ILAR Journal Online, Volume 40(1) 1999: Bioethics of Laboratory Animal Research

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ILAR Journal V40(1) 1999
Bioethics of Laboratory Animal Research

US Laws and Norms Related to Laboratory Animals
John L. VandeBerg, Sarah Williams-Blangero, and Thomas L. Wolfle

John L. VandeBerg, Ph.D., is Scientific Director at the Southwest Founda-tinn for Biomedical Research; Sarah Williams-Blangero, Ph.D., is a Scientist at the Southwest Foundation; and Thomas L. Wolfle, D.V.M., Ph.D., is a former Director of ILAR.

Two documents provide the basis for the laws related to the care and use of laboratory animals in the United States: the Animal Welfare Act (AWA¹)(AWA 9 CFR Subchapter A) and the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS¹Policy) (PHS 1996). Both of these regulatory documents are based to a large extent on a third document, the Guide for the Care and Use of Laboratory Animals (Guide) (NRC 1996), which is a consensus document reflecting the state of the art of scientifically based laboratory animal care and use. The AWA is enforced through federal regulations; compliance with the PHS Policy and adherence to the standards in the Guide are conditions for eligibility of institutions to receive federal funding from the PHS for animal research. The AWA is administered by the US Department of Agriculture (USDA¹)Animal Plant Health Inspection Service/Animal Care (APHIS/AC¹). The PHS Policy is administered by the Office for Protection from Research Risks (OPRR¹). Compliance with USDA regulations, the standards of the Guide, and PHS Policy is also monitored by a voluntary institutional accreditation program administered by the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC¹International). Additional detailed information and supplementary guidelines pertaining to animal care and use for certain types of animals and/or research situations are developed and distributed by the Institute for Laboratory Animal Research (ILAR¹)on a continuing basis.

Animal Welfare Act

The first version of the AWA (called the Laboratory Animal Welfare Act) was passed in 1966 in response to public claims that pet dogs and cats were being used in research. It initially covered only the care and transportation of animals and made provisions to prevent the sale of stolen animals. Since 1966, there have been several amendments that provide detailed protection for laboratory animals. The most recent amendment was passed in 1985. The provisions are now complex and cover not only the care and transportation of animals but also broad aspects of use and justification of the use of animals in research. The species subject to the AWA regulations are "any live or dead dog, cat, nonhuman primate, guinea pig, hamster, rabbit, or any other warm-blooded animal, which is being used, or is intended for use for research, teaching, testing, experimentation, or exhibition purposes...." Laboratory-bred rats and mice and birds are currently exempted from the AWA regulations.

The branch of USDA charged with the responsibility of enforcing the AWA regulations is APHIS, within which Animal Care (AC) is the responsible unit. Inspectors conduct unannounced inspections at least once a year at institutions that use animals in research and institutions that house research animals available for sale. When minor violations of the AWA are found and cited, the institution has the opportunity to correct the problem within a reasonable time frame. However, major violations can lead to substantial fines and suspension of registration as a USDA-licensed research institution, or of the license to produce animals for sale to a research institution.

One provision of the AWA is that each institution must have an institutional animal care and use committee (IACUCI), which has broad powers within the institution. The IACUC must have at least three members, including one laboratory animal veterinarian with direct or delegated responsibility for animals in the institution's research program and one member who has no affiliation with the institution and who will represent general community interests in appropriate animal care and use. The IACUC must approve all proposed experiments before they are initiated, review the institution's animal care and use program at least once every 6 mo, inspect the animal facilities at least once every 6 mo, and submit a report on each inspection to the responsible official of the research facility. Other provisions of the AWA pertain to housing and transport conditions for the animals, appropriate use of anesthetics and analgesics, consideration of alternatives to the use of animals in research protocols, and documented confirmation by investigators that proposed experiments are not duplications of former laboratory work.

The USDA inspection process has been criticized by some members of the research community from a number of perspectives. Some investigators and institutional representatives argue that the inspection system is flawed because inspectors are not trained in laboratory animal medicine, research methodology, or animal behavior; and they complain that the turnover rate for inspectors is unacceptably high. They argue that the interpretation of the regulations varies widely among inspectors as a consequence of insufficient training and experience. In response to these criticisms, USDA has begun sending small groups of inspectors for 6-wk assignments to work with laboratory animal veterinarians in academic and pharmaceutical research facilities. Others argue that the range of USDA oversight is inadequate. As noted above, the AWA regulations specifically exempt rats of the genus Rattus, mice of the genus Mus, and birds. Because rats and mice comprise more than 90% of the animals used in research, the USDA would require an estimated 30% increase in its budget if it had to provide inspectors to oversee the use of rats and mice. USDA published a request for public comment in January 1999 regarding the regulation of rats, mice, and birds (Federal Register 1999).

PHS Policy

PHS Policy was issued in 1971, revised in 1986, and reprinted in 1996 (PHS 1996). It is administered by OPRR of the PHS, within the US Department of Health and Human Services. PHS Policy applies to all vertebrate animals and to all institutions that use vertebrates in research sponsored by the PHS. The National Institutes of Health (NIH^l)comprises one unit of the PHS and provides most of the federal funding for individual investigator-initiated biomedical research in the United States. Thus, PHS policy applies to most academic and research institutions that conduct biomedical research.

One major mandate of PHS Policy is that institutions adhere to the provisions of the AWA, the Guide, and the US Government Principles (IRAC 1985). Other mandates include record-keeping requirements to ensure clear accountability for the quality of the animal care program and reporting requirements to enable oversight by federal funding agencies.

PHS Policy establishes a "trust relationship" between OPRR and each institution receiving PHS funds. It requires these institutions to provide written assurance of compliance with PHS Policy and a detailed explanation of the programs and procedures in place to ensure that PHS Policy is enforced. This document is called an "institutional assurance."

"For cause" inspections of institutions are generally conducted only if there is believed to be a break in the trust relationship by the institution and only if written communication has failed to resolve a suspected instance of noncompliance. PHS inspections are conducted by a team of qualified scientists and veterinarians. A severe and uncorrected violation of PHS Policy can result in revocation of the institutional assurance and loss of all PHS funding to the entire institution.

The Guide

Produced by ILAR, the Guide (NRC 1996) was first published by the Animal Care Panel (predecessor of the American Association for Laboratory Animal Science) at the request of the NIH in 1963, prior to the AWA (1966) and the PHS Policy (1971). More than 500,000 copies have been distributed. The 7th edition, which was completed in 1996, was prepared by a balanced committee of 15 members comprising highly qualified scientists, veterinarians, an ethicist, and a layperson. Previous editions were funded exclusively by the NIH, but the 7th edition also received funding from the USDA and the Veterans Administration. The 7th edition of the Guide was published by the National Academy Press, which holds the copyright.

The Guide is a critically important document that provides guidelines for scientifically, technically, and humanely appropriate animal care and use. This document is used by all federal agencies and many private, commercial, and federal research organizations. The emphasis on guidelines rather than absolute standards is an important characteristic of the Guide. These guidelines are intended to provide a basis for informed decisions pertaining to the care and use of animals within the context of specific circumstances that exist at an institution, specific aspects of experimental design, and specific characteristics of the individual animals that will be used in an experiment. The 7th edition of the Guide incorporates many changes from the previous (NRC 1985) edition based on advances in state-of-the-art science pertinent to the care and use of laboratory animals.

The 7th edition applies to all animals, including farm animals used in biomedical research whether they are housed in a laboratory animal setting or in a farm setting. A related document, the 2nd edition of the Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching, published by the Consortium for Developing a Guide for the Care and Use of Animals in Agricultural Research and Testing (1999), applies to research and teaching that have agricultural rather than biomedical objectives.

One of the most controversial aspects of both the Guide and the AWA regulations is the emphasis on performance standards rather than engineering standards. Performance standards do not prescribe rigid methods for achieving an objective, but rather allow the use of professional judgment to develop optimal approaches for attaining specific goals or outcomes. The 7th edition's emphasis on performance standards is even greater than in previous editions.

For example, the physical characteristics of an animal's environment are not absolutely prescribed by the Guide; instead, specific goals or outcomes that depend on judgment of the individual animal's performance in its environment are provided. Engineering standards would rigidly define the physical environment of the animal without making allowances for the individual animal's characteristics or circumstances; for example, the size of its cage, the number of animals per cage, the duration of exercise each day, and so forth would all be prescribed. Compliance with engineering standards does not require any attention to the animals themselves, whereas compliance with performance goals requires that persons well trained in the biology and behavior of the species pay careful attention to the animals. A performance approach allows assessments of behavioral characteristics or physiological measures reflective of stress to be used in developing optimal physical environments for individual animals under specified research conditions.

Similarly, the social environment of nonhuman primates is best enhanced using a performance approach. Whereas one monkey might require companions for psychological well-being, another of the same species might be threatened or overly aggressive in a social setting. The committee that prepared the Guide, and most other scientists and veterinarians, agree that each animal deserves individual consideration because it has a unique genetic makeup (except members of an inbred strain) and a unique repertoire of lifetime experiences. Furthermore, there may be many alternative methods for providing a satisfactory environment for an animal, and an individual animal's needs may change over its lifetime. A recently published ILAR report entitled Psychological Well-Being of Nonhuman Primates (NRC 1998) addresses these issues in detail.

The greater emphasis on performance standards in the 7th edition is reflected in the designation of cage sizes as recommendations, rather than as absolutes or minimums. IACUCs are assigned responsibility for assessing the appropriateness of cage sizes based on professional judgment and performance-based outcomes. Significant changes have been made in cage size recommendations for nonhuman primates, with more specific recommendations for apes and large monkeys. A footnote on page 2 of the Guide notes that on a few matters_Dthe Guide differs from the AWA regulations and the PHS policy, and that users regulated by the AWA regulations or the PHS policy must comply with them.

Oversight of the implementation of the guidelines in the Guide and of the decisions that are made for individual animals and experiments is provided by the IACUC. Sometimes the judgments and interpretations required to satisfy the guidelines are difficult to make, leading to inconsistencies between institutions and conflicts within institutions between investigators and their IACUCs.

AAALAC International

AAALAC International is a private nonprofit organization whose mission is to promote the highest standards of laboratory animal care. The qualifications for AAALAC International accreditation are stringent and depend on meeting the provisions of the AWA, PHS Policy, and the Guide. Each institution is evaluated every 3 yr by highly qualified laboratory animal veterinarians and scientists. Institutions are provided a reasonable period of time to correct any deficiencies that are detected. If deficiencies are not corrected in the requisite time period, an institution is placed on probation; and withdrawal of accreditation is the ultimate penalty. The AAALAC International program promotes high-quality care of laboratory animals in research and helps to standardize the norms of care among institutions.

ILAR

ILAR is a unit of the National Research Council of the National Academy of Sciences, a private nonprofit organization that exists to provide expert scientific advice to the government and to the public. ILAR's mission is to develop guidelines and to disseminate information on the "scientific, technological, and ethical use of animals and related biological resources in research, testing, and education" (NRC 1996, p 109).

ILAR is responsible for preparing and distributing many documents in addition to the Guide. These include detailed guidelines for the care and use of specific species of laboratory animals (for example, Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use [NRC 1997]) as well as more general discussions of animal research topics (for example, Occupational Health and Safety in the Care and Use of Research Animals [NRC 1997]). Such documents are used as adjuncts to the Guide by scientists, veterinarians, IACUC members, and AAALAC International staff. They have a significant impact on the norms of animal care and use in the United States and in other countries. For example, as of January 1999, the 7th edition of the Guide has been translated and published in Japanese and two Chinese versions. Translations into Spanish, Korean, French, Russian, and Portuguese are in various stages of preparation.

Summary and Conclusion

The laws, policies, guidelines, and practices pertaining to laboratory animal research in the United States are complex. They emphasize performance standards, which provide a mechanism for incorporating professional judgment and the most up-to-date scientific knowledge in effort to provide excellent laboratory animal care and to use research animals in a judicious, wise, and humane manner. They place a heavy burden of responsibility for implementation and monitoring of those standards at the level of the institutions where animals are used, and they mandate detailed reporting by the institutions and stringent oversight by regulatory agencies. This system functions in concert with the voluntary AAALAC International accreditation program and dissemination of documents prepared by ILAR. The outcome is high-quality animal care and healthy animals, optimal and humane use of animals in research, and rapid scientific progress.

¹Abbreviations used in this paper: AAALAC, Association for the Assessment and Accreditation of Laboratory Animal Care; APHIS/AC, Animal Plant Health Inspection Service/Animal Care unit; AWA, Animal Welfare Act; Guide, Guide for the Care and Use of Laboratory Animals; IACUC, institutional animal care and use committee; ILAR, Institute for Laboratory Animal Research: NIH, National Institutes of Health; OPRR, Office for Protection from Research Risks; PHS, Public Health Service; USDA, US Department of Agriculture.

References

AWA [Animal Welfare Act]. 9 CFR Subchapter A. Washington DC: Office of the Federal Register.

Committees to Revise the Guide for the Care and Use of Animals in Agricultural Research and Teaching. 1999. Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching. Savoy IL: Federation of Animal Science Societies. Federal Register. January 28, 1999. Vol 64 No 18. p 4356-4367.

IRAC [Interagency Research Animal Committee[. 1985. U.S. Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training. Federal Register, May 20, 1985. Washington DC: Office of Science and Technology Policy.

NRC [National Research Council]. 1997. Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use. Washington DC: National Academy Press.

NRC [National Research Council]. 1985. Guide for the Care and Use of Laboratory Animals. 6th ed. Washington DC: GPO.

NRC [National Research Council]. 1996. Guide for the Care and Use of Laboratory Animals. 7th ed. Washington DC: National Academy Press.

NRC [National Research Council]. 1997. Occupational Health and Safety in the Care and Use of Research Animals. Washington DC: National Academy Press.

NRC [National Research Council]. 1998. Psychological Well-Being of Nonhuman Primates. Washington DC: National Academy Press.

PHS [Public Health Service]. 1996. Public Health Service Policy on Humane Care and Use of Laboratory Animals. Washington DC: US Department of Health and Human Services. {PL 99-158 Health Research Extension Act, 1785.]