The studies of the hepatoxic and hepatocarcinogenic pyrrolizidine alkaloids (PA) have shown that (a) The conventional testing for toxicity and its evaluation on the basis of death occurring a few days after dosing is meaningless for carcinogenic agents. (b) A single dose of a water-soluble substance, the main part of which is metabolized and excreted in a few hours after ingestion and which does not cause immediately obvious illness, can induce tumors that become apparent a long time after its administration. The induction of tumors appears to resemble a ripening process, which can be accelerated by repeated dosage of the same or of certain other compounds (and presumably could also be delayed). (c) The first impact of a carcinogenic agent on a cell is the inhibition of its division, possibly through interference with a “mitotic factor.” (d) The very young are more susceptible than adults to PA's; if ingested by lactating females, the latter may remain unscathed, while the suckling young will suffer the ill effects and may develop tumors when still very young. (e) The elimination of the toxin in the milk may be a factor in the greater resistance of the lactating female to such agents. (f) Sexual hormones affect the response to PA's, adult males are more susceptible than adult females to these hepatotoxins. (g) The hepatotoxic entity is probably a product formed from pyrrolizidine alkaloids in the course of their metabolism in the liver and possibly also in other tissues. The effects of age, sex, diet, and animal species may thus be related to the concomitant variations in the metabolism of PA's. (h) Hepatotoxic PA's induce in primates mainly pulmonary and venoocclusive lesions. (i) Man is also susceptible to the hepatotoxic PA's. Vascular lesions described as Chiari's syndrome in South Africa and as “venoocclusive disease” in Jamaica have been correlated with the ingestion of PA's.

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