Laboratory Animals: Regulations and Recommendations for Global Collaborative Research

1

Same Principles, Some Differences

Javier Guillén¹ and Patri Vergara²,    ¹AAALAC International,    ²International Council for Laboratory Animal Science (ICLAS)

Abstract

The importance of applying the same existing principles in the context of a diverse regulatory framework is highlighted. International organizations can be the best tool to harmonize the implementation of these principles, that represent the common ground for animal research globally.

Keywords

Ethical principles; Animal research; Harmonization

Animals play an essential role in the development of many areas of science. Science, as in many other activities of human life, is being globalized, and the care and use of animals in science is being subjected to this transformation. Globalization of science implies an increase in the level of collaborative research, which may be affected by different cultural and legal requirements. Societal ethical concerns on animal use for scientific purposes have led to the development and implementation of regulatory frameworks in many geographical areas. And even in those areas where specific regulations do not exist, practices in the field are greatly influenced by them. Communication and the spread of science, as well as increasing interinstitutional collaboration and outsourcing, are also important factors.

When reviewing the existing regulations described in this book, one easily realizes that although there are differences in the way they are implemented, they share the same ethical core principles. The same principles also underlie most nonstatutory guidelines, or recommendations, on the care and use of laboratory animals.

However, there are still differences in the way these principles are defined—both within the regulations and in their implementation. When principles are enshrined in legislation, legislators inevitably feel the need to provide definition and to establish clear boundaries between what is legal and what is not. This is the reason for the variation in standards that we so frequently find across countries or geopolitical areas. Why do they differ? We can identify a number of reasons including tradition, politics, financial implications, pragmatism, culture, etc. The outcome is the large variation in requirements and standards for such things as regulatory bodies, personal responsibilities, cage and enclosure dimensions, etc. This creates the current situation where we all speak about the same aims and follow the same principles, but where animals are treated differently in practice; differences that can have an adverse effect on collaborative research.

However, there is also a very positive side to this development. The increased use of laboratory animal welfare legislation has created new regulations in areas where they did not exist before and has prompted the revision and improvement of existing laws and guidelines. While it is true that the same outcomes can be achieved by different means, the use of performance standards is spreading, thus providing a very powerful tool for harmonization. And this is mainly thanks to the interest, energy, and enthusiasm of the laboratory animal professionals who are continuously seeking to spread knowledge, ethical principles, and good practices across the world. International organizations are the key to achieving these, and there are very good examples. The International Council for Laboratory Animal Science (ICLAS), with its national, scientific, institutional, associate, and affiliate members, is playing an important role. For example, ICLAS has collaborated with Council for International Organizations for Medical Sciences to revise the International Guiding Principles for Biomedical Research Involving Animals.¹ These principles, which are in accordance with the principles of the regulations described in this book, can facilitate the advancement of international collaboration in biomedical sciences. The Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC International) has accredited around 900 animal care and use programs in almost 40 countries around the globe, serving as a unique tool for the improvement and harmonization of animal care and use standards and practices. Several AAALAC members have contributed to this book due to their international expertise. The World Organization for Animal Health has focused on animal welfare and the use of animals in research and education in different chapters of the Terrestrial Code.² The principles described in Chapter 6.1 are perfectly aligned with the principles in all laboratory animal regulations and are developed for animals used in research and education in Chapter 6.8.

At a more regional level, national associations have established umbrella organizations that contribute to the same aim. The recommendations of the Federation of European Laboratory Animal Science Associations (FELASA) are well known and recognized,³ and similar organizations such as the Asian Federation of Laboratory Animal Science Associations and the Federation of South American Laboratory Animal Science Associations exist in Asia and South America. It is noteworthy to mention the initiative of FELASA and the American Association for Laboratory Animal Science (AALAS) to create the AALAS-FELASA Liaison Body, which is working on the development of common sets of recommendations.

This book includes the main regulations and guidelines used in 11 geographical areas of the world, from the most regulated environments (e.g. Europe) to others where it is hardly possible to identify specific regulations (e.g. Africa). Some information will not be included in this book; in some instances, it was not possible to detail as in the case of multinational areas; in other cases, it was not possible to get specific information, as for example, from Arabian countries. Although no such regulations are included in this book, there are an increasing number of institutions in several Arabian countries establishing quality animal care and use programs in modern facilities.

If science is to advance faster and for the benefit of humans, animals, and the environment, then ideally, laboratory animal regulations should have no political frontiers. Over time, reference books may become outdated. We hope this book becomes outdated soon, provided the reason is that there is no need to describe multiple regulations—only one.

References

1. Council for International Organizations for Medical Sciences; and International Council for Laboratory Animal Science 2012. International Guiding Principles for Biomedical Research Involving Animals. Available at: www.iclas.org.

2. World Health Organization. Terrestrial Animal Health Code 2012. Available at: http://www.oie.int/international-standard-setting/terrestrial-code/access-online/.

3. Guillen J. FELASA guidelines and recommendations. J Am Assoc Lab Anim Sci. 2012;51(3):311–321.

Chapter 2

Oversight of Research Animal Welfare in the United States

John F. Bradfield¹, B. Taylor Bennett² and Cynthia S. Gillett³,    ¹AAALAC International, Frederick, MD, USA,    ²National Association for Biomedical Research, Washington, DC, USA,    ³University of Minnesota, Minneapolis, MN, USA

Abstract

The use of animals in research in the United States (US) is governed by a number of longstanding regulations and guidelines aimed to ensure that animal well-being is of principle importance in the course of scientific investigation. The core principles of animal care and use in research are contained in the nine US Government Principles for the Utilization ad Care of Vertebrate Animals Used in Testing, Research, and Training. The Animal Welfare Act and Regulations promulgated by the United States Department of Agriculture, Animal Plant Health Inspection Service, governs specifically defined vertebrate animals used for research, testing, teaching, exhibition, and commerce. This federal law provides specific requirements for animal care which encompasses aspects from justification and institutional review to veterinary care and reporting. Unannounced inspections provide the basis for ensuring the requirements of law are met. Under the provision of the Health Research Extension act, the US Public Health Service revised its Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy) which describes the requirements for each institution receiving public health service funds for research involving animals. The PHS Policy covers all vertebrate animals involved in PHS-funded research. The National Institutes of Health, Office of Laboratory Animal Welfare oversees the implementation of the PHS Policy. The PHS Policy requires awardee institutions to use the Guide for the Care and Use of Laboratory Animals (NRC, 2011, Guide), as a basis for managing their animal care and use programs. The Guide provides a detailed set of performance standards encompassing major topics such as Institutional Animal Care and Use Committee (IACUC) structure and function, occupational health and safety, animal environment and management, veterinary care, and physical plant. For agricultural animals used in research and teaching, the Federation of Animal Science Societies has published recommendations specifically for the use of agricultural species. The Guide for the Care and Use of Agricultural Animals in Research and Teaching (FASS, 2011) provides detailed recommendations for a variety of animal species under varying conditions of use. The cornerstones of US regulations and guidelines are the IACUC, the institutional official, and the central role of the attending veterinarian. All must work together in providing an animal care and use program that ensures the well-being of animals and the integrity of science.

Keywords

Agricultural Guide; Animal welfare; Animal welfare act; Animal welfare regulations; Guide

Chapter Outline

Introduction

The Animal Welfare Act (Public Law 89-544)¹

Public Health Service Policy (PHS Policy)²

The Guide for the Care and Use of Laboratory Animals (NRC 2011)⁵

Guide for the Care and Use of Agricultural Animals in Research and Teaching (FASS, 2010)⁶

US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (Federal Register, Vol. 50, No. 97, 1985)²¹ (US Government Principles)

The American Veterinary Medical Association Guidelines on Euthanasia

The Association for the Assessment and Accreditation of Laboratory Animal Care, International

The Cornerstones of Research Animal Oversight in the US

The Principles

AWA/AWR’s

PHS Policy and OLAW

Scope/Applicability

AWA/AWR’s

PHS Policy and OLAW

Authorization of User-Breeding Institutions/Inspections/Penalties by Competent Authorities

AWA/AWR’s

PHS Policy and OLAW

AAALAC International

Nonhuman Primates: Special Considerations and Restrictions

AWA/AWR’s

PHS Policy and OLAW

Genetically Altered Animals: Special Consideration

AWA/AWR’s

PHS Policy and OLAW

Institutional and Designated Personnel Responsibilities

AWA/AWR’s

PHS Policy and OLAW

Oversight and Ethical Review Process

AWA/AWR’s

PHS Policy and OLAW

Reuse

AWA/AWR’s

PHS Policy and OLAW

Setting Free/Rehoming

AWA/AWR’s

PHS Policy and OLAW

Occupational Health and Safety

AWA/AWR’s

PHS Policy and OLAW

Occupational Health and Safety in the Care and Use of Research Animals

Education, Training, and Competence of Personnel

AWA/AWR’s

PHS Policy and OLAW

Transport

AWA/AWR’s

PHS Policy and OLAW

Housing and Enrichment

AWA/AWR’s

PHS Policy and OLAW

Husbandry and Environment

AWA/AWRs

PHS Policy and OLAW

Veterinary Care

AWA/AWRs

PHS Policy and OLAW

Conduct of Experimental Procedures

AWA/AWRs

PHS Policy, OLAW

Euthanasia

AWA/AWRs

AVMA Guidelines on Euthanasia

PHS Policy and OLAW

Equipment and Facilities

AWA/AWRs

PHS Policy and OLAW

Miscellaneous

AWA/AWRs

Introduction

The United States (US) has many regulations and guidelines regarding the care and use of animals. A comprehensive review of all laws, regulations, and guidelines in the US regarding the welfare, care, and use of animals is beyond the scope of this chapter, but the key regulations and guidelines that impact the care and use of animals in research and teaching will be covered. In many ways the oversight framework for animal use is a reflection of societal values and priorities regarding the overall standing of animals in society. The regulatory landscape in the US, as in many other countries, is continuously evolving and as one reviews the current standards, it must be kept in mind that the implementation of animal use oversight is a rather dynamic process which depends on our evolving understanding of animals, their needs and our obligation to be good stewards when they are in our care.

The careful consideration of animal welfare guidelines and policies involves an international perspective. The US has animal welfare laws, guidelines, and policies that are by their very nature, US-based. However, there is a global view of animal welfare that impacts the US landscape in tangible ways. While non-US-based laws and guidelines do not carry a statutory requirement in the US, they are often used as appropriate resources that impact animal care and use in this country.

The key regulations and guidelines that will be the focus of this chapter include the Animal Welfare Regulations as mandated in US law, the Animal Welfare Act (PL-89-544),¹ the Public Health Service Policy on Humane Care and Use of Laboratory Animals² (PHS Policy), which is a statutory mandate of the Health Research Extension Act of 1985, Animals in Research (PL-99-158),³ and the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training.⁴ Apart from the Animal Welfare Regulations, the Guide for the Care and Use of Laboratory Animals (Guide, NRC, 2011),⁵ further details the requirements of the PHS Policy and is used by institutions to comply with the PHS Policy. For agricultural animals used in research and teaching, a similar set of guidelines has been published by the Federation of Animal Science Societies, the "Guide for the Care and Use of Agricultural Animals in Research and Teaching" (Ag Guide, FASS, 2010).⁶ Another set of guidelines with universal use are the Guidelines on Euthanasia (2013) published by the American Veterinary Medical Association (AVMA).⁷

The focus of these regulations and guidelines are not meant to imply that the many others that impact animal use and welfare are not important, but simply to direct attention to the core of animal welfare standards in the US which focus on animals in research, teaching, and testing. The US has many relevant guidelines and regulations about animals and welfare, several of which are listed below. The breadth and scope of these laws and guidelines are simply too great to include in one chapter, but these help provide the overall framework in the US regarding the consideration of animal welfare.

A partial list of additional regulations and guidelines in the US include: the Humane Methods of Slaughter Act,⁸ Horse Protection Act,⁹ Twenty-Eight Hour Law,¹⁰ Guidelines for the Humane Transportation of Research Animals,¹¹ Guidelines of the American Society of Mammalogists for the Use of Wild Mammals in Research,¹² Guidelines to the Use of Wild Birds in Research,¹³ Psychological Well-Being of Nonhuman Primates,¹⁴ Guidelines for the Welfare and Use of Animals in Cancer Research,¹⁵ Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research,¹⁶ Guidelines for Use of Live Amphibians and Reptiles in Field and Laboratory Research,¹⁷ and Environmental Enrichment for Nonhuman Primates Resource Guide.¹⁸

These and many other guidelines are used throughout the US as they apply to a particular species, or discipline of research and are often developed by the various research societies engaged in animal-related research that consider the humane care and use of animals paramount in the conduct of high quality science.

Brief overviews of the core documents that comprise the focus of this chapter are described.

The Animal Welfare Act (Public Law 89-544)¹

The Animal Welfare Act (AWA) originally enacted in 1966 and was entitled the Laboratory Animal Welfare Act. Its title was changed to the current title when the Act was amended in 1970 (PL-91-579). The purposes of the original act were to protect against theft of pet dogs and cats, prevent the sale or use of dogs and cats that had been stolen, and ensure that research facilities provided humane animal care and use. The AWA covers all warm-blooded animals used, or intended for use in research, teaching, testing, experimentation, or exhibition purposes, or as a pet. This does not include birds, rats of the genus Rattus, and mice of the genus Mus, bred for use in research; horses not used for research purposes; and other farm animals used or intended for use for food or fiber, for improving animal nutrition, breeding, management, or production efficiency, or for improving the quality of food or fiber.

The AWA authorized the Secretary of Agriculture, United States Department of Agriculture (USDA), and the Animal and Plant Inspection Service (APHIS) to develop regulations to implement the Act. These Animal Welfare Regulations (AWRs) are set forth in Title 9 of the Code of Federal Regulations (CFR) Chapter, 1, Subchapter A—Animal Welfare, Part 1—Definitions, Part 2—Regulations, and Part 3—Standards.¹⁹ Enforcement duties are the responsibility of the APHIS Deputy Administrator for Animal Care. To comply with the AWA, the USDA-APHIS requires all registered research facilities to adhere to the AWRs. As part of ensuring that institutions follow the regulations, USDA-APHIS conducts unannounced inspections of research facilities by Veterinary Medical Officers (VMO) who inspect at least annually and more often if deemed necessary by the Agency. The USDA uses a risk-based inspection system to support and focus its inspection strategy, allowing more frequent and in-depth inspections at facilities experiencing problems and fewer at those that are consistently in compliance. The process uses several objective criteria including past compliance history to determine inspection frequency.

The AWA has been amended six times since 1966 with the most significant changes made in 1985 in which an amendment entitled the Improved Standards for Laboratory Animals Act strengthened the standards for providing laboratory animal care, increased enforcement of the AWA, provided for collection and dissemination of information to reduce unintended duplication of experiments using animals, and mandated training for those who handle animals. The 1985 amendment also included standards for exercise of dogs, psychological well-being of primates, limitation of multiple survival surgeries, and a requirement that investigators consult with a veterinarian in the design of experiments which have the potential for causing pain, to ensure the proper use of anesthetics, analgesics, and tranquilizers. Investigators must also consider alternatives to procedures that may cause pain or distress. Each research facility must demonstrate upon inspection and annually report, that professional standards of animal care, treatment, and use are employed during research, teaching, or testing.

Perhaps most significant, the 1985 amendment required the Chief Executive Officer (CEO) of each research facility to appoint an Institutional Animal Care and Use Committee (IACUC) consisting of at least three members including a doctor of veterinary medicine and one member who is not affiliated with the institution. The IACUC is charged to act as an agent of the research facility in assuring compliance with the AWA. Central to this charge is the authority of the IACUC mandated in the AWR’s. The role and authority of the IACUC in the care, use, and oversight of research animals cannot be overstated and it is somewhat a unique premise that is at the core of animal use oversight in the US. The AWRs stipulate that the IACUC is required to conduct a variety of activities to ensure compliance with the regulations. These responsibilities include inspection of all animal facilities and study areas at least once every six months, and review the research facility’s program of animal care and use once every six months. The IACUC must file a report of its inspection with the Institutional Official (IO) of the research facility. If significant deficiencies or deviations are not corrected in accordance with the specific plan approved by the IACUC, the USDA and any federal funding agencies must be notified in writing. The IACUC must also review and approve all proposed activities involving the care and use of animals in research, testing, or teaching procedures and all subsequent significant changes of ongoing activities. As part of this review, the IACUC must evaluate procedures which minimize discomfort, distress, and pain, and when an activity is likely to cause pain, and a veterinarian has been consulted in planning for the administration of anesthetics, analgesics, tranquilizers, and that paralytic agents are not employed except in the anesthetized animal. The IACUC must also determine that animals which experience severe or chronic pain are euthanatized consistent with the design of study, that the living conditions meet the species’ needs, that necessary medical care will be provided, that all procedures will be performed by qualified individuals, that survival surgery will be performed aseptically, and that no animal will undergo more than one operative procedure unless justified and approved by the IACUC. Methods of euthanasia must be consistent with the definition contained in the regulations.

On behalf of the research facility, the IACUC must also assure that the principal investigator (PI) considered alternatives to painful procedures and that the work being proposed does not unnecessarily duplicate previous experiments. To provide this assurance, the IACUC must review the written narrative description provided by the investigator and the description must include the methods and sources used in determining that appropriate alternatives were not available. The IACUC can grant exceptions to the regulations and standards, if they have been justified in writing by the principal investigator.

The research facility is required to provide training to scientists, animal technicians, and other personnel involved with the care and use of animals and training must include humane practices of experimentation, methods that minimize pain and distress, the proper use of anesthetics, analgesics and tranquilizers, the use of appropriate information services such as the National Agricultural Library, and methods to report deficiencies in animal care and treatment.

Public Health Service Policy (PHS Policy)²

The National Institutes of Health (NIH) are a major component of the Public Health Service of the US, Department of Health and Human Services (the largest funding source for biomedical research in the US). In 1971, the NIH issued its first policy on the care and treatment of laboratory animals (NIH Policy, Care and Treatment of Laboratory Animals. [NIH 4206], NIH Guide for Grants and Contracts, No.7, June 14, 1971). The Policy required that institutions receiving NIH grant awards provide written assurance that a committee of at least three members, one of which was a veterinarian, had been established or that the institution was accredited by a professional accrediting body. The policy was revised in 1973 and 1979 with a significant revision in 1985 as a result of the passage of the Health Research Extension Act (HREA, 1985) (Public Law 99-158).³ The HREA provided statutory authority of the PHS Policy for PHS-funded research involving live vertebrate animals used (or intended for use) in biomedical and behavioral research. An additional revision of the policy was released in September, 1986 which reflected the changes required by the HREA. In 2002, another revision occurred to reflect changes in the process of submitting IACUC approval and the information that must be included in the Animal Welfare Assurance.

Under the PHS Policy, each institution using animals in PHS-sponsored projects must provide acceptable written assurance of its compliance with the policy. In this Animal Welfare Assurance the institutions must describe:

1. The Institutional Program for the Care and Use of Animals

2. The Institutional Status

3. The Institutional Animal Care and Use Committee.

The institutional program must include a list of every branch and major component, the lines of authority for administering the program, the qualifications, authority, and responsibility of the veterinarian(s), the membership of the Institutional Animal Care and Use Committee and the procedures which they follow must be stated. The employee health program must be described for those who have frequent animal contact. A training or instruction program in the humane practices of animal care and use must be available to scientists, animal technicians, and other personnel involved in animal care, treatment, and use.

The institutional status must be stated as either Category one (1) (The American Association for Accreditation of Laboratory Animal Care (AAALAC) accredited) or Category two (2) (nonaccredited). Institutions in Category two (2) must establish a reasonable plan with a specific timetable for correcting any departures from the recommendations in the Guide for the Care and Use of Laboratory Animals (NRC, 2011).

The IACUC must be appointed by the CEO, who can delegate that authority to the Institutional Official. The IACUC must consist of at least five members; one of whom is a veterinarian with program responsibility, a practicing scientist, an individual whose expertise is in a nonbiological science, and an individual who is not affiliated with the institution. The functions of this committee are analogous to those required under the AWA with the exception that it must use the Guide to review the animal facilities and the institutional program for humane care and use of animals. The other major difference is that the PHS Policy covers all vertebrate animals.

The institution is responsible for maintaining all the necessary records to document compliance with the PHS Policy and for filing annual reports developed by the IACUC which detail any changes in the program and indicate the dates of the semiannual inspections and programmatic reviews. Institutions must also report any serious or continuing noncompliance with the policy, any serious deviations from the provisions of the Guide, and any IACUC suspension of an activity.

The PHS Policy is intended to implement and supplement the U.S. Government Principles for the Utilization and Care of Vertebrate Animals in Testing, Research and Training (US Government Principles). The nine principles are published in the PHS Policy and in the Appendix of the Guide.

The National Institutes of Health, Office of Laboratory Animal Welfare (OLAW) is tasked with oversight of animal care and use for PHS-funded research. OLAW requires that institutions base their animal care and use programs on the Guide and as previously described, each institution receiving PHS funds for animal research must maintain a PHS Assurance Statement that has been approved by OLAW. OLAW endorses the performance-based concepts of the Guide and provides guidance as to how institutions can best implement and comply with the PHS Policy and the Guide. Institutions with PHS-assurances must self-report instances of noncompliance with the Guide and PHS Policy and the means to correct them. In addition to this self-reporting to ensure compliance, OLAW sometimes conducts on-site evaluations of programs to ensure they comply with the Guide, PHS Policy, and the details of the institution’s assurance statement.

The Guide for the Care and Use of Laboratory Animals (NRC 2011)⁵

The original "Guide" was first published in 1963 by the US Department of Health, Education, and Welfare, Public Health Service and was titled the, Guide for Laboratory Animal Facilities and Care. It has been revised or updated seven times since in 1965, 1968, 1972, 1978, 1985, 1996, and 2011 with more recent editions published by the Institute for Laboratory Animal Resources (ILAR). Eventually it became the "Guide for the Care and Use of Laboratory Animals", commonly referred to as the Guide. The PHS Policy requires institutions that receive PHS funding adhere to the standards of the Guide. The Guide states on page XIII that it is intended to "assist institutions in caring for and using animals in ways judged to be scientifically, technically, and humanely appropriate and is also intended to assist investigators in fulfilling their obligation to plan and conduct animal experiments in accord with the highest scientific, humane, and ethical principles." The 1996 version (7th edition) stressed the importance of performance standards in developing acceptable standards for the care and use of laboratory animals. The performance standards approach requires clearly defined appropriate outcomes; the criteria for determining how outcomes are achieved; and the methods for evaluating the outcomes, without specifying exactly how the outcome is accomplished. The performance-based approach described in the 1996 Guide is in contrast to the engineering approach in which both the outcome and methods to achieve them are specified. The performance-based approach recognizes the wide array of scientific disciplines and animal models employed. It allows institutions to best determine how to achieve the standards described in the Guide based on the needs of the animals and the type of research conducted. The current, 2011 edition of the Guide (8th edition) extends the performance-based approach and underscores the need for the IO, IACUC, Attending Veterinarian and principal investigator to collaborate when implementing the standards of the Guide. The 8th edition contains five chapters: Key Concepts; Animal Care and Use Program; Environment, Housing, and Management; Veterinary Care; and Physical Plant. The purpose of the Guide is to assist institutions in laying the foundation for a comprehensive animal care and use program that relies on the use of performance standards and professional judgment to assure that such use is in accordance with the highest scientific, humane, and ethical principles. The Guide strongly affirms the principle that those who care for and use laboratory animal must assume responsibility for their well-being. Laboratory animals are defined as any vertebrate animal used in research, testing, and teaching. Key terms in the Guide that help the reader prioritize the importance of the recommendations are: "must which denotes an imperative or mandatory requirement; should is a string recommendation for achieving a goal; and may," which is a suggestion for consideration.

Guide for the Care and Use of Agricultural Animals in Research and Teaching (FASS, 2010)⁶

The Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching was published originally in 1988 and revised in 1999 and 2010 and is commonly referred to as the Ag Guide. The current 3rd edition, published by the Federation of Animal Science Societies, is intended to provide standards for agricultural animals involved in research and teaching with the viewpoint stated in the preface that, "Farm animals have certain needs and requirements and these needs and requirements do not necessarily change because of the objectives of the research or teaching activity. Therefore, regardless of the teaching or research objectives, the FASS Ag Guide should serve as a primary reference document for the needs and requirements of agricultural animals." Similar to the Guide, the Ag Guide emphasizes the use of performance standards and professional judgment when implementing institutional standards described in the Ag Guide, to be applicable among diverse institutions and their agricultural programs.

The 3rd edition of the Ag Guide contains 11 chapters: Institutional Policies, Agricultural Animal Health Care, Husbandry, Housing and Biosecurity, Environmental Enrichment, Animal Handling and Transport, Beef Cattle, Dairy Cattle, Horses, Poultry, Sheep and Goats, and Swine. There are many similarities between the standards of the Ag Guide and the Guide with the exception that standards unique to individual species of farm animals are described in separate chapters. Many aspects of animal care and use are described in this comprehensive document devoted to the care and use of agricultural animals.

US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (Federal Register, Vol. 50, No. 97, 1985)²¹ (US Government Principles)

The US Government Principles were drafted by the Interagency Research Animal Committee in response to public interest in the care and use of laboratory animals. This document stresses compliance with federal laws, policies, and guidelines and establishes overarching principles that should be applied when using animals, or sponsoring the use of animals, in research, teaching, and testing. There are nine principles:

I The transportation, care, and use of animals should be in accordance with the Animal Welfare Act (7 U.S.C. 2131 et. seq.) and other applicable Federal Laws, guidelines, and policies.¹

II Procedures involving animals should be designed and performed with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society.

III The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid results. Methods such as mathematical models, computer stimulation, and in vitro biological systems should be considered.

IV Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals.

V Procedures with animals that may cause more than momentary or slight pain or in distress should be performed with appropriate sedation, analgesia, or anesthesia. Surgical or other painful procedures should not be performed on unanesthetized animals paralyzed by chemical agents.

VI Animals that would otherwise suffer severe or chronic pain or distress that cannot be relieved should be painlessly killed at the end of the procedure or, if appropriate, during the procedure.

VII The living conditions of animals should be appropriate for their species and contribute to their health and comfort. Normally, the housing, feeding, and care of all animals used for biomedical purposes must be directed by a veterinarian or other scientist trained and experienced in the proper care, handling, and use of the species being maintained or studied. In any case, veterinary care shall be provided as indicated.

VIII Investigators and other personnel shall be appropriately qualified and experienced for conducting procedures on living animals. Adequate arrangements shall be made for them in service training, including the proper and humane care and use of laboratory animals.

IX Where exceptions are required in relation to the provisions of these principles, the decisions should not rest with the investigators directly concerned, but should be made, with due regard to Principle II, by an appropriate review group such as an institutional animal research committee. Such exceptions should not be made solely for the purposes of teaching or demonstration.

The US Government Principles are featured prominently in the PHS Policy, the Guide, the Ag Guide and many other animal care and use guidelines and have become the foundation for laboratory animal care and use in the US.

The American Veterinary Medical Association Guidelines on Euthanasia

The first report of the AVMA Panel on Euthanasia was published in the AVMA Journal in 1963. The Panel report was revised in 1972, 1978, 1986, 1993, 2000, and 2013. In 2007, the guidelines were updated and renamed the AVMA Guidelines on Euthanasia. The guidelines are intended for veterinarians who carry out or oversee euthanasia of animals and as a result have become widely used by research institutions in the US. Many IACUCs have developed institutional policies that require euthanasia procedures that conform to the recommendations of the AVMA Guidelines on Euthanasia. The 2013 guidelines titled AVMA Guidelines for the Euthanasia of Animals: 2013 Edition, provide a comprehensive discussion of many aspects of euthanasia for a variety of species.⁷ The 2013 updated guidelines include detailed, expanded explanation of methods, techniques, and agents of euthanasia to assist veterinarians in applying their professional judgment.

The Association for the Assessment and Accreditation of Laboratory Animal Care, International

The Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) was first established in 1965 as a private nonprofit organization that accredits animal care and use programs. The founders of AAALAC envisioned a voluntary, collaborative, peer-reviewed evaluation of animal care and use programs that engaged both the scientific and laboratory animal care communities to promote high standards of animal care and use. AAALAC is governed by a Board of Trustees comprised of scientific organizations and relies upon members of the Council on Accreditation and Ad Hoc consultant specialists to conduct site visits to participating institutions. This triennial site visit process is the basis for rigorous, peer-reviewed assessments to ensure high standards of animal care and use are met by the participating institutions. In 1996, AAALAC was renamed the Association for the Assessment and Accreditation of Laboratory Animal Care, International to reflect its growth worldwide. Until recently, AAALAC used the Guide as the primary standard by which programs were evaluated and in 2011 also added two additional documents as primary standards of accreditation, the Ag Guide for research programs that involve agricultural animals and the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, Council of Europe, European Treaty Series 123 (ETS 123),²⁰ for accredited programs in Europe. In addition to these primary standards of accreditation, there are many other documents used by AAALAC International as reference resources to aid in the accreditation process. Accreditation by AAALAC International is voluntary but over the years, accreditation has come to represent a standard of excellence in proactive, continuous self-improvement in animal care. The peer review accrediting process fosters collaboration among stakeholders to ensure high quality science through the promotion of high quality animal welfare. The impact of the AAALAC International accreditation process in the US has been the establishment of a system of self-assessment and improvement that has become the benchmark of quality animal research programs and includes many institutions across the spectrum of animal care and use; industry, academia, hospitals, nonprofit, and governmental organizations.

The Cornerstones of Research Animal Oversight in the US

The Animal Welfare Act and Regulations, the PHS Policy, the Guide, and the Ag Guide, all describe the central role of the IACUC in providing the necessary institutional oversight of animals used in research. It is the IACUC that is responsible for oversight and monitoring to ensure that the regulations and guidelines are fully implemented. The concept and importance of this committee is vital in animal use oversight in the US. The AWR’s, PHS Policy, Guide, and Ag Guide also stipulate the key roles of the IO and Attending Veterinarian (AV). The prominent role and authority given to the AV in the US may be considered somewhat unique by those in other countries. The AV and the program of veterinary care comprise key aspects of animal health, welfare, and oversight in the US. The Guide also describes the requirement for the IO, the IACUC, and the AV to collaborate in the implementation and oversight of the entire animal care and use program and it is this concept that provides the basis for effective animal care and use oversight. Although these three entities are crucial to the effective institutional oversight of animal care and use, one must not overlook the critical role of the investigator and research team. The Guide places a high degree of responsibility on those engaged in research to be good stewards of the animals with which they work. It is these four principal entities that form the fabric of research animal compliance in the US.

The Principles

AWA/AWR’s

Section 2131 of the AWA titled, Congressional statement of policy on page one states, congress finds that—"(3) measures which eliminate or minimize the unnecessary duplication of experiments on animals can result in more productive use of Federal funds and (4) measures which help meet the public concern for laboratory animal care and treatment are important in assuring that research will continue to progress." The animal welfare regulations further state that the IACUC review of proposed animal activities will include consideration of the following principles: procedures will avoid or minimize discomfort, distress, and pain to the animals; ensure that the principal investigator has considered alternatives to procedures that may cause more than momentary or slight pain or distress to the animals and has provided a written narrative description used to determine that alternatives were not available; and further that a written assurance be provided that activities do not unnecessarily duplicate previous experiments; procedures that may cause more than momentary or slight pain of distress will be performed with appropriate sedative, analgesics, or anesthetics unless withholding such agents is justified for scientific reasons and will continue for only the necessary period of time; that paralytics be used only with anesthetics; that a veterinarian be involved in the planning of the experiment; and that timely euthanasia be performed.

PHS Policy and OLAW

The Health Research Extension Act of 1985, Public Law 99-158, Animals In Research provides the statutory mandate for the PHS Policy. The introduction of the policy states, "It is the Policy of the Public Health Service (PHS) to require institutions to establish and maintain proper measures to ensure the appropriate care and use of all animals involved in research, research training, and biological testing activities (hereinafter referred to as activities) conducted or supported by the PHS. The PHS endorses theUS Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training developed by the Interagency Research Animal Committee. This Policy is intended to implement and supplement those Principles."

The introductory paragraph of the US Government Principles states, in part, "Whenever U.S. Government agencies develop requirements for testing, research, or training procedures involving the use of vertebrate animals, the following principles shall be considered; and whenever these agencies actually perform or sponsor such procedures, the responsible Institutional Official shall ensure that these principles are adhered to. The Principles were incorporated into the PHS Policy in 1986 and continue to provide a framework for conducting research in accordance with the Policy.

The 3Rs are not specifically mentioned in the PHS Policy or the US Government Principles. However, several of the US Government Principles directly relate to the concept of the 3Rs. Principle III relates to using only the minimum number of animals necessary and Principle IV indicates that animal pain and distress should be minimized or avoided and procedures that cause pain or distress in humans may cause pain or distress in other animals. Principle V specifies that appropriate use of sedatives, anesthetics, and analgesics should be employed to minimize pain or distress. Principle VI states that humane euthanasia should be employed to relieve chronic or severe pain or distress. Also, the PHS Policy does require adherence to the USDA Animal Welfare Act which requires that "The principal investigator has considered alternatives to procedures that may cause more than momentary or slight pain or distress to the animals, and has provided a written narrative description of the methods and sources, e.g. the Animal Welfare Information Center, used to determine that alternatives were not available. OLAW has provided further clarification that the US Government Principles are a federal mandate and that Principles III and IV embody key aspects of the 3-Rs. OLAW further states that consideration of the three "Rs" should be incorporated into IACUC review, as well as other aspects of the institution’s