CHRONI POISoNwIG by a hepatotoxic pyrroliz: idine alkaloid 1" produces a liver lesion c by megalocytosis of the liver paren-chyma that persists long after the toxic insult It is sometimes ac-oompanied by bileduct proliferation, fibrosis, vascular damage, and neroas." This lesion n be produced experimentay by adnistra-tion of the alkalod either as a single large dose47 (of the order of an acute LDo) or as repeated mal doses over a long period of time. 5 Consideration of these two methlods of producing the chronic lesion suggested the possibility that devepment of megalocytsis was initi-ated by long-lasting mitotic ihibition iduced in hepatocytes by a single low dose of ah oic pyrrolizidine alkalid" and promoted by the stimulus for regenertion provided by the necrogenic action of the lkaloi Because massive centrlobular necros is a feature of the acute damage pduced by a arge dose of a hepatotoxic pyrrolizidine aka1old, o'low doses were used to iD the ic disease by re-peated tion (doses of up to 0.2 acute LDs5,); these low doses, although not high enough to cause obvious necrosis, could cause death of isolated cells or fimctional cell damage sufficient to provide a low-level stimulus for regeneration.

If the mitotic mihibiton and the stimulus for regeneration are two separate actios, itshould be possible to prouce meegalytos by initi-ating it with a low dose of a h x pyrrolizidine alkalid and pro moting it with a liver damag agent other than a pyrroizidine alkaloid. Furtemore, a single low dose of alkalid should produce in young, rapidlygrowing animal a lesion of much greater severty tha that produced by an equivalent dose in an adult animal. This paper reports e dence sistentwith this hypothesis. Maliae andm ds