Humane Endpoints for Laboratory Animals Used in Regulatory Testing William S. Stokes Abstract Laboratory animals are used for regulatory testing to assess the safety, efficacy, and/or potential adverse health effects of new chemicals and products such as vaccines, medicines, food additives, pesticides, and industrial chemicals. Testing results are used for risk assessment decisions intended to safeguard human and animal health. However, chemical toxicity and vaccine testing can cause injury, disease, and mortality involving significant pain and distress. Alleviation of pain and distress in animals during testing is problematic because regulations allow treatment only if the treatment does not interfere with the study. One approach to this prob- lem has been to identify criteria that can serve as the basis for ending a test procedure sooner in an effort to terminate or avoid pain and distress while still allowing attainment of study objectives. These criteria are referred to as humane endpoints because they reduce the severity and/or duration of pain and distress experienced by an animal. New and revised test methods and approaches that incorporate hu- mane endpoints are being considered and adopted by na- tional and international regulatory testing authorities. The prerequisite for adoption of these methods is a determina- tion that the methods have been adequately validated and that they provide equivalent or better information for risk assessment. Further progress in reducing animal pain and distress resulting from regulatory testing is expected as sci- entific and technological advances are incorporated into testing procedures and strategies. Key Words: alternatives; humane endpoints; laboratory animals; pain and distress; refinement; regulatory testing; toxicology Introduction R egulatory testing requires the use of animals to assess the safety, efficacy, and/or potential adverse health effects of new chemicals and products such as vac- cines, medicines, food additives, pesticides, and industrial chemicals. This testing information provides the basis for risk assessment decisions to safeguard human and animal health. However, adverse effects on animals can be caused during such testing from acute and chronic chemical toxic- ity and by induced infections that occur during vaccine po- tency testing. Resulting injury, disease, and mortality can involve significant pain and/or distress in experimental animals. Pain management for laboratory animals was addressed in original animal protection laws and is addressed in cur- rent animal care and use policies (PHS 1996), guidelines (NRC 1992), and regulations (USDA 1998a). More re- cently, clinical pain management standards have also been established for humans, with recognition that pain can be a common part of the patient experience and that unrelieved pain has adverse physical and psychological effects (JCAHO 1999). Clinical standards assert that all patients have a right to pain relief (JCAHO 1999). The goal of these standards is to ensure that all pain in humans is appropri- ately managed. Both human and animal pain management guidelines and standards seek to minimize the occurrence, duration, and severity of unrelieved pain. As stated in animal welfare regulations, procedures that cause more than momentary or slight pain and distress should be performed with appropriate sedation, analgesia, or anesthesia (USDA 1998a). However, some research and testing studies involve pain that cannot be relieved with drugs because they would interfere with the scientific ob- jectives of the study. To avoid possible confounding effects from pain-relieving medications, animals used in testing are rarely treated with such drugs. Testing regulations allow treatment of animals only if the treatment does not interfere with the study (EPA 1998; FDA 1999). When animals must experience unrelieved pain and dis- tress, federal regulations and policies mandate that discom- fort must be limited to what is unavoidable for the conduct of scientifically valuable research and that the pain and distress should continue only for the duration necessary to accomplish the scientific objectives (USDA 1998a). As fur- ther stated in the Public Health Service Policy on the Hu- mane Care and Use of Laboratory Animals, 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). The number of animals experiencing unrelieved pain and distress in the United States cannot be determined ac- curately because there are no reporting requirements for rats and mice, two of the most commonly used species in tox- William S. Stokes, D.V.M., is Associate Director for Animal and Alter- native Resources and Director of the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. Volume 43, Supplement 2002 S31