Laws, Guidelines and Policies Governing the Use of Mice in Research

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Judy A. MacArthur Clark Animals in Science Regulation Unit, Home Office, London, UK

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Introduction The mouse (Mus musculus) is the most commonly used mammal in the laboratory. This use has increased in recent years with the development of techniques to successfully modify the mouse genome. A number of laws, guidelines and policies exist to protect animals, including mice, from unnecessary pain or distress as part of the research process. Additionally, regulations exist which provide guidance on other aspects such as the transportation of mice, both locally and The Laboratory Mouse Ó 2012 Elsevier Ltd. All rights reserved. ISBN 978-0-12-382008-2

internationally, and the prevention of the spread of disease. It is very important for all those engaged in research with mice to be familiar with these instruments and to ensure full compliance.

General principles A global framework Over the last quarter of a century, two significant documents have created a global framework for

DOI: 10.1016/B978-0-12-382008-2.00035-0

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Joanne Zurlo Center for Alternatives to Animal Testing, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

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the regulation of the use of animals in research. The first, developed in 1985 by the Council for International Organizations of Medical Sciences (CIOMS), is the International Guiding Principles for Biomedical Research Involving Animals [1]. CIOMS is a non-governmental, non-profit organization established jointly by the World Health Organization and the United Nations in 1949 and represents a substantial proportion of the biomedical scientific community. These principles for animal experimentation were, in part, created because national and international ethical codes and laws mandated that new substances or devices should not be used for the first time in human beings unless previous tests on animals had provided a reasonable presumption of their safety. The principles have provided a framework for ethical animal use for the last 25 years. The second document is Chapter 7.8 of the Terrestrial Code of the World Animal Health Organization (OIE), which covers the use of animals in research and education [2]. This chapter, approved by the OIE Code Commission and General Assembly in May 2010, provides advice and assistance to the 178 OIE member countries and territories when formulating regulatory requirements. It recommends that members should address all the essential elements identified in the chapter in formulating a regulatory framework that is appropriate to their local conditions and it accepts that the framework may be delivered through a combination of national, regional and institutional jurisdictions and that both public and private sector responsibilities should be clearly defined. Meanwhile, the 1985 CIOMS International Guiding Principles are in the process of being revised by an ad hoc committee of experts which began by collecting statements, guidance and principles regarding the humane care and use of animals in research, testing and teaching from 33 national and professional societies. The resulting draft [3] is designed to assist ethics committees, animal care committees, organizations, societies and countries in developing programmes for the humane care and use of animals in research and education, especially those operating without federal or national regulations. Hence the combination of the OIE chapter and the revised CIOMS principles can be expected to deliver sound guidance on the

development of an appropriate regulatory framework for any country, no matter how developed its scientific expertise.

Alternatives: implementing the Three Rs William M. S. Russell and Rex L. Burch first presented the concepts of the ‘Three Rs’ in a book entitled The Principles of Humane Experimental Technique [4]. Although the book was published in 1959, its principles were not universally accepted for over 30 years. Now, the Three Rs form the basis for the guidelines and regulations governing the use of laboratory animals throughout the world. The Three Rs represent replacement, reduction and refinement of animal use. 1. Replacement may be absolute, whereby nonanimal methods such as in vitro methods, or computer models are used, or it may be relative, where animals on a lower phylogenetic scale are used, such as C. elegans or zebrafish rather than a mouse or a non-human primate. 2. Reduction describes methods for obtaining comparable amounts of information from fewer animals, or for obtaining more information from a given number of animals, so that in the long run fewer animals are needed for a given purpose. Reduction relies on proper experimental design and the use of appropriate statistics in data analysis. 3. Refinement pertains to methods that minimize or eliminate pain and distress and that enhance animal well-being. Such methods include appropriate use of anaesthesia and analgesia, optimal veterinary care and monitoring and environmental enrichment to promote species-specific behaviour. The Three Rs govern the thought process by which animal experimentation is planned and by which protocols involving animals are reviewed.

Environmental enrichment Greater knowledge of animal behaviour has increased the importance of environmental enrichment for laboratory animals. Environmental enrichment will differ depending on the species, but generally involves the inclusion of

Management of pain and distress

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A key to achieving optimal welfare in laboratory animals is the minimization or elimination of pain and distress. Ensuring that alleviation of pain is a primary concern of those working with laboratory animals is key to engendering public support for animal research. Pain, as defined by the International Association for the Study of Pain, is ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’ [13]. Fundamental to alleviating pain in animals is the ability to recognize its occurrence. In mice, the signs of pain are often difficult to ascertain; thus close attention to their behaviour may be necessary to detect subtle changes. A recent controversial study [14] reported the development of a mouse grimace scale, which provides a standardized behavioural code to assess pain levels in mice. This system is similar to facial action evaluation systems in humans. While purposefully inflicting pain on mice to develop a system to assess pain has been criticized, the

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Many countries have regulations or guidelines relating to ethical review of proposed research projects. Usually these apply to the objectives of the review, legal requirements, the scope of work reviewed and general principles for the process including factors to be considered. The participants in the review process, and whether the review should be performed at a local institutional, regional or national level, are usually defined. The need for ongoing review after initial authorization is recognized and the concept of a formal retrospective review at the end of the project is becoming more common. FELASA elicited information about ethical review in 20 European countries through a questionnaire and published a synopsis of the results with a series of recommendations [7, 8]. These included the concept of a cost-benefit assessment in which the harms likely to be caused to the animals should be considered with a view to reducing them, and that the quality of justification for such work should also be considered, including the potential and likely benefits.

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Perhaps the most comprehensive review of this cost-benefit assessment was reported by the UK Animal Procedures Committee [9], which identifies the factors to be considered and how the practice and process can be enhanced so that it can be, and be seen to be, more critical and comprehensive. Nevertheless, the report acknowledges the challenge to all involved in the field to make progress in this difficult area. A subsequent review by the Nuffield Council on Bioethics [10] acknowledged that the costbenefit assessment was not merely a role for ethical review committees and regulators, but that all those involved in study design and implementation were responsible for setting out the costs and benefits of their research. There should be active and continued scrutiny of the costs and benefits from all those involved, before, during and after research. The concept of postapproval monitoring was the topic of an ILAR Journal issue in 2008 [11] and the impact of regulatory burden on the research enterprise was also considered by Haywood and Greene [12].

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sensory stimuli, or housing complexity, to foster species-specific behaviour. Examples may include foraging challenges for non-human primates, availability of nest-building materials for rodents, toys or bones for dogs, perches for cats, etc. These items promote psychological well-being and help to prevent boredom, stereotypic behaviour and fighting with conspecifics. They allow animals some control over their environment and may serve to help animals cope with environmental stressors [5] (see Chapter 4.3). In the last decade, more attention has been paid to environmental enrichment for mice and its effects on mouse physiological parameters. For example, mice housed in cages with a variety of enrichment devices, such as ladders, tunnels and running wheels, showed decreased anxiety-like behaviour and higher activity in behavioural tests, as well as attenuated stress responses and enhanced natural killer cell activity [6]. Several studies have also shown that including nesting material and deep bedding allows mice to better control their temperature (see [5] and Chapter 4.1).

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mouse grimace approach may ultimately provide the best information about assessing pain in mice and may lead to major changes in the conduct of pain research and to animal husbandry in general [15]. However, until a more definitive system for assessing pain in mice is adopted, the fall-back position is that if a procedure is likely to cause pain in humans, it should be assumed that it would also cause pain in mice, e.g. postoperatively [16] (see Chapter 5.4). Distress is more difficult both to define and to recognize. It may be considered an aversive state in which an animal fails to adapt to a significant level of stress and it may cause pathological or behavioural changes in the animal. Improper housing conditions, such as singly housing normally social animals for a prolonged period of time, may cause distress, as may chronic pain. Following the Three Rs is the best way to avoid distress in animals [17].

Regulatory balance The regulatory balance is a guiding principle that can be illustrated as a Venn diagram of three overlapping circles [18]. In any regulatory system, it is essential to ensure that bureaucracy and rules do not become so burdensome as to inhibit scientists from developing good-quality scientific proposals that will address important research questions. However, it is also important to ensure that animals do not suffer unnecessarily in such

Figure 6.1.1 The regulatory balance for the use of animals in research [18].

research projects. Thus, there needs to be a balance between the needs of science and the needs of the animals (Figure 6.1.1). Furthermore, there is strong evidence to show that good animal welfare leads to good scientific outcomes (the overlapping area A). It is this balance between science and welfare that provides the public with confidence in the regulatory system. The public wants to benefit from scientific advances, but also wants to be reassured that animals are not suffering unnecessarily (the overlapping areas B and C in Figure 6.1.1). The nature of this balance will differ between different countries, taking into consideration their diverse cultural, economic, religious and social factors. However the guiding principle of the regulatory balance can be fruitfully applied in any country in determining an appropriate approach to regulation of animal use in research.

Adequate veterinary care Many governmental, professional and nongovernmental organizations have issued guidelines for adequate veterinary medical care for laboratory animals [19, 20]. Such care is generally considered to be an essential and integral part of animal care and use programmes. The guidelines generally provide standards for qualifications of veterinarians working in laboratory animal research programmes, their authority in oversight of facilities and experiments and their unique and special role in reviewing protocols involving laboratory animals. The training required for a qualified veterinarian to deliver adequate veterinary care has recently been reviewed [21]. The United States, Canada and the European Union (EU) all require that veterinarians working in laboratory animal facilities have training or experience in the management of the species maintained in the facility. The primary role of veterinarians in animal research is to monitor the health and well-being of the animals under their care, provide appropriate treatment to sick animals and ensure that euthanasia is administered properly. Health monitoring includes preventive care as well as handling disease outbreaks in the facility. The veterinarian also oversees the appropriate use of anaesthetics, analgesics and other

pharmaceuticals, reviews and approves surgical, postsurgical and postprocedural care, and should have the authority to apply euthanasia to an animal that is experiencing severe pain or distress (in consultation with the investigator performing the study) [22, 23].

Inspection and compliance monitoring

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There are two major bodies that accredit laboratory animal care programmes: the Canadian Council on Animal Care (CCAC) and the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). The CCAC, founded in 1968, is an accrediting body that limits itself to institutions located in Canada and will be described under Canadian regulations later in the chapter. AAALAC is a non-profit organization founded in 1965 that accredits programmes globally. AAALAC bases its accreditation process on compliance with the US Guide for the Care and Use of Laboratory Animals [5], national laws, regulations and policies and other scientifically based standards called ‘reference resources’ that address specific subject areas.

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The primary purpose of inspection is to monitor for non-compliance with the regulations and to take appropriate action. Hence, most inspection systems are operated by governmental bodies. However, some inspectorates play a more wideranging role within the regulatory system, offering advice on appropriate care and use of animals, on government policies for animal use, for the implementation of the Three Rs and dissemination of best practice. Depending on the skills and experience of those recruited to the inspectorate, this wider role can be enormously valuable. In addition, an inspectorate can play a significant role in advising on the ethical evaluation and authorization of projects. This has the advantage that inspectors who have reviewed project applications are able to then inspect those projects for non-compliance with a great degree of understanding. Generally the nature of inspections falls into two categories. Firstly, those which occur relatively infrequently and involve a major audit of all aspects of the animal care and use programme. To be effective, these inspections are often announced in advance so that the staff of the establishment to be inspected can prepare appropriate documentation. Usually the inspection is performed by a team of two or three inspectors who may have clearly defined and diverse roles. A detailed report will normally be produced at the end of such an inspection. The report provides a snapshot of the status of the establishment at the time of the inspection. However, much can change between inspections without the knowledge of the inspectorate. The second model of inspection is less frequently practised but possibly more effective. In this model, an inspector is assigned to an establishment and becomes familiar with the work at

that place through frequent visits. Where a specific purpose for the visit has been defined, a visit may be announced. However, a significant proportion of visits will be unannounced, giving the inspector the opportunity to view the place under normal working conditions. An advantage of this type of inspection may be that the inspector gains a genuine familiarity with the place and the research. Some elements of a visit can take an audit approach, for example, if inspecting animal health records or records of training. Other elements can be more discursive, discovering through discussion and observation. Whichever model of inspection is adopted, it is appropriate to base the frequency of inspection on an objective assessment of the risk presented by the establishment. Assessing the risk might include consideration of objective measures such as the number and species of animals used, number and severity of projects and history of compliance. But a major aspect should be an assessment of the culture of the place and the quality of management. This will inevitably be subjective but should consider a list of factors including the effectiveness of local veterinary and animal care services, the operation of the local ethical review committee, the quality of communication between all those involved in the animal care programme, the quality of facility maintenance, the status of training plans and records, along with any contingency plans.

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Accreditation, which is voluntary, includes an extensive review of the organization’s laboratory animal care programme and an announced site visit performed by members of AAALAC’s Council on Accreditation (or adjuncts) every 3 years. An annual report is also required. If an institution does not conform to AAALAC’s standards, it will receive a notification that full accreditation has not been granted, and must provide a timeline for correcting deficiencies. If these deficiencies remain uncorrected, accreditation may be revoked. A full description of AAALAC’s international programmes is available at their website [23].

Training The importance of adequate training for all those involved in animal care and use is underscored by the emphasis it receives in regulations and policies in most jurisdictions. For example, training is a prominent theme in the European Directive (2010/63/EU) on the protection of animals used for scientific purposes (European Commission, 2010) and in the US Guide for the Care and Use of Laboratory Animals [5, 24]. Over the last decade there have been moves towards both regionalization and internationalization of training standards. A particularly strong example is the development of training guidelines across Europe. These were based on the Council of Europe Resolution on education and training of persons working with laboratory animals [25], which defined four categories of people working with laboratory animals and the broad principles of their training needs: 1. Category A: persons taking care of animals 2. Category B: persons carrying out procedures 3. Category C: persons responsible for directing or designing procedures 4. Category D: laboratory animal science specialists. The Federation of European Laboratory Animal Science Associations (FELASA) has since elaborated on the training requirements for each of these categories to produce training guidelines together with an accreditation scheme for provision of this training [26]. However, the relatively inflexible nature of these guidelines has recently been questioned and, under Directive

2010/63/EU, proposals are emerging from bodies, including FELASA, for a more tailored approach to training which considers the individual needs of each trainee, and uses modern open-source methodologies to deliver quality training to meet those needs. In the USA, the Animal Welfare Regulations and PHS Policy require institutions to ensure that people caring for, or using, animals are qualified to do so. The Animal Welfare Regulations stipulate a number of key topics that must be included in the institution’s training programme. The US Guide [5] urges that adequate training should also be provided to members serving on the Institutional Animal Care and Use Committee (IACUC) so that they can appropriately discharge their responsibilities. In addition, it recommends that the professional and technical personnel caring for animals should be trained, as should investigators, research technicians, trainees (including students) and visiting scientists. It also endorses training in occupational health and safety, in procedures that are specific to an employee’s job, and in procedures specific to research (e.g. anaesthesia, surgery, euthanasia, recognition of the signs of pain and/or distress). The focus on training standards with opensource access and flexible delivery is also seen in the training of those who care for animals. The UK Institute of Animal Technology (IAT) has revised its traditional certification programme to offer a unit-based framework for animal care training across Europe [27]. Diploma-level programmes in husbandry, as well as science and technology, are offered in four languages with open-source access and clear learning outcomes. With these modules, IAT is influencing training across Europe through the European Federation of Animal Technicians (EFAT). Similar approaches are being offered by the American Association for Laboratory Animal Science across the Americas. Laboratory animal veterinarians have, for many years, recognized the speciality of laboratory animal medicine through the creation of specialist colleges such as the American, European, Japanese and Korean Colleges of Laboratory Animal Medicine. Each college sets standards for the achievement of specialist status through experience and examination. More recently, there have been moves to share

standards for specialization by the formation of an International Association of Colleges of Laboratory Animal Medicine (IACLAM) [28].

Regulations especially relevant to laboratory mice Genetic modification

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Laboratory mice comprise a small but important part of the global transport of live animals. This is partly due to the large-scale commercial production of mice in specialized facilities with rigorous

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The widespread use of genetically modified mice presents special animal welfare concerns principally because of unanticipated outcomes. The insertion or deletion of a gene into or from mice may result in phenotypic characteristics that compromise the health or well-being of the animals, for example immunodeficiencies or physical deformities that could prevent mobility and hence access to food. When a new genetically modified animal is developed, the first generation of animals should be monitored regularly up to adulthood to detect any possible adverse phenotypes that might result in pain or distress. If the animals are determined to be experiencing pain or distress resulting from genetic manipulation, they should be euthanized. If a newly created animal model is known to be compromised, the earliest humane end-point should be established so that data may be collected, but also so that the animals are not subjected to unnecessary pain and/or distress. Regulations for performing genetic modification, maintaining colonies of genetically altered animals, and importing and exporting such animals, are complex. They vary between different countries and may be related to environmental risks as well as welfare concerns. It is critically important to ensure full understanding and compliance with all the local regulations before embarking upon any of these procedures.

disease control measures; the animals then need to be moved to the research facilities in which they will be used. However, small groups of mice that have been genetically modified are increasingly being moved for collaborative purposes between research facilities. The general principles of transportation are the same in both situations, though lack of experience may make the latter particularly challenging. Animal transportation includes the entire period from packing through dispatch, carriage, receiving and unpacking at the final destination. It is important to understand the biological needs of the animals as well as the regulatory requirements for proper documentation (e.g. veterinary certification) for both the consigning and receiving countries. This means drawing up a comprehensive journey plan, which includes allowance for contingencies if needed. For those who do not routinely transport groups of mice, it is strongly recommended to engage the services of a professional adviser and to follow a written set of procedures and checklist to ensure all eventualities have been considered. In general, animals being transported should be in good health with minimal phenotypic abnormalities that may impact their welfare. It is generally considered unwise to transport pregnant mice during the last 10% of gestation, nor nursing litters, since dams may reject their pups under the stress of transport. Appropriate containers should be used which ensure provision of sufficient ventilation, protection from microbial contamination and prevention of escape. The animals’ needs in terms of bedding, food and hydration should be addressed, as well as protection from extreme temperatures. The IATA Live Animals Regulations have been generally accepted as guidelines for the air transportation of laboratory animals [29]. Other useful guidance for all modes of transport is available from the Institute for Laboratory Animal Research [30] and a comprehensive guide to transporting all laboratory species, including mice, is provided by White et al. [31]. Correct documentation is essential to avoid delays in transit. An Export Health Certificate, the format of which will be defined by the competent authorities of both the exporting and the receiving countries, will normally need to be signed by an official veterinarian. Other

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documents may include import licences issued by the state veterinary service, invoices for customs purposes, authorization for transfer from bodies specifically regulating laboratory animal use and, in the case of ground transportation, vehicle registration details and insurance. Most countries have a limited number of designated locations where animals can enter the country. Here, animal consignments are inspected by officials and therefore may need to arrive during defined working hours or with prior warning. The receiving institute should be alerted to the planned arrival time so that cages can be prepared in advance. On arrival, animals should be removed from their transport containers and examined without delay. A thorough description of the health status of the consigning colony should have been provided in advance to ensure that appropriate measures are taken to avoid animals introducing unwanted infections into the receiving colony. This may include quarantine for a period usually defined by the local veterinarian, during which animals will be observed for clinical signs and possibly tested for evidence of infections.

Regional laws, guidelines and policies North America USA The earliest legislation protecting laboratory animals in the USA is the Animal Welfare Act, first passed by Congress as the Laboratory Animal Welfare Act in 1966, primarily to prevent the theft of pets and their sale to research laboratories. Authority for oversight of laboratory animals under this law was given to the US Department of Agriculture (USDA) [32]. The Animal Welfare Act was amended in 1970, 1976, 1985 and 1990 to broaden the scope of the law, including the mandate for establishing Institutional Animal Care and Use Committees to review and approve all protocols for laboratory animals. The 1970 amendment to the Animal

Welfare Act stated that an animal was defined as: ‘any live or dead dog, cat, monkey (non-human primate animal), guinea-pig, hamster, rabbit, or other such warm-blooded animal as the Secretary may determine is being used, or is intended for use, for research, testing, experimentation, or exhibition purposes, or as a pet.’ In this way, the Secretary of the Department of Agriculture was provided with the authority to determine which animals would be covered by the Act. In 1977 the USDA promulgated regulations that specifically excluded rats, mice and birds from the definition of ‘animal.’ The Helms amendment to the 2002 Farm Bill specifically excluded rats (of the genus Rattus), mice (of the genus Mus) and birds from the Act. Because the USDA regulates only those species covered by the Animal Welfare Act, the passage of this bill into law removed USDA oversight of these species. Thus, for the purposes of this book, which is dedicated to the laboratory mouse primarily of the genus Mus, the Animal Welfare Act is not applicable. Another piece of legislation safeguarding laboratory animals in the US is the Health Research Extension Act of 1985 that put into law the Public Health Service [33] Policy on the care and use of all vertebrate animals (including rats, mice and birds). This law was initially passed in 1973 and modified in 1979 and applies to all institutions that are funded by any branch of the PHS, including the National Institutes of Health (NIH), Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC). Any institution receiving funding from the PHS is required to hold on file an Animal Welfare Assurance Statement with the Office of Laboratory Animal Welfare (OLAW) at the NIH. This statement avers that the institution abides by the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training [34], which are largely based on the CIOMS principles [1] and the US Guide [5]. Like the Animal Welfare Act, PHS policy requires an institution to have an Institutional Animal Care and Use Committee (IACUC). The Assurance Statement must describe in detail: the animal care and use programme for the institution and include a list of all components of the institution including satellite facilities; the clear

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Canada has a quasi-regulatory peer review system for overseeing the use of animals in science administered through the Canadian Council on Animal Care (CCAC). CCAC, which was created in 1968 in response to public concerns about the use of animals in research, provides guidelines for the use of animals primarily through the two-volume CCAC Guide to Care and Use of Experimental Animals [38], but also through other specific guidelines and policy statements. At the local level, the Animal Care Committee (ACC) at each institution provides primary oversight for animal use. In addition to its guidelines programme, the CCAC also has an assessment and certification programme, somewhat similar to that of AAALAC International

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The IACUC must also review and approve any proposed work that involves the use of animals. Specifically, the proposed protocol must contain a detailed description of the proposed work, including species, strain, sex, age and number of animals to be used; a justification for the use of the specified animals; information on the veterinary care of the animals; documentation that all those who will work with the animals are appropriately trained; an explanation of how pain, distress, discomfort and/or injury will be eliminated or minimized; and a description of the method of euthanasia that will be used as well as the reason for the chosen method. With regard to euthanasia, a justification must be provided if the proposed method does not conform to the current American Veterinary Medical Association’s euthanasia guidelines [35]. The USA has been criticized for not regulating the animals that constitute the majority of research animals, i.e. rats and mice. Although there are undoubtedly some institutions that escape any regulation (i.e. those that only have rats and mice and do not receive any funds from the PHS), an estimated 95% of these animals are subjected to oversight by PHS policy. There are other guidelines for animal use related to safety testing for drugs and chemicals, but these are more focused on standardization of protocols (Good Laboratory Practice or GLP) rather than specifying conditions related to animal husbandry and welfare [36, 37].

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lines of authority and responsibility for institutional oversight of the work, inclusive of a designated ‘institutional official’ (IO) who is ultimately responsible for the animal care and use programme; identification of a veterinarian(s) involved in the programme and his/her qualifications; a description of the occupational health and safety programme for relevant personnel; a synopsis of mandated training in humane animal care and use; and a description of the facility. Organizations with an Assurance Statement must submit an annual report to OLAW that indicates any change in their status and the dates on which the semi-annual review of the programme and animal facilities occurred. The report must also detail any serious or continuing issue of non-compliance with PHS policy, any serious deviations from provisions in the Guide and/or any suspension of an activity by the IACUC. The Assurance is renegotiated with OLAW every 5 years. OLAW can approve, disapprove, restrict or withdraw approval of the Assurance. Approval by OLAW is often achieved by an institution obtaining AAALAC accreditation. NIH provides the oversight of the PHS policy, but does not perform regular inspections. An assured institution is required to self-report any issues of non-compliance to OLAW and continued non-compliance with the policy may result in withdrawal of funding to the institution. PHS policy also describes in detail the characteristics of the IACUC. The IACUC must consist of at least five members, include one veterinarian with training and experience in laboratory animal science and medicine, one practicing scientist experienced in animal research, one non-scientist, and one individual not affiliated with the institution in any way except as an IACUC member (who may not be a member of the immediate family of anyone affiliated with the institution). The IACUC must review the institution’s animal care and use programme every 6 months and perform a site visit of all animal facilities in the institution. The committee must provide a summary report and evaluation of these reviews to submit to the IO. They must also review any concerns they may have about animal welfare at the institution and make recommendations to the IO regarding any aspect of the programme.

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whereby panels of experts conduct on-site reviews on a 3-year basis. Institutions that achieve a CCAC status of Compliance or Conditional Compliance are awarded a CCAC Certificate of Good Animal Practice (GAP). In addition to guidelines, assessment and certification, CCAC also has programmes in the Three Rs and in education, training and communications. The Three Rs programme promotes the development and implementation of reduction, refinement and replacement of animals, and the education, training and communications programme supports the development and implementation of education and training opportunities for CCAC constituents.

Europe The use of animals in scientific procedures in Europe was, until recently, covered by two similar legal instruments. The first is the Council of Europe Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes [39]. However, ratification of the Convention is not mandatory and, thus far, less than half of the 47 members of the Council of Europe have ratified it. Perhaps the greatest impact of the Convention has been Appendix A, which describes standards in animal care and husbandry of research animals. This was updated in June 2006 [40] following several years of discussions informed by working parties comprising representatives of science, industry and animal welfare groups.

European Union The second instrument, applicable in the member states of the European Union, is the EU Council Directive 86/609/EEC on the protection of animals used for experimental and other scientific purposes [41]. Directives must be implemented through national law by all the Member States of the EU (currently 27) and adopted by any new State that joins the EU. Annex II to Directive 86/609/EEC adopted much of the content of Appendix A of the Convention as guidance. In June 2007, following revision of Appendix A, a Commission Recommendation (2007 526 EC) replaced Annex II guidance with the revised Council of Europe guidelines

(Appendix A of Convention ETS 123) on accommodation and care of laboratory animals [42]. Directive 86/609/EEC provides a framework that Member States may choose to develop into more demanding regulations and guidance when implementing their own national provisions. This has led to considerable variation in the implementation across Europe and is perceived to have placed some Member States at a competitive disadvantage within the internal market. Consequently, in November 2008 the European Commission published its proposals for a new Directive with three principal aims: 1. To increase the focus on the Three Rs achieved through the regulatory system 2. To raise standards of animal welfare applied across Europe 3. To harmonize the regulations implemented in all Member States [43]. The Commission’s 2008 draft was extensively debated in both the European Parliament and Council of Ministers, resulting in a text agreed by all three parties in November 2010 [44]. Among the key provisions of the new Directive (2010/63/EU) are the following requirements: 1. All places where animal research is to be done must be authorized by the national competent authority (CA), normally a government department. At each place a specified individual is responsible for ensuring compliance. 2. Other specified individuals include those responsible: for overseeing animal care and welfare; for access to information about relevant species; for ensuring appropriate training, supervision and competence; and a designated veterinarian who will advise on the well-being and treatment of animals. 3. Each proposed project must be authorized by the CA applying a harm-benefit analysis and for a maximum of 5 years. Many projects will require a non-technical summary to be published and a retrospective review to be performed on conclusion. 4. Project applicants must show they have applied the Three Rs, and humane end-points to avoid death as an end-point wherever possible, in all types of research. Within regulatory testing, alternatives to using animals are mandatory where an appropriate non-animal test is legally recognized in the EU.

Russia

China In China, the Statute on the Administration of Laboratory Animals, which was passed in 1988, provides general oversight over laboratory

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Russian regulations (Sanitary Regulations for the Organization, Equipment and Maintenance of Animal Facilities for Experimental Biology) were established in 1973 [45] and describe the location and design of animal facilities, sanitation requirements, housing and husbandry requirements, acquisition and quarantine of animals, and standards for personal hygiene. The regulations also describe standards for the humane treatment of animals, including the requirement to minimize pain experienced by an animal through the use of anaesthetics and analgesics. Additional regulations [46] specify some further controls but these are largely to provide for human safety in the vivarium. The US Guide [24] has been translated into Russian and is used by some facilities on a voluntary basis. In addition, a number of the larger institutes also have committees similar to IACUCs. Although all of these regulations tend to focus on facilities, hygiene, husbandry and human safety, in practice, establishments are becoming increasingly aware of the broader issues, through translations of key publications into Russian and international accreditation schemes, and are applying ethical and welfare considerations voluntarily.

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The new Directive (2010/63/EU) requires all Member States to transpose its provisions into

national legislation within 2 years and to commence implementation by January 2013. Hence this Directive will shortly become the regulation for animal care and use throughout the EU. Meanwhile, the standards of accommodation and care in Appendix A of the Convention ETS123, in so far as they have been adopted into Annex III of the new Directive, will become the mandatory minimum standards for animal care and husbandry, possibly with extended Codes of Practice prepared by individual Member States to include some of the additional advisory text in Appendix A not transposed into Annex III.

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5. Procedures, unless performed entirely under anaesthesia, must be classified according to severity: mild, moderate or severe. An upper pain threshold will apply which can only be exceeded with specific authority from the Commission. 6. Each place must appoint an Animal Welfare Body whose role includes a strong emphasis on ongoing implementation of the Three Rs. 7. The use of non-human primates is especially restricted, and only those bred in captivity will, in due course, be permitted for use. The use of great apes is banned unless specifically authorized by the Commission. 8. Reuse of animals in more than one procedure is restricted based upon the actual severity that has been experienced in earlier procedures. 9. Statistics on animal use will be collected annually and will be based upon retrospective reporting of the actual severity experienced by animals. 10. All Member States will have an inspectorate who will carry out inspections based upon a risk-assessed frequency. A minimum frequency is defined. 11. Minimum standards of care and accommodation will become mandatory in 2017. Thereafter, exemptions will only be permitted for scientific, animal welfare or animal health reasons. 12. Approved methods of humane killing are listed. Other methods must either be shown to be equally humane or justified in the project authorization. 13. All vertebrates are protected, as well as some invertebrates. Protection for mammals generally starts from two thirds of gestation. 14. Minimum requirements for education and training, including continuing professional development, are likely to be harmonized as the Commission has stated that free movement of staff throughout the EU is an objective. 15. Member States may apply stricter national measures, provided these were already in force in November 2010, when the new Directive entered into force. However they may not use these to impede the internal market.

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animal procedures for experimental and other scientific purposes. Compliance with this Statute is encouraged by the Ministry of Science and Technology (MOST) nationally, by the provincial departments of science and technology regionally, and by the IACUCs institutionally. A series of other laws have been passed since then, establishing a laboratory animal quality control network, a programme for quarantine and infectious disease control, a licensing system for laboratory animal users and breeders and the establishment of national laboratory animal seed centres to breed laboratory animals. The first regulation dealing with animal welfare and focusing on possible problems in husbandry, feeding, use and transport was passed in 2006 by MOST entitled Guidelines on the Humane Treatment of Laboratory Animals. These guidelines function similarly to the US Guide for the Care and Use of Laboratory Animals [5]. At the regional level, some provinces have strengthened their laboratory animal administration policies. In particular, Guidelines of Beijing Municipality on the Review of Welfare and Ethics of Laboratory Animals was passed in 2005 and several other provinces have passed, or are developing, similar guidelines. In general, China is working to improve its animal care policies to meet the requirements of those companies that are establishing research or testing laboratories [47]. Efforts include more emphasis on AAALAC accreditation; at the time of writing, there are 32 institutions whose animal care programmes have attained AAALAC accreditation [23].

India The Animal Welfare Board of India was set up in 1962 under the Prevention of Cruelty to Animals Act, 1960 [48]. Since 1998, the Board has been the responsibility of the Ministry of Social Justice and Empowerment and, amongst its functions, advises the government on the prevention of unnecessary pain or suffering in captive animals, including experimental animals. The Act also includes the authority for government to appoint a national Committee for the Purpose of Control and Supervision of Experiments on Animals. The Committee must ensure that animals are not subjected to unnecessary pain or suffering before, during or after experiments and develops

rules regarding animal experimentation. These rules pertain to: minimization of animal pain by the use of anaesthesia and euthanasia; consideration of alternatives to animals; ensuring that pre- and postprocedural care is provided; ensuring appropriate qualifications of individuals conducting experiments; and maintenance of suitable records. The Committee can authorize inspection of animal facilities and can suspend animal work by an individual or an institution. Permission to conduct research on larger animals must be obtained from a subcommittee of the Committee. However most research is conducted on small laboratory animals (e.g. mice, rats, guinea-pigs, rabbits), proposals for which are reviewed and authorized at a local level by the Institutional Animal Ethics Committee (IAEC). IAECs operate according to guidelines developed by the Indian National Science Academy and each IAEC must include a member of the national Committee in its membership.

Japan In 2006, the Science Council of Japan [49] issued guidelines for proper conduct of animal experiments following amendment of the Law for the Humane Treatment and Management of Animals in 2005. Subsequently, the Ministry of the Environment issued regulatory standards relating to the care and management of laboratory animals and relief of pain in 2006. Regulatory guidelines and policy statements were then prepared for universities by the Ministry of Education, Culture, Sports, Science and Technology, and for hospitals by the Ministry of Health, Labour and Welfare [50]. Ultimate responsibility for all experiments lies with the director of the research institution who is required to form a local committee for protocol review. The committee provides advice to the director who must approve the protocol. The size of the committee varies according to the size and complexity of the institution, but should include researchers who conduct animal experiments, laboratory animal specialists, and ‘other persons of knowledge and experience’. The primary role of the committee is to evaluate the scientific merit of a proposed study, taking into consideration the relevant law, standards, guidelines and policies. The committee is also

Korea

In 2004, Singapore developed Guidelines on the Care and Use of Animals for Scientific Purposes [52]. These guidelines carry legal authority and cover animal care and use for scientific purposes based on

The Taiwan Animal Protection Law of 1998 [53] addresses the use of animals for commercial purposes (e.g. meat, milk, fur, etc.), science (teaching and research) and for animals kept as pets. The law precludes the killing of animals, with certain exceptions, such as killing for scientific purposes. It also specifies the conditions for the scientific use of animals including the requirement that the minimum number of animals necessary will be used in ways that cause the minimum amount of pain or injury. Each research institution must form an Animal Experimentation Management Unit and must also establish an Ethics Committee, which must include a veterinarian and a representative of a private animal protection group. The institution may employ an Animal Protection Inspector, or use voluntary Animal Protectors to assist with the supervision of animal use, including facility inspections. The law is administered by the Council of Agriculture which, in 2001, announced regulations for institutions using vertebrate animals to establish Laboratory Animal Care and Use Panels and developed guidelines for the care and use of laboratory animals, for use by these panels.

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Singapore

Taiwan

POLICIES

The first Korean Animal Protection Law that formally permitted the use of animals for teaching, research or other scientific study was passed in 1991 and was amended in 2007, with a 1 year period for institutions to come into compliance [51]. The amended law addresses several key principles including harm-benefit analysis, the Three Rs, pain mitigation, euthanasia, and ensuring appropriate training of investigators. It also requires the appointment of an Animal Experimentation Ethics Committee at each facility to oversee the protection and ethical treatment of research animals. The composition of this committee is specified as a chair and 3–15 members, at least one third of whom must be independent of the institution. The Committee must include a veterinarian, a representative of an animal welfare group and a lawyer. The Committee is appointed by the director of the facility and must submit an annual report to the Minister of Agriculture and Forestry.

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ethical, legal, and scientific considerations. They bind the institution via the IACUC, Institutional Official (IO) and Attending Veterinarian (AV) to function similarly to the system in the USA, drawing heavily on the 7th edition of the US Guide [24]. Implementation is institution based, and draws heavily on US, Australian and Canadian standards for husbandry, care and protocol authorization, and on US and European standards for training guidelines. The programme is evaluated at least annually by the Agri-Food Veterinary Authority. Oversight includes training at all levels, protocol approval, various institutional policies, disaster/ emergency planning, and shared responsibilities (with the AV taking leadership) on animal husbandry, veterinary care, and physical plant matters. The IO is ultimately responsible although the IACUC holds authority over many aspects of the programme and can thus ensure appropriate and ethical animal care and use. AAALAC accreditation is strongly encouraged.

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charged with reviewing and making recommendations on the education and training of the investigator. The amended law and standards require, for the first time, that attention be given to the Three Rs in the planning and conduct of research, with particular emphasis placed on refinement. The guidelines provide general considerations for reviewing protocols including the facility and equipment, animal restraint, food and water restriction, surgical procedures, analgesics and anaesthetics, humane end-points, euthanasia, education and training, and retrospective reporting. Other topics include animal selection and receipt, animal health, care and management including cage spacedwhich should consider the animal’s characteristics and behaviour in determining appropriate cage size, or should use the US Guide [5]. A government inspection system does not exist to validate conformance but a third-party audit system is encouraged.

Australia and New Zealand

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Australia

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The Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (the Code), published by the National Health and Medical Research Council (NHMRC), is currently in its 7th edition, having been revised last in 2004 [54]. It is currently undergoing another major revision at the time of writing. The Code is a national standard of practice that requires justification for the use of animals in research and teaching, identifies responsibilities of investigators, teachers and institutions, including the functions of the Animal Ethics Committees, and specifies that the acquisition, care and use of animals for all scientific purposes in Australia must be done in compliance with the Code, as well as with Commonwealth, State or Territory legislation. The Three Rs form the basis for consideration of animal use in the Code. In 2008, the NHMRC published a supplementary set of guidelinesdGuidelines to Promote the Wellbeing of Animals Used for Scientific Purposes: the Assessment and Alleviation of Pain and Distress in Research Animals [55]. Part of the rationale for these guidelines is to address the effects of animal well-being on scientific outcomes. The guidelines include factsheets with guidance on specific, potentially painful or distressful procedures, as well as information on environmental enrichment for common laboratory species. Animal welfare guidance has also been strengthened by the Australian Animal Welfare Strategy (AAWS) [56], a national effort to provide direction for the development of future animal welfare policies in Australia. The AAWS covers the uses of all animals throughout Australia and was developed in conjunction with state and territory governments, animal industry organizations, animal welfare groups and the general public.

New Zealand The Animal Welfare Act of New Zealand was originally passed as the Animal Protection Act in 1960 and revised in 1999 through the Ministry of Agriculture and Forestry [57]. It covers most animals capable of feeling pain, either domesticated or wild. Its main tenets are to provide for

animals’ physical, health and behavioural needs, and to alleviate pain and distress. The Act provides core obligations of people, codes of welfare and specific regulations. Part 6 of the Act is specific for the use of animals in research, testing and teaching and requires that any person (or organization) who uses animals for these purposes must have an approved code of ethical conduct (CEC). The Director-General of the MAF must approve the CEC. The CEC is a document that describes the policies and procedures to be adopted by the code holder, and the Animal Ethics Committee (AEC) that will oversee the use of animals in research. (Part 6 of the Animal Welfare Act describes the criteria by which the committee reviews animal use protocols, and the composition of the committee.) The CEC also assures that all persons working with the animals are sufficiently trained. The CEC may be approved for 5 years, and then may be reviewed and renewed by the National Animal Ethics Advisory Committee (NAEAC). A guidance document to aid investigators in the preparation of a CEC was published in 2006 [58]. In order to help investigators to comply with the goals of the Animal Welfare Act to provide for animals’ physical, health and behavioural needs, the NAEAC and MAF published guidelines for good practice that address the key issues relating to the maintenance of laboratory animal care and welfare [59].

Latin America Brazil A Brazilian federal law on the scientific use of animals was passed in 2008. It established the National Council for the Control of Animal Experimentation (CONCEA), which is a governing and advisory body under the Ministry of Science and Technology, and is empowered to accredit registered institutions and licence activities that use animals for scientific purposes. The law also requires that each institution establishes an Ethics Committee to oversee activities in which animals are used. Even with the passage of this law, many challenges remain regarding its implementation. CONCEA is faced with harmonizing the country’s many legal provisions while not impeding research activities. And, while refinement is specified in the law, there is little

mention of reduction or replacement. CONCEA is thus also faced with promoting the Three Rs in practice. These activities will be important as Brazil has the most dynamic research enterprise in Latin America [60].

Mexico

Other significant regions

In most parts of Africa there are no specific laws that regulate animal research, apart from some old and poorly enforced guidelines and regulations. General animal protection laws, wildlife protection laws and animal disease laws provide peripheral oversight. However, voluntary requirements for ethical review (e.g. [63]) and international accreditation are now emerging and are leading to consideration of regulation,

[1] Council for International Organizations of Medical Sciences. In: Bankowski Z, HowardJones N, editors. International Guiding Principles for Biomedical Research Involving Animals. Geneva: CIOMS; 1986. [2] World Animal Health Organization. OIE Terrestrial Animal Health Code. In: Use of Animals in Research and Education. Paris: OIE. Chapter 7.8, http://www.oie.int/index. php?id¼169&L¼0&htmfile¼chapitre_1.7.8. htm; 2010 (accessed 29 May 2011). [3] Council for International Organizations of Medical SciencesdInternational Council on Laboratory Animal Science. Draft revision of International Guiding Principles for Biomedical Research Involving Animals, http://ora.msu.edu/ICLAS/index.html; 2011 (accessed 30 May 2011). [4] Russell W, Burch R. The Principles of Humane Experimental Technique. London: Methuen, http://altweb.jhsph.edu/pubs/ books/humane_exp/het-toc; 1959 (accessed 29 May 2011). [5] National Research Council. Guide for the Care and Use of Laboratory Animals. 8th ed. Washington DC: National Academies Press; 2011. [6] Benaroya-Milshtein N, Hollander N, Apter Al, Kukulansky T, Raz N, Wilf A, et al. Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. Eur J Neurosci 2004;20:1341–7.

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Africa

References

POLICIES

The Prevention of Cruelty to Animals Law (Experiments on Animals) was passed in 1994 and amended in 2001 [62]. The law establishes a review system and standards that are similar to the US institution-based system. The main control body is a 23-member National Council for Animal Experimentation, which includes scientists and animal welfare representatives. The Council mandates that the smallest number of animals be used while mitigating animal suffering. It oversees the institutional committees, approves applications (either directly or through the institutional committees) and visits animal facilities, often unannounced. Researchers are also required to undergo appropriate training.

The authors would like to acknowledge the contribution of Dr Kathryn Bayne in helping to structure an early draft of this chapter and providing many of the relevant references. Our thanks go also to our colleagues, too numerous to list, for reviewing the geographical text for accuracy.

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Israel

Acknowledgements

LAWS, GUIDELINES

The Norma Oficial Mexicana NOM-062-ZOO1999 (technical specifications for the production, care and use of laboratory animals) was last updated in 2008. The Ministry of Agriculture, Livestock, Rural Development, Fisheries and Food promulgates this law, which covers rodents, rabbits, carnivores, non-human primates and pigs. The law provides guidelines for housing and husbandry as well as requirements for an Internal Committee for the Care and Use of Laboratory Animals [61].

particularly for non-human primates, in a number of countries such as Kenya and Uganda. Often these are based upon the relevant chapter in the OIE Terrestrial Code [2].

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[7] FELASA. Principles and practice in ethical review of animal experiments across Europe: summary of the report of a FELASA working group on ethical evaluation of animal experiments. Lab Anim 2007;41:143–60. [8] FELASA. Principles and Practice in Ethical Review of Animal Experiments Across Europe: Summary of the Report of a FELASA Working Group on Ethical Evaluation of Animal Experiments, http:// la.rsmjournals.com/cgi/reprint/41/2/143? maxtoshow¼&hits¼10&RESULTFORMAT¼ 1&title¼principlesþandþpracticeþinþ&and orexacttitle¼and&andorexacttitleabs¼and& andorexactfulltext¼and&searchid¼1&FIRST INDEX¼0&sortspec¼relevance&resource type¼HWCIT (accessed 30 May 2011). [9] Animal Procedures Committee. Review of Cost-Benefit Assessment in the Use of Animals in Research. London: Home Office, http://www.homeoffice.gov.uk/publications/ agencies-public-bodies/apc/key-reports/ cost-benefit-assessment?view¼Binary; 2003 (accessed 30 May 2011). [10] Nuffield Council on Bioethics. The Ethics of Research using Animals. London: Nuffield Council on Bioethics. p. 274–5, http:// www.nuffieldbioethics.org/go/ourwork/ animalresearch/introduction; 2005 (accessed 30 May 2011). [11] Institute for Laboratory Animal Research. Animal use oversight: balancing risk management with burden. ILAR J 369–434, http://dels-old.nas.edu/ilar_n/ilarjournal/ 49_4/html/, 2008;49 (accessed 30 May 2011). [12] Haywood JR, Greene M. Avoiding an overzealous approach: a perspective on regulatory burden. ILAR J 426–34, http://dels-old. nas.edu/ilar_n/ilarjournal/49_4/pdfs/v4904 Haywood.pdf, 2008;49 (accessed 30 May 2011). [13] International Association for the Study of Pain. An Internationally Accepted Definition of Pain, http://www.iasp-pain.org/AM/ Template.cfm?Section¼Pain_Defi.isplay.cfm &ContentID¼1728#Pain; 1979 (accessed 29 May 2011). [14] Langford DJ, Bailey AL, Chanda ML, Clarke SE, Drummond TE, Echols S, et al. Coding of facial expressions of pain in the laboratory mouse. Nat Meth 2010;7:447–9. [15] Flecknell PA. Do mice have a pain face? Nature Meth. 2010;7:437–8. [16] National Research Council. Recognition and Alleviation of Pain in Laboratory Animals.

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de laboratorio. Mexico: Norma Oficial Mexicana NOM-062-ZOO-1999, Servicio Nacional de Sanidad, Inocuidad y Calidad Agroalimentaria, http://www.senasica.gob. mx/?doc¼743; 2001 (accessed 1 June 2011). [62] Hebrew University. Prevention of Cruelty to Animals Law. English translation, http:// animals.huji.ac.il/upload/105PREVENTIONOF-CRUELTY-TO-ANIMALS-LAW-(EXPE RIMENTS-ON-ANIMALS)-5754–1994.pdf; 2001 (accessed 29 May 2011). [63] South African Medical Research Council. Use of Animals in Research and Training, http://www.sahealthinfo.org/ethics/book3. htm; 2004 (accessed 29 May 2011).

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