2nd Edition 2002 arena/olaw institutional Animal Care and Use Committee Guidebook



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References

CCAC (Canadian Council on Animal Care). 1998. CCAC guidelines on choosing an appropriate endpoint in experiments using animals for research, teaching, and testing. Canadian Council on Animal Care. Ottawa, Canada.


Carstens E., and O.P.Moberg. 2000. Recognizing pain and distress in laboratory animals. ILAR J 41:62-71.
Dennis M. 2000. Humane endpoints for genetically engineered animal models. ILAR J 41:94-98.
Hendriksen C.F.M., and D.B. Morton, editors. 1999. Humane Endpoints in Animal Experiments for Research. In: Proceedings of the International Conference, November 22- 25, 1998, Zeist, The Netherlands. London: Royal Society of Medicine Press Limited.
Hendriksen C.F.M., and B. Steen. Refinement of vaccine potency testing with the use of humane endpoints. ILAR J 41:105-113.
Montgomery, C.A. Oncologic and toxicologic research: alleviation and control of pain and distress in laboratory animals. Cancer Bulletin. 1990; 42:230-237.
Morton D.B. 2000. A systematic approach for establishing humane endpoints. ILAR J 41:80-86.
NRC [National Research Council]. 1992. Recognition and Alleviation of Pain and distress in Laboratory Animals. National Academy Press, Washington D.C.
Olfert E.D., and D.L. Godson. 2000. Humane endpoints for infectious disease animal models. ILAR J 41:99-104.
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OECD (Organization for Economic Cooperation and Development). 1998. Harmonized Integrated Hazard Classification System for Human Health and Environmental Effects of Chemical Substances. Paris, France: Organization for Economic Cooperation and Development.
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Stokes W.S., and R.N. Hill. 2000. The Role of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) in the Evaluation of New Toxicological Testing Methods. In: Proceedings of the 3rd World Congress on Alternatives and Animal Use in the Life Sciences, Bologna, Italy, August 31 -September 2, 1999. New York: Elsevier Sciences (Forthcoming).
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C.2.d. Minimization of Pain and Distress

It is the responsibility of the IACUC to critically evaluate all research proto-cols for the potential to cause pain or distress and assess the steps that are to be taken to enhance animal well-being.


As required by the PHS Policy and the AWRs, and reiterated in the Guide, the IACUC is mandated to review protocols to ensure that pain and distress are minimized in laboratory animals. The AWRs stipulate that the IACUC determine that the principal investigator has considered alternatives to pro-cedures that may cause more than momentary or slight pain or distress to the animal and has provided a written narrative description of the methods and sources used to determine that alternatives were not available. Addi-tional guidance from the USDA on this subject is provided in their policies. The Guide states that the IACUC should ensure the protocol addresses:


  • appropriate sedation, analgesia, and anesthesia;

  • criteria for timely intervention, removal of animals from study, or euthanasia if painful or stressful outcomes are anticipated; and

  • details of postprocedural care.

The protocol must provide adequate information for the IACUC to assess the potential animal pain and/or distress resulting from the study and the effectiveness of the pain- and distress-relieving agents proposed for use. Criteria for re-dosing the animal should also be established. The AV must be consulted for any procedure that has the potential to cause more than momentary pain or distress.


Examples of procedures which the Guide suggests may have the potential to cause pain or distress, include:

  • physical restraint,

  • survival surgeries,

  • food or water restriction,

  • death as an endpoint,

  • noxious stimuli,

  • skin or corneal irritancy testing,

  • tumor burdens,

  • intracardiac or orbital sinus blood sampling, and

  • abnormal environmental conditions.


Assessing Pain and Distress
Numerous references indicate that both laboratory animals and humans receive and process noxious stimuli using similar mechanisms and with similar thresholds of awareness. The pain tolerance, or maximum stimulus intensity voluntarily accepted, varies between species and between individ-uals of the same species, including humans. Pain typically results from stimuli that damage tissue or have the potential to damage tissue. An animal's response to pain is often adaptive to reduce movement to minimize reinjury and aid recuperation. However, this response may lead to physiological and behavioral changes which impact negatively on both the animal's well-being and the research results.
Fundamental to the relief of pain is the ability to recognize its clinical signs in various species of animals. Due to the inability of animals to verbalize, it is essential that animal care staff and researchers receive adequate training on how to recognize clinical signs of pain and distress. Tables A, B, and C at the end of this section identify some of the indicators.
According to the NRC report on pain and distress, while there are no generally accepted criteria for distress, there are a number of metabolic, physiologic and behavioral parameters that are altered in distressed animals. These include changes in reproductive performance, elevation in glucocorticoid levels and elevation in catecholamine levels. It is necessary to use objective assessments, which means choosing appropriate param-eters and quantifying observations. Numerous models for scoring pain and distress have been published and involve assigning a numeric score to

observations with the aid of descriptors. It is often useful to start with a general set of observations for assessing pain and distress such as change in body weight, physical appearance/posture or changes in unprovoked and provoked behavior. The assessment system should then be modified on a case-by-case basis using specific changes that may be anticipated in a particular study.


Alleviation of Pain and Distress
Accepted best practices for dealing with the possibility of unrelieved pain and distress should be considered and incorporated into protocols unless there is a sound scientific rationale for deviation from those practices. The investigator must also provide an assurance that unrelieved pain will con-tinue for only the minimum period of time necessary to attain the study objectives.
Protocol methodology should be considered which decreases the potential for pain or distress. In addition to thorough searches of the literature, this can be done through the careful use of pilot studies to determine earlier endpoints or less invasive alternatives.

Pharmacologic treatment of pain or distress should be given as consistent with the type of pain/distress and the needs of the research question. The veterinarian must be consulted for all such protocols and should provide guidance to investigators and the IACUC. The responses of different spe-cies to different anesthetics, analgesics or tranquilizers vary and are not fully defined. Often the effects of a given drug have only been examined in a single species and definitive information, for example, on cardiovascular and respiratory function or on the ability to relieve the perception of noxious stimuli, is missing. As a result, dosages have been developed on the basis of the amount required to produce cessation of movement when the animal is confronted by what is assumed to be a painful manipulation, in conjunc-tion with an adequate recovery. Because of the imprecise nature of the studies, dosage ranges are often quite wide, requiring a very conservative approach to their use. The use of drug mixtures further complicates the choice of an adequate dose. Numerous reference texts exist and IACUCs may request that the veterinarian prepare current charts of recommended doses as an institutional resource for investigators.


Non-pharmacologic treatments should also be employed. This may include special housing considerations, dietary and other environmental enrich-

ments, adjustments and careful supportive care.



Summary
It is the responsibility of the investigator to show she or he has considered all the options for minimizing pain and distress that do not compromise the scientific validity of the experiment. The committee’s deliberations regard-ing the management of potential pain and distress in a protocol should be documented. Personnel should be trained in pain and distress manage-ment. The IACUC should ensure that there is a mechanism in place for prompt reporting of sick animals to the veterinary staff.



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