Since its inception 25 years ago, EPA [the US Environmental Protection Agency] has applied the same logic to hundreds of other substances, extrapolating from high levels in animal studies to arrive at acceptable levels for humans. But that approach, say scientists both inside and outside the federal government, may no longer be the best way to safeguard public health...EPA's new emphasis on molecular data is based on a growing body of evidence that extrapolations from megadoses can provide a misleading picture of the effects of low-level exposure. Chloroform is a good example. EPA's current strict standards were derived from a study in which mice developed liver tumors after exposure to massive daily doses of chloroform pumped into their stomachs over several months. However, those findings may not be relevant to human exposures, according to a paper picked by the Society of Toxicology as the best published last year in its journal.
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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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Even when drugs with evidence of anticancer activity in preclinical in vivo models are given at their maximum tolerated doses, they frequently fail to produce useful activity in humans.
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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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[Regarding tamoxifen, an anti-cancer drug] 'Experimentally, tamoxifen has carcinogenic potential. In some strains of rat, but not mouse or hamster, tamoxifen can cause liver cancers at doses as low as 5mg/kg per day... However, there are doubts about the correlation of [the results] with the risk of malignant disease even in rats, let alone in other rodents, mammals, or human beings. There are many uncertainties in extrapolating these experimental data from rats to women. The effect depends on bioavailability, hepatic [liver] blood flow, and hepatic [liver] metabolism to active genotoxic carcinogens, all of which differ enormously between rat and man.
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Enthusiasm - a distemper of youth, curable by small doses of repentance in connection with outward applications of experience.
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The people are to be taken in very small doses.
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Happiness is a small and unworthy goal for something as big and fancy as a whole lifetime, and should be taken in small doses.
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Enthusiasm. A distemper of youth, curable by small doses of repentance in connection with outward applications of experience.
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