Recognition and Alleviation of Distress in Laboratory Animals (2008)

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1 Introduction In 1992, the National Research Council published a report titled Rec- ognition and Alleviation of Pain and Distress in Laboratory Animals “to help scientists, research administrators, institutional animals care and use committees, and animal care staff to address the difficult questions of the presence and alleviation of animal pain and distress” (NRC 1992, p. 1). The need for assistance in this area has persisted, and, with the advent of new scientific discoveries, the generation of genetically modified animals, and continued regulatory emphasis on minimizing pain and distress in laboratory animals, it became evident that the 1992 report had become outdated. The Institute for Laboratory Animal Research (ILAR) received several requests from the veterinary and biomedical communities to convene a Committee to update the report. After many discussions with constituents and several sponsors, the National Academies opted to update the 1992 report as two separate reports, one on distress and one on pain, because although they are linked in regulation, they are quite different scientifically. Regulations Governing Pain and Distress in Laboratory Animals Public concern for laboratory animals focuses on their pain and dis- tress, and so, although a majority of the public supports the use of animals in biomedical research, that support diminishes when the animals are subjected to pain and/or distress. In response to these views government policies and laws mandate the minimization or elimination of pain and distress. For example, according to U.S. Government Principle IV for the  

10 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training, “Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific prac- tices, 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” (IRAC 1985). Similarly, the federal Animal Welfare Act Regulations (USDA 2005), the Guide for the Care and Use of Laboratory Animals (NRC 1996), U.S. Public Health Service Policy for the Humane Care and Use of Animals (DHHS 2002), and policies of the Association for Assessment and Accreditation for Laboratory Animal Care International (AAALAC International) all require the identification, minimization, and elimination of sources of pain and distress in laboratory animals, consistent with the goals of the research. These policies address pain and distress jointly as both are considered unpleasant and potentially harmful to the animal subjects. From a scien- tific perspective, however, pain and distress are quite different and should be examined separately so that each receives appropriate emphasis. This is especially true for distress, as it has been difficult to define and there is relatively little research in this area. In fact, only a small portion of the 1992 report discussed distress because at that time very little scientific informa- tion was available. While more information was available for this report, it is still difficult to pinpoint exact measures of distress. Due to the paucity of information and the lack of a clear, widely accepted definition for distress, the biomedical research community, includ- ing investigators, veterinarians, animal care staff, and IACUCs, has not had reliable guidance in recognizing, assessing, or alleviating distress. Because regulations call for the minimization or elimination of distress, it is impera- tive to attempt an evaluation of the state of the science and to translate current scientific knowledge into practical guidelines for use in laboratory animal facilities. Specifically, the Committee was tasked with preparing a report on stress and distress [that] will review the current scientific litera- ture regarding mechanisms of stress and distress for animal models used in biomedical research as well as the literature regarding methods for recog- nizing and alleviating distress. Emphasis will be placed on: the scientific understanding of causes and functions of stress and distress; determining when stress becomes distress; and identifying principles for recognition and alleviation of distress. Specific emphasis will be placed on the iden- tification of humane endpoints in situations of distress and principles for minimizing distress in laboratory animals. . . . [G]eneral guidelines and examples will be given to aid IACUC members, investigators and animal care staff in making decisions about protocols using laboratory animals under current federal regulations and policies. Recommendations will be 

INTRODUCTION 11 based on the most current scientific data where such data are available. The Committee will also identify gaps in the scientific literature where additional research data are needed. Organization of the Report This report is the result of the Committee’s work to address this charge, and it is organized as follows. In the common vernacular, stress and dis- tress are used almost interchangeably without consideration of the cause or scientific implications. However, the Committee attempted to the best of its ability to make a clear distinction between the scientific concepts of stress and distress, noting, in particular, that the causes and consequences of the latter are less well defined. Although a distinct definition of distress was not produced, Chapter 2 presents a balanced discussion of stress and distress that incorporates animal welfare perspectives based on the members’ best professional judgment. The report embraces the idea (also reflected in the U.S. Government Principles) that pain and distress are clearly two different things. Distress is caused by more than momentary painful situations (both acute and chronic), while non-pain-related distress exists as well. In fact, the latter, given the insidiousness of its causes, may be even more prevalent, as painful insults are easier to recognize and deal with than, for example, inadequate husbandry conditions. In addition to compiling the most up-to-date information on the physi- ology of stress and distress, the Committee in Chapter 3 used its expertise in the area of animal behavior to provide the most current scientifically based information on normal and abnormal behaviors of some of the most com- monly used laboratory species. While this information is not exhaustive, it does include pertinent examples of situations in which laboratory animals may experience distress. An important point of this chapter is that in order to recognize distress in animals, it is necessary to know their normal indi- vidual behaviors. Additional information on behaviors and score sheets for several commonly used laboratory species are included in the Appendix. One way to minimize or eliminate distress, however, is to avoid it alto- gether. Chapter 4 outlines current practices and highlights specific issues to be considered for alleviating, minimizing, or preventing distress. Some measures for distress prevention include optimization of housing, enrich- ment, and socialization conditions based on the needs of the individual species or strains being used. Although much general information is avail- able about acceptable conditions for maintaining animals in laboratories, in many instances scientific evidence is minimal or lacking. In those cases it is necessary to rely on the expert opinion of the professionals who work directly with the animals on a regular basis. In addition, research protocols for studies in which animal distress is anticipated should consider humane 

12 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS endpoints as well as the use of appropriate statistics and experimental design to minimize the number of animals that must be used. ­Investigators should establish a partnership with the veterinarians and animal care staff and make provisions in cases of either anticipated or unanticipated distress. The intent of this report is to assist investigators, veterinarians, animal care staff, and IACUCs in understanding distress so that it can be recog- nized, alleviated, or prevented. The Committee urges readers to consider the information in this report very carefully and to exercise professional judgment in evaluating situations where distress occurs or is likely to occur. As new information becomes available, it should be incorporated into practice and decision making in the care of laboratory animals. The Com- mittee hopes that this report will be useful in assisting readers to comply with regulations, to achieve reliable scientific outcomes, and, especially, to provide the best possible care for their animal subjects. REFERENCES DHHS (Department of Health and Human Services), National Institutes of Health, Office of Laboratory Animal Welfare. 2002. Public Health Service Policy on Humane Care and Use of Laboratory Animals. Available at: http://grants.nih.gov/grants/olaw/references/phspol. htm. Accessed January 30, 2008. IRAC (Interagency Research Animal Committee). 1985. The U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training. F ­ ederal Register Vol. 50, No. 97 (May 20, 1985). Office of Science and Technology Policy. Available at: http://grants.nih.gov/grants/olaw/references/phspol.htm#USGovPrinciples. Accessed January 30, 2008. NRC (National Research Council). 1992. Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academy Press. NRC. 1996. Recognition and Alleviation of Pain and Distress in Laboratory Animals. Wash- ington, DC: National Academy Press. USDA (U.S. Department of Agriculture). 2005. 9CFR2.31. Code of Federal Regulations, title 9, Volume 1, part 2, subpart C, section 2.31 (d) (1) (i): Institutional Animal Care and Use Committee. Available at: http://www.aphis.usda.gov/animal_welfare/downloads/ awr/9cfr2.31.txt. Accessed January 30, 2008.