Use of Animals in Scientific Research and as Sources of Bioengineered Products (disponible en anglais seulement)

Table of Contents

Executive Summary

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Executive Summary

The total number of animals used in Canada for scientific research, regulatory testing and teaching oscillated between 2.0 and 1.5 million over the last decade, with mice, fish, rats and chickens comprising more than 87% of the total number of animals used. Overall, there is an increasing trend in the number of farm animals used (chickens, cattle, sheep and particularly swine).

It is estimated that the number of animals used for studies involving the creation and use of transgenic animals in Canada increased by 73% from 1997 to 1998, compared to 29% for UK and 20% for US.

The fact that the rapid developments in biotechnology are having an impact on the use of animals in research was recognized by the Canadian Council on Animal Care (CCAC) in 1996, through the adoption of an expanded definition of the universal application of its program into the realm of the commercial use of animals, to ensure oversight of animal welfare. The publication of the CCAC guidelines on: transgenic animals in 1997 as an enforcement tool for CCAC’s activities in this matter further recognized the growing influence of biotechnology on animal use in Canada.

The CCAC is the national organization overseeing the care and use of animals for research, testing and teaching in Canada since 1968. CCAC was established as a voluntary control program, subject to peer judgement and committed to implementing the guiding principles of an independent advisory body. Created as a standing committee of the Association of Universities and Colleges of Canada, the contemporary CCAC was incorporated as a non-profit and autonomous body in 1982. It is mostly funded by public monies through three-year grants from the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council (NSERC), with additional contributions from federal science-based departments and agencies (SBDAs) and private institutions. Since 1993, the CCAC has operated on the basis of distributed management involving nearly 2000 scientists, veterinarians, animal welfare movement and public representatives across the country, participating in CCAC programs of assessment, guidelines development and education, and on 224 institutional Animal Care Committees (ACCs), the keystone of the Canadian system.

The CCAC has not implemented a common ethical framework for the review of protocols, believing that ACCs are in the best position to develop their own process, and that the system used must be appropriate for each individual institution. Some tests proposed as objective ways to describe welfare aspects of animal-based research have been tested by ACCs and found to be too restrictive and not sufficiently reflective of the complexity and intricacy of ethical decisionmaking in the practical context. CCAC guidelines on: animal use protocol reviewprovide guiding principles on 13 aspects of protocol review to assist ACCs with their work.

The CCAC conducts in-depth assessment visits of about 170 institutions using animals every three years, and follow-up visits by members of the CCAC Secretariat are also carried out, often unannounced. Institutions assessed by the CCAC and which achieve a CCAC status of Compliance or Conditional Compliance are awarded a Certificate of Good Animal Practice® (GAP), which became CCAC’s registered trademark in August 2000. The list of holders of a GAP Certificate is public information.

CCAC is recognized in several documents of the SBDAs as the organization responsible for setting standards for all research involving animals. CCAC standards are also recognized as equivalent or superior to those applied outside Canada. CCAC is the Canadian signatory to The European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, and is an Organisation for Economic Co-operation and Development (OECD) Health Effects Expert for the Test Guidelines Program. CCAC is the home of the International Council for Laboratory Animal Science (ICLAS).

Even though Canada did not promulgate national legislation to govern animal use, as this matter is a provincial jurisdiction under the Canadian Constitution 1867, the CCAC pioneered the establishment of institutional ACCs which were subsequently emulated in many other countries overseeing animal use through legislation, as the ultimate mechanism to ensure public accountability. The value of this fundamental contribution has been acknowledged by the UK, US and several other countries. This is a Canadian asset which should be considered as a competitive advantage in view of the increasing tendency to determine, disseminate and implement best international practices and standards in relation to the care and use of animals.

The challenges posed by the new genetic technologies in relation to animal welfare can be divided into two groups of issues: pain/distress and meeting the needs of science/industry/ decision-makers and the public. Canada’s regulatory framework for regulating products derived from biotechnology, involving six principles and four SBDAs, was announced in 1993. In 1998, the CCAC suggested a framework for animal welfare oversight bridging the gap between the research environment and the production environment to ensure a seamless animal welfare oversight and regulation between the CCAC and the pertinent SBDAs. This bridging framework has been successfully implemented in collaboration with Health Canada in relation to the use of animals for xenotransplantation.

The implementation of the bridging framework in collaboration with Agriculture and Agri-Food Canada and the Canadian Food Inspection Agency (CFIA) is at mid-stage as it relates to livestock derived from biotechnology. While no collaborative work has been initiated yet on animals used as bioreactors for the production of biologicals, it is expected that this matter will follow a path similar to the positive interface with Health Canada (HC) on xenotransplantation.

CCAC is successfully overseeing the use of Genetically Modified Animals (GMAs) in all academic institutions with mandatory enforcement mechanisms provided by CIHR and NSERC. No such enforcement mechanism has been developed yet in the government and private sectors, where participation in the CCAC program is exclusively on a voluntary basis. While several pharmaceutical and biotech companies and many federal and provincial laboratories are participating in and supportive of the CCAC program, unlike the academic sector, the CCAC has no enforcement tools to ensure that they ALL participate. This is the major issue that needs to be addressed in adapting CCAC’s approach to new biotechnologies.

In line with Canada’s Biotechnology Strategy and the Federal S&T Strategy, it is suggested that Industry Canada undertake the role of fiduciary for the governmental and industrial sectors. This would make the federal government fully accountable to the Canadian public by ensuring the universal implementation of CCAC’s program to all sectors.

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A. Animals Used in Scientific Research

1. Types of Uses of Research Animals

In 1998, a total of 1,765,973 animals used in research, teaching and testing was reported to the Canadian Council on Animal Care (CCAC). In order to permit a refined analysis, numbers of animals used are broken down per species, per Purposes of Animal Use and per Categories of Invasiveness as defined by the CCAC (see Appendix A, Table I to III).

The most commonly used species; mice (32.5%), fish (22.6%), rats (19.5%) and chickens (12.7%) comprised 87.3% of the total of animals used, followed in decreasing order of numbers of animals used, by guinea pigs (2.0%), swine (1.8%), cattle (1.3%), and rabbits (0.9%). From 1989 to 1998, the top four species used remain the same and comprised more than 87% of the total number of animals used in each year except for 1993 (80%, see Table II).

58.5% of 1,765,973 animals were used in studies of a fundamental nature (PAU=1), 17.4% were used in studies for medical purposes, including veterinary medicine, that relate to human or animal disease or disorders (PAU=2), 14.3% were used for regulatory testing of products for the protection of humans, animals or the environment (PAU=3), 6.6% were used in studies for the development of products or appliances for human or veterinary medicine (PAU=4), and 3.2% were used in education and training of individuals in post-secondary institutions or facilities (PAU=5) (see Table III).

Classifying animals in research, teaching and testing according to the Categories of Invasiveness (CI) as defined by the CCAC in the policy statement of February 1991¹, shows that animals were used for experiments with invasiveness levels B (39.8%), C (26.4%), D (30.7%) and E (3.1%) (see Table III) where the level of invasiveness increases in alphabetical order.

Although more animals were used in 1998 than in 1997 (due mostly to greater numbers of fish, mice and rats), the number of animals used in 1998 remained inferior to the numbers used, on an annual basis, from 1975 through 1996. Trends in experimental use of common farm species (chickens, cattle, sheep and swine) from 1989 to 1998 (see Table IV) show an overall increase in the number of farm animals used. Detailed results on the CCAC Survey of Animal Use - 1998 have been published in the Fall 2000 edition of the CCAC newsletter RESOURCE².

a) Genetically Modified Animals (GMA)

Genetic modification takes many forms, including the generation of transgenic and knock-out animals, the development of techniques for somatic cell gene therapy, and the introduction of genetic modifiers that do not change the gene itself, but change how or when it is expressed. Cloning falls into the domain of reproductive technology and refers both to embryo-splitting, which generates clones from embryos and to cloning of an adult, by transfer of the nuclei of adult cells into enucleated embryos. The use of GMAs in Canada falls into the same categories as elsewhere in the world: basic research; source of organs for xenotransplantation; disease models; production of therapeutic proteins, medical devices and recombinant proteins for industrial application; agricultural manipulation of livestock production; vaccine testing; and toxicity testing.

The fact that biotechnology is having an impact on the use of animals in research was recognized in 1997 through the publication of CCAC guidelines on: transgenic animals³. The guidelines require that proposals to create novel transgenics initially be assigned a Category of Invasiveness D; the subsequent experimental manipulations of these animals are subject to separate use proposals which are assigned an appropriate level of invasiveness depending on the phenotype and the invasiveness of the procedure.

A CCAC in-house computer search for the term “transgen” has yielded the estimated numbers of animals used in studies involving the creation and use of transgenic animals in Canada over the past three years. These numbers are given below. These estimates reveal that the number of animals involved in transgenic studies in Canada increased by 73% from 1997 to 1998, the most recent year for which preliminary data are available. Over 92% of transgenic animals created and used over the past three years are mice, with a notable increase in farm animals (chicken, swine and goats) appearing in 1998. Transgenic studies accounted for approximately 3.1%, 4.0% and 5.7% of all animals used in 1996, 1997 and 1998 respectively, with mice accounting for the vast majority of this increasing trend.

The annual UK Home Office report on the Statistics of Scientific Procedures on Living Animals: Great Britain 1998⁴ reported that overall GMAs accounted for 20% of all the animals used and that the use of such animals increased by 29% from 1997 (352,752) to 1998 (447,612) and of these, 96% were mice. A 20% annual increase in the number of transgenic mice has also been reported in the United States⁵.

Animals Used for Transgenic Studies in Canada
(Estimated numbers)

Species	1996	1997	1998
Mice	57,263	54,756	100,271
Rats	791	241	740
Hamsters	463	78	0
Rabbits	0	1	42
Fish	3,060	4,220	279
Chickens	0	0	1,005
Swine	0	0	207
Goats	0	17	77
Cattle	0	0	2
Total	61,577	59,313	102,623

It is known that about 10% of all embryos subjected to genetic manipulation successfully incorporate the genetic trait⁶. Animals which do not incorporate the trait can be used for other purposes, which is encouraged by the CCAC. On the other hand, the use of nuclear transfer technology could dramatically reduce the number of animals used during founder transgenic animal production. Evidence for this was provided by a Canadian biotech company where the pronuclear microinjection program with goats is 5% successful. Using nuclear transfer for incorporation of the genetic trait would approach a 100% success rate as the gene of interest would be introduced into a cell in cell culture and the integration confirmed prior to production of the cloned goats. The precision of the genetic modification resulting from nuclear transfer reduces the number of insertion and expression problems normally associated with the microinjection approach. Although nuclear transfer is useful to introduce genes into the animal genome, this particular biotech company rejects its use for the production of large numbers of identical animals in order to maintain genetic diversity. The limitation to an increased use of the cloning approach is also related to the fact that it is more expensive and few people have the skills to perform the nuclear transfer procedure.

The CCAC is now designing a form to collect statistics on the nature and size of breeding colonies, transgenic and non-transgenic, maintained at participating institutions for implementation in 2001-2002.

2. The Canadian Ethical Review and Oversight of Animal Care and Use System

The 1950s and 1960s were a period of phenomenal growth in Canadian scientific research, particularly in the biomedical sciences, with an associated expression of public concern over the use of animals in research. The early recognition of those concerns as legitimate and the concomitant linkage of users and non-users of animals in designing and participating in an effective mechanism to empower all parties, including non-user members of the public, to participate at the local level in an informed decision-making pocess, gave rise to and still nurtures the CCAC.

CCAC’s ethical review system is designed to balance the needs of the scientists, the animals and the community at the local level, and to set standards for the care and use of animals in science at the national level. The CCAC is acknowledged⁷ as the first organization, worldwide, to establish the concept of the Animal Care Committee (ACC). Establishment of ACCs have subsequently been emulated by a number of countries including Australia, the US through the Animal Welfare Act (1986) and has been a requirement in the UK from April 1999.

a) History

In 1963, the Medical Research Council (MRC), now known as the Canadian Institutes of Health Research (CIHR), requested that the National Research Council (NRC) establish a committee to investigate the care and use of experimental animals in Canada. The report of the Special Committee on the Care of Experimental Animals⁸ (1966) recommended the creation of a voluntary control program exercised by scientists in each institution, subject to peer judgement and committed to implementing the guiding principles of an independent advisory body. A feasibility study of these proposals was undertaken in 1967⁹ and, as a result, all universities and government departments where animals were used agreed to support the formation of a Canadian council on animal care¹⁰.

The CCAC was established in 1968 as a standing committee of the Association of Universities and Colleges of Canada (AUCC) comprising 12 member organizations, including the Canadian Federation of Humane Societies (CFHS). It was incorporated as a non-profit, independent and autonomous body in 1982. Ten years later, a decision was taken to increase representation of national organizations representing non-users of animals on Council to 20%; this move towards greater fairness and inclusiveness catalyzed trust building between all stakeholders culminating, for the first time in 1999, in the election of the former President of the CFHS, Ms Eleanor Dawson as Chair of the CCAC. Recently appointed as Judge at the Federal Court, the last article she signed as Chair of CCAC was published in the Fall 1999 edition of CCAC’s newsletter RESOURCE under the visionary title “Universality: Beyond Legislation”. The size and structure of the CCAC Council is currently under review by the Standing Committee on Planning and Priorities to propose additional ways to ensure that all stakeholders have a voice and that they feel that their voice is heard.

The CCAC is mostly funded by public monies through the CIHR and NSERC, with additional contributions from federal science-based departments and private institutions. While the CCAC operates on an annual budget, it is funded through three-year grants from CIHR and NSERC allowing the development of long term policy. The performance of the CCAC is reviewed every three years upon grant renewal. The review is not conducted by the granting councils, but by an external panel. The CCAC was recently assessed by the Centre on Governance of the University of Ottawa as a model for the development of a national ethical process for research involving human subjects. They concluded:

“There is much to commend the CCAC as a model...one element [basic criterion] that exists between the CCAC, its funders, and the research community is credibility and trust”¹¹.

Centre on Governance, University of Ottawa, March 2000

“The purpose of the Canadian Council on Animal Care is to act in the interests of the people of Canada to ensure through programs of education, assessment and persuasion that the use of animals, where necessary, for research, teaching and testing employs optimal physical and psychological care according to acceptable scientific standards, and to promote an increased level of knowledge, awareness and sensitivity to relevant ethical principles.”¹²

The contemporary CCAC is a national, peer review organization comprising 22 member organizations (Appendix B), whose representatives include scientists, educators, veterinarians and delegates from industry and the animal welfare movement. In 1993, the CCAC decided to move to a distributed management system whereby the Council sets policy and budgets, with the majority of actual work being done through five Standing Committees (Assessments, Guidelines, Education and Training, Finance, and Planning and Priorities) and the Board of Directors in concert with a Secretariat staffed by 10 individuals based in Ottawa. Additional expertise not available from Council is achieved by appointment of ad hoc members to any Standing Committee as needed. Nearly 2000 volunteers across the country participate in the CCAC programs of assessment, guidelines development and education, and on institutional ACCs.

b) The Institutional Animal Care Committee

In Canada, the responsibility for monitoring the continuing appropriateness of the work rests with the local ACC, whose operation is overseen by the CCAC. The CCAC pioneered the establishment of institutional ACCs. There are now over 224 ACCs that ensure the ethical use of animals in their institution. Their membership includes scientists using animals, a veterinarian, an institutional non-animal user and at least one community representative. ACCs are the keystone of the Canadian system.

Each protocol involving animals must be approved as being ethically acceptable before animals can be used. Additionally, ACCs ensure that evaluation of the scientific merit of research projects has been conducted through adequate peer review. It is also the responsibility of the ACCs to monitor the progression of the projects to ensure that there is no unnecessary pain or distress to the animals involved. Details on the membership, authority, and responsibilities of ACCs will be found in the Terms of Reference for Animal Care Committees¹³ (Appendix C).

The CCAC has not implemented a common ethical framework for the review of protocols, believing that ACCs are in the best position to develop their own process, and that the system used must be appropriate for each individual institution. Some tests (Bateson cube¹⁴, Porter scores¹⁵) have been proposed as objective ways to describe welfare aspects of animal-based research. Dr Porter’s ethical score sheets have been tested by a few ACCs. However, ACCs found that their application was too restrictive and did not facilitate good discussion and flexibility in dealing with the many components examined during a good protocol review. Observations made by ACCs about Dr Porter’s scoring system were echoed in the latest scholarly publication on the matter in the following terms:

“Philosophers have offered a variety of theories and principles for judging the ethical acceptability of animal experiments. We think that these theories do not live up to the complexity and intricacy of ethical decision-making in a practical context. Rather they ignore and reduce this complexity by imposing too broad and simple principles (Singer 1990, 1995), pre-emptive norms (Taylor, 1986)) or fundamental rights of animals (Regan, 1983) on the balancing process.”¹⁶

CCAC guidelines on: animal use protocol review (Appendix D) provide guiding principles on 13 aspects of protocol review to assist ACCs with this task. The fulfilment of an ACC’s responsibility is ensured during CCAC assessments and follow-up visits. The CCAC's emphasis on well-functioning ACCs has received international recognition and acceptance in all industrialized countries, with varying degrees of compliance with the Canadian system as it relates to the mandatory or optional nature of the participation of the community representative on the ACC. In Canada, it is mandatory, and many ACCs have more than one community representative.

c) Assessment Program

Assessments are carried out by CCAC assessment panels composed of scientists, veterinarians and members of the animal welfare movement nominated by the CFHS with the objective of evaluating animal care and use in Canadian universities, community colleges, hospitals, and government and private sector facilities. The CCAC conducts in-depth assessment visits to about 170 institutions using animals at about every three years, and follow-up visits by members of the CCAC Secretariat are also carried out, often unannounced. Assessments are based on CCAC’s Guide to the Care and Use of Experimental Animals, Volumes 1¹⁷ and 2¹⁸ and accompanying guidelines and policies as revised from time to time. The complementary roles of the CCAC Secretariat, the assessment panel members, the CCAC Assessment Committee and the institutional ACCs in the Assessment Program are detailed in Appendix F.

Institutions assessed by the CCAC and which achieve a CCAC status of Compliance or Conditional Compliance are awarded a Certificate of Good Animal Practice®. This Certificate provides clear evidence that an institution meets the high national standard for the care and use of experimental animals used in research, teaching and testing in Canada, including not only laboratory animals, but wildlife and farm animals as well. From July 1999, the CCAC has been posting the list of holders of the Certificate of Good Animal Practice® on its website (http://www.ccac.ca). CCAC standards are recognized internationally to be as high, or superior to standards developed in other countries (see section A.4.a and b).

Compliance with CCAC standards is a mandatory requirement for all academic institutions receiving funds from Canada’s federal granting councils. Failure to comply can result in the loss of federal research funding. Although a similar enforcement tool is not presently available to ensure the universal implementation of the CCAC program in the other two sectors, it should be noted that most science-based federal departments and agencies using animals participate in the CCAC program, and recipients of contracts from some departments are requested to comply with CCAC guidelines and policies. For private sector institutions, a Certificate of Good Animal Practice®, for which the CCAC has a registered trademark associated specifically with its Assessment Program, validates the maintenance of humane, scientifically administered animal care and use for research, teaching and testing.

d) Guidelines Development

Prior to CCAC’s establishment, the only guidelines which had been defined for the care and use of experimental animals in Canada had been the Canadian Federation of Biological Societies’ one-page Guiding Principles for the Care of Experimental Animals (1961). Within its first year, the Council published comprehensive guidelines entitled Care of Experimental Animals: A Guide for Canada¹⁹ covering the following areas: pain, environmental factors, structural considerations, husbandry, procurement and transportation, information on individual species, safety, efficiency of operations, and responsibility for animal care. This seminal document which was both simple and comprehensive, provided the basic tool needed by members of institutional ACCs in beginning to deliver their ethical mandate and by CCAC assessment panels as a reliable basis for their recommendations.

Volume 1 of the CCAC Guide to the Care and Use of Experimental Animals (1980) and its second edition in 1993¹⁷, as well as Volume 2 of the CCAC Guide published in 1984¹⁸ provided the learning tools essential to foster social learning needed to address ethical issues over the subsequent two decades. The two volumes of the CCAC Guide are well known worldwide. Volume 1 and 2 are undergoing revision. Volume 1 is available in English, French, Chinese and Spanish.

In addition to ongoing revision of guidelines, CCAC also develops guidelines on issues of current and emerging concerns. Guidelines addressing emerging needs relating to animal use protocol review (Appendix D) and to transgenic animals (Appendix E) have both been published in 1997. Canada was the first country to publish guidelines on: choosing an appropriate endpoint in experiments using animals for research, teaching and testing²⁰ in 1998, a section of which was incorporated in the OECD’s guidance document on endpoints²¹. CCAC’s guidelines on: endpoints and the OECD draft guidance document were recognized as effective refinement tools at the 1999 Third World Congress on Alternatives and Animal Use in the Life Sciences in Italy. CCAC published its guidelines on: institutional animal user training with an accompanying Recommended Syllabus for Institutional Training Programs²² in 1999.

Guidelines on: the use of wildlife in research, teaching and testing are scheduled to be published in 2001 and guidelines on: the use of farm animals in research, teaching and testing are scheduled to be published in 2002. While a section of the CCAC guidelines on: farm animals will cover the care of livestock emerging from biotechnology, the guidelines on wildlife are needed to address the emergence of ecological ethics among other issues.

e) Universal Implementation of CCAC Programs and Biotechnology

Historically, the CCAC has had the universal implementation of its programs as an organizational goal. However, it is only at its September 1996 meeting, upon a recommendation from its Planning and Priorities Committee, that the Council adopted a motion defining clearly the scope of universality for the CCAC. For the purpose of the present study, it is useful to know that the main objectives of the CCAC in adopting the definition appearing below were to:

• maintain the distinction between organizational and individual responsibility;
• clarify the scope of the terms research (clause a), teaching (clause b) and testing (clause c), and
• expand the domain of the CCAC into the realm of the commercial use of animals to ensure the oversight of animal welfare in situations where the animal is the factory (clause d) because of rapid developments in the biotechnology industry.

“Universal application of the programs of the CCAC means that they apply to all animals used by: i) members, ii) individuals, and iii) employees, agents or owners acting on behalf of organizations or businesses registered or operating in Canada for any of the following purposes:

a) to investigate or to search carefully for fact or truth in order to produce knowledge about humans and/or animals;

b) to transfer or to permit the acquisition of knowledge; or, to develop or improve skills;

c) to use an established or legislated procedure to demonstrate, determine or verify a fact or findings. This includes, but is not limited to: the testing of sera, vaccines, diagnostics or medical/veterinary/biological products or conducting biological tests; performing toxicological or pharmacological procedures; identifying or detecting pregnancy, disease or other physiological conditions, or characteristics other than those used in normal and proper veterinary treatment;

d) to produce products for the purpose of generating profit. This includes, but is not limited to: the manufacture of sera, vaccines, diagnostics, or medical/veterinary/biological products; the capture, production or transportation of animals for use in research, teaching, testing or manufacturing; and agricultural quality improvement programs.”²³

f) National and International Recognition

• “The CCAC sets the standards for all research involving animals.”
  -Government Response to the Report of the Commons
  Standing Committee on Health, Organ and
  Tissue Donation and Transplantation:
  A Canadian Approach, September 1999
  
  
• In 1996, under the sponsorship of UK, the CCAC was admitted by the Council of Europe as the first non-international expert organization to become one of the signatories (the only Canadian representative) of The European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes. CCAC is currently participant on the Working Party amending the Convention, the main document guiding European countries in this matter.
  
  
• The Organisation for Economic Co-operation and Development (OECD recognized the CCAC as one of the Health Effects Experts for the Test Guidelines Program in September 1999. CCAC provides input on OECD documents involving animal studies on a regular basis.
  
  
• On August 8, 1999, on the basis of a thorough evaluation of the CCAC program, the American College of Laboratory Animal Medicine (ACLAM) confirmed that Canadian institutions holding a CCAC Certificate of Good Animal Practice are exempt from the requirement to be accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International for the purpose of providing an ACLAM recognized formal training program in laboratory medicine.
  
  
• The Office for Protection from Research Risks (OPRR) of the National Institutes of Health, US (now known as the Office of Laboratory Animal Welfare (OLAW)) confirmed in 1997 and in 2000 that “OPRR fully accepts the Canadian system of animal welfare oversight for US Public Health Service funding purposes” received by Canadian institutions.
  
  
• CCAC is Canada’s national member on the International Council for Laboratory Animal Science (ICLAS) and became it’s home in June 1999 for four years. ICLAS has been established in 1956 under the auspices of UNESCO to promote international collaboration as a worldwide resource of knowledge in laboratory animal science.

g) Genetically Modified Animals: Pertinent Guidelines

In 1995, the CCAC realized that the increase in the use of GMAs warranted additional regulation. For the CCAC, this meant the production of peer-based guidelines on the care and use of transgenic animals. These were developed by the CCAC’s scientific subcommittee and were published in 1997. The CCAC guidelines on: transgenic animals (Appendix E) were intended to supplement the basic guidance given to institutions (CCAC Guide to the Care and Use of Experimental Animals¹⁷). At the time of publication, it was recognized that in this rapidly evolving area, these guidelines would need to be re-examined, and revised if necessary, on a regular basis. The CCAC guidelines on: transgenic animals were produced:

• to assist ACC members and investigators in evaluating the ethical and technological aspects of the proposed creation, care and use of GMAs;
• to ensure that GMAs are used in accordance with the CCAC Policy on Ethics of Animal Investigation²⁴; and
• to ensure that the well-being of Canadians and the environment is protected.

A list of procedures involving GMAs, which would not be considered ethically acceptable under any circumstances, does not exist per se in Canada. However, according to the CCAC guidelines on: animal use protocol review (Appendix D) all animal use protocols must be examined for their ethical merit and must have undergone scientific merit review (institutions must use either the merit review of a granting agency, or review by two investigators with no vested interest in the study and external to the ACC). Any studies which have the potential to cause pain and distress to the animals involved warrant special attention, and ACCs must not approve studies where it is considered that the costs to the animals are not matched by the scientific promise of the study.

According to the CCAC guidelines on: transgenic animals (Appendix E), submission of a protocol for the creation of a transgenic strain of animals requires the ACC to ensure that the investigator has placed such studies in Category of Invasiveness D (experiments which cause moderate to severe distress or discomfort²⁵) to begin with, the intention being to cover the worst case scenario, that the insertion or deletion of a gene might lead to a phenotype causing pain and/or distress. The category of invasiveness is re-evaluated once the phenotype is known.

For all transgenic creation proposals, the guidelines on: transgenic animals recommend that approval should be provisional, limited to a 12 month period, and subject to the requirement that the investigator report back to the ACC as soon as possible on the animals’ phenotype, noting particularly any evidence of pain and/or distress”. Protocols, in any case must be renewed by an ACC on an annual basis, at this time, the progress of the work and any causes for concern are discussed.

It is also important to produce GMA models that model early stages of a disease. This is vital to ensure that the potential for pain and/or distress is minimized. In this respect, the CCAC places importance on establishing early endpoints for animal models which have the potential to progress to causing animal suffering. The CCAC guidelines on: transgenic animals include a Transgenic Information Sheet as an Appendix, requiring investigators to describe monitoring and recording procedures for detecting physical and behavioural abnormalities which are indicative of pain and/ or distress. This has been further addressed in the CCAC guidelines on: choosing an appropriate endpoint in experiments using animals for research, teaching and testing²⁰, which are applicable to GMAs, as well as non-GMAs.

Finally, the CCAC views appropriate training to be a key component of an effective institutional animal care and use program. Many institutions across Canada already have excellent training programs in place for their animal users. The CCAC has published guidelines on: institutional animal user training²² to assist institutions in developing and improving training programs and to work towards a national standard for training. Clearly, personnel involved in the generation and use of transgenic animals need to attend courses which emphasize the particular problems raised by use of GMAs.

3. The Three Rs (Replacement, Reduction, Refinement)

The CCAC policy statement on the Ethics of Animal Investigation²⁴ states that an approved protocol should support the premise “that animals should be used only if the researcher's best efforts to find an alternative have failed. A continuing sharing of knowledge, review of the literature and adherence to the Russell & Burch (1959) ‘Three Rs’ (Reduction, Replacement and Refinement) are also requisites. Those using animals should employ the most humane methods on the smallest number of appropriate animals required to obtain valid information.” Since its inception, the CCAC has promoted the “Three Rs” concept.

Refinement of animal use includes meeting the social and behavioral needs of animals. The need for appropriate and adequately sized enclosures that are clean, safe, secure and suitably bedded is well-established in CCAC’s guidelines. The CCAC encourages provision for the social and behavioral requirements of experimental animals through social interaction and enrichment devices.

It is clear that the improvements offered by GMAs must be dramatic when compared to what is possible by other accepted approaches. Benefits to patients, producers and consumers must be tangible and outweigh the costs in animal welfare, royalties, license fees, biocontainment, regulatory and public acceptance. See Griffin and Gauthier for a detailed discussion on the Three Rs and GMAs²⁶.

“The regulatory framework to oversee GMAs in the production environment are not yet in place. Ensuring that CCAC is responsible for the oversight of the welfare of these animals until all the research questions have been answered provides assurance that non-animal methods have been considered, and that the minimum number of animals have been used, with careful attention paid to minimizing any potential pain and/or distress. This should be seen as a necessary component of the regulatory framework for genetically modified animals.”²⁶

4. Comparison of Legislative and Regulatory Frameworks

a) Legislation in the United Kingdom

The UK’s Animals (Scientific Procedures) Act 1986, which replaced the century-old Cruelty to Animals Act 1876, gives the Home Secretary the responsibility for judging the scientific merit of the research he authorizes, for which he will be answerable to parliament. Section 5(4) states that “In determining whether and on what terms to grant a project licence, the Secretary of State shall weigh the likely adverse effects on the animals concerned against the benefit likely to accrue as a result of the program to be specified in the licence.”

The Act also calls for a statutory 21-member Animal Procedures Committee (APC) which has wide powers to advise the Home Secretary, who controls the overall severity permitted. The APC was to provide the mechanism for ethical debates. However, a former member Judith Hampson, also former Animal Experiments Officer with the Royal Society for the Protection of Cruelty to Animals (RSPCA), has stated that the committee deals only with a few cases referred to it by the Home Office and “has failed to deal adequately with issues of particular concern to the public...and there is very little public accountability”²⁷. Subsequently, the RSPCA published a paper describing the basis for the composition and function of ethics committees in 1994²⁸ and ultimately convinced the Home Office of their value. The UK began to implement a system of institutional ACCs in April 1999; however, the participation of representatives from the public on these ACCs is not yet mandatory, as it is the case in Canada. In a letter sent to the MRC and copied to the CCAC as part of the granting councils’ latest three-year review of the CCAC, the Chief Inspector of the Home Office, Dr Jon Richmond, conveyed the following evaluation of the CCAC:

“From our own domestic perspective we have benefitted from the efforts of CCAC in producing sensible, informed, practical guidance on a number of issues: indeed CCAC guidance documents are used as part of our own induction training packages...

From the international perspective we believe that Europe has benefitted from CCAC’s outward facing attitude and presence at international meetings. We perceive the future involving increasing activity to determine, disseminate and implement best international practices and standards. CCAC documents are also in wide circulation amongst other European National Competent Authorities. I work on a number of animal protection issues with the International Standards Organisation and have been surprised, to date, not to encounter CCAC staff as part of any Canadian delegation...

From my personal perspective, I would hope that CCAC will continue to make its expertise available to other countries - Canada has a good story to tell on animal protection issues.”

Dr Jon Richmond, Chief Inspector
Home Office, UK, December 4, 1998

b) Legislation in the United States

In the US, two primary federal laws govern animal use. The Health Research Extension Act (or National Institutes of Health-NIH Authorization Act) passed in 1985 requires establishment of Institutional Animal Care and Use Committees (IACUCs) and IACUC inspections. The Animal Welfare Act (1985) includes in its requirements provision of adequate veterinary care with appropriate use of anesthetic, analgesic, tranquillizing drugs, or euthanasia, consideration by the principal investigator of alternatives to any procedure likely to produce pain and distress, and establishment of IACUCs, which must include a veterinarian.

The US Department of Agriculture (USDA), Animal and Plant Health Inspection Service, March 15, 1989 published Animal Welfare; Proposed Rules in the Federal Register (pgs. 33447-33531) to amend the Animal Welfare Act (7 U.S.C. 2131-2157), which itself was an amendment to the Farm Bill (1985). Eventually, the Final Regulations, issued February 15, 1991, and published in the Federal Register (pgs. 6426-6505) were “performance based,” i.e., the health of the animals would be of greater importance than details of their housing. By August 14, 1991, institutions had to produce written plans for providing exercise for dogs and improving the psychological well-being of non-human primates. However, a US judge invalidated the regulations because they did not set minimum standards. Such standards were subsequently introduced. Since the late 1980s, standards have been developed and performance-based assessments have been implemented progressively by the CCAC in Canada with the collaboration of institutions participating in its program.

January 8, 1992, as the result of a lawsuit launched by the Humane Society of the United States and the Animal Legal Defence Fund , the US district court in Washington DC ruled that the USDA had violated the federal Animal Welfare Act by denying basic protection to America’s 15 million mice, rats and birds used annually in research. The government subsequently appealed this decision which has not yet been resolved. In addition to vertebrates (including rats, mice, birds and many additional species), CCAC monitors the use of cephalopods, a subphylum of the invertebrates, and reports publicly on an annual basis the number of animals used per species, per animal use and per category of invasiveness.

“CCAC has done a marvelous job in Canada and has served as a “non-legislative” role model for many countries of the world, such as Australia and New Zealand...AALAS is convinced that CCAC is an international asset. The CCAC does a tremendous amount of good for animal care and use, and animal welfare...CCAC has taken a leadership role in Canada while communicating and assisting in the development of US policy and programs. CCAC has paved the way to assuring responsible, ethical animal research assurance in Canada. The partnership between the United States and Canada is of vital importance to improvements in laboratory animal science in the international arena.”

George W. Irving, DVM
President, American Association for
Laboratory Animal Science (AALAS)
December 30, 1998

c) Legislation in Canada

Legislative Jurisdiction Over Animals Used in Teaching, Testing and Research

In 1989, the CFHS proposed federal legislation governing experimental animals, which included economic sanctions and more power for non-user members of institutional ACCs. The CFHS proposal was later refused by the then Minister of National Health and Welfare, The Hon. Perrin Beatty, who considered it would be more expensive than CCAC’s program, and “would not improve the already excellent level of care given to animals in Canadian laboratories”¹⁷.

In 1998, as an aid in determining the most effective means of achieving universal application of its programs, the CCAC commissioned a legal opinion on the locus of legislative jurisdiction over the care of animals used in research, teaching, testing and production (except for food and fibre) under the Canadian Constitution. Legislative Jurisdiction Over Animals Used in Teaching, Testing and Research (Appendix G) is a most comprehensive and current analysis of the division of powers between the federal and provincial governments in relation to relevant laws’ pith and substance test to review whether:

“under the Constitution Act, 1867 there is any power for the federal government, or for the provincial level of government, to legislate standards for the humane treatment of animals used in research, testing and/or production of medical/veterinary/biological/pharmacological products; and

under the Constitution Act, 1867, there is any authority for the federal government to implement programs or policies (non-legislated mechanisms) to encourage or set standards for the humane treatment of animals used in research, testing and/or production.” (Appendix G, p.2)

i) The Criminal Code of Canada

The Criminal Code of Canada, Section 446, Cruelty to Animals, forbids “causing unnecessary suffering.” The century-old (1892) Code states that: “Everyone commits an offence who wilfully causes or, being the owner, wilfully permits to be caused unnecessary pain, suffering or injury to an animal or bird....”

The Law Reform Commission of Canada, after 15 years' preparation and considerable public input, proposed widespread amendments to the Criminal Code in a report entitled Report 31 Recodifying Criminal Law in 1988. The proposed changes relating to animals centred on treating animals as sentient beings, and not merely chattel put here for humans’ use, a position the Canadian Veterinary Medical Association, among others, considered merited support. Chapter 20, Title IV, Crimes Against the Natural Order, Crimes Against Animals, focused on three areas: cruelty to animals, organizing sporting events and animal neglect. It noted, for example, that “Everyone commits a crime who unnecessarily causes injury or serious physical pain to an animal.” Scientific research is exempt “unless the risk of injury or serious physical pain is disproportionate to the benefit expected from the research.” Although tabled in Canada’s House of Commons, May 19, 1988, no action has been taken to date to implement the report.

Proposed amendments to the Criminal Code (Bill C-17), including a section on cruelty to animals, passed first reading by the House of Commons on December 1999. While the Bill contains a general statement regarding “conventional use of animals”, scientific research is not specifically excluded from the proposed amendments. If adopted, these amendments would result in animals no longer being treated as property, as it is the case now, except for wild animals. “Constitutional jurisdiction over real or personal property in Canada is explicitly and exclusively conferred upon the provinces under the “Property and Civil Rights” heading in CA 1867.” (Appendix G, p.6)

While all of the provinces have legislated in the area of animal welfare in some form or another (p.7), only Alberta, Prince Edward Island, Manitoba and Ontario have specifically occupied the field of animals acquired and used for research and teaching purposes. Prince Edward Island, Manitoba and Ontario’s legislation are truly universal in their field of application as they are not restricted to the academic milieu and so apply to all animal research, teaching and testing activities. Ontario’s legislation, the Animals for Research Act, is unique in that it provides for a positive licensing regime over and above the negative prohibition regime (p.8). These observations led CCAC’s legal advisors to conclude:

“Having reviewed the authorities in the area of jurisdiction over health, agriculture, and trade and commerce, it is our view that use of these mechanisms would result in colourable attempts by the federal government to achieve what it cannot achieve directly...However, leaving the issue up to the provinces results in the current state of uneven regulation and enforcement across the different provinces.” (Appendix G, p.4)

The CCAC’s current approach is one of certification. “The head of federal power offering the most promise, the criminal law head, has already been occupied by the federal government in the form of Criminal Code prohibitions against cruelty to animals. The limitation of this approach is that it is of limited usefulness in achieving a positive licensing or certification-based scheme, since criminal law, by definition, must have as its dominant characteristic, prohibitions which operate by way of negative coercion, rather than positive persuasion.” (Appendix G, p.5).

ii) The Federal Spending Power

The federal spending power is recognized by the authors of the legal opinion as one of the most powerful instruments available to the federal government for setting national standards which is not strictly speaking legislative in nature (Appendix G, p.15). This manifestation of the federal power is what has underpinned the universal implementation of CCAC standards in the academic sector since 1968. As mentioned under section A.2.c) below, the federal granting councils supporting medical (CIHR) and life sciences (NSERC) research require that applicants for their respective research funds be in compliance with CCAC guidelines, policies and programs. The CCAC is bound by agreement with these granting councils to inform them diligently of the names of academic institutions being placed in noncompliance. This federal mechanism to lend support to the humane treatment of animals is optimally effective and has never been challenged by the provinces over the past three decades, as it is not subject to federal-provincial consensus (Appendix G, p.16).

iii) CCAC as a Canadian Standard: Good Animal Practice®

The CCAC is engaged in discussions with some provinces to try to have reference made to CCAC guidelines, policies and programs in appropriate legislation or regulations. Since its inception in May 1999, CCAC is a member of the Animals for Research Act Advisory Committee mandated “to foster the appropriate care of animals in Ontario pounds, animal supply, teaching and research facilities by providing advice to the Ontario Ministry of Agriculture, Food and Rural Affairs”²⁹. In addition to this long-term approach, the CCAC has sought to obtain a trade-mark for the words “GAP-Good Animal Practice” with specific reference to the CCAC assessment services. The Trade-marks Certificate of Registration was granted to the CCAC in August 2000. This Certification by the Canadian Intellectual Property Office of Industry Canada identifies “services which meet a standard set by a governing organization”.

5. Challenges and Issues in Adapting CCAC’s Approach

a) Potential Challenges Posed by the New Technologies

i) Animal Welfare: Pain and Distress

The impact on animal welfare, or actual suffering experienced by the GMAs depends in large part on the nature of the genetic manipulation performed and the level of invasiveness of their intended use. Testing of novel therapeutics will always carry with it the risk of adverse and unexpected side effects. The use of genetic manipulation to develop animal models of disease may generate animals that have that disease. While this is not the case with embryo-splitting, cloning from adult cells has been reported to result in frequent congenital abnormalities, particularly cardiac problems. Cloning of any sort reduces the genetic diversity that is crucial to the survival of any species, a consideration that has greater weight when the manipulations are being performed on rare or endangered species.

There are potential animal health implications of genetic manipulations which need to be evaluated on a case-by-case basis, but which may include: developmental abnormalities (e.g., as observed with insertional mutations), deleterious pleiotropic effects (multiple harmful effects of one or more genes on the phenotype), novel and unanticipated health problems or complications (e.g., nutritional deficiencies, sterility, etc.).

The welfare of GMAs may also be compromised as routine procedures (usually not stressful to the non-GMA) may not be as well-tolerated, or may cause additional distress for already compromised animals.

ii) Meeting the Needs of Science, Industry, the Public and Decision-Makers: The Precautionary Principle

Recent government decisions in the areas of natural resources management (e.g., fish stocks) and public health and safety (e.g., the blood supply) have contributed to public concern regarding the ability of government to effectively address science-based issues. Biotechnology and its regulation is also a science-based issue. In its May 1999 Report to the Cabinet Committee on Economic Union, Science Advice for Government Effectiveness (SAGE)³⁰, the Council of Science and Technology Advisors (CSTA) developed key principles which are helpful in characterizing issues relating to biotechnology.

• Early Identification
  Current genetic engineering techniques are still “hit and miss”, therefore, it is impossible to predict the resultant phenotype.
  
  
• Inclusiveness
  In order to respond appropriately to research/industry challenges there needs to be a sustainable and progressive development of guidelines achieved through consultation with industry, researchers, veterinarians and public representatives. From the public perspective, there is a stated need for accurate and timely information concerning organisms derived from biotechnologies in general. Regulatory systems, therefore, need to be as transparent and publicly accountable as possible.
  
  
• Sound Science and Science Advice
  Animals should not be considered to be outside controls until all questions concerning their welfare/performance have been answered; this can be viewed as a legitimate research/testing activity. Even then, they may need to be released under certain “conditions”, for example, requirements for different husbandry practices, different degree of biosecurity and containment, maintenance of genetic diversity, and feedback concerning adverse effects.
  
  
• Uncertainty and Risk
  This degree of uncertainty, and the potential for pain and distress in a novel GMA, require the application of the precautionary principle, which dictates that action to reduce risk should not await scientific certainty. This approach is already prescribed by the CCAC guidelines on: transgenic animals (mandatory requirement to put protocols involving the creation of transgenic animals under Category of Invasiveness D until the phenotype is known) implemented across Canada since 1997 via the institutional ACC structure.
  
  
• Review
  The ACCs can decide to move a protocol to a lower category of invasiveness, once there is science-based evidence that the GMA has a normal phenotype.

b) Issues in Adapting the CCAC Approach to New Biotechnologies

CCAC has successfully overseen the use of GMAs in all academic institutions using them for biomedical (MRC/CIHR funded) or life sciences (NSERC funded) research since 1997 with no major problem to report. Each granting council actually contributes $560K per year to fund CCAC’s core activities, and concomitantly provides the enforcement tool for them (and the federal government) to be accountable to the Canadian public by linking public funding for research to mandatory compliance with CCAC programs and high ethical standards.

Gene-technological research is particularly active in the private sector. It is to be expected that regulatory authorities will have to be well-informed and well-versed in emerging technologies if they are to regulate them. While many pharmaceutical and biotech companies and many federal and provincial laboratories are participating in the CCAC program on a voluntary basis, unlike the academic institutions, the CCAC has no enforcement tools to ensure that they ALL participate. This is the major issue that needs to be addressed in adapting CCAC’s approach to new biotechnologies.

As detailed below, CCAC has developed over the past two years a powerful enforcement tool on xenotransplantation in collaboration with Health Canada. In collaboration with Treasury Board and Industry Canada, additional enforcement tools could be designed (for example, by requiring that data submitted to the Patent Office must have originated in a CCAC certified institution, linkage of Scientific Research and Experimental Development (SR&ED) tax credits involving the use of animals to a Certificate of Good Animal Practice®, ...etc.) to ensure that ALL sciencebased departments and agencies (SBDAs) and ALL users of animals in the biotech industry and in the industrial sector overall are participants in the CCAC programs. It is estimated that about $1.2 million would be needed to expand the implementation of the CCAC program to achieve universality in the governmental and private sectors while maintaining renowned high quality.

Industry Canada would be an appropriate fiduciary for both Canadian industry and the SBDAs, as this matter falls under the Canadian Biotechnology Strategy as well as the Federal S&T Strategy. In turn, Industry Canada could enforce sanctions to institutions placed in noncompliance, ensuring de facto the expansion of the universal implementation of CCAC program to industry and governmental laboratories, a measure supported by several pharmaceutical and biotech companies. Such an innovative approach to support an hybrid regulatory/oversight mechanism for the use of animals in biotechnology as a cross-departmental issue would also implement one of the key recommendations made by the CSTA in their recent Report on the Federal Roles in Performing Science and Technology, Building Excellence in Science and Technology (BEST).

“S&T performed and funded by the federal government must be tied in with other activities within the federal government, with the other sectors in the Canadian innovation system, and with the global pool of knowledge and technology...

The Council recommends that the government and departments implement and fund new models for S&T that move away from a vertical approach to a more horizontal (i.e., across government and the innovation system), competitive, multi-stakeholder approach.”³¹

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B. Animals Used for the Production of Chemicals, Tissues/Organs

1. Trends in Animal Use

Historically, the CCAC’s involvement in product development has occurred during both the developmental phases and the quality or safety assessment stages. The former is incorporated into the CCAC’s programs under the term “research”; the latter under the term “testing”. Implicitly, the assumption has been that the manufacture of the product has occurred through some chemically or mechanically engineered process. The advent of GMAs has made this assumption invalid: the animal is now the factory of chemicals, cells, tissues and organs.

To date, sheep and goats have been genetically modified to express proteins of biological relevance to humans in their milk. In addition, boars are being explored as a potential source of protein to be produced within semen³². Resulting transgenic proteins such as alpha-1-antitrypsin, Factor IX, and anti-thrombin III for treatment respectively of cystic fibrosis, hemophilia, and heart disease are currently in late-stage, Phase II/Phase III human clinical trial. These species have been successfully cloned, allowing a faster expansion of the herds in the future and enabling higher levels and faster delivery of therapeutic products to patients. As shown on Table I, the number of goats used in transgenic studies in Canada increased from 0 to 17 between 1996 and 1997, to reach 77 in 1998.

Heart and kidney transplants are now commonplace in Canada, with an expanding gap between the needs and the number of available organs for transplant. In 1997, 6,600 heart transplants were needed and only 180 actually performed; 5,900 kidney transplants were needed and 940 were performed³³. To meet this need, transplantation of animal organs is being considered, with genetically modified pigs evolving as the likely end source animals²⁶, and the necessary development of other discordant species model for xenotransplant research³⁴ (e.g., guinea pig to transplant into rat). On March 14, 2000, PPL Therapeutics Inc., the company responsible in 1996 for cloning the world’s first sheep known as Dolly, announced the birth of five piglets resulting from nuclear transfer using adult pig cells; the cloning of pigs has the potential for revolutionizing the field of organ transplantation. As indicated on Table I, it is estimated that about 207 pigs were used in xenotransplantation associated studies in 1998 in Canada, while none were reported in the previous year.

2. Regulatory Framework for Livestock and Biologicals Derived from Biotechnology

Canada’s regulatory framework for regulating products derived from biotechnology was announced in 1993. It involves three federal departments, Health Canada (HC), Fisheries and Oceans Canada (DFO), Environment Canada (EC) and one federal agency closely associated with Agriculture and Agri-Food Canada (AAFC), the Canadian Food Inspection Agency (CFIA). The products regulated within the framework and relevant legislations are summarized below for each of the four key players.

The regulatory framework consists of the following six principles³⁵:

• maintain high standards for protection of health, safety and the environment;
• use existing legislation and regulatory institutions;
• develop clear guidelines for evaluating products of biotechnology;
• provide for a sound scientific database on which to assess risk and evaluate products;
• consultation on the development and enforcement of Canadian biotechnology regulations; and
• fostering a favorable climate for investment, development, innovation and adoption of sustainable Canadian biotechnology products.

Department/Agency	Legislation	Product Regulated
Health Canada	Food and Drug Act Pest Control Products Act	Novel Foods Drugs and Food Additives Medical Devices Pest Control Products
Canadian Food Inspection Agency	Feeds Act Seeds Act Fertilizer Act Health of Animals Act	Novel Livestock Feeds Plants and Novel Traits Biofertilizers Veterinary Biologics
Fisheries and Oceans Canada	Fisheries Act	Aquatic Organisms
Environment Canada	Canadian Environmental Protection Act	“Safety Net” e.g., Bioremediation micro-organisms

3. Framework for Animal Welfare Oversight

How should the gap between the research environment and the production environment be bridged to ensure a seamless animal welfare oversight and regulation between the CCAC and governmental regulatory agencies?

In line with the expanded definition of universality (described under section A.2.d) adopted by the CCAC Council in 1996, the CCAC presented the framework for animal welfare regulation in the field of biotechnology appearing below at a seminal November 1998 Consultation on Regulating Livestock Animals and Fish Derived from Biotechnology sponsored by HC, CFIA, AAFC, and DFO. As detailed below, this scheme has been followed subsequently to build linkages with the departments and agencies involved in the regulatory framework described in the previous section.

While the CCAC guidelines on: transgenic animals (Appendix E) were developed primarily to apply to laboratory animals, the basic principles are equally relevant to research on animals intended for production of food or biopharmaceuticals. In particular, the guidelines distinguish between the “creation” of transgenic animals and the “use” of transgenic animals.

The creation of a new transgenic strain of animals will be carried out within a research facility, as shown in the flow chart. According to the CCAC guidelines, protocols for this work must be reviewed by an ACC and must be assigned a category of invasiveness “D” initially, to reflect the uncertainty about the outcome of the insertion of a gene on the subsequent well-being of an animal. Once the impact of the transgenic modification on the welfare of the animal has been evaluated, the category may be reassigned as less invasive. This approach recognizes that the development of the processes for production of GMAs are still experimental.

Once the transgenic strain has been created and found to be acceptable in terms of the effects of the transgene on the welfare of the animal, it will be moved into a “full production” setting, if released from the research protocol. The CCAC would have no regulatory interest at this stage, animals would be kept and monitored according to AAFC Codes of Practice (see section 3c) “users” manual), unless special monitoring is needed to answer research questions as discussed under section 3c.

Animal welfare and animal husbandry concerns were identified by participants in the November 1998 Consultation as “key considerations in any scheme to regulate transgenic animals”, and the animal welfare framework proposed by the CCAC was “viewed favorably by the group as an important development”. The scope of the challenge facing the CCAC and the regulatory departments and agencies was put to participants in the following terms at the end of the meeting:

“In transgenic animal release assessments, we need to consider a broad spectrum of issues that cover animal health, disease susceptibility, zoonotic potential, animal welfare, animal husbandry, impact on domestic and wild populations, biodiversity, ability to survive in the farm environment, monitoring and screening capability”.³⁶

4. Challenges and Issues in Adapting the CCAC’s Approach for Production

a) Production of Tissues/Organs

The federal Food and Drug Act and Regulations (August 5, 1982), cover use of animals in the testing of new drugs and vaccines, and for toxins in foods. HC’s Bureau of Biologics is responsible for the monitoring of biologics, the virulence and efficacy of which can usually be tested only in the living animal.

Under the authority of the Act, xenografts are considered therapeutics, and HC has the authority to regulate xenotransplantation as a new technology. A company wanting to “market” cells or organs for transplantation would have to submit pre-clinical trial data and undergo the full Investigational New Drug/Device review.

The CCAC has worked in close collaboration with the Therapeutic Products Program, Health Protection Branch, HC over the past two years to ensure that all use of animals for xenotransplantation will be overseen by the CCAC, by mandating adherence to CCAC guidelines, policies and assessment by the CCAC as a requirement in the Proposed Canadian Standard on Xenotransplantation³⁷. This was important, as beyond the clinical trial phase, the animals could be viewed as a production procedure which would not necessarily require oversight by CCAC. The CCAC is the only non-governmental entity invited as a guest participant in the meetings of the Interdepartmental Committee on Xenotransplantation sponsored by the Therapeutic Products Programme of HC. This is an effective mechanism to ensure that animal welfare issues are considered in view of the coming public consultation on xenotransplantation.

“All animal facilities associated with xenotransplantation programs must be full participants in the CCAC programs.”

-Proposed Canadian Standards for Xenotransplantation
Health Canada, September 1999

b) Animals as Bioreactors

To date not much has been achieved in consideration of regulation for GMAs to be used as “factories” producing biologicals and other materials. Animals to be used as bioreactors will need to be subject to the same framework as described under section 3c, i.e., the effect of the genetic modification on the well-being of the GMA strain must be evaluated prior to the animal being considered for production. Unlike GMAs used for food or fibre production, bioreactor animals are extremely valuable and, therefore, are afforded high standards of care. Like GMAs used for xenotransplantation (section 3a), it may also be the case that some animal welfare difficulties may be accepted, because of the value of the products, and that animals will be given additional care and attention to mitigate these effects. The development of high standards of care may offer the opportunity for further development of best practices for the livestock industry. Other issues which may be addressed in conjunction with CFIA, include biocontainment issues, in particular sewage treatment, and decisions on whether or not these animals should be permitted to enter the food chain as a source of animal or human food.

Where the products are biologicals, these will be regulated under Health Canada’s Bureau of Biologics, to ensure the safety and efficacy for human use. Health Canada could partner here with the CCAC to require that the biological is produced in facilities which are part of the CCAC program, and are holders of a CCAC Certificate of Good Animal Practice®. This would be somewhat equivalent to the requirement for adherence to the principles of Good Manufacturing Practice in production of other pharmaceuticals and adherence to the principles of Good Laboratory Practice in generation of safety and efficacy data for submission to the regulatory agencies. Animals used as producers of materials such as spider silk, if these materials are used for applications other than medical needs, would likely be regulated by another department than HC.

c) Production of Livestock

The federal Health of Animals Act, C-66 (June, 1990, rev. March, 1992); 38-39 Elizabeth II, Chapter 21 (replacing the Animal Disease and Protection Act and Part III of the Livestock and Livestock Products Act) is aimed at protecting Canadian livestock from contagious diseases such as tuberculosis and brucellosis, and keeping out foreign diseases. Under Regulations, the Act states that “the Governor in Council may make regulations for the purpose of protecting human and animal health...including regulations...

• for the humane treatment of animals and generally governing the care, handling and disposition of animals;
• governing the manner in which animals are transported within, into or out of Canada; and
• providing for the treatment or disposal of animals that are not cared for, handled or transported in a humane manner.”

The CCAC collaborated in the development of Codes of Practice published by AAFC on pigs, veal calves, poultry, dairy cattle, beef cattle, ranched fox and mink (Agriculture Canada, 1771/E, 1984; 1821/E, 1988; 1757/E, 1989; 1853/E, 1990; 1870/E, 1992; 1831/E, 1989; 1819/E, 1988). The Codes represent the current industry standards and, for the most part, are the minimum CCAC requires for research institutions undertaking agricultural research. Researchers and others working with agricultural animals must be fully conversant with these Codes.

The CFIA is operating under the Health of Animals Act and Regulations. AAFC is represented on the CCAC Council and all the units operated by CFIA participate in the CCAC program. Reference to CCAC’s Guide to the Care and Use of Experimental Animals have been found in 10 sections of CFIA’s Guidelines for Inspection of Veterinary Biologics Manufacturers and Importers³⁸. CFIA’s Requirement Report for Importation of Animals requires that “The facility of destination must operate in accordance with standards for the care and maintenance of experimental animals published by the Canadian Council on Animal Care and other relevant federal, provincial and municipal legislation”³⁹. It is interesting to note that CCAC’s decision to publish the list of Canadian institutions holding a Certificate of Good Animal Practice® on its website provided, since July 1999, an effective and essential tool for CFIA to enforce the latter import requirement.

The position statement on animal welfare now in use at CFIA is a document developed by the AAFC. This basic 10-page document devotes one full page of reference to the CCAC with respect to several issues such as the maintenance of high standards in humane care of animals, the commitment to use alternatives in animals in biomedical and product testing research where feasible, and transgenic animals.

“When ethical issues concerning transgenic (bio-engineered) animals need to be considered by the department, our position will be guided by the CCAC and its project review process, which is conducted by the local Animal Care Committees.”⁴⁰

experts on Animal Husbandry of Livestock Animals Derived from Biotechnology sponsored by AAFC and mandated to consider what research is needed to provide the information necessary to facilitate informed decision-making regarding the propriety of the use of GMAs as well as their management to optimize their genetic potential and ensure their well-being.

“The Panel of Experts agreed that prior to the release of genetically-modified livestock animals into the commercial agricultural sector, the impact of the genetic alteration on the wellness of the animal needs to be assessed within the context of the end-user environment and the management systems that will apply.

The information derived from this process should be documented, detailing the susceptibilities of the animals, the management strategies to promote wellness as well as the identification of potential mitigation measures, in the form of, for example, a code of practice (or a users’ manual) for the care of the particularly modified animal.”⁴¹

At its February 2000 meeting, the Panel of Experts discussed a first draft of the Guide to Research Needs. Several issues have to be considered in the Guide in the form of questions. With the current emphasis on improving the health of animals and reducing the use of antibiotics, it is essential to ensure that genetic modification has no negative effects on animal health. For example, problems of unbalanced muscle/bone growth, leading to inactivity, lameness are common problems when animals are selected for high growth. Genetic modification to increase growth is likely to lead to similar problems. In such cases, it is important to ask if care of the animals requires a particularly high standard of husbandry that may not be achievable in most commercial conditions. This is only one of the many issues to be addressed.

The CCAC should be responsible for the oversight of the care and use of livestock derived from biotechnology until all the research questions have been answered. This phase may include an evaluation of the animal’s performance in a production setting, which is not actually performed by the CCAC. There must also be thought given to continual monitoring of these animals once they are moved to the production setting, in terms of ensuring that any special requirements to mitigate the potential welfare complications continue to be in place, and also to ensure that any unforseen complications are reported (similar to adverse events reporting for new drugs).

d) Fisheries and Oceans Canada (DFO)

A/F Protein Inc. (Altman, M.A.) has 10,000 to 20,000 transgenic salmon in indoor tanks at three facilities in the Canadian Maritime provinces. Commercialization of transgenic salmon in the US will depend upon the pending regulatory approval by the Food and Drug Administration (FDA). A/F hopes that these fish will become the broodstock for producing eggs for commercial aquaculture in Canada, New Zealand, Chile and the US.

While no releases have been made of transgenic fish into the wild in Canada, two main laboratory studies are underway, one on Sockeye salmon in Vancouver and another in Nova Scotia. In the Fall of 1998, DFO invited comments on their Draft Policy on Research with and Rearing of, Transgenic Aquatic Organisms, which should be subject to a Policy announcement in the Fall of 2000. Pointing to the fact that Norway, a leader in aquaculture, has established bans on maintaining reproductively fit transgenics from any housing system other than on-land containment, the CCAC expressed, in a September 14, 1998 letter to DFO, the following concern which remains a major and pressing issue:

“The potential ecological impact of escape of transgenic organisms is, as yet, uncharacterized. The CCAC considers this to be a matter of concern. CCAC guidelines on: transgenic animals state that those approving proposals for creation or use of transgenics must be assured that risks to human health and the environment are minimized to an acceptable level. Proposal should include containment and security procedures in animal facilities; plans for recapture should a breach of containment occur; and consequences to human health or wild populations should containment fail.”

The limitations of the current technology for producing transgenic fish and the resulting impact on the welfare of animals created/used is another issue. The “transgenes” are limited to short constructs and are inserted randomly and in variable numbers of copies in each individual. This creates difficulty in stabilizing genetic modifications in a breeding population. There may be uncontrolled expression of the transgene. It may be expressed all the time; it cannot be turned off. Insertion sites for the transgenes may inadvertently affect the expression of other genes by disabling them or turning them on at an inappropriate time.

e) Environment Canada (EC)

As indicated in the schematic representation of the federal regulatory framework, the Canadian Environmental Protection Act (CEPA) acts as the “safety net”. There is a requirement under section 106(6) of the CEPA,1 999, proclaimed into law on March 31, 2000, indicating that, for biotechnology products regulated under another Act to be exempt from the CEPA program for “new substances”, that other Acts must provide for notice before manufacture, import or sale and an assessment of “toxic”. Since there are no such provisions in the CFIA Acts or Regulations, then GMAs default to CEPA.

EC is represented on CCAC Council, and their laboratories participate in the CCAC program. On February 2000, CCAC was among the few non-governmental organizations invited to participate in EC Workshop on Potential Ecosystem Effects of Genetically Modified Organisms. EC brought together all the participants in the federal regulatory framework for biotechnology. The major objectives of the workshop were:

• “to develop a common understanding of the potential risks to ecosystem health of genetically-modified organisms (GMOs) used in sectors such as agriculture, forestry and fisheries, how the federal government’s regulatory regime currently assesses environmental risks of GMOs, and current relevant research in other government departments;
• to identify areas of uncertainty in the environmental risk assessment of GMOs, and areas where Environment Canada could and should be involved; and
• to contribute to the development of a strategy and action plan for Environment Canada to ensure that GMOs are used in an environmentally sustainable manner.”⁴²

After two years of strenuous work in bringing together regional directors of federal and provincial departments of Environment and several other stakeholders, including US experts, the CCAC is working on its first guidelines on: the use of wildlife in research, teaching and testing, with publication expected in 2001. These guidelines will be instrumental in addressing complex issues relating to ecological ethics in Canada.

“Ecological science assists in the generation of a radical view of ethics because such an ethic, stressing as it does, a view of life as a complex adaptive system, runs counter to the atomism of previous ethical frameworks...Ecosystems feature the co-evolution of species and the environment within which species live. It is impossible to tease them apart and argue that one part of the system is more valuable than another part. ... Whether we like it or not, humans are part of such systems.”⁴³

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C. Concluding Remarks

“We cannot expect a branch of philosophy, ethics, to deliver rapid social change. Ethics is largely a descriptive endeavour; a sub-discipline that attempts to describe what is good and can only hope that individuals will translate that understanding of the good into practice and action. Prescriptive measures, by contrast, are largely the products of moralists, policy makers and politicians.”⁴²

The CCAC has developed an effective, fully integrated ethical review system for the care and use of animals in research, teaching and testing which facilitates communications between institutional decision-makers, scientists, veterinarians, the animal welfare movement and representatives of the public in reaching a common understanding of “what is good” over the past 32 years. To ensure “that individuals will translate that understanding of the good into practice and action”, the CCAC has also implemented successfully an oversight role with mandatory enforcement mechanisms provided by CIHR and NSERC in the academic sector. No such enforcement mechanisms has been developed yet in the governmental and in the private sector, where participation in the CCAC program is exclusively on a voluntary basis.

While a federal regulatory framework for biotechnology is in place in Canada since 1993, this legal framework cannot cover the ethical review of animal welfare which is a provincial jurisdiction as per the Canadian Constitution. However, the federal government could make use of it’s spending power to provide the enforcement tools needed to ensure Canadians that all science-based departments and agencies and all industries using animals in research and testing in Canada participate in the CCAC program. Such a linkage with the CCAC would de facto make the national system of oversight universal and make the federal government accountable to the Canadian public, not only for the appropriate oversight of GMAs, but for all laboratory, wild and domestic animals used for research and testing in Canada.

“To have a good regulatory process it must:

• be efficient and inexpensive;
• be effective, but not obstructive in enforcement;
• use the best technical expertise;
• permit stakeholder/citizen involvement in policy and use;
• adapt easily and encourage self-regulation;
• be cooperative rather than legalistic;
• have an educational role and raise standards continuously; and
• be able to share international best practices and reduce regulatory burden through acceptance of equivalence...

The CCAC hits on many of these particular features. It uses volunteers almost exclusively for its activities and has the use of a huge army of very good people in the scientific and animal welfare fields.”⁴⁴

Dr Mark Bisby
Director of Programs, MRC/CIHR
CFIA/HC/AAFC/DFO Consultation on Regulating
Livestock Animals and Fish Derived from Biotechnology
Ottawa ON, November 1998

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D. List of Appendices

Appendix A
Table I - Animal Use Surveys - 1996, 1997 and 1998
Table II - Animal use from 1975 to 1998
Table III - Number of animals used in 1998 per PAU and per CI
Table IV - Trends in animal use by institutions reporting to the CCAC from 1989 to 1998

Appendix B: CCAC Membership List
http://www.ccac.ca/english/member.htm

Appendix C: CCAC policy statement on: Terms of Reference for Animal Care Committees, 1997.
http://www.ccac.ca/english/terms.htm

Appendix D: CCAC guidelines on: animal use protocol review, 1997.
http://www.ccac.ca/english/gdlines/protocol/protgde.htm

Appendix E: CCAC guidelines on: transgenic animals, 1997.
http://www.cccac.ca/english/gdlines/transgen/transge1.htm

Appendix F: CCAC policy statement on: The Assessment Program of the CCAC, 1999.
http://www.ccac.ca/english/assess.htm

Appendix G: Legislative Jurisdiction Over Animals Used in Teaching, Testing and Research,
Osler, Hoskin & Harcourt, Barristers & Solicitors, 19p., November 26, 1998.
http://www.ccac.ca/english/legal/legalen.htm

Table I - Animal Use Surveys - 1996, 1997 and 1998

Main Species (MSP)	Total AU/Yr per MSP in 1996	Total AU/Yr per MSP in 1997	Total AU/Yr per MSP in 1998
Amphibia	18,936	17,521	13,647
Cephalopods	0	50	5
Fish	699,485	307,483	399,101
Marine mammals	1,663	1,537	1,523
Reptiles	2,144	3,449	3,115
Domestic birds	226,531	197,762	223,463
Cats	2,179	2,426	2,634
Dogs	7,367	7,812	6,978
Farm animals	53,058	55,622	61,451
Gerbils	1,486	1,570	1,817
Guinea pigs	40,142	36,706	34,581
Hamsters	7,941	6,994	6,203
Miniature swine	14	58	263
Mice	524,655	483,368	574,472
Rats	298,696	302,689	345,048
Rabbits	28,978	18,155	16,028
Non-human primates	2,150	1,621	875
Fur animals	1,261	1,508	1,405
Wild species	35,359	25,280	73,305
Others	0	0	59
Total	1,952,045	1,471,611	1,765,973

Table II - Animal use from 1975 to 1998

Year	Research	Teaching	Testing	Total
1975				2,699,012
1985	1,757,667	91,481	226,775	2,075,923
1989	1,553,377	82,725	313,863	1,949,965
1991	1,987,084	65,716	227,674	2,280,474
1992	1,833,476	80,649	200,881	2,115,006
1993	1,688,690	95,263	257,833	2,041,786
1994	1,997,673	134,060	203,582	2,335,315
1995	1,784,512	55,724	147,972	1,988,208
1996	1,337,6201	71,2282	347,5683	1,756,4164 (1,952,045)
1997	1,076,2841	59,5362	291,4523	1,427,2725 (1,471,611)
1998	1,458,1851	56,0192	251,7693	1,765,973

Notes:

1. In 1996, 1997 and 1998, under research three categories have been grouped (PAU=1, 2 and 4):
2. In 1996, 1997 and 1998, teaching corresponds to PAU=5;
3. In 1996, 1997 and 1998, testing corresponds to PAU=3;
4. Due to insufficient data provided, only 1,756,416 animals were categorized according to the Purpose of their use (PAU=1, 2, 3, 4 or 5), while the overall number of animals used in the institutions assessed by the CCAC is 1,952,045 (please note that 1,756,416 = 90% of 1,952,045).
5. Due to insufficient data provided, only 1,427,272 animals were categorized according to the Purpose of their use (PAU=1, 2, 3, 4 or 5), while the overall number of animals used in the institutions assessed by the CCAC is 1,471,611 (please note that 1,427,272 = 97% of 1,471,611).

Definitions

Number of animals used per year (AU/Yr)

Purpose of animal use (PAU)

PAU = 1 Studies of a fundamental nature in sciences relating to essential structure or function (e.g., biology, psychology, biochemistry, pharmacology, physiology, etc.).

PAU = 2 Studies for medical purposes, including veterinary medicine, that relate to human or animal disease or disorders.

PAU = 3 Studies for regulatory testing of products for the protection of humans, animals, or the environment.

PAU = 4 Studies for the development of products or appliances for human or veterinary medicine.

PAU = 5 Education and training of individuals in post-secondary institutions or facilities.

Categories of invasiveness (CI)
B — Experiments which cause little or no discomfort or stress.
C — Experiments which cause minor stress or pain of short duration.
D — Experiments which cause moderate to severe distress or discomfort.
E — Experiments which cause severe pain near, at, or above the pain tolerance threshold of unanesthetized conscious animals.

Table III - Number of animals used in 1998 per PAU and per CI

	PAU=1	PAU=2	PAU=3	PAU=4	PAU=5	Total per CI
CI=B	525,765	61,856	63,550	11,489	39,291	701,951
CI=C	293,789	93,914	48,039	17,894	12,360	465,996
CI=D	212,095	147,538	90,856	88,048	4,368	542,905
CI=E	2,268	3,448	49,324	81	0	55,121
Total per PAU	1,033,917	306,756	251,769	117,512	56,019	1,765,973

Table IV - Trends in animal use by institutions reporting to the CCAC from 1989 to 1998

Species	1989*	1991	1992	1993	1994	1995	1996	1997	1998
NHP	2.1	2.8	1.9	1.9	1.5	1.4	2.2	1.6	0.9
Dogs	10.3	9.1	8.6	8.3	7.9	7.3	7.4	7.8	7.0
Cats	3.9	4.1	3.7	3.5	3.5	2.6	2.2	2.4	2.6
Rabbits	29.6	22.4	23.6	20.6	23.3	20.2	29.0	18.1	16.0
Guinea pigs	38.5	32.6	39.1	45.0	19.7	16.9	40.1	36.7	34.6
Mice	818.6	604.2	560.8	586.5	556.1	543.9	524.7	483.4	574.5
Rats	396.0	365.1	369.2	312.6	367.2	343.1	298.7	302.7	345.0
Fish	280.3	865.3	779.4	547.8	946.4	704.5	699.5	307.5	399.1
Chickens	221.7	207.4	210.1	191.8	213.8	213.6	205.9	191.4	223.5
Cattle	20.5	14.9	13.9	12.1	17.7	13.7	22.8	17.9	23.0
Sheep	17.3	9.3	5.6	7.4	6.7	5.1	6.3	4.0	4.9
Swine	17.6	26.0	24.8	15.9	27.3	38.9	21.9	31.7	31.0
Total	1,950.0	2,280.5	2,115.0	2,041.8	2,335.3	1,988.2	1,952.0	1,471.6	1,766.0

Note: Table values are in thousands. The grand totals cover all species reported, not only those in this table.
* In 1989 fish were included in protocols for research, but not for teaching or testing.

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¹ Categories of Invasiveness in Animal Experiments, CCAC policy statement, Canadian Council on Animal Care, Ottawa ON, February 1991.

² CCAC Survey of Animal Use - 1998, RESOURCE 24(1), p.11-12, 2000.

³ CCAC guidelines on: transgenic animals, Canadian Council on Animal Care, Ottawa ON, p.4, 1997.

⁴ Scientific Procedures on Living Animals in Great Britain 1998, Cm 4418, 108pp. London, UK: HMSO (1999).

⁵ IACUC Assessment of Mutant, Transgenic, and Knock-out Mice, Dr M.B. Dennis, American Association for Laboratory Animal Science, 1999 National Meeting, Indianapolis IN, USA.

⁶ Genetic Engineering and Animal Welfare: Preparing for the 21st Century, Scientist Center for Animal Welfare, October 1999, p.24.

⁷ Bio-Ethics ‘89: A Report of the Proceedings of an international symposium on the control of the use of animals in scientific research, Animal Welfare Foundation of Canada, 1989.

⁸ Special Committee on the Care of Experimental Animals. Report. Ottawa ON: National Research Council, 1966.

⁹ Report of a feasibility survey on the establishment of a Canadian Council on Animal Care. Rowsell, H.C., Ottawa ON: Association of Universities and Colleges of Canada, 1967.

¹⁰ Animal care council outlined, Toronto Globe and Mail, August 1, 1967.

¹¹ Governance of the Ethical Process for Research Involving Human Subjects, Final Report, Centre on Governance, University of Ottawa, p.36, March 15, 2000.

¹² CCAC By-Laws, (art. 4), May 27, 1998.

¹³ Terms of Reference for Animal Care Committees, Policy Statement, Canadian Council on Animal Care, Ottawa ON, 6pp., 1997.

¹⁴ When to experiment on animals, Bateson, P., New Scientist 109:30-32, 1986.

¹⁵ Ethical scores for animal experiments, Porter, D.G., Nature 356:101-102, 1992.

¹⁶ The Ethical acceptability of animal experiments: a proposal for a system to support decisionmaking, Stafleu, F.R., Tramper, R., Vorstenbosch, J. and Joles, J.A. Laboratory Animals 33:295-303, 1999.

¹⁷ Guide to the Care and Use of Experimental Animals, Volume 1, 2nd Edn., Canadian Council on Animal Care, Ottawa ON, 1993.

¹⁸ Guide to the Care and Use of Experimental Animals, Volume 2, Canadian Council on Animal Care, Ottawa ON, 1984.

¹⁹ Care of Experimental Animals: A Guide for Canada, Canadian Council on Animal Care, Ottawa ON, 1968.

²⁰ CCAC guidelines on: choosing an appropriate endpoint in experiments using animals for research, teaching and testing, Canadian Council on Animal Care, Ottawa ON, 1998.

²¹ OECD Draft Guidance Document on the Recognition, Assessment and Use of Clinical Signs as Humane Endpoints for Experimental Animals Used in Safety Evaluation, Environment Directorate, Organisation for Economic Co-operation and Development, Paris, 2000.

²² CCAC guidelines on: institutional animal user training, Canadian Council on Animal Care, Ottawa ON, 1999.

²³ Minutes of the CCAC Council Meeting, Canadian Council on Animal Care, Ottawa ON. Motion #11-Amended, September 28, 1996.

²⁴ Ethics of Animal Investigation, Canadian Council on Animal Care policy statement, p.3, 1989.

²⁵ Categories of Invasiveness in Animal Experiments, Canadian Council on Animal Care policy statement, Ottawa ON, p.3, 1991.

²⁶ Alternatives to the Use of Animals for Research, Testing and as Sources of Bioengineered Products, Griffin, G. and Gauthier, C. Industry Canada background paper, March 2000.

²⁷ The secret world of animal experiments, Hampson, J. New Scientist, April 11, 1992:24-27.

²⁸ Ethics committees for laboratory animals: A basis for their composition and function, Jennings, M., Research Animals Department, RSPCA Headquarters, May 1994.

²⁹ Minutes of the May 3, 1999 meeting. Animals for Research Act Advisory Committee, Ontario Ministry of Agriculture, Food and Rural Affairs, Toronto ON, p.1.

³⁰ Science Advice for Government Effectiveness (SAGE): A Report of the Council of Science and Technology Advisors, Industry Canada, May 5, 1999.

³¹ Building Excellence in Science and Technology (BEST): The Federal Roles in Performing Science and Technology, A Report of the Council of Science and Technology Advisors, December 16, 1999.

³² Seminal vesicle production and secretion of growth hormone into seminal fluid. Dyck, M.K. et al., Nature Biotechnology 17:1087-90, 1999.

³³ Proposed Canadian Standard on Xenotransplantation, Health Canada, p.1, July 1999.

³⁴ Modification of vascular responses in xenotransplantation: Inflammation and apoptosis, Bach, F.H. et al., Nature Medicine 3:944-948, 1997.

³⁵ Canada’s Regulatory Framework for Biotechnology, Kenny, M., Consultation on Regulating Livestock Animals and Fish Derived from Biotechnology, Session Report, April 1999.

³⁶ Environmental Release of Transgenic Animals, Consultation on regulating livestock animals and fish derived from biotechnology, Government of Canada, April 1999.

³⁷ Proposed Canadian Standard on Xenotransplantation, Therapeutic Products Programme, Health Canada, Ottawa ON, 1999.

³⁸ Guidelines for Inspection of Veterinary Biologics Manufacturers and Importers, Veterinary Biologics Guideline 3.11E, Canadian Food Inspection Agency, September 1997.

³⁹ Requirement Report for Importation of Animals, Automated Import System, Canadian Food Inspection Agency, p.2, June 1999.

⁴⁰ Agriculture and Agri-Food Canada’s Role in Animal Welfare, 10pp., November 1994.

⁴¹ Report of the Panel of Experts on Animal Husbandry of Livestock Animals Derived from Biotechnology, Agriculture and Agri-Food Canada, 16pp., February, 1999.

⁴² Potential Ecosystem Effects of Genetically-Modified Organisms, Environment Canada Workshop, Canada Centre for Inland Waters, Burlington ON, February 28-29, 2000.

⁴³ A case for and some consequences of employing an ecological ethic to guide wildlife research, Albrecht, G., Proceedings of the Conference held at Dubbo, NSW, Australia, p.116, May 1999.

⁴⁴ Ethical Considerations in the Use of Animals Derived from Biotechnology: Can the Laboratory Experience be Applied to the Livestock Industry? Dr M. Bisby, Consultation on Regulating Livestock Animals and Fish Derived from Biotechnology, Session Report, April 1999.