IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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IARC MONOGRAPHS VOLUME 82
In pigs, clearance of [ 14 C]fumonisin B 1 from blood after an intravenous injection was
best described by a three-compartment model (half-lives, 2.2, 10.5 and 182 min, respectively,
averaged over five animals). Cannulation of the bile duct (which prevents enterohepatic
circulation) resulted in much more rapid clearance, which was best described by
a two-compartment model. A similar effect of bile removal was observed whether the
dosing was intravenous or intragastric. The elimination half-life in pigs dosed intragastrically
without bile removal was 96 min (averaged over four animals). The studies
with pigs clearly show the importance of enterohepatic circulation of fumonisin B 1 in
pigs. As with rats, over 90% of radioactivity was recovered in the faeces, with less than
1% recovered in urine after an oral dose of [ 14 C]fumonisin B 1 (Prelusky et al., 1994).
After intraperitoneal injection in rats, fumonisin B 1 was excreted unchanged in bile
(Shephard et al., 1994c). In vervet monkeys after intravenous injection, there was evidence
of metabolism to partially hydrolysed fumonisin B 1 and to a much lesser extent the
fully hydrolysed aminopentol backbone in faeces. In urine, 96% of the radioactivity was
recovered as fumonisin B 1 (Shephard et al., 1994a). In further experiments, it was shown
that metabolism was likely to be mediated by the bacteria in the gut, since partially
hydrolysed and fully hydrolysed fumonisin B 1 were recovered in faeces but not bile of
vervet monkeys (Shephard et al., 1995b).
In-vitro studies using primary rat hepatocytes with microsomal preparations
(Cawood et al., 1994) and with a renal epithelial cell line (Enongene et al., 2002a,b) indicated
that there was no metabolism of fumonisin B 1 in these systems.
In rats given three oral doses of [ 14 C]fumonisin B 1 at 24-h intervals, the specific
radioactivity in liver and kidney increased with each successive dose and remained
unchanged for at least 72 h after the last dose (Norred et al., 1993). In pigs, it was estimated
that exposure to dietary fumonisin B 1 at 2–3 mg/kg feed would require a withdrawal
period of at least two weeks for the [ 14 C]radiolabel to be eliminated from liver
and kidney (Figure 1; Prelusky et al., 1996b). Fumonisins B 1, B 2 and B 3 and aminopolyol
hydrolysis products were detected in the hair of vervet monkeys exposed to fumonisin B 1
in the feed and of Fischer rats after oral exposure to culture material of F. verticillioides
containing fumonisins (Sewram et al., 2001).
Fumonisins do not appear to be metabolized in animal systems in vitro or in vivo,
apart from some evidence for removal of the tricarboxylic acid side-chains. This is
thought to be effected by the microbial flora of the gut.
4.1.3 Comparison of humans and animals
Several experiments have indicated that the rate of elimination of fumonisin B 1 is a
function of body weight. In mice, elimination is very rapid, whereas fumonisin B 1 is
predicted to be retained much longer in humans (Figure 2; Delongchamp & Young,
2001).