FUMONISIN B-1 DOSIMETRY IN RELATION TO CANCER INITIATION IN RAT-LIVER

Dose response studies regarding the cancer initiating potential of fum onisin B-1 (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 w hich was equivalent to that of the controls after 21 days. Based on th e feed intake records the effective dosage level (EDL) for cancer init iation 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 FB1/10 0 g body wt. Over a period of 14 days the amount of FB1 required for c ancer 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 s tudy 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 d osage of 29.7 mg/100 mg body wt over 7 days did not initiate cancer wh ilst a similar dose (30.8 mg/100 body wt) over 21 days did. FB1 effect ively delayed hepatocyte cell proliferation when fed at a dietary leve l of 250 mg FB1/kg (the lowest dietary level tested to effect cancer i nitiation over 21 days) or by a single gavage dose of 5 mg FB1/100 g b ody wt 6 h following partial hepatectomy. This inhibitory effect of FB I on cell proliferation appears to be the reason why the fumonisins ar e slow cancer initiators. The present data suggest that a balance exis ts between the compensatory cell proliferation due to the hepatotoxici ty induced by FB1 and the inhibitory effect on the subsequent hepatocy te cell proliferation. Therefore, a threshold level for cancer initiat ion exists which, as a function of time, will be determined by the dos age used and the subsequent inhibitory effect on cell proliferation.