Guide for the Care and Use of Laboratory Animals - Office of ...

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ANIMAL CARE ANd USE PROGRAM2Special Considerations for IACUC ReiewCertain animal use protocols include procedures or approaches thatrequire special consideration during the IACUC review process due to theirpotential for unrelieved pain or distress or other animal welfare concerns.The topics below are some of the most common requiring special IACUCconsideration. For these and other areas the IACUC is obliged to weighthe objectives of the study against potential animal welfare concerns. Byconsidering opportunities for refinement, the use of appropriate nonanimalalternatives, and the use of fewer animals, both the institution and theprincipal investigator (PI) can begin to address their shared obligations forhumane animal care and use.Experimental and humane Endpoints The experimental endpoint of a studyoccurs when the scientific aims and objectives have been reached. Thehumane endpoint is the point at which pain or distress in an experimentalanimal is prevented, terminated, or relieved. The use of humane endpointscontributes to refinement by providing an alternative to experimental endpointsthat result in unrelieved or severe animal pain and distress, includingdeath. The humane endpoint should be relevant and reliable (Hendriksenand Steen 2000; Olfert and Godson 2000; Sass 2000; Stokes 2002). Formany invasive experiments, the experimental and humane endpoints areclosely linked (Wallace 2000) and should be carefully considered duringIACUC protocol review. While all studies should employ endpoints thatare humane, studies that commonly require special consideration includethose that involve tumor models, infectious diseases, vaccine challenge,pain modeling, trauma, production of monoclonal antibodies, assessmentof toxicologic effects, organ or system failure, and models of cardiovascularshock.The PI, who has precise knowledge of both the objectives of the studyand the proposed model, should identify, explain, and include in the animaluse protocol a study endpoint that is both humane and scientifically sound.The identification of humane endpoints is often challenging, however,because multiple factors must be weighed, including the model, species(and sometimes strain or stock), animal health status, study objectives,institutional policy, regulatory requirements, and occasionally conflictingscientific literature. Determination of humane endpoints should involve thePI, the veterinarian, and the IACUC, and should be defined when possiblebefore the start of the study (Olfert and Godson 2000; Stokes 2000).Information that is critical to the IACUC’s assessment of appropriate endpointconsideration in a protocol includes precise definition of the humaneendpoint (including assessment criteria), the frequency of animal observation,training of personnel responsible for assessment and recognition of the
28 GUIdE FOR ThE CARE ANd USE OF LAbORATORy ANIMALShumane endpoint, and the response required upon reaching the humaneendpoint. An understanding of preemptive euthanasia (Toth 2000), behavioralor physiologic definitions of the moribund state (ibid.), and the use of studyspecificanimal assessment records (Morton 2000; Paster et al. 2009) canaid the PI and IACUC when considering or developing proposed endpoints.When novel studies are proposed or information for an alternative endpointis lacking, the use of pilot studies is an effective method for identifying anddefining humane endpoints and reaching consensus among the PI, IACUC,and veterinarian. A system for communication with the IACUC should bein place both during and after such studies. Numerous publications addressspecific proposals for the application and use of humane endpoints (e.g.,CCAC 1998; ILAR 2000; OECD 1999; Toth 1997; UKCCCR 1997).Unexpected Outcomes Fundamental to scientific inquiry is the investigationof novel experimental variables. Because of the potential for unexpectedoutcomes that may affect animal well-being when highly novelvariables are introduced, more frequent monitoring of animals may berequired. With their inherent potential for unanticipated phenotypes, GMAsare an example of models for which increased monitoring for unexpectedoutcomes could be implemented (Dennis 1999).GMAs, particularly mice and fish, are important animal models, andnew methods and combinations of genetic manipulation are constantlybeing developed (Gondo 2008). Regardless of whether genetic manipulationis targeted or random, the phenotype that initially results is often unpredictableand may lead to expected or unexpected outcomes that affect theanimal’s well-being or survival at any stage of life. For example, in someinstances genetic modification has led to unforeseen immunodeficiency,requiring the GMA offspring to be held under specialized bioexclusionconditions (Mumphrey et al. 2007); and the promoter sequences used todirect expression of transgenes to specific tissues have varying degrees ofspecificity (“leakiness”) that can lead to unanticipated phenotypes (Mooreheadet al. 2003). These examples illustrate the diversity of unanticipatedoutcomes and emphasize the need for diligent monitoring and professionaljudgment to ensure the animals’ well-being (Dennis 2000). The first offspringof a newly generated GMA line should be carefully observed frombirth into early adulthood for signs of disease, pain, or distress. Investigatorsmay find that the phenotype precludes breeding of particular genotypes orthat unexpected infertility occurs, situations that could lead to increases inthe numbers of animals used and revision of the animal use protocol. Whenthe initial characterization of a GMA reveals a condition that negativelyaffects animal well-being, this should be reported to the IACUC, and moreextensive analysis may be required to better define the phenotype (Brown etal. 2000; Crawley 1999; Dennis 2000). Such monitoring and reporting may
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GUIDEFOR THE CARE AND USE OFLABORAT
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4Veterinary CareVeterinary care is
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VETERINARy CARE10from these sources
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VETERINARy CARE10In all cases, appr
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VETERINARy CARE 111Depending on the
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VETERINARy CARE 113and serology. If
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VETERINARy CARE 115RecordkeepingMed
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VETERINARy CARE11traffic (AORN 2006
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VETERINARy CARE11Specific steriliza
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VETERINARy CARE 121(all), anorexia
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VETERINARy CARE 123used in combinat
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VETERINARy CARE 125Arndt SS, Lohave
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VETERINARy CARE12Haines DC, Gorelic
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VETERINARy CARE12Morton CM, Reid J,
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VETERINARy CARE 131Stoskopf MK. 199
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156 AddENdUM4. Page 32. Original se
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Appendices
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appendixBU.S. Government Principles
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appendixCStatement of TaskThe use o
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appendixDAbout the AuthorsJanet C.
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APPENdIX d: AbOUT ThE AUThORS 205of
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APPENdIX d: AbOUT ThE AUThORS20Amer
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IndexAAcclimation and adaptation, 1
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INdEX 211Behavioral and social mana
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INdEX 213Disinfection, 20, 51, 52,
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INdEX 215Hydrogen peroxide, 72Hygie
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INdEXrecommended reading, 169-170re
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INdEX21pain and distress, 121-122re
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