Stephen Potkay, VMD, Nelson L. Garnett, DVM, John G. Miller, DVM, Cynthia L. Pond, DVM, MS, and Denis J. Doyle

The article was prepared by staff members of the Division of Animal Welfare, Office for Protection from Research Risks, National Institutes of Health, 6100 Executive Boulevard, Suite 3B01, MSC 7507, Rockville, MD 20892-7507. [The Animal Welfare Division of OPRR was renamed Office of Laboratory Animal Welfare (OLAW) in 2000.]

The Office for Protection from Research Risks (OPRR) of the National Institutes of Health (NIH) develops, implements, and oversees compliance with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (Policy) ¹. The PHS Policy and the U.S. Department of Agriculture's (USDA) Animal Welfare Regulations ², are the two principal federal documents that set forth requirements for animal care and use by institutions using animals in research, testing, and education. One of OPRR's primary functions is to assist institutions in implementing PHS Policy by responding to policy-related questions ^{3 , 4}. The following represent several frequently asked questions from institutions and the OPRR responses:

1. The Institutional Animal Care and Use Committee (IACUC) at our institution is uncertain about what criteria to use in determining what constitutes a "significant change" to an approved research protocol, so that it can implement the appropriate review mechanism. How should we interpret the PHS Policy in this regard?

Owing to the great diversity of research performed at assured institutions, it is not possible for this Office to anticipate all of the changes that investigators might potentially make to approved protocols and provide an exhaustive listing of those considered significant. However, institutions have requested OPRR to evaluate a variety of situations in which the significance of protocol changes was a primary concern. As a result, we have identified several kinds of significant changes that may serve as examples to guide the IACUC in its determinations. They include but are not limited to: changes in the objectives of a study; proposals to switch from nonsurvival to survival surgery; changes in the degree of invasiveness of a procedure or discomfort to an animal; changes in species or in the approximate number of animals used; changes in personnel involved in animal procedures; and changes in anesthetic agent(s), the use or withholding of analgesics, and methods of euthanasia. Additional factors may involve changes in the duration, frequency, or number of procedures performed on an animal. Based on these considerations, IACUCs should develop guidelines to follow at their institution and ensure they inform each principal investigator. It must become institutional policy that no one may implement changes categorized as significant prior to IACUC review and approval.

2. Our institution purchases antibodies from commercial sources for use in various PHS-supported studies conducted in its facilities. Does the PHS Policy require that the commercial source have an Animal Welfare Assurance on file with the OPRR?

In the case that standard reagent antibodies (e.g. mouse-antihuman) are produced by a commercial supplier using their own resources and offering them for general sale, for example, through a catalogue, the institution may consider the antibodies to be "off-the-shelf" reagents, and the supplier is not required to file an Assurance with OPRR. If, on the other hand, a supplier or contractor produces custom antibodies using antigen(s) provided by or at the request of a principal investigator, the antibodies are considered "customized" and the vendor or subcontractor must file an Assurance with OPRR.

Usually it is known in advance that someone intends to perform this kind of work under a PHS grant. In such cases, the applicant must mark the PHS Grant Application (PHS Form 398) "yes" for vertebrate animal involvement and include the appropriate Animal Welfare Assurance number(s), verification of project-specific date of IACUC protocol review, and the identification of all project performance sites. All animal-related activities supported by the PHS must be conducted at Assured institutions and must be reviewed and approved by an IACUC. When both the PHS Grantee and its Contractor hold OPRR-approved Assurances, some latitude is allowed in determining which IACUC (if not both) will review the proposal. However, the institution which subcontracts or subgrants any animal activity retains partial accountability for providing effective oversight mechanisms to ensure compliance with the PHS Policy. Part of that responsibility includes ensuring that subgranted/subcontracted animal-related activities are conducted only at an Assured institution.

3. How extensive must the animal care and use training program be in our small institution, and at what frequency should it be offered?

Each Assured Institution is responsible for training its staff to meet the performance requirements cited in paragraph IV.C.1.a.- g. of the PHS Policy, and guidelines have been developed to assist institutions to meet these objectives ^{5 , 6};. OPRR recognizes research programs vary from one institution to another, and are relative to the size and nature of the institution, staffing, numbers of species and individual animals maintained, and the kinds of research conducted. Therefore, the scope and depth of instructional programs and the frequency at which they are offered will also vary. At a minimum, however, the Policy requires institutions to ensure that individuals who use or provide care for animals are trained and qualified in the appropriate, species-specific housing methods, husbandry procedures, and handling techniques. The institution must ensure that research staff members performing experimental manipulation, including anesthesia and surgery, are qualified through training or experience to accomplish such procedures humanely and in a scientifically acceptable fashion. They must also provide training or instruction in research and testing methods that minimize the number of animals required to obtain valid results and minimize animal distress. Institutions must also ensure that professional staff whose work involves hazardous biological, chemical, or physical agents have training or experience to assess potential dangers and select and oversee the implementation of appropriate safeguards. Finally, OPRR strongly recommends that institutions offer their staff access to training leading to certification in animal technology such as that available from AALAS or a formally designated academic program. Institutions should also know and ensure compliance with any initial and continuing education State requirements for the licensing of veterinary or animal health technicians.

4. In the event that our IACUC reports a serious noncompliance with the PHS Policy or deviation from the Guide, we understand that the report must fully explain the circumstances and actions taken to correct the situation. How soon after the noncompliance or deviation is identified must we submit the report? How closely is our institution held to meeting its self-imposed schedule for correction?

The PHS Policy requires institutions report promptly any serious or continuing noncompliance with the Policy or serious deviation from the provisions of the Guide. Examples of noncompliance and deviations include: conducting an animal-related activity without appropriate IACUC review and approval; the temporary or permanent interruption of an activity involving animals by the IACUC; and conditions that jeopardize the health or well-being of an animal. The USDA's Animal Welfare Regulations are more specific, requiring institutions report such matters to the Animal Plant and Health Inspection Service (APHIS) and the funding agency if not resolved within 15 business days of the completion date specified in the IACUC's initial corrective plan and schedule. The IACUC should use the interval to investigate and develop a definitive corrective plan and a schedule for implementation. In many cases, it also provides ample opportunity for total resolution of the problem. One should note, however, that solution of the problem does not dismiss the institution's obligation to file a report with OPRR and APHIS. When the IACUC cannot completely resolve the noncompliance or deviation within the allotted time, the institution must present a specific and reasonable corrective plan and schedule. If the situation directly involves animals and threatens their health and safety, such plans are to contain interim measures, including possible relocation of the animals at risk. OPRR's acceptance of a plan and schedule is usually conditioned on notification when the corrective action is complete. It is recognized that circumstances which are beyond the institution's control may arise and prevent the scheduled completion of the plan. In such cases, OPRR will consider requests to extend the schedule if the circumstances are adequately described and the proposed new deadline is reasonable.

5. Our institution receives funding from PHS and non-PHS sources. Must we include those programs, projects, and facilities which are not supported by the PHS in our Assurance of Compliance?

OPRR advises institutions that the maintenance of uniform and consistent standards is an essential ingredient in the development and implementation of a quality animal care and use program. Only when an institution can document that the animal care and use program funded by a non-PHS source is entirely separate and distinct, physically and programmatically, from PHS-supported activities will OPRR consider its exclusion from the Institutional Assurance. Unless there is such total separation, OPRR cannot accept the potential risks presented to animals involved in PHS-funded research. Institutions should also keep in mind the public perception that institutions not wishing to conduct portions of their animal research programs in accordance with the Policy may be applying a double standard of animal care to the detriment of overall animal health and well-being.

6. Our institution uses animals as sentinels in the animal disease surveillance program, in breeding programs, and as donors for blood and blood products. Since these animals are not used in research per se, is it necessary to develop protocols for the review and approval of our IACUC?

PHS Policy applicability is not limited to research. It also includes all activities involving animals including testing and teaching. OPRR has determined that although animals used as sentinels, breeding stock, chronic donors of blood and blood products, or for other similar objectives may not be part of specific research protocols, their use for these purposes contributes significantly to the institutional research program and constitutes activities involving animals. Consequently, the IACUC must receive and approve of protocols and appropriate systems to monitor the use of animals prior to the commencement of such activities, and should then perform reviews at the appropriate intervals (IV.C. of the PHS Policy).

7. Could you describe the kind and extent of the employee health program required by the PHS Policy?

Principal requirements for an institutional occupational health program are outlined in the Guide for the Care and Use of Laboratory Animals. Institutional research programs vary regarding the animal species used and the potential hazards presented by them. The biological, chemical, or physical agents employed in the course of the research likewise vary. Thus, the institution must base their health program on an assessment of the risks present in its particular animal research program, including those in cagewashing and other support activities. Basic elements of any health program, however, should provide: a pre-employment medical evaluation and history; immunization against tetanus; detailed training on how to perform required procedures safely; instruction in personal hygiene, zoonoses, and precautions for pregnant women and others at risk; protective clothing and devices; instruction in first aid procedures appropriate to potential hazards; and access to medical attention for the treatment of animal bites, scratches, allergies and other job-related injuries or illnesses. When there is risk of exposure to rabies through the use of random-source dogs and cats and certain wildlife species, the institution should offer preexposure immunization, and should regularly schedule tuberculin testing for all personnel exposed to nonhuman primates. The institution should have precautions in place and a zoonoses surveillance mechanism established when work involves exposure to nonhuman primates and species likely to harbor the causative agents of diseases such as Q fever, tularemia, hantavirus pulmonary syndrome, and plague. When research involves infectious diseases, such as hepatitis B, for which there are safe and effective vaccines, the use of prophylactic immunizations should also be considered. A health program is required not only for persons having "frequent contact with animals," but for all "personnel who work in laboratory animal facilities." These include not only animal caretakers, technicians, students, volunteers, investigators, and veterinarians but facilities maintenance engineers, housekeepers, security, and other staff. OPRR recommends that the foregoing phrases be interpreted in the context of the potential risks to which the persons are exposed. For example, those working full time in closed, pathogen-free rodent colonies where no hazardous agents are employed are at considerably less risk than individuals exposed for brief periods to nonhuman primates, random source dogs and cats, or to hazardous biological, chemical, or physical agents. Each institution's risk assessment and the implementation of its health program should rely heavily on input from persons knowledgeable in occupational safety and health, biosafety, and radiation safety, and include both preventive as well as diagnostic and treatment features.

Received 8/18/95; accepted 9/7/95

1. Public Health Service (PHS). Public Health Service Policy on Humane Care and Use of Laboratory Animals. US Department of Health and Human Services. (Available from: National Institutes of Health, Office for Protection from Research Risks, 6100 Executive Boulevard, Suite 3B01, MSC 7507, Rockville, MD 20892-7507) Washington, DC, 1986.

2. Animal Welfare Regulations. Code of Federal Regulations, Title 9 (Animals and Animal Subproducts), Subchapter A (Animal Welfare), Parts 1-3 (9 CFR 1-3). (Available from Regulatory Enforcement and Animal Care, U.S. Department of Agriculture, Unit 84, 4700 River Road, Riverdale, MD, 20737).

3. Division of Animal Welfare, Office for Protection from Research Risks. The Public Health Service Responds to Commonly Asked Questions. ILAR News 33:68-70, 1991.

4. Division of Animal Welfare, Office for Protection from Research Risks. Frequently Asked Questions about the Public Health Service Policy on Care and Use of Laboratory Animals. ILAR News 35:47-49, 1993.

5.. Education and Training in the Care and Use of Laboratory Animals: A Guide for Developing Institutional Programs. Committee on Educational Programs in Laboratory Animal Science, ILAR, Commission on Life Sciences, National Research Council. Washington: National Academy Press, Washington, DC, 1991.

6. Bennett BT, Brown MJ, Schofield. Essentials for Animal Research: a primer for research personnel, 2nd Ed. 1994. AWIC, National Agricultural Library, Beltsville, MD, 1994.