Summary

This report is the first of two reports prepared as an update to the 1992 National Research Council (NRC) report Recognition and Alleviation of Pain and Distress in Laboratory Animals. In the 15 years since the first NRC publication on this subject, there has been considerable scientific progress in the areas of animal welfare and behavior, including attention to the subjects of stress and distress. U.S. regulations promulgated by the Animal Welfare Act and Public Health Service Policy as well as standards and practices promoted by the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC International) and the Guide for the Care and Use of Laboratory Animals (NRC 1996) mandate that pain and distress in laboratory animals be minimized or eliminated, except when scientifically justified. These policies address pain and distress jointly because both are considered unpleasant and potentially harmful to the animal subjects. From a scientific 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, which has historically been difficult to define and on which there has been relatively little research.

SCOPE OF THE STUDY

Due to both the paucity of information and the lack of a clear, widely accepted definition for distress, the scientific community using animals in research, including investigators, veterinarians, animal care staff, and animal care and use committees, has not had reliable guidance in recognizing,



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Summary This report is the first of two reports prepared as an update to the 1992 National Research Council (NRC) report Recognition and Alleiation of Pain and Distress in Laboratory Animals. In the 15 years since the first NRC publication on this subject, there has been considerable scientific progress in the areas of animal welfare and behavior, including attention to the subjects of stress and distress. U.S. regulations promulgated by the Animal Welfare Act and Public Health Service Policy as well as standards and practices promoted by the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC International) and the Guide for the Care and Use of Laboratory Animals (NRC 1996) mandate that pain and distress in laboratory animals be minimized or eliminated, except when scientifically justified. These policies address pain and distress jointly because both are considered unpleasant and potentially harmful to the animal subjects. From a scientific 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, which has historically been difficult to define and on which there has been relatively little research. SCOPE OF THE STuDy Due to both the paucity of information and the lack of a clear, widely accepted definition for distress, the scientific community using animals in research, including investigators, veterinarians, animal care staff, and ani- mal care and use committees, has not had reliable guidance in recognizing, 1

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2 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS assessing, or alleviating distress. Because minimization or elimination of distress experienced by laboratory animals is not only a regulatory require- ment but also a moral obligation, it is imperative 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 reiew the current scientific literature regarding mechanisms of stress and distress for animal models used in biomedical research as well as the literature regarding methods for recognizing and alleiating distress. Emphasis will be placed on: the scien- tific understanding of causes and functions of stress and distress; determin- ing when stress becomes distress; and identifying principles for recognition and alleiation 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. While all possible scenarios cannot be included in this document, general guidelines and examples will be gien to aid Institutional Animal Care and Use Committee (IACUC) members, inestigators and animal care staff in making decisions about protocols using laboratory animals under current federal regulations and policies. Recommendations will be based on the most current scientific data where such data are aailable. The Committee will also identify gaps in the scientific literature where additional research data are needed. The Committee approached its task from the perspective of performance standards without describing—among others—factors such as intensity, duration, or types of perturbations, in part because this is an advisory docu- ment about an insufficiently understood phenomenon, but also because the Committee members believe that—within the current state of science—the best approach to recognize and alleviate distress is through best practices and professional judgment. STRESS vERSuS DISTRESS Various views, definitions, and language have been used in the discus- sion of stress and distress. Current scientific knowledge supports the concept that stress is a real or perceived perturbation to an organism’s physiological homeostasis or psychological well-being. In its stress response, the body uses behavioral or physiological mechanisms to counter the perturbation. Events that precipitate stress (called stressors) can elicit any of a number of coping mechanisms or adaptive changes, including behavioral reactions, activation of the sympathetic nervous system and adrenal medulla, secre- tion of stress hormones (e.g., glucocorticoids and prolactin), and mobiliza- tion of the immune system.

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3 SUMMARY Both stress and distress are meaningful terms that describe a state of being. While the biological responses to stress are better understood, the scientific, regulatory, and animal welfare communities disagree with respect to a universally accepted definition of distress. Although most definitions of distress characterize it as an aversive, negative state in which coping and adaptation processes in response to stressors fail to return an organ- ism to physiological and/or psychological homeostasis, philosophical dif- ferences center on the inclusion of emotions and feelings affected by this state of being. Similarly, while it is accepted that failure of the organism to return to homeostasis adversely impacts an animal’s well-being and leads to poor welfare, defining well-being without relying on some form of anthropomorphic measures is a challenge. Scientific research does not yet support objective criteria or principles with which to qualify distress, objective scientific assessment of subjective emotional states cannot be made, and while there is often a measure of agreement on the interpretation of physiologic and/or behavioral variables as indicators of stress, distress, or welfare status, there is not always a direct link. Further, the Committee postulates that even if a universally accepted definition existed, it could not be applied across all species and all conditions, because of the differential impact of the strain, age, gender, genetic background, and environment. The transition to distress, which occurs when the body cannot cope against the assault of one or more stressors, depends on several factors. Of clear importance are stressor duration, stressor intensity, and the capacity of the individual animal to respond; changes in any of these increases the like- lihood of behavioral or physical signs of distress. Thus, minor perturbations may be stressful and/or negatively affect an animal’s moment-to-moment emotional state but they would not impair its adaptive capacity and there- fore not cause distress (this may be unrelated to the state of the animal’s welfare as illustrated in Figure 2-2). In contrast, a major homeostatic dis- ruption (e.g., postsurgical infection), which causes measurable behavioral (e.g., withdrawal) and physiological (e.g., fever) changes that impair an animal’s adaptive capacity, would be considered distressful and indicative of poor welfare. However, distress may not manifest itself with recognizable “maladaptive behaviors, such as abnormal feeding or aggression” (NRC 2003a, page 16) but instead begin with subclinical pathological changes (e.g., hypertension or immunosuppression) that can lead to overt disease. These physiological concepts should be integrated within and evaluated in concert with animal welfare principles. RECOgNITION AND ASSESSMENT OF STRESS AND DISTRESS While there are some specific behavioral measures of stress, relatively little is known about behavioral correlates of stress (i.e., behavioral changes

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4 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS directly attributed to the presence of stress), and even less about those of distress. Thus, recognizing stress and distress in laboratory animals based on behavioral changes remains a significant challenge to investigators and animal care staff. A first-order approach to this challenge is to understand the animals’ normal behaviors, while keeping in mind that such behav- iors are neither invariant nor universal. Although normal behaviors may sometimes be characterized simply by a lack of atypical behavior, such as stereotypic (i.e., repetitive) or self-injurious behavior, some species and strain differences are not always easy to discern, and further complications are introduced by gender, age, physiological state, genetics, and genetic modification of the animals. Furthermore, it is not possible to recreate the full range of species-specific behaviors in the laboratory setting, as some types of behavior (e.g., severe aggression) are clearly undesirable from a management perspective. Physiological effects of stress are mediated through the endocrine, neural, and immune systems and changes in stress hormone levels such as cortisol as well as the actions of the autonomic nervous system in response to known stressors have been well documented. However, research has not necessarily focused on deciphering these complex mechanisms in situations of suspected distress. Assessment for the presence of stress should consider conditions that reliably produce it (e.g., exposure to a predator) and may be based on clini- cal and biochemical parameters such as activation of the hypothalamic- pituitary-adrenal (HPA) axis, changes in other hormones (e.g., prolactin), and changes in blood pressure and heart rate, and behavioral measures. An effective assessment of distress is predicated upon solid knowledge of physi- ologic behavior for each species and careful observation. It should integrate information from multiple behavioral and physiological parameters and should involve a team approach that includes researchers, veterinarians, and animal caretakers/technicians, as distress levels will vary in relation to the species, husbandry conditions, and experimental protocol as well as with each individual animal. The Committee points out that although the differentiation between abnormal behaviors associated with or caused by stress/distress and those observed in disease states (for example, both distressed and sick animals may not clean themselves and have matted fur coat) may be conceptually difficult, poor health means poor welfare. It is the Committee’s opinion that, until more research is available, validated prac- tices seeking what is best for the animals while maintaining the integrity of research protocols (i.e., the use of performance standards) should be used.

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 SUMMARY AvOIDINg, MINIMIZINg, AND ALLEvIATINg DISTRESS Efforts to avoid or minimize distress should follow the principles of the Three Rs: refine, reduce, and replace, which apply to daily husbandry as well as experimental procedures. Because most laboratory animals live outside normal habitats, they should, to the extent possible in an artificial environment, have the opportunity to express species-specific behaviors. Animal welfare evaluations should consider conditions of housing, hus- bandry, enrichment, and socialization. The Committee’s philosophy has been to motivate investigators, veterinarians, and Institutional Animal Care and Use Committees (IACUCs) to embrace the Three Rs and through those criteria to act in the best interest of the animals while safeguarding the integrity of the research process. Consideration of humane endpoints should be part of the experimental protocol in order to minimize or avoid subjecting an animal to adverse conditions. Pilot studies can be an effective option (for example in protocols known or anticipated to elicit distress, in dose-response or LD50 studies), while sound experimental design and statistical analysis are essential to ensure the use of appropriate number of animals. New minimally or non- invasive technologies that allow sophisticated tracking of disease progres- sion, allow for reduction in animal numbers and/or earlier termination of experiments, thus avoiding prolonged and/or unnecessary discomfort to the animals. To address situations of unanticipated distress, the investiga- tor, veterinary staff, and animal care personnel, working as a team and in compliance with the current regulations, should establish a plan to allevi- ate the distress, for example by removing an animal from the study, or through pharmacological treatment with anxiolytics, antidepressants, or neuroleptics. The study of distress itself is important for both human and animal health. However, investigators who engage in research on distress using laboratory animal models, should, in consultation with the veterinarian and the IACUC, develop a plan that establishes limits to the levels of dis- tress allowed in the experimental protocol. Appropriate methods to refine distress-related experimental designs include taking steps to alleviate dis- tress after completion of the procedures or upon attainment of the research aims (e.g., maximum allowable weight loss as a percentage of normal body weight). As new methodologies and/or data from these studies become available, current practices in addressing stress and distress should be evalu- ated and modified accordingly.

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6 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS FuTuRE STuDIES AND RECOMMENDATIONS Many questions in the field of laboratory animal distress remain unan- swered. The Committee, therefore, offers the following suggestions for research directions that can improve our understanding of distress: • determine whether there are biomarkers of distress that may be easily measured; • use genomic and proteomic technologies to study the physiology and pathophysiology of stress and distress; • develop possible distress predictors to be used as outcomes scores (i.e., to predict severity in clinical outcomes, mortality, etc., and adopt humane or surrogate endpoints) for laboratory animals, simi- lar to the predictive severity scoring system used in human inten- sive care units; • delineate the mechanisms of possible associations between stress/distress and disease behaviors or abnormal behaviors (e.g., stereotypies); • study the influence of an organism’s characteristics (e.g., gender, age, or genetic makeup) on the development of distress; • identify refinements in euthanasia methods; • study the potential use of historical controls in appropriate research protocols; • determine parameters for optimal husbandry conditions for labora- tory animals; and • determine the appropriateness of experimental designs currently used for human research in studies that depend on laboratory ani- mal models. The Committee also provides the following recommendations: 1. The Three Rs (refinement, reduction, and replacement) should be the standard for identifying, modifying, avoiding, and minimizing most causes of distress in laboratory animals. While research on distress and methods of alleviating distress (e.g., the development of anesthesia or analgesia) may unavoidably cause animal suffering, the optimum goal of research and veterinary teams should be to reduce and alleviate distress in laboratory animals to the minimum necessary to achieve the scientific objective. 2. Protocols should include efforts to improve housing and hus- bandry conditions through the judicious employment of strategies for enrichment, animal training, and socialization. Well-trained,

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 SUMMARY competent, and attentive research and animal care personnel are crucial in providing relief from unintended distress that originates from the care and use of laboratory animals. 3. Institutional support for and embrace of a commitment to animal welfare of the laboratory animals is essential. veterinarians and animal care personnel who work with research animals on a daily basis should have adequate time and contact with the animals to properly evaluate their well-being. Funding for training programs is crucial to the training and development of specialized laboratory animal veterinarians and animal behaviorists and should increase, because in addition to such objective measurements as weight loss or lack of grooming, clinical judgment is vital to effective assess- ments of stress and distress. 4. Appropriate statistical methodologies are an essential tool for the avoidance, minimization, and alleviation of distress. 5. There should be a clearinghouse (or some other venue such as a website or a specialized peer-reviewed journal) for publication of research on the effects of enrichment strategies on parameters such as physiology, distress, and endpoints for all laboratory animals (one useful example is the Primate Enrichment Database hosted by the Animal Welfare Institute).1 Although a variety of journals (such as Lab Animal, Applied Animal Behaiour Science, Animal Wel- fare, Laboratory Animals, Contemporary Topics in Laboratory Ani- mal Science, Comparatie Medicine) publish research pertaining to animal welfare, the highly specialized nature of the field makes it difficult for the larger scientific community to remain informed about recent advances and ongoing debates. Peer-reviewed bio- medical research journals should be more open to submissions from scientists whose research focuses on animal welfare issues so that concerns about research interference or unjustified expenses can be debated on scientific, ethical, or regulatory grounds. 6. Obtaining funding for welfare research is often difficult, especially when project applications compete against other fields of science due to lack of an appropriate/separate research oversight body. In the United Kingdom the funds available for welfare research have increased dramatically with the founding of the National Center for the Replacement, Refinement and Reduction of Animals in 1 http://www.awionline.org/SearchResultsSite/enrich.aspx.

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8 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Research (NC3Rs).2 In the United States, the National Institutes of Health, Environmental Protection Agency, and other federal insti- tutions have occasionally provided funding to develop or validate nonanimal or nonvertebrate alternatives. Funding for laboratory animal welfare research, however, is usually available only in small amounts from nongovernmental organizations such as the Animal Welfare Institute, the Johns Hopkins Center for Alternatives to Animal Testing, the American College of Laboratory Animal Medicine, and the American Association for Laboratory Animal Science. given the impact of better animal welfare on science as well as the growing public interest in the treatment of labora- tory animals, federal agencies and large foundations that support biomedical and behavioral research should make funds available specifically for the avenues of investigation listed above and for other related topics. 7. Animal welfare scientists and researchers and scientists who use animal models should communicate with each other more frequently in order to compare objectives and progress and to identify opportunities for collaboration. Neutral groups and/or other established research and science policy entities can provide platforms and venues for such exchanges. REFERENCE NRC (National Research Council). 2003a. Guidelines for the Care and Use of Mammals in Neuroscience and Behaioral Research. Washington, DC: The National Academies Press. 2 NC3Rs website: www.nc3rs.org.uk.