Safety and Efficacy Testing of Hormones and Related Products

The Report and Recommendations of ECVAM Workshop 91,2

Reprinted with minor amendments from ATLA 23, 699-712.

Appendix A

Guidelines for the Humane Treatment and Care of Animals Used in the Quality Control of Hormones and Other Biological Products

Although the number of research activities concerned with the replacement of tests which involve the use of animals is increasing, it is believed that we cannot do without animal tests in the near future, particularly for quality control purposes.

National and international laws exist for the protection of laboratory animals. Within Europe, two important requirements are the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (1) and Directive 86/609/EEC (2). In these regulations, laboratory animals are afforded protection as living, sentient beings to which we have a moral obligation.

Article 23 of Directive 86/609/EEC states that ".. the Commission and Member States should encourage research into the development and validation of alternative techniques which could provide the same level of information as that obtained in experiments using animals but which involve fewer animals or which entail less painful procedures and shall take such other steps as they consider appropriate to encourage research in this field" (2).

General Recommendations

The following recommendations are based, in part, on those given by Corvino et al (3), Howard-Jones (4), and Acred et al (5).

  1. Whenever possible, validated procedures which do not use animals at all should be employed (2, Article 7).
  2. It is a legal and ethical obligation for all those involved in the quality control of hormones and related products to have a humane regard for their animal subjects, to prevent as far as possible pain and distress, and to be constantly aware of the possibilities of achieving the same result without resort to living animals (2, Articles 5, 7, and 23).
  3. An expert in laboratory animal science/medicine (veterinarian) should be responsible for animal health care. Animal caretakers and animal technicians should have proper schooling and additional training in animal models used for the quality control of hormones and related products. They should be familiar with common clinical signs, as well as with signs of pain, suffering, and distress (2, Articles 14 and 19).
  4. It is the responsibility of the management to ensure that employees involved in conducting procedures using animals have appropriate qualifications and/or experience (2, Articles 7, 16, and 19)
  5. Only clinically healthy animals should be used (5). Animals being used in an ongoing experiment should be observed daily for their general health and for signs of pain, suffering and/or distress. If there is an increased risk of adverse effects or disease, animals should be observed at least twice a day (2, Article 5).
  6. Animals should be properly housed under species-species conditions. Steps should be taken to improve housing conditions by environmental enrichment appropriate to the species. In particular, animal cages should be of adequate size, and appropriate bedding (sawdust or tissues) must be used. However, housing conditions should not interfere with the observations to be made during the experimental procedure (2, Articles 5 and 19).
  7. Animals should be adequately supplied with food and water. This must be readily accessible to animals suffering from the experimental procedures, for example, moistened bread could be supplied (2, Articles 5 and 19).

Experimental Design

  1. In order to ensure consistency in testing and to avoid unnecessary duplication, procedures using laboratory animals should be performed according to Standard Operating Procedures and nationally implemented laws (2, Articles 7, 19, and 22).
  2. The minimum number of animals per group and the minimum number of dose levels should be employed, in line with the level of confidence required. Information on minimising the number of animals may be obtained by retrospective analysis of data and/or by statistical analysis (2, Articles 7, 19, and 22).

    Critical events and adequate measures for reducing theassociated pain and suffering of the animals should beidentified. Clinical symptoms of experimentally induceddiseases should be recognised early and whenever possible,measures to reduce suffering should be taken without affectingthe experimental design (2, Article 8).

  3. Whenever possible, lethality as an endpoint should be replaced with other parameters which do not involve death or severe clinical signs (2, Article 8).
  4. Humane endpoints should be kept under constant review and refined in the light of experience.
  5. Bulk production, and the production of monoclonal antibodies for therapeutic and diagnostic purposes, by the mouse ascites technique should not be permissible. The use of in vitro methods for small-scale production of monoclonal antibodies should also be encouraged.

References

  1. Anon. (1986). European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, 51 pp. Strasbourg: Council of Europe.
  2. Anon. (1986). Council Directive 86/609/EEC of 24 November 1996 on the approximation of laws, regulations, and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes. Official Journal of the European Communities L358: 1-29.
  3. Covino, B.G., Dubner, R., Gybels, J., Kosterlitz, H.W., Liebeskind, J.C., Sternbach, R.A., Vyklicky, L., Yamamura, H. & Zimmermann, M. (1980). Ethical standards for investigations of experimental pain in animals. Pain 9: 141-143.
  4. Howard-Jones, N.A. (1985). A CIOMS ethical code for animal experimentation. WHO Chronicle 39, 51-56.
  5. Acred, P., Hennessey, T.D., MacArthur-Clark, J.A., Merrikin, D.J., Ryan, D.M., Smulders, H.C., Troke, P.F., Wilson, R.G. & Straughan, D.W. (1994). Guidelines for the welfare of animals in rodent protection tests. A report from the Rodent Protection Test Working Party. Laboratory Animals 28: 13-18.

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