GUIDELINES FOR ALTERNATIVES SEARCHING

• The Concept of Alternatives
• Information Resources
• Alternative Terminology

The Concept of Alternatives

"Alternatives" in the context of animal research means more than just not using animals. It also means reducing, through a variety of methods, the amount of distress experienced by the animals. Animal welfare, regulatory, economic, safety, and scientific considerations have all contributed to a growing interest in the reduction of animal use in biomedical research in the last decade. Concern for laboratory animals is a fundamental principle of ethical animal research and the scientific community is sensitive to public concerns about animal welfare. Scientific advances have reduced the numbers of animals used and research in alternative methods continues. The use of laboratory animals, however, remains necessary except where valid, scientific alternatives are available. In vitro methods, such as tissue culture, and computer models, while helpful, are unlikely to satisfy all testing requirements. Where live animals are used, scientists are obligated to carefully consider methods to avoid or minimize pain and distress.

Federal regulations mandate specific requirements concerning alternatives to the use of live animals in research, testing, and teaching programs. The Animal Welfare Act requires that the principal investigator must consider alternatives to procedures that may cause more than momentary or slight pain or distress to animals. A written narrative description of the methods and sources used to determine that alternatives were not available must be included on the Animal Use Form. It is the responsibility of the Intstitutional Animal Care and Use Committee to review each Animal Use Form submission for compliance with this requirement. Michigan State University must submit a report each year to USDA which assures that each principal investigator has considered alternatives to painful procedures. Additionally, USDA requires that the University provide training and instruction to personnel using animals on alternatives to the use of live animals in research. PHS policy requires that the University give written assurance annually that instruction and training is available on research and testing methods that limit the use of animals or limit pain and distress.

Russell and Birch introduced the concept of alternatives in 1959 with the publication of Principles of Humane Experimental Technique. In it they defined the now widely recognized "3 R's":

• Replacement: Substitution of insentient material for animals or substitution of a lower species, which might be less sensitive to pain and distress, for a higher species.
• Reduction: Reduction in the number of animals used to obtain information of a certain amount and precision.
• Refinement: Decrease in the incidence or severity of pain and distress in those animals that are used.

Dr. David B. Morton, Department of Biomedical Science and Ethics, The Medical School, University of Birmingham, Birmingham, England, further expanded this concept to the Fifteen R's which may be used as a self assessment tool for all personnel utilizing animals:

• Reduce the number used.
• Refine end points and procedures.
• Replace with in vitro, ex vitro methods when possible.
• Respect all animals regardless of species.
• Recognize any adverse effects.
• Relieve pain with analgesics, distress with anxiolytics.
• Refuse to carry out some procedures if concerned.
• Reconsider protocol if unsure.
• Read about the science and the ethical issues.
• Reflect on the work you have carried out.
• Reason out why you are doing the research.
• Record all your observations carefully.
• Reward rather than cause harm and for happiness.
• Reappraise techniques for efficacy.
• Resolve to learn new techniques.

The consideration of alternatives does not preclude the use of animals, but rather requires that their use be carefully conceived and planned so that discomfort and distress are eliminated or avoided wherever possible. Information resources should be consulted to determine if alternatives are available.

When designing research or teaching protocols the following are some of the questions that should be considered:

• Do the potential results of the project justify its likely effects on the animals?
• Can procedures be modified to prevent or minimize pain and distress?
• What signs might indicate pain or distress in the study species?
• Can analgesics, anesthetics, tranquilizers, or sedatives be used?
• How will the animals be monitored during and following stressful procedures such as surgery, anesthesia, or administration of hazardous agents?
• Can a less sensitive species be used?
• Does the model reliably and accurately reproduce the process or characteristic being studied?
• Is the model readily available to other researchers?
• Is the model well characterized in the literature?
• Have in vitro and other alternative methods been considered?
• Has an appropriate statistical design been applied to determine appropriate number of animals to use?

One of the most effective methods to minimize animal pain and distress is to train the people who handle them. Training to develop technical skills can often be accomplished on inanimate models designed for this purpose. Where live animals are used for training they may be anesthetized to prevent pain while allowing trainees hands-on experience to gain technical proficiency. Well trained personnel, with well developed technical skills, greatly reduce animal stress. When procedures are conducted with expertise, animal numbers may be reduced by avoidance of error or injury. Replacement, reduction, and refinement are all achieved through an effective training program. University Laboratory Animal Resources offers training on request in a wide variety of clinical techniques.

Information Resources

It is the responsibility of Michigan State University to provide training and guidance that includes information on the following:

• The concept, availability, and use of research or testing methods which limit the use of animals or minimize animal distress.
• Utilization of services (e.g., National Agricultural Library, National Library of Medicine) available to provide the following information:
  • appropriate methods of animal care and use;
  • alternatives to the use of live animals in research;
  • unintended and unnecessary duplication of research involving animals;
  • the intent and requirements of the Animal Welfare Act.

The 1985 amendment to the Animal Welfare Act authorized the establishment of an information service at the National Agricultural Library (NAL) to assist scientists in compliance with specific requirements of the Act. The National Agricultural Library, in cooperation with the National Library of Medicine, provides information pertinent to employee training:

• which could prevent unintended duplication of animal experimentation;
• on improved methods of animal experimentation, including methods which could reduce or replace animal use and minimize pain and distress to animals, such as anesthetic and analgesic procedures.

This information service, established at NAL in 1986, was designated the Animal Welfare Information Center (AWIC).

Sample Narrative for the Literature Section of the Animal Use Form

The USDA believes that database searches remain the most effective and efficient method for demonstrating compliance with the requirement to consider alternatives to painful/distressful procedures.

When a database search is the primary means of meeting this requirement, the narrative about the search must include the following:

• The names of the databases used (there must be a minimum of two searched)
• The date on which the search was performed
• What years were covered by each search
• The keywords or search strategy used for each database

An example narrative would be: Agricola (1970-2002) was searched on July 1, 2002 for alternatives for using dogs for training of emergency procedures such as intubation. The keywords used were: (dogs or dog or canine or canidae or canis) and (intubation or cardiopulmonary resuscitation) and (alternative to animal testing or reduce or refine or replace or computer simulation or virtual reality or cadaver or model). MEDLINE (1990-2002) was searched on July 1, 2002 using the keywords: (dog or canine or canis or canidae or dogs) and (intubation or cardiopulmonary resuscitation) and (alternatives to animal testing or reduce or refine or replace or cadaver or virtual reality or model or computer simulation).

For a list of possible terms for alternatives to animal testing, please see http://www.lib.msu.edu/behm/ular. If you need help developing a computer search, call: Leslie M. Behm, M.S.L.S., MPH, Librarian, Main Reference, (517/432-6123, ext 164), email: behm@msu.edu

Alternative Terminology

Terms for searching for animal testing alternatives. Any method that can be considered to reduce, replace, or refine research utilizing animals. Also an in-depth discussion of the appropriateness of an animal model for a particular disease can be important when considering alternatives. Such methods and technologies may include:

The terms alternatives to animal testing, reduction, refinement, and replacement are the minimum that need to be used. The research will determine which other terms to use such as: Computer simulation, Computer aided instruction, mannequins, and virtual reality/surgery for training and education. For research involving animals and looking at physiologic responses, terms such as tissue culture, organ culture, and in-vitro might be used.

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