Fumonisin B1 dosimetry in relation to cancer initiation in rat liver

Abstract

Dose response studies regarding the cancer initiating potential of fumonisin B₁ (FB₁) were conducted as a function of time. Feeding studies over 21 days indicated that FB₁ induced a feed refusal effect in rats at dietary levels of 250, 500 and 750 mg FB₁/kg diet. This effect was overcome after 14 days and the feed intake profiles reached a level which was equivalent to that of the controls after 21 days. Based on the feed intake records the effective dosage level (EDL) for cancer initiation over a period of 21 days is 14.2 < EDL < 30.8 mg FB₁/100 g body wt. This is equivalent to a daily intake of 0.7 < EDL < 1.5 mg FB₁/100 g body wt. Over a period of 14 days the amount of FB₁ required for cancer initiation is 9.6 < EDL < 23.3 mg FB₁/100 g body wt. The latter values were markedly higher than the EDL values obtained in a gavage study where a fixed amount of FB₁ was dosed to rats over 14 days (5.39 < EDL < 11.56 mg FB₁/100 g body wt). The dietary level of FB₁ required for cancer initiation is dependent on the duration of exposure as a dosage of 29.7 mg/100 mg body wt over 7 days did not initiate cancer whilst a similar dose (30.8 mg/100 body wt) over 21 days did. FB₁ effectively delayed hepatocyte cell proliferation when fed at a dietary level of 250 mg FB₁/kg (the lowest dietary level tested to effect cancer initiation over 21 days) or by a single gavage dose of 5 mg FB₁/100 g body wt 6 h following partial hepatectomy. This inhibitory effect of FB₁ on cell proliferation appears to be the reason why the fumonisins are slow cancer initiators. The present data suggest that a balance exists between the compensatory cell proliferation due to the hepatotoxicity induced by FB₁ and the inhibitory effect on the subsequent hepatocyte cell proliferation. Therefore, a threshold level for cancer initiation exists which, as a function of time, will be determined by the dosage used and the subsequent inhibitory effect on cell proliferation.