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Responsibilities of Animal Care and Use Committees PROGRAM OVERSIGHT The Animal Welfare Regulations, or AWRs (9 CFR 2.31), mandate that each institution in which warm-blooded animals other than birds, rodents of the genera Mus and Rattus, and farm animals are used in research, testing, or education have an institutional animal care and use committee (IACUC) to oversee the institution's animal care and use program. Public Health Service Policy on Humane Care and Use of Laboratory Animals, or PHS Policy (PHS, 1996), has the same requirement for each PHS-funded institu- tion that uses live vertebrates. Program oversight is more than semiannual facility inspections and protocol reviews; it places a more global responsi- bility on the IACUC for general oversight of the animal program. In a quality program, the highest standards of science and ethics are understood and supported at every level of animal use, from the animal-care technician to the program administrator. Program oversight should include consideration of all institutional functions, policies, or practices that directly affect the care and use of laboratory animals. It might include training; occupational health and safety; the vet- erinary-care program; use of animals in teaching; consistency of institu- tional policies with local, state, and federal regulations; interactions with other internal groups, such as those responsible for space allocation, re- search administration, and biosafety; interactions with external groups, such as funding agencies; specific concerns or complaints about animal use; in 6

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RESPONSIBILITIES OF ANIMAL CARE AND USE COMMITTEES 7 vestigation of unauthorized activities involving the use of animals; and ef- fective communication between investigators, animal-care staff, and admin- istrators. An IACUC customarily reviews programs at the same time that it con- ducts semiannual facility inspections. It is important to document that both the program and the facilities have been reviewed by the IACUC and to note program improvements, as well as program deficiencies. Results of semiannual reviews must be provided to the institutional official and must include a plan for correcting deficiencies and minority views (9 CFR 2.31c3; 9 CFR 2.35a3; PHS, 1986). PROTOCOL REVIEW One of the many important responsibilities of an IACUC is to review the protocols for research, testing, or teaching projects in which any species covered by the AWRs or PHS Policy will be used. The protocol-review mechanism is designed to ensure that investigators consider the care and use of their animals and that procedures comply with federal, state, and institutional regulations and policies. In addition, the review mechanism enables an IACUC to become an important institutional resource, assisting investigators in all areas involving the use of animals. Each research protocol should include the following information, much of which is required by the AWRs, PHS Policy, or both: . animal; the purpose of the study; the rationale for selection of the species and the numbers of ani- mals to be used; the strain, sex, and age of the animals to be used; the living conditions of the animals, particularly special housing and husbandry requirements; the experimental methods and manipulations; justification of multiple major survival surgeries on any individual preprocedural and postprocedural care and medications; procedures that will be undertaken to avoid or minimize more than momentary discomfort, pain, and distress, including, where appropriate, the use of anesthetics, analgesics, and tranquilizers; if experimental manipulation is likely to cause more than momen- tary or slight pain or distress that for scientifically valid reasons cannot be relieved by appropriate drugs, the process undertaken to ensure that there are no appropriate alternatives (some types of research, such as trauma studies and studies in which death is the end point, are particularly sensitive in this regard);

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8 RODENTS: LABORATORYANIMAL MANAGEMENT procedures that will be used to monitor the animals in studies in which close monitoring is required, for example, those involving food or water deprivation and tumor growth (studies that require close monitoring should include specific end points); . procedures and justification for long-term restraint; the euthanasia method, including a justification if it is not consis- tent with the recommendations of the American Veterinary Medical Asso- ciation Panel on Euthanasia (AVMA, 1993 et seq.~; assurance that the protocol does not unnecessarily duplicate previ- ous work; and the qualifications of personnel who will perform the procedures . outlined. Protocol submission and review formats differ widely from one institu- tion to another and depend on a number of variables, including the size and mission of the institution, other levels of scientific review to which the protocol will be subjected, and past experiences of the IACUC. Thorough and careful preparation of a protocol will facilitate the review process and reduce delay. One review approach used by IACUCs, particularly in large institutions, is to assign a knowledgeable committee member to each proto- col as the primary reviewer. The primary reviewer deals directly with the investigator to clarify issues in question. Changes or clarifications in the protocol that result from the reviewer's discussions with the investigator are submitted to the IACUC in writing. Later, at an IACUC meeting, the primary reviewer presents and discusses the protocol and relates discussions with the investigator. After the reviewer's presentation of the protocol, the reviewer recommends a course of action, which is then discussed and voted on by the IACUC. Another kind of protocol review (which is especially effective in small institutions with few protocols) is initial review by the entire IACUC. Many committees rely on additional review by experts (ei- ther on or outside the committee) in specific subjects; for example, a veteri- narian should review protocols for appropriateness of the proposed anesthe- sia and analgesia, and a statistician might review statistically complicated study designs. In some institutions, such as pharmaceutical companies, some kinds of studies (e.g., pharmaceutical development and toxicology screening) are based on standard operating procedures. Nevertheless, IACUC review and approval are required before study initiation. Several outcomes of protocol review are possible: approval, approval contingent on receipt of additional information (to respond to minor prob- lems with the protocol) deferral and rereview after receipt of additional information (to respond to major problems with the protocol), and with- holding of approval. If approval of a protocol is withheld, an investigator should be given the opportunity to respond to the critique of the IACUC in

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RESPONSIBILITIES OF ANIMAL CARE AND USE COMMITTEES 9 writing, to appear in person at an IACUC meeting to present his or her viewpoint, or both. It is also important that expedited review be possible; however, the use of expedited review does not negate the requirement (9 CFR 2.31; PHS, 1996, Section IV.C.2) that each IACUC member be given the opportunity to review every protocol and to call for a full committee review before approval is given (McCarthy and Miller, 1990~. The question of protocol review for scientific merit has been handled in a variety of ways by IACUCs. Many protocols are subjected to extensive, external scientific review as part of the funding process; in such instances, the IACUC can be relatively assured of appropriate scientific review. For studies that will not undergo outside review for scientific merit, many IACUCs require signoff by the investigators, department chairmen, or internal re- view committees; this makes signers responsible for providing assurance that the proposed studies have been designed and will be performed "with due consideration of their relevance to human or animal health, the ad- vancement of knowledge, or the good of society" (NRC, 1996, p.ll6; PHS, 1996, p.l). Occasionally, IACUC members and scientists differ as to the relevance of proposed studies to human and animal health and the advance- ment of knowledge. Each institution should develop guidelines for dealing with this potential conflict. It is important that the IACUC document the protocol-review process, so that it is clear that all aspects of a project, especially aspects that might seriously affect animal well-being, have been thoroughly considered by the IACUC; minority views must be included (9 CFR 2.311. IACUCs should keep accurate records, pay careful attention to semantics, and be familiar with local, state, and federal "freedom of information" laws that make records available to the general public on request. PERSONNEL QUALIFICATIONS AND TRAINING Job applicants for positions that require access to an animal facility should be carefully screened. Checks for records of criminal activity might be war- ranted. Potential employees should understand clearly the nature of the work. Education of animal-care and research personnel regarding proper security procedures is critical to ensuring facility security. This training should be part of new-employee orientation and should be reinforced frequently. Both PHS Policy (PHS, 1996) and the AWRs (9 CFR 3.32) require that institutions provide training on the care and use of animals. It is the re- sponsibility of the IACUC to ensure that animal-care and research staff are appropriately trained (PHS, 1996~. As part of program oversight, the IACUC must ensure that procedures for providing and documenting training are in place; however, the responsibility for design and implementation of training

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10 RODENTS: LABORATORYANIMAL MANAGEMENT programs varies. Responsibilty for course objectives and format is fre- quently shared by staff from various functional units, such as veterinary staff, employee-health personnel, safety officers, and IACUC members. People for whom it is required that training be made available (9 CFR 2.32) include those who provide animal husbandry (caretakers), those who perform technical procedures on animals (research staff and animal techni- cians and technologists), those who provide veterinary medical care and treatment (veterinarians and veterinary technicians). The National Research Council has recommended that training also be provided to other personnel, including administrative and housekeeping staffs. Training is also impor- tant for those who are responsible for oversight (IACUC members and ad- ministrators). The varied backgrounds and responsibilities of the people for whom training is provided, the size and nature of the institution, the variety and numbers of animals used, and the nature of animal use (i.e., research, teaching, and testing) are important in the design of an institutional training program. The program should be tailored to meet the institution's specific needs and designed with ease of use and convenience in mind. Although the format and content might vary considerably between institutions, there is some agreement on minimal information that should be provided. The following topics are considered by the National Research Coucil to be es- sential elements of a basic training program (NRC? 19911: laws, regulations, and policies that affect the care and use of ani- mals; ethical and scientific issues; alternatives to the use of animals; responsibilities of the IACUC and the research and veterinary staffs; pain and distress; anesthetics, analgesics, tranquilizers, and neuromuscular blocking agents; survival surgery and postsurgical care; euthanasia; husbandry, care, and the importance of the environment; and resources for additional information. For each of those elements, all personnel should be provided a general overview that is designed to promote understanding of and facilitate com- pliance with regulations and policies. Depending on the audience and the topic, it might not be necessary to provide a high degree of detail. For example, the discussion of survival surgery should familiarize the audience with regulations and acceptable standards for surgical procedures and post- surgical care, but it need not provide details of specific surgical methods, which would be important only to those performing or assisting with the surgery or postsurgical care.

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RESPONSIBILITIES OF ANIMAL CARE AND USE COMMITTEES 11 In contrast, substantial detail should be provided to people in direct contact with animals, and the content should be appropriate to their respon- sibilities for animal care or use. For example, detailed information on species-specific housing methods, husbandry procedures, and handling techniq- ues should be provided to animal caretakers; research staff should be spe- cifically qualified through training or experience for each approved proce- dure in the designated species; and veterinary staff should be appropriately trained in relevant aspects of laboratory animal medicine. Training is provided in various ways. Many people are qualified in animal care, use, or specific procedures by having formal training in degree or certification programs (e.g., veterinarians certified in laboratory animal medicine, certified animal technologists and technicians, and physicians with surgical specialties). Others might be qualified by having previous experi- ence (e.g., investigators who have research experience with a particular animal model). Regardless of the extent of previous training, it is wise for each institution to provide information about the standards, requirements, and expectations of the institution and an updated overview of key issues to all personnel involved with animal care or use. Institutions often need to provide extensive training to staff that provide daily care and observation of animals or to research personnel without previ- ous or recent experience in a particular technique or species. Various methods can be used, including lectures and seminars, videotaped lectures and demon- strations, and observation by experienced personnel. Continuing-education courses are available in many areas, particularly at or near large institutions or universities, and attendance can be encouraged by tuition-reimbursement pro- grams. Each method has advantages and disadvantages, and each institution should select the format that serves the needs of its staff best. Resources for developing training programs include qualified institu- tional staff, formal courses by recognized organizations (e.g.j the American Association for Laboratory Animal Science), and written and audiovisual training aids (see NRC, 1991, part IV, chapter 3~. It is important not only to ensure or provide appropriate training, but to document that all personnel who care for or use animals are appropriately trained. Training and education can be documented in a variety of ways. For example, previous training can be documented by records, publications, and signed statements of experience, and training provided by the institu- tion can be documented by attendance records, signed statements, and notes to personnel files. A powerful method for documenting or monitoring the qualifications of personnel is observation of animal procedures by a quali- fied person. This method provides an accurate assessment of the expertise of the person performing the procedure, as well as information about the health status of the animal during the procedure. Such observation is usu- ally considered to be an appropriate component of veterinary oversight.

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12 RODENTS: LABORATORYANIMAL MANAGEMENT OCCUPATIONAL HEALTH AND SAFETY An occupational health and safety program is an important component of the operation of any institution in which animals are used (NRC, In press). This program should seek to safeguard the health of employees that work with laboratory animals by developing standard operating procedures to minimize the chance of exposure to zoonotic diseases and providing the necessary training so that employees will understand the risks associated with working with animals and the importance of complying with institu- tional procedures. The program can also serve the animals being main- tained by screening employees for zoonotic diseases and, where appropri- ate, providing immunizations that will minimize the likelihood of introduction of zoonotic agents into the animal facility. The design of an occupational health and safety program should be based on a careful review of the potential hazards that exist in the animal facilities. The program must comply with Occupational Safety and Health Administration (OSHA) standards (29 CFR 110-114) and should be de- signed with the aid of medical personnel who are knowledgeable in occupa- tional medicine and familiar with zoonotic diseases. Each aspect of the program should be carefully and realistically evaluated with respect to the magnitude of risk involved, the legal and practical enforceability of man- dated components of the program, and the costs relative to the likelihood of detecting or preventing a problem. A legal review of the final proposed program is advisable because local, state, and federal laws might preclude adoption or enforcement of some of its components. Oversight of occupational health and safety programs varies among institutions. It is frequently assigned to employee-health staff, but in some institutions it is the renonsibilitv of personnel. human-resources. veterinary, or other administrative staffs. -A - - - ~ ~ Generally, an IACUC verifies during its semiannual review that the occupational health and safety program is in place and that its components are appropriate to the institution's animal care and use program. Few general rules can be applied to occupational health and safety programs for rodent facilities. Only a few rodent diseases pose a threat to humans, and many of these have a very low prevalence (e.g., the diseases caused by Hantaan virus, lymphocytic choriomeningitis virus, some Salmo- nella species, Hymenolepis nana, and Streptobacillus moniliformis). In most cases, prophylactic immunizations do not exist for rodent zoonotic organ- isms; if immunizations do exist, the risks associated with them should be balanced against the likelihood of contracting the disease. Personnel should be instructed to notify their supervisors of bite wounds, unusual illnesses, and suspected health hazards. Facilities often maintain records of indi- vidual work assignments and of employee-reported problems. That infor

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RESPONSIBILITIES OF ANIMAL CARE AND USE COMMITTEES 13 mation, if kept accurately and evaluated regularly, can be of value in alert- ing both the institution and employees to unusual patterns of illness that could indicate an animal-related disease. Other occupational hazards, including allergies, should be recognized, and methods should be developed for minimizing the risks and treating problems if they occur. Animal-care personnel are generally at greater risk of contracting tetanus than other segments of the workforce because the greater frequency with which they handle animals puts them at greater risk of being bitten. Therefore, it is important that immunization against tetanus be offered to animal-care personnel and that a record of prophylactic immu- nizations be kept. Exposure to potentially toxic materials and ergonomic practices associ- ated with lifting and moving equipment and materials are also of concern in rodent facilities. The animal facilities and related support areas should be evaluated for the need for protective devices (e.g., respirators, lifting-sup- port belts and gloves, and ear and eye protection) and for the need to develop safety measures peculiar to the tasks being conducted. If animal- care, research, and maintenance personnel could be exposed to potentially hazardous biologic, chemical, or physical agents, the exposure to such agents should be monitored. Specific safety procedures designed to minimize the risk of exposure should be developed in consultation with appropriate health and safety professionals. The gathering of pre-employment health information by questionnaire, physical examination conducted by a physician, or both might be deemed appropriate, provided that such information is related specifically to evalu- ating the employee's potential for carrying zoonotic organisms or having predisposing conditions (e.g., allergies, immunosuppression, pregnancy, and heart disease) that would make exposure to animals hazardous to his or her health. All medical records must be kept confidential, should be reviewed by a competent health care professional, and must not be used to gather information on non-animal-related health matters that could be used to pre- vent hiring the employee. Conditions identified that might affect the animal care and use program (e.g., a positive result of a test for tuberculosis) or might put an employee at increased risk (e.g., pregnancy) should be com- municated to appropriate personnel to minimize unnecessary risk to em- ployees, animals, or both. The conditions for employment and use of em- ployee-health information should be precisely defined in advance by the institution and should comply with local, state, and federal requirements. Periodic physical examinations might be offered to some employees in some job categories. In some institutions, programs have also been estab- lished to obtain and store individual serum samples taken before hiring and during employment for future diagnostic purposes. In general, such serum- banking procedures are seldom undertaken in rodent facilities and, when

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4 RODENTS: LABORATORYANIMAL MANAGEMENT offered, are usually voluntary. In institutions in which research involving the use of zoonotic agents in rodents is conducted and in which there is a substantial risk of infection, prophylactic vaccinations, if available, should be offered to employees at risk; in such cases, it is important that employ- ees be informed by trained medical personnel of both the benefits and the risks associated with the vaccinations. An important component of the occupational health and safety program is employee education. Each institution should have in place a course of study consisting of lectures or seminars, self-help materials, or both to instruct personnel who work with animals about zoonoses, allergies to ani- mals, the importance of personal hygiene, special risks associated with pregnancy, and other appropriate topics. This course of study should also include information on hazardous materials that are used in the facilities, including those regulated by the Environmental Protection Agency and the Nuclear Regulatory Commission and those used in procedures evaluated by OSHA. Of particular importance are chemical agents used in routine animal-care operations, including disinfectants, cage-cleaning solutions, and sterilizing agents. USE OF HAZARDOUS AGENTS Biomedical experimentation frequently involves the use of hazardous agents, which can be classified as chemical (e.g., chemical carcinogens and chemotherapy agents), physical (e.g., radioisotopes), or biologic (e.g., in- fectious agents and recombinant DNA). In addition to the common con- cerns associated with handling and storage, the use of these agents in ani- mals introduces unique concerns, including hazards associated with administra- tion of the agents to the animals, the mode and quantity of excretion of the agents by the animals, contact with contaminated animal tissues, and dis- posal of carcasses, bedding, and excrement. It is the responsibility of the IACUC to ensure that the procedures for use and monitoring of hazardous agents have been reviewed and are appro- priate (NRC, 1996 et seq.~. That is commonly and most readily accom- plished by requiring that any use of hazardous agents be approved by an appropriate institutional safety committee (e.g., radiation-safety committee, infectious-agents committee, biosafety committee, or recombinant-DNA-use committee) before IACUC consideration. Formal programs should be in place to review the procedures, facilities, and staff competence for the pro- posed studies and to monitor compliance with federal, state, and local regu- lations and institutional policies during the conduct of the research. Re- quirements of both hazard containment and good animal husbandry should be met. Areas in which hazardous agents are approved for use should be visited as part of the IACUC semiannual inspection. Review should include

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RESPONSIBILITIES OF ANIMAL CARE AND USE COMMITTEES 15 assurance that there are universal warning signs where hazardous agents are contained and used and that all involved personnel are familiar with and are using approved procedures. In addition to hazardous agents for which regulations or guidelines are well established such as radioisotopes (10 CFR 20), infectious agents (NCI, 1974; NIH, 1984; Richmond and McKinney, 1993), and human-blood prod- ucts (29 CFR 1910) it is important that there be equal oversight of the use of experimental agents not usually thought of as hazardous, such as some categories of agents for human therapy, fresh tissue from humans or ani- mals, cultured cell lines that might harbor pathogens, and volatile anesthet- ics. A list of publications pertaining to regulations and guidelines for the use of hazardous agents can be found in the Guide (NRC, 1996 et seq.~. REFERENCES AVMA (American Veterinary Medical Association). 1993. 1993 Report of the AVMA Panel on Euthanasia. J. Am. Vet. Med. Assoc. 202:229-249. McCarthy, C. R., and J. G. Miller. 1990. OPRR Reports, May 21, 1990. Available from Office for Protection from Research Risks (OPRR), National Institutes of Health, 6100 Executive Boulevard, MSC 7507, Rockville, MD 20892-7507. NCI (National Cancer Institute). 1974. Safety Standards for Research Involving Oncogenic Viruses. DHEW Pub. No. (NIH) 75-790. Washington, D.C.: U.S. Department of Health, Education and Welfare. 20 pp. NIH (National Institutes of Health). 1984. Guidelines for Research Involoving Recombinant DNA Molecules. Fed. Regist. 49(227):46266-46291. NRC (National Research Council), Institute of Laboratory Animal Resources, Committee to Revise the Guide for the Care and Use of Laboratory Animals. 1996. Guide for the Care and Use of Laboratory Animals, 7th edition. Washington, D.C.: National Academy Press NRC (National Research Council), Institute of Laboratory Animal Resources, Committee on Educational Programs in Laboratory Animal Science. 1991. Education and Training in the Care and Use of Laboratory Animals: A Guide for Developing Institutional Pro- grams. Washington, D.C.: National Academy Press. 139 pp. NRC (National Research Council), Institute of Laboratory Animal Resources, Committee on - Occupational Safety and Health in Research Animal Facilities. Occupational Health and Safety in the Care and Use of Research Animals. Washington, D.C.: National Academy Press. PHS (Public Health Service). 1996. Public Health Service Policy on Humane Care and Use of Laboratory Animals. Washington, D.C.: U.S. Departmentof Health and Human Services. 16 pp. Available fromthe Office for Protection from Research Risks, National Institutes of Health, 6100 Executive Boulevard, MSC 7507, Suite 3B01, Rockville, MD 20892-7507. Richmond, J. Y., and R. W. McKinney, eds. 1993. Biosafety in Microbiological and Biomedi- cal Laboratories, 3rd ed. HHS Pub. No. (CDC) 93-8395. Washington, D.C.: U.S. Department of Health and Human Services. Available from Superintendent of Docu- ments, U.S. Government Printing Office, Washington, DC 20402.