Animals used to study tumor biology, to develop new cancer therapies, and to evaluate the carcinogenic potential of substances may experience pain and distress. Frequent and appropriate monitoring of animals during tumor development is necessary to allow for appropriate intervention before signi-ficant deterioration or death. Effective monitoring systems and endpoints should include limits on tumor size and severity of tumor-associated disease. Altered physiologic, biochemical, and other biomarkers may be potentially more objective and reproducible endpoints than clinical signs for such studies.
Genetically engineered animal models are sometimes accompanied by unintended and unpredicted alterations that adversely affect animal well-being. Investigators need to establish a plan for addressing unanticipated adverse outcomes for genetically altered animals. There should be a plan for systematic characterization of phenotypes to facilitate assessment of their possible utility and timely decisions on disposition or retention. IACUCs should provide oversight of such studies to ensure that animal welfare problems are handled in an effective and prompt manner.
Animals with induced infections may experience significant pain and/or distress during progression of the disease. Early physiologic and bio-chemical changes during infection have been found to be useful humane endpoints rather than death or moribund condition. Specific decreases in body temperature have been found to be effective early predictors of eventual death for some infections in rodents. Vaccine potency testing typically involves challenging immunized animals with infectious agents. While such testing has commonly used lethality as the endpoint indicative of insufficient protection, some regulatory authorities now allow euthanasia of moribund animals.
Animals used in toxicity testing can experience pain and distress when toxic effects are produced. Toxicity testing regulations allow treatment of pain and distress in test animals only if there is no interference with the study. As a result, animals are rarely treated in toxicology studies because of the potential confounding effects of analgesics. Consequently, management of pain and distress in toxicity studies is accomplished largely by euthanizing animals that are experiencing significant pain and distress.
Current regulatory guidelines state that animals in toxicology studies ob-viously in pain or showing signs of severe and enduring distress should be euthanized, rather than allowing them to survive to the end of the scheduled study. Humane endpoints should be established and used for toxicology studies in order to further minimize pain and distress.
Death as an Endpoint
Since it provides an objective and unequivocal data point, death has historically been used as an endpoint in cancer, infectious disease and other animal studies, especially for regulatory purposes (e.g., drug safety/ efficacy studies). Increased public interest and regulation have led to a re-evaluation of this practice. Much of the concern arose from the use of traditional LD50 tests for chemicals and drugs to determine acute toxicity. However, regulatory testing requirements for acute toxicity now allow for animals that are moribund or exhibiting clinical signs of severe pain and distress to be euthanized rather than to die spontaneously. Euthanasia also provides tissues more appropriate for subsequent study and alleviates potential suffering by the animal. Hence, euthanasia is often preferable to death for both scientific and ethical reasons.
The use of death as an endpoint is discouraged and must always be justi-fied. Endpoints other than death must always be considered and should be used whenever the research objective can be attained with non-lethal end-points. Use of death as an endpoint must be justified in writing in proposals and its use must be approved by the IACUC prior to beginning a study.
C.2.c. Table A. Examples of Humane Endpoints for Studies with