Regulatory and Ethical Considerations
The regulatory environment governing the use of animals in neuroscience research is extensive, multilayered, and continuously evolving. Excellent recent reviews of the historical development and current status of that environment can be found in publications by Silverman et al. (2000) and ARENA-OLAW (ARENA-OLAW, 2002). The following is a brief summary of its main elements.
US ANIMAL WELFARE ACT
The US Animal Welfare Act (AWA; http://www.aphis.usda.gov/ac/awa.html) traces its origins to the Laboratory Animal Welfare Act of 1966. Amended several times over the succeeding years, the AWA names the US Department of Agriculture (USDA) as the federal agency responsible for its implementation and enforcement. Within USDA, the Animal Care unit of the Animal and Plant Health Inspection Service (APHIS/AC) meets this responsibility. Acting under the authority of the AWA, various secretaries of agriculture have developed and promulgated the Animal Welfare Regulations (AWRs; http://www.aphis.usda.gov/ac/publications.html), detailed standards and regulations that govern many aspects of animal care and use programs, including registration of research facilities, institutional animal care and use committees (IACUCs), the attending veterinarian and adequate veterinary care, recordkeeping, reporting, and the procurement, handling, care, treatment, and transportation of animals (9 CFR, Part 2, Subpart C). In addition to the AWRs, there are the Animal Care Policies (APHIS/AC Policies), which were written to further clarify the intent of the AWA. The AWA, AWRs, and the APHIS/AC Policies apply to warm-blooded vertebrates that are
bred for use in research—except birds, rats of the genus Rattus, mice of the genus Mus, and farm animals used in production agriculture. The AWA, AWRs, and the APHIS/AC Policies are available online at http://www.aphis.usda.gov/ac/publications.html.
PUBLIC HEALTH SERVICE POLICY ON HUMANE CARE AND USE OF LABORATORY ANIMALS
The Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS Policy) was introduced in 1973 and revised in 1979 and 1986. The PHS Policy (NIH, 1986) applies to all institutions that use live vertebrates in research supported by any component of PHS: the Agency for Health Care Research and Quality, the Centers for Disease Control and Prevention, the Food and Drug Administration, the Health Resources and Services Administration, the Indian Health Service, the National Institutes of Health (NIH), and the Substance Abuse and Mental Health Services Administration. Bolstered by the statutory mandate of the US Health Research Extension Act of 1985 (HREA), the PHS Policy requires institutions to establish and maintain proper measures to ensure the appropriate care and use of animals involved in research, research training, and biologic testing activities. The PHS Policy mandates compliance with the AWA and the AWRs and requires institutions to base their programs of animal care and use on the National Research Council’s Guide for the Care and Use of Laboratory Animals (NRC, 1996). General administration and coordination of the PHS Policy are the responsibility of the NIH Office of Laboratory Animal Welfare (OLAW). The PHS Policy describes the Animal Welfare Assurance statement, which all covered institutions must submit to OLAW, assuring the office of their compliance with the policy. It also defines the functions of the IACUC, mandates IACUC review of all PHS-conducted or -supported research projects, lists the information required in PHS applications and proposals for awards, and stipulates recordkeeping and reporting requirements. The PHS Policy is available online at http://grants1.nih.gov/grants/olaw/references/phspol.htm.
GUIDE FOR THE CARE AND USE OF LABORATORY ANIMALS
The National Research Council’s Guide for the Care and Use of Laboratory Animals (the Guide) traces its origin to a 1963 publication by the Animal Care Panel, a group of professionals with an interest in research-animal care that evolved into the American Association for Laboratory Animal Science (AALAS, 2000). The second and all subsequent editions were drafted by committees of the Institute for Laboratory Animal Research and published by the National Research Council. The seventh and most recent edition of the Guide was published in 1996 (NRC, 1996). The Guide is designed to promote the humane care of animals used in biomedical and behavioral research, teaching and testing; the
basic objective is to provide information that will enhance animal well-being, the quality of biomedical research, and the advancement of biologic knowledge that is relevant to humans or animals. It provides guidelines on institutional policies and responsibilities; animal environment, housing, and management; veterinary medical care; and physical plant. In making its recommendations, the Guide adopts a performance approach, in which users are charged with achieving well-specified animal-welfare outcomes but can determine individually how best to produce the outcomes, given the constraints and strengths of specific situations. That approach requires that investigators, veterinarians, and IACUCs use professional judgment in designing, reviewing, implementing, and overseeing animal care and use in research, testing, and teaching. Both PHS Policy and the Association for Assessment and Accreditation of Laboratory Animal Care International require that institutions base their programs of animal care and use on the Guide. The Guide is available online at http://dels.nas.edu/ilar.
US GOVERNMENT PRINCIPLES FOR THE UTILIZATION AND CARE OF VERTEBRATE ANIMALS USED IN TESTING, RESEARCH, AND TRAINING
The US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (US Government Principles) were drafted in 1985 by the Interagency Research Animal Committee (IRAC, 1985), made up of individuals drawn from federal agencies that use or require the use of animals in research or testing. Its nine statements address compliance with the AWA and other applicable federal laws, guidelines, and policies (such as AWRs, HREA, and the Guide) and generally provide a set of overarching principles for ensuring that the use of research animals is justified and humane. Compliance with the US Government Principles is mandated by the PHS Policy and the Guide. The US Government Principles are available online at http://grants1.nih.gov/grants/olaw/references/phspol.htm.
ASSOCIATION FOR ASSESSMENT AND ACCREDITATION OF LABORATORY ANIMAL CARE INTERNATIONAL
The Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC International) is a private, nonprofit organization that promotes the humane treatment of animals in science through a program of voluntary accreditation. Incorporated in 1965, AAALAC International uses the Guide as its primary reference document and augments it with reference resources in the peer-reviewed literature. Compliance with AAALAC International’s standards is determined through review of an institution’s detailed written description of its overall program of animal care and use, which is submitted in advance of a thorough on-site evaluation by a team of AAALAC
International’s expert members. Compliant institutions are awarded AAALAC accreditation for a period of 3 years, at the end of which the entire review process is repeated.
THE 3 Rs
“. . . by now it is widely recognized that the [most humane] possible treatment of experimental animals, far from being an obstacle, is actually a prerequisite for successful animal experiments.”
Russell and Burch, 1959
The Principles of Humane Experimental Technique
Every major animal-welfare policy—including the AWA, the PHS Policy, the US Government Principles, and the Guide—is based on the principles of the 3 Rs put forth by Russell and Burch in The Principles of Humane Experimental Technique (1959). Those principles are:
Replacement. Use of nonanimal systems or less-sentient animal species to partially or fully replace animals.
Reduction. Reduction in the number of animals utilized to the minimum required to obtain scientifically valid data.
Refinement. Use of a method that lessens or eliminates pain and/or distress and therefore enhances animal well-being.
The AWA was amended in 1985, specifically to “reflect the importance of the ‘3 Rs’” (Hamilton, 1991). The application of the principles was clearly laid out in APHIS/AC Policy 12 “Consideration of Alternatives to Painful/Distressful Procedures”:
the regulations state that any proposed animal activity, or significant changes to an ongoing animal activity, must include:
a rationale for involving animals, the appropriateness of the species, and the number of animals to be used;
a description of procedures or methods designed to assure that discomfort and pain to animals will be limited to that which is unavoidable in the conduct of scientifically valuable research and that analgesic, anesthetic, and tranquilizing drugs will be used where indicated and appropriate to minimize discomfort and pain to animals;
a written narrative description of the methods and sources used to consider alternatives to procedures that may cause more than momentary or slight pain or distress to the animals;
the written assurance that the activities do not unnecessarily duplicate previous experiments.
The principles of the 3 Rs are also reflected in the Guide, which says that the following topics should be considered in the development and review of animal protocols (p. 10):
Justification of the species and number of animals requested.
Availability or appropriateness of the use of less-invasive procedures, other species, isolated organ preparation, cell or tissue culture, or computer simulation.
Appropriate sedation, analgesia, and anesthesia.
Unnecessary duplication of experiments.