La experimentación animal, además de haber producido un infinito dolor y muerte a millones de víctimas inocentes[1], es un fraude científico[2], pues los resultados científicos de la experimentación animal no son extrapolables y precisan de una posterior experimentación por parte de los consumidores, pudiéndoles causar graves daños en su salud e incluso la muerte. Para muestra, aquí se dejan unos ejemplos (pendientes de ser traducidos al español):
PARTE 1
FK506
Animal experiments indicated that FK506, an anti-rejection drug, was too toxic for human use.[1][2] However, when used on human liver transplant patients, the results were found to be 'promising'.[3]
[1] R. Allison, Journal of the American Medical Association, 4 April 1990, p.1766.
[2] R. Y. Calne, et al, Lancet, 22 July 1989, p.227.
[3] J. Neuberger, Hepatology, vol. 13, pp.1259-1260.
Radiation
The Committee of Official Enquiry into the incidence of leukaemia in children near the Sellafield nuclear plant, declared the plant was not the cause; this decision was based on animal testing.[1] However, later research did support the view that the plant was responsible.[2]
[1] E. Millstone, in Animal Experiments: The Consensus Changes, ed. G. Langley (Macmillan, 1989).
[2] M. J. Gardner, et al, British Medical Journal, 17 February 1990, pp.423-429.
Methysergide
No life-threatening symptoms were observed when this drug, for migraine, was tested on animals[1], and the British Medical Journal acknowledged that it had not been possible to produce fibrotic lesions in laboratory animals[2]. And yet the British National Formulary (1993), found it necessary to warn that the drug should only be administered to humans by trained medical staff as it had been found that the drug had serious side-effects which arose from fibrous tissue (retroperitoneal fibrosis) and these included heart failure.
[1] R. Heywood in Animal Toxicity Studies: Their Relevance For Man, eds. C. E. Lumley and S. R. Walker (Quay Pub: 1990).
[2] K. A. Misch, British Medical Journal, May 18 1974, pp.365- 366.
Suprofen/suprol
This, an arthritis drug, was withdrawn globally in 1987 after reports of kidney problems and pain.[1] Those who reported these problems had to have their kidneys monitored for two years after they stopped using the drug.[2] And yet it was reported: 'In animal studies, Suprofen has been shown to have an excellent safety profile. No significant effects were observed on cardiac, renal [kidney] or central nervous system...in several species.[3]
[1] Drug Withdrawal from Sale, C. Spriet-Pourra and M. Auriche (PJB Publications, 1988).
[2] FDA Drug Review: Postapproval Risks, 1976-1985 (US General Accounting Office, April 1990).
[3] A. Yeardon, et al, Pharmacology, 1983, vol. 27, Suppl. 1, pp.87-94.
Alcohol
Until the twentieth century, alcohol was considered to be poisonous for the liver.[1] This view changed after experiments on animals,[1][2] and in 1934, animal testing concluded that there was no evidence for alcohol causing cirrhosis.[3][4]
Alcohol is of course today considered to be a liver toxin, but some still question this in view of the difficulty in inducing cirrhosis in laboratory animals.[5] In addition to this, alcohol appears to be more harmful to the circulatory system of human beings than animals. For example, excessive consumption raises the blood pressure in alcoholics, and yet this is not usually the case with rats.[6]
Furthermore, alcohol is able to damage the human heart but studies involving various animals who were given 'large amounts' of alcohol found that none suffered heart failure.[6]
Animal experiments also showed that Librium could assist in dealing with withdrawal although as some animals died, it also suggested there was a lethal side-effect.[7] In fact clinical tests carried out at an earlier time had already revealed that Librium was effective,[8] and it continues to be used in relation to alcohol withdrawal.
[1] H. J. Zimmerman, Alcoholism: Clinical and Experimental Research, 1986, vol. 10, pp.3-15.
[2] C. S. Lieber and L. M. DeCarli, Journal of Hepatology, 1991, vol. 12. pp.394-401.
[3] V. H. Moon, Archives of Pathology, 1934, vol. 18, pp.381- 424.
[4] As [2].
[5] R. F. Derr, et al, Journal of Hepatology, 1990, vol. 10, pp.381-386.
[6] J. V. Jones, et al, Journal of Hypertension, 1988, vol. 6, pp.419-422.
[7] D. B. Goldstein, Journal of Pharmacology and Experimental Therapeutics, 1972, vol. 183, pp.14-22.
[8] G. Sereny and H. Kalant, British Medical Journal, 9 January 1965, pp.92-97.
Pesticides
In 1986, the British Parliament's Agriculture Committee instigated a review into pesticides. Despite the general faith placed in animal experiments, the Committee was forced to concede that 'similar tests in different animal species often yield quite different results'.[1] One example was the organophosphate pesticide dipterex which caused nerve damage in human beings but not in animals.[2] One physician member of the National Poisons Unit advised the Committee that one documented case of human poisoning was worth 20,000 animal experiments.[1]
In view of the findings, the Committee declared: 'It cannot be satisfactory to rely on animals so much as a means of testing and, as other forms of testing becomes available, we recommend that they be adopted...we are satisfied from the evidence that we have received that animal testing can produce misleading results'.
[1] Special Report of the House of Commons Agriculture Committee, rep. FRAME News, 1987, No. 16, p.2.
[2] A. N. Worden, in Animals and Alternatives in Toxicity Testing, eds. M. Balls, et al (Academic Press, 1983).
Arsenic
For some seventy years, researchers were unable to connect arsenic with cancer due to being unable to verify the suspicion with animal experiments. Although arsenic had been connected with cancer as early as 1809, a report published in 1947 stated that the many animal experiments which had been conducted had only produced 'doubtful results'.[1]
Experiments continued after this date and even by 1969, researchers acknowledged that while it was believed there was a connection between cancer and arsenic, animal experiments had not offered any supporting evidence for this.[2] In 1977, a report yet again said that animal experiments had not produced supporting evidence of a link.[3] It was not until the end of the 1980s that researchers were finally able to produce the cancer in animals - nearly 200 years after the link had first been suggested.
[1] O.Neubauer, British Journal of Cancer, 1947, vol. 1, pp.192- 251.
[2] A. M. Lee and J. F. Fraumeni Jr., Journal of the National Cancer Institute, 1969, vol. 42, pp.1045-1052.
[3] F. W. Sunderman Jr., in Advances in Modern Technology, vol. 2, eds. R. A. Goyer and M. A. Mehlman (Wiley, 1977).
Benzene
As Benzene was widely used, e.g., for the manufacture of detergents, pharmaceuticals, etc., there was concern as there appeared to be a link with cancer. Animal experimentation did not support this view,[1] and some fourteen animal trials failed to show any connection between benzene and cancer.[2] Therefore workers were put at considerable risk in view of there being no 'evidence' of a link. It was not until the late 1980s, after dosing animals with benzene that cancer was induced.
[1] L. B. Lave, The American Statistician, 1982, vol. 36, pp.260-261.
[2] D. M. De Marini, et al, in Benchmarks: Alternative Methods in Toxicology, ed. M. A. Mehlman (Princeton Scientific Publishing, 1989).
Lindane
Lindane, while primarily known as an agricultural insecticide, it is also used in different forms, in a diluted amount, for lice and similar afflictions. However these can cause serious eye irritation,[1] and the British National Formulary 1993, warns that eye contact should be avoided. And yet in rabbits, when a far more concentrated solution was used, the effects were minimal. Additionally, exposure to lindane dust caused no problem to rabbits, but caused irritation to the eyes and respiratory systems of some people.[1]
[1] W. M. Grant, Toxicology of the Eye, 2nd edn (Charles Thomas, 1974).
Dinitrophenol
After considerable animal testing, this product was used as a treatment for obesity but after human usage it was noted that some patients were developing cataracts. Attempts were then made to replicate this in rats, rabbits, guinea pigs, and dogs, and yet none of the experiments produced any change to the lens of the eye.[1] A summary of the experimentation stated: 'All attempts to produce experimental cataracts in laboratory animals by various and repeated doses of dinitrophenol have been unsuccessful'.[2] It was only later that an experiment accidentally discovered that birds dosed with dinitrophenol developed cataracts.[1]
A similar situation arose with triparanol intended to reduce cholesterol levels. While the cataracts noticed in humans could be induced in rats and dogs (after very high doses) they could not be in rabbits and monkeys.[3] The product was withdrawn.
[1] B. H. Robbins, Journal of Pharmacology, 1944, vol. 80, pp.264-269.
[2] Rep. in ref [1].
[3] W. M. Grant, Toxicology of the Eye, 2nd edn (Charles Thomas, 1974).
Chymotrypsin
This product is used for ophthalmic surgery when dealing with cataracts. While recommended for human use,[1] it is harmful to a rabbit's eye, resulting in severe swelling of the cornea and sometimes causing perforation.[1] It is stated: 'The rabbit cornea appears to differ significantly from the human cornea in its reaction to a-chymotrypsin'.[2]
[1] British National Formulary, No.26 (BMA and The Royal Pharmaceutical Society of G.B., 1993).
[2] Morton Grant, Toxicology of the Eye, (1974).
Corticosteroids: Shock
The idea for this medication arose after animal experiments when the survival rate of animals improved after being given the treatment just before, or after, shock.[1][2] Corticosteroids were then prescribed for people who required treatment for septic shock, which can often result in heart, respiratory and kidney failure.
However when The Drug and Therapeutic Bulletin analysed the trials it reported that: 'high-dose corticosteroids are ineffective for the prevention or treatment of shock associated with sepsis. They do not improve outcome, and make secondary infection worse. They may harm patients with impaired renal [kidney] function'.[1] In fact, one trial found that corticosteroids not only failed, but actually appeared to increase death among patients.[3]
[1] Drug and Therapeutics Bulletin, 1990, vol. 28, pp.74-75.
[2] S. G. Hershey, in Anaesthesiology, Proceedings of the VI World Congress of Anaesthesiology, Mexico City, April 1976, eds. E. Hulsz, et al (Excerpta Medica, 1977).
[3] R. C. Bone, et al. New England Journal of Medicine, 10 September 1987, pp.653-658.
Acetylcholine
This chemical (produced by nerve endings) was believed, after experiments with dogs, to dilate the coronary arteries. However when used with humans, it was found to narrow the blood vessels which can result in heart spasm.[1] Another body chemical, bradykinin, relaxes blood vessels in human brain tissue but contracts them in dogs.[2]
[1]S. Kalser, Journal of Physiology, 1985, vol. 358, pp.509-526.
[2]K. Schror and R. Verheggen, Trends in Pharmacological Sciences, 1988, vol. 9, pp.71-74.
Leukotrienes (LT).
Those leukotrienes known as LTC4 and LTD4, constrict blood vessels in the skin of the guinea pig, but dilate corresponding issue originating from human beings and pigs.[1]
[1]P.J. Piper, et al, Annals of the New York Academy of Sciences, 1988, vol. 524, pp.133-141.
Prostaglandins (PG).
These are a family of substances in human seminal fluid. In the heart tissue from cats and rabbits, PGE1 has no effect on contractile force or heart rate, and yet in rats, guinea pigs and chickens, it increases them.[1]
Because of such anomalies, some pharmacologists concede that the extrapolation from animals to humans is often invalid and acknowledge the increased interest in using tissue from human beings to overcome those restrictions which arise when using animal tissue.[2]
[1]S. Bergstrom, et al, Pharmacological Review, 1968, vol. 20, pp.1-48.
[2]Trends in Pharmacological Sciences, 1987, vol. 8, pp.289-290.
Clonidine.
Animal experiments during the 1960s indicated that clonidine might be useful in treating migraine (Experiments with cats showed that the drug affected those processes believed to cause headaches). The drug was therefore introduced in 1969, but later research indicated that it was largely useless.[1].
However after being used as a nasal decongestant, it was discovered that clonidine could be effective when used to treat high blood pressure.[2]. However serious side-effects were then noted. Furthermore, attempts to replicate the condition in dogs and cats only provided inconsistent results,[3] and in the case of testing with rats, there were even more difficulties and disagreements.[4] The Drug and Therapeutic Bulletin therefore deems clonidine to be obsolete for the treatment of high blood pressure.[5]
[1]Drugs and Therapeutics Bulletin, 1990, vol. 28, pp.79-80.
[2]A. S. Niles in Clinical Pharmacology: Basic Principles in Therapeutics, 2nd edn, eds, K. L. Melmon and H. F. Morrelli (MacMillan, 1978).
[3]L. Hansson, et al, American Heart Journal, 1973, vol. 85, pp.605-610.
[4]M. J. M. C. Thoolen, et al, General Pharmacology, 1981, vol. 12, pp.303-308.
[5]Drug and Therapeutics Bulletin, 1984, vol. 22, pp.42-43.
Isoprenaline.
During the 1960s, at least 3,500 young asthma sufferers died after using isoprenaline aerosol inhalers.[1] Fatalities occurred when the aerosol delivered 0.4mg of isoprenaline per spray.[2][3]
Attempts to replicate the same effects in laboratory animals were problematic and the New York Food and Drug Research Laboratory was forced to admit: 'Intensive toxicological studies with rats, guinea pigs, dogs and monkeys at dosage levels far in excess of current commercial metered dose vials...have not elicited similar adverse effects'.[4] It was only after artificially reducing the oxygen in the animals' tissue that vivisectors were able to increase the toxic effects of isoprenaline.[5]
[1]W. H. Inman, Monitoring for Drug Safety, ed. W. H. Inman (MTP Press, 1980).
[2]P. D. Stolley, American Review of Respiratory Diseases, 1972, vol. 105, pp.883-890.
[3]P. D. Stolley and R. Schimmar, Lancet, 27 October 1979, p.896.
[4]S. Carson, et al, Pharmacologist, 1971, vol. 18, p.272.
[5]British Medical Journal, 25 November 1972, pp.443-444.
Phenacetin.
From the early 1950s, kidney damage associated with the prolonged use of combination painkillers was noted. Despite animal experiments, the reason for the damage could not be ascertained. It transpired that the animal experiments only served to further confuse the issue as while phenacetin was thought to be responsible, the damage could not be reproduced in the animals.[1] Furthermore, the experiments suggested it was the aspirin component that was causing the damage,[2] as aspirin, unlike phenacetin, readily induces kidney damage in laboratory animals.
It was only when human studies took place that it was realized that phenacetin was the cause,[3] leading to it being withdrawn in 1980 (when there was also the suspicion that it caused cancer).
An analysis concluded that if the research had only used animals the effects would not have been suspected or predicted.[1]
[1]I. Rosner, CRC Critical Reviews in Toxicology, 1976, vol. 4, pp.351-352.
[2]British Medical Journal, 17 October 1970, pp.125-126.
[3]K. G. Koutsaimanis and H. E. de Wardener, British Medical Journal, 17 October 1970, pp.131-134.
Clioquinol.
During the 1960s there was an epidemic of drug-induced disease in Japan, related to clioquinol, the principal ingredient of Ciba- Geigy's antidiarrhoea drugs Enterovioform and Mexaform. It is believed that between 10,000 and 30,000 people fell victim to SMON (subacute myelo-optic neuropathy) which produced numbness, paralysis and eye problems including the loss of sight.[1] In 1970, the drug was banned in Japan, and fifteen years later, it was withdrawn globally.
Despite all the serious problems caused by the drug, those experiments carried out on animals, which included rats, cats, beagles and rabbits, revealed 'no evidence that clioquinol is neurotoxic'.[2]
Although there have been claims to have produced toxicity from clioquinol in mongrel dogs,[3] it has also been noted that different species yield different results, e.g., monkeys, hens, cocks and mice were only mildly affected even after they were given high doses while it was discovered that beagle dogs were 3-4 times less sensitive to clioquinol than mongrels.
[1]Lancet, 5 March 1977, p.534.
[2]R. Hess, et al, Lancet, 26 August 1972, pp.424-425.
[3]J. Tateishi, et al, Lancet, 10 June 1972, pp.1289-1290.
Oral Contraception.
Studies of the pill have shown that of the side-effects which can occur, the most serious is that of problems with the circulatory system, i.e., blood clots, strokes and heart disease. By 1980 the CSM (Committee on Safety on Medicines) had received reports of over 400 deaths,[1] and further studies showed that some women using the pill had raised blood pressure. However none of these problems had been identified during animal experiments;[2] in fact the oral conceptive had produced the opposite effect (i.e., making it more difficult for the blood to clot) in some species.[3]
Prof. Briggs of Deakin University, Australia, noted: 'At multiples of the human dose no adverse effect on blood clotting was found in mice, rats, dogs, or non-human primates. Indeed, far from accelerating blood coagulation, high doses of oestrogens in rats and dogs prolonged clotting times. In sum, there is no appropriate animal model for the coagulation changes in women using oral contraceptives'.[4] In 1972 the CSM described how the tests which had been conducted on some 13,000 animals revealed that there was a connection between high doses of oral contraceptives and cancer.[5] And yet the rats and mice were so prone to cancer that even those who were not dosed with the oral contraceptive ('the control animals') developed high levels of disease; lung and liver tumours were found in 25% and 23% of the control mice, and adrenal, pituitary and breast tumours were found in 26%, 30% and 99% of the control rats.
In view of this, the British Medical Journal stated: 'It is difficult to see how experiments on strains of animals so exceedingly liable to develop tumours of these various kinds can throw any useful light on the carcinogenity of any compound for man'.[5]
Thus, it is those women who have used the pill who have really been the 'guinea pigs' for the drug.
[1]G. R. Venning, British Medical Journal, 22 January 1983, pp.289-292.
[2]R. Heywood, in Animal Toxicity Studies: Their Relevance for Man, eds, C. E. Lumley and S. R. Walker (Quay Publishing, 1990).
[3]R. Heywood and P. F. Wadsworth in Pharmacology of Estrogens, ed. R. R. Chaudhury (Pergamon Press, 1981).
[4]M. H. Briggs in Biomedical Research Involving Animals, eds. Z. Bankowski and N. Howard-Jones (CIOMS, 1984).
[5]British Medical Journal, 28 October 1972, p.190.
Chloramphenicol.
Animal experiments indicated that chloramphenicol, an anti-biotic, was safe although it was equally clear that the drug produced side- effects in humans. Due to the serious side-effects, the drug was withdrawn in France.[1]
In 1952 American physicians discovered that chloramphenicol affected the nerve cells and they related how one patient had almost became blind and could only walk with great pain after taking chloramphenicol for just five months. This was only one of many reported cases when chloramphenicol produced optical and peripheral neuritis, and yet animal experimentation showed that the drug was virtually free of side-effects, even after prolonged use.[2]
A far more serious side-effect was the fact that chloramphenicol caused aplastic anaemia, an often fatal blood disease. Once again, animal experimentation did not provide any indication of this occurring and the British Medical Journal noted that chloramphenicol resulted in nothing worse than transient anaemia in dogs when injected for long periods: furthermore, no problems occurred when administered by mouth.[3]
It is now known that chloramphenicol is deadly by test-tube studies with human bone marrow cells.[4]
[1]C. Spriet-Pourra and M. Auriche, Drug Withdrawal From Sale, (PJB Publications, 1988).
[2]I. Wallenstein and J. Snyder, Annals of Internal Medicine 1952, vol. 26, pp.1526-1528.
[3]British Medical Journal, 19 July 1952, pp.136-138.
[4]G, M. I. Gyte and J. R. B. Williams, ATLA, 1985, vol. 13, pp.38-47.
Halothane.
Halothane was introduced in 1956 and viewed as a considerable advance in anaesthesia. However it was soon found to be harmful to the liver and within five years there were over three hundred reported cases of 'halothane hepatitis'. The effects were sometimes fatal and nearly two hundred deaths in Britain were attributed to halothane.[1]
And yet animal experimentation had not provided any evidence of liver damage,[2] and despite many animal experiments and different 'animal models', the significance of their application to human beings was considered 'doubtful'.[3]
Even by 1986, when Britain's Committee on Safety of Medicine increased the warnings about liver toxicity,[4]. it was still unclear whether the same results could be induced in animals.[5]
[1]British Medical Journal, 5 April 1986, pp.949.
[2]Anaesthesiology, 1963, vol. 24, pp.1990-110.
[3]D. C. Ray and G. B. Drummond, British Journal of Anaesthesia, 1991, vol. 67, pp.84-99.
[4]Scrip, 2 October 1987, p.2.
[5]C. E. Blogg, British Medical Journal, 28 June 1986, pp.1691-1692.
Butadiene.
This product was believed to produce cancer as cancer arose when it was tested on certain strains of laboratory mice, an animal widely used when seeking to assess the risk-element of chemical substances. When the dose was very high, cancer also arose in rats.
In view of the results of the animal experimentation, America's National Institute of Occupational Safety and Health (NIOSH) classified butadiene as a carciinogen.
And yet when humans who worked with butadiene were monitored, no extra cancer arose. In fact the number of deaths from cancer was less than the national average.[1] An editorial in Science therefore called for a review of the methodology which was used when considering the risk.
[1]P. H. Abelson, Science, 19 June 1992, p.1609.
Pneumoconiosis.
Due to animal experimentation, it was believed that pneumoconiosis, a lung disease suffered by miners, was caused by silica rather than coal dust. Therefore mines, in which there was no exposure to silica, were viewed as being safe. Believing the problem was understood, there was no information about miners' pneumoconiosis until the early 1960s.[1]
As noted by the British Medical Journal, the idea that coal dust was safe arose from animal experimentation,[2] which not only absolved coal dust, but made silica the most likely culprit.[3] Nonetheless, the findings from the animal experimentation were shown to be suspect when miners, who only worked with pure coal dust or carbon, were found to have developed pneumoconiosis.[1][2] Thus it was shown that coal dust caused pneumoconiosis without any silica being present.
The results of the animal experimentation was further weakened when coal dust, collected from a mine where the incidence of pneumoconiosis was high, was found to be harmless to laboratory rats.[2] Naturally there is the question of how much serious illness was suffered by miners, and many deaths occurred, due to the incorrect information gleaned from animal experimentation.
[1]W. K. C. Morgan, in Occupational Lung Diseases, eds. W. K. C. Morgan and A. Seaton (Saunders, 1982).
[2]British Medical Journal, 17 January 1953, pp.144-146.
[3]I. U. Gardner, Journal of the American Medical Association, 19 November 1938, pp.1925-1936. Chronic Pulmonary Disease in South Wales III Experimental Studies, MRC special report series no. 250 (HMSO, 1945).
Dermatitis.
Dermatitis, a skin condition, arises in many people when they come into contact with nickel compounds.[1] In fact nickel is considered to be the most common cause of dermatitis in women; in some cases it can result in severe eczema and disability.[2]
And yet in most animal testing, nickel is not found to be a skin sensitizer,[3] and, for example, the draize test on guinea pigs suggests that nickel does not produce an allergic reaction. Even in the two most widely used forms of animal testing, nickel produces no response (the Buehler test) or only a moderate response (the Maximization test).
[1]Medical Toxicology, eds. M J. Ellenhorn and D. G. Barceloux (Elsevier, 1988).
[2]Textbook of Dermatology, vol. 1, 5th edn, eds. R. H. Champion, et al (Blackwell Scientific Publications, 1992).
[3]P. A. Botham et al, Food and Chemical Toxicology, 1991, vol. 29, pp.275-286.
Malaria.
Experiments using monkeys in malaria research led to the suggestion that coma in humans was caused by an increased amount of protein in the cerebro-spinal fluid, and this could be resolved by using steriods.[1] But in contrast to the animal experiments, it was ascertained that humans were not assisted by steroids when in a coma and if anything they were harmful.[2]
It was found that the time of coma was lengthened by some sixteen hours and serious complications, e.g., pneumonia, urinary tract infections, convulsions, etc., also occurred more often in those patients using steroids. Later research reported 'that the monkey model may simply not be relevant'.[1]
[1]Lancet, 2 May 1987, p.1016.
[2]D. A. Warrell, et al, New England Journal of Medicine, 11 February 1982, pp.313-319.
Mianserin.
This drug, an antidepressant, can produce potentially fatal blood disorders and the British National Formulary recommends that people using the drug have full blood counts every 4 weeks in the first months of usage.[1] By 1988, the World Health Organisation had over 300 reports relating to white cell disorders.
Despite these problems, the animal experimentation which had been conducted had not predicted these effects,[2] although later test tube studies with human tissue did allow the effects to be observed.[3]
[1]British National Formulary, No. 26 (BMA and the Royal Pharmaceutical Society of GB, 1993).
[2]H. M. Clink, British Journal of Clinical Pharmacology, 1983, vol. 15, pp.2915-2935.
[3]P. Roberts, Drug Metabolism and Disposition, 1991, vol. 19, pp.841-843.
Caged ball valve.
Dogs are preferred in cardiac experiments which include tests to develop an artificial mitral valve although these valves are known to produce fatal blood clots in the dogs.[1] Because of this, many surgeons have been deterred from carrying out human trials.[2]
To overcome the blood clots which occur, two experimental surgeons decided on a 'caged ball' valve,[3] as other devices proved fatal to those dogs on which they had been tested. Of the 7 dogs that received the caged ball valve, 6 died within 17 days and only one survived and this was for a few months. Despite this failure in dogs, the device was much more successful in clinical trials where blood clotting was not a problem.[4] The surgeons concluded: 'The marked propensity of the dog to thrombotic occlusion [blood clotting] ...from a mitral prosthesis is not shared by the human being'.[5]
The surgeons intended carrying out further experiments with their caged ball valve on animals but as it invariably resulted in the death of the animals, the surgeons had to produce a different valve made specially for use in the dogs. One would have thought this would have been sufficient to indicate animal experimentation was of no value in respect of human health, but they continued and found that while the different valve did not kill so many dogs so quickly, nearly 80% died in 46 days. The surgeons admitted that 'the species differences' forced them to design one type of valve for use in humans and another type for use in the laboratory animals.[5] Finally, the successful clinical use of another design of mitral valve replacement gave further proof that animal experimentation is of no use as none of the dogs used in the preclinical testing survived more than 40 hours.[6]
[1]A. V. Doumanian and F. H. Ellis, Journal of Thoracic and Cardiovascular Surgery, 1961, vol. 41, pp.683-695.
[2]G. H. A. Clowes, jr., Annals of Surgery, 1961, vol. 154, p.740.
[3]A. Starr, American College of Surgeons, Surgical Forum, 1960, vol. 11, pp.258-260.
[4]A. Starr and M. L. Edwards, Annals of Surgery, 1961, vol. 154, pp.726-740.
[5]A. Starr and M. L. Edwards, Journal of Thoracic and Cardiovascular Surgery, 1961, vol. 42, pp.673-682.
[6]N. S. Braunwald, et al, Journal of Thoracic and Cardiovascular Surgery, 1960, vol. 40, pp.1-11.
Surgam.
This, an anti-inflammatory drug used for arthritis, was considered an improvement on other anti-inflammatory preparations as it did not damage the stomach, a major problem with this type of drug. It was advertised as providing 'gastric protection', being based on animal experimentation. However this claim could not be confirmed by clinical trials and as a consequence, Roussel, the manufacturer, was fined twenty thousand pounds for misleading advertising. The Lancet described how expert witnesses for both sides 'agreed that animal data could not safely be extrapolated to man'.[1]
[1]J. Collier and A. Herxheimer, Lancet, 10 January 1987, pp.113-114.
Selacryn.
This diuretic product was tested on animals and no harmful effects were detected.[1] After being introduced in 1979, it had to be withdrawn in America the following year when over 300 cases of liver damage were reported, which included 24 deaths.[1] Development of the drug was cancelled in many countries including Britain.[2]
[1]S. Takagi, et al, Toxicology Letters, 1991, vol. 55, pp.287-293.
[2]C. Spriet-Pourra and M. Auriche, Drug Withdrawal From Sale (PJB Publications, 1988).
Perhexiline.
This, a treatment for angina, was originally marketed in France in the 1970s. When it became linked to liver damage, it was withdrawn in Britain while other countries did not licence it at all. In fact some considered that it should never have been licensed.[1]
The animal experimentation conducted did not indicate the danger,[2] and even when high doses were administered to several different species for up to two years, there was no indication that the drug affected the liver.[3]
The company responsible for marketing perhexiline said: 'there has been an inordinate amount of animal work done...At this point we simply have been unable to induce hepatic [liver] damage in any species'.[4]
[1]D. G. McDevitt and A. M. MacConnachie, in Meyler's Side Effects of Drugs, 11th edn., ed. M. N. G. Dukes (Elsevier, 1988).
[2]C. T. Eason, et al, Regulatory Toxicology and Pharmacology, 1990, vol. 11, pp,288-307.
[3]J. W. Newberne, Postgraduate Medical Journal, 1973, vol. 49, April Suppl., pp.125-129.
[4]Ibid., p.130.
Menthol.
Menthol is included in a number of cough and cold remedies, and is also used as an inhalent when conditions such as bronchitus and sinusitis arise. It is also used as a ointment. If it comes into contact with the eye it will produce burning sensation which can last up to thirty minutes although there are no after-effects. In stark contrast, menthol causes severe damage to the eye of the rabbit.[1]
[1]W. M. Grant, Toxicology of the Eye (Charles Thomas, 1974).
Selenium disulphide (Selsun).
In view of this product being successful as an antidandruff shampoo, it was suggested that it might be of assistance for blepharitis, a painful and similar condition of the eyelids. Trials were then conducted in which a preparation with 0.5% selenium disulphide was applied to the lid margins. It was noted that if it came into contact with the conjunctivita there was irritation, and one patient developed conjunctivitis.[1] And yet animal experiments showed that: 'Selenium disulphide 0.5% ophthalmic ointment is nontoxic to rabbit corneas or conjunctivitas'.[2]
[1]G. C. Bahn, Southern Medical Journal, 1954, vol. 47, pp.749-752.
[2]J. W. Rosenthal and H. Adler, Southern Medical Journal, March 1962, p.318.
Domestic and cosmetic products.
Researchers discovered that while coconut soap had a negligible effect on human skin, it causes skin irritation in rabbits. Pine oil cleaner also produced a 'moderate' reaction in rabbits and guinea pigs, whereas it only had a slight effect on human skin. Other substances have been found to have different effects on animals and humans, e,g., high and low carbonate detergents, phosphate detergents, enzyme detergents, sodium carbonate and lemon juice all had an insignificant effect on human skin while causing irritation in animals. Overall, only 6 of the 24 products tested on animals and humans had the same effect on humans, rabbits and guinea pigs. The report concluded: 'Neither the rabbit nor the guinea pig provides an accurate model for human skin. The skin responses of these animals differ in both degree and in kind from those found in human skin'.[1]
Similar findings arose with cosmetic ingredients. Researchers at the New Jersey Warner Lambert Research Institute observed that: 'Animal skin is entirely differently from human skin and that there may be no correlation between the mildness of a raw material on a rabbit's back and its safety during use on a human face'. They offer the example of isopropyl myristate which is deemed safe for human use but causes irritation in rabbits.[2]
[1]G. A. Nixon, et al, Toxicology and Applied Pharmacology, 1975, vol. 31, pp.481-490.
[2]M. M. Rieger and G. W. Battista, Journal of the Society of Cosmetic Chemists, 1964, vol. 15, pp.161-172.
Domperidone.
This is used to treat nausea and vomiting, particularly those instances caused by anti-cancer treatment. The injectable form was withdrawn globally in 1986,[1] due to hazardous heart rhythm disturbances. However, this danger was not predicted by animal experimentation.[2] Dogs, the animal often used to test effects on the heart, were given 70 times the recommended human dosage, and yet no changes in the electrocardiogram occurred.[3]
[1]C. Spriet-Pourra and M. Auriche Drug Withdrawal From Sale (PJB Publications, 1988).
[2]R. Heywood, in Animal Toxicity Studies: Their Relevance For Man, eds. C. E. Lumley and S. R. Walker (Quay Publications, 1990).
[3]R. N. Brogden, et al, Drugs, 1982, vol. 24, pp.360-400.
Squalene.
This is a natural constituent of human sebum, the substance formed by sebaceous glands surrounding the root of the hair; this keeps the skin lubricated and supple. It is extensively and safely used in cosmetics.[1] However, when used on the skin of rabbits and guinea pigs, it produces loss of hair, the very opposite of what occurs in human beings.[2]
[1]M. M. Rieger and G. W. Battista, Journal of the Society of Cosmetic Chemists, 1964, vol. 15, pp.161-172.
[2]B. Boughton, et al, Journal of Investigative Dermatology, 1955, vol. 24, pp.179-189.
Prenylamine.
This product, a treatment for angina, was removed from the American market in 1988,[1] in view of it causing ventricular tachycardia, i.e., the heart beats abnormally fast and patients can faint. In stark contrast to this, animal experimentation revealed that prenylamine reduced the heart rate by up to 25% in cats, rabbits and guinea-pigs.[2]
[1]C. Spriet-Pourra and M. Auriche, Drug Withdrawal From Sale, (PJB Publications, 1988).
[2]H. Obianwu, Ata Pharmacology et Toxicology, 1967, vol. 25, pp.127-140.
Furmethide.
Warnings had to be issued to ophthalmologists against the prolonged use of this product when treating glaucoma,[1] as it was noted that the tear passage became permanently obstructed in over 70% of those patients who used it for more than three months.
And yet those who conducted the animal experimentation related to this product (on rats, guinea pigs and rabbits) declared it 'entirely safe' and worthy of clinical trial.[2]
[1]R. N. Shaffer and W. L. Ridgway, American Journal of Opthalmology, 1951, vol. 34, pp.718-720.
[2]A. Myerson and W. Thau, Archives of Opthalmology, 1940, vol. 24, pp.758-760.
Phenylbutazone (Butazolidine).
This was once widely used to treat arthritis, but was withdrawn in several countries and restricted in others, due to reports of aplastic anaemia (an often fatal blood disease caused by damage to the bone marrow) arising.[1]
Animal testing had indicated phenylbutazone to be a safe medication with no side effects even when ten times the dosage recommended for humans was administered to the animals.[2] The animal testing had certainly not suggested phenylbutazone would have a harmful effect on the bone marrow,[3] and a year after marketing, researchers said 'there have been no published reports of serious effects...on the hemopoietic [blood forming] system...in the experimental animal'.[4]
Noteworthy is the fact that later research involving test tube experiments using human bone marrow cell showed the dangers could be identified.[5]
It has been estimated that phenylbutazone and oxyphenbutazone (a closely related drug that has also caused aplastic anaemia which was withdrawn in 1985), have been responsible for 10,000 deaths worldwide.[6]
[1]C. Spriet-Pourra and M. Auriche, Drug Withdrawal From Sale, (PJB Publications, 1988).
[2]C. Hinz and I. M. Gaines, Journal of the American Medical Association, 1953, vol. 151, pp.38-39.
[3]R. Heywood in Animal Toxicity Studies: Their Relevance For Man, eds. C. E. Lumley and S. R. Walker (Quay Publishing, 1990).
[4]O. Steinbrocker, et al, Journal of the American Medical Association, 15 November 1952, pp.1087-1091.
[5]C. S. Smith, et al, Biochemical Pharmacology, 1977, vol. 26, pp.847-852.
[6]Estimate by Dr. Sidney Wolfe, in Lancet, 11 February 1984, p.353.
Chloroform.
Deaths from chloroform were regularly reported in the second half of the nineteenth century; it was believed that it caused respiratory failure but this could be minimized by careful administration and monitoring. Regrettably animal experimentation supported the idea that chloroform affected respiration rather than the heart.[1]
Launder Brunton, in a communication to the Lancet,[2] summarized the results from the Second Commission: 'four hundred and ninety dogs, horses, goats, cats and rabbits used. Results most instructive. Danger from chloroform is asphyxia or overdose: none whatever heart direct'. With this confirmation, from animal experimentation, that chloroform did not stop the heart, anaesthetists continued to use chloroform.
In 1893, clinical observations completely contradicted the previous findings and showed that heart failure is the most common cause of death from chloroform.[1]
[1]K. B. Thomas, Proceedings of the Royal Society of Medicine, 1974, vol. 67, pp.723-730.
[2]Lancet, 7 December 1889, p.1183.
Anaemia and iron.
When patients suffer iron deficiency, physicians prefer that they take iron by mouth, but if this is unsuccessful, iron is injected.[1] Due to animal experimentation, this option could have easily been discarded. Experiments which involved anaemia being induced in animals by iron deficiency or by repeated haemorrhage led the experimenters to conclude that injecting iron had no therapeutic value.[2] Fortunately, non-animal studies proved that human patients could be treated by iron injection.
Iron sorbitol is one type of injectable iron that could have been rejected for a different reason. Administration to rats and rabbits caused cancer at the injection site but once again non-animal trials showed that there was no hazard to human patients.[3]
[1]British National Formulary, no.276 (BMA and Royal Pharmaceutical Society of GB, 1993).
[2]G. N. Burger and L. J. Witts, Proceedings of the Royal Society of Medicine, 1934, vol. 27, pp.447-455.
[3]M. Weatherall, Nature, 1 April 1982, pp.387-390.
Spinal injuries.
During the previous century, vivisectors attempted to develop an animal that would mimic spinal cord injuries (SCI) in humans.[1] One method used to achieve such injuries was dropping weights onto the spinal cord of cats.*** Through this, it was intended to devise therapies for SCI. Despite all the suffering experienced by laboratory animals, virtually no treatments were developed that work in human patients.[1]
In 1988, Dennis Maiman of the Dept. of Neurosurgery at the Medical College of Wisconsin, said: 'In the last two decades at least 22 agents have been found to be therapeutic in experimental SCI. Unfortunately, to date none of these have been proven effective in clinical SCI'.[1] In 1990 clinical trials showed that high doses of steroids could be beneficial. While this was subjected to animal testing, the fact remains that the testing was not only unnecessary but the animals gave inconsistent results, with some tests indicating the therapy would not work.[2]
[1]D. Maiman, Journal of the American Paraplegia Society, 1988, vol. 11, pp.23-25.
[2]S. R. Kaufman, Perspectives on Medical Research, 1990, vol. 2, pp.1-12.
Psicofuranine.
When vivisectors tested psicofuranine for an anti-cancer treatment, the rats and mice used gave contradictory evidence.[1] The drug was effective against tumours in rats but had no effect on three different cancers in mice.
Physicians were also unable to properly assess the drug against human cancer as it caused severe side-effects in early human trials. It was found that the drug damaged the heart and yet no cardiac toxicity was found in the mice, rats, dogs or monkeys used in the testing.[1]
Although clinical study of psicofuranine was abandoned, animal experiments continued in an attempt to reproduce the heart ailments in humans. Yet again, no cardiac toxicity could be observed even when the animals (dogs and monkeys), were given up to 10 times the dose that would be harmful to humans.[1]
[1]C. G. Smith, et al, Journal of International Medical Research, 1973, vol. 1, pp.489-503.
Sparsomycin.
During clinical trials, sparsomycin, an anti-cancer drug, was found to produce eye damage. And yet while sparsomycin was highly toxic in several animal species (as would be expected for an anti-cancer drug), no specific effect on the eye was found.[1]
After the eye damage was reported, vivisectors sought to induce the condition in rats and monkeys, but these attempts were unsuccessful even though the rats were dosed every day for two weeks with up to 300 times the amount that was found to harm humans.[1] No retinal toxicity was noted in additional animal tests and the drug was abandoned.
[1]C. G. Smith et al, Journal of International Medical Research, 1973, vol. 1, pp.489-503.
Corticosteroids: the unborn.
Experimentation involving pregnant mice and rabbits indicate that corticosteroids are very dangerous to the unborn human child. In the case of mice, cortisone produces cleft palate in up to 100% of the offspring of some species.[1] And in the case of rabbits, corticosteroids affect the heart and they can also cause severe growth retardation in the uterus, and death of the foetus. In stark contrast, rats and monkeys are very tolerant to corticosteroids in pregnancy.[2]
Researchers have noted the 'very wide species variation',[2] and despite the results of animal testing, cortisone is not considered harmful to human babies.[1]
[1]R. M. Ward and T. P. Green, Pharmacology and Therapeutics, 1988, vol. 36, pp.326.
[2]R. K. Sidhu in Drugs and Pregnancy: Human Teratogenesis and Related Problems, ed. D. F. Hawkins (Churchill Livingstone, 1983).
Iproniazid.
This was originally manufactured for the treatment of tuberculosis, but was subsequently used as an anti-depressant. Although it was considered 'harmless' on the basis of animal tests,[1] iproniazid produced fatal cases of liver damage in humans, and the drug was eventually abandoned.[2]
[1]J. Boyer in Clinical Pharmacology: Basic Principles in Therapeutics, 2nd edn., eds. K. I. Melmon and H. F. Morrelli (Macmillan, 1978).
Thalidomide.
This was first introduced as a sedative by the German drug company Chemie Grünenthal in 1957, and by the Distillers company in Britain a year later. Although animals could tolerate massive doses without ill-effect,[1] thalidomide was soon found to cause peripheral neuritis in human patients.
William McBride, an Australian obstetrician, was alerted to thalidomide's most notorious side-effect after seeing three babies born with very unusual birth defects. Regrettably, his warnings to the medical profession were delayed because he attempted to confirm his suspicions by experiments on mice and guinea pigs, both of which were resistant to the drug.[2] It was only after he saw more human cases, did McBride publish his findings.
Although it was not specifically tested for birth defects before it was marketed, subsequent experiments revealed 'extreme variability in species' susceptibility to thalidomide'.[3] For example, mice could safely tolerate eight thousand times the dose which was found harmful to human babies.[4]
In his book, Drugs as Teratogens, Schardein writes: 'In approximately ten strains of rats, fifteen strains of mice, eleven breeds of rabbits, two breeds of dogs, three strains of hamsters, eight species of primates, and in other such varied species as cats, armadillos, guinea pigs, swine and ferrets, in which thalidomide had been tested, teratogenic effects [birth defects] have been induced only occasionally'.
Scientists eventually found that birth defects similar to those occurring in humans could be induced in certain types of rabbit and primate. Nonetheless, New Zealand white rabbits had to be dosed with three hundred times the amount that was dangerous to humans.[5]
The thalidomide tragedy prompted additional extensive testing of drugs and chemicals in pregnant animals, but some scientists believe that: 'Animal malformations seldom correlate with those of humans'.[6] Additionally, 'No animal model has been found which responds satisfactorily to all known teratologic agents in humans to permit reliable screening of substances for their teratologic potential. Careful surveillance, reporting and prospective study...remain the mainstays for detection of adverse effects following foetal drug exposure'.[6]
[1]R. D. Mann, Modern Drug Use, an Enquiry on Historical Principles (MTP Press, 1984).
[2]The Sunday Times 'Insight' Team: Suffer the Children: the Story of Thalidomide, (Andre Deutsche, 1979).
[3]T. H. Shepard, Catalogue of Teratogenic Agents (John Hopkins Press, 1976).
[4]S. K. Keller and M. L. Smith, Teratogenesis, Carcinogenesis and Mutagenesis, 1982, vol. 2, pp.361-374.
[5]New Zealand White rabbits were sensitive to doses of 150mg/Kg of thalidomide (ref. 6), while the dangerous human dose was 0.5mg/Kg (ref. 4).
[6]R. M. Ward and T. P. Green, Pharmacology and Therapeutics, 1988, vol. 36, p.326.
Mitoxantrone.
This drug was produced for the treatment of cancer without side- effects on the heart. After beagles, on whom the drug was tested , 'failed to demonstrate cardiac failure',[1] researchers believed that it was safe. However in clinical trials, a number of patients suffered side-effects including heart failure; more widespread use of the drug confirmed that cardiac toxicity was a major problem with the drug.
Data from over three thousand patients who were given the drug included nearly a hundred reports of cardiac side-effect with twenty- nine of heart failure.[2] A recent study indicated that 20% of patients develop cardiotoxicity after using mitoxantrone.[3]
[1]R. Stuart Harris, et al, Lancet. 28 July 1984, pp.219- 220.
[2]Martindale: The Extra Pharmacopoeia, 29th edn., ed. J. E. F. Reynolds (Pharmaceutical Press, 1989).
[3]A. Stanley and G. Blackledge, Side Effects of Drugs, Annual 15, eds. M. N. G. Dukes and J. K. Aronson (Elsevier, 1991).
Carbenoxalone.
This was introduced during the 1960s for the treatment of peptic ulcers. Before being marketed it was tested on animals and the tests indicated that carbenoxalone was safe and there were no harmful effects.[1] When vivisectors realized that humans metabolized carbenoxalone differently to rats, mice and rabbits, further experiments were carried out on monkeys, but yet again, there was no evidence of toxicity.[1]
When carbenoxalone began to be used by human patients, salt and water retention occurred and this led to high blood pressure, swelling, weight gain, muscle weakness and heart failure. The British National Formulary advises other drugs are preferred and if carbenoxalone is used, treatment must be carefully monitored.[2]
[1]C. T. Eason, et al, Regulatory Toxicology and Pharmacology, 1990, vol. 11, pp.288-307.
[2]British National Formulary, no.26 (BMA and the Royal Pharmaceutical Society of G.B., 1993).
Clindamycin.
After the antibiotic clindamycin was given to rats and dogs every day for a year, it was found that the animals could tolerate twelve times the recommended human dose.[1]
However, Britain's Committee on the Safety of Medicines was forced to warn the medical profession about the dangers of clindamycin, one of which was the sometimes-fatal intestinal disease, pseudomembraneous colitis. By 1980, 36 deaths had been reported.[2] Although the problem can occur with other antibiotics, it is more frequently seen with clindamycin and the British National Formulary warns that patients should stop using clindamycin immediately if side-effects develop.
[1]The British National Formulary (No. 26, 1993) says the maximum oral dose for severe infections is 450mg every six hours, i.e., 25mg/kg for a person weighing 70 kg taking 4 doses in 24 hours. Rats and dogs could tolerate more than 300mg/kg (J. E. Gray, et al, Toxicology and Applied Pharmacology, 1972, vol. 21, pp.516- 531).
[2]G. R. Venning, British Medical Journal, 15 January 1983, pp.199-202.
Leukaemia treatment.
For decades, in an attempt to find a treatment for leukemia, tens of thousands of chemicals have been used in mice which have been given leukaemia. This has proved highly ineffective. One scientist has estimated that for every 30-40 drugs that are effective in treating mice with cancer, only one will work with humans.[1]. During the 1980s, researchers admitted that the American NCI (National Cancer Institute) was failing to identify promising new treatments.[2][3]
A new strategy involves test tube studies rather than mice, at least for the preliminary experiments. Drugs that appear to be promising are then tested on animals so the prospect of misleading results is still very much there.[4]
[1]D. D. Von Hoff, Journal of the American Medical Association, 10 August 1979, p.503.
[2]R. Kolberg, Journal of NIH Research, 1990, vol. 2, pp.82- 84.
[3]A. Pihl, International Journal of Cancer, 1986, vol. 37, pp.1-5.
[4]S. E. Salmon, Cloning of Human Tumor Stem Cells (Alan Liss, 1980).
Pronethalol and Propranolol.
The first agents used as beta-blockers, for the treatment of heart conditions, were pronethalol and propranolol. While pronethalol was found to be safe and effective with laboratory animals, but failed the clinical tests, propranolol appeared to be toxic in numerous animal experiments, and yet it is widely used in clinical practice, i.e., treating humans.
Pronethalol was 'well tolerated' by rats and dogs in prolonged toxicity tests at high doses except for occasional effects on the central nervous system.[1] In complete contrast, clinical trials revealed an unacceptable number of side-effects,[2] including heart failure - a hazard not predicted by the animal experiments which had been conducted.[1] Shortly after, long-term tests in a particular strain of laboratory mouse produced cancer of the thymous gland but no carcinogenic effects were ever found in rats, guinea pigs, dogs, monkeys or other types of mouse.[1]
Pronethalol was promptly replaced by propranolol but tests in rats, dogs and mice resulted in further development being jeopardized.[3] Moderate to high doses caused rats to collapse and dogs to vomit severely.[1] Deaths also occurred in mice shortly after dosing. When the amount of the drug was reduced to the dosage that would be used by humans, propranolol was said to be 'well tolerated', although even then, some of the rats still had heart lesions.[1]
[1]M. Cruickshank, et al, Safety Testing of New Drugs, eds. D. R. Lawrence, et al (Academic Press, 1984).
[2]W. Sneader, Drug Discovery: The Evolution of Modern Medicine (Wiley, 1985).
[3]D. R, Laurence, et al, eds., Safety Testing of New Drugs (Academic Press, 1984).
Librium and Valium.
These were the first of a new type of tranquillizing drug which appeared in the 1960s. Soon after their introduction, the medical profession became aware of cases of dependence although it was nevertheless believed that high doses were necessary.[1] At the usual therapeutic doses, dependence was thought to be uncommon and not a serious problem and this idea prevailed for some twenty years as laboratory research confirmed it: 'animal experiments...do not indicate the potential for the development in the human of dependence at therapeutic dosage levels'.[2]
At the same time it is also known that 'animal studies...do not predict clinical dependence potential reliability',[3] and careful human observations revealed that tranquillizers could in fact induce dependence at ordinary doses. By the mid-1980s, some 500,000 people in Britain alone were addicted to this treatment.[4]
[1]H. Peturrson and M. Lader, Dependence on Tranquillizers (OUP, 1984).
[2]J. Marks, The Benzodiazepines (MTP Press, 1978).
[3]Drug and Therapeutics Bulletin, 1989, vol. 27,28.
[4]The Benzodiazepines in Current Clinical Practice, eds., H. Freeman and Y. Rue (Royal Society of Medicine Services, 1987).
Rifampicin.
In the early 1970s, doctors became aware of women who, while using 'the pill', became pregnant.[1] Of 88 women who used oral contraceptives in addition to the antituberculous drug rifampicin, 75% suffered disturbances to their menstrual cycle and 5 became pregnant. The British National Formulary (1993) advised doctors who prescribed rifampicin to recommend to patients that they use additional means of contraception.
It was discovered that rifampicin accelerates the breakdown of other medicines,[2] and in these cases it had stimulated the patient's liver to metabolize/breakdown the pill. Another example was methadone where rifampicin led to withdrawal symptoms by reducing the amount of the drug. In one case, a patient rejected a kidney graft because rifampicin reduced the dose of the immunosuppresive drug which had been given.
Rifampicin's peculiar effects had not been predicted by animal experimentation.[3] After the discovery of the effects in humans, further animal experimentation was conducted but this proved contradictory. For example. the drug's action could not be reproduced in rats.[4] In mice however, prolonged treatment with rifampicin did stimulate the liver's metabolic processes; however a single dose had the opposite effect of slowing down metabolism.[4] If rifampicin had been tested on human liver tissue rather than on live animals, it is likely the problems would have been predicted.[5]
[1]Reported in J. P. Mumford, British Medical Journal, 11 May 1974, pp.333-334.
[2]H. Meyer, et al, in Meyer's Side Effect of Drugs, 11th edn., ed. M. N. G. Dukes (Elsevier, 1988).
[3]E. Nieschlag, Pharmacology and Therapeutics, 1979, vol. 5, pp.407-409.
[4]D. Pessayre and P. Mazel, Biochemical Pharmacology, 1976, vol. 25, pp.943-949.
[5]A. M. Jezequel, et al, Gut, 1971, vol. 12, pp.984-987.
Taxoxifen.
This was developed during the 1960s as an oral contraceptive. However, while it prevented ovulation and terminated pregnancy in rats,[1] it stimulated ovulation in women and became listed as a treatment for infertility.[2]
It is used also in breast cancer therapy as it blocks the action of oestrogen in breast tissue. In monkeys, and rats at low doses, it also acts as an anti-oestrogen, but in mice, dogs, and rats at high doses, it has the opposite effect, behaving like an oestrogen.[1] Due to the different results of animal experimentation, it was admitted that 'significant species variation has been observed in target tissue response to oestrogens and anti-oestrogens making it hazardous to predict therapeutic activity in the human by extrapolation of effects in experimental animals'.[3]
Other conflicting results from animal testing has occurred, e.g., taxoxifen produces liver tumours in rats but not in mice,[4] and does not appear to do so in humans. Due to the conflicting results the two leading British cancer charities disagreed over taxoxifen and the Medical Research Council withdrew its support and decided to initiate new tests. The Imperial Cancer Research fund said: 'We are going to be in a position where the animal rights people are going to be saying to us: 'you ignore animal data when you choose to'.'[5]
Yet further doubts arose through a subsequent study which suggested an increased risk of womb cancer among the breast cancer patients being tested with the drug. However overall, the drug is said to have few side-effects and according to the manufacturer, the main reason to stop taking the drug is if nausea and vomiting begin.[1] This comes as a surprise as it had been noted: 'None of the toxicological studies produced any evidence of vomiting even though high doses were used in dogs which we consider to be a predictive species for vomiting in man.[1].
[1]M. J. Tucker, Safety Testing of New Drugs, eds. D. R. Laurence, et al (Academic Press, 1984).
[2]British National Formulary, No. 26 (BMA and the Royal Pharmaceutical Company of GB, 1993).
[3]P. K. Devi, in Pharmacology of Estrogens, ed. R. R. Chaudhury (Pergamon Press, 1981).
[4]I. N. White, et al, Biochemical Pharmacology, 1993, vol. 45, pp.21-30.
[5]P. Brown, New Scientist, 21 March 1992, p.9.
Steroids.
Corticosteroid drugs are widely used in medicine although they have many side-effects. It is admitted that there are 'remarkable differences in susceptibility to glucocorticosteroids between various species' with animals classified as steroid-resistant or steroid-sensitive.[1]
In mice, a single dose of cortisone produces a 90% decrease in the thymus (an organ that plays a crucial role in immunity). In contrast, the same dose of cortisone given to a guinea-pig every day for a week, only produces a 37% decrease. Furthermore, the same effect is difficult to achieve in other species.[1]
Much of the research on corticosteroids have been carried out on steroid-sensitive animals (e.g., mice, rats, rabbits, and hamsters) whereas human beings fall into the steroid-resistant category.[1] Researchers at the University of Dundee acknowledged: 'the mode of action of these drugs is very complicated, so it is regrettable that most of the extensive literature on animal experimental work is irrelevant to human therapeutics since many species respond in a very different manner from man'.[2]
[1]H. N. Claman, New England Journal of Medicine, 24 August 1972, pp.388-397.
[2]J. S. Beck and M. C. K. Browning, Journal of the Royal Society of Medicine, 1983, vol. 76, pp.473-479.
X-rays.
In 1956, the British medical profession drew attention to a link between X-rays during pregnancy and subsequent childhood cancers.[1] Within a short time, similar findings were reported in respect of American children. And yet for a quarter of a century, scientists doubted that X-rays could cause such cancer and cited animal experimentation to argue that the foetus is not particularly sensitive to radiation.[2]
In fact, compared with other species, the human foetus is more susceptible to the carcinogenic effects of X-rays,[2] and this was confirmed during the 1980s.[3]
[1]A. M. Stewart, et al, Lancet, 1 September 1956. p.447; British Medical Journal, 28 June 1958, pp.1495-1508.
[2]E. B. Harvey, et al, New England Journal of Medicine, 28 February 1985, pp.541-545.
[3]E. G. Knox, et al, Journal of the Society of Radiological Protection, 1987, vol 7, pp.3-15; E. A. Gilman, et al, Journal of the Society of Radiological Protection, 1988, vol. 8, p.308.
Methanol.
This is used in a wide range of consumer products, e.g., solid fuel, antifreeze, paint remover and varnishes. It is also consumed as a heap alternative to alcohol.
Although methanol is a highly poisonous, potentially lethal substance, this was not realized for some years.[1] Laboratory animals such as rats and mice are resistant to its effects,[2] and animal experiments in the early part of the twentieth century gave the impression that methanol was only marginally toxic, and far less poisonous than alcohol.[3]
In reality, methanol is ten times more toxic; a single dose of methanol can result in temporary or permanent blindness in human beings.[4] However, this does not occur in rats, mice, dogs, cats, rabbits or chickens.[3] It was only in the 1960s and again in the next decade that the actual symptoms of methanol poisoning were induced in monkeys.[2]
As is obvious from the above, animal experimentation was both highly misleading and dangerous. Some good treatment results were obtained in the earlier part of the twentieth century by using bicarbonate to treat human poisoning, but the results were undermined by animal experimentation. In 1955 an analysis stated: 'It is indeed deplorable that about thirty years before the good effects of this treatment became commonly known...it seems that the authors of medical textbooks have paid more attention to the results of animal experimentation than to clinical observations'.[3] The treatment not only failed in animals but actually proved fatal, prompting some researchers to advise against using it.
Another method involves administering alcohol to reduce the toxicity of methanol. While this is effective in human beings, animal tests suggested that this practice would increase the danger of methanol. Once again, animal experimentation discouraged using this method of treating human poisoning.[3]
[1]M. J. Ellenhorn and D. G. Barceloux, Medical Toxicology: Diagnosis and Treatment of Human Poisoning (Elsevier, 1988).
[2]T. R. Tephly, Life Sciences, 1991, vol. 48, pp.1031- 1041.
[3]O. Roe, Pharmacological Reviews, 1955, vol. 7, pp.399- 412.
[4]P. Wingate, Medical Encyclopedia, (Penguin, 1983).
Aminorex.
During the 1960s, physicians in Switzerland became aware of a sudden rise in obstructive pulmonary hypertension, a dangerous lung disease. The cause was traced to the drug aminorex which had been used for treating obesity.[1] The drug was found to cause chest pains, difficulty in breathing, fainting, heart problems and in some cases, death.[2] The deadly side-effects of this drug had not been predicted by the animal experimentation which had been conducted.[3]. In view of its dangers, the drug was withdrawn in 1968.
Animal experimentation continued after withdrawal and even then, long administration to rats failed to induce the disease.[2] In dogs, the drug increased lung pressure,[1] but its relevance to the human condition is unclear since later analysis concluded that: 'pulmonary hypertension cannot by induced in experimental animals even with aminorex'.[4]
[1]F. Follath, et al, British Medical Journal, 30 January 1971, pp.265-266.
[2]E. H. Ellinwood and W. J. K. Rockwell in Meyler's Side Effects of Drugs, 11th edn, ed. M. N. G. Dukes (Elsevier, 1988).
[3]A. D. Dayan in Risk-Benefit Analysis in Drug Research, ed. J. F. Cavalla (MTP Press, 1981).
[4]P. H. Connell in Side Effects of Drugs Annual - 3, ed. M. N. G. Dukes (Excerpta Medica, 1979).
Diethylstilbestrol (DES).
On the basis of what animal experimentation revealed, the synthetic oestrogen Diethylstilbestrol (DES) was suggested as a means by which miscarriage could be avoided.[1] Although no proper clinical, i.e., human, trials were conducted,[2] the procedure became widely accepted and to 1971, up to 3 million pregnant women in America alone were given DES.
However, DES was found to be ineffective; in 1953 trials had shown that DES did not work,[3] although this study failed to report that DES increased abortion, neonatal deaths and premature deaths, a conclusion that could have been made from the available data.[4]
Thus, DES was not only ineffective, it was dangerous and in 1971, researchers discovered how dangerous it was when they traced a link between exposure to DES and a previously rare form of vaginal and cervical cancer in the daughters of those women who had taken the drug while pregnant.[5] Nearly six hundred cases were reported,[6] and DES proved to be a biological time-bomb as its side-effects continued to appear in the sons and daughters of women who took the drug.
Although, in 1938, it was found that DES caused breast cancer in male mice, this information was of no value as the cancer-causing potential of other oestrogens varied according to the strain of mouse used.[7] Furthermore, the consensus among vivisectors at the time was that oestrogens did not produce cancer,[7] rather they gave male mice mammary glands and therefore made them susceptible to the same cancer-causing factors that arose in female animals. In fact, a summary of the animal data found 'only meagre evidence' that oestrogens caused cancer of the cervix.[7]
It was not until the 1970s that it became clear that in contrast to the majority of animal experiments, DES was a potent cause of cervical cancer in women.
[1]Health Action International, 'Problem Drugs' pack, 13 May 1986.
[2]D. Brahams, Lancet, 15 October 1988, p.916.
[3]W. J. Dieckmann, et al, American Journal of Obstetrics and Gynaecology, 1953, vol. 66, pp.1062-1081.
[4]Y. Brackbill and H. W. Berendes, Lancet, 2 September 1978, p.520.
[5]A. L. Herbst, et al, New England Journal of Medicine, 22 April 1971, pp.878-881.
[6]C. Vanchieri, Journal of the National Cancer Institute, 1992, vol. 84, pp.565-566.
[7]S. Peller, Cancer in Man (Macmillan, 1952).
Pethidine.
On the basis of experiments with dogs, the narcotic analgesic pethidine was considered to be non-addictive.[1] This error was not realized because in dogs, the drug was metabolized (broken down) much more quickly, resulting in less exposure to the drug. In fact, dogs metabolize pethidine six times faster than humans.[2]
Such differences in metabolism are the rule rather than the exception;[2,3] a former director of Wellcome Research Laboratories admitted that 'every species has its own metabolic pattern, and no two species are likely to metabolize a drug identically'.[4]
[1]B. Brodie, Pharmacologist, 1964, vol. 6, pp.12- 26.
[2]R. Levine, Pharmacology, Drug Actions and Reactions (Little, Brown and Co, 1978).
[3]G. Zbinden, Advances in Pharmacology, 1963, vol. 2, pp.1-112.
[4]M. Weatherall, Nature, 1 April 1982, pp.387-390.
Digoxin and Digitoxin.
These heart drugs are pure substances extracted from digitalis, the value of which in treating heart failure and cardiac arrhythmias originated from the studies of human patients;[1,2] (despite its value, care must be taken over high doses which can be toxic). Fortunately the drugs did not derive from animal experiments as the doses which were considered safe for rats, guinea-pigs, dogs and cats can in fact kill human beings.[3] Digoxin's lethal dose is now more accurately determined by test-tube studies using human cells.[4]
Animal experimentation also indicated that digitalis raised the blood pressure and as a result of this, the drug was widely considered to be dangerous for certain patients and should not be prescribed to them. Fortunately, studies, not using animals, showed this to be false and digitalis can be, and is used for the treatment of human patients with great benefit.[2]
[1]W. Sneader, Drug Discovery: The Evolution of Modern Medicine (Wiley, 1985).
[2]T. Lewis, Clinical Science (Shaw and Sons Ltd, 1934).
[3]G. T. Okita, Federation Proceedings, 1967, vol. 26, pp.1125-1130.
[4]R. Jover, et al, Toxicology In Vitro, 1992, vol. 6, pp.47-52.
Detergents.
Detergents are not only used in domestic and industrial settings, i.e., experimentation which sought to increase the penetration of therapeutic drugs across the cornea used a number of dilute detergents which were assessed in the eyes of human volunteers. Although these were deemed 'generally harmless to rabbit eyes', some caused pain and irritation in the human volunteers.
For example, Brij 58 resulted in 'alarming' changes to the surface of the human eye, accompanied by discomfort and impaired vision.[1] And yet in rabbits, Brij 58 is designated a 'non-irritant'.[2]
A 3% solution of a similar product called Brij 35 produced delayed irritation in volunteers but was once again non- irritating to the rabbit eye, and this was even when undiluted.[1] Another detergent, dupanol, caused immediate severe pain in human subjects,[1] but was deemed to only have moderate effects in the eyes of rabbits.[3]
[1]R. J. Marsh and D. M. Maurice, Experimental Eye Research, 1971, vol. 11, pp.43-48.
[2]M. Cornelis, et al, ATLA, 1991, vol. 19, pp.324- 326.
[3L.W. Hazelton, Proceedings of the Scientific Section of the T.G.A, 1952, vol. 17, pp.509.
Cancer treatment.
Many cancer patients suffered unnecessarily when it was believed that large doses of anticancer drugs were necessary for efficient treatment. It was held that to reduce the tumour size, chemotherapy also had to be toxic.[1]
This idea was based on animal experimentation,[1,2] even though there were early warning signs that patients survived longer when treated with comparatively non-toxic doses, despite the drug having a smaller effect on the tumour size.[3]
Studies in the 1960s concluded that toxicity was not necessary and could be counterproductive.[2] In 1976, cancer specialists in London found that the data from animal experimentation, on which the high dose concept was based, are not necessarily valid for human patients,[1] and argued that 'alternative methods of improving the selectivity of cancer chemotherapy must be explored'.
[1]M. H. N.Tattersall and J. S. Tobias, Lancet, 13 November 1976, pp.1073-1074.
[2]I. D. Bross, Perspectives on Animal Research, 1989, vol. 1, pp.83-108.
[3]M. A. Schneiderman and M. J. Krant, Cancer, Chemotherapy Reports, 1966, vol. 50, pp.107-112.
AIDS.
The fact that even chimpanzees do not develop AIDS when infected with HIV naturally casts doubts on whether animal experimentation concerned with AIDS can have any possible value.[1] Some AIDS researchers appear to have grasped this fact as vaccines which failed to protect chimpanzees from HIV were nevertheless tried in human trials.[2]
Animal experimentation has the potential to be dangerous as the failure to induce AIDS in laboratory animals has led some to argue that HIV is not the cause of AIDS.[3]
There is a further danger by producing an 'animal model' of AIDS as this may simply produce an animal version of AIDS and could also promote hazardous changes in the manner in which AIDS is spread.
[1]P. Newmark, Nature, 19 October 1989, pp.566-567.
[2]A. S. Fauci and P. J. Fischinger, Public Health Reports, 1988, vol. 103, pp.203-236.
[3]New Scientist, 3 March 1988, p.34.
[4]J. Marx, Science, 16 February 1990, p.809. P. Lusso, et al, Science, 16 February 1990, pp.848-852.
Furosemide.
Furosemide is successfully used for the treatment of cardiovascular and kidney disease in human beings. However, in mice it causes massive liver damage and similar effects have been found in rats and hamsters.[1] And yet liver toxicity is not a major problem for human patients.[2] The harmful effects in mice have been traced to a breakdown product of furosemide which is not found to any serious extent in the human body.[3] Fortunately the adverse effects in mice were reported after the safety in people had been established.[3] If it had been otherwise, the drug may have never been introduced.
A comparison of human and animal test data shows that the case of furosemide is not an isolated instance. At most, only one out of every four side-effects produced by animal tests actually occurs in human beings.[4] Consequently animal testing leads to the rejection of medicines which are potentially valuable for treating human illnesses.
[1]R. M. Walker and T. F. McElligott Journal of Pathology, 1981, vol. 135, pp.301-314.
[2]M. N. G. Dukes in Meyler's Side Effects of Drugs, 11th edition, ed. M. N. G. Dukes (Elsevier, 1988).
[3]M. Weatherall, Nature, 1 April 1982, pp.387-390.
[4]A. P. Fletcher, Journal of the Royal Society of Medicine, 1978, vol. 71, pp.693-698.
Cyclosporin.
This is used to prevent the rejection of transplanted organs: while hailed as a major advance over existing drugs, side- effects are common and sometimes dangerous. The most serious hazard is kidney damage,[1] an effect that was not predicted by the initial animal experimentation.[2] And yet kidney toxicity has been reported in almost 80% of kidney transplant patients receiving the drug.[2] Some heart transplant patients who were treated with cyclosporin required dialysis because their kidneys failed.[3]
Subsequent animal experiments showed that only extremely high doses of cyclosporin could induce kidney toxicity in rats,[1] although dogs and rhesus monkeys were still unaffected.[2] Researchers believe that: '...failure to produce renal dysfunction [kidney damage] experimentally that is similar to that seen clinically may result from species differences in metabolism'.[2]
Although cyclosporin can prevent the rejection of transplanted organs in both animals and human beings, an early review of the drug found sufficient variation in experimental results to indicate: 'the immunosuppressive effects of cyclosporin have...differed considerably between species, limiting any direct inference that may be made regarding use in human organ transplantation...'[1]
[1]D. J. Cohen, et al, Annals of Internal Medicine, 1984, vol. 101, pp.667-682.
[2]W. M. Bennett and J. P. Pulliam, Annals of Internal Medicine, 1983, vol. 99, pp.851-854.
[3]Lancet, 22 February 1986, pp.419-420.
Zelmid.
In September 1987, the antidepressant zimelidine (Zelmid) was withdrawn worldwide after potentially serious side-effects, including nerve damage, leading to the loss of sensation or paralysis.[1]
Some patients experienced hypersensitivity reactions such as fever, joint pains and liver problems. The drug had been introduced only a year earlier but Britain's Committee on Safety of Medicine had received over 300 reports of adverse reactions, 60 of which were serious; there were 7 deaths.[2]
And yet prolonged testing in rats and dogs showed no evidence of toxicity even when they were given five times the human dose.[3]
[1]B. Blackwell in Side Effects of Drugs Annual, vol. 8, eds M. N. G. Dukes and J. Elis (Elsevier, 1984).
[2]R. D. Mann, Modern Drug Use; An Inquiry on Historical Principles (MTP Press, 1984).
[3]R. C. Heel, et al, Drugs, 1982, vol. 24, pp.169- 206.
PARTE 2
Zipeprol.
In 1984 a Milan poison control centre reported 32 patients suffering severe neurological side-effects following an overdose with zipeprol, a cough suppressant.[1] Symptoms included seizures and comas. Animal testing had given no warning of severe neurological problems despite higher doses being given to the animals that were used.[2]
[1] C. Moroni, et al, Lancet, 7 January 1984, p.45.
[2] D. Cosnier, et al, Drug Research, 1976, vol. 26, pp.848-854. G. Rispat, et al, Drug Research, 1976, vol. 26, pp.523-530.
Evicromil.
This was submitted for clinical (i.e., human) trials as an antiasthmatic after being tested on mice, rats, hamsters, rabbits, ferrets, squirrel monkeys, cynomolgus monkeys, stump- tail monkeys and baboons. Despite giving the animals doses many times greater than would be taken by humans, no harmful effects were noted, including the liver.[1] However, 20% of patients participating in the trial developed symptoms of liver damage, which prevented any further development of the drug.[2] Subsequent tests showed that liver toxicity could only be induced in dogs.[1,2]
[1]D. V. Parke, in Animals and Alternatives in Toxicity Testing, eds., M. Balls, et al (Academic Press, 1983).
[2]C. T. Easton, et al, Regulatory Toxicology and Pharmacology, 1990, vol.11 pp.288-307.
Fenclozic acid.
During clinical trials (i.e., on humans), ICI's anti-arthritic drug fenclozic acid produced jaundice in some patients. This was unexpected as testing which was undertaken on rats, mice, dogs and monkeys had given no hint of liver problems.[1] Not content with these results, there were further experiments with rabbits, guinea pigs, ferrets, cats, pigs, horses, neonatal rats and mice, along with a different strain of rat: yet again, no evidence of liver damage could be found.[1]
The ICI researcher commented: 'the quite unexpected onset of jaundice in a few patients caused withdrawal of the drug from humans and initiated a vast programme of experimental work. This search for hepatotoxicity [liver damage] in different species or any indication of its likelihood has so far been unrewarding [in other words, unsuccessful].
[1]S. J. Alcock, Proceedings of the European Society for the Study of Drug Toxicity, 1971, vol. 12, pp.184-190.
Ketoconazole.
In 1985, Britain's Committee on Safety of Medicines issued a warning about serious liver damage associated with the antifungal drug ketoconazole (Nizeral).[1] The Committee referred to 82 cases, with 5 deaths. The warnings followed a similar action by the American FDA in 1982.[2]
Despite this, no evidence of liver toxicity was found in the animal testing.[3]
[1]Lancet, 12 January 1985, p.121.
[2]C. B. M. Tester-Dalderup in Meyler's Side-Effects of Drugs, 11th edn, ed. M. N. G. Dukes (Elsevier, 1988).
[3]J. K. Heiberg and E. Svejgaard, British Medical Journal, 26 September 1981, p.825.
Nutrition.
During the early part of the previous century there was interest in the possibility that a lack of food during childhood might interfere with the development of the brain. Regrettably almost of the research was carried out on animals which showed that starving baby or adult rats had no effect on the brain. The issue was abandoned and not revived until the late 1950s when children with histories of undernutrition were found to persistently underachieve.[1]
Researchers then realized that the earlier animal testing had not taken 'brain growth spurt' into account, this being the time of fastest growth when the brain is most vunerable. Additionally, the timing varies between the different species, i.e., in human babies the brain growth spurt begins during the final period of pregnancy and lasts for about a year, whereas in guinea pigs, it occurs almost wholly during the foetal period, and yet in rats, it occurs during the first three weeks after being born.[2]
Despite the number of starving humans in the world today, there appears to be no shortage of funds for vivisectors who claim to be researching early life undernutrition in animals.
[1]J. Dobbing in Early Nuitrition and Later Behaviour, ed. J. Dobbing (Academic Press, 1987).
[2]J. Dobbing and J. L. Smart, British Medical Bulletin, 1974, vol. 30, pp.154-168.
Eraldin.
Eraldin (Practolol), marketed during the 1970s, was said to be 'particularly notable for the thoroughness with which its toxicity was studied in animals, to the satisfaction of the regulatory authorities'.[1]
In time, serious effects began to be noted, i.e., skin, eye and abdominal disorders. In some cases, patients suffered blindness; sclerosing peritonitis also occurred, resulting in 23 deaths being reported.[2] The manufacturers (ICI) paid compensation to over 1000 victims.[3]
The side-effects of the drug (for the treatment of heart conditions) were not predicted by the animal testing that was conducted. Moreover, subsequent to the drug being withdrawn from the market in 1976, it has not been possible to replicate the side- effects in laboratory animals.[1]
[1]M. Weatherall, Nature, 1 April 1982, pp.387-390.
[2]G. R. Venning, British Medical Journal, 15 January 1983, pp.199-202. 22 January 1983, pp.289-292.
[3]A Question of Balance, Office of Health Economics, 1980.
[4]F. H. Gross and W. H. Inman, Drug Monitoring (Academic Press, 1977).
Cortisone: the eye.
One of the principal side-effects of treating the eye with steroids is glaucoma (high pressure arises within the eye which can lead to loss of sight). And yet when corticosteroids were used in ophthalmology, the animal testing conducted indicated that cortisone did not affect the pressure within the eye.[1]
Later attempts to induce glaucoma in monkeys and rabbits were either difficult or impossible.[2] One group of researchers admitted to: 'the differing response of the eye of man and animals to repeated topical [surface] application of corticosteroids'. They added 'Such a procedure is without effect on tension of the eye of many experimental mammals, but increases tension in the human eye'.[3]
Another side-effect of using steroid treatment which is difficult to replicate in the laboratory animal is the cataract. While slight changes in the lens of the rabbit's eye have been produced - after repeated high doses - they do not mimic the severity of the condition as found in humans.[2]
[1]L. H. Leopold, et al, American Journal of Ophthalmology, 1951, vol. 34, pp.361-371.
[2]W. M. Grant, Toxicology of the Eye, 2nd edn (Charles Thomas, 1974).
[3]B. Ballantyne and D. W. Swanston in Current Approaches in Toxicology, ed. B. Ballantyne (Wright and Sons, 1977).
Talcum powder.
When experiments, using vast amounts of talcum powder, were conducted on animals, these suggested that using talcum powder presented no danger. In 1977 hamsters were exposed to high grade cosmetic talc at nearly two thousand times the amount that babies would encounter, and yet there was no damage to the lungs.[1] Another experiment in the same year involved rats being forced to breathe talc at doses nearly six thousand times the amount used in infant care; despite the amount used, there was only a slight effect on the lungs.[1]
However, subsequent to this time the medical profession had to issue warnings about using talc, e.g. in 1991 physicians at one hospital in Southern England warned that inhaling babies' talcum powder could be fatal.[2] Eight deaths were attributed to inhalation of talc.
[1]Lancet, 25 June 1977, pp.1348-1349.
[2]P. W. Pairaudean, et al, British Medical Journal, 18 May 1991, pp.1200-1201.
CS Gas.
Animal experimentation was responsible for providing incorrect and dangerous information about CS gas. When CR was applied to a rabbit's eye, only 'minor transient changes' occurred in respect of pressure in the eye. However, when a smaller amount was applied to a human eye, this resulted in a 40% increase in pressure in 5 minutes - while in rabbits, this only produced a 3% rise after 10 minutes.[1]
Tests found that human beings are 18 times more sensitive to CS than rabbits, and 90 times more sensitive to CR, another irritant.[2]
Tests involving application to the skin showed CR was a more potent irritant than CS and yet the very opposite was found when tested on rodents.[3] The research also determined that VAN, another sensory irritant, was less potent than CR which, once again, was the very opposite when tested on animals.
[1]B. Ballantyne, et al, in Current Approaches in Toxicology, ed. B. Ballantyne (Wright and Sons, 1977).
[2]D. W. Swanston in Animals and Alternatives in Toxicity Testing, eds. M. Balls, et al (Academic Press, 1983).
[3]R. W. Foster, et al, Pain, 1986, vol. 25, pp.269-278.
Fluoride.
Fluoridation of the water supply is considered to be a primary reason for the decline in dental decay. The adding of fluoride to the water supply does not appear to have caused any health problems.[1]
However, experimentation involving rats gave some indication that it might cause cancer,[2] and yet after an intensive study, the American DHHS (Dept. of Health and Human Services) reported that it had not found any evidence of fluoride causing cancer. Tests involving animals have also suggested other detrimental effects, but the DHHS reported that different species react divergently to fluoride and this made it difficult to apply to humans.[3]
[1]E.g., R. Peto and R. Doll, The Causes of Cancer (OUP, 1981).
[2]Journal of NIH Research, 1991, vol. 3, p.46.
[3]C. Anderson, Nature, 28 February 1991, p.732.
Coumarin.
Coumarin is obtained from the tonka bean, having been used for many years, in consumer items and as a therapeutic agent. However, in the 1950s, there were questions concerning its safety due to animal experimentation that resulted in liver damage in rats. Because of this, coumarin was prohibited as a food flavouring agent.[1]
Later research revealed there was a considerable variation in reactions by different species, e.g. although dogs suffered liver toxicity (as rats), there were only slight effects in baboons.[2] Furthermore those amounts which damaged the liver of rats were harmless to gerbils.[3] The nonsense of vivisection was further demonstrated when it was found that different strains of the same species reacted differently to coumarin.
Patients who receive coumarin, even in high doses, for therapeutic reasons, rarely experience liver toxicity,[1] and rats and dogs are therefore now viewed as unreliable models for testing the substance as they metabolize it in totally different ways.[1,2,3]
[1]J.H. Fentum, et al, Toxicology, 1992, vol. 71, pp.129- 136.
[2]J. G. Evans, et al, Food and Cosmetic Toxicology, 1979, vol. 17, pp.187-193.
[3]W. Endell and G. Seidsel, Agents and Actions, 1978, vol. 8, pp.299-302.
Formaldehyde.
Concern for those people who worked with formaldehyde arose after it was discovered that the substance caused cancer in rats.[1] Despite this, epidemiological studies did not give any indication of cancer arising in such people: additionally, monitoring of workers also found no evidence of this danger.
In fact the rats had been forced to breathe high doses - 7-15 times the amount that workers inhaled - resulting in formaldehyde causing tissue damage and cancers in them.
[1]P. Grasso, Journal of the Royal Society of Medicine, 1989, vol. 82, pp.470-473.
Epilepsy models.
Vivisectors have produced numerous methods of producing fits in laboratory animals; the reason for this is because no particular method is wholly trustworthy.[1]
After suggestions that high amounts of aspartame could cause seizures in some people, the London Institute of Psychiatry conducted experiments, sponsored by Nutrasweet Company and the Wellcome Trust, which involved flashing lights to produce fits in photosensitive baboons. In fact aspartame had no effect on the baboons although conflicting evidence has arisen in other animals. For example aspartame enhances chemically-induced convulsions in mice, but has no effect on electric-shock-induced or sound-induced seizures in these animals.[2]
Similar variations are found with different species. Although the drug THIP reduced convulsions in mice and baboons, it was ineffective when used with epileptic patients.[3]
[1]R. S. Fisher, Research Reviews, 1989, vol. 14, pp.245- 278.
[2]B. S. Meldrum, et al, Epilepsy Research, 1989, vol. 4, pp.107.
[3]Lancet, 26 January 1985, pp.198-200.
Glass Fibre.
Products made from glass wool were produced for decades with animal testing suggesting no health risk. Experiments involving rats, guinea pigs, rabbits and monkeys who were forced to breathe in glass wool fibres showed no damage to lungs.[1]
Subsequent tests during the 1980s confirmed 'an increase in lung tumours or mesothelioma has not been observed following long-term inhalation studies in several animal species including rats, hamsters, guinea pigs, mice, monkeys and baboons, exposed to glass fibres, glass wool or mineral wool'.[2]
Those experiments when rats developed cancer were dismissed as having no relevance for human health. This was due to the fibres being implanted into the membrane of the animal's lung which is in contrast to how humans become exposed, i.e., through breathing; additionally, rats are known to develop cancer when solid substances are implanted in their bodies.[1]
However, in 1991 the American Occupational Safety and Health administration declared that products made of glass fibre were a potential cancer risk.[3] This was after studies involving people working with glass fibre showed an increased risk of lung cancer. In Occupational Lung Disorders, Raymond Parkes notes that 'the production of malignant tumours in animals by direct implantation experiments is unlikely to have any relevance to human exposure'.
[1]Rep. in R. Parkes, Occupational Lung Disorders (Butterworths, 1982).
[2]C. S. Wheeler, Toxicology and Industrial Health, 1990, vol. 6, pp.293-307.
[3]Letter from G. F. Scannell, assistant secretary for OSH, Washington DC, to Richard Munson, Chairman of Victims of Fibreglass, 6 May 1991. The Guardian, 20 July 1991.
Depo-Provera.
In the 1960s, women who used the steroid Depo-Provera to deal with premature labour found that there was a delay in returning to fertility after their babies were born. Because of this, there was an investigation as to whether it could be used as a contraceptive.[1]
When tested on beagle dogs there was a range of serious side- effects including abnormal growths, breast cancer and death from pyometra (pus building up in the uterus), and yet none of these side-effects occurred in women who used Depo-Provera.[2] Researchers could only say that these side-effects were due to the physiological differences between human beings and dogs.[1]
In fact high doses of Depo-Provera can cause cancer in monkeys but the relevance of this is questioned as the tumours arise from a type of cell not found in women. Ironically, the type of cancer produced in monkeys is actually successfully treated by Depo- Provera in women.[1]
In 1991, the Lancet called for certain countries to 'reassess' their existing policies on Depo-Provera as they might be depriving women of a 'reliable, effective and safe method of contraception'.[2] Shortly afterwards, the American FDA then approved Depo-Provera as a long-acting contraceptive for women to use.
[1]Bulletin of the World Health Organisation, 1982, vol. 60, pp.199-210.
[2]Lancet, 5 October 1991, pp.856-857.
Silicosis.
During the late 1930s researchers discovered that the inhalation of metallic aluminium prevented silicosis in rabbits.[1] Consequently, this was used as a means of treating and preventing silicosis in workers,[2] who had to pass through an aluminium dusting chamber in which they inhaled the powder.
In the following decade, studies revealed the process did not work and the Industrial Pulmonary Disease Committee of Britain's Medical Research Council advised against this procedure being used.[3]
In fact the 'treatment' had considerable dangers. While large amounts of aluminium were found to be harmless to animals,[4], lung damage and cancer were reported amongst those working with aluminium.[5] Further studies have shown that Canadian workers who inhaled aluminium powder to prevent silicosis, have symptoms that agree with the idea that aluminium may produce Alzheimer's Disease.[6]
[1]J. J. Denny, et al, Canadian Medical Association Journal, 1939, vol. 40, p.213.
[2]W. R. Parkes, Occupational Lung Disorders, (Butterworths, 1982).
[3]M. C. S. Kennedy, British Journal of Industrial Medicine, 1956, vol. 13, pp.211-223.
[4]L. U. Gardner, et al, Journal of Industrial Hygiene and Toxicology, 1944, vol. 26, pp.211-223.
[5]M. J. Ellenhorn and D. G. Barceloux, Medical Toxicology (Elsevier, 1988).
[6]Lord Walton of Detchant, Journal of the Royal Society of Medicine, 1992, vol. 85, pp.69-70.
Diet and cancer.
Studies of people of different nationalities have revealed that the consumption of too much fat, particularly saturated fat, can lead to cancer of the colon. In contrast, animal experimentation, while confirming excessive fat can be dangerous, indicate that it is not saturated but polyunsaturated fat which is responsible.[1]
Clinical (i.e., human) studies have also shown that a high fibre diet is preferable for health but when tested on animals, there have been conflicting results: some tests have indicated a higher risk of cancer, whereas others suggest a lower risk.[2] Additionally, studies have shown diets which are high in animal protein are hazardous,[3] and yet animal testing indicates this protein is of no relevance.[2]
Human studies confirm that diets which include fruit and vegetables offer protection against colon cancer. However, the natural substances which fruit and vegetables have evolved to ensure protection against predators, actually produce cancer when administered to mice and rats.[4]
[1]J. L. Freudenheim and S. Graham, Epidemiologic Reviews, 1989, vol. 11, pp.229-235.
[2]D. Galloway, Cancer Surveys, 1989, vol. 8, pp.169- 188.
[3]B. Armstrong and R. Doll, International Journal of Cancer, 1975, vol. 15, pp.617-631.
[4]P. H. Abelson, Science, 21 September 1990, p.1357.
Prednisone.
Although Prednisone is a useful drug for treating leukaemia and other cancers which occur in human beings, it does not work in respect of animal tumours, and this includes two types of leukaemia in mice.[1]
Prednisone is even more effectual when used with other anti- cancer medications although yet again animal experimentation provided spurious results, i.e., of six combinations which showed an improvement in health, only one of these was predicted by animal testing.[1]
The background of Prednisone provides further examples of animal testing delaying effective medicine. When researchers claimed they could cure human cancer with adrenal gland extracts in the 1930s, the result was animal testing which was negative and the treatment was therefore jettisoned.[2] It was only later when researchers confirmed that adrenal extracts could be useful in combating some cancers that human trials led to such analogues as Prednisone.
[1]R. J. Johnson and A. Goldin, Cancer Treatment Reviews, 1975, vol. 2, pp.1-31.
[2]B. Reines, Cancer Research on Animals: Impact and Alternatives, (Chicago: NAVS, 1986).
Polio.
Despite the fanciful claims made by pro-vivisectionists that polio is an example of how vivisection can combat human illness, the reality is that animal experimentation delayed a proper insight of polio for many years.[1]
In 1908 there was the announcement that the polio virus had been discovered. Tissue from an infected human resulted in spinal cord disease when injected into monkeys; the animals died with one developing paralysis in both legs. However, negative results had arisen with rabbits, guinea pigs, and mice and it was little more than chance that the researchers had selected Old World monkeys which are susceptible to the disease: if they had used New World monkeys they would have had different results from the experimentation as these monkeys are resistant to the disease.
Believing that a replica of the human form was now available, researchers concentrated on artificially inducing the disease in monkeys; these experiments gave support for the view that the poliovirus entered the system through the nose and it only attacked the CNS (Central Nervous System].[1,2]
And yet in 1907, a study of human cases had revealed that poliomyelitis was not wholly a disease of the CNS, and the gastrointestinal tract was the most likely route of the infection[1]. By 1912, other studies confirmed the intestinal tract as the means by which infection entered the body.
Regrettably because animal experimentation dominated research, most researchers, up to 1937, rejected the view that polio was an intestinal disease. The fact of whether the virus entered the body through the mouth or the nose was of course of major importance as the route dictated the best action to prevent its spread. In 1937, a nasal spray which prevented infection in monkeys was produced; not surprisingly it failed, also sometimes having a lasting side-effect, when it was used by human beings.[1]
It was only after the idea of the nasal route of infection, based on animal testing, was rejected and it was recognized that the polio virus entered the mouth and first resided in the intestines that a vaccine, orally administered could be produced. A solution was further delayed when monkeys were then used in time-consuming and expensive testing for the presence of the virus; tissue was inoculated into monkeys who were then examined for spinal cord damage. Progress was made when in 1949, Enders, Weller and Robins showed that the polio virus could be grown in human tissue culture; in this environment changes in infected cells, produced by the virus, could be monitored by microscope. If this alternative had been adopted an at earlier stage, there can be no doubt that progress would have been quicker, and both animal and human suffering would have been far less. However, valuable time was wasted through vivisectors asserting that the virus could only grow in the CNS, and the 'monkey model' of polio delaying the tissue culture development which was crucial to discovering a vaccine.[1,3]
[1]J. R. Paul, A History of Poliomyelitis (Yale University Press, 1971).
[2]H. F. Dowling, Fighting Infection (Harvard University Press, 1977.
[3]A Critical Look at Animal Research (Medical Research Modernization Committee, New York, 1990).
Antibiotics.
Particular animals, i.e., guinea pigs and hamsters, are especially sensitive to the negative effects of anti-biotic treatment. Ampicillin, Amoxycillin and Oxytetracycline are anti- biotics widely used by human beings but they are deemed 'toxic' and therefore inappropriate for guinea pigs and hamsters.[1] In the case of the Erythromycin, the usual human dose will kill a hamster.[2]
In Drug Development: From Laboratory to Clinic, Dr Walter Sneader noted that if guinea pigs had been used when penicillin was first tested, this valuable treatment would have almost certainly been abandoned as these animals are hypersensitive to penicillin. Florey, one of the scientists who carried out animal testing after Fleming's discovery of penicillin , admitted: 'If we had used guinea pigs exclusively, we should have said that pencillin was toxic, and we probably should not have proceeded to try and overcome the difficulties of producing the substance for...man'.[3] Thus, this is yet another example of how different animals provide different results in testing, and once again shows that the use of animals can, and does, impede medical progress.
[1]A. A. Tuffery (ed.), Laboratory Animals - An Introduction for New Experimenters, (Wiley, 1987).
[2]A single minimum recommended dose of erythromycin is 250-500mg every 6 hours, i.e., 3.5-7.0 mg/kg for a 70kg person. The lethal dose for hamsters is 3.5mg/kg.
[3]H. Florey, Conquest, January 1953.
Cancer.
In the first decade of the last century, epidemiology had identified a number of causes of cancer.[1] One of the earliest observations was that of Potts, an English surgeon who in the eighteenth century identified soot as a carcinogen in chimney sweeps. However, attempts to replicate his findings in animals failed,[2] although in 1918 researchers in Japan announced that cancer could be produced - on the ear of a rabbit by continually painting it with tar.
Progress was delayed by a dependence upon animals: the British epidemiologist Sir Richard Doll observes that human observational data was often dismissed because it was felt that success would be found in the laboratory.[1] When studies correctly reported that people who consumed high large amounts of fruit and vegetable were less likely to develop cancer,[3] little attention was given.[1]
Due to the lack of human epidemiological data, erroneous ideas arising from animal experimentation abounded; although only 5% of Western cancers are connected to viral infections,[4], e.g., some scientists believed that most, possibly all cases, were caused by viruses, an idea which arose from animal testing. One animal researcher even claimed that women should not breast feed their babies because, as in mice, a virus caused breast cancer which could be acquired in the mother's milk.[5]
After the Second World War, there was a greater interest in epidemiology with the realization that smoking caused lung cancer. In the years following there has been a greater awareness that the vast majority of instances of cancer can be prevented. Noteworthy is the 1980 US Congress Office of Technology Assessment Report on the causes of cancer which relied more far more on epidemiology than laboratory testing as these 'cannot provide reliable risk assessment'.[4]
Sadly, the curse of cancer is still very much with us and is likely to continue as long as animal experimentation is used in attempts to find the solution.
[1]R. Doll, Cancer, 1980, vol. 45, pp.2475-2485.
[2]W. H. Woglom, Archives of Pathology, 1926, vol. 2, pp.533-576.
[3]P. Stocks and M. N. Karn, Annals of Eugenics, 1933, vol. 5, pp.237-280.
[4]R. Peto and R. Doll, The Causes of Cancer (OUP, 1981).
[5]J. Furth, Bulletin of the New York Academy of Medicine, 1964, vol. 40, pp.421-431.
Opren.
Opren (Oraflex in America), to treat arthritis, was withdrawn in August 1982 after reports of deaths and serious liver damage after people had used the drug.[1] Since 1980, when it first appeared in the UK, there were some 3,500 reports of adverse effects with 61 deaths, mainly involving the elderly.[2]
Researchers declared Opren was a drug where the injuries could not be predicted from animal experimentation,[3] and Dista, which marketed Opren in Britain acknowledged that after Opren was studied for a year using rhesus monkeys, 'there were no apparent adverse effects on survival'.
[1]E. M. B. Sorensen, Toxicology Letters, 1986, vol. 34, pp.277-286.
[2]British Medical Journal, 14 August 1982, pp.459- 460.
[3]C. T. Eason, et al, Regulatory Toxicology and Pharmacology, 190, vol. 11, pp.288-307.
Stroke treatment.
Experimentation on rabbits, dogs, gerbils and monkeys suggested that the use of barbiturates could offer protection against the effects of a stroke,[1] and yet in humans, barbiturates were found to offer little or no protection.[2] In fact between 1978 and 1988, some 25 drugs which were found to be useful in treating animals with artificially-induced stokes did not come into general use.[2]
Some researchers have argued that an over-reliance on animal models may impede progress in treating the disease,[2] and Mayo Clinic researchers also acknowledged 'the answers to many of our questions regarding the underlying pathophysiology and treatment of stroke do not lie with continued attempt to model the human situation perfectly in animals, but rather with the development of techniques to enable the study of...living humans'.[2]
[1]Stroke, vol. 6, pp.28-33, 1974, vol. 5, pp.107, 1972, vol. 3, pp.726-732, Neurology, 1975, vol. 425, pp.870-874, Annals of Neurology, 1979, vol. 5, pp.59-64.
[2]D. O. Wiebers, et al, Stroke, 1990, vol. 21, pp.1-3.
Omeprazole.
A new test, developed by Glaxo, raised concerns about Omeprazole, an ulcer treatment produced by Astra, in respect of causing stomach cancer. The test involves dosing rats with a drug/substance and then removing tissue which is analysed for effects on the DNA. Interference with DNA is deemed to be a possible first step to cancer.
The test showed that Omeprazole damaged the DNA while it also showed that Ranitidine (Zantac), Glaxo's own anti-ulcer drug, did not.[1] Because of the test result, Glaxo ended the comparative trials of Ranititide and Omeprazole which the Lancet commented would almost certainly affect prescription.[2]
Astra responded by claiming that Glaxo's testing method was 'scientifically unsound' and the results had 'no clinical consequences'.[3] Astra went on to say that its own tests showed that after administering Omeprazole to rats for up to 2 years, to mice for 18 months, and to dogs for 12 months, there was 'no evidence for a direct carcinogenic potential in the stomach or elsewhere' - the very opposite of Glaxo's conclusion after its animal testing.
[1]B. Burlinson, et al, Lancet, 17 February 1990, p.419.
[2]Lancet, 17 February 1990, p.386.
[3]L. Ekman, et al, Lancet, 17 February 1990, pp.419- 420.
Encainide and Flecainide.
A study conducted in America discovered that two drugs which were designed to prevent irregular heart beats could cause certain types of patients to have heart attacks. CAST (Cardiac Arrhythmia Suppression Trial) commenced in 1987 but was concluded within two years after physicians discovered that more deaths occurred in those patients using encainide and flecainide than those who received a placebo (a dummy pill).[1]
These findings led to estimates that nationally, some 3000 people may have prematurely died after using these drugs,[2] and yet animal testing had indicated that encainide and flecainide were safe and effective.[3]
[1]CAST Investigators, New England Journal of Medicine, 10 August 1989, pp.406-412.
[2]Dr. J. Morganroth reported in Washingon Times, 26 July 1989.
[3]Flecainide: B. Holmes and R. C. Heel, Drugs, 1985, vol. 29, pp.1-33. Encainide: D. C. Harrison, et al, American Heart Journal, 1980, vol. 1090, pp.1046-1054, and J. E. Byrne et al, Journal of Pharmacology and Experimental Therapeutics, 1977, vol. 200, pp.147-154.
Olive Oil.
Olive oil has been used without any noticeable ill-effect on the human body for thousands of years.[1] And yet testing undertaken at New York University showed that olive oil had a harmful effect when it was applied to the skin of rats, e.g., swelling.[2]
[1]M. M. Rieger and G. W. Battista, Journal of the Society of Cosmetic chemists, 1964, vol. 15, pp.161-172.
[2]E. O. Butcher, Journal of Investigative Dermatology, 1951, vol. 16, pp.85-90.
Skin tests.
Rabbits and guinea-pigs are frequently used in respect of assessing irritancy; this is despite the fact that these animals do not provide accurate results. For example, animal experiments indicate that hypochlorite bleach is safe for human usage as it only results in 'slight visible irritation' in rabbits and guinea pigs.[1] In reality, in humans, it causes severe skin reactions.
[1]G. A. Nixon, et al, Toxicology and Applied Pharmacology, 1975, vol. 31, pp.481-490.
Cancer and smoking.
In 1954, the results of an investigation into smoking was published; this showed that the likelihood of developing lung cancer increased in accordance with the number of cigarettes which were smoked.[1] By this time, a number of other reports had also been published asserting much the same thing. However researchers continued to argue that claiming lung cancer and smoking were linked was unwarranted due to the disease not being produced in laboratory animals.[2]
In 1956, the British Empire Cancer Campaign (the forerunner to the Cancer Research Campaign) advised that during two years of experimentation with mice, rabbits and other animals which involved them being exposed to tobacco derivatives by inhalation, feeding, injection and skin painting, none had developed cancer.[3]
Consequently, due to the negative results of the animal experimentation, health warnings about the dangers of smoking were delayed for several years: further experimentation showed that it was either difficult or impossible to induce lung cancer in animals using the inhalation method.[4]
[1]R. Doll and A. B. Hill, British Medical Journal, 26 June 1954, pp.1451-1455.
[2]Reported in S. Peller, Quantitative Research in Human Biology (J. Wright and Sons, 1967).
[3]Reported in E. Northrup, Science Looks at Smoking (Conrad-McCann, 1957).
[4]Lancet, 25 June 1977, pp.1348-1349. See also F. T. Gross, et al, Health Physics, 1989, vol. 56, p.256.
Asbestosis.
In 1907, the lung disease asbestosis (caused by breathing in asbestos) was recognised. Although research into this condition, using animals, commenced in 1925, most of the results were contradictory. For example, in 1930 on the basis of the animal testing conducted, researchers designated the chrysotile, amosite and crocidolite forms of asbestos as harmless .[1] And yet others determined that while chrysotile caused lung damage in guinea pigs, it did not do so in rabbits.[2]
Researchers using animals then reported that injuries caused by asbestos began to heal when the animals were removed from the asbestos-dust environment.[2] This is in stark contrast to humans when asbestosis advances even after the person is no longer exposed. It was only later that animal researchers were able to mimic this feature in animals.[3]
Concern grew when it was announced that there was a link between asbestos and lung cancer, and yet attempts to induce cancer in animals were unsuccessful. Because of this, even though there was considerable evidence of the link from asbestos workers, there was doubt about the carcinogenic effect of asbestos until the 1960s.[4,5] It was only then that researchers could mimic the condition in animals.
The Annals of the New York Academy of Sciences says that before this: 'a large literature on experimental studies has failed to furnish any definite evidence for induction of malignant tumours in animals exposed to various varieties and preparations of asbestos'.[6]
[1]Reported in L. U. Gardner, Journal of the American Medical Association, 19 November 1938, pp.1925-1936.
[2]J. C. Wagner, British Journal of Industrial Medicine, 1963, vol. 20, pp.1-12.
[3]J. C. Wagner, et al, British Journal of Cancer, 1974, vol. 29,. pp.252-269.
[4]P. E. Enterline in Epidemiology and Health Risk Assessment, ed. L. Gordis (OUP, 1988).
[5]P. E. Enterline. American Review of Respiratory Diseases, 1978, vol. 118, pp.975-978.
[6]W. E. Smith, et al, Annals of the New York Academy of Sciences, 1965, vol. 132, pp.456-488.
Ibufenac.
This anti-inflammatory medication became available in Britain during the mid-1960s but had to be withdrawn within two years after deaths occurred; the primary cause being liver damage.
This happened despite 'extensive' animal testing in which mice, rats and dogs were used; these showed no indication of liver damage (apart from a slight effect in rats exposed to a lethal dose).[1]
Dr M. F. Cuthbert of the British Department of Health and Social Security's Medicine Division admitted: 'Evidence of liver damage is sometimes detected in animal studies of non-steroidal anti- inflammatory drugs, but usually no such evidence is forthcoming even in circumstances when a drug is eventually shown to be hepatotoxic [liver-damaging] to man'.[1]
[1]M. F. Cuthbert, Current Approaches in Toxicology, ed. B. Ballantyne (Wright and Sons, 1977).
Fialuridine (FIAU).
Trials at America's National Institutes of Health of a new drug to combat hepatitis B were halted in the Summer of 1993 after complications and deaths occurred among those involved in the trials. Although fialuridine was supposed to improve the condition of persons suffering from liver disease, many of those who had prolonged treatment experienced a deterioration in their health; some died from liver failure.[1]
And yet the drug was found to be safe in animal experiments,[1] reducing the amount of the virus in the preferred animal model used; tests for toxicity were also conducted in mice, rats and rhesus monkeys. Indeed one of the principal investigators asked: 'Why didn't the animal toxicity studies show any abnormality at all due to the drug?'.[2]
In fact the metabolism of anti-viral drugs is considered to be very different in animals and humans.[3].
[1]N. Touchette, The Journal of NIH Research, 1993. 5, pp.33-55.
[2]J. Hoofnagle, reported in [1].
[3]C. Macilwain, Nature, 22 July 1993, p.275.
Hytrin (Abbott Laboratories Ltd)
Containing terazosin as terazosin hydrochloride.
Use: Hytrin is indicated in the treatment of mild to moderate hypertension.
Contra-indications, warnings etc: Carcinogenicity: Hytrin has been shown to produce tumours in male rats when administered at a high dose over a long period of time. No such occurrences were seem in a similar study in mice. The relevance of these findings with respect to the clinical use of the drug in man is unknown.
Losec (Astra Pharmaceuticals Ltd)
Contains omeprazole as enteric-coated granules.
Use: Treatment of reflux oesophagitis. Treatment of duodenal and benign gastric ulcers including those complicating NSAID therapy.
Contra-indications, warnings, etc: Animal toxicology: Gastric ECL-cell hyperplasia and carcinoids, localised to the oxyntic mucosa, have been observed in life-long studies in rats. These changes have been related to sustained hypergastrinaemia secondary to acid inhibition, and not from a direct effect of any individual drug. No treatment related mucosal changes have been observed in patients treated continuously for periods up to 5 years.
Dtic-dome (Bayer plc)
Active ingredient: 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide prepared as the citrate salt (dacarbazine).
Use: metastatic malignant melanoma, sarcoma, Hodgkin's disease.
Contra-indications, warnings, etc: Studies have demonstrated this agent to have a carcinogenic and teratogenic effect when used on animals.
Ridaura Tiltab tablets (Bencard)
Containing 3 mg auranofin.
Use: In the management of adults with active progressive rheumatoid arthritis only when non-steroidal anti-inflammatory drugs have been found to be inadequate alone to control the disease, i.e. when second-line therapy is required.
Contra-indications, warnings, etc: Gold has been shown to be carcinogenic in rodents although there was no evidence of carcinogenicity in 7 year dog studies.
Bezalip (Boehringer Mannheim UK (Pharmaceuticals) Ltd)
Contains bezafibrate.
Use: In hyperlipidaemias of Type 11a, 11b, 111, 1V and V.
Contra-indications, warnings, etc: Warnings: The chronic administration of a high dose of bezafibrate to rats was associated with hepatic tumour formation in females. This dosage was in the order of 30 to 40 times the human dosage. No such effect was apparent at reduced intake levels approximating more closely to the lipid-lowering dosage in humans.
(Author's note: Drug companies often excuse animal results by claiming that the dosage used in animal tests was far higher than that used in human beings. If such studies are irrelevant because of the high dosage then why do them?)
Spiroctan (Boehringer Mannheim UK)
Contains spironolactone
Use: Spiroctan is recommended for the treatment of congestive cardiac failure, cirrhosis with ascites and oedema, malignant ascites, nephrotic syndrome and also for diagnosis and treatment of primary hyperaldosteronism.
Contra-indications, warnings, etc: Carcinogenicity: Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain.
Bicnu (Bristol-Myers Pharmaceuticals)
Contains a 30 ml vial containing 100 mg carmustine and a 5 ml vial containing 3 ml sterile ethanol diluent.
Use: BiCNU is indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following:
1. Brain tumours - Glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumours.
2. Multiple myeloma - in combination with prednisone.
3. Hodgkin's Disease - As secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
4. Non-Hodgkin's lymphomas - As secondary therapy as above.
Contra-indications, warnings, etc: BiCNU is carcinogenic in rats and mice, producing a marked increase in tumour incidence in doses approximating those employed clinically.
Apresoline (Ciba Laboratories)
Contains Hydralazine Hydrochloride.
Use: Hypertension
Contra-indications, warnings etc: Warnings: Hydralazine, in lifetime carcinogenicity studies, caused, towards the end of the experiments, small but statistically significant increases in lung tumours in mice and in hepatic and testicular tumours in rats. These tumours also occur spontaneously with fairly high frequency in aged rodents.
With due consideration of these animal and in-vitro toxicological findings, hydralazine in therapeutic doses does not appear to bear a risk that would necessitate a limitation of its administration. Many years of clinical experience have not suggested that human cancer is associated with hydralazine use.
Tolectin 200/400 Mg capsules (Cilag Ltd)
Contains tolmetin sodium dihydrate.
Use: Rheumatoid arthritis,; osteoarthritis; ankylosing spondylitis; peri-articular disorders such as fibrositis and bursitis.
Contra-indications, warnings, etc: Renal papillary necrosis has occurred in animals after long term administration although there has been no evidence of renal toxicity in clinical trials.
Chendol 125, and Chendol 250 (CP Pharmaceuticals)
Contains chenodeoxycholic acid.
Use: For dissolution of radiolucent cholesterol-rich gallstones in functioning gall bladders. It has a particular place where surgery is contra-indicated or those patients anxious to avoid surgery.
Contra-indications, warnings, etc: Precautions: Chenodeoxycholic acid, given in long term studies at doses of 600 mg/kg/day to rats and 1000 mg/kg/day to mice, induced malignant liver cell tumours in female rats and male mice. The clinical significance of these findings is not known.
Normax (Evans Medical Ltd)
Contains danthron docusate sodium.
Use: Constipation in geriatric practice. Analgesic-induced constipation in terminally ill patients of all ages. Constipation in cardiac failure and coronary thrombosis (conditions in which defaecation must be free of strain).
Contra-indications, warnings, etc: Precautions: In experimental animals, danthron has been associated with adenocarcinomas in the bowel and tumours in the liver.
Farlutal (Farmitalia Carlo Erba Ltd)
Contains medroxyprogesterone acetate.
Use: Palliative treatment of hormone-sensitive malignancies. Farlutal has been successfully used to produce regressions in breast, endometrial, prostatic and renal cell carcinoma.
Contra-indications, warnings, etc: Precautions: It should be noted that long term administration of medroxyprogesterone acetate to beagle dogs has resulted in the development of mammary nodules which were occasionally found to be malignant. The relevance of these findings to humans has, however, not been established.
Pharmorubicin rapid dissolution (Farmitalia Carlo Erba Ltd)
Contains epirubicin hydrochloride with lactose and hydroxybenzoate.
Use: Antimitotic and cytotoxic.
Contra-indications, warnings, etc: Like most other anticancer agents, epirubicin has shown mutagenic and carcinogenic properties in animals.
Zavedos (Farmitalia Carlo Erba Ltd)
Contains idarubicin hydrochloride with lactose.
Use: Antimitotic and cytotoxic agent.
Contra-indications, warnings, etc: Warnings: Like most other cytotoxic agents, idarubicin has mutagenic properties and it is carcinogenic in rats.
Tegretol (Geigy Pharmaceutical)
Active ingredient: Carbamazepine.
Use: Epilepsy generalised tonic-clonic and partial seizures.
Contra-indications, warnings, etc: Precautions: In rats treated with carbamazepine for two years, the incidence of tumours of the liver was found to be increased. There is, however, no evidence to indicate that this observation has any significant bearing on the therapeutic use of the drug.
Grisovin tablets (Glaxo Laboratories Ltd)
Contain griseofulvin.
Use: The treatment of fungal infections of the skin, scalp, hair or nails where topical therapy is considered inappropriate or has failed.
Contra-indications, warnings etc: Precautions: Long term administration of high doses of griseofulvin with food has been reported to induce hepatomas in mice and thyroid tumours in rats but not hamsters. The clinical significance of these findings is not known.
Lasilactone capsules (Hoechst)
Contain Frusemide and Spironolactone.
Use: In the treatment of resistant oedema where this is associated with secondary hyperaldosteronism; conditions include chronic congestive cardiac failure and hepatic cirrhosis.
Contra-indications, warnings, etc: Carcinogenicity: Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain.
Atromid (ICI Pharmaceuticals)
Contains Clofibrate.
Use: In the treatment of severe hyperlipoproteinaemia where full investigation has been performed to define the abnormality.
Contra-indications, warnings, etc: Clofibrate has been shown to produce liver tumours in rats and mice. The liver changes found in rodents have not been seen in other species, including sub-human primates and man. The relevance of this finding to man has not been established.
Nolvadex, Nolvadex - D, and Nolvadex - Forte tablets (ICI Pharmaceuticals)
Containing Tamoxifen Citrate.
Use: The treatment of breast cancer and the treatment of anovulatory infertility.
Contra-indications, warnings, etc: Gonadal tumours in mice and liver tumours in rats receiving tamoxifen have been reported in long-term studies. The clinical relevance of these findings has not been established.
Zoladex (ICI Pharmaceuticals)
Containing goserelin acetate.
Use:
1. Prostate cancer.
2. Advanced breast cancer in pre- and peri-menopausal women suitable for hormonal manipulation.
3. Endometriosis.
Contra-indications, warnings, etc: General: Following long-term repeated dosing with Zoladex, an increased incidence of benign pituitary tumours has been observed in male rats. Whilst this finding is similar to that previously noted in this species following surgical castration, any relevance to man has not been established.
In mice, long term repeated dosing with multiples of the human dose produced histological changes in some regions of the digestive system manifested by pancreatic islet cell hyperplasia and a benign proliferative condition in the pyloric region of the stomach, also reported as a spontaneous lesion in this species. The clinical relevance of these findings is unknown.
Novantrone injection (Lederle Laboratories)
Contains mitozantrone hydrochloride.
Use: For the treatment of advanced breast cancer, non-Hodgkin's lymphoma and adult acute non-lymphocytic leukaemia. Novantrone has also been used in the palliation of non-resectable primary hepatocellular carcinoma.
Contra-indications, warnings, etc: Warnings: Novantrone is mutagenic in vitro and in vivo in the rat. In the same species there was a possible association between administration of the drug and development of malignant neoplasia. The carcinogenic potential in man is unknown.
Prostap SR (Lederle Laboratories)
Contains leuprorelin acetate.
Use: In the treatment of advanced prostatic cancer and the management of endometriosis, including pain relief and reduction of endometriotic lesions.
Contra-indications, warnings, etc: Warnings: Men: Whilst the development pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long term clinical studies with Prostap.
Thiotepa (Lederle Laboratories)
Contains Thiotepa (N,N',N'' triethylenethiophosphoramide)
Use: A polyfunctional alkylating agent used alone or in combination with other cytotoxic drugs, hormones, radiotherapy or surgery in the treatment of neoplastic diseases.
Contra-indications, warnings, etc: Thiotepa has been reported to possess mutagenic activity on the basis of bacterial, plant and mammalian mutagenicity tests. It has also been reported to be carcinogenic in mice and rats. These effects are consistent with its activity as an alkylating agent. The carcinogenic potential in humans has not been clearly established.
Celace (Eli Lilly and Co Ltd)
Contains pergolide base.
Use: Adjunctive treatment to levodopa in the management of the signs and symptoms of Parkinson's disease.
Contra-indications, warnings, etc: Carcinogenesis, mutagenesis and impairment of fertility: Two year carcinogenicity studies in mice and rats used doses up to 340 and 12 times the maximum human oral dose (6 mg or 6000 micrograms/day equivalent to 120 micrograms/kg/day). A low incidence of uterine neoplasms occurred in both rats and mice. Endometrial adenomas and carcinomas were observed in rats. Endometrial sarcomas were observed in mice. These occurrences are probably attributable to the high oestrogen/progesterone ratio, which would occur in rodents as a result of the prolactin-inhibiting action of pergolide mesylate.
These endocrine mechanisms are not present in humans. However, there are no human data with pergolide to substantiate this conclusion concerning the lack of potential for human risk.
Mutagenic potential was evaluated in a battery of tests. A weak response was noted in one test but the other 3 tests were negative. The relevance to humans is unknown.
Seconal Sodium (Eli Lilly and Co Ltd)
Contains Secobarbitone Sodium.
Use: For the short-term treatment of severe, intractable insomnia.
Contra-indications, warnings, etc Carcinogenesis: Animal data show that phenobarbitone can be carcinogenic after lifetime administration.
Sodium Amytal Injections (Eli Lilly and Co Ltd)
Contains Amylobarbitone Sodium.
Use: May be used parenterally to control status epilepticus, but it is not the barbiturate of choice in the routine treatment of grand mal epilepsy.
Contra-indications, warnings, etc: Carcinogenesis: Animal data show that phenobarbitone can be carcinogenic after lifetime administration.
Destolit (Marion Merrell Dow Ltd)
Contains ursodeoxycholic acid.
Use: For the dissolution of radiolucent (i.e. non-radio opaque) cholesterol gallstones in patients with a functioning gallbladder.
Contra-indications, warnings, etc: A product of this class has been found to be carcinogenic in animals. The relevance of these findings to the clinical use of ursodeoxycholic acid has not been established.
Sabril tablets (Marion Merrell Dow Ltd)
Contains vigabatrin.
Use: For the treatment of epilepsy which is not satisfactorily controlled by other antiepileptic drugs.
Contra-indications, warnings, etc: Warning: Animal safety studies indicate that vigabatrin causes intramyelinic oedema in the brain white matter tracts. Currently there is no evidence to suggest that this effect occurs in man.
Dolobid (Thomas Morson Pharmaceuticals)
Contains Diflunisal.
Use: For the relief of pain and also inflammation associated with osteoarthritis and rheumatoid arthritis.
Contra-indications, warnings, etc: Precautions: In rats and dogs, high oral doses of diflunisal (50-200 mg/kg/day) as with aspirin, produced similar pathological changes (gastro-intestinal ulceration and renal papillary oedema). These dosages are approximately 3 to 12 times the maximum dosages recommended in man.
Ortho dienoestrol cream (Ortho)
Contains Dienoestrol.
Use: Atrophic vaginitis and kraurosis vulvae in post menopausal women, and for the treatment of pruritus vulvae and dyspareunia when associated with the atrophic vaginal epithelium.
Contra-indications, warnings, etc: Long term continuous administration of natural and synthetic oestrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina and liver. There is now evidence that oestrogens increase the risk of carcinoma of the endometrium in humans.
At the present time there is no satisfactory evidence that oestrogens given to post-menopausal women increase the risk of cancer of the breast, although a recent long-term follow up of a single physician has raised this possibility. However, because of animal data there is a need for caution in prescribing oestrogens for women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms.
(Author's Note: Do oestrogens only increase the risk of cancer in female animals who have a strong family history of breast cancer, or who have breast nodules, fibrocystic disease or abnormal mammograms?).
Retin-a Lotion, Gel, Cream (Ortho)
Contains Tretinoin.
Use: For topical application in the treatment of acne vulgaris in which comedones, papules and pustules predominate.
Contra-indications, warnings, etc: Recent studies in mice treated with the active ingredient (tretinoin) of Retin-A and exposed to artificial sunlight suggest that tretinoin may speed up the appearance of sunlight induced skin tumours. Laboratory mice treated with tretinoin but not exposed to sunlight did not develop skin tumours. The significance of these studies as related to human beings is unknown. High oral doses of tretinoin (retinoic acid), like Vitamin A, are teratogenic in animals.
Lopid (Parke-Davis Research Laboratories)
Contains gemfibrozil and polysorbate 80 PhEur.
Use: For the primary prevention of coronary heart disease in men between 40-55 years of age and with hyperlipidaemias who have not responded to diet and other appropriate measures.
Contra-indications, warnings, etc: Precautions: Long-term toxicity studies in rats and mice were carried out at one and ten times the human dose on a weight for weight basis. In male rats receiving ten times the human dose, there was a significant increase in incidence of benign liver nodules and liver carcinomas. Male rats receiving a dose equivalent to the human dose had no statistically significant increase in the incidence of liver carcinomas. At all dose levels, there were no statistically significant differences from controls in the incidence of liver tumours in female rats, or in mice of either sex.
Electron microscopy demonstrated a marked hepatic peroxisome proliferation following Lopid administration to the male rat. Similar changes have been sought but not found in the human liver at up to 27 months continuous gemfibrozil therapy. Male rats had a dose-related increase of benign Leydig cell tumours. Subcapsular bilateral cataracts occurred in 10%, and unilateral cataracts in 6.3% of the high dose males.
Mithracin (Pfizer Ltd)
Contains plicamycin, mannitol and disodium phosphate.
Use: For the treatment of refractory hypercalcaemia associated with a variety of neoplasms.
Contra-indications, warnings, etc: Warnings: Antineoplastic and cytotoxic agents have been shown to be mutagenic and carcinogenic in animals and possibly man.
Only limited animal and in vitro mutagenicity studies have been carried out with plicamycin; the possibility that plicamycin has similar effects to other antineoplastic cytotoxic agents should be borne in mind.
Calcitare (Rhone-Poulenc Rorer Ltd)
Contains Calcitonin (Pork).
Use: For short term treatment in:
i) Paget's disease of bone
ii) Hypercalcaemia.
Contra-indications, warnings, etc: A species and strain-specific dose-related increase of pituitary adenomas has been observed in long term toxicity studies in the rat. As the significance of these findings to man is uncertain, long term use is not recommended.
Calsynar (Rhone-Poulenc Rorer Ltd)
Contains synthetic Salmon Chloride. The solution also contains Sodium Chloride, Sodium Acetate, Acetic Acid and Phenol.
Use: For the short term treatment of:
a) Paget's disease of bone.
b) Advancing osteolytic hypercalcaemia of malignancy.
c) Pain associated with advanced metastatic bone cancer.
d) Postmenopausal osteoporosis.
Contra-indications, warnings, etc: Precautions: Rat carcinogenicity studies have shown a dose related excess of pituitary tumours. As the significance of this finding is uncertain, long term use is not recommended.
Roaccutane (Roche Products Ltd)
Contains isotretinoin.
Use: For the treatment of cystic and conglobate acne and severe acne which has failed to respond to an adequate course of a systemic antimicrobial agent.
Contra-indications, warnings, etc: Precautions: At the completion of a lifespan study in rats there was an increased incidence of phaeochromocytoma in animals given isotretinoin at dosages of 32 and 8 mg/kg/day, but not 2 mg/kg/day. Since rats are particularly prone to develop this tumour type, the significance of this finding for use of Roaccutane in man is uncertain; nevertheless, repeated courses of treatment are not normally recommended.
Negram (Sanofi Winthrop)
Contains Nalidixic Acid.
Use: For the treatment of acute or chronic infections.
Contra-indications, warnings, etc: Nalidixic acid has been shown to induce lesions in weight-bearing joints of young animals. The relevance of this to man is unknown.
Androcur (Schering Health Care)
Contains cyproterone acetate.
Use: Control of libido in severe hypersexuality and/or sexual deviation in the adult male.
Contra-indications, warnings, etc: Warnings/side-effects: Cyproterone acetate has been found to cause liver abnormalities in animals, including the development of tumours.
Cyprostat (Schering Health Care)
Contains cyproterone acetate.
Use: Palliative treatment of prostatic carcinoma.
Contra-indications, warnings, etc: Cyproterone acetate has been found to cause liver abnormalities in animals, including the development of tumours.
Dianette (Schering Health Care)
Contains anti-androgen cyproterone acetate and oestrogen ethinyloestradiol.
Use: In women only: (i)severe acne, refractory to prolonged oral antibiotic therapy and (ii)idiopathic hirsutism of mild to moderate degree.
Contra-indications, warnings, etc: Warnings: Like many other steroids, cyproterone acetate, when given in very high doses and for the majority of the animal's life-span, has been found to cause an increase in the incidence of tumours, including carcinoma, in the liver of rats. The relevance of this finding to humans is unknown. Dianette has been shown to have good liver tolerance in women given prolonged treatment.
Aldactide (Searle)
Contains Spironolactone and Hydroflumethiazide.
Use: Congestive cardiac failure.
Contra-indications, warnings, etc - Warnings: Carcinogenicity: Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain.
Cytotec (Searle)
Contains misprostol
Use: for the healing of duodenal ulcer and gastric ulcer including those induced by non steroidal anti inflammatory drugs (NSAID) in arthritic patients at risk, whilst continuing their NSAID therapy.
Further information: Cytotec in multiples of the recommended therapeutic dose in animals has produced gastric mucosal hyperplasia. This characteristic response of E prostaglandins reverts to normal on discontinuation of the compound. In patients, histological examination of gastric biopsies taken before and after treatment with misoprostol after up to one year's duration have shown no adverse tissue response attributable to misoprostol.
Napratec (Searle)
Contains Naproxen and Cytotec (containing misoprostol)
Uses: Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthritis (degenerative arthritis) and ankylosing spondylitis. Cytotec is indicated for the prophylaxis of nonsteroidal anti-inflammatory drug induced gastroduodenal ulceration.
Further information: Cytotec in multiples of the recommended therapeutic dose in animals has produced gastric mucosal hyperplasia. This characteristic response of E prostaglandins reverts to normal on discontinuation of the compound. In patients, histological examination of gastric biopsies taken before and after treatment with misoprostol after up to one year's duration have shown no adverse tissue response attributable to misoprostol.
Dolmatil tablets (E. R. Squibb and Sons Ltd)
Contains sulpiride (and hydrated silica, lactose, magnesium stearate, methyl cellulose, potato starch, talc).
Use: Acute and chronic schizophrenia.
Contra-indications, warnings, etc: Warnings: In long term animal studies with neuroleptic drugs, including sulpiride, an increased incidence of various endocrine tumours (some of which have occasionally been malignant) has been seen in some but not all strains of rats and mice studied. The significance of these findings to man is not known; there is no evidence of an association between Dolmatil use and tumour risk in man.
Chenofalk (Thames Laboratories Ltd)
Contains chenodeoxycholic acid (CDCA). (And gluten).
Use: Dissolution of radiolucent gallstones measuring up to 15 mm diameter.
Contra-indications, warnings, etc: Warnings: Chenodeoxycholic acid given in long-term studies at doses of 600 mg/kg/day to rats and 1000 mg/kg/day to mice, induced malignant liver cell tumours in female rats and benign liver cell tumours in female rats and male mice. The clinical significance of these findings is not known.
Ursofalk (Thames Laboratories Ltd)
Contains ursodeoxycholic acid (UDCA) and gluten.
Use: Dissolution of radiolucent gallstones measuring up to 15 mm diameter.
Contra-indications, warnings, etc: A product of this class has been found to be carcinogenic in animals. The relevance of these findings to the clinical use of UDCA has not been established.
Sulpitil (Tillotts Laboratories)
Contains sulpiride.
Use: For the treatment of acute and chronic schizophrenia.
Contra-indications, warnings, etc: Warnings and precautions: In long term animal studies with neuroleptic drugs, including sulpiride, an increased incidence of various endocrine tumours, some of which have occasionally been malignant, has been seen in some, but not all, strains of rats and mice studied. The significance of these findings to man is not known. There is no current evidence of an association between neuroleptic use and tumour risk in man.
Depo-Provera (Upjohn Ltd)
Contains medroxyprogesterone acetate.
Use: Progestogen: for the treatment of endometriosis.
Contra-indications, warnings, etc: Warnings, precautions, side-effects: Endometrial tumours have developed in monkeys given fifty times the human contraceptive dose but the relevance of this to man has not been established.
Hemabate Sterile Solution (Upjohn Ltd)
Contains carboprost as the tromethamine salt.
Use: Treatment of post-partum haemorrhage due to uterine atony and refractory to conventional methods of treatment with oxytocic agents and ergometrine used either alone or in combination.
Contra-indications, warnings, etc: Precautions: Animal studies lasting several weeks at high doses have shown that prostaglandins of the E and F series can induce proliferation of bone.
Prostin E2 (Upjohn Ltd)
Contains dinoprostone.
Use: Oxytocic agent.
For the induction of labour when there are no foetal or maternal contra-indications.
Contra-indications, warnings, etc: Precautions: Animal studies lasting several weeks at high doses have shown that prostaglandins of the E and F series can induce proliferation of bone.
Myleran tablets (Wellcome Medical Division)
Contains Busulphan.
Use: For the palliative treatment of the chronic phase of chronic granulocytic leukaemia.
Contra-indications, warnings, etc: Precautions: Busulphan has been shown to be mutagenic in various systems, including bacteria, fungi, Drosophila and cultured mouse lymphoma cells. In vivo cytogenetic studies in rodents have shown an increased incidence of chromosome abberations in both germ cells and somatic cells after busulphan treatment.
NB. Busulphan interferes with spermatogenesis in experimental animals.
Retrovir capsules and syrup (Wellcome Medical Division)
Contains zidovudine.
Use: For the management of patients with advanced HIV disease.
Contra-indications, warnings, etc: Mutagenicity: Zidovudine was weakly mutagenic in a mouse lymphoma cell assay and was positive in an in vitro cell transformation assay. Clastogenic effects (chromosome damage) were observed in an in vitro study in human lymphocytes and in in- vivo oral repeat dose micronucleus studies in rats and mice. An in vivo cytogenetic study in rats did not show chromosomal damage. The clinical significance of these findings is unclear.
Carcinogenicity: Zidovudine was administered orally at three dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60 and 120 mg/kg/day and 80, 220 and 600 mg/kg/day in mice and rats respectively. The doses in mice were reduced to 20, 30 and 40 mg/kg/day after Day 90 because of treatment-related anaemia, whereas in rats only the high dose was reduced (to 450 and then 300 mg/kg/day on Days 91 and 279, respectively).
In mice, seven late-appearing (after 19 months) vaginal neoplasms (5 squamous cell carcinomas, one squamous cell papilloma and one squamous cell polyp) occurred at the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumours were found at the lowest dose.
In rats, two late-appearing (after 20 months) vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumours occurred at the middle or low doses in rats.
The predictive value of rodent carcinogenicity studies for humans is uncertain and thus the clinical significance of these findings is unclear.
Author's Comments: In addition to the general warnings I have recorded above there are many drug companies which warn doctors not to give specific products to patients who are pregnant. These companies invariably report having performed experiments on pregnant animals but then often go on to admit (something like): 'the relevance of these studies to human beings is not known'. It is difficult to avoid asking the question: 'Why do the studies if the relevance is not known?' As can be seen from the above, a huge number of drug companies seem to be doing animal tests without knowing their relevance to human patients.
On other occasions drug companies report that animal experiments have shown that their drugs cause problems - but that human experience suggests that the drug is entirely safe so the animal experiments can be safely ignored! Animal experiments provide answers for all seasons. It is not surprising that drug companies love them.
In some of the examples which follow drug companies seem uncertain about the significance of the animal experiments which have been done. If the relevance of the animal experiments is not known or the experiments cannot be relied upon then why on earth does anyone do them? Just as puzzling are the many instances where drug companies state that animal experiments have not indicated that there will be any problems if their drugs are given to pregnant women - but still advise doctors against giving those drugs to pregnant women.
These short sections are intended only to illustrate the point I want to make and are not intended to provide useful information about the drugs concerned.
Dr Vernon Coleman.
PARTE 1
FK506
Animal experiments indicated that FK506, an anti-rejection drug, was too toxic for human use.[1][2] However, when used on human liver transplant patients, the results were found to be 'promising'.[3]
[1] R. Allison, Journal of the American Medical Association, 4 April 1990, p.1766.
[2] R. Y. Calne, et al, Lancet, 22 July 1989, p.227.
[3] J. Neuberger, Hepatology, vol. 13, pp.1259-1260.
Radiation
The Committee of Official Enquiry into the incidence of leukaemia in children near the Sellafield nuclear plant, declared the plant was not the cause; this decision was based on animal testing.[1] However, later research did support the view that the plant was responsible.[2]
[1] E. Millstone, in Animal Experiments: The Consensus Changes, ed. G. Langley (Macmillan, 1989).
[2] M. J. Gardner, et al, British Medical Journal, 17 February 1990, pp.423-429.
Methysergide
No life-threatening symptoms were observed when this drug, for migraine, was tested on animals[1], and the British Medical Journal acknowledged that it had not been possible to produce fibrotic lesions in laboratory animals[2]. And yet the British National Formulary (1993), found it necessary to warn that the drug should only be administered to humans by trained medical staff as it had been found that the drug had serious side-effects which arose from fibrous tissue (retroperitoneal fibrosis) and these included heart failure.
[1] R. Heywood in Animal Toxicity Studies: Their Relevance For Man, eds. C. E. Lumley and S. R. Walker (Quay Pub: 1990).
[2] K. A. Misch, British Medical Journal, May 18 1974, pp.365- 366.
Suprofen/suprol
This, an arthritis drug, was withdrawn globally in 1987 after reports of kidney problems and pain.[1] Those who reported these problems had to have their kidneys monitored for two years after they stopped using the drug.[2] And yet it was reported: 'In animal studies, Suprofen has been shown to have an excellent safety profile. No significant effects were observed on cardiac, renal [kidney] or central nervous system...in several species.[3]
[1] Drug Withdrawal from Sale, C. Spriet-Pourra and M. Auriche (PJB Publications, 1988).
[2] FDA Drug Review: Postapproval Risks, 1976-1985 (US General Accounting Office, April 1990).
[3] A. Yeardon, et al, Pharmacology, 1983, vol. 27, Suppl. 1, pp.87-94.
Alcohol
Until the twentieth century, alcohol was considered to be poisonous for the liver.[1] This view changed after experiments on animals,[1][2] and in 1934, animal testing concluded that there was no evidence for alcohol causing cirrhosis.[3][4]
Alcohol is of course today considered to be a liver toxin, but some still question this in view of the difficulty in inducing cirrhosis in laboratory animals.[5] In addition to this, alcohol appears to be more harmful to the circulatory system of human beings than animals. For example, excessive consumption raises the blood pressure in alcoholics, and yet this is not usually the case with rats.[6]
Furthermore, alcohol is able to damage the human heart but studies involving various animals who were given 'large amounts' of alcohol found that none suffered heart failure.[6]
Animal experiments also showed that Librium could assist in dealing with withdrawal although as some animals died, it also suggested there was a lethal side-effect.[7] In fact clinical tests carried out at an earlier time had already revealed that Librium was effective,[8] and it continues to be used in relation to alcohol withdrawal.
[1] H. J. Zimmerman, Alcoholism: Clinical and Experimental Research, 1986, vol. 10, pp.3-15.
[2] C. S. Lieber and L. M. DeCarli, Journal of Hepatology, 1991, vol. 12. pp.394-401.
[3] V. H. Moon, Archives of Pathology, 1934, vol. 18, pp.381- 424.
[4] As [2].
[5] R. F. Derr, et al, Journal of Hepatology, 1990, vol. 10, pp.381-386.
[6] J. V. Jones, et al, Journal of Hypertension, 1988, vol. 6, pp.419-422.
[7] D. B. Goldstein, Journal of Pharmacology and Experimental Therapeutics, 1972, vol. 183, pp.14-22.
[8] G. Sereny and H. Kalant, British Medical Journal, 9 January 1965, pp.92-97.
Pesticides
In 1986, the British Parliament's Agriculture Committee instigated a review into pesticides. Despite the general faith placed in animal experiments, the Committee was forced to concede that 'similar tests in different animal species often yield quite different results'.[1] One example was the organophosphate pesticide dipterex which caused nerve damage in human beings but not in animals.[2] One physician member of the National Poisons Unit advised the Committee that one documented case of human poisoning was worth 20,000 animal experiments.[1]
In view of the findings, the Committee declared: 'It cannot be satisfactory to rely on animals so much as a means of testing and, as other forms of testing becomes available, we recommend that they be adopted...we are satisfied from the evidence that we have received that animal testing can produce misleading results'.
[1] Special Report of the House of Commons Agriculture Committee, rep. FRAME News, 1987, No. 16, p.2.
[2] A. N. Worden, in Animals and Alternatives in Toxicity Testing, eds. M. Balls, et al (Academic Press, 1983).
Arsenic
For some seventy years, researchers were unable to connect arsenic with cancer due to being unable to verify the suspicion with animal experiments. Although arsenic had been connected with cancer as early as 1809, a report published in 1947 stated that the many animal experiments which had been conducted had only produced 'doubtful results'.[1]
Experiments continued after this date and even by 1969, researchers acknowledged that while it was believed there was a connection between cancer and arsenic, animal experiments had not offered any supporting evidence for this.[2] In 1977, a report yet again said that animal experiments had not produced supporting evidence of a link.[3] It was not until the end of the 1980s that researchers were finally able to produce the cancer in animals - nearly 200 years after the link had first been suggested.
[1] O.Neubauer, British Journal of Cancer, 1947, vol. 1, pp.192- 251.
[2] A. M. Lee and J. F. Fraumeni Jr., Journal of the National Cancer Institute, 1969, vol. 42, pp.1045-1052.
[3] F. W. Sunderman Jr., in Advances in Modern Technology, vol. 2, eds. R. A. Goyer and M. A. Mehlman (Wiley, 1977).
Benzene
As Benzene was widely used, e.g., for the manufacture of detergents, pharmaceuticals, etc., there was concern as there appeared to be a link with cancer. Animal experimentation did not support this view,[1] and some fourteen animal trials failed to show any connection between benzene and cancer.[2] Therefore workers were put at considerable risk in view of there being no 'evidence' of a link. It was not until the late 1980s, after dosing animals with benzene that cancer was induced.
[1] L. B. Lave, The American Statistician, 1982, vol. 36, pp.260-261.
[2] D. M. De Marini, et al, in Benchmarks: Alternative Methods in Toxicology, ed. M. A. Mehlman (Princeton Scientific Publishing, 1989).
Lindane
Lindane, while primarily known as an agricultural insecticide, it is also used in different forms, in a diluted amount, for lice and similar afflictions. However these can cause serious eye irritation,[1] and the British National Formulary 1993, warns that eye contact should be avoided. And yet in rabbits, when a far more concentrated solution was used, the effects were minimal. Additionally, exposure to lindane dust caused no problem to rabbits, but caused irritation to the eyes and respiratory systems of some people.[1]
[1] W. M. Grant, Toxicology of the Eye, 2nd edn (Charles Thomas, 1974).
Dinitrophenol
After considerable animal testing, this product was used as a treatment for obesity but after human usage it was noted that some patients were developing cataracts. Attempts were then made to replicate this in rats, rabbits, guinea pigs, and dogs, and yet none of the experiments produced any change to the lens of the eye.[1] A summary of the experimentation stated: 'All attempts to produce experimental cataracts in laboratory animals by various and repeated doses of dinitrophenol have been unsuccessful'.[2] It was only later that an experiment accidentally discovered that birds dosed with dinitrophenol developed cataracts.[1]
A similar situation arose with triparanol intended to reduce cholesterol levels. While the cataracts noticed in humans could be induced in rats and dogs (after very high doses) they could not be in rabbits and monkeys.[3] The product was withdrawn.
[1] B. H. Robbins, Journal of Pharmacology, 1944, vol. 80, pp.264-269.
[2] Rep. in ref [1].
[3] W. M. Grant, Toxicology of the Eye, 2nd edn (Charles Thomas, 1974).
Chymotrypsin
This product is used for ophthalmic surgery when dealing with cataracts. While recommended for human use,[1] it is harmful to a rabbit's eye, resulting in severe swelling of the cornea and sometimes causing perforation.[1] It is stated: 'The rabbit cornea appears to differ significantly from the human cornea in its reaction to a-chymotrypsin'.[2]
[1] British National Formulary, No.26 (BMA and The Royal Pharmaceutical Society of G.B., 1993).
[2] Morton Grant, Toxicology of the Eye, (1974).
Corticosteroids: Shock
The idea for this medication arose after animal experiments when the survival rate of animals improved after being given the treatment just before, or after, shock.[1][2] Corticosteroids were then prescribed for people who required treatment for septic shock, which can often result in heart, respiratory and kidney failure.
However when The Drug and Therapeutic Bulletin analysed the trials it reported that: 'high-dose corticosteroids are ineffective for the prevention or treatment of shock associated with sepsis. They do not improve outcome, and make secondary infection worse. They may harm patients with impaired renal [kidney] function'.[1] In fact, one trial found that corticosteroids not only failed, but actually appeared to increase death among patients.[3]
[1] Drug and Therapeutics Bulletin, 1990, vol. 28, pp.74-75.
[2] S. G. Hershey, in Anaesthesiology, Proceedings of the VI World Congress of Anaesthesiology, Mexico City, April 1976, eds. E. Hulsz, et al (Excerpta Medica, 1977).
[3] R. C. Bone, et al. New England Journal of Medicine, 10 September 1987, pp.653-658.
Acetylcholine
This chemical (produced by nerve endings) was believed, after experiments with dogs, to dilate the coronary arteries. However when used with humans, it was found to narrow the blood vessels which can result in heart spasm.[1] Another body chemical, bradykinin, relaxes blood vessels in human brain tissue but contracts them in dogs.[2]
[1]S. Kalser, Journal of Physiology, 1985, vol. 358, pp.509-526.
[2]K. Schror and R. Verheggen, Trends in Pharmacological Sciences, 1988, vol. 9, pp.71-74.
Leukotrienes (LT).
Those leukotrienes known as LTC4 and LTD4, constrict blood vessels in the skin of the guinea pig, but dilate corresponding issue originating from human beings and pigs.[1]
[1]P.J. Piper, et al, Annals of the New York Academy of Sciences, 1988, vol. 524, pp.133-141.
Prostaglandins (PG).
These are a family of substances in human seminal fluid. In the heart tissue from cats and rabbits, PGE1 has no effect on contractile force or heart rate, and yet in rats, guinea pigs and chickens, it increases them.[1]
Because of such anomalies, some pharmacologists concede that the extrapolation from animals to humans is often invalid and acknowledge the increased interest in using tissue from human beings to overcome those restrictions which arise when using animal tissue.[2]
[1]S. Bergstrom, et al, Pharmacological Review, 1968, vol. 20, pp.1-48.
[2]Trends in Pharmacological Sciences, 1987, vol. 8, pp.289-290.
Clonidine.
Animal experiments during the 1960s indicated that clonidine might be useful in treating migraine (Experiments with cats showed that the drug affected those processes believed to cause headaches). The drug was therefore introduced in 1969, but later research indicated that it was largely useless.[1].
However after being used as a nasal decongestant, it was discovered that clonidine could be effective when used to treat high blood pressure.[2]. However serious side-effects were then noted. Furthermore, attempts to replicate the condition in dogs and cats only provided inconsistent results,[3] and in the case of testing with rats, there were even more difficulties and disagreements.[4] The Drug and Therapeutic Bulletin therefore deems clonidine to be obsolete for the treatment of high blood pressure.[5]
[1]Drugs and Therapeutics Bulletin, 1990, vol. 28, pp.79-80.
[2]A. S. Niles in Clinical Pharmacology: Basic Principles in Therapeutics, 2nd edn, eds, K. L. Melmon and H. F. Morrelli (MacMillan, 1978).
[3]L. Hansson, et al, American Heart Journal, 1973, vol. 85, pp.605-610.
[4]M. J. M. C. Thoolen, et al, General Pharmacology, 1981, vol. 12, pp.303-308.
[5]Drug and Therapeutics Bulletin, 1984, vol. 22, pp.42-43.
Isoprenaline.
During the 1960s, at least 3,500 young asthma sufferers died after using isoprenaline aerosol inhalers.[1] Fatalities occurred when the aerosol delivered 0.4mg of isoprenaline per spray.[2][3]
Attempts to replicate the same effects in laboratory animals were problematic and the New York Food and Drug Research Laboratory was forced to admit: 'Intensive toxicological studies with rats, guinea pigs, dogs and monkeys at dosage levels far in excess of current commercial metered dose vials...have not elicited similar adverse effects'.[4] It was only after artificially reducing the oxygen in the animals' tissue that vivisectors were able to increase the toxic effects of isoprenaline.[5]
[1]W. H. Inman, Monitoring for Drug Safety, ed. W. H. Inman (MTP Press, 1980).
[2]P. D. Stolley, American Review of Respiratory Diseases, 1972, vol. 105, pp.883-890.
[3]P. D. Stolley and R. Schimmar, Lancet, 27 October 1979, p.896.
[4]S. Carson, et al, Pharmacologist, 1971, vol. 18, p.272.
[5]British Medical Journal, 25 November 1972, pp.443-444.
Phenacetin.
From the early 1950s, kidney damage associated with the prolonged use of combination painkillers was noted. Despite animal experiments, the reason for the damage could not be ascertained. It transpired that the animal experiments only served to further confuse the issue as while phenacetin was thought to be responsible, the damage could not be reproduced in the animals.[1] Furthermore, the experiments suggested it was the aspirin component that was causing the damage,[2] as aspirin, unlike phenacetin, readily induces kidney damage in laboratory animals.
It was only when human studies took place that it was realized that phenacetin was the cause,[3] leading to it being withdrawn in 1980 (when there was also the suspicion that it caused cancer).
An analysis concluded that if the research had only used animals the effects would not have been suspected or predicted.[1]
[1]I. Rosner, CRC Critical Reviews in Toxicology, 1976, vol. 4, pp.351-352.
[2]British Medical Journal, 17 October 1970, pp.125-126.
[3]K. G. Koutsaimanis and H. E. de Wardener, British Medical Journal, 17 October 1970, pp.131-134.
Clioquinol.
During the 1960s there was an epidemic of drug-induced disease in Japan, related to clioquinol, the principal ingredient of Ciba- Geigy's antidiarrhoea drugs Enterovioform and Mexaform. It is believed that between 10,000 and 30,000 people fell victim to SMON (subacute myelo-optic neuropathy) which produced numbness, paralysis and eye problems including the loss of sight.[1] In 1970, the drug was banned in Japan, and fifteen years later, it was withdrawn globally.
Despite all the serious problems caused by the drug, those experiments carried out on animals, which included rats, cats, beagles and rabbits, revealed 'no evidence that clioquinol is neurotoxic'.[2]
Although there have been claims to have produced toxicity from clioquinol in mongrel dogs,[3] it has also been noted that different species yield different results, e.g., monkeys, hens, cocks and mice were only mildly affected even after they were given high doses while it was discovered that beagle dogs were 3-4 times less sensitive to clioquinol than mongrels.
[1]Lancet, 5 March 1977, p.534.
[2]R. Hess, et al, Lancet, 26 August 1972, pp.424-425.
[3]J. Tateishi, et al, Lancet, 10 June 1972, pp.1289-1290.
Oral Contraception.
Studies of the pill have shown that of the side-effects which can occur, the most serious is that of problems with the circulatory system, i.e., blood clots, strokes and heart disease. By 1980 the CSM (Committee on Safety on Medicines) had received reports of over 400 deaths,[1] and further studies showed that some women using the pill had raised blood pressure. However none of these problems had been identified during animal experiments;[2] in fact the oral conceptive had produced the opposite effect (i.e., making it more difficult for the blood to clot) in some species.[3]
Prof. Briggs of Deakin University, Australia, noted: 'At multiples of the human dose no adverse effect on blood clotting was found in mice, rats, dogs, or non-human primates. Indeed, far from accelerating blood coagulation, high doses of oestrogens in rats and dogs prolonged clotting times. In sum, there is no appropriate animal model for the coagulation changes in women using oral contraceptives'.[4] In 1972 the CSM described how the tests which had been conducted on some 13,000 animals revealed that there was a connection between high doses of oral contraceptives and cancer.[5] And yet the rats and mice were so prone to cancer that even those who were not dosed with the oral contraceptive ('the control animals') developed high levels of disease; lung and liver tumours were found in 25% and 23% of the control mice, and adrenal, pituitary and breast tumours were found in 26%, 30% and 99% of the control rats.
In view of this, the British Medical Journal stated: 'It is difficult to see how experiments on strains of animals so exceedingly liable to develop tumours of these various kinds can throw any useful light on the carcinogenity of any compound for man'.[5]
Thus, it is those women who have used the pill who have really been the 'guinea pigs' for the drug.
[1]G. R. Venning, British Medical Journal, 22 January 1983, pp.289-292.
[2]R. Heywood, in Animal Toxicity Studies: Their Relevance for Man, eds, C. E. Lumley and S. R. Walker (Quay Publishing, 1990).
[3]R. Heywood and P. F. Wadsworth in Pharmacology of Estrogens, ed. R. R. Chaudhury (Pergamon Press, 1981).
[4]M. H. Briggs in Biomedical Research Involving Animals, eds. Z. Bankowski and N. Howard-Jones (CIOMS, 1984).
[5]British Medical Journal, 28 October 1972, p.190.
Chloramphenicol.
Animal experiments indicated that chloramphenicol, an anti-biotic, was safe although it was equally clear that the drug produced side- effects in humans. Due to the serious side-effects, the drug was withdrawn in France.[1]
In 1952 American physicians discovered that chloramphenicol affected the nerve cells and they related how one patient had almost became blind and could only walk with great pain after taking chloramphenicol for just five months. This was only one of many reported cases when chloramphenicol produced optical and peripheral neuritis, and yet animal experimentation showed that the drug was virtually free of side-effects, even after prolonged use.[2]
A far more serious side-effect was the fact that chloramphenicol caused aplastic anaemia, an often fatal blood disease. Once again, animal experimentation did not provide any indication of this occurring and the British Medical Journal noted that chloramphenicol resulted in nothing worse than transient anaemia in dogs when injected for long periods: furthermore, no problems occurred when administered by mouth.[3]
It is now known that chloramphenicol is deadly by test-tube studies with human bone marrow cells.[4]
[1]C. Spriet-Pourra and M. Auriche, Drug Withdrawal From Sale, (PJB Publications, 1988).
[2]I. Wallenstein and J. Snyder, Annals of Internal Medicine 1952, vol. 26, pp.1526-1528.
[3]British Medical Journal, 19 July 1952, pp.136-138.
[4]G, M. I. Gyte and J. R. B. Williams, ATLA, 1985, vol. 13, pp.38-47.
Halothane.
Halothane was introduced in 1956 and viewed as a considerable advance in anaesthesia. However it was soon found to be harmful to the liver and within five years there were over three hundred reported cases of 'halothane hepatitis'. The effects were sometimes fatal and nearly two hundred deaths in Britain were attributed to halothane.[1]
And yet animal experimentation had not provided any evidence of liver damage,[2] and despite many animal experiments and different 'animal models', the significance of their application to human beings was considered 'doubtful'.[3]
Even by 1986, when Britain's Committee on Safety of Medicine increased the warnings about liver toxicity,[4]. it was still unclear whether the same results could be induced in animals.[5]
[1]British Medical Journal, 5 April 1986, pp.949.
[2]Anaesthesiology, 1963, vol. 24, pp.1990-110.
[3]D. C. Ray and G. B. Drummond, British Journal of Anaesthesia, 1991, vol. 67, pp.84-99.
[4]Scrip, 2 October 1987, p.2.
[5]C. E. Blogg, British Medical Journal, 28 June 1986, pp.1691-1692.
Butadiene.
This product was believed to produce cancer as cancer arose when it was tested on certain strains of laboratory mice, an animal widely used when seeking to assess the risk-element of chemical substances. When the dose was very high, cancer also arose in rats.
In view of the results of the animal experimentation, America's National Institute of Occupational Safety and Health (NIOSH) classified butadiene as a carciinogen.
And yet when humans who worked with butadiene were monitored, no extra cancer arose. In fact the number of deaths from cancer was less than the national average.[1] An editorial in Science therefore called for a review of the methodology which was used when considering the risk.
[1]P. H. Abelson, Science, 19 June 1992, p.1609.
Pneumoconiosis.
Due to animal experimentation, it was believed that pneumoconiosis, a lung disease suffered by miners, was caused by silica rather than coal dust. Therefore mines, in which there was no exposure to silica, were viewed as being safe. Believing the problem was understood, there was no information about miners' pneumoconiosis until the early 1960s.[1]
As noted by the British Medical Journal, the idea that coal dust was safe arose from animal experimentation,[2] which not only absolved coal dust, but made silica the most likely culprit.[3] Nonetheless, the findings from the animal experimentation were shown to be suspect when miners, who only worked with pure coal dust or carbon, were found to have developed pneumoconiosis.[1][2] Thus it was shown that coal dust caused pneumoconiosis without any silica being present.
The results of the animal experimentation was further weakened when coal dust, collected from a mine where the incidence of pneumoconiosis was high, was found to be harmless to laboratory rats.[2] Naturally there is the question of how much serious illness was suffered by miners, and many deaths occurred, due to the incorrect information gleaned from animal experimentation.
[1]W. K. C. Morgan, in Occupational Lung Diseases, eds. W. K. C. Morgan and A. Seaton (Saunders, 1982).
[2]British Medical Journal, 17 January 1953, pp.144-146.
[3]I. U. Gardner, Journal of the American Medical Association, 19 November 1938, pp.1925-1936. Chronic Pulmonary Disease in South Wales III Experimental Studies, MRC special report series no. 250 (HMSO, 1945).
Dermatitis.
Dermatitis, a skin condition, arises in many people when they come into contact with nickel compounds.[1] In fact nickel is considered to be the most common cause of dermatitis in women; in some cases it can result in severe eczema and disability.[2]
And yet in most animal testing, nickel is not found to be a skin sensitizer,[3] and, for example, the draize test on guinea pigs suggests that nickel does not produce an allergic reaction. Even in the two most widely used forms of animal testing, nickel produces no response (the Buehler test) or only a moderate response (the Maximization test).
[1]Medical Toxicology, eds. M J. Ellenhorn and D. G. Barceloux (Elsevier, 1988).
[2]Textbook of Dermatology, vol. 1, 5th edn, eds. R. H. Champion, et al (Blackwell Scientific Publications, 1992).
[3]P. A. Botham et al, Food and Chemical Toxicology, 1991, vol. 29, pp.275-286.
Malaria.
Experiments using monkeys in malaria research led to the suggestion that coma in humans was caused by an increased amount of protein in the cerebro-spinal fluid, and this could be resolved by using steriods.[1] But in contrast to the animal experiments, it was ascertained that humans were not assisted by steroids when in a coma and if anything they were harmful.[2]
It was found that the time of coma was lengthened by some sixteen hours and serious complications, e.g., pneumonia, urinary tract infections, convulsions, etc., also occurred more often in those patients using steroids. Later research reported 'that the monkey model may simply not be relevant'.[1]
[1]Lancet, 2 May 1987, p.1016.
[2]D. A. Warrell, et al, New England Journal of Medicine, 11 February 1982, pp.313-319.
Mianserin.
This drug, an antidepressant, can produce potentially fatal blood disorders and the British National Formulary recommends that people using the drug have full blood counts every 4 weeks in the first months of usage.[1] By 1988, the World Health Organisation had over 300 reports relating to white cell disorders.
Despite these problems, the animal experimentation which had been conducted had not predicted these effects,[2] although later test tube studies with human tissue did allow the effects to be observed.[3]
[1]British National Formulary, No. 26 (BMA and the Royal Pharmaceutical Society of GB, 1993).
[2]H. M. Clink, British Journal of Clinical Pharmacology, 1983, vol. 15, pp.2915-2935.
[3]P. Roberts, Drug Metabolism and Disposition, 1991, vol. 19, pp.841-843.
Caged ball valve.
Dogs are preferred in cardiac experiments which include tests to develop an artificial mitral valve although these valves are known to produce fatal blood clots in the dogs.[1] Because of this, many surgeons have been deterred from carrying out human trials.[2]
To overcome the blood clots which occur, two experimental surgeons decided on a 'caged ball' valve,[3] as other devices proved fatal to those dogs on which they had been tested. Of the 7 dogs that received the caged ball valve, 6 died within 17 days and only one survived and this was for a few months. Despite this failure in dogs, the device was much more successful in clinical trials where blood clotting was not a problem.[4] The surgeons concluded: 'The marked propensity of the dog to thrombotic occlusion [blood clotting] ...from a mitral prosthesis is not shared by the human being'.[5]
The surgeons intended carrying out further experiments with their caged ball valve on animals but as it invariably resulted in the death of the animals, the surgeons had to produce a different valve made specially for use in the dogs. One would have thought this would have been sufficient to indicate animal experimentation was of no value in respect of human health, but they continued and found that while the different valve did not kill so many dogs so quickly, nearly 80% died in 46 days. The surgeons admitted that 'the species differences' forced them to design one type of valve for use in humans and another type for use in the laboratory animals.[5] Finally, the successful clinical use of another design of mitral valve replacement gave further proof that animal experimentation is of no use as none of the dogs used in the preclinical testing survived more than 40 hours.[6]
[1]A. V. Doumanian and F. H. Ellis, Journal of Thoracic and Cardiovascular Surgery, 1961, vol. 41, pp.683-695.
[2]G. H. A. Clowes, jr., Annals of Surgery, 1961, vol. 154, p.740.
[3]A. Starr, American College of Surgeons, Surgical Forum, 1960, vol. 11, pp.258-260.
[4]A. Starr and M. L. Edwards, Annals of Surgery, 1961, vol. 154, pp.726-740.
[5]A. Starr and M. L. Edwards, Journal of Thoracic and Cardiovascular Surgery, 1961, vol. 42, pp.673-682.
[6]N. S. Braunwald, et al, Journal of Thoracic and Cardiovascular Surgery, 1960, vol. 40, pp.1-11.
Surgam.
This, an anti-inflammatory drug used for arthritis, was considered an improvement on other anti-inflammatory preparations as it did not damage the stomach, a major problem with this type of drug. It was advertised as providing 'gastric protection', being based on animal experimentation. However this claim could not be confirmed by clinical trials and as a consequence, Roussel, the manufacturer, was fined twenty thousand pounds for misleading advertising. The Lancet described how expert witnesses for both sides 'agreed that animal data could not safely be extrapolated to man'.[1]
[1]J. Collier and A. Herxheimer, Lancet, 10 January 1987, pp.113-114.
Selacryn.
This diuretic product was tested on animals and no harmful effects were detected.[1] After being introduced in 1979, it had to be withdrawn in America the following year when over 300 cases of liver damage were reported, which included 24 deaths.[1] Development of the drug was cancelled in many countries including Britain.[2]
[1]S. Takagi, et al, Toxicology Letters, 1991, vol. 55, pp.287-293.
[2]C. Spriet-Pourra and M. Auriche, Drug Withdrawal From Sale (PJB Publications, 1988).
Perhexiline.
This, a treatment for angina, was originally marketed in France in the 1970s. When it became linked to liver damage, it was withdrawn in Britain while other countries did not licence it at all. In fact some considered that it should never have been licensed.[1]
The animal experimentation conducted did not indicate the danger,[2] and even when high doses were administered to several different species for up to two years, there was no indication that the drug affected the liver.[3]
The company responsible for marketing perhexiline said: 'there has been an inordinate amount of animal work done...At this point we simply have been unable to induce hepatic [liver] damage in any species'.[4]
[1]D. G. McDevitt and A. M. MacConnachie, in Meyler's Side Effects of Drugs, 11th edn., ed. M. N. G. Dukes (Elsevier, 1988).
[2]C. T. Eason, et al, Regulatory Toxicology and Pharmacology, 1990, vol. 11, pp,288-307.
[3]J. W. Newberne, Postgraduate Medical Journal, 1973, vol. 49, April Suppl., pp.125-129.
[4]Ibid., p.130.
Menthol.
Menthol is included in a number of cough and cold remedies, and is also used as an inhalent when conditions such as bronchitus and sinusitis arise. It is also used as a ointment. If it comes into contact with the eye it will produce burning sensation which can last up to thirty minutes although there are no after-effects. In stark contrast, menthol causes severe damage to the eye of the rabbit.[1]
[1]W. M. Grant, Toxicology of the Eye (Charles Thomas, 1974).
Selenium disulphide (Selsun).
In view of this product being successful as an antidandruff shampoo, it was suggested that it might be of assistance for blepharitis, a painful and similar condition of the eyelids. Trials were then conducted in which a preparation with 0.5% selenium disulphide was applied to the lid margins. It was noted that if it came into contact with the conjunctivita there was irritation, and one patient developed conjunctivitis.[1] And yet animal experiments showed that: 'Selenium disulphide 0.5% ophthalmic ointment is nontoxic to rabbit corneas or conjunctivitas'.[2]
[1]G. C. Bahn, Southern Medical Journal, 1954, vol. 47, pp.749-752.
[2]J. W. Rosenthal and H. Adler, Southern Medical Journal, March 1962, p.318.
Domestic and cosmetic products.
Researchers discovered that while coconut soap had a negligible effect on human skin, it causes skin irritation in rabbits. Pine oil cleaner also produced a 'moderate' reaction in rabbits and guinea pigs, whereas it only had a slight effect on human skin. Other substances have been found to have different effects on animals and humans, e,g., high and low carbonate detergents, phosphate detergents, enzyme detergents, sodium carbonate and lemon juice all had an insignificant effect on human skin while causing irritation in animals. Overall, only 6 of the 24 products tested on animals and humans had the same effect on humans, rabbits and guinea pigs. The report concluded: 'Neither the rabbit nor the guinea pig provides an accurate model for human skin. The skin responses of these animals differ in both degree and in kind from those found in human skin'.[1]
Similar findings arose with cosmetic ingredients. Researchers at the New Jersey Warner Lambert Research Institute observed that: 'Animal skin is entirely differently from human skin and that there may be no correlation between the mildness of a raw material on a rabbit's back and its safety during use on a human face'. They offer the example of isopropyl myristate which is deemed safe for human use but causes irritation in rabbits.[2]
[1]G. A. Nixon, et al, Toxicology and Applied Pharmacology, 1975, vol. 31, pp.481-490.
[2]M. M. Rieger and G. W. Battista, Journal of the Society of Cosmetic Chemists, 1964, vol. 15, pp.161-172.
Domperidone.
This is used to treat nausea and vomiting, particularly those instances caused by anti-cancer treatment. The injectable form was withdrawn globally in 1986,[1] due to hazardous heart rhythm disturbances. However, this danger was not predicted by animal experimentation.[2] Dogs, the animal often used to test effects on the heart, were given 70 times the recommended human dosage, and yet no changes in the electrocardiogram occurred.[3]
[1]C. Spriet-Pourra and M. Auriche Drug Withdrawal From Sale (PJB Publications, 1988).
[2]R. Heywood, in Animal Toxicity Studies: Their Relevance For Man, eds. C. E. Lumley and S. R. Walker (Quay Publications, 1990).
[3]R. N. Brogden, et al, Drugs, 1982, vol. 24, pp.360-400.
Squalene.
This is a natural constituent of human sebum, the substance formed by sebaceous glands surrounding the root of the hair; this keeps the skin lubricated and supple. It is extensively and safely used in cosmetics.[1] However, when used on the skin of rabbits and guinea pigs, it produces loss of hair, the very opposite of what occurs in human beings.[2]
[1]M. M. Rieger and G. W. Battista, Journal of the Society of Cosmetic Chemists, 1964, vol. 15, pp.161-172.
[2]B. Boughton, et al, Journal of Investigative Dermatology, 1955, vol. 24, pp.179-189.
Prenylamine.
This product, a treatment for angina, was removed from the American market in 1988,[1] in view of it causing ventricular tachycardia, i.e., the heart beats abnormally fast and patients can faint. In stark contrast to this, animal experimentation revealed that prenylamine reduced the heart rate by up to 25% in cats, rabbits and guinea-pigs.[2]
[1]C. Spriet-Pourra and M. Auriche, Drug Withdrawal From Sale, (PJB Publications, 1988).
[2]H. Obianwu, Ata Pharmacology et Toxicology, 1967, vol. 25, pp.127-140.
Furmethide.
Warnings had to be issued to ophthalmologists against the prolonged use of this product when treating glaucoma,[1] as it was noted that the tear passage became permanently obstructed in over 70% of those patients who used it for more than three months.
And yet those who conducted the animal experimentation related to this product (on rats, guinea pigs and rabbits) declared it 'entirely safe' and worthy of clinical trial.[2]
[1]R. N. Shaffer and W. L. Ridgway, American Journal of Opthalmology, 1951, vol. 34, pp.718-720.
[2]A. Myerson and W. Thau, Archives of Opthalmology, 1940, vol. 24, pp.758-760.
Phenylbutazone (Butazolidine).
This was once widely used to treat arthritis, but was withdrawn in several countries and restricted in others, due to reports of aplastic anaemia (an often fatal blood disease caused by damage to the bone marrow) arising.[1]
Animal testing had indicated phenylbutazone to be a safe medication with no side effects even when ten times the dosage recommended for humans was administered to the animals.[2] The animal testing had certainly not suggested phenylbutazone would have a harmful effect on the bone marrow,[3] and a year after marketing, researchers said 'there have been no published reports of serious effects...on the hemopoietic [blood forming] system...in the experimental animal'.[4]
Noteworthy is the fact that later research involving test tube experiments using human bone marrow cell showed the dangers could be identified.[5]
It has been estimated that phenylbutazone and oxyphenbutazone (a closely related drug that has also caused aplastic anaemia which was withdrawn in 1985), have been responsible for 10,000 deaths worldwide.[6]
[1]C. Spriet-Pourra and M. Auriche, Drug Withdrawal From Sale, (PJB Publications, 1988).
[2]C. Hinz and I. M. Gaines, Journal of the American Medical Association, 1953, vol. 151, pp.38-39.
[3]R. Heywood in Animal Toxicity Studies: Their Relevance For Man, eds. C. E. Lumley and S. R. Walker (Quay Publishing, 1990).
[4]O. Steinbrocker, et al, Journal of the American Medical Association, 15 November 1952, pp.1087-1091.
[5]C. S. Smith, et al, Biochemical Pharmacology, 1977, vol. 26, pp.847-852.
[6]Estimate by Dr. Sidney Wolfe, in Lancet, 11 February 1984, p.353.
Chloroform.
Deaths from chloroform were regularly reported in the second half of the nineteenth century; it was believed that it caused respiratory failure but this could be minimized by careful administration and monitoring. Regrettably animal experimentation supported the idea that chloroform affected respiration rather than the heart.[1]
Launder Brunton, in a communication to the Lancet,[2] summarized the results from the Second Commission: 'four hundred and ninety dogs, horses, goats, cats and rabbits used. Results most instructive. Danger from chloroform is asphyxia or overdose: none whatever heart direct'. With this confirmation, from animal experimentation, that chloroform did not stop the heart, anaesthetists continued to use chloroform.
In 1893, clinical observations completely contradicted the previous findings and showed that heart failure is the most common cause of death from chloroform.[1]
[1]K. B. Thomas, Proceedings of the Royal Society of Medicine, 1974, vol. 67, pp.723-730.
[2]Lancet, 7 December 1889, p.1183.
Anaemia and iron.
When patients suffer iron deficiency, physicians prefer that they take iron by mouth, but if this is unsuccessful, iron is injected.[1] Due to animal experimentation, this option could have easily been discarded. Experiments which involved anaemia being induced in animals by iron deficiency or by repeated haemorrhage led the experimenters to conclude that injecting iron had no therapeutic value.[2] Fortunately, non-animal studies proved that human patients could be treated by iron injection.
Iron sorbitol is one type of injectable iron that could have been rejected for a different reason. Administration to rats and rabbits caused cancer at the injection site but once again non-animal trials showed that there was no hazard to human patients.[3]
[1]British National Formulary, no.276 (BMA and Royal Pharmaceutical Society of GB, 1993).
[2]G. N. Burger and L. J. Witts, Proceedings of the Royal Society of Medicine, 1934, vol. 27, pp.447-455.
[3]M. Weatherall, Nature, 1 April 1982, pp.387-390.
Spinal injuries.
During the previous century, vivisectors attempted to develop an animal that would mimic spinal cord injuries (SCI) in humans.[1] One method used to achieve such injuries was dropping weights onto the spinal cord of cats.*** Through this, it was intended to devise therapies for SCI. Despite all the suffering experienced by laboratory animals, virtually no treatments were developed that work in human patients.[1]
In 1988, Dennis Maiman of the Dept. of Neurosurgery at the Medical College of Wisconsin, said: 'In the last two decades at least 22 agents have been found to be therapeutic in experimental SCI. Unfortunately, to date none of these have been proven effective in clinical SCI'.[1] In 1990 clinical trials showed that high doses of steroids could be beneficial. While this was subjected to animal testing, the fact remains that the testing was not only unnecessary but the animals gave inconsistent results, with some tests indicating the therapy would not work.[2]
[1]D. Maiman, Journal of the American Paraplegia Society, 1988, vol. 11, pp.23-25.
[2]S. R. Kaufman, Perspectives on Medical Research, 1990, vol. 2, pp.1-12.
Psicofuranine.
When vivisectors tested psicofuranine for an anti-cancer treatment, the rats and mice used gave contradictory evidence.[1] The drug was effective against tumours in rats but had no effect on three different cancers in mice.
Physicians were also unable to properly assess the drug against human cancer as it caused severe side-effects in early human trials. It was found that the drug damaged the heart and yet no cardiac toxicity was found in the mice, rats, dogs or monkeys used in the testing.[1]
Although clinical study of psicofuranine was abandoned, animal experiments continued in an attempt to reproduce the heart ailments in humans. Yet again, no cardiac toxicity could be observed even when the animals (dogs and monkeys), were given up to 10 times the dose that would be harmful to humans.[1]
[1]C. G. Smith, et al, Journal of International Medical Research, 1973, vol. 1, pp.489-503.
Sparsomycin.
During clinical trials, sparsomycin, an anti-cancer drug, was found to produce eye damage. And yet while sparsomycin was highly toxic in several animal species (as would be expected for an anti-cancer drug), no specific effect on the eye was found.[1]
After the eye damage was reported, vivisectors sought to induce the condition in rats and monkeys, but these attempts were unsuccessful even though the rats were dosed every day for two weeks with up to 300 times the amount that was found to harm humans.[1] No retinal toxicity was noted in additional animal tests and the drug was abandoned.
[1]C. G. Smith et al, Journal of International Medical Research, 1973, vol. 1, pp.489-503.
Corticosteroids: the unborn.
Experimentation involving pregnant mice and rabbits indicate that corticosteroids are very dangerous to the unborn human child. In the case of mice, cortisone produces cleft palate in up to 100% of the offspring of some species.[1] And in the case of rabbits, corticosteroids affect the heart and they can also cause severe growth retardation in the uterus, and death of the foetus. In stark contrast, rats and monkeys are very tolerant to corticosteroids in pregnancy.[2]
Researchers have noted the 'very wide species variation',[2] and despite the results of animal testing, cortisone is not considered harmful to human babies.[1]
[1]R. M. Ward and T. P. Green, Pharmacology and Therapeutics, 1988, vol. 36, pp.326.
[2]R. K. Sidhu in Drugs and Pregnancy: Human Teratogenesis and Related Problems, ed. D. F. Hawkins (Churchill Livingstone, 1983).
Iproniazid.
This was originally manufactured for the treatment of tuberculosis, but was subsequently used as an anti-depressant. Although it was considered 'harmless' on the basis of animal tests,[1] iproniazid produced fatal cases of liver damage in humans, and the drug was eventually abandoned.[2]
[1]J. Boyer in Clinical Pharmacology: Basic Principles in Therapeutics, 2nd edn., eds. K. I. Melmon and H. F. Morrelli (Macmillan, 1978).
Thalidomide.
This was first introduced as a sedative by the German drug company Chemie Grünenthal in 1957, and by the Distillers company in Britain a year later. Although animals could tolerate massive doses without ill-effect,[1] thalidomide was soon found to cause peripheral neuritis in human patients.
William McBride, an Australian obstetrician, was alerted to thalidomide's most notorious side-effect after seeing three babies born with very unusual birth defects. Regrettably, his warnings to the medical profession were delayed because he attempted to confirm his suspicions by experiments on mice and guinea pigs, both of which were resistant to the drug.[2] It was only after he saw more human cases, did McBride publish his findings.
Although it was not specifically tested for birth defects before it was marketed, subsequent experiments revealed 'extreme variability in species' susceptibility to thalidomide'.[3] For example, mice could safely tolerate eight thousand times the dose which was found harmful to human babies.[4]
In his book, Drugs as Teratogens, Schardein writes: 'In approximately ten strains of rats, fifteen strains of mice, eleven breeds of rabbits, two breeds of dogs, three strains of hamsters, eight species of primates, and in other such varied species as cats, armadillos, guinea pigs, swine and ferrets, in which thalidomide had been tested, teratogenic effects [birth defects] have been induced only occasionally'.
Scientists eventually found that birth defects similar to those occurring in humans could be induced in certain types of rabbit and primate. Nonetheless, New Zealand white rabbits had to be dosed with three hundred times the amount that was dangerous to humans.[5]
The thalidomide tragedy prompted additional extensive testing of drugs and chemicals in pregnant animals, but some scientists believe that: 'Animal malformations seldom correlate with those of humans'.[6] Additionally, 'No animal model has been found which responds satisfactorily to all known teratologic agents in humans to permit reliable screening of substances for their teratologic potential. Careful surveillance, reporting and prospective study...remain the mainstays for detection of adverse effects following foetal drug exposure'.[6]
[1]R. D. Mann, Modern Drug Use, an Enquiry on Historical Principles (MTP Press, 1984).
[2]The Sunday Times 'Insight' Team: Suffer the Children: the Story of Thalidomide, (Andre Deutsche, 1979).
[3]T. H. Shepard, Catalogue of Teratogenic Agents (John Hopkins Press, 1976).
[4]S. K. Keller and M. L. Smith, Teratogenesis, Carcinogenesis and Mutagenesis, 1982, vol. 2, pp.361-374.
[5]New Zealand White rabbits were sensitive to doses of 150mg/Kg of thalidomide (ref. 6), while the dangerous human dose was 0.5mg/Kg (ref. 4).
[6]R. M. Ward and T. P. Green, Pharmacology and Therapeutics, 1988, vol. 36, p.326.
Mitoxantrone.
This drug was produced for the treatment of cancer without side- effects on the heart. After beagles, on whom the drug was tested , 'failed to demonstrate cardiac failure',[1] researchers believed that it was safe. However in clinical trials, a number of patients suffered side-effects including heart failure; more widespread use of the drug confirmed that cardiac toxicity was a major problem with the drug.
Data from over three thousand patients who were given the drug included nearly a hundred reports of cardiac side-effect with twenty- nine of heart failure.[2] A recent study indicated that 20% of patients develop cardiotoxicity after using mitoxantrone.[3]
[1]R. Stuart Harris, et al, Lancet. 28 July 1984, pp.219- 220.
[2]Martindale: The Extra Pharmacopoeia, 29th edn., ed. J. E. F. Reynolds (Pharmaceutical Press, 1989).
[3]A. Stanley and G. Blackledge, Side Effects of Drugs, Annual 15, eds. M. N. G. Dukes and J. K. Aronson (Elsevier, 1991).
Carbenoxalone.
This was introduced during the 1960s for the treatment of peptic ulcers. Before being marketed it was tested on animals and the tests indicated that carbenoxalone was safe and there were no harmful effects.[1] When vivisectors realized that humans metabolized carbenoxalone differently to rats, mice and rabbits, further experiments were carried out on monkeys, but yet again, there was no evidence of toxicity.[1]
When carbenoxalone began to be used by human patients, salt and water retention occurred and this led to high blood pressure, swelling, weight gain, muscle weakness and heart failure. The British National Formulary advises other drugs are preferred and if carbenoxalone is used, treatment must be carefully monitored.[2]
[1]C. T. Eason, et al, Regulatory Toxicology and Pharmacology, 1990, vol. 11, pp.288-307.
[2]British National Formulary, no.26 (BMA and the Royal Pharmaceutical Society of G.B., 1993).
Clindamycin.
After the antibiotic clindamycin was given to rats and dogs every day for a year, it was found that the animals could tolerate twelve times the recommended human dose.[1]
However, Britain's Committee on the Safety of Medicines was forced to warn the medical profession about the dangers of clindamycin, one of which was the sometimes-fatal intestinal disease, pseudomembraneous colitis. By 1980, 36 deaths had been reported.[2] Although the problem can occur with other antibiotics, it is more frequently seen with clindamycin and the British National Formulary warns that patients should stop using clindamycin immediately if side-effects develop.
[1]The British National Formulary (No. 26, 1993) says the maximum oral dose for severe infections is 450mg every six hours, i.e., 25mg/kg for a person weighing 70 kg taking 4 doses in 24 hours. Rats and dogs could tolerate more than 300mg/kg (J. E. Gray, et al, Toxicology and Applied Pharmacology, 1972, vol. 21, pp.516- 531).
[2]G. R. Venning, British Medical Journal, 15 January 1983, pp.199-202.
Leukaemia treatment.
For decades, in an attempt to find a treatment for leukemia, tens of thousands of chemicals have been used in mice which have been given leukaemia. This has proved highly ineffective. One scientist has estimated that for every 30-40 drugs that are effective in treating mice with cancer, only one will work with humans.[1]. During the 1980s, researchers admitted that the American NCI (National Cancer Institute) was failing to identify promising new treatments.[2][3]
A new strategy involves test tube studies rather than mice, at least for the preliminary experiments. Drugs that appear to be promising are then tested on animals so the prospect of misleading results is still very much there.[4]
[1]D. D. Von Hoff, Journal of the American Medical Association, 10 August 1979, p.503.
[2]R. Kolberg, Journal of NIH Research, 1990, vol. 2, pp.82- 84.
[3]A. Pihl, International Journal of Cancer, 1986, vol. 37, pp.1-5.
[4]S. E. Salmon, Cloning of Human Tumor Stem Cells (Alan Liss, 1980).
Pronethalol and Propranolol.
The first agents used as beta-blockers, for the treatment of heart conditions, were pronethalol and propranolol. While pronethalol was found to be safe and effective with laboratory animals, but failed the clinical tests, propranolol appeared to be toxic in numerous animal experiments, and yet it is widely used in clinical practice, i.e., treating humans.
Pronethalol was 'well tolerated' by rats and dogs in prolonged toxicity tests at high doses except for occasional effects on the central nervous system.[1] In complete contrast, clinical trials revealed an unacceptable number of side-effects,[2] including heart failure - a hazard not predicted by the animal experiments which had been conducted.[1] Shortly after, long-term tests in a particular strain of laboratory mouse produced cancer of the thymous gland but no carcinogenic effects were ever found in rats, guinea pigs, dogs, monkeys or other types of mouse.[1]
Pronethalol was promptly replaced by propranolol but tests in rats, dogs and mice resulted in further development being jeopardized.[3] Moderate to high doses caused rats to collapse and dogs to vomit severely.[1] Deaths also occurred in mice shortly after dosing. When the amount of the drug was reduced to the dosage that would be used by humans, propranolol was said to be 'well tolerated', although even then, some of the rats still had heart lesions.[1]
[1]M. Cruickshank, et al, Safety Testing of New Drugs, eds. D. R. Lawrence, et al (Academic Press, 1984).
[2]W. Sneader, Drug Discovery: The Evolution of Modern Medicine (Wiley, 1985).
[3]D. R, Laurence, et al, eds., Safety Testing of New Drugs (Academic Press, 1984).
Librium and Valium.
These were the first of a new type of tranquillizing drug which appeared in the 1960s. Soon after their introduction, the medical profession became aware of cases of dependence although it was nevertheless believed that high doses were necessary.[1] At the usual therapeutic doses, dependence was thought to be uncommon and not a serious problem and this idea prevailed for some twenty years as laboratory research confirmed it: 'animal experiments...do not indicate the potential for the development in the human of dependence at therapeutic dosage levels'.[2]
At the same time it is also known that 'animal studies...do not predict clinical dependence potential reliability',[3] and careful human observations revealed that tranquillizers could in fact induce dependence at ordinary doses. By the mid-1980s, some 500,000 people in Britain alone were addicted to this treatment.[4]
[1]H. Peturrson and M. Lader, Dependence on Tranquillizers (OUP, 1984).
[2]J. Marks, The Benzodiazepines (MTP Press, 1978).
[3]Drug and Therapeutics Bulletin, 1989, vol. 27,28.
[4]The Benzodiazepines in Current Clinical Practice, eds., H. Freeman and Y. Rue (Royal Society of Medicine Services, 1987).
Rifampicin.
In the early 1970s, doctors became aware of women who, while using 'the pill', became pregnant.[1] Of 88 women who used oral contraceptives in addition to the antituberculous drug rifampicin, 75% suffered disturbances to their menstrual cycle and 5 became pregnant. The British National Formulary (1993) advised doctors who prescribed rifampicin to recommend to patients that they use additional means of contraception.
It was discovered that rifampicin accelerates the breakdown of other medicines,[2] and in these cases it had stimulated the patient's liver to metabolize/breakdown the pill. Another example was methadone where rifampicin led to withdrawal symptoms by reducing the amount of the drug. In one case, a patient rejected a kidney graft because rifampicin reduced the dose of the immunosuppresive drug which had been given.
Rifampicin's peculiar effects had not been predicted by animal experimentation.[3] After the discovery of the effects in humans, further animal experimentation was conducted but this proved contradictory. For example. the drug's action could not be reproduced in rats.[4] In mice however, prolonged treatment with rifampicin did stimulate the liver's metabolic processes; however a single dose had the opposite effect of slowing down metabolism.[4] If rifampicin had been tested on human liver tissue rather than on live animals, it is likely the problems would have been predicted.[5]
[1]Reported in J. P. Mumford, British Medical Journal, 11 May 1974, pp.333-334.
[2]H. Meyer, et al, in Meyer's Side Effect of Drugs, 11th edn., ed. M. N. G. Dukes (Elsevier, 1988).
[3]E. Nieschlag, Pharmacology and Therapeutics, 1979, vol. 5, pp.407-409.
[4]D. Pessayre and P. Mazel, Biochemical Pharmacology, 1976, vol. 25, pp.943-949.
[5]A. M. Jezequel, et al, Gut, 1971, vol. 12, pp.984-987.
Taxoxifen.
This was developed during the 1960s as an oral contraceptive. However, while it prevented ovulation and terminated pregnancy in rats,[1] it stimulated ovulation in women and became listed as a treatment for infertility.[2]
It is used also in breast cancer therapy as it blocks the action of oestrogen in breast tissue. In monkeys, and rats at low doses, it also acts as an anti-oestrogen, but in mice, dogs, and rats at high doses, it has the opposite effect, behaving like an oestrogen.[1] Due to the different results of animal experimentation, it was admitted that 'significant species variation has been observed in target tissue response to oestrogens and anti-oestrogens making it hazardous to predict therapeutic activity in the human by extrapolation of effects in experimental animals'.[3]
Other conflicting results from animal testing has occurred, e.g., taxoxifen produces liver tumours in rats but not in mice,[4] and does not appear to do so in humans. Due to the conflicting results the two leading British cancer charities disagreed over taxoxifen and the Medical Research Council withdrew its support and decided to initiate new tests. The Imperial Cancer Research fund said: 'We are going to be in a position where the animal rights people are going to be saying to us: 'you ignore animal data when you choose to'.'[5]
Yet further doubts arose through a subsequent study which suggested an increased risk of womb cancer among the breast cancer patients being tested with the drug. However overall, the drug is said to have few side-effects and according to the manufacturer, the main reason to stop taking the drug is if nausea and vomiting begin.[1] This comes as a surprise as it had been noted: 'None of the toxicological studies produced any evidence of vomiting even though high doses were used in dogs which we consider to be a predictive species for vomiting in man.[1].
[1]M. J. Tucker, Safety Testing of New Drugs, eds. D. R. Laurence, et al (Academic Press, 1984).
[2]British National Formulary, No. 26 (BMA and the Royal Pharmaceutical Company of GB, 1993).
[3]P. K. Devi, in Pharmacology of Estrogens, ed. R. R. Chaudhury (Pergamon Press, 1981).
[4]I. N. White, et al, Biochemical Pharmacology, 1993, vol. 45, pp.21-30.
[5]P. Brown, New Scientist, 21 March 1992, p.9.
Steroids.
Corticosteroid drugs are widely used in medicine although they have many side-effects. It is admitted that there are 'remarkable differences in susceptibility to glucocorticosteroids between various species' with animals classified as steroid-resistant or steroid-sensitive.[1]
In mice, a single dose of cortisone produces a 90% decrease in the thymus (an organ that plays a crucial role in immunity). In contrast, the same dose of cortisone given to a guinea-pig every day for a week, only produces a 37% decrease. Furthermore, the same effect is difficult to achieve in other species.[1]
Much of the research on corticosteroids have been carried out on steroid-sensitive animals (e.g., mice, rats, rabbits, and hamsters) whereas human beings fall into the steroid-resistant category.[1] Researchers at the University of Dundee acknowledged: 'the mode of action of these drugs is very complicated, so it is regrettable that most of the extensive literature on animal experimental work is irrelevant to human therapeutics since many species respond in a very different manner from man'.[2]
[1]H. N. Claman, New England Journal of Medicine, 24 August 1972, pp.388-397.
[2]J. S. Beck and M. C. K. Browning, Journal of the Royal Society of Medicine, 1983, vol. 76, pp.473-479.
X-rays.
In 1956, the British medical profession drew attention to a link between X-rays during pregnancy and subsequent childhood cancers.[1] Within a short time, similar findings were reported in respect of American children. And yet for a quarter of a century, scientists doubted that X-rays could cause such cancer and cited animal experimentation to argue that the foetus is not particularly sensitive to radiation.[2]
In fact, compared with other species, the human foetus is more susceptible to the carcinogenic effects of X-rays,[2] and this was confirmed during the 1980s.[3]
[1]A. M. Stewart, et al, Lancet, 1 September 1956. p.447; British Medical Journal, 28 June 1958, pp.1495-1508.
[2]E. B. Harvey, et al, New England Journal of Medicine, 28 February 1985, pp.541-545.
[3]E. G. Knox, et al, Journal of the Society of Radiological Protection, 1987, vol 7, pp.3-15; E. A. Gilman, et al, Journal of the Society of Radiological Protection, 1988, vol. 8, p.308.
Methanol.
This is used in a wide range of consumer products, e.g., solid fuel, antifreeze, paint remover and varnishes. It is also consumed as a heap alternative to alcohol.
Although methanol is a highly poisonous, potentially lethal substance, this was not realized for some years.[1] Laboratory animals such as rats and mice are resistant to its effects,[2] and animal experiments in the early part of the twentieth century gave the impression that methanol was only marginally toxic, and far less poisonous than alcohol.[3]
In reality, methanol is ten times more toxic; a single dose of methanol can result in temporary or permanent blindness in human beings.[4] However, this does not occur in rats, mice, dogs, cats, rabbits or chickens.[3] It was only in the 1960s and again in the next decade that the actual symptoms of methanol poisoning were induced in monkeys.[2]
As is obvious from the above, animal experimentation was both highly misleading and dangerous. Some good treatment results were obtained in the earlier part of the twentieth century by using bicarbonate to treat human poisoning, but the results were undermined by animal experimentation. In 1955 an analysis stated: 'It is indeed deplorable that about thirty years before the good effects of this treatment became commonly known...it seems that the authors of medical textbooks have paid more attention to the results of animal experimentation than to clinical observations'.[3] The treatment not only failed in animals but actually proved fatal, prompting some researchers to advise against using it.
Another method involves administering alcohol to reduce the toxicity of methanol. While this is effective in human beings, animal tests suggested that this practice would increase the danger of methanol. Once again, animal experimentation discouraged using this method of treating human poisoning.[3]
[1]M. J. Ellenhorn and D. G. Barceloux, Medical Toxicology: Diagnosis and Treatment of Human Poisoning (Elsevier, 1988).
[2]T. R. Tephly, Life Sciences, 1991, vol. 48, pp.1031- 1041.
[3]O. Roe, Pharmacological Reviews, 1955, vol. 7, pp.399- 412.
[4]P. Wingate, Medical Encyclopedia, (Penguin, 1983).
Aminorex.
During the 1960s, physicians in Switzerland became aware of a sudden rise in obstructive pulmonary hypertension, a dangerous lung disease. The cause was traced to the drug aminorex which had been used for treating obesity.[1] The drug was found to cause chest pains, difficulty in breathing, fainting, heart problems and in some cases, death.[2] The deadly side-effects of this drug had not been predicted by the animal experimentation which had been conducted.[3]. In view of its dangers, the drug was withdrawn in 1968.
Animal experimentation continued after withdrawal and even then, long administration to rats failed to induce the disease.[2] In dogs, the drug increased lung pressure,[1] but its relevance to the human condition is unclear since later analysis concluded that: 'pulmonary hypertension cannot by induced in experimental animals even with aminorex'.[4]
[1]F. Follath, et al, British Medical Journal, 30 January 1971, pp.265-266.
[2]E. H. Ellinwood and W. J. K. Rockwell in Meyler's Side Effects of Drugs, 11th edn, ed. M. N. G. Dukes (Elsevier, 1988).
[3]A. D. Dayan in Risk-Benefit Analysis in Drug Research, ed. J. F. Cavalla (MTP Press, 1981).
[4]P. H. Connell in Side Effects of Drugs Annual - 3, ed. M. N. G. Dukes (Excerpta Medica, 1979).
Diethylstilbestrol (DES).
On the basis of what animal experimentation revealed, the synthetic oestrogen Diethylstilbestrol (DES) was suggested as a means by which miscarriage could be avoided.[1] Although no proper clinical, i.e., human, trials were conducted,[2] the procedure became widely accepted and to 1971, up to 3 million pregnant women in America alone were given DES.
However, DES was found to be ineffective; in 1953 trials had shown that DES did not work,[3] although this study failed to report that DES increased abortion, neonatal deaths and premature deaths, a conclusion that could have been made from the available data.[4]
Thus, DES was not only ineffective, it was dangerous and in 1971, researchers discovered how dangerous it was when they traced a link between exposure to DES and a previously rare form of vaginal and cervical cancer in the daughters of those women who had taken the drug while pregnant.[5] Nearly six hundred cases were reported,[6] and DES proved to be a biological time-bomb as its side-effects continued to appear in the sons and daughters of women who took the drug.
Although, in 1938, it was found that DES caused breast cancer in male mice, this information was of no value as the cancer-causing potential of other oestrogens varied according to the strain of mouse used.[7] Furthermore, the consensus among vivisectors at the time was that oestrogens did not produce cancer,[7] rather they gave male mice mammary glands and therefore made them susceptible to the same cancer-causing factors that arose in female animals. In fact, a summary of the animal data found 'only meagre evidence' that oestrogens caused cancer of the cervix.[7]
It was not until the 1970s that it became clear that in contrast to the majority of animal experiments, DES was a potent cause of cervical cancer in women.
[1]Health Action International, 'Problem Drugs' pack, 13 May 1986.
[2]D. Brahams, Lancet, 15 October 1988, p.916.
[3]W. J. Dieckmann, et al, American Journal of Obstetrics and Gynaecology, 1953, vol. 66, pp.1062-1081.
[4]Y. Brackbill and H. W. Berendes, Lancet, 2 September 1978, p.520.
[5]A. L. Herbst, et al, New England Journal of Medicine, 22 April 1971, pp.878-881.
[6]C. Vanchieri, Journal of the National Cancer Institute, 1992, vol. 84, pp.565-566.
[7]S. Peller, Cancer in Man (Macmillan, 1952).
Pethidine.
On the basis of experiments with dogs, the narcotic analgesic pethidine was considered to be non-addictive.[1] This error was not realized because in dogs, the drug was metabolized (broken down) much more quickly, resulting in less exposure to the drug. In fact, dogs metabolize pethidine six times faster than humans.[2]
Such differences in metabolism are the rule rather than the exception;[2,3] a former director of Wellcome Research Laboratories admitted that 'every species has its own metabolic pattern, and no two species are likely to metabolize a drug identically'.[4]
[1]B. Brodie, Pharmacologist, 1964, vol. 6, pp.12- 26.
[2]R. Levine, Pharmacology, Drug Actions and Reactions (Little, Brown and Co, 1978).
[3]G. Zbinden, Advances in Pharmacology, 1963, vol. 2, pp.1-112.
[4]M. Weatherall, Nature, 1 April 1982, pp.387-390.
Digoxin and Digitoxin.
These heart drugs are pure substances extracted from digitalis, the value of which in treating heart failure and cardiac arrhythmias originated from the studies of human patients;[1,2] (despite its value, care must be taken over high doses which can be toxic). Fortunately the drugs did not derive from animal experiments as the doses which were considered safe for rats, guinea-pigs, dogs and cats can in fact kill human beings.[3] Digoxin's lethal dose is now more accurately determined by test-tube studies using human cells.[4]
Animal experimentation also indicated that digitalis raised the blood pressure and as a result of this, the drug was widely considered to be dangerous for certain patients and should not be prescribed to them. Fortunately, studies, not using animals, showed this to be false and digitalis can be, and is used for the treatment of human patients with great benefit.[2]
[1]W. Sneader, Drug Discovery: The Evolution of Modern Medicine (Wiley, 1985).
[2]T. Lewis, Clinical Science (Shaw and Sons Ltd, 1934).
[3]G. T. Okita, Federation Proceedings, 1967, vol. 26, pp.1125-1130.
[4]R. Jover, et al, Toxicology In Vitro, 1992, vol. 6, pp.47-52.
Detergents.
Detergents are not only used in domestic and industrial settings, i.e., experimentation which sought to increase the penetration of therapeutic drugs across the cornea used a number of dilute detergents which were assessed in the eyes of human volunteers. Although these were deemed 'generally harmless to rabbit eyes', some caused pain and irritation in the human volunteers.
For example, Brij 58 resulted in 'alarming' changes to the surface of the human eye, accompanied by discomfort and impaired vision.[1] And yet in rabbits, Brij 58 is designated a 'non-irritant'.[2]
A 3% solution of a similar product called Brij 35 produced delayed irritation in volunteers but was once again non- irritating to the rabbit eye, and this was even when undiluted.[1] Another detergent, dupanol, caused immediate severe pain in human subjects,[1] but was deemed to only have moderate effects in the eyes of rabbits.[3]
[1]R. J. Marsh and D. M. Maurice, Experimental Eye Research, 1971, vol. 11, pp.43-48.
[2]M. Cornelis, et al, ATLA, 1991, vol. 19, pp.324- 326.
[3L.W. Hazelton, Proceedings of the Scientific Section of the T.G.A, 1952, vol. 17, pp.509.
Cancer treatment.
Many cancer patients suffered unnecessarily when it was believed that large doses of anticancer drugs were necessary for efficient treatment. It was held that to reduce the tumour size, chemotherapy also had to be toxic.[1]
This idea was based on animal experimentation,[1,2] even though there were early warning signs that patients survived longer when treated with comparatively non-toxic doses, despite the drug having a smaller effect on the tumour size.[3]
Studies in the 1960s concluded that toxicity was not necessary and could be counterproductive.[2] In 1976, cancer specialists in London found that the data from animal experimentation, on which the high dose concept was based, are not necessarily valid for human patients,[1] and argued that 'alternative methods of improving the selectivity of cancer chemotherapy must be explored'.
[1]M. H. N.Tattersall and J. S. Tobias, Lancet, 13 November 1976, pp.1073-1074.
[2]I. D. Bross, Perspectives on Animal Research, 1989, vol. 1, pp.83-108.
[3]M. A. Schneiderman and M. J. Krant, Cancer, Chemotherapy Reports, 1966, vol. 50, pp.107-112.
AIDS.
The fact that even chimpanzees do not develop AIDS when infected with HIV naturally casts doubts on whether animal experimentation concerned with AIDS can have any possible value.[1] Some AIDS researchers appear to have grasped this fact as vaccines which failed to protect chimpanzees from HIV were nevertheless tried in human trials.[2]
Animal experimentation has the potential to be dangerous as the failure to induce AIDS in laboratory animals has led some to argue that HIV is not the cause of AIDS.[3]
There is a further danger by producing an 'animal model' of AIDS as this may simply produce an animal version of AIDS and could also promote hazardous changes in the manner in which AIDS is spread.
[1]P. Newmark, Nature, 19 October 1989, pp.566-567.
[2]A. S. Fauci and P. J. Fischinger, Public Health Reports, 1988, vol. 103, pp.203-236.
[3]New Scientist, 3 March 1988, p.34.
[4]J. Marx, Science, 16 February 1990, p.809. P. Lusso, et al, Science, 16 February 1990, pp.848-852.
Furosemide.
Furosemide is successfully used for the treatment of cardiovascular and kidney disease in human beings. However, in mice it causes massive liver damage and similar effects have been found in rats and hamsters.[1] And yet liver toxicity is not a major problem for human patients.[2] The harmful effects in mice have been traced to a breakdown product of furosemide which is not found to any serious extent in the human body.[3] Fortunately the adverse effects in mice were reported after the safety in people had been established.[3] If it had been otherwise, the drug may have never been introduced.
A comparison of human and animal test data shows that the case of furosemide is not an isolated instance. At most, only one out of every four side-effects produced by animal tests actually occurs in human beings.[4] Consequently animal testing leads to the rejection of medicines which are potentially valuable for treating human illnesses.
[1]R. M. Walker and T. F. McElligott Journal of Pathology, 1981, vol. 135, pp.301-314.
[2]M. N. G. Dukes in Meyler's Side Effects of Drugs, 11th edition, ed. M. N. G. Dukes (Elsevier, 1988).
[3]M. Weatherall, Nature, 1 April 1982, pp.387-390.
[4]A. P. Fletcher, Journal of the Royal Society of Medicine, 1978, vol. 71, pp.693-698.
Cyclosporin.
This is used to prevent the rejection of transplanted organs: while hailed as a major advance over existing drugs, side- effects are common and sometimes dangerous. The most serious hazard is kidney damage,[1] an effect that was not predicted by the initial animal experimentation.[2] And yet kidney toxicity has been reported in almost 80% of kidney transplant patients receiving the drug.[2] Some heart transplant patients who were treated with cyclosporin required dialysis because their kidneys failed.[3]
Subsequent animal experiments showed that only extremely high doses of cyclosporin could induce kidney toxicity in rats,[1] although dogs and rhesus monkeys were still unaffected.[2] Researchers believe that: '...failure to produce renal dysfunction [kidney damage] experimentally that is similar to that seen clinically may result from species differences in metabolism'.[2]
Although cyclosporin can prevent the rejection of transplanted organs in both animals and human beings, an early review of the drug found sufficient variation in experimental results to indicate: 'the immunosuppressive effects of cyclosporin have...differed considerably between species, limiting any direct inference that may be made regarding use in human organ transplantation...'[1]
[1]D. J. Cohen, et al, Annals of Internal Medicine, 1984, vol. 101, pp.667-682.
[2]W. M. Bennett and J. P. Pulliam, Annals of Internal Medicine, 1983, vol. 99, pp.851-854.
[3]Lancet, 22 February 1986, pp.419-420.
Zelmid.
In September 1987, the antidepressant zimelidine (Zelmid) was withdrawn worldwide after potentially serious side-effects, including nerve damage, leading to the loss of sensation or paralysis.[1]
Some patients experienced hypersensitivity reactions such as fever, joint pains and liver problems. The drug had been introduced only a year earlier but Britain's Committee on Safety of Medicine had received over 300 reports of adverse reactions, 60 of which were serious; there were 7 deaths.[2]
And yet prolonged testing in rats and dogs showed no evidence of toxicity even when they were given five times the human dose.[3]
[1]B. Blackwell in Side Effects of Drugs Annual, vol. 8, eds M. N. G. Dukes and J. Elis (Elsevier, 1984).
[2]R. D. Mann, Modern Drug Use; An Inquiry on Historical Principles (MTP Press, 1984).
[3]R. C. Heel, et al, Drugs, 1982, vol. 24, pp.169- 206.
PARTE 2
Zipeprol.
In 1984 a Milan poison control centre reported 32 patients suffering severe neurological side-effects following an overdose with zipeprol, a cough suppressant.[1] Symptoms included seizures and comas. Animal testing had given no warning of severe neurological problems despite higher doses being given to the animals that were used.[2]
[1] C. Moroni, et al, Lancet, 7 January 1984, p.45.
[2] D. Cosnier, et al, Drug Research, 1976, vol. 26, pp.848-854. G. Rispat, et al, Drug Research, 1976, vol. 26, pp.523-530.
Evicromil.
This was submitted for clinical (i.e., human) trials as an antiasthmatic after being tested on mice, rats, hamsters, rabbits, ferrets, squirrel monkeys, cynomolgus monkeys, stump- tail monkeys and baboons. Despite giving the animals doses many times greater than would be taken by humans, no harmful effects were noted, including the liver.[1] However, 20% of patients participating in the trial developed symptoms of liver damage, which prevented any further development of the drug.[2] Subsequent tests showed that liver toxicity could only be induced in dogs.[1,2]
[1]D. V. Parke, in Animals and Alternatives in Toxicity Testing, eds., M. Balls, et al (Academic Press, 1983).
[2]C. T. Easton, et al, Regulatory Toxicology and Pharmacology, 1990, vol.11 pp.288-307.
Fenclozic acid.
During clinical trials (i.e., on humans), ICI's anti-arthritic drug fenclozic acid produced jaundice in some patients. This was unexpected as testing which was undertaken on rats, mice, dogs and monkeys had given no hint of liver problems.[1] Not content with these results, there were further experiments with rabbits, guinea pigs, ferrets, cats, pigs, horses, neonatal rats and mice, along with a different strain of rat: yet again, no evidence of liver damage could be found.[1]
The ICI researcher commented: 'the quite unexpected onset of jaundice in a few patients caused withdrawal of the drug from humans and initiated a vast programme of experimental work. This search for hepatotoxicity [liver damage] in different species or any indication of its likelihood has so far been unrewarding [in other words, unsuccessful].
[1]S. J. Alcock, Proceedings of the European Society for the Study of Drug Toxicity, 1971, vol. 12, pp.184-190.
Ketoconazole.
In 1985, Britain's Committee on Safety of Medicines issued a warning about serious liver damage associated with the antifungal drug ketoconazole (Nizeral).[1] The Committee referred to 82 cases, with 5 deaths. The warnings followed a similar action by the American FDA in 1982.[2]
Despite this, no evidence of liver toxicity was found in the animal testing.[3]
[1]Lancet, 12 January 1985, p.121.
[2]C. B. M. Tester-Dalderup in Meyler's Side-Effects of Drugs, 11th edn, ed. M. N. G. Dukes (Elsevier, 1988).
[3]J. K. Heiberg and E. Svejgaard, British Medical Journal, 26 September 1981, p.825.
Nutrition.
During the early part of the previous century there was interest in the possibility that a lack of food during childhood might interfere with the development of the brain. Regrettably almost of the research was carried out on animals which showed that starving baby or adult rats had no effect on the brain. The issue was abandoned and not revived until the late 1950s when children with histories of undernutrition were found to persistently underachieve.[1]
Researchers then realized that the earlier animal testing had not taken 'brain growth spurt' into account, this being the time of fastest growth when the brain is most vunerable. Additionally, the timing varies between the different species, i.e., in human babies the brain growth spurt begins during the final period of pregnancy and lasts for about a year, whereas in guinea pigs, it occurs almost wholly during the foetal period, and yet in rats, it occurs during the first three weeks after being born.[2]
Despite the number of starving humans in the world today, there appears to be no shortage of funds for vivisectors who claim to be researching early life undernutrition in animals.
[1]J. Dobbing in Early Nuitrition and Later Behaviour, ed. J. Dobbing (Academic Press, 1987).
[2]J. Dobbing and J. L. Smart, British Medical Bulletin, 1974, vol. 30, pp.154-168.
Eraldin.
Eraldin (Practolol), marketed during the 1970s, was said to be 'particularly notable for the thoroughness with which its toxicity was studied in animals, to the satisfaction of the regulatory authorities'.[1]
In time, serious effects began to be noted, i.e., skin, eye and abdominal disorders. In some cases, patients suffered blindness; sclerosing peritonitis also occurred, resulting in 23 deaths being reported.[2] The manufacturers (ICI) paid compensation to over 1000 victims.[3]
The side-effects of the drug (for the treatment of heart conditions) were not predicted by the animal testing that was conducted. Moreover, subsequent to the drug being withdrawn from the market in 1976, it has not been possible to replicate the side- effects in laboratory animals.[1]
[1]M. Weatherall, Nature, 1 April 1982, pp.387-390.
[2]G. R. Venning, British Medical Journal, 15 January 1983, pp.199-202. 22 January 1983, pp.289-292.
[3]A Question of Balance, Office of Health Economics, 1980.
[4]F. H. Gross and W. H. Inman, Drug Monitoring (Academic Press, 1977).
Cortisone: the eye.
One of the principal side-effects of treating the eye with steroids is glaucoma (high pressure arises within the eye which can lead to loss of sight). And yet when corticosteroids were used in ophthalmology, the animal testing conducted indicated that cortisone did not affect the pressure within the eye.[1]
Later attempts to induce glaucoma in monkeys and rabbits were either difficult or impossible.[2] One group of researchers admitted to: 'the differing response of the eye of man and animals to repeated topical [surface] application of corticosteroids'. They added 'Such a procedure is without effect on tension of the eye of many experimental mammals, but increases tension in the human eye'.[3]
Another side-effect of using steroid treatment which is difficult to replicate in the laboratory animal is the cataract. While slight changes in the lens of the rabbit's eye have been produced - after repeated high doses - they do not mimic the severity of the condition as found in humans.[2]
[1]L. H. Leopold, et al, American Journal of Ophthalmology, 1951, vol. 34, pp.361-371.
[2]W. M. Grant, Toxicology of the Eye, 2nd edn (Charles Thomas, 1974).
[3]B. Ballantyne and D. W. Swanston in Current Approaches in Toxicology, ed. B. Ballantyne (Wright and Sons, 1977).
Talcum powder.
When experiments, using vast amounts of talcum powder, were conducted on animals, these suggested that using talcum powder presented no danger. In 1977 hamsters were exposed to high grade cosmetic talc at nearly two thousand times the amount that babies would encounter, and yet there was no damage to the lungs.[1] Another experiment in the same year involved rats being forced to breathe talc at doses nearly six thousand times the amount used in infant care; despite the amount used, there was only a slight effect on the lungs.[1]
However, subsequent to this time the medical profession had to issue warnings about using talc, e.g. in 1991 physicians at one hospital in Southern England warned that inhaling babies' talcum powder could be fatal.[2] Eight deaths were attributed to inhalation of talc.
[1]Lancet, 25 June 1977, pp.1348-1349.
[2]P. W. Pairaudean, et al, British Medical Journal, 18 May 1991, pp.1200-1201.
CS Gas.
Animal experimentation was responsible for providing incorrect and dangerous information about CS gas. When CR was applied to a rabbit's eye, only 'minor transient changes' occurred in respect of pressure in the eye. However, when a smaller amount was applied to a human eye, this resulted in a 40% increase in pressure in 5 minutes - while in rabbits, this only produced a 3% rise after 10 minutes.[1]
Tests found that human beings are 18 times more sensitive to CS than rabbits, and 90 times more sensitive to CR, another irritant.[2]
Tests involving application to the skin showed CR was a more potent irritant than CS and yet the very opposite was found when tested on rodents.[3] The research also determined that VAN, another sensory irritant, was less potent than CR which, once again, was the very opposite when tested on animals.
[1]B. Ballantyne, et al, in Current Approaches in Toxicology, ed. B. Ballantyne (Wright and Sons, 1977).
[2]D. W. Swanston in Animals and Alternatives in Toxicity Testing, eds. M. Balls, et al (Academic Press, 1983).
[3]R. W. Foster, et al, Pain, 1986, vol. 25, pp.269-278.
Fluoride.
Fluoridation of the water supply is considered to be a primary reason for the decline in dental decay. The adding of fluoride to the water supply does not appear to have caused any health problems.[1]
However, experimentation involving rats gave some indication that it might cause cancer,[2] and yet after an intensive study, the American DHHS (Dept. of Health and Human Services) reported that it had not found any evidence of fluoride causing cancer. Tests involving animals have also suggested other detrimental effects, but the DHHS reported that different species react divergently to fluoride and this made it difficult to apply to humans.[3]
[1]E.g., R. Peto and R. Doll, The Causes of Cancer (OUP, 1981).
[2]Journal of NIH Research, 1991, vol. 3, p.46.
[3]C. Anderson, Nature, 28 February 1991, p.732.
Coumarin.
Coumarin is obtained from the tonka bean, having been used for many years, in consumer items and as a therapeutic agent. However, in the 1950s, there were questions concerning its safety due to animal experimentation that resulted in liver damage in rats. Because of this, coumarin was prohibited as a food flavouring agent.[1]
Later research revealed there was a considerable variation in reactions by different species, e.g. although dogs suffered liver toxicity (as rats), there were only slight effects in baboons.[2] Furthermore those amounts which damaged the liver of rats were harmless to gerbils.[3] The nonsense of vivisection was further demonstrated when it was found that different strains of the same species reacted differently to coumarin.
Patients who receive coumarin, even in high doses, for therapeutic reasons, rarely experience liver toxicity,[1] and rats and dogs are therefore now viewed as unreliable models for testing the substance as they metabolize it in totally different ways.[1,2,3]
[1]J.H. Fentum, et al, Toxicology, 1992, vol. 71, pp.129- 136.
[2]J. G. Evans, et al, Food and Cosmetic Toxicology, 1979, vol. 17, pp.187-193.
[3]W. Endell and G. Seidsel, Agents and Actions, 1978, vol. 8, pp.299-302.
Formaldehyde.
Concern for those people who worked with formaldehyde arose after it was discovered that the substance caused cancer in rats.[1] Despite this, epidemiological studies did not give any indication of cancer arising in such people: additionally, monitoring of workers also found no evidence of this danger.
In fact the rats had been forced to breathe high doses - 7-15 times the amount that workers inhaled - resulting in formaldehyde causing tissue damage and cancers in them.
[1]P. Grasso, Journal of the Royal Society of Medicine, 1989, vol. 82, pp.470-473.
Epilepsy models.
Vivisectors have produced numerous methods of producing fits in laboratory animals; the reason for this is because no particular method is wholly trustworthy.[1]
After suggestions that high amounts of aspartame could cause seizures in some people, the London Institute of Psychiatry conducted experiments, sponsored by Nutrasweet Company and the Wellcome Trust, which involved flashing lights to produce fits in photosensitive baboons. In fact aspartame had no effect on the baboons although conflicting evidence has arisen in other animals. For example aspartame enhances chemically-induced convulsions in mice, but has no effect on electric-shock-induced or sound-induced seizures in these animals.[2]
Similar variations are found with different species. Although the drug THIP reduced convulsions in mice and baboons, it was ineffective when used with epileptic patients.[3]
[1]R. S. Fisher, Research Reviews, 1989, vol. 14, pp.245- 278.
[2]B. S. Meldrum, et al, Epilepsy Research, 1989, vol. 4, pp.107.
[3]Lancet, 26 January 1985, pp.198-200.
Glass Fibre.
Products made from glass wool were produced for decades with animal testing suggesting no health risk. Experiments involving rats, guinea pigs, rabbits and monkeys who were forced to breathe in glass wool fibres showed no damage to lungs.[1]
Subsequent tests during the 1980s confirmed 'an increase in lung tumours or mesothelioma has not been observed following long-term inhalation studies in several animal species including rats, hamsters, guinea pigs, mice, monkeys and baboons, exposed to glass fibres, glass wool or mineral wool'.[2]
Those experiments when rats developed cancer were dismissed as having no relevance for human health. This was due to the fibres being implanted into the membrane of the animal's lung which is in contrast to how humans become exposed, i.e., through breathing; additionally, rats are known to develop cancer when solid substances are implanted in their bodies.[1]
However, in 1991 the American Occupational Safety and Health administration declared that products made of glass fibre were a potential cancer risk.[3] This was after studies involving people working with glass fibre showed an increased risk of lung cancer. In Occupational Lung Disorders, Raymond Parkes notes that 'the production of malignant tumours in animals by direct implantation experiments is unlikely to have any relevance to human exposure'.
[1]Rep. in R. Parkes, Occupational Lung Disorders (Butterworths, 1982).
[2]C. S. Wheeler, Toxicology and Industrial Health, 1990, vol. 6, pp.293-307.
[3]Letter from G. F. Scannell, assistant secretary for OSH, Washington DC, to Richard Munson, Chairman of Victims of Fibreglass, 6 May 1991. The Guardian, 20 July 1991.
Depo-Provera.
In the 1960s, women who used the steroid Depo-Provera to deal with premature labour found that there was a delay in returning to fertility after their babies were born. Because of this, there was an investigation as to whether it could be used as a contraceptive.[1]
When tested on beagle dogs there was a range of serious side- effects including abnormal growths, breast cancer and death from pyometra (pus building up in the uterus), and yet none of these side-effects occurred in women who used Depo-Provera.[2] Researchers could only say that these side-effects were due to the physiological differences between human beings and dogs.[1]
In fact high doses of Depo-Provera can cause cancer in monkeys but the relevance of this is questioned as the tumours arise from a type of cell not found in women. Ironically, the type of cancer produced in monkeys is actually successfully treated by Depo- Provera in women.[1]
In 1991, the Lancet called for certain countries to 'reassess' their existing policies on Depo-Provera as they might be depriving women of a 'reliable, effective and safe method of contraception'.[2] Shortly afterwards, the American FDA then approved Depo-Provera as a long-acting contraceptive for women to use.
[1]Bulletin of the World Health Organisation, 1982, vol. 60, pp.199-210.
[2]Lancet, 5 October 1991, pp.856-857.
Silicosis.
During the late 1930s researchers discovered that the inhalation of metallic aluminium prevented silicosis in rabbits.[1] Consequently, this was used as a means of treating and preventing silicosis in workers,[2] who had to pass through an aluminium dusting chamber in which they inhaled the powder.
In the following decade, studies revealed the process did not work and the Industrial Pulmonary Disease Committee of Britain's Medical Research Council advised against this procedure being used.[3]
In fact the 'treatment' had considerable dangers. While large amounts of aluminium were found to be harmless to animals,[4], lung damage and cancer were reported amongst those working with aluminium.[5] Further studies have shown that Canadian workers who inhaled aluminium powder to prevent silicosis, have symptoms that agree with the idea that aluminium may produce Alzheimer's Disease.[6]
[1]J. J. Denny, et al, Canadian Medical Association Journal, 1939, vol. 40, p.213.
[2]W. R. Parkes, Occupational Lung Disorders, (Butterworths, 1982).
[3]M. C. S. Kennedy, British Journal of Industrial Medicine, 1956, vol. 13, pp.211-223.
[4]L. U. Gardner, et al, Journal of Industrial Hygiene and Toxicology, 1944, vol. 26, pp.211-223.
[5]M. J. Ellenhorn and D. G. Barceloux, Medical Toxicology (Elsevier, 1988).
[6]Lord Walton of Detchant, Journal of the Royal Society of Medicine, 1992, vol. 85, pp.69-70.
Diet and cancer.
Studies of people of different nationalities have revealed that the consumption of too much fat, particularly saturated fat, can lead to cancer of the colon. In contrast, animal experimentation, while confirming excessive fat can be dangerous, indicate that it is not saturated but polyunsaturated fat which is responsible.[1]
Clinical (i.e., human) studies have also shown that a high fibre diet is preferable for health but when tested on animals, there have been conflicting results: some tests have indicated a higher risk of cancer, whereas others suggest a lower risk.[2] Additionally, studies have shown diets which are high in animal protein are hazardous,[3] and yet animal testing indicates this protein is of no relevance.[2]
Human studies confirm that diets which include fruit and vegetables offer protection against colon cancer. However, the natural substances which fruit and vegetables have evolved to ensure protection against predators, actually produce cancer when administered to mice and rats.[4]
[1]J. L. Freudenheim and S. Graham, Epidemiologic Reviews, 1989, vol. 11, pp.229-235.
[2]D. Galloway, Cancer Surveys, 1989, vol. 8, pp.169- 188.
[3]B. Armstrong and R. Doll, International Journal of Cancer, 1975, vol. 15, pp.617-631.
[4]P. H. Abelson, Science, 21 September 1990, p.1357.
Prednisone.
Although Prednisone is a useful drug for treating leukaemia and other cancers which occur in human beings, it does not work in respect of animal tumours, and this includes two types of leukaemia in mice.[1]
Prednisone is even more effectual when used with other anti- cancer medications although yet again animal experimentation provided spurious results, i.e., of six combinations which showed an improvement in health, only one of these was predicted by animal testing.[1]
The background of Prednisone provides further examples of animal testing delaying effective medicine. When researchers claimed they could cure human cancer with adrenal gland extracts in the 1930s, the result was animal testing which was negative and the treatment was therefore jettisoned.[2] It was only later when researchers confirmed that adrenal extracts could be useful in combating some cancers that human trials led to such analogues as Prednisone.
[1]R. J. Johnson and A. Goldin, Cancer Treatment Reviews, 1975, vol. 2, pp.1-31.
[2]B. Reines, Cancer Research on Animals: Impact and Alternatives, (Chicago: NAVS, 1986).
Polio.
Despite the fanciful claims made by pro-vivisectionists that polio is an example of how vivisection can combat human illness, the reality is that animal experimentation delayed a proper insight of polio for many years.[1]
In 1908 there was the announcement that the polio virus had been discovered. Tissue from an infected human resulted in spinal cord disease when injected into monkeys; the animals died with one developing paralysis in both legs. However, negative results had arisen with rabbits, guinea pigs, and mice and it was little more than chance that the researchers had selected Old World monkeys which are susceptible to the disease: if they had used New World monkeys they would have had different results from the experimentation as these monkeys are resistant to the disease.
Believing that a replica of the human form was now available, researchers concentrated on artificially inducing the disease in monkeys; these experiments gave support for the view that the poliovirus entered the system through the nose and it only attacked the CNS (Central Nervous System].[1,2]
And yet in 1907, a study of human cases had revealed that poliomyelitis was not wholly a disease of the CNS, and the gastrointestinal tract was the most likely route of the infection[1]. By 1912, other studies confirmed the intestinal tract as the means by which infection entered the body.
Regrettably because animal experimentation dominated research, most researchers, up to 1937, rejected the view that polio was an intestinal disease. The fact of whether the virus entered the body through the mouth or the nose was of course of major importance as the route dictated the best action to prevent its spread. In 1937, a nasal spray which prevented infection in monkeys was produced; not surprisingly it failed, also sometimes having a lasting side-effect, when it was used by human beings.[1]
It was only after the idea of the nasal route of infection, based on animal testing, was rejected and it was recognized that the polio virus entered the mouth and first resided in the intestines that a vaccine, orally administered could be produced. A solution was further delayed when monkeys were then used in time-consuming and expensive testing for the presence of the virus; tissue was inoculated into monkeys who were then examined for spinal cord damage. Progress was made when in 1949, Enders, Weller and Robins showed that the polio virus could be grown in human tissue culture; in this environment changes in infected cells, produced by the virus, could be monitored by microscope. If this alternative had been adopted an at earlier stage, there can be no doubt that progress would have been quicker, and both animal and human suffering would have been far less. However, valuable time was wasted through vivisectors asserting that the virus could only grow in the CNS, and the 'monkey model' of polio delaying the tissue culture development which was crucial to discovering a vaccine.[1,3]
[1]J. R. Paul, A History of Poliomyelitis (Yale University Press, 1971).
[2]H. F. Dowling, Fighting Infection (Harvard University Press, 1977.
[3]A Critical Look at Animal Research (Medical Research Modernization Committee, New York, 1990).
Antibiotics.
Particular animals, i.e., guinea pigs and hamsters, are especially sensitive to the negative effects of anti-biotic treatment. Ampicillin, Amoxycillin and Oxytetracycline are anti- biotics widely used by human beings but they are deemed 'toxic' and therefore inappropriate for guinea pigs and hamsters.[1] In the case of the Erythromycin, the usual human dose will kill a hamster.[2]
In Drug Development: From Laboratory to Clinic, Dr Walter Sneader noted that if guinea pigs had been used when penicillin was first tested, this valuable treatment would have almost certainly been abandoned as these animals are hypersensitive to penicillin. Florey, one of the scientists who carried out animal testing after Fleming's discovery of penicillin , admitted: 'If we had used guinea pigs exclusively, we should have said that pencillin was toxic, and we probably should not have proceeded to try and overcome the difficulties of producing the substance for...man'.[3] Thus, this is yet another example of how different animals provide different results in testing, and once again shows that the use of animals can, and does, impede medical progress.
[1]A. A. Tuffery (ed.), Laboratory Animals - An Introduction for New Experimenters, (Wiley, 1987).
[2]A single minimum recommended dose of erythromycin is 250-500mg every 6 hours, i.e., 3.5-7.0 mg/kg for a 70kg person. The lethal dose for hamsters is 3.5mg/kg.
[3]H. Florey, Conquest, January 1953.
Cancer.
In the first decade of the last century, epidemiology had identified a number of causes of cancer.[1] One of the earliest observations was that of Potts, an English surgeon who in the eighteenth century identified soot as a carcinogen in chimney sweeps. However, attempts to replicate his findings in animals failed,[2] although in 1918 researchers in Japan announced that cancer could be produced - on the ear of a rabbit by continually painting it with tar.
Progress was delayed by a dependence upon animals: the British epidemiologist Sir Richard Doll observes that human observational data was often dismissed because it was felt that success would be found in the laboratory.[1] When studies correctly reported that people who consumed high large amounts of fruit and vegetable were less likely to develop cancer,[3] little attention was given.[1]
Due to the lack of human epidemiological data, erroneous ideas arising from animal experimentation abounded; although only 5% of Western cancers are connected to viral infections,[4], e.g., some scientists believed that most, possibly all cases, were caused by viruses, an idea which arose from animal testing. One animal researcher even claimed that women should not breast feed their babies because, as in mice, a virus caused breast cancer which could be acquired in the mother's milk.[5]
After the Second World War, there was a greater interest in epidemiology with the realization that smoking caused lung cancer. In the years following there has been a greater awareness that the vast majority of instances of cancer can be prevented. Noteworthy is the 1980 US Congress Office of Technology Assessment Report on the causes of cancer which relied more far more on epidemiology than laboratory testing as these 'cannot provide reliable risk assessment'.[4]
Sadly, the curse of cancer is still very much with us and is likely to continue as long as animal experimentation is used in attempts to find the solution.
[1]R. Doll, Cancer, 1980, vol. 45, pp.2475-2485.
[2]W. H. Woglom, Archives of Pathology, 1926, vol. 2, pp.533-576.
[3]P. Stocks and M. N. Karn, Annals of Eugenics, 1933, vol. 5, pp.237-280.
[4]R. Peto and R. Doll, The Causes of Cancer (OUP, 1981).
[5]J. Furth, Bulletin of the New York Academy of Medicine, 1964, vol. 40, pp.421-431.
Opren.
Opren (Oraflex in America), to treat arthritis, was withdrawn in August 1982 after reports of deaths and serious liver damage after people had used the drug.[1] Since 1980, when it first appeared in the UK, there were some 3,500 reports of adverse effects with 61 deaths, mainly involving the elderly.[2]
Researchers declared Opren was a drug where the injuries could not be predicted from animal experimentation,[3] and Dista, which marketed Opren in Britain acknowledged that after Opren was studied for a year using rhesus monkeys, 'there were no apparent adverse effects on survival'.
[1]E. M. B. Sorensen, Toxicology Letters, 1986, vol. 34, pp.277-286.
[2]British Medical Journal, 14 August 1982, pp.459- 460.
[3]C. T. Eason, et al, Regulatory Toxicology and Pharmacology, 190, vol. 11, pp.288-307.
Stroke treatment.
Experimentation on rabbits, dogs, gerbils and monkeys suggested that the use of barbiturates could offer protection against the effects of a stroke,[1] and yet in humans, barbiturates were found to offer little or no protection.[2] In fact between 1978 and 1988, some 25 drugs which were found to be useful in treating animals with artificially-induced stokes did not come into general use.[2]
Some researchers have argued that an over-reliance on animal models may impede progress in treating the disease,[2] and Mayo Clinic researchers also acknowledged 'the answers to many of our questions regarding the underlying pathophysiology and treatment of stroke do not lie with continued attempt to model the human situation perfectly in animals, but rather with the development of techniques to enable the study of...living humans'.[2]
[1]Stroke, vol. 6, pp.28-33, 1974, vol. 5, pp.107, 1972, vol. 3, pp.726-732, Neurology, 1975, vol. 425, pp.870-874, Annals of Neurology, 1979, vol. 5, pp.59-64.
[2]D. O. Wiebers, et al, Stroke, 1990, vol. 21, pp.1-3.
Omeprazole.
A new test, developed by Glaxo, raised concerns about Omeprazole, an ulcer treatment produced by Astra, in respect of causing stomach cancer. The test involves dosing rats with a drug/substance and then removing tissue which is analysed for effects on the DNA. Interference with DNA is deemed to be a possible first step to cancer.
The test showed that Omeprazole damaged the DNA while it also showed that Ranitidine (Zantac), Glaxo's own anti-ulcer drug, did not.[1] Because of the test result, Glaxo ended the comparative trials of Ranititide and Omeprazole which the Lancet commented would almost certainly affect prescription.[2]
Astra responded by claiming that Glaxo's testing method was 'scientifically unsound' and the results had 'no clinical consequences'.[3] Astra went on to say that its own tests showed that after administering Omeprazole to rats for up to 2 years, to mice for 18 months, and to dogs for 12 months, there was 'no evidence for a direct carcinogenic potential in the stomach or elsewhere' - the very opposite of Glaxo's conclusion after its animal testing.
[1]B. Burlinson, et al, Lancet, 17 February 1990, p.419.
[2]Lancet, 17 February 1990, p.386.
[3]L. Ekman, et al, Lancet, 17 February 1990, pp.419- 420.
Encainide and Flecainide.
A study conducted in America discovered that two drugs which were designed to prevent irregular heart beats could cause certain types of patients to have heart attacks. CAST (Cardiac Arrhythmia Suppression Trial) commenced in 1987 but was concluded within two years after physicians discovered that more deaths occurred in those patients using encainide and flecainide than those who received a placebo (a dummy pill).[1]
These findings led to estimates that nationally, some 3000 people may have prematurely died after using these drugs,[2] and yet animal testing had indicated that encainide and flecainide were safe and effective.[3]
[1]CAST Investigators, New England Journal of Medicine, 10 August 1989, pp.406-412.
[2]Dr. J. Morganroth reported in Washingon Times, 26 July 1989.
[3]Flecainide: B. Holmes and R. C. Heel, Drugs, 1985, vol. 29, pp.1-33. Encainide: D. C. Harrison, et al, American Heart Journal, 1980, vol. 1090, pp.1046-1054, and J. E. Byrne et al, Journal of Pharmacology and Experimental Therapeutics, 1977, vol. 200, pp.147-154.
Olive Oil.
Olive oil has been used without any noticeable ill-effect on the human body for thousands of years.[1] And yet testing undertaken at New York University showed that olive oil had a harmful effect when it was applied to the skin of rats, e.g., swelling.[2]
[1]M. M. Rieger and G. W. Battista, Journal of the Society of Cosmetic chemists, 1964, vol. 15, pp.161-172.
[2]E. O. Butcher, Journal of Investigative Dermatology, 1951, vol. 16, pp.85-90.
Skin tests.
Rabbits and guinea-pigs are frequently used in respect of assessing irritancy; this is despite the fact that these animals do not provide accurate results. For example, animal experiments indicate that hypochlorite bleach is safe for human usage as it only results in 'slight visible irritation' in rabbits and guinea pigs.[1] In reality, in humans, it causes severe skin reactions.
[1]G. A. Nixon, et al, Toxicology and Applied Pharmacology, 1975, vol. 31, pp.481-490.
Cancer and smoking.
In 1954, the results of an investigation into smoking was published; this showed that the likelihood of developing lung cancer increased in accordance with the number of cigarettes which were smoked.[1] By this time, a number of other reports had also been published asserting much the same thing. However researchers continued to argue that claiming lung cancer and smoking were linked was unwarranted due to the disease not being produced in laboratory animals.[2]
In 1956, the British Empire Cancer Campaign (the forerunner to the Cancer Research Campaign) advised that during two years of experimentation with mice, rabbits and other animals which involved them being exposed to tobacco derivatives by inhalation, feeding, injection and skin painting, none had developed cancer.[3]
Consequently, due to the negative results of the animal experimentation, health warnings about the dangers of smoking were delayed for several years: further experimentation showed that it was either difficult or impossible to induce lung cancer in animals using the inhalation method.[4]
[1]R. Doll and A. B. Hill, British Medical Journal, 26 June 1954, pp.1451-1455.
[2]Reported in S. Peller, Quantitative Research in Human Biology (J. Wright and Sons, 1967).
[3]Reported in E. Northrup, Science Looks at Smoking (Conrad-McCann, 1957).
[4]Lancet, 25 June 1977, pp.1348-1349. See also F. T. Gross, et al, Health Physics, 1989, vol. 56, p.256.
Asbestosis.
In 1907, the lung disease asbestosis (caused by breathing in asbestos) was recognised. Although research into this condition, using animals, commenced in 1925, most of the results were contradictory. For example, in 1930 on the basis of the animal testing conducted, researchers designated the chrysotile, amosite and crocidolite forms of asbestos as harmless .[1] And yet others determined that while chrysotile caused lung damage in guinea pigs, it did not do so in rabbits.[2]
Researchers using animals then reported that injuries caused by asbestos began to heal when the animals were removed from the asbestos-dust environment.[2] This is in stark contrast to humans when asbestosis advances even after the person is no longer exposed. It was only later that animal researchers were able to mimic this feature in animals.[3]
Concern grew when it was announced that there was a link between asbestos and lung cancer, and yet attempts to induce cancer in animals were unsuccessful. Because of this, even though there was considerable evidence of the link from asbestos workers, there was doubt about the carcinogenic effect of asbestos until the 1960s.[4,5] It was only then that researchers could mimic the condition in animals.
The Annals of the New York Academy of Sciences says that before this: 'a large literature on experimental studies has failed to furnish any definite evidence for induction of malignant tumours in animals exposed to various varieties and preparations of asbestos'.[6]
[1]Reported in L. U. Gardner, Journal of the American Medical Association, 19 November 1938, pp.1925-1936.
[2]J. C. Wagner, British Journal of Industrial Medicine, 1963, vol. 20, pp.1-12.
[3]J. C. Wagner, et al, British Journal of Cancer, 1974, vol. 29,. pp.252-269.
[4]P. E. Enterline in Epidemiology and Health Risk Assessment, ed. L. Gordis (OUP, 1988).
[5]P. E. Enterline. American Review of Respiratory Diseases, 1978, vol. 118, pp.975-978.
[6]W. E. Smith, et al, Annals of the New York Academy of Sciences, 1965, vol. 132, pp.456-488.
Ibufenac.
This anti-inflammatory medication became available in Britain during the mid-1960s but had to be withdrawn within two years after deaths occurred; the primary cause being liver damage.
This happened despite 'extensive' animal testing in which mice, rats and dogs were used; these showed no indication of liver damage (apart from a slight effect in rats exposed to a lethal dose).[1]
Dr M. F. Cuthbert of the British Department of Health and Social Security's Medicine Division admitted: 'Evidence of liver damage is sometimes detected in animal studies of non-steroidal anti- inflammatory drugs, but usually no such evidence is forthcoming even in circumstances when a drug is eventually shown to be hepatotoxic [liver-damaging] to man'.[1]
[1]M. F. Cuthbert, Current Approaches in Toxicology, ed. B. Ballantyne (Wright and Sons, 1977).
Fialuridine (FIAU).
Trials at America's National Institutes of Health of a new drug to combat hepatitis B were halted in the Summer of 1993 after complications and deaths occurred among those involved in the trials. Although fialuridine was supposed to improve the condition of persons suffering from liver disease, many of those who had prolonged treatment experienced a deterioration in their health; some died from liver failure.[1]
And yet the drug was found to be safe in animal experiments,[1] reducing the amount of the virus in the preferred animal model used; tests for toxicity were also conducted in mice, rats and rhesus monkeys. Indeed one of the principal investigators asked: 'Why didn't the animal toxicity studies show any abnormality at all due to the drug?'.[2]
In fact the metabolism of anti-viral drugs is considered to be very different in animals and humans.[3].
[1]N. Touchette, The Journal of NIH Research, 1993. 5, pp.33-55.
[2]J. Hoofnagle, reported in [1].
[3]C. Macilwain, Nature, 22 July 1993, p.275.
Hytrin (Abbott Laboratories Ltd)
Containing terazosin as terazosin hydrochloride.
Use: Hytrin is indicated in the treatment of mild to moderate hypertension.
Contra-indications, warnings etc: Carcinogenicity: Hytrin has been shown to produce tumours in male rats when administered at a high dose over a long period of time. No such occurrences were seem in a similar study in mice. The relevance of these findings with respect to the clinical use of the drug in man is unknown.
Losec (Astra Pharmaceuticals Ltd)
Contains omeprazole as enteric-coated granules.
Use: Treatment of reflux oesophagitis. Treatment of duodenal and benign gastric ulcers including those complicating NSAID therapy.
Contra-indications, warnings, etc: Animal toxicology: Gastric ECL-cell hyperplasia and carcinoids, localised to the oxyntic mucosa, have been observed in life-long studies in rats. These changes have been related to sustained hypergastrinaemia secondary to acid inhibition, and not from a direct effect of any individual drug. No treatment related mucosal changes have been observed in patients treated continuously for periods up to 5 years.
Dtic-dome (Bayer plc)
Active ingredient: 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide prepared as the citrate salt (dacarbazine).
Use: metastatic malignant melanoma, sarcoma, Hodgkin's disease.
Contra-indications, warnings, etc: Studies have demonstrated this agent to have a carcinogenic and teratogenic effect when used on animals.
Ridaura Tiltab tablets (Bencard)
Containing 3 mg auranofin.
Use: In the management of adults with active progressive rheumatoid arthritis only when non-steroidal anti-inflammatory drugs have been found to be inadequate alone to control the disease, i.e. when second-line therapy is required.
Contra-indications, warnings, etc: Gold has been shown to be carcinogenic in rodents although there was no evidence of carcinogenicity in 7 year dog studies.
Bezalip (Boehringer Mannheim UK (Pharmaceuticals) Ltd)
Contains bezafibrate.
Use: In hyperlipidaemias of Type 11a, 11b, 111, 1V and V.
Contra-indications, warnings, etc: Warnings: The chronic administration of a high dose of bezafibrate to rats was associated with hepatic tumour formation in females. This dosage was in the order of 30 to 40 times the human dosage. No such effect was apparent at reduced intake levels approximating more closely to the lipid-lowering dosage in humans.
(Author's note: Drug companies often excuse animal results by claiming that the dosage used in animal tests was far higher than that used in human beings. If such studies are irrelevant because of the high dosage then why do them?)
Spiroctan (Boehringer Mannheim UK)
Contains spironolactone
Use: Spiroctan is recommended for the treatment of congestive cardiac failure, cirrhosis with ascites and oedema, malignant ascites, nephrotic syndrome and also for diagnosis and treatment of primary hyperaldosteronism.
Contra-indications, warnings, etc: Carcinogenicity: Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain.
Bicnu (Bristol-Myers Pharmaceuticals)
Contains a 30 ml vial containing 100 mg carmustine and a 5 ml vial containing 3 ml sterile ethanol diluent.
Use: BiCNU is indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following:
1. Brain tumours - Glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumours.
2. Multiple myeloma - in combination with prednisone.
3. Hodgkin's Disease - As secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
4. Non-Hodgkin's lymphomas - As secondary therapy as above.
Contra-indications, warnings, etc: BiCNU is carcinogenic in rats and mice, producing a marked increase in tumour incidence in doses approximating those employed clinically.
Apresoline (Ciba Laboratories)
Contains Hydralazine Hydrochloride.
Use: Hypertension
Contra-indications, warnings etc: Warnings: Hydralazine, in lifetime carcinogenicity studies, caused, towards the end of the experiments, small but statistically significant increases in lung tumours in mice and in hepatic and testicular tumours in rats. These tumours also occur spontaneously with fairly high frequency in aged rodents.
With due consideration of these animal and in-vitro toxicological findings, hydralazine in therapeutic doses does not appear to bear a risk that would necessitate a limitation of its administration. Many years of clinical experience have not suggested that human cancer is associated with hydralazine use.
Tolectin 200/400 Mg capsules (Cilag Ltd)
Contains tolmetin sodium dihydrate.
Use: Rheumatoid arthritis,; osteoarthritis; ankylosing spondylitis; peri-articular disorders such as fibrositis and bursitis.
Contra-indications, warnings, etc: Renal papillary necrosis has occurred in animals after long term administration although there has been no evidence of renal toxicity in clinical trials.
Chendol 125, and Chendol 250 (CP Pharmaceuticals)
Contains chenodeoxycholic acid.
Use: For dissolution of radiolucent cholesterol-rich gallstones in functioning gall bladders. It has a particular place where surgery is contra-indicated or those patients anxious to avoid surgery.
Contra-indications, warnings, etc: Precautions: Chenodeoxycholic acid, given in long term studies at doses of 600 mg/kg/day to rats and 1000 mg/kg/day to mice, induced malignant liver cell tumours in female rats and male mice. The clinical significance of these findings is not known.
Normax (Evans Medical Ltd)
Contains danthron docusate sodium.
Use: Constipation in geriatric practice. Analgesic-induced constipation in terminally ill patients of all ages. Constipation in cardiac failure and coronary thrombosis (conditions in which defaecation must be free of strain).
Contra-indications, warnings, etc: Precautions: In experimental animals, danthron has been associated with adenocarcinomas in the bowel and tumours in the liver.
Farlutal (Farmitalia Carlo Erba Ltd)
Contains medroxyprogesterone acetate.
Use: Palliative treatment of hormone-sensitive malignancies. Farlutal has been successfully used to produce regressions in breast, endometrial, prostatic and renal cell carcinoma.
Contra-indications, warnings, etc: Precautions: It should be noted that long term administration of medroxyprogesterone acetate to beagle dogs has resulted in the development of mammary nodules which were occasionally found to be malignant. The relevance of these findings to humans has, however, not been established.
Pharmorubicin rapid dissolution (Farmitalia Carlo Erba Ltd)
Contains epirubicin hydrochloride with lactose and hydroxybenzoate.
Use: Antimitotic and cytotoxic.
Contra-indications, warnings, etc: Like most other anticancer agents, epirubicin has shown mutagenic and carcinogenic properties in animals.
Zavedos (Farmitalia Carlo Erba Ltd)
Contains idarubicin hydrochloride with lactose.
Use: Antimitotic and cytotoxic agent.
Contra-indications, warnings, etc: Warnings: Like most other cytotoxic agents, idarubicin has mutagenic properties and it is carcinogenic in rats.
Tegretol (Geigy Pharmaceutical)
Active ingredient: Carbamazepine.
Use: Epilepsy generalised tonic-clonic and partial seizures.
Contra-indications, warnings, etc: Precautions: In rats treated with carbamazepine for two years, the incidence of tumours of the liver was found to be increased. There is, however, no evidence to indicate that this observation has any significant bearing on the therapeutic use of the drug.
Grisovin tablets (Glaxo Laboratories Ltd)
Contain griseofulvin.
Use: The treatment of fungal infections of the skin, scalp, hair or nails where topical therapy is considered inappropriate or has failed.
Contra-indications, warnings etc: Precautions: Long term administration of high doses of griseofulvin with food has been reported to induce hepatomas in mice and thyroid tumours in rats but not hamsters. The clinical significance of these findings is not known.
Lasilactone capsules (Hoechst)
Contain Frusemide and Spironolactone.
Use: In the treatment of resistant oedema where this is associated with secondary hyperaldosteronism; conditions include chronic congestive cardiac failure and hepatic cirrhosis.
Contra-indications, warnings, etc: Carcinogenicity: Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain.
Atromid (ICI Pharmaceuticals)
Contains Clofibrate.
Use: In the treatment of severe hyperlipoproteinaemia where full investigation has been performed to define the abnormality.
Contra-indications, warnings, etc: Clofibrate has been shown to produce liver tumours in rats and mice. The liver changes found in rodents have not been seen in other species, including sub-human primates and man. The relevance of this finding to man has not been established.
Nolvadex, Nolvadex - D, and Nolvadex - Forte tablets (ICI Pharmaceuticals)
Containing Tamoxifen Citrate.
Use: The treatment of breast cancer and the treatment of anovulatory infertility.
Contra-indications, warnings, etc: Gonadal tumours in mice and liver tumours in rats receiving tamoxifen have been reported in long-term studies. The clinical relevance of these findings has not been established.
Zoladex (ICI Pharmaceuticals)
Containing goserelin acetate.
Use:
1. Prostate cancer.
2. Advanced breast cancer in pre- and peri-menopausal women suitable for hormonal manipulation.
3. Endometriosis.
Contra-indications, warnings, etc: General: Following long-term repeated dosing with Zoladex, an increased incidence of benign pituitary tumours has been observed in male rats. Whilst this finding is similar to that previously noted in this species following surgical castration, any relevance to man has not been established.
In mice, long term repeated dosing with multiples of the human dose produced histological changes in some regions of the digestive system manifested by pancreatic islet cell hyperplasia and a benign proliferative condition in the pyloric region of the stomach, also reported as a spontaneous lesion in this species. The clinical relevance of these findings is unknown.
Novantrone injection (Lederle Laboratories)
Contains mitozantrone hydrochloride.
Use: For the treatment of advanced breast cancer, non-Hodgkin's lymphoma and adult acute non-lymphocytic leukaemia. Novantrone has also been used in the palliation of non-resectable primary hepatocellular carcinoma.
Contra-indications, warnings, etc: Warnings: Novantrone is mutagenic in vitro and in vivo in the rat. In the same species there was a possible association between administration of the drug and development of malignant neoplasia. The carcinogenic potential in man is unknown.
Prostap SR (Lederle Laboratories)
Contains leuprorelin acetate.
Use: In the treatment of advanced prostatic cancer and the management of endometriosis, including pain relief and reduction of endometriotic lesions.
Contra-indications, warnings, etc: Warnings: Men: Whilst the development pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long term clinical studies with Prostap.
Thiotepa (Lederle Laboratories)
Contains Thiotepa (N,N',N'' triethylenethiophosphoramide)
Use: A polyfunctional alkylating agent used alone or in combination with other cytotoxic drugs, hormones, radiotherapy or surgery in the treatment of neoplastic diseases.
Contra-indications, warnings, etc: Thiotepa has been reported to possess mutagenic activity on the basis of bacterial, plant and mammalian mutagenicity tests. It has also been reported to be carcinogenic in mice and rats. These effects are consistent with its activity as an alkylating agent. The carcinogenic potential in humans has not been clearly established.
Celace (Eli Lilly and Co Ltd)
Contains pergolide base.
Use: Adjunctive treatment to levodopa in the management of the signs and symptoms of Parkinson's disease.
Contra-indications, warnings, etc: Carcinogenesis, mutagenesis and impairment of fertility: Two year carcinogenicity studies in mice and rats used doses up to 340 and 12 times the maximum human oral dose (6 mg or 6000 micrograms/day equivalent to 120 micrograms/kg/day). A low incidence of uterine neoplasms occurred in both rats and mice. Endometrial adenomas and carcinomas were observed in rats. Endometrial sarcomas were observed in mice. These occurrences are probably attributable to the high oestrogen/progesterone ratio, which would occur in rodents as a result of the prolactin-inhibiting action of pergolide mesylate.
These endocrine mechanisms are not present in humans. However, there are no human data with pergolide to substantiate this conclusion concerning the lack of potential for human risk.
Mutagenic potential was evaluated in a battery of tests. A weak response was noted in one test but the other 3 tests were negative. The relevance to humans is unknown.
Seconal Sodium (Eli Lilly and Co Ltd)
Contains Secobarbitone Sodium.
Use: For the short-term treatment of severe, intractable insomnia.
Contra-indications, warnings, etc Carcinogenesis: Animal data show that phenobarbitone can be carcinogenic after lifetime administration.
Sodium Amytal Injections (Eli Lilly and Co Ltd)
Contains Amylobarbitone Sodium.
Use: May be used parenterally to control status epilepticus, but it is not the barbiturate of choice in the routine treatment of grand mal epilepsy.
Contra-indications, warnings, etc: Carcinogenesis: Animal data show that phenobarbitone can be carcinogenic after lifetime administration.
Destolit (Marion Merrell Dow Ltd)
Contains ursodeoxycholic acid.
Use: For the dissolution of radiolucent (i.e. non-radio opaque) cholesterol gallstones in patients with a functioning gallbladder.
Contra-indications, warnings, etc: A product of this class has been found to be carcinogenic in animals. The relevance of these findings to the clinical use of ursodeoxycholic acid has not been established.
Sabril tablets (Marion Merrell Dow Ltd)
Contains vigabatrin.
Use: For the treatment of epilepsy which is not satisfactorily controlled by other antiepileptic drugs.
Contra-indications, warnings, etc: Warning: Animal safety studies indicate that vigabatrin causes intramyelinic oedema in the brain white matter tracts. Currently there is no evidence to suggest that this effect occurs in man.
Dolobid (Thomas Morson Pharmaceuticals)
Contains Diflunisal.
Use: For the relief of pain and also inflammation associated with osteoarthritis and rheumatoid arthritis.
Contra-indications, warnings, etc: Precautions: In rats and dogs, high oral doses of diflunisal (50-200 mg/kg/day) as with aspirin, produced similar pathological changes (gastro-intestinal ulceration and renal papillary oedema). These dosages are approximately 3 to 12 times the maximum dosages recommended in man.
Ortho dienoestrol cream (Ortho)
Contains Dienoestrol.
Use: Atrophic vaginitis and kraurosis vulvae in post menopausal women, and for the treatment of pruritus vulvae and dyspareunia when associated with the atrophic vaginal epithelium.
Contra-indications, warnings, etc: Long term continuous administration of natural and synthetic oestrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina and liver. There is now evidence that oestrogens increase the risk of carcinoma of the endometrium in humans.
At the present time there is no satisfactory evidence that oestrogens given to post-menopausal women increase the risk of cancer of the breast, although a recent long-term follow up of a single physician has raised this possibility. However, because of animal data there is a need for caution in prescribing oestrogens for women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms.
(Author's Note: Do oestrogens only increase the risk of cancer in female animals who have a strong family history of breast cancer, or who have breast nodules, fibrocystic disease or abnormal mammograms?).
Retin-a Lotion, Gel, Cream (Ortho)
Contains Tretinoin.
Use: For topical application in the treatment of acne vulgaris in which comedones, papules and pustules predominate.
Contra-indications, warnings, etc: Recent studies in mice treated with the active ingredient (tretinoin) of Retin-A and exposed to artificial sunlight suggest that tretinoin may speed up the appearance of sunlight induced skin tumours. Laboratory mice treated with tretinoin but not exposed to sunlight did not develop skin tumours. The significance of these studies as related to human beings is unknown. High oral doses of tretinoin (retinoic acid), like Vitamin A, are teratogenic in animals.
Lopid (Parke-Davis Research Laboratories)
Contains gemfibrozil and polysorbate 80 PhEur.
Use: For the primary prevention of coronary heart disease in men between 40-55 years of age and with hyperlipidaemias who have not responded to diet and other appropriate measures.
Contra-indications, warnings, etc: Precautions: Long-term toxicity studies in rats and mice were carried out at one and ten times the human dose on a weight for weight basis. In male rats receiving ten times the human dose, there was a significant increase in incidence of benign liver nodules and liver carcinomas. Male rats receiving a dose equivalent to the human dose had no statistically significant increase in the incidence of liver carcinomas. At all dose levels, there were no statistically significant differences from controls in the incidence of liver tumours in female rats, or in mice of either sex.
Electron microscopy demonstrated a marked hepatic peroxisome proliferation following Lopid administration to the male rat. Similar changes have been sought but not found in the human liver at up to 27 months continuous gemfibrozil therapy. Male rats had a dose-related increase of benign Leydig cell tumours. Subcapsular bilateral cataracts occurred in 10%, and unilateral cataracts in 6.3% of the high dose males.
Mithracin (Pfizer Ltd)
Contains plicamycin, mannitol and disodium phosphate.
Use: For the treatment of refractory hypercalcaemia associated with a variety of neoplasms.
Contra-indications, warnings, etc: Warnings: Antineoplastic and cytotoxic agents have been shown to be mutagenic and carcinogenic in animals and possibly man.
Only limited animal and in vitro mutagenicity studies have been carried out with plicamycin; the possibility that plicamycin has similar effects to other antineoplastic cytotoxic agents should be borne in mind.
Calcitare (Rhone-Poulenc Rorer Ltd)
Contains Calcitonin (Pork).
Use: For short term treatment in:
i) Paget's disease of bone
ii) Hypercalcaemia.
Contra-indications, warnings, etc: A species and strain-specific dose-related increase of pituitary adenomas has been observed in long term toxicity studies in the rat. As the significance of these findings to man is uncertain, long term use is not recommended.
Calsynar (Rhone-Poulenc Rorer Ltd)
Contains synthetic Salmon Chloride. The solution also contains Sodium Chloride, Sodium Acetate, Acetic Acid and Phenol.
Use: For the short term treatment of:
a) Paget's disease of bone.
b) Advancing osteolytic hypercalcaemia of malignancy.
c) Pain associated with advanced metastatic bone cancer.
d) Postmenopausal osteoporosis.
Contra-indications, warnings, etc: Precautions: Rat carcinogenicity studies have shown a dose related excess of pituitary tumours. As the significance of this finding is uncertain, long term use is not recommended.
Roaccutane (Roche Products Ltd)
Contains isotretinoin.
Use: For the treatment of cystic and conglobate acne and severe acne which has failed to respond to an adequate course of a systemic antimicrobial agent.
Contra-indications, warnings, etc: Precautions: At the completion of a lifespan study in rats there was an increased incidence of phaeochromocytoma in animals given isotretinoin at dosages of 32 and 8 mg/kg/day, but not 2 mg/kg/day. Since rats are particularly prone to develop this tumour type, the significance of this finding for use of Roaccutane in man is uncertain; nevertheless, repeated courses of treatment are not normally recommended.
Negram (Sanofi Winthrop)
Contains Nalidixic Acid.
Use: For the treatment of acute or chronic infections.
Contra-indications, warnings, etc: Nalidixic acid has been shown to induce lesions in weight-bearing joints of young animals. The relevance of this to man is unknown.
Androcur (Schering Health Care)
Contains cyproterone acetate.
Use: Control of libido in severe hypersexuality and/or sexual deviation in the adult male.
Contra-indications, warnings, etc: Warnings/side-effects: Cyproterone acetate has been found to cause liver abnormalities in animals, including the development of tumours.
Cyprostat (Schering Health Care)
Contains cyproterone acetate.
Use: Palliative treatment of prostatic carcinoma.
Contra-indications, warnings, etc: Cyproterone acetate has been found to cause liver abnormalities in animals, including the development of tumours.
Dianette (Schering Health Care)
Contains anti-androgen cyproterone acetate and oestrogen ethinyloestradiol.
Use: In women only: (i)severe acne, refractory to prolonged oral antibiotic therapy and (ii)idiopathic hirsutism of mild to moderate degree.
Contra-indications, warnings, etc: Warnings: Like many other steroids, cyproterone acetate, when given in very high doses and for the majority of the animal's life-span, has been found to cause an increase in the incidence of tumours, including carcinoma, in the liver of rats. The relevance of this finding to humans is unknown. Dianette has been shown to have good liver tolerance in women given prolonged treatment.
Aldactide (Searle)
Contains Spironolactone and Hydroflumethiazide.
Use: Congestive cardiac failure.
Contra-indications, warnings, etc - Warnings: Carcinogenicity: Spironolactone has been shown to produce tumours in rats when administered at high doses over a long period of time. The significance of these findings with respect to clinical use is not certain.
Cytotec (Searle)
Contains misprostol
Use: for the healing of duodenal ulcer and gastric ulcer including those induced by non steroidal anti inflammatory drugs (NSAID) in arthritic patients at risk, whilst continuing their NSAID therapy.
Further information: Cytotec in multiples of the recommended therapeutic dose in animals has produced gastric mucosal hyperplasia. This characteristic response of E prostaglandins reverts to normal on discontinuation of the compound. In patients, histological examination of gastric biopsies taken before and after treatment with misoprostol after up to one year's duration have shown no adverse tissue response attributable to misoprostol.
Napratec (Searle)
Contains Naproxen and Cytotec (containing misoprostol)
Uses: Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthritis (degenerative arthritis) and ankylosing spondylitis. Cytotec is indicated for the prophylaxis of nonsteroidal anti-inflammatory drug induced gastroduodenal ulceration.
Further information: Cytotec in multiples of the recommended therapeutic dose in animals has produced gastric mucosal hyperplasia. This characteristic response of E prostaglandins reverts to normal on discontinuation of the compound. In patients, histological examination of gastric biopsies taken before and after treatment with misoprostol after up to one year's duration have shown no adverse tissue response attributable to misoprostol.
Dolmatil tablets (E. R. Squibb and Sons Ltd)
Contains sulpiride (and hydrated silica, lactose, magnesium stearate, methyl cellulose, potato starch, talc).
Use: Acute and chronic schizophrenia.
Contra-indications, warnings, etc: Warnings: In long term animal studies with neuroleptic drugs, including sulpiride, an increased incidence of various endocrine tumours (some of which have occasionally been malignant) has been seen in some but not all strains of rats and mice studied. The significance of these findings to man is not known; there is no evidence of an association between Dolmatil use and tumour risk in man.
Chenofalk (Thames Laboratories Ltd)
Contains chenodeoxycholic acid (CDCA). (And gluten).
Use: Dissolution of radiolucent gallstones measuring up to 15 mm diameter.
Contra-indications, warnings, etc: Warnings: Chenodeoxycholic acid given in long-term studies at doses of 600 mg/kg/day to rats and 1000 mg/kg/day to mice, induced malignant liver cell tumours in female rats and benign liver cell tumours in female rats and male mice. The clinical significance of these findings is not known.
Ursofalk (Thames Laboratories Ltd)
Contains ursodeoxycholic acid (UDCA) and gluten.
Use: Dissolution of radiolucent gallstones measuring up to 15 mm diameter.
Contra-indications, warnings, etc: A product of this class has been found to be carcinogenic in animals. The relevance of these findings to the clinical use of UDCA has not been established.
Sulpitil (Tillotts Laboratories)
Contains sulpiride.
Use: For the treatment of acute and chronic schizophrenia.
Contra-indications, warnings, etc: Warnings and precautions: In long term animal studies with neuroleptic drugs, including sulpiride, an increased incidence of various endocrine tumours, some of which have occasionally been malignant, has been seen in some, but not all, strains of rats and mice studied. The significance of these findings to man is not known. There is no current evidence of an association between neuroleptic use and tumour risk in man.
Depo-Provera (Upjohn Ltd)
Contains medroxyprogesterone acetate.
Use: Progestogen: for the treatment of endometriosis.
Contra-indications, warnings, etc: Warnings, precautions, side-effects: Endometrial tumours have developed in monkeys given fifty times the human contraceptive dose but the relevance of this to man has not been established.
Hemabate Sterile Solution (Upjohn Ltd)
Contains carboprost as the tromethamine salt.
Use: Treatment of post-partum haemorrhage due to uterine atony and refractory to conventional methods of treatment with oxytocic agents and ergometrine used either alone or in combination.
Contra-indications, warnings, etc: Precautions: Animal studies lasting several weeks at high doses have shown that prostaglandins of the E and F series can induce proliferation of bone.
Prostin E2 (Upjohn Ltd)
Contains dinoprostone.
Use: Oxytocic agent.
For the induction of labour when there are no foetal or maternal contra-indications.
Contra-indications, warnings, etc: Precautions: Animal studies lasting several weeks at high doses have shown that prostaglandins of the E and F series can induce proliferation of bone.
Myleran tablets (Wellcome Medical Division)
Contains Busulphan.
Use: For the palliative treatment of the chronic phase of chronic granulocytic leukaemia.
Contra-indications, warnings, etc: Precautions: Busulphan has been shown to be mutagenic in various systems, including bacteria, fungi, Drosophila and cultured mouse lymphoma cells. In vivo cytogenetic studies in rodents have shown an increased incidence of chromosome abberations in both germ cells and somatic cells after busulphan treatment.
NB. Busulphan interferes with spermatogenesis in experimental animals.
Retrovir capsules and syrup (Wellcome Medical Division)
Contains zidovudine.
Use: For the management of patients with advanced HIV disease.
Contra-indications, warnings, etc: Mutagenicity: Zidovudine was weakly mutagenic in a mouse lymphoma cell assay and was positive in an in vitro cell transformation assay. Clastogenic effects (chromosome damage) were observed in an in vitro study in human lymphocytes and in in- vivo oral repeat dose micronucleus studies in rats and mice. An in vivo cytogenetic study in rats did not show chromosomal damage. The clinical significance of these findings is unclear.
Carcinogenicity: Zidovudine was administered orally at three dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60 and 120 mg/kg/day and 80, 220 and 600 mg/kg/day in mice and rats respectively. The doses in mice were reduced to 20, 30 and 40 mg/kg/day after Day 90 because of treatment-related anaemia, whereas in rats only the high dose was reduced (to 450 and then 300 mg/kg/day on Days 91 and 279, respectively).
In mice, seven late-appearing (after 19 months) vaginal neoplasms (5 squamous cell carcinomas, one squamous cell papilloma and one squamous cell polyp) occurred at the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumours were found at the lowest dose.
In rats, two late-appearing (after 20 months) vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumours occurred at the middle or low doses in rats.
The predictive value of rodent carcinogenicity studies for humans is uncertain and thus the clinical significance of these findings is unclear.
Author's Comments: In addition to the general warnings I have recorded above there are many drug companies which warn doctors not to give specific products to patients who are pregnant. These companies invariably report having performed experiments on pregnant animals but then often go on to admit (something like): 'the relevance of these studies to human beings is not known'. It is difficult to avoid asking the question: 'Why do the studies if the relevance is not known?' As can be seen from the above, a huge number of drug companies seem to be doing animal tests without knowing their relevance to human patients.
On other occasions drug companies report that animal experiments have shown that their drugs cause problems - but that human experience suggests that the drug is entirely safe so the animal experiments can be safely ignored! Animal experiments provide answers for all seasons. It is not surprising that drug companies love them.
In some of the examples which follow drug companies seem uncertain about the significance of the animal experiments which have been done. If the relevance of the animal experiments is not known or the experiments cannot be relied upon then why on earth does anyone do them? Just as puzzling are the many instances where drug companies state that animal experiments have not indicated that there will be any problems if their drugs are given to pregnant women - but still advise doctors against giving those drugs to pregnant women.
These short sections are intended only to illustrate the point I want to make and are not intended to provide useful information about the drugs concerned.
Dr Vernon Coleman.
REFERENCIAS
- PARTE 1: Extracts from Science on Trial: The Human Cost of Animal Experiments, by Dr Robert Sharpe (Awareness, 1994)
- PARTE 2: Extracts from Betrayal of Trust, by Dr Vernon Coleman: European Medical Journal.
Ambas partes fueron extraidas en 2009/2010 de la siguiete web: The errors of vivesection, que ya no está online.
MÁS INFORMACIÓN
- prescriptiondrugs.procon.org - 35 FDA-Approved Prescription Drugs Later Pulled from the Market
