IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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and litters on postnatal day 21. Litter weight gain in the 10- and 55-mg/kg groups was
slightly decreased; however, gross litter weight and physical development of offspring
were not affected. Increased sphinganine/sphingosine ratios were found in the livers of
dams from the high-dose group on gestation day 15. However, sphinganine/sphingosine
ratios in abdominal slices containing liver and kidney of fetuses from the control and
high-dose groups did not differ. In an additional experiment, two dams were given an
intravenous injection of 101 μg [ 14 C]fumonisin B 1 on gestation day 15. After 1 h, about
98% of the dose had disappeared from the maternal blood, but only negligible amounts
of radioactivity were found in the fetuses (Voss et al., 1996b).
(b) Mechanistically oriented developmental toxicity studies
Doses of 0.8 or 8 mg/kg bw of fumonisin B 1 were given subcutaneously to male
Sprague Dawley rats on postnatal day 12. Brain tissue and blood were collected at ten
time points up to 24 h after fumonisin B 1 administration. The sphinganine levels in brain
and plasma showed dose-dependent increases; the brain sphinganine level during the
24 h was much higher than plasma sphinganine, with an area under the concentration–time
curve (AUC) ratio of 40:1. In addition, fumonisin B 1 was found in the brain
tissue after the higher dose. These data indicate that alterations of the brain sphinganine
levels are the result of a direct action of fumonisin B 1 on the brain rather than transport
of peripheral sphinganine to the brain (Kwon et al., 1997a).
Subcutaneous dosing of Sprague-Dawley rats with 0.4 or 0.8 mg/kg bw fumonisin B 1
from postnatal day 3 to day 12 resulted in reduced body weight gain and decreased
survival. Both sphinganine concentration and sphinganine/sphingosine ratios in the brain
were increased at the higher dose. To investigate the effects of limited nutrition on
sphinganine levels and myelinogenesis, rats were given 0.8 mg/kg bw fumonisin B 1 or
subjected to limited nutrition (temporary removal from dam in the postnatal period) and
compared with a saline control group. Sphinganine levels were increased in rats treated
with 0.8 mg/kg fumonisin B 1, but not in those given limited nutrition. Myelin deposition
was decreased in both the nutritionally limited and the fumonisin B 1-exposed rats. These
data indicate that sphingolipid metabolism in developing rats is vulnerable to
fumonisin B 1, while hypomyelination associated with fumonisin B 1 may be mediated by
limited nutrition (Kwon et al., 1997b).
Concentration- and time-dependent increases in sphinganine/sphingosine ratios were
found in developing chick embryos after injection of 72 or 360 μg of fumonisin B 1 per
egg. A close correlation was observed between disruption of sphingolipid metabolism
and tissue lesions detectable by light microscopy (Zacharias et al., 1996).
4.4 Genetic and related effects
4.4.1 Humans
IARC MONOGRAPHS VOLUME 82
No data were available to the Working Group.