means for the animal to cope. The simplest approach is to follow the principles developed by Russell and Burch known as the Three Rs (Russell and Burch 1959). The Three Rs are (1) refinement of the protocol to minimize or eradicate distress for the species used (e.g., by employing nonclinical [e.g., molecular measurements] or defined [e.g., tumor growth instead of survival] endpoints; giving positive rewards; changing or refining the data/sample collection methods; or instituting species-specific husbandry refinements such as enrichment); 2) reduction of the number of animals used to the absolute minimum necessary (based on appropriate statistical sample size determination or other field-specific methods), particularly if they are likely to experience unavoidable distress; and (3) replacement of an animal with a nonanimal model or a less sentient species, usually of a lower phylogenetic order, such as a primitive invertebrate.

As discussed in Chapters 2 and 3, distress may result from a single intense or prolonged stressful experience or from several simultaneous stressors that might individually cause stress but not likely distress. Therefore, mitigating some potentially stressful circumstances, such as husbandry schedules, may allow an animal to better adapt to other stressors such as experimental procedures. It is important to weigh any possibly adverse impact of replacement, refinement, and reduction on scientific outcome against both the negative impact of failure to avoid, minimize, or alleviate stress and distress on the research data and the numbers of potentially wasted animal lives.

This chapter identifies approaches to avoid or minimize distress through the alleviation and minimization of stress, in both the care and use of laboratory animals. The chapter also suggests ways to alleviate distress that cannot be avoided or minimized because of scientifically justified research protocols, and addresses the challenges and compromises that arise when the object of research itself is the study of stress and distress. This chapter is not intended to be comprehensive but to provide investigators and IACUC members with an awareness of common problems and useful strategies. The Committee encourages all who are involved in laboratory animal care and use to think creatively when considering solutions to specific circumstances.

AVOIDING OR MINIMIZING DISTRESS IN LABORATORY ANIMAL CARE

Most animals are able to cope with a relatively wide range of naturally occurring environments, but such environments are not usually characteristic of laboratory animal facilities. Research environments are generally designed as a compromise between the needs of the animal, the user, and



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