ILAR Journal Online, Volume 41(2) 2000: Humane Endpoints for Animals Used in Biomedical Research and Testing

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ILAR Journal V41(2) 2000
Humane Endpoints for Animals Used in Biomedical Research and Testing

Introduction

Reducing Unrelieved Pain and Distress in Laboratory Animals Using Humane Endpoints
William S. Stokes

These statements acknowledge the common occurrence of pain in human patients and the importance the medical profession and society place on recognizing and relieving pain. Similarly, the importance of managing pain in laboratory animals led to the establishment of policies (PHS 1996), guidelines (NRC 1992), and regulations (USDA 1998) for pain management in laboratory animals many years ago. Both human and animal standards seek to minimize the occurrence of unrelieved pain. The new JCAHO standards seek to ensure that all pain in humans is appropriately managed. However, for some laboratory animals, management of unrelieved pain remains problematic because pain-reducing agents cannot be used.

Animals used in biomedical research and testing experience pain from induced diseases, procedures, and toxicity. Animal welfare regulations state that procedures that cause more than momentary or slight pain and distress should be performed with appropriate sedation, analgesia, or anesthesia (USDA 1998). However, research and testing studies often involve pain that cannot be relieved with such agents because they would interfere with the scientific objectives of the study. Accordingly, federal regulations and policies mandate that discomfort to animals must be limited to what is unavoidable for the conduct of scientifically valuable research. They state that unrelieved pain and distress should continue only for the duration necessary to accomplish the scientific objectives (USDA 1998). Animals that would otherwise suffer unrelieved severe or chronic distress should be painlessly killed at the end of the procedure, or if appropriate, during the procedure (PHS 1996).

Researchers are required to report unrelieved pain and distress in certain species of animals to the United States Department of Agriculture. In 1998, this occurred in 9% of reported animals and totaled 110,909 animals (USDA 1999). However, an estimated 90% of animals used in research and testing are rats and mice, for which there are no USDA reporting requirements. Thus, the total number of laboratory animals experiencing unrelieved pain and distress likely exceeds one million each year. These numbers indicate that many animals continue to experience unrelieved pain before the end of experimental protocols.

Is it possible to reduce the number of animals that experience unrelieved pain and distress? A recent international conference suggests that progress is being made and that more progress is possible (Hendriksen and Morton 1998). The approach involves ending studies earlier to avoid or terminate unrelieved pain and/or distress. To do this, criteria---referred to as humane endpoints---must be identified and validated to ensure that study objectives will still be met even if the study is ended early. Criteria that can be used to end studies before the onset of pain and distress are ultimately the ideal humane endpoints. This issue of ILAR Journal is devoted to the discussion of humane endpoints for animals used in research and testing. An outstanding group of experts have prepared papers that describe approaches and considerations for establishing humane endpoints for common research and toxicology studies that may involve unrelieved pain and distress.

In the lead article, Earl Carstens and Gary Moberg (2000) discuss the biologic basis of pain and distress and review important aspects of recognizing and assessing pain and distress. They emphasize that procedures that cause pain or distress in humans should also be considered to cause pain and distress in animals, unless the contrary is established. Due to the inability of animals to verbalize, they describe the need for animal care staff and researchers to know how to recognize clinical signs of pain and distress. A model of an animal's biologic response to stress is provided, showing that stress leads to distress when major shifts in biologic function threaten the animal's well-being.

The use of moribund condition as a humane experimental endpoint is discussed by Linda Toth (2000). In studies where there is the induction of severe disease states and high rates of mortality, preemptive euthanasia of moribund animals can terminate and prevent further pain and distress. She describes how to develop objective data-based criteria that are predictive of impending death and that can be used to implement timely euthanasia to avoid spontaneous deaths.

David Morton (2000) describes the use of clinical score sheets as another general approach for establishing humane endpoints for experimental studies. The score sheets can be used to record clinical signs and conditions associated with a particular experimental model. They also can be used later to identify individual or multiple clinical signs that are predictive of the current experimental endpoint but that can be used as earlier more humane endpoints.

Large numbers of animals are used to study tumor biology, develop new therapeutic approaches, and evaluate the potential for substances to cause cancer. James Wallace (2000) emphasizes the need for frequent and appropriate monitoring during tumor development to allow for appropriate intervention before significant deterioration or death. Effective monitoring systems and endpoints should include limits on the tumor burden and severity of tumor-associated disease. Altered physiologic, biochemical, and other biomarkers are suggested as potentially more objective and reproducible endpoints than clinical signs.

Genetically engineered animal models are often accompanied by unintended and unpredicted alterations that adversely affect animal well-being. As discussed by Melvin Dennis (2000) there is a need to establish a plan for addressing unanticipated adverse outcomes for genetically altered animal models. Dennis reviews the responsibilities of the institutional animal care and use committee in providing oversight of such studies and ensuring that animal welfare problems are handled in an effective and prompt fashion. He provides examples of strategies that can be used to enhance animal welfare for genetically altered animals, including the use of protocols to systematically characterize phenotypes to assess their possible utility.

Ernest Olfert and Dale Godson (2000) discuss humane endpoint considerations for animals used as models for infectious disease studies. They point out that animals are needed to further understand infectious disease processes and to develop effective treatment and prevention strategies. However, animals with induced infections may experience significant pain and/or distress during progression of the disease. They discuss early physiologic and biochemical changes during infection that 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. They also describe how the biologic consequences of cytokine production during infections, such as increased levels of acute phase proteins, have been found to be useful earlier endpoints.

Coenraad Hendriksen and Björn Steen (2000) discuss the use of humane endpoints in vaccine potency testing. Vaccines must be tested to ensure that they are safe and can effectively provide protective immunity. However, such testing typically involves challenging animals that have been immunized with multiple dilutions of the vaccine. Lethality is commonly the outcome indicative of insufficient protection, although some authorities now allow euthanasia of moribund animals. They describe an approach for developing and validating humane endpoints and provide an example of a humane endpoint developed for potency testing of the Pertussis vaccine.

Toxicity testing is conducted to identify potential adverse effects that may result from exposure to various products and chemicals. Neil Sass (2000) reviews the various types of acute toxicity testing procedures commonly used for such assessments. Acute toxicity testing is conducted to determine the potential of substances to cause acute lethality, dermal irritation and corrosion, and ocular irritation. Current early endpoints in toxicity testing largely involve euthanasia of moribund animals and animals exhibiting signs of severe pain and distress. Sass discusses how the use of tiered or stepwise testing that incorporates in vitro methods and humane endpoints can potentially reduce the severity of pain and distress for acute testing procedures. Recent establishment of the Interagency Coordinating Committee on the Validation of Alternative Methods now provides a mechanism by which new testing methods that incorporate more humane endpoints can be evaluated and adopted (Stokes 2000; Stokes and Hill 2000).

Ethical considerations for using animals in studies involving unrelieved pain have been reviewed by Jerrold Tannenbaum in a prior issue of ILAR Journal devoted to the topic of Animal Models of Pain (Tannenbaum 1999). In his discussion, Tannenbaum examines the legal requirement and moral obligation for members of institutional animal care and use committees and scientists to consider the ethical treatment of animals used in research. Readers interested in the issue of ethics and pain in laboratory animals are encouraged to refer to his article.

As described by the authors in this issue, the development and use of humane endpoints can reduce the severity and duration of unrelieved pain and distress when pain-relieving agents cannot be used. Establishing and implementing humane endpoints requires commitment and innovation on the part of scientists, veterinarians, and animal care staff. Public support for such efforts is reflected in recent legislation directing the National Institutes of Health to conduct and support research into methods of medical research and experimentation that produce less pain and distress in animals (USC 1993). Although some initial progress has been made, additional significant progress could potentially evolve from incorporating scientific advancements in our understanding of diseases and toxicity, such as molecular and cellular mechanisms. In some cases, the development and use of humane endpoints may require commitment of additional resources. However, any such costs should be considered in light of the potential benefits of humane endpoints, which include enhanced animal welfare and more efficient and effective research and testing.

In The Principles of Humane Experimental Technique, William Russell and Rex Burch presented the concept of the replacement, reduction, and refinement of animal use, commonly referred to as the "Three Rs." They defined refinement as any development leading to a "decrease in the incidence or severity of inhumane procedures applied to those animals which have to be used" (Russell and Burch 1959, p. 64). Undoubtedly, the rapidly expanding development and use of humane endpoints epitomizes their concept of refinement as a means to achieve more humane use of animals. According to Russell and Burch, "The greatest scientific experiments have always been the most humane and the most aesthetically attractive, conveying that sense of beauty and elegance which is the essence of science at its most successful" (Russell and Burch 1959, p. 157).

References

Carstens E, Moberg GP. 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 CFM, Morton DB, editors. 1999. Humane Endpoints in Animal Experiments for Biomedical Research. In: Proceedings of the International Conference, November 22-25, 1998, Zeist, The Netherlands. London: Royal Society of Medicine Press Limited.

Hendriksen CFM, Steen B. Refinement of vaccine potency testing with the use of humane endpoints. ILAR J 41:105-113.

JCAHO [Joint Commission on the Accreditation of Healthcare Organizations]. 1999. Pain Assessment and Management Standard, Comprehensive Accreditation Manual for Hospitals: The Official Handbook (CAMH), Standard RI.1.2.8, URL: <www.jcaho.org.standard/pm_hap.html#ri12>, August 1999, p 3.

Morton DB. 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. Washington DC: National Academy Press.

Olfert ED, Godson DL. 2000. Humane endpoints for infectious disease animal models. ILAR J 41:99-104.

PHS [Public Health Service]. 1996. Public health service policy on humane care and use of laboratory animals. Washington DC: US Department of Health and Human Services.

Russell WMS, Burch RL. 1959. The Principles of Humane Experimental Technique. London: Methuen & Co. LTD. [Reissued: 1992, Universities Federation for Animal Welfare, Herts, England.]

Sass N. 2000. Humane endpoints and acute toxicity testing. ILAR J 41:114-123.

Stokes WS. 2000. Humane Endpoints for Laboratory Animals Used in Toxicity Testing. 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).

Stokes WS, Hill RN. 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).

Tannenbaum J. 1999. Ethics and pain research in animals. ILAR J 40:97-110.

Toth LA. 2000. Moribund condition as an endpoint for animals used in research and testing. ILAR J 41:72-79.

USC [US Code]. 1993. National Institutes of Health Revitalization Act. PL 103-43. 42 USC. Washington DC: US GPO.

USDA [US Department of Agriculture]. 1998. Animal Welfare Report. Fiscal Year 1998. Animal and Plant Health Inspection Service. APHIS 41-35-059. Washington DC: USDA.

Wallace J. 2000. Humane endpoints and cancer research. ILAR J 41:87-93.