ILAR Journal Online, Volume 32(4) 1990: Issues for Institutional Animal Care and Use Committees (IACUCs)

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ILAR Journal V32(4) 1990
Issues for Institutional Animal Care and Use Committees (IACUCs)

Review Standards for Animal Research: A Closer Look
Rebecca Dresser, J.D.

Rebecca Dresser, J.D., is an associate professor in the School of Law, Case Western Reserve University, Cleveland, Ohio.

INTRODUCTION

In the past 4 years, institutional animal care and use committees have become a familiar part of the contemporary research landscape. Although some committees existed before that time, their institutional presence and influence on animal experimentation increased dramatically in late 1985, when the U.S. Public Health Service (PHS) issued its revised Policy on Humane Care and Use of Laboratory Animals. The policy requires research institutions seeking PHS support to establish committees that include veterinarian, nonscientist, and community members. It assigns to these committees the responsibility to review scientific proposals for vertebrate animal use.

The PHS policy also incorporates certain standards governing laboratory animal use, as shown in Table 1 (PHS, 1986). The policy gives committees the duty to ensure that animal use proposals are consistent with these principles. The principles themselves are quite general, and many are open to varied interpretation.

Their role in applying the broad federal standards puts committees in the ethical and political spotlight. Our society is in the midst of a fierce debate over the morality of animal use in a wide range of settings. Animal use in science has become one focal point of the debate, and the loudest voices often come from the absolutists: on one side, those endorsing complete scientific freedom from external constraints on research; on the other side, those advocating complete equality of treatment for human and nonhuman research subjects. According to these groups, institutional committees are bound either to impede unnecessarily the conduct of important research or rubber stamp whatever animal use investigators propose.

In sum, institutional committees face the formidable task of forging and implementing a defensible middle position. It is the committees that must determine when a specific proposal involves "unnecessary" pain or distress or is insufficiently "relevant" to important health or other objectives. How are they coping with the challenge?

To investigate this question, in 1987-1988, I conducted a study of the committee review process. For the study, committees reviewed four hypothetical protocols and submitted their institutions' protocol review form for analysis. The study has been reported in an article in the Journal of the American Veterinary Association (Dresser, 1989). The article summarizes the committees' responses to the hypothetical protocols and the subject matter covered by their review forms. Because a more detailed description of the committees' comments and protocol review forms may be of interest to committees and others concerned with ethical standards for laboratory animal use, an expanded report of the committees' responses and the content of their review forms is presented below. This article is intended to supplement, not duplicate, the earlier report. Interested readers should refer to the earlier report to obtain a complete picture of the study, as well as my conclusions.

HYPOTHETICAL PROTOCOLS

Tables 2 through 5 present the full range of committee comments on the four hypothetical protocols. Protocol 1 involved hybridoma production in mice. Protocol 2 involved the induction of gastric ulcers in rats by two methods: (1) intragastric injections of HCI by oral gavage and (2) immobilization in small wire-mesh cages for 6 hours. In Protocol 3, cats would be used in a neuronal learning study that included surgery and subsequent use of a neuromuscular blocking agent for neuronal cell testing. In Protocol 4, squirrel monkeys would be kept in primate chairs for up to 10 weeks, deprived of water for 23.5 hours daily, and subjected to blood sampling to study the relationship of glucocorticoids and emotional arousal.

A review of the tables reveals several noteworthy findings. The majority of committee comments were addressed to refinement of animal methods, which Russell and Butch (1959) define as "any decrease in the incidence or severity of inhumane procedures applied to . . . animals." Committees devoted less attention to replacement (the "substitution for conscious living animals of insentient material") and reduction ("reduction in the numbers of animals used to obtain information of given amount and precision"). Yet replacement and reduction clearly were considered relevant by many committees, as is evident from the information presented in the tables. Requests to furnish additional justification for the investigator's choice of animal method and proposed number of animals are not uncommon. Committees sometimes asked whether nonanimal methods could be substituted for the proposed animal use, and it is striking that five committees asked why the data sought in Protocol 4 could not be obtained through ethically acceptable research on humans.

Committees were most active in the refinement area, however. A number of their questions and comments are of interest. Complete Freund's adjuvant, orbital bleeding, and ascites production were matters of concern for many committees (Table 2). Indeed, a few went so far as to say that they would never approve footpad injections of complete Freund's adjuvant, death as an end point in ascites fluid production, or ascites tumor burdens greater than 10 percent of an animal's body weight. Cervical dislocation also attracted some committee's attention, and six committees wanted animals sedated or anesthetized prior to the procedure, if possible.

Responses to the ulcerogenesis protocol (Table 3) illustrate how committees are coping with the situation in which some pain or distress must be imposed on animals to produce the desired scientific objective. Here the obvious committee goal was to reduce pain and distress to the minimum necessary. There were also many questions pertaining to the necessity for the proposal procedures over other potentially more humane procedures. Table 3 shows that ether use provoked concern about potential harm to both humans and animals.

Table 4 illustrates that committees paid close attention to surgery and postsurgical care. Not surprisingly, they also focused their attention on the proposed use of a paralytic agent on conscious animals. Again, the major committee goal was to ensure that pain and distress were kept to a minimum. Five committees asserted that the procedure would have to be altered if it would cause pain and distress to animals. Five committees were also concerned enough to want to see the testing facility or to have the veterinary staff present during the testing process.

Surgery and postsurgical care were also the subjects of committee inquiry in the squirrel monkey protocol (Table 5). Committees were unquestionably disturbed by the proposal to restrain monkeys in primate chairs for such a lengthy period, and over one-third of them said they would disapprove the procedure. The proposed water deprivation was also of concern; again, some committees reported that they would not permit it as proposed.

The tables also show that committees are inevitably confronting the issue of scientific merit. Committees often wanted greater assurance that the protocols would produce valid data, particularly when investigators proposed procedures of "high ethical cost" (Orlans, 1987). They also wanted evidence that the research team was sufficiently trained and experienced to perform the procedures properly, so that the resultant data would be scientifically acceptable and the animals would not be wasted. It is interesting that two committees recommended the use of purpose-bred over random-source cats in Protocol 3, presumably because the former would be more likely to provide valid data.

Committees also raised some questions about merit in a broader sense. They often wanted to know more about how a proposed protocol would benefit society. Sometimes they raised questions about unnecessary duplication as well. Their questions on scientific and social merit reflected the committees' efforts to apply the federal principle holding that animal use proposals should be "designed and performed with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society" (see Table 1).

PROTOCOL REVIEW FORMS

A committee protocol review form supplies the framework for communication with the investigator. Forms usually determine the degree of relevance and precision with which an investigator initially responds to the protocol review requirement. Although committees can obtain additional information and clarification by contacting an investigator, committee efficiency can suffer if lengthy contact is routinely required (Dresser, 1987).

The analysis presented in Table 6 evidences a range of specificity in the protocol review forms. Committee forms were designed to obtain a variety of information. Most common were specific inquiries on the rationale for choosing an animal method and the particular number of animals, how they would be used, measures to minimize pain and distress, the justification for omitting such measures, surgical procedures, and euthanasia methods. Committees sought detailed information in a number of areas. Of particular interest are the forms requesting investigators to estimate or categorize the severity of pain, distress, or discomfort animals would experience. In addition, a review of the procedures specifically addressed in several of the forms furnishes insight into the relatively common types of animal use that raise particular ethical concerns for committees. Finally, Table 6 shows that eight committee forms were designed to ensure that investigators' proposals would be comprehensible to nonscientist committee members, and five offered guidance to investigators on how to justify their proposed animal method and number and species of animals.

CONCLUSION

The data in Tables 2 through 6 provide a glimpse of how one group of committees is fulfilling its assigned role. Although there was some variation among the particular approaches to the area, committees uniformly sought to minimize pain and distress to laboratory animals. They frequently questioned the need for a proposed method entailing harm to animals and often offered less harmful alternative methods. Many also grappled with the complex and difficult problems of assessing a proposal's merit, but committees appeared less confident and certain about this dimension of their responsibilities. At minimum, however, requiring investigators to prepare statements on the importance of and need for their proposed projects should have a "consciousness-raising" effect on investigators, encouraging them to consider these matters as they plan their future work.

It is my hope that others will continue and refine my effort to discover how institutional animal care and use committees are interpreting the broad federal principles. The information generated from such studies may furnish committees with potentially helpful ideas for their own work. Moreover, as committees become more accustomed to the review process, new approaches will undoubtedly emerge. Studying this process over time is one way to measure the ongoing development of ethical standards for animal research.

REFERENCES

Dresser, R. 1987. Refining the ACUC process (newsletter). Scientists Center for Animal Welfare. 9(2):3-5.

Dresser, R. 1989. Developing standards in animal research review. J. Am. Vet. Med. Assoc. 194:1184-1191.

Orlans, B. 1987. Research protocol review for animal welfare. Invest. Radiol. 22:253-258.

PHS (Public Health Service). 1986. Public Health Service Policy on Humane Care and Use of Laboratory Animals. Washington, D.C.: U.S. Department of Health and Human Services. 28 pp. Available from: Office for Protection from Research Risks, Building 31, Room 4B09, NIH, Bethesda, MD 20892.

Russell, W. M. S., and R. L. Burch. 1959. P. 64 in The Principles of Humane Experimental Technique. London: Methuen.

TABLE 1 Selected Federal Principles

PHS Policy on Humane Care and Use of Laboratory Animals

Procedures with animals will avoid or minimize discomfort, distress, and pain to the animals, consistent with sound research design.
Procedures that may cause more than momentary or slight pain or distress to the animals will be performed with appropriate sedation, analgesia, or anesthesia, unless the procedure is justified for scientific reasons in writing by the investigator.
Animals that would otherwise experience severe or chronic pain or distress that cannot be relieved will be painlessly sacrificed at the end of the procedure or, if appropriate, during the procedure.
Personnel conducting procedures on the species being maintained or studied will be appropriately qualified and trained in those procedures.
Methods of euthanasia used will be consistent with the recommendations of the American Veterinary Medical Association (AVMA) Panel on Euthanasia, unless a deviation is justified for scientific reasons in writing by the investigator.

U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training

Procedures involving animals should be designed and performed with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society.
The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid results. Methods such as mathematical models, computer simulation, and in vitro biological systems should be considered.
Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals.

TABLE 2 Responses to Mouse Protocol (Hybridoma Production) (n = 32)

Number of Committees Commenting	Comments
Methods
14	Further correlate methods with scientific goals
7	Further justify rejection of nonanimal alternative
19	Further justify number of animals
Freund's Adjuvant
14	Justify use of complete Freund's versus alternatives
3	Committee recommends specific alternatives to complete Freund's
1	Reduce amount injected of complete Freund's
2	Committee would disapprove use of complete Freund's
22	Justify use of footpad injection site
2	Anesthetize if injecting complete Freund's into footpad or justify why not
6	Committee would disapprove footpad injections of complete Freund's
6	Describe site and frequency of incomplete Freund's injections
Orbital Bleeding
3	Justify need for orbital bleeding
22	Anesthetize or sedate mice during bleeding or justify why not
1	Limit number of times mouse is bled
1	Use alternate eyes
2	Ensure that person performing technique is adequately trained
Ascites Production
15	Further describe monitoring plan for ascites-producing mice
7	Establish criteria for tapping fluid based on animal's appearance
3	Tap fluid more often than once a week
9	Limit number of times fluid taken from one animal (two or three times) or justify why not
4	Reduce amount of Pristane oil injected
2	Specify size of needle used to tap fluid
4	Anesthetize animals during fluid collection
2	Reduce amount of fluid removed from animals
20	Establish criteria for early euthanasia based on behavior, appearance, tumor burden
8	Justify need for lethal end point or tumor burden greater than 10% body weight
3	Committee would disapprove lethal end point or tumor burden greater than 10% body weight
Cervical Dislocation
6	Sedate or anesthetize animals before cervical dislocation or justify why not
4	Ensure that person performing technique is adequately trained
Other
12	Further describe investigator and technician training and experience
2	Arrange for technician training
2	Arrange for veterinary consultation

TABLE 3 Responses to Rat Protocol (Ulcerogenesis) (n = 32)

Number of Committees Commenting	Comments
Methods
15	Further explain study's potential benefits
7	Further address scientific merit issues
1	Independent scientific merit review needed
3	Explain why study could not be performed using in vitro techniques
4	Justify need for both animal models, instead of just one
11	Explain how rats with ulcers will be used
4	Explain how ulcers will be assessed
17	Further justify number of animals
3	Further justify animal species
HCl Model
19	Further justify HCl model (vs. alternatives)
4	Provide additional information on reliability of HCIl model for ulcer production
20	Anesthetize rats when HCI is administered or justify why not
5	Describe amount of HCl administered
1	Reduce or justify strength of HCl
14	Further describe assessment and relief of possible pain and distress from HCl administration
5	Further explain when death occurs and justify need for different lengths of survival
Restraint Model
19	Further justify restraint model (vs. alternatives)
7	Further explain scientific basis of restraint model
6	Further describe restraint system and environmental conditions
4	Explain why shorter restraint period would be scientifically unacceptable
2	Explain why more comfortable restraint would be scientifically unacceptable
1	Consider anesthetizing animals during restraint
5	Justify why restrained animals must be fasted prior to restraint
3	Justify why restrained animals have no access to food and water
7	Describe assessment and relief of pain and distress during restraint
5	Arrange for veterinary staff and committee members to view and approve restraint
Ether
17	Committee would disapprove protocol or recommend alternative to ether use because of hazard to personnel
6	Explain how ether will be safely administered
3	Committee critical of ether use because of negative effects on animals
2	Prevent direct contact between ether and animals
Other
8	Further describe investigator and technician training and experience

TABLE 4 Responses to Cat Protocol (Surgery and Neuronal Recording) (n = 32)

Number of Committees Commenting	Comments
Methods
8	Further explain study's potential benefits
14	Further address scientific merit issues
4	Independent scientific merit review needed
2	Explain why study will not unnecessarily duplicate existing research
11	Further justify number of animals
9	Further justify species
2	Committee recommends use of purpose-bred animals
Surgery
27	Further describe surgery and postsurgical care
8	Modify anesthetic dose and route of administration
12	Change anesthetic agent
4	Explain need for burr hole
3	Lengthen postsurgical recovery time before testing
Testing
11	Further describe testing procedure
21	Further justify use of paralytic agent on conscious animal
9	Justify why animals cannot be sedated or anesthetized during testing
5	Committee would require testing procedure to be modified if it would cause pain and distress to animals
14	Further describe monitoring for pain and distress during testing
4	Further describe relief of pain and distress during testing
5	Explain how harm from stereotaxoc apparatus will be avoided
4	Modify doese of paralytic agent
2	Modify route of administration of paralytic agent
2	Change paralytic agent
1	Provide eye care during testing
1	Explain why testing cannot be performed in conjunction with surgery
5	Consider alternatives allowing recording of neuronal responses for freely moving conscious animals
2	Arrange for committee members to inspect testing facility
3	Arrange for veterinary staff to assist with project
Other
11	Further describe investigator and technican training and experience
1	Arrange for technician training

TABLE 5 Responses to Monkey Protocol (Arousal and Blood Sampling) (n = 31)

Number of Committes Commenting	Comments
Method
7	Further explain study's potential benefits
14	Further address scientific merit issues
9	Independent scientific merit review needed
4	Explain why study will not unnecessarily duplicate existing research
2	Discuss availability of nonanimal alternatives
5	Further justify number of animals
12	Further justify need to use primates
2	Further justify need to use squirrel monkeys (vs. rhesus)
5	Justify why data cannot be obtained humans
Surgery
5	Further describe surgery pain
20	Further describe postsurgical and catheter care
4	Further describe catheter
13	Modify anesthetic regimen
Physical Restraint
20	Further justify prolong chairing (vs. alternatives)
11	Committee would disapprove 10 weeks of continuous chairing
15	Further describe "special care" to avoid health problems from restraint
1	Precondition animals to chairs using positive reinforcement
1	Remove animals weekly for veterinary examinations
1	Arrange for veterinary staff to assist in animal monitoring and care
2	Provide exercise periods during chairing
6	Describe plan for monitoring and addressing possible behavioral impairment during chairing
2	Describe behavioral enrichment provided during chairing
Arousal Testing
9	Justify need for water deprivation
7	Committee would disapprove water deprivation
13	Document that water deprivation is safe and describe monitoring plan to ensure against dehydration
7	Further explain how nutritional needs are satisfied during water deprivation
17	Further describe amount and frequency of blood removed and its replacement
4	Explain how monkeys are trained to press buttons
1	Justify duratinon of tone
1	Describe loudness of tone
Other
9	Further describe investigator and technician training and experience
1	Conduct pilot study to assess possible complications
6	Arrange for veterinary staff assistance
7	Further describe plan for animals upon study's completion
1	Committee concerned about study's public relations implications

TABLE 6 Analysis of Protocol Review Forms (n = 24)

Number of Committees Commenting	Comments
Provide rationale for
19	Animal use (including rejection of nonanimal alternatives)
20	Number of animals
16	Species
5	Guideance provided on acceptable evidence (e.g., statistical data, literature references
Provide description of
14	Study's purpose
9	Study's potential value to society
21	How animals are to be used (4 commented that a time frame/flow chart should be included)
12	Research staff qualifications
9	Anticipated pain, discomfort, distress, or injury to animals
18	Analgesics, anesthetics, tranquilizers, other measures to minimize animal harm
6	Criteria for early euthanasia
14	Estimate or categorize severity of harm to animals (9 commented that examples of procedures deemed to involve significant harm should be provided)
18	Provide justification for omission of analgesics, anesthetics, tranquilizers, or early euthanasia to minimize harm
9	Provide assurance that harm will be limited to what is scientifically necessary
8	Respond in terms comprehensible to nonscientists
Separate review required for scientific merit
3	All proposals
1	Internally funded proposals
Specific qustions on
17	Nonsurvival surgery
19	Survival surgery
16	Postsurgical care
13	Multiple survival surgery
4	Muscle paralytics
6	Food restriction
5	Water restriction
5	Behavioral conditioning/noxious stimuli exposure
7	Environmental stress
18	Physical restraint of conscious animals (other than normal caging, handling)
8	Body fluid/tissue collection
5	Adjuvant administration
5	Substance administration
9	Tumor/pharmacologic/toxicologic studies (effect on animals)
5	Radiation studies (effect on animals)
5	Induced disease
3	Trauma/other physiologic impairment
21	Euthanasia