Fumonisin B1 dosimetry in relation to cancer initiation in rat liver.
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 23.3 < EDL < 33.3 mg [corrected] 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.
Gelderblom
W C
WC
Programme on Mycotoxins and Experimental Carcinogenesis, Tygerberg, South Africa.
Cawood
M E
ME
Snyman
S D
SD
Marasas
W F
WF
D000818:Animals; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D037341:Fumonisins; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D009183:Mycotoxins / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344
D002274:Carcinogens, Environmental; D037341:Fumonisins; D009183:Mycotoxins; C056933:fumonisin B1