Animal Care and Use Program
The proper care and use of laboratory animals in research, testing, teaching, and production (animal use) require scientific and professional judgment based on the animals’ needs and their intended use. An animal care and use program (hereafter referred to as the Program) comprises all activities conducted by and at an institution that have a direct impact on the well-being of animals, including animal and veterinary care, policies and procedures, personnel and program management and oversight, occupational health and safety, institutional animal care and use committee (IACUC) functions, and animal facility design and management.
Program: The activities conducted by and at an institution that have a direct impacton the well-being of animals, including animal and veterinary care, policies and procedures, personnel and program management and oversight, occupational health and safety, IACUC functions, and animal facility design and management.
This chapter defines the overall Program and key oversight responsibilities and provides guidelines to aid in developing an effective Program. Chapters 3, 4, and 5 cover the details of Program components: environment, housing, and management; veterinary care; and physical plant, respectively. Each institution should establish and provide sufficient resources for a Program that is managed in accord with the Guide and in compliance with applicable regulations, policies, and guidelines.
REGULATIONS, POLICIES, AND PRINCIPLES
The use of laboratory animals is governed by an interrelated, dynamic system of regulations, policies, guidelines, and procedures. The Guide takes into consideration regulatory requirements relevant to many US-based activities, including the Animal Welfare Regulations (USDA 1985; US Code, 42 USC § 289d) and the Public Health Service Policy on Humane Care and Use of Laboratory Animals (PHS 2002). The use of the Guide by non-US entities also presumes adherence to all regulations relevant to the humane care and use of laboratory animals applicable in those locations. The Guide also takes into account the U.S. Government Principles for Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training (IRAC 1985; see Appendix B) and endorses the following principles:
consideration of alternatives (in vitro systems, computer simulations, and/or mathematical models) to reduce or replace the use of animals
design and performance of procedures on the basis of relevance to human or animal health, advancement of knowledge, or the good of society
use of appropriate species, quality, and number of animals
avoidance or minimization of discomfort, distress, and pain
use of appropriate sedation, analgesia, and anesthesia
establishment of humane endpoints
provision of adequate veterinary care
provision of appropriate animal transportation and husbandry directed and performed by qualified persons
conduct of experimentation on living animals exclusively by and/or under the close supervision of qualified and experienced personnel.
Interpretation and application of these principles and the Guide require knowledge, expertise, experience, and professional judgment. Programs should be operated in accord with the Guide and relevant regulations, policies, and principles. Also, institutions are encouraged to establish and periodically review written procedures to ensure consistent application of Guide standards. Supplemental information on various aspects of animal care and use is available in other publications prepared by the Institute for Laboratory Animal Research (ILAR) and other organizations (Appendix A). References in the Guide provide the reader with additional information that supports statements made in the Guide. In the absence of published literature, some information in the Guide is derived from currently accepted practice standards in laboratory animal science (see Chapter 1). The body
of literature related to animal science and use of animals is constantly evolving, requiring Programs to remain current with the information and best practices.
An effective Program requires clearly defined roles that align responsibility with regulatory and management authority. US federal law creates a statutory basis for the institutional official (IO), the attending veterinarian (AV), and the institutional animal care and use committee (IACUC). The Guide endorses these concepts as important operating principles for all US and non-US animal care and use programs. Effective leadership in and collaboration among these three components, which not only oversee but also support animal users, are necessary (Lowman 2008; Van Sluyters 2008). In addition, interactions with regulatory and funding agencies and accreditation organizations are an integral part of the Program.
As summarized here and discussed throughout the Guide, the primary oversight responsibilities in the Program rest with the IO, the AV, and the IACUC. Their roles fit in a defined organizational structure where the reporting relationships, authorities, and responsibilities of each are clearly defined and transparent. Together they establish policies and procedures, ensure regulatory compliance, monitor Program performance, and support high-quality science and humane animal use. A Program that includes these elements and establishes a balance among them has the best chance of efficiently using resources while attaining the highest standards of animal wellbeing and scientific quality (Bayne and Garnett 2008; Van Sluyters 2008).
Program Management Responsibility
The Institutional Official
The institutional official (IO) bears ultimate responsibility for the Program, although overall Program direction should be a shared responsibility among the IO, AV, and IACUC. The IO has the authority to allocate the resources needed to ensure the Program’s overall effectiveness. Program needs should be clearly and regularly communicated to the IO by the AV, the IACUC, and others associated with the Program (e.g., facilities management staff, occupational health and safety personnel, scientists). As a
Institutional official: The individual who, as a representative of senior administration, bears ultimate responsibility for the Program and is responsible for resource planning and ensuring alignment of Program goals with the institution’s mission.
representative of senior administration, the IO is responsible for resource planning and ensuring the alignment of Program goals of quality animal care and use with the institution’s mission.
The Attending Veterinarian
The attending veterinarian (AV) is responsible for the health and wellbeing of all laboratory animals used at the institution. The institution must provide the AV with sufficient authority, including access to all animals, and resources to manage the program of veterinary care. The AV should oversee other aspects of animal care and use (e.g., husbandry, housing) to ensure that the Program complies with the Guide.
Attending veterinarian: The veterinarian responsible for the health and well-being of all laboratory animals used at the institution.
Institutional mission, programmatic goals, including the nature of animal use at the institution, and Program size will determine whether fulltime, part-time, or consultative veterinary services are needed. If a full-time veterinarian is not available on site, a consulting or part-time veterinarian should be available in visits at intervals appropriate to programmatic needs. In such instances, there must be an individual with assigned responsibility for daily animal care and use and facility management. While institutions with large animal care and use programs may employ multiple veterinarians, the management of veterinary medicine, animal care, and facility operations by a single administrative unit is often an efficient mechanism to administer all aspects of the Program.
The Guide endorses the American College of Laboratory Animal Medicine’s (ACLAM) “Guidelines for Adequate Veterinary Care” (ACLAM 1996). These guidelines include veterinary access to all animals and their medical records, regular veterinary visits to facilities where animals are or may be housed or used, provisions for appropriate and competent clinical, preventive, and emergency veterinary care, and a system for legal animal procurement and transportation. Other responsibilities of the AV are outlined in the Program Oversight section below and in later chapters. For a Program to work effectively, there should be clear and regular communication between the AV and the IACUC.
The Institutional Animal Care and Use Committee
The IACUC (or institutional equivalent) is responsible for assessment and oversight of the institution’s Program components and facilities. It should have sufficient authority and resources (e.g., staff, training, comput-
ers and related equipment) to fulfill this responsibility. Detailed information on the role and function of the IACUC is provided later in this chapter.
Interinstitutional collaboration has the potential to create ambiguities about responsibility for animal care and use. In cases of such collaboration involving animal use (beyond animal transport), the participating institutions should have a formal written understanding (e.g., a contract, memorandum of understanding, or agreement) that addresses the responsibility for offsite animal care and use, animal ownership, and IACUC review and oversight (AAALAC 2003). In addition, IACUCs from the participating institutions may choose to review protocols for the work being conducted.
Training and Education
All personnel involved with the care and use of animals must be adequately educated, trained, and/or qualified in basic principles of laboratory animal science to help ensure high-quality science and animal well-being. The number and qualifications of personnel required to conduct and support a Program depend on several factors, including the type and size of the institution, the administrative structure for providing adequate animal care, the characteristics of the physical plant, the number and species of animals maintained, and the nature of the research, testing, teaching, and production activities. Institutions are responsible for providing appropriate resources to support personnel training (Anderson 2007), and the IACUC is responsible for providing oversight and for evaluating the effectiveness of the training program (Foshay and Tinkey 2007). All Program personnel training should be documented.
Veterinary and Other Professional Staff Veterinarians providing clinical and/or Program oversight and support must have the experience, training, and expertise necessary to appropriately evaluate the health and wellbeing of the species used in the context of the animal use at the institution. Veterinarians providing broad Program direction should be trained or have relevant experience in laboratory animal facility administration and management. Depending on the scope of the Program, professionals with expertise in other specific areas may be needed—in, for example, facility design and renovation, human resource management, pathology of laboratory animals, comparative genomics, facility and equipment maintenance, diagnostic laboratory operations, and behavioral management. Laboratory
animal science and medicine are rapidly changing and evolving disciplines. The institution should provide opportunities and support for regular professional development and continuing education to ensure both that professional staff are knowledgeable about the latest practices and procedures and that laboratory animals receive high-quality care (Colby et al. 2007).
Animal Care Personnel Personnel caring for animals should be appropriately trained (see Appendix A, Education), and the institution should provide for formal and/or on-the-job training to facilitate effective implementation of the Program and the humane care and use of animals. Staff should receive training and/or have the experience to complete the tasks for which they are responsible. According to the Program scope, personnel with expertise in various disciplines (e.g., animal husbandry, administration, veterinary medical technology) may be required.
There are a number of options for training animal care personnel and technicians (Pritt and Duffee 2007). Many colleges have accredited programs in veterinary technology (AVMA 2010); most are 2-year programs that award Associate of Science degrees, some are 4-year programs that award Bachelor of Science degrees. Nondegree training, via certification programs for laboratory animal technicians and technologists, is available from the American Association for Laboratory Animal Science (AALAS), and there are various commercially available training materials appropriate for self-guided study (Appendix A).
Personnel caring for laboratory animals should also regularly engage in continuing education activities and should be encouraged to participate in local and national laboratory animal science meetings and in other relevant professional organizations. On-the-job training, supplemented with institution-sponsored discussion and training programs and reference materials applicable to their jobs and the species in their care, should be provided to each employee responsible for animal care (Kreger 1995).
Coordinators of institutional training programs can seek assistance from the Animal Welfare Information Center (AWIC), the Laboratory Animal Welfare and Training Exchange (LAWTE), AALAS, and ILAR (NRC 1991). The Guide to the Care and Use of Experimental Animals by the Canadian Council on Animal Care (CCAC 1993) and guidelines from other countries are valuable additions to the libraries of laboratory animal scientists (Appendix A).
The Research Team The institution should provide appropriate education and training to members of research teams—including principal investigators, study directors, research technicians, postdoctoral fellows, students, and visiting scientists—to ensure that they have the necessary knowledge and expertise for the specific animal procedures proposed and the species
used (Conarello and Shepard 2007). Training should be tailored to the particular needs of research groups; however, all research groups should receive training in animal care and use legislation, IACUC function, ethics of animal use and the concepts of the Three Rs, methods for reporting concerns about animal use, occupational health and safety issues pertaining to animal use, animal handling, aseptic surgical technique, anesthesia and analgesia, euthanasia, and other subjects, as required by statute. Continuing education programs should be offered to reinforce training and provide updates that reflect changes in technology, legislation, and other relevant areas. Frequency of training opportunities should ensure that all animal users have adequate training before beginning animal work.
The IACUC It is the institution’s responsibility to ensure that IACUC members are provided with training opportunities to understand their work and role. Such training should include formal orientation to introduce new members to the institution’s Program; relevant legislation, regulations, guidelines, and policies; animal facilities and laboratories where animal use occurs; and the processes of animal protocol and program review (Greene et al. 2007). Ongoing opportunities to enhance their understanding of animal care and use in science should also be provided. For example, IACUC members may meet with animal care personnel and research teams; be provided access to relevant journals, materials, and web-based training; and be given opportunities to attend meetings or workshops.
Occupational Health and Safety of Personnel
Each institution must establish and maintain an occupational health and safety program (OHSP) as an essential part of the overall Program of animal care and use (CFR 1984a,b,c; DHHS 2009; PHS 2002). The OHSP must be consistent with federal, state, and local regulations and should focus on maintaining a safe and healthy workplace (Gonder 2002; Newcomer 2002; OSHA 1998a). The nature of the OHSP will depend on the facility, research activities, hazards, and animal species involved. The National Research Council’s publication Occupational Health and Safety in the Care and Use of Research Animals (NRC 1997) contains guidelines and references for establishing and maintaining an effective, comprehensive OHSP (also see Appendix A). An effective OHSP requires coordination between the research program (as represented by the investigator), the animal care and use Program (as represented by the AV, IO, and IACUC), the environmental health and safety program, occupational health services, and administration (e.g., human resources, finance, and facility maintenance personnel). Establishment of a safety committee may facilitate communication and promote ongoing evaluation of health and safety in the workplace. In some cases
there is a regulatory requirement for such a committee. Operational and day-to-day responsibility for safety in the workplace resides with the laboratory or facility supervisor (e.g., principal investigator, facility director, or a staff veterinarian) and depends on safe work practices by all employees.
Control and Prevention Strategies A comprehensive OHSP should include a hierarchy of control and prevention strategies that begins with the identification of hazards and the assessment of risk associated with those hazards. Managing risk involves the following steps: first, the appropriate design and operation of facilities and use of appropriate safety equipment (engineering controls); second, the development of processes and standard operating procedures (SOPs; administrative controls); and finally, the provision of appropriate personal protective equipment (PPE) for employees. Special safety equipment should be used in combination with appropriate management and safety practices (NIH 2002; OSHA 1998a,b). Managing risk using these strategies requires that personnel be trained, maintain good personal hygiene, be knowledgeable about the hazards in their work environment, understand the proper selection and use of equipment, follow established procedures, and use the PPE provided.
Hazard Identification and Risk Assessment The institutional OHSP should identify potential hazards in the work environment and conduct a critical assessment of the associated risks. An effective OHSP ensures that the risks associated with the experimental use of animals are identified and reduced to minimal and acceptable levels. Hazard identification and risk assessment are ongoing processes that involve individuals qualified to assess dangers associated with the Program and implement commensurate safeguards. Health and safety specialists with knowledge in relevant disciplines should be involved in risk assessment and the development of procedures to manage such risks.
Potential hazards include experimental hazards such as biologic agents (e.g., infectious agents or toxins), chemical agents (e.g., carcinogens and mutagens), radiation (e.g., radionuclides, X-rays, lasers), and physical hazards (e.g., needles and syringes). The risks associated with unusual experimental conditions such as those encountered in field studies or wildlife research should also be addressed. Other potential hazards—such as animal bites, exposure to allergens, chemical cleaning agents, wet floors, cage washers and other equipment, lifting, ladder use, and zoonoses—that are inherent in or intrinsic to animal use should be identified and evaluated. Once potential hazards have been identified, a critical ongoing assessment of the associated risks should be conducted to determine appropriate strategies to minimize or manage the risks.
The extent and level of participation of personnel in the OHSP should be based on the hazards posed by the animals and materials used (the
severity or seriousness of the hazard); the exposure intensity, duration, and frequency (prevalence of the hazard); to some extent, the susceptibility (e.g., immune status) of the personnel; and the history of occupational illness and injury in the particular workplace (Newcomer 2002; NRC 1997). Ongoing identification and evaluation of hazards call for periodic inspections and reporting of potential hazardous conditions or “near miss” incidents.
Facilities, Equipment, and Monitoring The facilities required to support the OHSP will vary depending on the scope and activities of the Program. Their design should preferentially use engineering controls and equipment to minimize exposure to anticipated hazards (also see Chapter 5). Because a high standard of personal cleanliness is essential, changing, washing, and showering facilities and supplies appropriate to the Program should be available.
Where biologic agents are used, the Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) publication Biosafety in Microbiological and Biomedical Laboratories (BMBL; DHHS 2009) and the USDA standards (USDA 2002) should be consulted for appropriate facility design and safety procedures. These design and safety features are based on the level of risk posed by the agents used. Special facilities and safety equipment may be needed to protect the animal care and investigative staff, other occupants of the facility, the public, animals, and the environment from exposure to hazardous biologic, chemical, and physical agents used in animal experimentation (DHHS 2009; Frasier and Talka 2005; NIH 2002). When necessary, these facilities should be separated from other animal housing and support areas, research and clinical laboratories, and patient care facilities. They should be appropriately identified and access to them limited to authorized personnel.
Facilities, equipment, and procedures should also be designed, selected, and developed to reduce the possibility of physical injury or health risk to personnel (NIOSH 1997a,b). Engineering controls and equipment that address the risk of ergonomic injury in activities such as the lifting of heavy equipment or animals should be considered (AVMA 2008). Those are also frequently used to limit or control personnel exposure to animal allergens (Harrison 2001; Huerkamp et al. 2009). The potential for repetitive motion injuries in animal facilities (e.g., maintenance of large rodent populations and other husbandry activities) should also be assessed.
The selection of appropriate animal housing systems requires professional knowledge and judgment and depends on the nature of the hazards in question, the types of animals used, the limitations or capabilities of the facilities, and the design of the experiments. Experimental animals should be housed so that possibly contaminated food and bedding, feces, and urine can be handled in a controlled manner. Appropriate facilities, equipment,
and procedures should be used for bedding disposal. Safety equipment should be properly maintained and its function periodically validated. Appropriate methods should be used for assessing and monitoring exposure to potentially hazardous biologic, chemical, and physical agents where required (e.g., ionizing radiation) or where the possibility of exceeding permissible exposure limits exists (CFR 1984b).
Personnel Training As a general rule, safety depends on trained personnel who rigorously follow safe practices. Personnel at risk should be provided with clearly defined procedures and, in specific situations, personal protective equipment to safely conduct their duties, understand the hazards involved, and be proficient in implementing the required safeguards. They should be trained regarding zoonoses, chemical, biologic, and physical hazards (e.g., radiation and allergies), unusual conditions or agents that might be part of experimental procedures (e.g., the use of human tissue in immunocompromised animals), handling of waste materials, personal hygiene, the appropriate use of PPE, and other considerations (e.g., precautions to be taken during pregnancy, illness, or immunosuppression) as appropriate to the risk imposed by their workplace.
Personal Hygiene The use of good personal hygiene will often reduce the possibility of occupational injury and cross contamination. Appropriate policies should be established and enforced, and the institution should supply suitable attire and PPE (e.g., gloves, masks, face shields, headcovers, coats, coveralls, shoes or shoe covers) for use in the animal facility and laboratories in which animals are used. Soiled attire should be disposed of, laundered, or decontaminated by the institution as appropriate, and may require that special provisions be implemented if outside vendors are used. Personnel should wash and/or disinfect their hands and change clothing as often as necessary to maintain good personal hygiene. Outer garments worn in the animal rooms should not be worn outside the animal facility unless covered (NRC 1997). Personnel should not be permitted to eat, drink, use tobacco products, apply cosmetics, or handle or apply contact lenses in rooms and laboratories where animals are housed or used (DHHS 2009; NRC 1997; OSHA 1998a).
Animal Experimentation Involving Hazards When selecting specific safeguards for animal experimentation with hazardous agents, careful attention should be given to procedures for animal care and housing, storage and distribution of the agents, dose preparation and administration, body fluid and tissue handling, waste and carcass disposal, items that might be used temporarily and removed from the site (e.g., written records, experimental devices, sample vials), and personal protection.
Institutions should have written policies and procedures governing experimentation with hazardous biologic, chemical, and physical agents. An oversight process (such as the use of a safety committee) should be developed to involve persons who are knowledgeable in the evaluation and safe use of hazardous materials or procedures and should include review of the procedures and facilities to be used for specific safety concerns. Formal safety programs should be established to assess hazards, determine the safeguards needed for their control, and ensure that staff have the necessary training and skills and that facilities are adequate for the safe conduct of the research. Technical support should be provided to monitor and ensure compliance with institutional safety policies. A collaborative approach involving the investigator and research team, attending veterinarian, animal care technician, and occupational health and safety professionals may enhance compliance.
The BMBL (DHHS 2009) and NRC (1997) recommend practices and procedures, safety equipment, and facility requirements for working with hazardous biologic agents and materials. Facilities that handle agents of unknown risk should consult with appropriate CDC personnel about hazard control and medical surveillance. The use of highly pathogenic “select agents and toxins” in research requires that institutions develop a program and procedures for procuring, maintaining, and disposing of these agents (CFR 1998, 2002a,b; NRC 2004; PL 107-56; PL 107-188; Richmond et al. 2003). The use of immunodeficient or genetically modified animals (GMAs) susceptible to or shedding human pathogens, the use of human tissues and cell lines, or any infectious disease model can lead to an increased risk to the health and safety of personnel working with the animals (Lassnig et al. 2005; NIH 2002).
Hazardous agents should be contained in the study environment, for example through the use of airflow control during the handling and administering of hazardous agents, necropsies on contaminated animals (CDC and NIH 2000), and work with chemical hazards (Thomann 2003). Waste anesthetic gases should be scavenged to limit exposure.
Personal Protection While engineering and administrative controls are the first considerations for the protection of personnel, PPE appropriate for the work environment, including clean institution-issued protective clothing, should be provided as often as necessary. Protective clothing and equipment should not be worn beyond the boundary of the hazardous agent work area or the animal facility (DHHS 2009). If appropriate, personnel should shower when they leave the animal care, procedure, or dose preparation areas. Personnel with potential exposure to hazardous agents or certain species should be provided with PPE appropriate to the situation (CFR 1984c); for example, personnel exposed to nonhuman primates should have PPE such
as gloves, arm protectors, suitable face masks, face shields, and goggles (NRC 2003a). Hearing protection should be available in high-noise areas (OSHA 1998c). Personnel working in areas where they might be exposed to contaminated airborne particulate material or vapors should have suitable respiratory protection (Fechter 1995; McCullough 2000; OSHA 1998d), with respirator fit testing and training in the proper use and maintenance of the respirator (OSHA 1998d; Sargent and Gallo 2003).
Medical Evaluation and Preventive Medicine for Personnel Development and implementation of a program of medical evaluation and preventive medicine should involve input from trained health professionals, such as occupational health physicians and nurses. Confidentiality and other medical and legal factors must be considered in the context of appropriate federal, state, and local regulations (e.g., PL 104-191).
A preemployment health evaluation and/or a health history evaluation before work assignment is advisable to assess potential risks for individual employees. Periodic medical evaluations are advisable for personnel in specific risk categories. For example, personnel required to use respiratory protection may also require medical evaluation to ensure that they are physically and psychologically able to use the respirator properly (Sargent and Gallo 2003). An appropriate immunization schedule should be adopted. It is important to immunize animal care personnel against tetanus (NRC 1997), and preexposure immunization should be offered to people at risk of infection or exposure to specific agents such as rabies virus (e.g., if working with species at risk for infection) or hepatitis B virus (e.g., if working with human blood or human tissues, cell lines, or stocks). Vaccination is recommended if research is to be conducted on infectious diseases for which effective vaccines are available. More specific recommendations are available in the BMBL (DHHS 2009). Preemployment or preexposure serum collection is advisable only in specific circumstances as determined by an occupational health and safety professional (NRC 1997). In such cases, identification, traceability, retention, and storage conditions of samples should be considered, and the purpose for which the serum samples will be used must be consistent with applicable federal and state laws.
Laboratory animal allergy has become a significant issue for individuals in contact with laboratory animals (Bush and Stave 2003; Gordon 2001; Wolfle and Bush 2001; Wood 2001). The medical surveillance program should promote the early diagnosis of allergies (Bush 2001; Bush and Stave 2003; Seward 2001) and include evaluation of an individual’s medical history for preexisting allergies. Personnel training should include information about laboratory animal allergies, preventive control measures, early recognition and reporting of allergy symptoms, and proper techniques for working with animals (Gordon et at. 1997; Schweitzer et al. 2003; Thulin
et al. 2002). PPE should be used to supplement, not replace, engineering or process controls (Harrison 2001; Reeb-Whitaker et al. 1999). If PPE for respiratory protection is necessary, appropriate fit testing and training should be provided.
Zoonosis surveillance should be a part of an OHSP (DHHS 2009; NRC 1997). Personnel should be instructed to notify their supervisors of potential or known exposures and of suspected health hazards and illnesses. Nonhuman primate diseases that are transmissible to humans can be serious hazards (NRC 2003a). Animal technicians, veterinarians, investigators, students, research technicians, maintenance workers, and others who have contact with nonhuman primates or their tissues and body fluids or who have duties in nonhuman primate housing areas should be routinely screened for tuberculosis. Because of the potential for exposure to Macacine herpesvirus 1 (formerly Cercopithecine herpesvirus 1 or Herpes B virus), personnel who work with or handle biologic samples (blood and tissues) from macaques should have access to and be instructed in the use of bite and scratch emergency care stations (Cohen et al. 2002). Injuries associated with macaques, their tissues or body fluids, or caging and equipment with which the animals have had direct contact, should be carefully evaluated and appropriate postexposure treatment and follow-up implemented (ibid.; NRC 2003a).
Clear procedures should be established for reporting all accidents, bites, scratches, and allergic reactions (NRC 1997), and medical care for such incidents should be readily available (Cohen et al. 2002; DHHS 2009).
While contingency plans normally address natural disasters, they should also take into account the threats that criminal activities such as personnel harassment and assault, facility trespassing, arson, and vandalism pose to laboratory animals, research personnel, equipment and facilities, and biomedical research at the institution. Preventive measures should be considered, including preemployment screening and physical and information technology security (Miller 2007).
Investigating and Reporting Animal Welfare Concerns
Safeguarding animal welfare is the responsibility of every individual associated with the Program. The institution must develop methods for reporting and investigating animal welfare concerns, and employees should be aware of the importance of and mechanisms for reporting animal welfare concerns. In the United States, responsibility for review and investigation of these concerns rests with the IO and the IACUC. Response to such reports should include communication of findings to the concerned
employee(s), unless such concerns are reported anonymously; corrective actions if deemed necessary; and a report to the IO of the issue, findings, and actions taken. Reported concerns and any corrective actions taken should be documented.
Mechanisms for reporting concerns should be posted in prominent locations in the facility and on applicable institutional website(s) with instructions on how to report the concern and to whom. Multiple points of contact, including senior management, the IO, IACUC Chair, and AV, are recommended. The process should include a mechanism for anonymity, compliance with applicable whistleblower policies, nondiscrimination against the concerned/reporting party, and protection from reprisals.
Training and regular communication with employees (including personnel such as custodial, maintenance, and administrative staff, who are farther removed from the animal use) about the institution’s animal use activities may reduce potential concerns.
The Role of the IACUC
IACUC Constitution and Function
The responsibility of the IACUC is to oversee and routinely evaluate the Program. It is the institution’s responsibility to provide suitable orientation, background materials, access to appropriate resources, and, if necessary, specific training to assist IACUC members in understanding their roles and responsibilities and evaluating issues brought before the committee.
Committee membership includes the following:
a Doctor of Veterinary Medicine either certified (e.g., by ACLAM, ECLAM, JCLAM, KCLAM) or with training and experience in laboratory animal science and medicine or in the use of the species at the institution
at least one practicing scientist experienced in research involving animals
at least one member from a nonscientific background, drawn from inside or outside the institution
at least one public member to represent general community interests in the proper care and use of animals.
Public members should not be laboratory animal users, affiliated in any way with the institution, or members of the immediate family of a person who is affiliated with the institution. The public member may receive
compensation for participation and ancillary expenses (e.g., meals, parking, travel), but the amount should be sufficiently modest that it does not become a substantial source of income and thus risk compromising the member’s association with the community and public at large.
For large institutions with many administrative units or departments, no more than three voting members should be associated with a single administrative unit (USDA 1985). The size of the institution and the nature and extent of the Program will determine the number of members of the committee and their terms of appointment. Institutions with broad research programs may need to choose scientists from a number of disciplines and experience to properly evaluate animal use protocols.
The committee is responsible for oversight and evaluation of the entire Program and its components as described in other sections of the Guide. Its oversight functions include review and approval of proposed animal use (protocol review) and of proposed significant changes to animal use; regular inspection of facilities and animal use areas; regular review of the Program; ongoing assessment of animal care and use; and establishment of a mechanism for receipt and review of concerns involving the care and use of animals at the institution. The committee must meet as often as necessary to fulfill its responsibilities, and records of committee meetings and results of deliberations should be maintained. Program review and facilities inspections should occur at least annually or more often as required (e.g., by the Animal Welfare Act and PHS Policy). After review and inspection, a written report (including any minority views) should be provided to the IO about the status of the Program.
The animal use protocol is a detailed description of the proposed use of laboratory animals. The following topics should be considered in the preparation of the protocol by the researcher and its review by the IACUC:
rationale and purpose of the proposed use of animals
a clear and concise sequential description of the procedures involving the use of animals that is easily understood by all members of the committee
availability or appropriateness of the use of less invasive procedures, other species, isolated organ preparation, cell or tissue culture, or computer simulation (see Appendix A, Alternatives)
justification of the species and number of animals proposed; whenever possible, the number of animals and experimental group sizes should be statistically justified (e.g., provision of a power analysis; see Appendix A, Experimental Design and Statistics)
unnecessary duplication of experiments
nonstandard housing and husbandry requirements
impact of the proposed procedures on the animals’ well-being
appropriate sedation, analgesia, and anesthesia (indices of pain or invasiveness might aid in the preparation and review of protocols; see Appendix A, Anesthesia, Pain, and Surgery)
conduct of surgical procedures, including multiple operative procedures
postprocedural care and observation (e.g., inclusion of post-treatment or postsurgical animal assessment forms)
description and rationale for anticipated or selected endpoints
criteria and process for timely intervention, removal of animals from a study, or euthanasia if painful or stressful outcomes are anticipated
method of euthanasia or disposition of animals, including planning for care of long-lived species after study completion
adequacy of training and experience of personnel in the procedures used, and roles and responsibilities of the personnel involved
use of hazardous materials and provision of a safe working environment.
While the responsibility for scientific merit review normally lies outside the IACUC, the committee members should evaluate scientific elements of the protocol as they relate to the welfare and use of the animals. For example, hypothesis testing, sample size, group numbers, and adequacy of controls can relate directly to the prevention of unnecessary animal use or duplication of experiments. For some IACUC questions, input from outside experts may be advisable or necessary. In the absence of evidence of a formal scientific merit review, the IACUC may consider conducting or requesting such a review (Mann and Prentice 2004). IACUC members named in protocols or who have other conflicts must recuse themselves from decisions concerning these protocols.
At times, protocols include procedures that have not been previously encountered or that have the potential to cause pain or distress that cannot be reliably predicted or controlled. Relevant objective information about the procedures and the purpose of the study should be sought from the literature, veterinarians, investigators, and others knowledgeable about the effects on animals. If little is known about a specific procedure, limited pilot studies, designed to assess both the procedure’s effects on the animals and the skills of the research team and conducted under IACUC oversight, are appropriate. General guidelines for protocol or method evaluation for some of these situations are provided below, but they may not apply in all instances.
Special Considerations for IACUC Review
Certain animal use protocols include procedures or approaches that require special consideration during the IACUC review process due to their potential for unrelieved pain or distress or other animal welfare concerns. The topics below are some of the most common requiring special IACUC consideration. For these and other areas the IACUC is obliged to weigh the objectives of the study against potential animal welfare concerns. By considering opportunities for refinement, the use of appropriate nonanimal alternatives, and the use of fewer animals, both the institution and the principal investigator (PI) can begin to address their shared obligations for humane animal care and use.
Experimental and Humane Endpoints The experimental endpoint of a study occurs when the scientific aims and objectives have been reached. The humane endpoint is the point at which pain or distress in an experimental animal is prevented, terminated, or relieved. The use of humane endpoints contributes to refinement by providing an alternative to experimental endpoints that result in unrelieved or severe animal pain and distress, including death. The humane endpoint should be relevant and reliable (Hendriksen and Steen 2000; Olfert and Godson 2000; Sass 2000; Stokes 2002). For many invasive experiments, the experimental and humane endpoints are closely linked (Wallace 2000) and should be carefully considered during IACUC protocol review. While all studies should employ endpoints that are humane, studies that commonly require special consideration include those that involve tumor models, infectious diseases, vaccine challenge, pain modeling, trauma, production of monoclonal antibodies, assessment of toxicologic effects, organ or system failure, and models of cardiovascular shock.
The PI, who has precise knowledge of both the objectives of the study and the proposed model, should identify, explain, and include in the animal use protocol a study endpoint that is both humane and scientifically sound. The identification of humane endpoints is often challenging, however, because multiple factors must be weighed, including the model, species (and sometimes strain or stock), animal health status, study objectives, institutional policy, regulatory requirements, and occasionally conflicting scientific literature. Determination of humane endpoints should involve the PI, the veterinarian, and the IACUC, and should be defined when possible before the start of the study (Olfert and Godson 2000; Stokes 2000).
Information that is critical to the IACUC’s assessment of appropriate endpoint consideration in a protocol includes precise definition of the humane endpoint (including assessment criteria), the frequency of animal observation, training of personnel responsible for assessment and recognition of the
humane endpoint, and the response required upon reaching the humane endpoint. An understanding of preemptive euthanasia (Toth 2000), behavioral or physiologic definitions of the moribund state (ibid.), and the use of study-specific animal assessment records (Morton 2000; Paster et al. 2009) can aid the PI and IACUC when considering or developing proposed endpoints. When novel studies are proposed or information for an alternative endpoint is lacking, the use of pilot studies is an effective method for identifying and defining humane endpoints and reaching consensus among the PI, IACUC, and veterinarian. A system for communication with the IACUC should be in place both during and after such studies. Numerous publications address specific proposals for the application and use of humane endpoints (e.g., CCAC 1998; ILAR 2000; OECD 1999; Toth 1997; UKCCCR 1997).
Unexpected Outcomes Fundamental to scientific inquiry is the investigation of novel experimental variables. Because of the potential for unexpected outcomes that may affect animal well-being when highly novel variables are introduced, more frequent monitoring of animals may be required. With their inherent potential for unanticipated phenotypes, GMAs are an example of models for which increased monitoring for unexpected outcomes could be implemented (Dennis 1999).
GMAs, particularly mice and fish, are important animal models, and new methods and combinations of genetic manipulation are constantly being developed (Gondo 2008). Regardless of whether genetic manipulation is targeted or random, the phenotype that initially results is often unpredictable and may lead to expected or unexpected outcomes that affect the animal’s well-being or survival at any stage of life. For example, in some instances genetic modification has led to unforeseen immunodeficiency, requiring the GMA offspring to be held under specialized bioexclusion conditions (Mumphrey et al. 2007); and the promoter sequences used to direct expression of transgenes to specific tissues have varying degrees of specificity (“leakiness”) that can lead to unanticipated phenotypes (Moorehead et al. 2003). These examples illustrate the diversity of unanticipated outcomes and emphasize the need for diligent monitoring and professional judgment to ensure the animals’ well-being (Dennis 2000). The first offspring of a newly generated GMA line should be carefully observed from birth into early adulthood for signs of disease, pain, or distress. Investigators may find that the phenotype precludes breeding of particular genotypes or that unexpected infertility occurs, situations that could lead to increases in the numbers of animals used and revision of the animal use protocol. When the initial characterization of a GMA reveals a condition that negatively affects animal well-being, this should be reported to the IACUC, and more extensive analysis may be required to better define the phenotype (Brown et al. 2000; Crawley 1999; Dennis 2000). Such monitoring and reporting may
help to determine whether proactive measures can circumvent or alleviate the impact of the genetic modification on the animal’s well-being and to establish humane endpoints specific to the GMA line.
Physical Restraint Physical restraint is the use of manual or mechanical means to limit some or all of an animal’s normal movement for the purpose of examination, collection of samples, drug administration, therapy, or experimental manipulation. Animals are restrained for brief periods, usually minutes, in many research applications.
Restraint devices should be suitable in size, design, and operation to minimize discomfort, pain, distress, and the potential for injury to the animal and the research staff. Dogs, nonhuman primates, and many other animals can be trained, through use of positive reinforcement techniques, to cooperate with research procedures or remain immobile for brief periods (Boissy et al. 2007; Laule et al. 2003; Meunier 2006; Prescott and Buchanan-Smith 2003; Reinhardt 1991, 1995; Sauceda and Schmidt 2000; Yeates and Main 2009).
Prolonged restraint, including chairing of nonhuman primates, should be avoided unless it is essential for achieving research objectives and is specifically approved by the IACUC (NRC 2003b). Systems that do not limit an animal’s ability to make normal postural adjustments (e.g., subcutaneous implantation of osmotic minipumps in rodents, backpack-fitted infusion pumps in dogs and nonhuman primates, and free-stall housing for farm animals) should be used when compatible with protocol objectives. Animals that do not adapt to necessary restraint systems should be removed from the study. When restraint devices are used, they should be specifically designed to accomplish research goals that are impossible or impractical to accomplish by other means or to prevent injury to animals or personnel.
The following are important guidelines for restraint:
Restraint devices should not be considered a normal method of housing, and must be justified in the animal use protocol.
Restraint devices should not be used simply as a convenience in handling or managing animals.
Alternatives to physical restraint should be considered.
The period of restraint should be the minimum required to accomplish the research objectives.
Animals to be placed in restraint devices should be given training (with positive reinforcement) to adapt to the equipment and personnel.
Animals that fail to adapt should be removed from the study.
Provision should be made for observation of the animal at appropriate intervals, as determined by the IACUC.
Veterinary care must be provided if lesions or illnesses associated with restraint are observed. The presence of lesions, illness, or severe behavioral change often necessitates the temporary or permanent removal of the animal from restraint.
The purpose of the restraint and its duration should be clearly explained to personnel involved with the study.
Multiple Survival Surgical Procedures Surgical procedures in the laboratory setting may be categorized as major or minor (USDA 1985). Whether a procedure is major or minor should be evaluated on a case-by-case basis, as determined by the veterinarian and IACUC (NRC 2003b; Silverman et al. 2007; for additional discussion see Chapter 4, Surgical Procedures).
Regardless of classification, multiple surgical procedures on a single animal should be evaluated to determine their impact on the animal’s wellbeing. Multiple major surgical procedures on a single animal are acceptable only if they are (1) included in and essential components of a single research project or protocol, (2) scientifically justified by the investigator, or (3) necessary for clinical reasons. Conservation of scarce animal resources may justify the conduct of multiple major surgeries on a single animal, but the application of such a practice on a single animal used in separate protocols is discouraged and should be reviewed critically by the IACUC. When applicable, the IO must submit a request to the USDA/APHIS and receive approval in order to allow a regulated animal to undergo multiple major survival surgical procedures in separate unrelated research protocols (USDA 1985, 1997a). Justifications for allowing animals not regulated by the USDA to undergo multiple survival procedures that meet the above criteria should conform to those required for regulated species. If multiple survival surgery is approved, the IACUC should pay particular attention to animal well-being through continuing evaluation of outcomes. Cost savings alone is not an adequate reason for performing multiple major survival surgical procedures.
Some procedures characterized as minor may induce substantial postprocedural pain or impairment and should similarly be scientifically justified if performed more than once in a single animal.
Food and Fluid Regulation Regulation of food or fluid intake may be required for the conduct of some physiological, neuroscience, and behavioral research protocols. The regulation process may entail scheduled access to food or fluid sources, so an animal consumes as much as desired at regular intervals, or restriction, in which the total volume of food or fluid consumed is strictly monitored and controlled (NRC 2003b). The objective when these studies are being planned and executed should be to use the
least restriction necessary to achieve the scientific objective while maintaining animal well-being.
The development of animal protocols that involve the use of food or fluid regulation requires the evaluation of three factors: the necessary level of regulation, potential adverse consequences of regulation, and methods for assessing the health and well-being of the animals (NRC 2003b). In addition, the following factors influence the amount of food or fluid restriction that can be safely used in a specific protocol: the species, strain, or stock, gender, and age of the animals; thermoregulatory demand; type of housing; time of feeding, nutritive value, and fiber content of the diet (Heiderstadt et al. 2000; Rowland 2007); and prior experimental manipulation. The degree of food or fluid restriction necessary for consistent behavioral performance is influenced by the difficulty of the task, the individual animal, the motivation required of the animal, and the effectiveness of animal training for a specific protocol-related task.
The animals should be closely monitored to ensure that food and fluid intake meets their nutritional needs (Toth and Gardiner 2000). Body weights should be recorded at least weekly and more often for animals requiring greater restrictions (NRC 2003b). Written records should be maintained for each animal to document daily food and fluid consumption, hydration status, and any behavioral and clinical changes used as criteria for temporary or permanent removal of an animal from a protocol (Morton 2000; NRC 2003b). In the case of conditioned-response research protocols, use of a highly preferred food or fluid as positive reinforcement, instead of restriction, is recommended. Caloric restriction, as a husbandry technique and means of weight control, is discussed in Chapter 3.
Use of Non-Pharmaceutical-Grade Chemicals and Other Substances The use of pharmaceutical-grade chemicals and other substances ensures that toxic or unwanted side effects are not introduced into studies conducted with experimental animals. They should therefore be used, when available, for all animal-related procedures (USDA 1997b). The use of non-pharmaceutical-grade chemicals or substances should be described and justified in the animal use protocol and be approved by the IACUC (Wolff et al. 2003); for example, the use of a non-pharmaceutical-grade chemical or substance may be necessary to meet the scientific goals of a project or when a veterinary or human pharmaceutical-grade product is unavailable. In such instances, consideration should be given to the grade, purity, sterility, pH, pyrogenicity, osmolality, stability, site and route of administration, formulation, compatibility, and pharmacokinetics of the chemical or substance to be administered, as well as animal welfare and scientific issues relating to its use (NIH 2008).
Field Investigations Investigations may involve the observation or use of nondomesticated vertebrate species under field conditions. Many field investigations require international, federal, state, and/or local permits, which may call for an evaluation of the scientific merit of the proposed study and a determination of the potential impact on the population or species to be studied.
Additionally, occupational health and safety issues, including zoonoses, should be reviewed by the institution’s health and safety committee or office, with assurances to the IACUC that the field study does not compromise the health and safety of either animals or persons in the field. Principal investigators conducting field research should be knowledgeable about relevant zoonotic diseases, associated safety issues, and any laws or regulations that apply. Exceptions to the above should be clearly defined and evaluated by the IACUC.
In preparing the design of a field study, investigators are encouraged to consult with relevant professional societies and available guidelines (see Appendix A). Veterinary input may be needed for projects involving capture, individual identification, sedation, anesthesia, surgery, recovery, holding, transportation, release, or euthanasia. Issues associated with these activities are similar if not identical to those for species maintained and used in the laboratory. When species are removed from the wild, the protocol should include plans for either a return to their habitat or their final disposition, as appropriate.
The Guide does not purport to be a compendium of all information regarding field biology and methods used in wildlife investigations, but the basic principles of humane care and use apply to animals living under natural conditions. IACUCs engaged in the review of field studies are encouraged to consult with a qualified wildlife biologist.
Agricultural Animals The use of agricultural animals in research is subject to the same ethical considerations as for other animals in research, although it is often categorized as either biomedical or agricultural because of government regulations and policies, institutional policies, administrative structure, funding sources, and/or user goals (Stricklin et al. 1990). This categorization has led to a dual system with different criteria for evaluating protocols and standards of housing and care for animals of the same species on the basis of stated biomedical or agricultural research objectives (Stricklin and Mench 1994). With some studies, differences in research goals may lead to a clear distinction between biomedical and agricultural research. For example, animal models of human diseases, organ transplantation, and major surgery are considered biomedical uses; and studies on food and fiber production, such as feeding trials, are usually considered agricultural uses. But when the distinction is unclear, as in the case of some nutrition and
disease studies, administrators, regulators, and IACUCs face a dilemma in deciding how to handle such studies (Stricklin et al. 1990). Decisions on categorizing research uses of agricultural animals and defining standards for their care and use should be made by the IACUC based on both the researcher’s goals and concern for animal well-being. Regardless of the category of research, institutions are expected to provide oversight of all research animals and ensure that pain and distress are minimized.
The protocol, rather than the category of research, should determine the setting (farm or laboratory). Housing systems for agricultural animals used in biomedical research may or may not differ from those used in agricultural research; animals used in either type of research can be housed in cages, stalls, paddocks, or pastures (Tillman 1994). Some agricultural studies need uniform conditions to minimize environmental variability, and some biomedical studies are conducted in farm settings. Agricultural research often necessitates that animals be managed according to contemporary farm production practices (Stricklin and Mench 1994), and natural environmental conditions might be desirable for agricultural research, whereas control of environmental conditions to minimize variation might be desirable in biomedical research (Tillman 1994).
The Guide applies to agricultural animals used in biomedical research, including those maintained in typical farm settings. For animals maintained in a farm setting, the Guide for the Care and Use of Agricultural Animals in Research and Teaching (FASS 2010) is a useful resource. Information about environmental enrichment, transport, and handling may be helpful in both agricultural and biomedical research settings. Additional information about facilities and management of farm animals in an agricultural setting is available from the Midwest Plan Service (1987) and from agricultural engineers or animal science experts.
Continuing IACUC oversight of animal activities is required by federal laws, regulations, and policies. A variety of mechanisms can be used to facilitate ongoing protocol assessment and regulatory compliance. Postapproval monitoring (PAM) is considered here in the broadest sense, consisting of all types of protocol monitoring after the IACUC’s initial protocol approval.
PAM helps ensure the well-being of the animals and may also provide opportunities to refine research procedures. Methods include continuing protocol review; laboratory inspections (conducted either during regular facilities inspections or separately); veterinary or IACUC observation of selected procedures; observation of animals by animal care, veterinary, and IACUC staff and members; and external regulatory inspections and assess-
ments. The IACUC, veterinary, animal care, and compliance staff may all conduct PAM, which may also serve as an educational tool.
Continuing protocol review typically consists of an annual update or review as well as the triennial review required by the PHS. The depth of such reviews varies from a cursory update to a full committee review of the entire protocol. Some institutions use the annual review as an opportunity for the investigator to submit proposed amendments for future procedures, to provide a description of any adverse or unanticipated events, and to provide updates on work progress. For the triennial review, many institutions require a complete new protocol submission and may request a progress report on the use of animals during the previous 3 years.
Both the Health Research Extension Act and the AWA require the IACUC to inspect animal care and use facilities, including sites used for animal surgeries, every 6 months. As part of a formal PAM program some institutions combine inspection of animal study sites with concurrent review of animal protocols. Based on risks to animals and their handlers, other study areas may require more or less frequent inspections. Examples of effective monitoring strategies include
examination of surgical areas, including anesthetic equipment, use of appropriate aseptic technique, and handling and use of controlled substances
review of protocol-related health and safety issues
review of anesthetic and surgical records
regular review of adverse or unexpected experimental outcomes affecting the animals
observation of laboratory practices and procedures and comparison with approved protocols.
Institutions may also consider the use of veterinary staff and/or animal health technicians to observe increased risk procedures for adverse events (e.g., novel survival surgeries, pain studies, tumor growth studies) and report their findings for review by the IACUC. The level of formality and intensity of PAM should be tailored to institutional size and complexity, and in all cases should support a culture of care focusing on the animals’ well-being (Klein and Bayne 2007). Regardless of the methods used or who conducts and coordinates the monitoring, PAM programs are more likely to succeed when the institution encourages an educational partnership with investigators (Banks and Norton 2008; Collins 2008; Dale 2008; Lowman 2008; Plante and James 2008; Van Sluyters 2008).
DISASTER PLANNING AND EMERGENCY PREPAREDNESS
Animal facilities may be subject to unexpected conditions that result in the catastrophic failure of critical systems or significant personnel absenteeism, or other unexpected events that severely compromise ongoing animal care and well-being (ILAR 2010). Facilities must therefore have a disaster plan. The plan should define the actions necessary to prevent animal pain, distress, and deaths due to loss of systems such as those that control ventilation, cooling, heating, or provision of potable water. If possible the plan should describe how the facility will preserve animals that are necessary for critical research activities or are irreplaceable. Knowledge of the geographic locale may provide guidance as to the probability of a particular type of disaster.
Disaster plans should be established in conjunction with the responsible investigator(s), taking into consideration both the priorities for triaging animal populations and the institutional needs and resources. Animals that cannot be relocated or protected from the consequences of the disaster must be humanely euthanized. The disaster plan should identify essential personnel who should be trained in advance in its implementation. Efforts should be taken to ensure personnel safety and provide access to essential personnel during or immediately after a disaster. Such plans should be approved by the institution and be part of the overall institutional disaster response plan that is coordinated by the IO or another senior-level administrator. Law enforcement and emergency personnel should be provided with a copy of the plan for comment and integration into broader, areawide planning (Vogelweid 1998).
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