ILAR Journal Online, Volume 36(2) 1994: Farm Animals in Biomedical Research

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ILAR Journal V36(2) 1994 [FORMERLY ILAR NEWS]
Farm Animals in Biomedical Research - Part Two

Issues for Institutional Animal Care and Use Committees (IACUCs)

Integrating Agricultural and Biomedical Research Policies: Conflicts and Opportunities
Philip Tillman

Philip Tillman, D.V.M., is campus veterinarian at the University of California, Davis.

OVERVIEW: BIOMEDICAL AND AGRICULTURAL USES OF FARM ANIMALS

Research facilities use farm animals in several ways. They may be used as "animal models," in which case the subject species is studied with the intention of applying the knowledge to human beings (or sometimes to another animal species). Farm animals may also be studied for their intrinsic interest to gain fundamental knowledge about animal biology. Chickens might be used to study animal behavior or avian evolution, which may have potential application in better characterizing animal models or the genetic components of a disease. These sorts of studies may be referred to as "biomedical" studies. Farm animals are also studied with the intention of applying the knowledge gained to the efficient production of food and fiber by the subject species. Such studies are clearly "agricultural" in nature. Agricultural studies are fundamental to the production agriculture departments of U.S. Land Grant Colleges.

Farm animals may also be used in ways that cross the boundary between biomedical and agricultural studies. For example, the agricultural production colonies of an institution may supply animals (or embryonated eggs) for biomedical research. A study may be collaborative between an agricultural scientist and a biomedical scientist--each employing the same procedures, but interested in the data for different reasons. A physiologist may be interested in the effects of a new beta adrenergic agonist because of its potential relevance to human physiology, while an animal scientist might be interested in the same data because of its relevance to meat production. In many cases, it isn't easy to categorize a particular project as biomedical or agricultural. The distinction becomes less and less clear as biochemists, physiologists, and biomedical engineers become more and more prevalent within our agricultural universities.

The sometimes "fuzzy" border between agricultural and nonagricultural studies has become a topic of great interest to university Institutional Animal Care and Use Committees (IACUCs). In 1990, the U.S. Department of Agriculture (USDA) announced its intention to draft standards for the use of farm animals in biomedical research (Federal Register, Vol. 55, No. 66, p. 12667, April 5, 1990). USDA animal welfare inspectors now visit research institutions and ask if particular animals are being used for biomedical or agricultural research. If the study is biomedical, the research project and the husbandry procedures under which the animal is maintained are matters of federal regulation.

Institutions conducting both agricultural and biomedical research must sooner or later decide what role, if any, the IACUC will play in the oversight of agricultural studies. If the IACUC is to play a role in the governance of agricultural studies, then it will have to determine what standards are applicable to agricultural studies.

REGULATORY REQUIREMENTS AND INSTITUTIONAL DECISIONS

In general, agricultural production studies in farm animals have been specifically excluded from the regulations and guidelines requiring IACUC oversight of animal research. The Federal Animal Welfare Act regulations specifically exempt "horses not used for research purposes and other farm animals, such as, but not limited to livestock or poultry, used or intended for use as food or fiber, or livestock or poultry used or intended for improving animal nutrition, breeding, management, or production efficiency, or for improving the quality of food or fiber" (9 CFR 1.1). The Health Research Extension Act (42 USC 289d) was amended November 20, 1985 by Public Law 99-158 to cover the care and use of animals in research. This law applies to all live vertebrate species, but only when they are used in Public Health Service (PHS) funded activities. Numerous other federal and private agencies require IACUC review of funding pro-
posals and adherence to the principles provided in the Guide for the Care and Use of Laboratory Animals (NIH Guide) (NRC, 1985; FDA, 1992; NSF, 1985), but in general these agencies do not fund agricultural research.

It is much less common for an agricultural funding entity to require IACUC review of submissions, although USDA's Cooperative State Research Service does require IACUC review of the agricultural production studies that it funds. Apart from the requirements of specific funding agencies, there is no legal requirement for any sort of oversight or review of purely agricultural studies.

An institution could choose to exclude all its agricultural units from IACUC review without violating any law or regulation. An institution could also develop an alternate means of oversight, perhaps a separate committee, for agricultural production facilities and studies. The Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching (Ag Guide) recommends committee oversight of agricultural studies, and discusses the possibility of a separate committee for review of agricultural activities (Consortium for Developing a Guide, 1988).

If an institution decides to monitor the care and use of animals in agricultural research, either through the IACUC or another mechanism, the institution must then decide what standard should be used to evaluate agricultural studies and husbandry methods.

Figure 1 (options for the oversight of agricultural animals in research) shows the cascade of decisions that determine what role the IACUC will have in the oversight of studies involving farm animals. Note that there are two entirely voluntary policy decisions that fall to the administration of the institution: (1) Should one IACUC have oversight over both agricultural studies and biomedical studies? and (2) Should the same standards be applied to agricultural and biomedical studies?

ONE IACUC OR TWO?

An institution might choose to appoint separate IACUCs for agricultural and nonagricultural studies. The arguments in either direction might be presented as follows:

An agriculture IACUC (Ag-IACUC) would be staffed largely by scientists with expertise in production agriculture. An Ag-IACUC might be seen as more credible and authoritative to an agricultural faculty than an IACUC composed largely of physicians, for example. Agricultural scientists would have greater knowledge of conditions in the agricultural industry, which might have to be modeled in research projects. Finally, in many instances, agricultural scientists might have greater knowledge of the particular species under study.

A disadvantage of a dual IACUC system would be its tendency to divide and fragment the institution rather than build consensus and uniformity. One might find that a given procedure could be approved in one department and not in another. One would have to establish policy which would determine to which committee a particular type of study should be submitted. Would the two IACUCs' areas of authority be based on the species under study, the academic department of the scientist, or the nature of the study? If the study had both agricultural and nonagricultural significance, which committee would have authority?

A single IACUC, representing both biomedical and agricultural scientists, also has its advantages. The single IACUC would represent the whole of, rather than a subunit of the institution. A single, broadly constituted IACUC could establish guidelines and policies that could apply across academic lines in an unbiased way. If the IACUC had to investigate and act on a complaint expressed by the general public, a broadly constituted IACUC might be seen as less biased than an IACUC more directly connected with a particular research group or department.

ONE POLICY, TWO, OR THREE?

After determining whether or not agricultural studies and nonagricultural studies should be reviewed by the same committee, the institution must then determine what standards are to be used in reviewing protocols and inspecting vivaria. The majority of governmental and private funding sources have used the NIH Guide for this purpose. The upcoming USDA standards for farm animals will apply to farm animals used in biomedical studies, but not to those used in agricultural studies. USDA was directed by congress to confer with the Department of Health and Human Services in drafting standards under the Animal Welfare Act, with the intent of establishing uniformity of standards between the two agencies.

In drafting new regulations, USDA is expected to make extensive use of existing documents, such as the NIH Guide and the Ag Guide. It remains to be seen which document will have greater influence on USDA's proposed rules. The Ag Guide has been widely advocated for use as a primary source document for the USDA regulations. Many researchers have praised the Ag Guide for its greater flexibility and more extensive discussions of agricultural practices.

There would be, however, potential conflict inherent in using the Ag Guide as the primary source document in lieu of the NIH Guide. The NIH Guide deals only with biomedical research, not with agricultural production research. USDA's farm animal standards will clearly regulate the biomedical studies for which the NIH Guide was written. USDA's regulations will clearly not regulate the studies for which the Ag Guide was written, since agricultural production studies fall outside USDA's jurisdiction. Ideally, USDA's regulations will draw from the best of each of these source documents, but they must adhere closely enough to the NIH Guide to avoid producing conflicting regulations for biomedical studies.

For agricultural production studies, there are a variety of other source documents, the most widely recognized of which is the Ag Guide. Those portions of the Ag Guide dealing with animal husbandry have been adopted by the American Association for Accreditation of Laboratory Animal Care (AAALAC) as an applicable standard for agricultural studies. AAALAC provides further guidance in a policy statement on farm animal facilities, which states, "... housing and care for farm animals should meet the standards that prevail on a high-quality, well-managed farm. These standards are those promulgated by state agricultural extension services and the land-grant universities" (AAALAC, 1991).

A single IACUC could review each facility and project and apply the most appropriate standards or guidelines (whether USDA Animal Welfare Regulations, the NIH Guide, or the Ag Guide). They could also use AAALAC's policy statement as a guideline and employ a community standard, by asking for each protocol, "Does this facility or study represent the standards of a high-quality, well-managed farm in our state?"

Of the various documents that might be used as standards, the NIH Guide is the most demanding. The cage sizes are often the largest, the requirements for sanitation are the most stringent, the climate control requirements the most exacting, and the programmatic requirements the most specific. A strong argument could be made that an institution establishing policy for animals should adopt the NIH Guide as the single standard. If the requirements for the NIH Guide are met uniformly throughout a campus, then every animal facility and every animal activity is fully qualified to seek funding from any granting agency. Adopting a dual standard might limit sources of funding to particular departments or particular animal facilities.

The NIH Guide states specifically that it does not deal with the use of farm animals in research intended for production agriculture (NRC, 1985, p. 2). However, it is a very flexible document, laying out general principles of animal care more frequently than it specifies particulars. For example, under "Food" the NIH Guide states, "Animals should be fed palatable, uncontaminated, and nutritionally adequate food daily or according to their particular requirements, unless the experimental protocol requires otherwise" (NRC, 1985, p. 22). There would be no difficulty applying this guideline to the care of animals in biomedical research, agricultural research, production agriculture, zoological parks, as well as to pet care.

The NIH Guide also clearly states, "Professional judgement is essential in the interpretation of these guidelines" (emphasis in original) (NRC, 1985, p. 2). The NIH Guide invites the reader to consider not only the specifics, but the rationale behind them, and allows the freedom to vary from the specifics of the NIH Guide when good reason can be given. For example, if a study must model conditions of a farm in order to be scientifically valid, it would not be in conflict with the NIH Guide to allow the use of commercial agricultural caging.

STANDARDS, DOUBLE STANDARDS, AND GUIDELINES

Given that it would fall within an IACUC's authority to apply agricultural standards to agricultural projects, how great a difference should the IACUC expect to observe between agricultural facilities and nonagricultural facilities? What will the differences be? What sorts of Judgements of Solomon will be required of the IACUC? A few examples of the more obvious differences between contemporary biomedical standards and agricultural standards are given below.

Space requirements

It's difficult to make direct comparisons between the space requirements of the NIH Guide and those of the Ag Guide. Each source gives space requirements in tabular formats, but the types of housing listed and the categories of animals often are not directly comparable. The differences between the two documents are often minimal, especially for the species, housing types, and weight ranges commonly used in biomedical studies*. Consider the examples of space requirements as given in the NIH Guide and the Ag Guide (Table 1).

Sanitation Practices

Sanitation practices are very different between biomedical and agricultural facilities. For example, the NIH Guide requires that wire bottom cages be washed at least every 2 weeks. Wire bottom poultry cages in agricultural facilities might only be sanitized between successive groups of animals; perhaps at intervals of several months. Even in the case of ruminants, swine, and horses, disinfection of a pri-maw enclosure is the exception rather than the rule. Most frequently, waste is simply removed, with disinfection reserved for periods when the enclosure is emptied between successive lots of animals.

Force Molting

Chickens used for egg production lay eggs for a period of months and then stop. They may be induced to molt and resume laying by a variety of techniques collectively known as "force molting." Several variants of force molting techniques have been developed by the Experiment Stations and agricultural faculty of land grant universities. All methods involve stress induction by deprivation of food or water. In the "California Program" water is provided freely, but all food is withdrawn for 10-14 days (North, 1984, pp. 341-356), during which time a small percentage of the animals may die. This agricultural practice is described in texts and in publications of Land Grant Colleges and Experiment Stations. Force molting could easily be employed on a "high quality, well-managed farm." The practice is not discussed in the Ag Guide.

Chickens are occasionally used in biomedical research as antibody producers, harvested from their eggs. If a valuable antibody producer comes to the end of a laying cycle, it is possible to "force molt" the chicken in order to accelerate its return to antibody production. The NIH Guide states that, "Animals should be fed palatable, uncontaminated, and nutritionally adequate food daily or according to their particular requirements, unless the experimental protocol requires otherwise" (NRC, 1985, p. 22). Should a biomedical investigator be allowed to force molt a chicken in order to return it to antibody production? Is a ten-day fast compatible with the NIH Guide? This question could easily be presented to an IACUC.

Surgical Facilities

Major operative procedures, as defined in the Animal Welfare Act regulations (9 CFR 1.1), are often performed under much less stringent conditions in commercial agriculture than in biomedical research. For example, in an agricultural setting, a bovine or ovine caesarian section would most often be performed in a procedure area of a barn. Sometimes the procedure might occur in an outdoor stanchion. It is highly unlikely that the animal would be prepared for surgery in a room other than the one in which the procedure took place. In a PHS funded biomedical study, similar procedures would require a dedicated survival surgery suite and the animal would be prepared for surgery in a room other than the operating room (NRC, 1985, p. 37). The NIH Guide, by its deference to professional judgement, would presumably allow the IACUC considerable latitude in determining exactly which procedures would require a dedicated surgical facility. The Animal Welfare Act regulations are likely to be more rigid.

Physical Facilities

Both agricultural and biomedical housing facilities seek to provide the animals with the necessities of life and health, however, some of the premises underlying facility design are quite different. The emphasis in a biomedical facility is on environmental control. The facility seeks to eliminate all possible variation among experiments by finely controlling variables such as temperature, ventilation, and light. The NIH Guide suggests that temperature in an ideal animal room should be controllable within one degree centigrade. This extreme degree of climatic control is not advocated to promote the well-being of the animal as much as to control variation among experiments.

A fundamental goal of agricultural facilities is efficiency and economy. An agricultural scientist's primary goal is the efficient production of food and fiber. An agricultural facility is designed to meet the animal's minimum needs at minimum expense. Accordingly, while agricultural facilities are likely to consume less energy, they demonstrate less climatic control. They may make use of ambient air and lighting, evaporative coolers, direct misting of animals for cooling, and other economies not normally seen in biomedical facilities.

Husbandry Procedures

In addition to the animal procedures required as a part of a particular study, there are a large number of normal agricultural practices that are incidental to the maintenance of the animals. A few of these common agricultural practices are subjects of controversy in their own right. The Ag Guide refers to these procedures as the "Special Category of Standard Agricultural Practices." Such practices, in addition to force molting, might include branding, dehorning, castration, tail-docking in swine, and beak-trimming in poultry. Key issues in evaluating the humaneness of these procedures would be the ages at which these procedures were performed, and whether anesthesia might be required for any these procedures.

Should the IACUC review and endorse the routine husbandry practices of the facility? Should the IACUC review the "Special Category of Standard Agricultural Procedures?" Or, should the IACUC review only the specific research proposal itself and defer to the animal care staff with respect to animal husbandry procedures? In the case of purely agricultural studies, and in the absence of any specific legislative mandate, the IACUC is not required to review such procedures. IACUCs may or may not review husbandry protocols, according to the charge given by the institutional official who appoints the IACUC.

The Ag Guide recommends that a committee, either the IACUC or a separately designated "Ag-IACUC," review the husbandry practices of the institution. In the absence of regulation, an IACUC would have tremendous latitude in evaluating such procedures. Review by an IACUC might help to ensure that procedures employed within the institution are consistent with the sentiments of a broad range of institutional scientists and staff.

MAKING THE SHOE FIT: WHICH STUDY GOES WHERE?

Although the published standards of agricultural research are often different from those shown in the NIH Guide, the IACUC has tremendous latitude and may use considerable "professional judgement" as it interprets the NIH Guide. For example, the NIH Guide recommends that horses housed in pens be allotted 144 sq ft. Let us suppose that an IACUC performing a semiannual inspection found a horse stall measuring only 11 ft by 12 ft (132 sq ft). If the IACUC found that the horse had adequate freedom of movement, that the conditions in the barn were otherwise conducive to the animal's well-being, and that the animal was allotted adequate exercise, it would be entirely compatible with the NIH Guide for the IACUC to exert its professional judgement and find that the housing was adequate.

USDA regulations, being regulations and minimum standards rather than guidelines, are much less likely to be flexible. Accordingly, the distinction between agricultural and biomedical studies will become even more important after the USDA standards for farm animals are written.

Consider the following hypothetical projects. How would your IACUC deal with these issues?

The Chicken and the Egg. Imagine a production facility of laying chickens. All the birds are in good health. The housing is of an agricultural type. The battery-type cages are fixed in place and a given chicken remains in the same cage during all its productive life. The floor is scraped clean every week, but the cages are only sanitized every several months between successive lots of birds. Imagine that half of these chickens are involved in an agricultural production study. The other half have been sensitized with an antigen and their eggs are being collected for antibody production. The latter chickens are owned by a biomedical researcher and the study is funded by the National Institutes of Health (NIH). All the chickens appear well, and one can only distinguish between the two groups of chickens by examining their cage cards. Can the IACUC allow the chickens in the NIH study to reside in the same barn with the chickens in the agricultural study? Is it rational for the IACUC to declare the sanitation program suitable for one group of chickens and unsuitable for another?

The Genetically Engineered Cow. Two dairy cattle, both the products of genetic engineering, live under agricultural conditions in adjacent outdoor paved pens. One has been genetically engineered to produce an enzyme in its milk that improves the quality of cheese. The other has been genetically engineered to produce a human clotting cofactor in its milk. The IACUC inspects the facility and finds the "biomedical" cow's pen is too small to satisfy the space recommendations of the NIH Guide. The "agricultural" cow may remain where it is. Must the "biomedical" cow be moved?

USDA Policy Memoranda

Although the USDA has not yet issued standards specific to the housing of farm animals, it has already made a number of policy determinations regarding the distinctions between agricultural and biomedical activities. In an August 28, 1990 policy memorandum to USDA personnel (USDA, 1990), a deputy administrator held that facilities keeping rabbits, goats, sheep, and other farm animals as blood producers were considered research facilities only when the animals produced antibodies. If the facility uses blood donor animals for blood products only, such as complement, serum, and agar plates, then it is considered a dealer (and therefore does not need an IACUC). If the blood collection is incidental to the slaughter of the animals, then the activity is agricultural and not regulated at all.

An April 23, 1992 USDA policy memorandum (USDA, 1992a) held that the use of farm animals for teaching purposes in veterinary schools is considered "biomedical" rather than "agricultural," and therefore a regulated activity. The implication of this ruling is that when veterinary students perform major operative procedures on university owned animals as a part of teaching exercises, the procedures are regulated. The procedures must be conducted in dedicated surgical facilities, and the IACUC must review protocols for these activities, inspect the facilities, and evaluate the program. Presumably the same consideration would apply to teaching animal science students. If animal science students were taught to perform laparotomies to collect embryos for embryo transplantation, the activity would be a teaching activity rather than an agricultural activity, and would therefore be regulated.

In a July 13, 1992 USDA policy memorandum (USDA, 1992b), USDA determined that if biologics were produced in farm animals for farm animals, the activity was agricultural and therefore not regulated. On the other hand, if the biologic was produced in farm animals for human beings or for nonfarm animals, then the activity was "biomedical" and the activity was regulated. In other words, if one horse produced tetanus antitoxin for use in horses, then agricultural standards would apply. On the other hand, if the horse in the next stall produced tetanus antitoxin for use in humans, then the activity would be "biomedical" and the activity would be regulated as biomedical research under the Animal Welfare Act.

THE RED RUBBER BALL

A newly appointed IACUC beginning a facility inspection with two or three different books of standards in their hands could easily feel a bit unnerved. All the more so since the standards for both biomedical and agricultural research are certain to change. Both the NIH Guide and the Ag Guide are in the early phases of revision, and the new USDA standards for farm animals will probably be drafted during the next year or two. However sincerely an institution attempts to follow all existing guidelines, compliance may prove to be a moving target.

IACUCs that find themselves responsible for both agricultural and biomedical studies will find opportunities as well as challenges. Members of such an IACUC will find themselves in conversation with agricultural and biomedical scientists at a time when both communities are engaged in introspection about animal care. The concept of animal well-being and its relationship to handling and to environmental enrichment has become not only a point of contention, but also a respected area of research. Our regulatory agencies and professional bodies need research that critically evaluates the animals' needs from the animals' perspective. Only such information will allow them to write coherent, unitary standards based on science rather than on anthropomorphism or tradition.

IACUCs should remain open-minded and should not hesitate to use the considerable professional judgement that the NIH Guide, the Ag Guide, and even the Animal Welfare Act regulations allow them. IACUCs that keep themselves informed about current issues in animal care will find that they can offer considerable assistance to the agricultural, biomedical, and regulatory communities during this period of change.

The appointment of an IACUC and creation of its charge is one of the most important administrative acts a Chief Executive Officer performs. Chief Executive Officers should appoint people they trust, people whose opinions they respect, people who believe in science, and people who represent a broad enough spectrum of the campus community to speak for the institution as a whole.

^*Since USDA has not yet published its standards for farm animals in Animal Welfare Act regulated research, comparisons with other standards are not possible. It is likely that USDA's standards will be similar to the Guide. In the conference report for the 1985 amendments to the Animal Welfare Act, Congress directed USDA to confer with other agencies in writing regulations. ^"... it is hoped that agencies continue an open communications to avoid conflicting regulations wherever possible or practical" (Congressional Record, 17 December 1985, Vol. 131, No. 175, Pt. II.)

REFERENCES

American Association for the Accreditation of Laboratory Animal Care (AAALAC). 1991. AAALAC Accreditation Program.

Consortium for Developing a Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching. 1988. Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching. (Available at a cost of $5.00 each from Association Headquarters, 309 West Clark Street, Champaign, IL 61820. Tel: 1-217-356-3182.)

National Research Council (NRC). 1985. Guide for the Care and Use of Laboratory Animals. A report of the Institute of Laboratory Animal Resources Committee on Care and Use of Laboratory Animals. Washington, D.C.: U.S. Department of Health and Human Services.

National Science Foundation (NSF). 1985. Policy on the Use of Animals in Research. Section 713 in National Science Foundation Grant Policy Manual.

North, M.O. 1984. Commercial Poultry Production Manual. Westport, Conn.: AVI Publishing Company.

U.S. Department of Agriculture (USDA). 1990. Policy Memorandum, Deputy Administrator Amoldi to REAC Personnel, August 28.

U.S. Department of Agriculture (USDA). 1992a. Policy Memorandum, Staff Veterinarian DePoyster to Sector Supervisors and Animal Care Specialists, April 23.

U.S. Department of Agriculture (USDA). 1992b. Policy Memorandum, Staff Veterinarian DePoyster to Animal Care Specialists, July 13.

U.S. Food and Drug Administration (FDA). 1992. Position Paper on Animal Use in Testing FDA-Regulated Products, October 7, 1992.

TABLE 1 Space requirements in the Guide and the Ag Guide

Species/Type	Body Size	Housing Type	*Guide*	*Ag Guide*
Dry Ewes	65-90 Kg	Dirt lot		2.32-3.72 m²
Dry Ewes	65-90 Kg	Paved lot		1.49 m²
Sheep	> 50 Kg	1-4 per pen	1.86 m²
Laying Hen	Leghorn-Type	Wire Cage		387 cm²
Chicken	> 3 Kg	Cage	285 cm²

FIGURE 1 Decision tree: options for the oversight of agricultural animals in research.