ATLA 27.S1, November 1999

//ATLA 27.S1, November 1999

Does the Use of Transgenic Animals Raise Particular Welfare and Ethical Concerns?

Michael Balls

There is a commonly held view that the protection of transgenic animals does not raise specific concerns and is adequately covered by existing controls on laboratory animal production and use, and that the transfer of genes among species, which is said to be a naturally occurring event in any case, does not involve any particular moral dilemmas. I do not share that opinion, nor did the authors of the ECVAM workshop report on The Use of Transgenic Animals in the European Union,1 which contained 39 conclusions and 14 recommendations, and is reproduced in full in this special issue of ATLA.
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The Use of Transgenic Animals in the European Union

T. Ben Mepham, Robert D. Combes, Michael Balls, Ottavia Barbieri, Harry J. Blokhuis, Patrizia Costa, Robert E. Crilly, Tjard de Cock Buning, Véronique C. Delpire, Michael J. O’Hare, Louis-Marie Houdebine, Coen F. van Kreijl, Miriam van der Meer, Christoph A. Reinhardt, Eckhard Wolf and Anne-Marie van Zeller

This is the report of the twenty-eighth of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). ECVAM’s main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine or replace the use of laboratory animals.
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Do Canadian Council on Animal Care Guidelines meet ECVAM Recommendations on Transgenic Animals?

Gilly Griffin and Clément Gauthier

The European Centre for the Validation of Alternative Methods (ECVAM) workshop report 28, on The Use of Transgenic Animals in the European Union (1), raises issues which need to be addressed in every country in which transgenic animals are used. While the systems of oversight of these animals vary among countries, since research and development crosses international boundaries, there must be recognition of the special considerations which need to be given to the creation and use of transgenic animals.
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Transgenic Models for Prion Disease: Have They Outlived Their Useful Purpose?

Elizabeth S. Jenkins and Robert D. Combes

Prions are a recently identified class of proteinaceous pathological agents. Prion diseases are fatal neurological disorders, the importance of which is exemplified by the recent emergence of a novel variant of Creutzfeldt-Jacob disease (CJD) in humans. During pathogenesis, prion proteins undergo a conformational change, which converts the normal isoform to a pathogenic isoform. Several approaches are available for studying prion disease. The predominant approach has involved in vivo studies, especially involving transgenic mice. In vitro alternatives available for studying prion disease include a cell-free conversion assay, cell culture systems, and an immunoassay for the pathogenic form of the prion protein. Prion-like proteins have been identified in yeast, and therefore this constitutes another non-animal approach. Four main areas of prion research are discussed in this paper, to illustrate the potential applications and limitations of the in vivo and alternative systems. From this study, we conclude that, while current in vitro approaches can be used initially, in vivo studies are still needed to confirm data obtained in vitro. Priority should be given to the non-animal alternatives, as well as to developing new methods, and these should be given primary consideration at the outset of a project.
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Transgenic Mouse Bioassays for Carcinogenicity Testing: A Step in the Right Direction?

Anne-Marie van Zeller and Robert D. Combes

The relevance of the rodent bioassay for assessing human risk to carcinogens has long been questioned. This has prompted several regulatory authorities and the International Conference on Harmonisation (ICH) to discuss the need for studies in two rodent species. Currently, six alternative tests are being evaluated in an interlaboratory collaborative study being organised by the International Life Sciences Institute (ILSI). These tests include four transgenic carcinogenicity assays in mice (the c-Ha-ras, Tg.AC, p53+/– and XPA systems). These assays are discussed in this review, and it is concluded that, to date, the data suggest that none of these assays is appropriate for inclusion in a carcinogenicity testing strategy. It is suggested that more emphasis should be placed on developing replacement alternative assays which are capable of identifying and characterising carcinogens of human relevance, rather than focusing on tests which are likely to merely duplicate the results of the rodent chronic bioassay. In this respect, the outcome of studies using the Syrian Hamster Embryo cell transformation assay, also being evaluated as part of the ILSI programme, will be of great interest. Ultimately, it is expected that cell transformation systems based on human cells will provide useful data for predicting human hazard from carcinogen exposures, and efforts to develop such systems should be encouraged.
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Bioethical Issues in the Generation and Use of Transgenic Farm Animals

T. Ben Mepham and Robert E. Crilly

The use of transgenic farm animals presents many challenges to the bioethicist, not least how to analyse the ethical issues within a framework that does not implicitly assume adherence to a normative ethical theory. One possible solution is to use a series of prima-facie principles applied to the interest groups affected by transgenesis. One such scheme is based on the four prima-facie principles of respect for non-maleficence, beneficence, autonomy and justice. This paper illustrates these with respect to transgenic farm animals. The aim of this is a systematic analysis, which includes positive and negative aspects, and which can therefore serve as a starting point for debate in which a range of views exist. One possible interpretation of this analysis is based on Three Rs concept. The use of transgenic farm animals appears to contradict this concept, because, although there is the potential for a reduction in animal numbers, at present, transgenesis is a rapidly expanding field, reversing the recent modest reductions in other areas of laboratory animal use. Moreover, transgenesis permits novel uses of farm animals, such as the production of proteins for human medicine where they were previously obtained from human blood (the opposite of replacement). The technique of transgenesis also misses the point as far as refinement is concerned, by refining the animal to suit the production or experimental protocol, instead of vice versa.
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Welfare Assessment of Transgenic Animals: Behavioural Responses and Morphological Development of Newborn Mice

Miriam van der Meer, Patrizia Costa, Vera Baumans, Berend Olivier and Bert van Zutphen

Four groups of mice of the same inbred strain, but with different transgenic backgrounds (no treatment; integration of a functional corticotrophin-releasing factor [CRF] gene construct; integration of a non-functional CRF gene construct; transgenic technique without integration of a DNA construct) were compared, in order to identify and quantify indicators of discomfort in transgenic animals. This approach enables us to differentiate between the effects of the technique of transgenesis and the effects caused by the expression of the transgene. This paper emphasises the search for differences in the early post-natal development of the animals. To this end, newborn mice have been subjected to various behavioural tests; moreover, their growth and morphological characteristics were measured from birth up to the age of 3 weeks.
The results indicate that the presence of the microinjected DNA-construct influences the survival rate during the first 2–3 days after birth. The average loss of pups was about 10%, in contrast to the groups without the DNA construct, in which none of the pups died. The increase in the relative body weight of pups with a functional CRF construct was significantly lower than in the other groups, but only during the first 11 days. No significant differences in morphological characteristics or behavioural development were observed between the four groups. This approach was found to be adequate for detecting a broad variety of behavioural and morphological characteristics. Before general conclusions about the extent to which the technique of transgenesis affects animal welfare can be drawn, more transgenic lines should be studied in this way.
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A Proposal for a New Ethical Scheme Addressing the Use of Laboratory Animals for Biomedical Purposes

Véronique C. Delpire, T. Ben Mepham and Michael Balls

Current European Union legislation relating to the use of laboratory animals, such as Directive 86/609/EEC, was implemented before the full implications of transgenesis were recognised. An analysis of selected existing cost-benefit guidelines has shown that they do not provide for an adequate evaluation of the use of transgenic animals. In this paper, a proposal is made for a new ethical scheme, comprising a specific cluster of questions dealing with transgenic animals and the wider implications of their use. It is suggested that this scheme could be used at the European level in reviewing project proposals involving animal experimentation.
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