In Tamoxifen’s case, a drug first developed as a potential contraceptive languished for many years before its present application was found. Furthermore, its propensity to cause liver tumours in rats, a toxicity problem that thankfully does not carry over into humans, was not detected until after the drug had been on the market for many years. If it had been found in preclinical testing, the drug would almost certainly have been withdrawn from the pipeline.
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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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… 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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