Journal of the Royal Society ofMedicine Volume 71 September 1978

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Symposium: Tests in laboratory animals are they valid for man?' Selection of animals suitable for biomedical investigations C R Coid PhD MRCVS Clinical Research Centre, Harrow, Middlesex HAl 3UJ

When considering the validity of animal tests for man and the selection of animals for such studies, two factors which apply to animal investigations in general should be taken into account. The quality of animals used for biomedical purposes is probably the most important single factor in any study. Also of some significance are the costs associated with the purchase and maintenance of these animals. No investigator denies that, for humanitarian reasons, it is most desirable, if not essential, for animals to be in good health and free from diseases likely to cause pain and suffering. Furthermore, scientists can do without the frustrations and additional costs, arising from the use of animals infected with pathogens or harbouring microorganisms which, though not considered serious in normal animals, may interfere with experiments. However, over the last thirty years or so there has been a marked improvement in the quality and availability of many species, particularly the smaller laboratory rodents. Such changes for the better have come about principally because scientists and their employing organizations have recognized that, apart from any humanitarian considerations, there are significant cost-benefit advantages which accrue from using good quality laboratory animals. Regrettably, however, there are still serious health problems associated with some species. It is now well-known, for example, that wild-caught monkeys, currently used for many purposes, carry infectious agents such as Herpesvirus simiae, rabies virus and enteric pathogens capable of infecting man as well as animals. In addition, other species obtained from inappropriate sources may also carry undesirable microorganisms. Costs must also be of concern to all workers, irrespective of the nature of their investigations. Not infrequently the choice of species is influenced considerably by the initial purchase price of animals and the kind of facilities required for their proper care and maintenance. For example, in veterinary investigations the ideal may be to use large animals such as cattle; but the initial costs and expensive overheads associated with their maintenance frequently preclude their use for many preliminary studies. Consequently, small animal models considered to be less than ideal scientifically may have to be used for economic reasons. In human medicine a similar situation can also apply but, although economic factors may not be ignored, the reasons for the choice of small animals are more likely to be ethical rather than economic. Where these unavoidable expediencies have to be adopted, it is then necessary for investigators to be aware of the disadvantages and difficulties of extrapolating results from one species to another. '

Papers read to Section of Comparative Medicine, 20 April 1977

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Journal of the Royal Society of Medicine Volume 71 September 1978

Some biological considerations influencing selection In many investigations involving the use of experimental animals, the results are not immediately applicable to clinical situations, either in the veterinary field or in human medicine. Illustrative of this is certain work carried out during the last few years involving the use of Coxsackievirus B3 in pregnant mice and its effect on fetal development (Coid & Ramsden 1973, Coid et al. 1974, Lansdown et al. 1975). This work was, to some extent, stimulated by a report of the World Health Organization Expert Committee on Maternal and Child Health (1961), which recommended that biological and clinical research should be undertaken to study various factors that might affect birthweight and maturation of the fetus; these factors included bacterial and viral infections (especially inapparent and subclinical) before and during pregnancy. It was found that when relatively small amounts of Coxsackievirus B3 are injected intramuscularly into pregnant mice, a mild and transient maternal illness is caused which is usually unapparent to the untrained observer. Nevertheless, even though the maternal disease is mild, the infection results in severe fetal growth retardation, retarded maturation of plasma protein development and embryonic resorption. These changes are due to the inability of the mother to metabolize her food following destruction of the acinar tissue of the pancreas by the virus. Such acinar destruction can be moderated significantly by feeding casein hydrolysate at the same time as the experimental animals are given the infection, thus illustrating that even though the virus may pass through the placenta to infect the fetus, the main damage results from the destruction of the maternal pancreas and the consequent secondary undernutrition of the fetus. In experiments of this kind, it cannot be claimed that a study of the interaction between pathogens and the host in animal models will necessarily reflect what happens in other species with different viral pathogens or, indeed, even with the same pathogen. Nevertheless, the use of these experimental models provides some idea of the mechanisms which may impair fetal development and result in small size at birth. Apart from infection in pregnancy there. are many contributory causes leading to intrauterine growth retardation;. these include vascular disease-in the mother, smoking and chromosomal abnormalities (Polani 1974, Widdowson 1974, Usher & McLean 1974). The problem has been investigated by workers using many different kinds of animals such as pigs, monkeys and rats. One of the most useful models for this was described by Wigglesworth (1964) in which he demonstrated the significance of uterine blood flow to the fetus of the pregnant rat. The same model has also been used by other workers to study, for example, biochemical changes associated with fetal growth retardation. Although the rat is suitable for many studies, it may be less valuable for investigating intrauterine influences on brain development for the very good reason that the rapid phase of brain growth occurs postnatally in this species. Dobbing (1974) has elegantly illustrated this by comparing the velocity of brain growth in the guinea-pig, domestic pig, man and rat. The brain 'growth spurt' in the rat is conveniently encompassed in the suckling period and lasting effects in the brain can only be imposed during this time. A reasonable degree of undernutrition, either before or after this time, produces no detectable effects. By contrast, mild nutritional restriction occupying a substantial proportion of the suckling period, when the spurt in brain growth normally occurs, leads to permanent distortions as well as deficits in the adult brain both in its physical configuration and in its behaviour. From these few examples related to problems of fetal growth, it is clearly desirable to select animals with care to make sure they are appropriate for the particular investigation. Sometimes, however, there is less need to be particularly discriminating in the choice of animal. This may be illustrated in studies related to certain transmitters in the brain, in particular the monoamines. Apparently these transmitter systems are very constant in their structure in both the lower vertebrates and man. Moreover, there are no marked differences in the interaction of monoamine systems with various pharmacological agents. Therefore, as far as is known at the present time, studies on the effects of neuroleptics on dopamine metabolism in the rat, and

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presumably in other species, are highly relevant to the human situation (T J Crow, personal communication). Although laboratory rodents are a popular species for biomedical research, increasing use has been made of nonhuman primates over the last twenty years or so. In some instances this is probably due to their phylogenetic similarity to man, but it is more likely to be because no other species is suitable for the investigation under consideration. For example, only in simians is it possible to carry out comparative neurovirulence tests on the three strains of poliovirus employed for the manufacture of vaccine. In another field, that of oral pathology, Cohen and his colleagues have made very valuable contributions to the study of dental caries using monkeys of the species Macaca fascicularis. These animals, when maintained on a diet normally used for human consumption, develop lesions closely resembling those seen in man (Cohen & Bowen 1966). However, because a species such as this is eminently suitable as a model for one study it does not follow that it will be suitable for other investigations. For example, Shackleton & Mitchell (1975) demonstrated the unsuitability of M. fascicularis as a model for a study of steroid endocrinology of pregnancy, since these monkeys have a very different metabolism from that of man and the great apes. This presentation has attempted to illustrate some of the more general aspects related to the selection and use of animals for comparative purposes. Many scientific factors must be evaluated when such decisions are being made, but, having made these decisions, it is no less important for the investigator to ensure that the animals selected are also acceptable in terms of health and quality as well as in their scientific suitability.

References Cohen B & Bowen W H (1966) British Dental Journal 121, 269-276 Coid C R & Ramsden D B (1973) Nature 241, 460-461 Coid C R, Ramsden D B & Healy M J R (1974) Medical Microbiology and Immunology 159, 285-289 Dobbing J (1974) Journal of Pediatrics 53, 2-6 Lansdown A B G, Coid C R & Ramsden D B (1975) Nature 254, 599-600 Polani P E (1974) In: Size at Birth, Ciba Foundation Symposium 27. Associated Scientific Publishers, Amsterdam; pp 127-165 Shackleton C H L & Mitchell F L (1975) In: Breeding Simians for Developmental Biology. Laboratory Animal Handbooks, vol 6. Eds. F T Perkins & P N O'Donoghue. Laboratory Animals Ltd, London; pp 159-183 Usher R H & McLean F H (1974) In: Scientific Foundation of Paediatrics. Eds. J A Davis & J Dobbing. Heinemann, London; pp 69-80 Widdowson E M (1974) In: Size at Birth, Ciba Foundation Symposium 27. Associated Scientific Publishers, Amsterdam; pp 65-83 Wigglesworth J S (1964) Journal ofPathology and Bacteriology 88, 1-13 World Health Organization (1961) Public Health Aspects of Low Birth Weight. Technical Report Series No. 217, Geneva

Use of animals in the quality control of vaccines F Sheffield MB ChB The National Institute for Biological Standards and Controls, Holly Hill, London NW3 6RB

The quality control of vaccines is a statutory requirement which has now been imposed on manufacturers for more than fifty years. The Therapeutic Substances Acts (1925, 1956) and the Diseases of Animals Act (1950) restricted the manufacture of vaccines to holders of licences and laid down, in broad terms, the manner in which vaccines were to be made and the qualities that they must possess. The Medicines Act (1968), which superceded the second Therapeutic Substances Act (1956) and which embraces all pharmaceuticals, continues the licensing system 0 1 41-0768/78/0071-0677/$O 1.00/0

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1978 The Royal Society of Medicine

Symposium: Tests in laboratory animals--are they valid for man? Selection of animals suitable for biomedical investigations.

Journal of the Royal Society ofMedicine Volume 71 September 1978 675 Symposium: Tests in laboratory animals are they valid for man?' Selection of an...
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