already included a statement on their policy in this respect. Boisvert (1997) screened 46 journals publishing animal-based research and found that 24 of these require authors to certify that the research as described in the submitted manuscript meets an established standard for the care and use of animals. In another sample of 83 journals, a comprehensive statement was included in 13 journals (16%) whereas the other journals have either a brief statement (25%) or no statement at all (59%) (Van Zutphen and Festing, 2000). In an attempt to further stimulate editorial boards to include a (comprehensive) statement on the ethical use of animals (or to refer to a separate document on this issue), guidelines have been prepared and were discussed at the 3rd World Congress on Animal Alternatives in Bologna (Van Zutphen and Festing, 2000). The guidelines have been sent through FRAME for consideration to the editorial boards of 124 journals that publish animal-based research. So far, only 21 editors have responded, but it is encouraging that the responses are generally positive and that several editors have indicated that they would (re)consider their policy in this respect.
6. Conclusion In this paper, we have detailed some of the developments that may be of particular interest for the implementation of the Three Rs in Europe. Besides the Three Rs policy of journals and the guidelines as formulated in ESF’s position paper on animal use, some emphasis is put on the (legal) provisions that exist in Europe for the evaluation of experimental protocols by animal ethics committees, and for the education, training and competence of persons involved in animal experiments. It is concluded that differences exist between countries in the interpretation of European legislation and that efforts should be made to harmonise national legislation. The developments on the implementation, as outlined in this paper, also illustrate that much has been achieved in the
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past 40 years. Nevertheless, major steps must still be taken in order to restore further the balance between human and animal interests.
References Balls, M., Goldberg, A.M., Fentem, J.H., Broadhead, C.L., Burch, R.L., Festing, M.F.W., Frazier, J.M., Hendriksen, C.F.M., Jennings, M., van der Kamp, M.D.O., Morton, D.B., Rowan, A.N., Russell, C., Russell, W.M.S., Spielman, H., Stephens, M.L., Stokes, W.S., Straughan, D.W., Yager, J.D., Zurlo, J., van Zutphen, B.F.M., 1995. The Three Rs: the way forward. ECVAM workshop report 11. ATLA 23, 838–866. Boisvert, D.J.P., 1997. Editorial policies and animal welfare. In: van Zutphen, L.F.M., Balls, M. (Eds.), Animal Alternatives, Ethics and Welfare. Elsevier Science, Amsterdam, pp. 399–404. CoE (Council of Europe) Resolution on education, training of persons working with laboratory animals. Council of Europe Multilateral Consultation, 1994. ICLAS News 4, 5–6. de Cock Buning, Tj., 1997. Training members of ethics committees. In: van Zutphen, L.F.M., Balls, M. (Eds.), Animal Alternatives, Ethics and Welfare. Elsevier Science, Amsterdam, pp. 379–383. de Greeve P. and de Leeuw, W., (1999). Ethics committees in Europe—an overview. In: Handbook of Animal Models of Infection. Academic Press, New York, pp. 13-18. European Commission, 1986. EEC Council Directive 86/609 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 Journal of the European Communities L 358, 1–29. ESF (European Science Foundation), 2000. Use of Animals in Research. European Science Foundation Policy Briefing 9, pp. 1–6 (http://www.esf.org). FEFELASA, 1995. Recommendations on the education and training of persons working with laboratory animals: Categories A and C. Reports of FELASA Working Group on Education. Laboratory Animals 29, 121–131. Johnston, N.E., Rusche, B., 1997. Ethics committees; how do they contribute to the Three Rs? Synopsis of a workshop. In: van Zutphen, L.F.M., Balls, M. (Eds.), Animal Alternatives, Ethics and Welfare. Elsevier Science, Amsterdam, pp. 391–395. Russell, W.M.S, Burch, R.L, 1959. The Principles of Humane Experimental Technique. Methuen & Co, London. van Zutphen, L.F.M., 1995. Education and training: a contribution to animal welfare and quality of experiments. Scandinavian Journal of Laboratory Animal Science 22, 51–56. van Zutphen, L.F.M., 1997. Education and training in laboratory animal science. In: P.N. O’Donoghue (Ed.), Harmonisation of Laboratory Animal Husbandry. Proceedings of the Federation of European Laboratory Animal Science Associations, 19–21 June 1996, Basel, pp. 160–166. van Zutphen, L.F.M., Van der Valk, J.B.F., 1995. Education and training: a basis for the introduction of the three Rs alternatives into animal research. ATLA 23, 123–127. van Zutphen, L.F.M., Blom, H.J.M., 2000. Education and training on the three Rs: requirements and implementation. In: Balls, M., van Zeller, A-M., Halder, M.E. (Eds.), Progress in the Reduction, Refinement and Replacement of Animal Experimentation. Elsevier Science, Amsterdam, pp. 1375–1382. van Zutphen, L.F.M., Festing, M.F.W., 2000. Update on policies of journals. In: Balls, M., van Zeller, A-M., Halder, M.E. (Eds.), Progress in the Reduction, Refinement and Replacement of Animal Experimentation. Elsevier Science, Amsterdam, pp. 1375–1382.
Developments on the implementation of the Three Rs in research and education L.F.M. van Zutphena,*, J.B.F. van der Valkb a Department of Laboratory Animal Science, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands Netherlands Centre for Alternatives to Animal Use, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
b
Abstract More than 40 years ago, Russell and Burch published their views on the implementation of the ‘Three Rs’ in animal experimentation. Since then, much has been achieved in this area. Recently, the European Science Foundation (ESF) has made a further step forward. In a position paper on the use of animals, ESF has formulated what it sees as prerequisites for the humane use of animals in research, testing and education. In this paper, we briefly report on these ESF guidelines. Also, an overview is presented on European legislative regulations for the (ethical) review of research protocols and for the education and training of persons involved in animal experiments. The great diversity between countries is illustrated with some examples and the need for harmonization is emphasised. The paper ends by highlighting the special role that editorial boards of journals can play in the further implementation of the Three Rs. # 2001 Elsevier Science Ltd. All rights reserved. Keywords: European Science Foundation (ESF); ESF guidelines; Animal ethics committees; Education
1. Introduction It is now generally accepted that animal alternatives are defined by the Three Rs, as elaborated by Russell and Burch (1959) in their book The Principles of Humane Experimental Technique. They have outlined the conditions that must be met when an experiment on live animals is considered and wrote in the Introduction: ‘‘We cannot do more than pick up a few trails for others to follow.’’ Their trails proved to be attractive and many have followed the signs and have explored new trails, using the Three Rs as their guide. During the last decades, much has been achieved in the fields of replacement, reduction and refinement of animal experiments, but nevertheless, there is still a long way to go. The further development and validation of Three Rs alternatives require input from many different disciplines. Their acceptance and implementation also depends heavily on the attitude of the persons involved in animal experimentation. In this paper, we describe some of the initiatives and developments that are relevant for the implementation of alternatives in Europe. * Corresponding author. Tel.: +31-30-253-2033; fax +31-30-2537997. E-mail address: [email protected] (L.F.M. van Zutphen).
We will focus on the position paper on the use of animals in research that has recently been prepared by the European Science Foundation and on developments regarding animal ethics committees, education and the policies of scientific journals. All three could have a major impact on the implementation of the Three Rs.
2. European Science Foundation (ESF) guidelines on animal use ESF is the European association of national organisations responsible for the support of scientific research. ESF is an influencing organisation, comprising 67 leading national science-funding agencies (e.g. research councils, academies of science) in 23 European countries. In 1999, the board of ESF established the ‘‘Expert Group on Biology and Society’’. One of the tasks of this Expert Group was to prepare for ESF a position paper on the use of animals in research. This document has recently been published (ESF, 2000; see also http:// www.esf.org). It contains guidelines and recommendations for the ethical use of animals in research. The main aspects covered by the guidelines of the position paper are the following:
0887-2333/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0887-2333(01)00065-0
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. ESF recognises that laboratory animals not only have an instrumental value, but also an intrinsic value (value in themselves) which must be respected; . While accepting the need of animal use for the advancement of scientific knowledge, and for promoting human and animal health and their wellbeing, ESF strongly endorses the principles of the Three Rs; . Research aiming at improving the welfare of animals should be encouraged and actively supported by ESF Member Organisations; . Prior to the performance of a programme of research, animal use should be subjected to independent expert review, for both scientific and animal welfare considerations. The assessment and weighing of the likely benefit and likely animal suffering should be an essential part of the review process; . Investigators should assume that procedures that would cause pain in humans also cause pain in other vertebrates, unless there is evidence to the contrary; . Investigators and other personnel involved in the design and performance of animal-based experiments should be adequately educated and trained. ESF Member Organisations should encourage the development and organisation of accredited courses on laboratory animal science, including information on animal alternatives, welfare and ethics; . ESF encourages the editorial board of journals publishing the results of animal-based research to include in the ‘‘instructions to authors’’ a statement on the ethical use of animals. The contents of this document clearly illustrate that the leading science organisations in Europe have chosen to endorse fully the Three Rs and to give high priority to aspects concerning animal welfare. The ESF guidelines can be considered, at least in part, as a reinforcement of developments, which have already been started in several countries but did not always receive full support of the scientific community. For the implementation of the Three Rs alternatives, the evaluation of protocols by animal ethics committees and the education and training in laboratory animal science are of particular importance. In the following paragraphs information on the requirements and the developments on these issues in Europe will be presented. Also, the Three Rs policy of journals publishing animal-based results will briefly be discussed.
3. Animal ethics committees In Section 12.1 of the ‘‘Council Directive on the protection of animals used for experimental and other scientific
purposes’’ (Directive 86/609/EEC, European Commission, 1986) it is indicated that ‘‘Member States shall establish procedures whereby experiments (. . .) shall be notified in advance to the authority’’. Section 12.2 states that ‘‘Where it is planned to subject an animal to an experiment in which it will, or may, experience severe pain which is likely to be prolonged, that experiment must be specifically declared and justified to, or specifically authorised by, the authority. The authority shall take appropriate judicial or administrative action if it is not satisfied that the experiment is of sufficient importance for meeting the essential needs of man or animal’’. These provisions have been the impetus for some EU member states to include into their national law the requirement that animal experiment protocols must be evaluated by a competent authority, usually an animal ethics committee, prior to the conduct of the experiment. de Greeve and de Leeuw (1999) have recently reviewed the situation on the implementation of the above-mentioned provisions in the Directive 86/609/ EEC. They concluded that in Sweden, Germany and the Netherlands, an experiment cannot begin unless there is a positive advice from a local or regional animal ethics committee. These committees evaluate research protocols on ethical and animal welfare bases. An experiment cannot be performed if, according to the judgement of the committee, the potential benefit does not outweigh the likely suffering of the animal(s) involved. In Finland, local committees on animal experimentation have the task of deciding on the degree of suffering involved in the experiment. If it is estimated that the experiments might cause severe suffering, the committee is not allowed to give it a licence, but must send the application to the Provincial State Office, that has the authority to grant a licence for such experiments. In Switzerland, any experiment with animals is subject to authorization by the cantonal authorities. Each canton appoints a committee of specialists for animal experiments that examines the proposal and offers advice to the authority entitled to authorise the experiment. The advice covers the supervision of the housing of the experimental animals as well as the conduct of the experiments. In the UK, licenses are granted by the Home Office. The Secretary of State requires that all designated scientific procedure establishments have a local ethical review process in place. There is no specific section in the law requiring that a protocol must be submitted to a (local) animal ethics committee. This is also not the case in several other European countries, for example, France, Italy and Norway, but this does not mean that in those countries there is no ethical evaluation prior to the conduct of the experiment. In the UK, there are over 250 designated establishments with some form of ethical review. In France many institutions have set up their own committees.
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Apart from the legal requirements, some granting bodies also require the advice of an animal ethics committee when a proposal, entailing the use of experimental animals, is submitted. Animal ethics committees often have an explicit role in stimulating the implementation of the Three Rs. Section 7.2 of Directive 86/609/EEC (European Commission, 1986) deals with replacement where it states that ‘‘An experiment should not be performed if another scientifically satisfactory method of obtaining the result sought, not entailing the use of an animal, is reasonably and practically available’’. In Section 7.3, requirements for the implementation of reduction and refinement procedures are covered: ‘‘When an experiment has to be performed, the choice of the species shall be carefully considered and, where necessary, explained to the authority. In a choice between experiments, those which use the minimum number of animals, involve animals with the lowest degree of neuro-physiological sensitivity, cause the least pain, suffering, distress or lasting harm and which are most likely to provide satisfactory results shall be selected’’. Protocols submitted to animal ethics committees should not only contain the information needed for weighing the potential benefit versus the animal’s suffering, but also for evaluating the question on how the requirements of Sections 7.2 and 7.3 have been addressed. This implies that the ethical evaluation is performed at the level of projects rather than programmes, and is thus preferably performed by local (or regional) committees, rather than by a national committee. In order to promote the implementation of the Three Rs through the ethical review of protocols, it is a prerequisite that the committee members are unbiased and competent. Most animal ethics committees are composed of persons with different expertise with respect to animal experimentation. Often laypersons or persons from outside the research institute are also members of the committee. Several authors have emphasised the importance of organizing training courses for members of animal ethics committees (de Cock Buning, 1997; Johnston and Rusche, 1997; de Greeve and de Leeuw, 1999). It might be of interest to give some details here on how in the Netherlands the ethical evaluation of animal experiments is organised. In most institutions where animal experiments are performed, an animal ethics committee was established more than 15 years ago. However, a legal basis for these committees was not provided until 1997, as a revision of the Dutch Experiments on Animals Act. Section 10 now states that: ‘‘No experiment on animals may be conducted unless (....) a recommendation has been made by an ethical review committee (....)’’. The committee must assess ‘‘whether the benefit of the experiment outweighs the animal’s suffering’’ and ‘‘whether or not the results can be achieved by means other than an animal experiment, or
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by means of an experiment using fewer animals or entailing less distress than described in the proposed protocol’’. Other aspects that must be assessed by the members of the committee are the competence of the persons involved in the experiment, the origin of the animals, and their housing and care. The animal ethics committee consists of at least seven members, with experts in the field of animal experiments, animal alternatives, animal welfare and ethics. At least two of these experts must not be involved in the conduct of animal experiments. Furthermore, the chairperson and two members must not be employed by the institute applying the protocol for review. There are now 29 committees, working for a total of 86 institutes (licence holders). Once per year, a 1-day training course is organised for members of these committees. Each year the committee must report to the Minister of Public Health.
4. Education, training and competence Persons involved in the design and conduct of animal experiments must be specifically educated and adequately trained. This is essential, both for the quality of experiments and for the welfare of animals (Balls et al., 1995). There are several sections dealing with competence in Directive 86/609/EEC: . Experiments shall be performed solely by competent authorised persons, or under the direct responsibility of such a person (Article 7.1); . Persons who carry out experiments or take part in them, and persons who take care of animals used for experiments, including duties of supervisory nature, shall have appropriate education and training. In particular, persons carrying out or supervising the conduct of experiments shall have received instruction in a scientific discipline relevant to the experimental work being undertaken and be capable of handling and taking care of laboratory animals; they shall also have satisfied the authority that they have attained a level of training sufficient for carrying out their tasks (Article 14); . In each user establishment sufficient trained staff shall be provided. A veterinarian or other competent person shall be charged with advisory duties in relation to the well being of the animals (Article 19 b, d).
The provisions on education and training in national laws of EU member states must be in line with the Directive 86/609/EEC. There is, however, a problem here. Although the objectives of the provisions on competence, as formulated in the Directive, are clear, there is still much room for interpretation when it comes to a
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practical implementation. In an attempt to harmonise the requirements on education and training at the European level, the Council of Europe (CoE, 1994), in collaboration with the Federation of European Laboratory Animal Science Associations (FELASA, 1995), has worked out the provisions in more detail. Four categories of persons, where appropriate education and training is considered essential, are distinguished: A. Persons taking care of animals Programmes in this category should include basic instruction in ethics and legal aspects of the care of laboratory animals; animal handling and husbandry; recognition of health and disease; recognition of pain, suffering and distress; (local) practices for security, administration, transport, receipt of animals and supplies; and the disposal of animals. Programmes should also include training for tasks supporting performance of specific experimental procedures. B. Persons carrying out procedures Programmes in this category should include all aspects in Category A and, in addition, some detailed knowledge of the anatomy, physiology and behaviour of animal species, breeds and strains; implications of the microbiological status of animals; practical aspects of health monitoring; experimental techniques and surgical procedures; anaesthesia, analgesia and euthanasia (including application of ‘humane end-points’); and appreciation of elements of experimental design, including replacement, reduction and refinement. Training for Category A and B persons must have a large practical component, which will usually be achieved by working under the supervision of someone with extensive relevant experience. C. Persons responsible for directing or designing animal experiments In addition to completion of a graduate study (bachelor’s or master’s degree) in a biomedical discipline, a person in this category also requires a basic course in laboratory animal science. This should include ethical and legal aspects; biology and husbandry of laboratory animals; microbiology and disease; design of animal experiments; anaesthesia, analgesia and experimental procedures; alternatives to animal use; and analysis of relevant scientific literature. It should take at least 80 h or the equivalent. D. Laboratory animal specialists Training should include the Category C items, but more in-depth and specialised knowledge and experience
should be achieved by training in areas such as microbiology of relevant species, quality control, health monitoring, pathology, disease prevention and treatment, ethical aspects and legislation, techniques of humane killing of animals and post-procedural pain relief and nursing care. These outlines provide guidance for the design of education and training courses that are organised in order to meet the requirements on competence, as demanded by the European Commission (Directive 86/ 609/EEC, European Commission, 1986) and by the Council of Europe (European Convention, ETS 123, 1986). In most EU countries, national laws on animal experimentation now contain a section on competence. Despite the programme outlines as recommended by CoE (1994) and FELASA (1995), specific requirements still differ between countries. For example, for the persons belonging to Category C, most countries require an academic degree in biology, medicine or veterinary medicine, but in some countries (e.g. UK, Portugal, Ireland and Denmark) the degree is not specified. Also, the recommended basic course in laboratory animal science of at least 80 h has not yet been implemented in all EU member states. In Sweden, Denmark, Finland, France, the Netherlands and the UK, a course has been made mandatory, but the length of the course varies (1– 3 weeks). In other countries, like Belgium, Spain and Germany, courses are organised at several universities, although such a course has not been made mandatory (for details on the differences in legal requirements, see: Van Zutphen, 1997). There is a need for harmonization in this respect, not only because the diversity that presently exists hampers the free exchange of scientists between member states, but also because harmonisation with respect to the Council of Europe and FELASA guidelines, will have a positive effect on the welfare of laboratory animals. In the Netherlands, a course on laboratory animal science was made compulsory in 1985. According to Dutch law, all scientists who intend to perform experiments that (may) involve the use of live animals, must have completed a graduate study in one of the biomedical disciplines and, in addition, must have taken a 3-week course in laboratory animal science. In designing the course, it was recognised that the content must not only contribute to the quality of research, but also to the welfare of the animals. Because of the crucial role of scientists in the implementation of the Three Rs in animal research, considerable emphasis is placed on personal responsibility and the adoption of an attitude of respect towards animals. The design of the course and the didactic approach have previously been published in some detail (Van Zutphen, 1995, 1997; Van Zutphen and Van der Valk, 1995; Van Zutphen and Blom, 2000).
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5. Three Rs policy of editorial boards Further to the ethical review of protocols and to the education of persons involved in animal experimentation, editorial boards of journals, publishing animalbased research, can play an important role in the implementation of the Three Rs. To this end, editorial boards should develop a policy on the ethical aspects of animal use and should formulate the prerequisite standard as for considering review and subsequent publication of any submitted animal research manuscript. Preferably, the journal’s policy should be explained in the ‘‘Instructions to Authors’’, or a reference can be made to a separate document. Several journals have already included a statement on their policy in this respect. Boisvert (1997) screened 46 journals publishing animal-based research and found that 24 of these require authors to certify that the research as described in the submitted manuscript meets an established standard for the care and use of animals. In another sample of 83 journals, a comprehensive statement was included in 13 journals (16%) whereas the other journals have either a brief statement (25%) or no statement at all (59%) (Van Zutphen and Festing, 2000). In an attempt to further stimulate editorial boards to include a (comprehensive) statement on the ethical use of animals (or to refer to a separate document on this issue), guidelines have been prepared and were discussed at the 3rd World Congress on Animal Alternatives in Bologna (Van Zutphen and Festing, 2000). The guidelines have been sent through FRAME for consideration to the editorial boards of 124 journals that publish animal-based research. So far, only 21 editors have responded, but it is encouraging that the responses are generally positive and that several editors have indicated that they would (re)consider their policy in this respect.
6. Conclusion In this paper, we have detailed some of the developments that may be of particular interest for the implementation of the Three Rs in Europe. Besides the Three Rs policy of journals and the guidelines as formulated in ESF’s position paper on animal use, some emphasis is put on the (legal) provisions that exist in Europe for the evaluation of experimental protocols by animal ethics committees, and for the education, training and competence of persons involved in animal experiments. It is concluded that differences exist between countries in the interpretation of European legislation and that efforts should be made to harmonise national legislation. The developments on the implementation, as outlined in this paper, also illustrate that much has been achieved in the
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past 40 years. Nevertheless, major steps must still be taken in order to restore further the balance between human and animal interests.
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