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, husbandry, 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 noninvasive technologies that allow sophisticated tracking of disease progression, 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 investigator, veterinary staff, and animal care personnel, working as a team and in compliance with the current regulations, should establish a plan to alleviate 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 distress allowed in the experimental protocol. Appropriate methods to refine distress-related experimental designs include taking steps to alleviate distress 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 evaluated and modified accordingly.

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