a refinement approach that makes it possible to measure tumors so precisely that the animal may be euthanized before any clinical signs arise. This method by itself may greatly reduce the numbers of animals estimated by the sample size determination. Other animal models that benefit from new imaging technologies include those for cardiovascular diseases (labeled cells; Jaffer et al. 2006) and inflammatory bowel diseases (colonoscopy; Becker et al. 2005).


As has been noted in Chapter 3, even with reasonable steps to avoid or minimize housing and husbandry-related stressors, distress may still unexpectedly appear once a protocol begins or following a change in husbandry. Many of the steps involved in the alleviation of distress, such as a team management approach and prompt veterinary action, are identical to the procedures described in Chapter 3 for recognizing and assessing the presence of distress. However, before implementing any response plan, the principal investigator/study director and veterinarian or designee should review the objectives of the protocol to determine if the alleviation of distress would adversely affect the research project. Identification of a refinement after approval of a protocol should include amendment of the protocol to adopt this change. If the distress is anticipated or results from a significant husbandry error, regulations require notification of the Institutional Animal Care and Use Committee (IACUC) and possibly of regulatory agencies as well, especially if animal distress results in protocol suspension (DHHS 2005; USDA 2005). Table 4-1 provides an algorithm for responding to unexpected animal distress.

Medical conditions unrelated to the study objectives (e.g., spontaneous self-injurious behavior, fight-related injuries, newly diagnosed ectoparasite infestations) may be treatable without compromising the study. However, additional diagnostic tests may be necessary and even, depending on the therapeutic interventions selected, the removal of the animal from the study, either temporarily or permanently. In addition to eliminating the underlying cause, treatment modalities to address the behavioral signs may include changing the environmental parameters (such as cagemate, caging type, or housing location [Fontenot et al. 2006]; administering analgesics or anxiolytics; engaging in behavior modification and training [Reinhardt 2003; Schapiro et al. 2001]); providing environmental enrichment; dispensing psychotropic medications; or, in severe cases, euthanizing the animal. In one case, environmental enrichment decreased abnormal behaviors in pigtail macaques that could not be socially housed (Kessel and Brent 1998). In contrast, the presence of puzzle feeders, which encouraged manipulation, did not reduce self-injurious behaviors in rhesus monkeys (Novak et

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