IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

248
experimental data in showing that, following dietary exposure to aflatoxins, modulation
of the metabolism of aflatoxins can lead to reduced levels of DNA adducts.
Aflatoxin B 1 is immunosuppressive in animals, with particularly strong effects on
cell-mediated immunity. Exposure to aflatoxin results in increased susceptibility to
bacterial and parasitic infections. Human monocytes treated with aflatoxin B 1 had
impaired phagocytic and microbicidal activity and decreases in specific cytokine
secretion. Studies have linked human exposure to aflatoxins to increased prevalence of
infection.
Aflatoxins cross the human placenta. Aflatoxin exposure has been associated with
growth impairment in young children. Malformations and reduced fetal weight have been
seen after mice were treated intraperitoneally with high doses of aflatoxin. In rats,
decreased pup weight and behavioural changes have been found at low doses. Effects
suggesting impairment of fertility have been reported in female and male rats and in male
rabbits.
Aflatoxin B 1 is genotoxic in prokaryotic and eukaryotic systems in vitro, including
human cells, and in vivo in humans and in a variety of animal species. It forms DNA and
albumin adducts and induces gene mutations and chromosomal alterations including
micronuclei, sister chromatid exchange and mitotic recombination.
In geographical correlation studies, exposure to aflatoxin is associated with a specific
G to T transversion in codon 249 of the TP53 gene in human hepatocellular carcinoma.
This alteration is consistent with the formation of the major aflatoxin B 1–N7-guanine
adduct and the observation that G to T mutations are predominant in cell and animal
model systems. The high prevalence of the codon 249 mutation in human hepatocellular
carcinoma, however, is not fully explained in experimental studies either by the
sequence-specific binding and mutation induced by aflatoxin B 1 or by altered function of
the p53 protein in studies of hepatocyte growth and transformation.
Current knowledge of the molecular mechanisms contributes to the understanding of
the nature of the interaction between hepatitis B virus and aflatoxins in determining risk
for hepatocellular carcinoma. Infection with hepatitis B virus may increase aflatoxin
metabolism; in hepatitis B virus-transgenic mice, liver injury is associated with increased
expression of cytochrome P450 (CYP) enzymes. Glutathione S-transferase activity is
also reduced in human liver in the presence of hepatitis B virus infection. Other
molecular mechanisms are, however, also likely to be relevant to aflatoxin-induced
carcinogenesis.
On the basis of the data described above, the existing Group 1 evaluation of naturally
occurring aflatoxins was reaffirmed.
5.5 Further research needs
IARC MONOGRAPHS VOLUME 82
Some research areas are identified here for the purpose of assisting in any future
update by an IARC Monographs Working Group. It is not implied that these areas listed