Yes, I think it is very clear to all of us who are engaged in the business of assessing toxicity data that, when volumes of data are proudly presented to us after a carcinogenicity study, showing that there was a tumour in this organ or that, we look at it and we scratch our heads, and we wonder what on earth we can make of it. This is especially true when huge doses are given, with nothing to suggest what would be expected at low doses. I think very often the carcinogenicity studies are a waste of everybody's time and a fearful waste of animals. They are conducted partly because we are not sure what to do instead, and partly because they are a political gesture and a very miserable one at that.
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Extrapolating from one species to another is fraught with uncertainty... For almost all of- the chemicals tested to date, rodent bio-assays have not been cost-effective. They give limited and uncertain information on carcinogenicity, generally give no indication of mechanism of action, and require years to complete.' [They are] 'rarely the best approach for deciding whether to classify a chemical as a human carcinogen.
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... numerous chemicals have been found to have potential toxicity/carcinogenicity in rat or mouse, which, we are reasonably certain, have little or no potential hazard in man. The reason for this is again species differences, for the biological defence mechanism which protects against toxic chemicals is most highly evolved in man, who therefore generally has a higher resistance to chemical toxicity and carcinogenicity than have rodents and other species.
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… Predictions of carcinogenicity from laboratory animals are without meaning for there is no evidence that the studies were conducted in a way that took into consideration the pharmacodynamics in the species investigated, or with any appreciation of end organ sensitivity (with respect to contraceptive steroids).
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Why the dog was ever considered as an appropriate animal for carcinogenicity testing is also not entirely clear... Despite the obvious problems of study design and interpretation, carcinogenicity tests in the dog, lasting 7 years, were requested by regulatory authorities from the late 1960s...One of the best known examples of the inappropriate use of the dog was the carcinogenicity testing of hormonal contraceptives. It is now understood that mammogenesis in the dog is very different from that in primates; quantitative and qualitative differences exist in the feedback control mechanisms, receptor content and behaviour, and target sensitivity and responsivity. As a result of this biological difference there was a high incidence of mammary tumours in long-term studies in dogs treated with progestagens/contraceptive steroids such as lynestrol. Ultimately pressure from the scientific community led, relatively recently, to the requirement for carcinogenicity studies in dogs being dropped.
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There are marked differences in carcinogenicity across sexes, strains and species. Often, the-same chemical will cause one kind of cancer in one experiment and another kind in another experiment Indeed, the most hard-bitten advocates of animal experiments do not claim to be able to predict which organ will be affected in humans by a chemical that is carcinogenic in animals.
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Elsewhere, I have pointed out that overfeeding of rats profoundly influences the incidence particularly of endocrine tumours. Furthermore, endocrine tumours and tumours of tissues, such as the breast and uterus, which are very directly under sex-hormone control, constitute a very high proportion of the tumours observed in most carcinogenicity studies in rats. [Comparing] the incidences of tumours in these categories in men and women with those in male and female rats... [shows] the differences between the two species are sufficiently striking to make one wonder how appropriate the laboratory rat is as a model for man in terms of the spectra of tumours to which they are prone.
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The principal method of determining potential carcinogenicity of substances is based on studies of daily administration of huge doses of chemicals to inbred rodents for a lifetime. Then by questionable models, which include large safety factors, the results are extrapolated to effects of minuscule doses in humans... The rodent MTD test that labels plant chemicals as cancer-causing in humans is misleading. The test is likewise of limited value for synthetic chemicals. The standard carcinogen tests that use rodents are an obsolescent relic of the ignorance of past decades.
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The standard carcinogenicity bioassay, which involves treating two rodent species for a minimum of 2 years, at a range of doses, is acknowledged to be an insensitive tool because of the background `noise' of spontaneous disease. Most strains of rat used in such studies have high incidence of pituitary and mammary tumours; some inbred rat strains frequently develop leukaemia or testicular tumours; mice strains show high incidence of malignant lymphomas and liver tumours.
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The problem with animal carcinogenicity tests is not their lack of sensitivity for human carcinogens, but rather their lack of human specificity. A positive result has poor predictive value for humans.
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[Regarding animal carcinogenicity tests on saccharin] Published risk estimates, starting from the same animal data but using various [statistical] models, differ by factors of over 5,000,000.
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[Animal carcinogenicity tests on new drugs are] inaccurate, often insensitive and generally misleading.
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