IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

genicity of naturally occurring mixtures of aflatoxins and of aflatoxins B 1, G 1 and M 1,
limited evidence for aflatoxin B 2 and inadequate evidence for aflatoxin G 2. The principal
tumours induced were liver tumours.
Carcinogenicity studies in experimental animals since 1993 were limited to a few
experiments in rats, trout, mice, tree shrews and woodchucks. Under certain conditions,
including increased pressure, decontamination of feed containing aflatoxins by ammoniation
almost completely eliminated the induction of hepatic tumours in rats. Studies in
trout showed that ammoniation of aflatoxin-contaminated maize significantly reduced
the incidence of liver tumours. In trout fed non-fat dried milk from cows fed ammoniated
or non-ammoniated aflatoxin-contaminated whole cottonseed, ammoniation almost eliminated
the liver tumour response. Less hepatic tumours were induced in trout after
exposure to aflatoxin M 1 than with aflatoxin B 1. One aflatoxin metabolite, aflatoxicol,
elicited a slightly higher hepatic tumour response in fry and fish embryos than aflatoxin
B 1.
A study in transgenic mice overexpressing transforming growth factor β showed no
increased susceptibility to induction of hepatocellular adenomas and carcinomas after
intraperitoneal administration of aflatoxin B 1. In another study, induction of hepatocellular
tumours by aflatoxin B 1 was significantly enhanced in transgenic mice heterozygous
for the TP53 gene and expressing hepatitis B surface antigen. The tumour
response for aflatoxin B 1 was reduced in the absence of either one of these risk factors.
The presence of the TP53 246 ser mutant not only enhanced the synergistic effect of hepatitis
B virus and aflatoxin B 1 but also increased tumorigenesis due to aflatoxin B 1 in the
absence of hepatitis B virus.
In tree shrews, the incidence of hepatocellular carcinomas was significantly
increased and the time of occurrence was shortened in animals treated with aflatoxin B 1
and infected with (human) hepatitis B virus compared with aflatoxin B 1-treated animals.
Woodchucks infected with woodchuck hepatitis virus were more sensitive to the carcinogenic
effects of aflatoxin B 1 than uninfected woodchucks. The combined woodchuck
hepatitis virus/aflatoxin B 1 treatment not only reduced the time of appearance but also
resulted in a higher incidence of liver tumours.
In conclusion, recent studies continue to confirm the carcinogenicity of aflatoxins in
experimental animals.
5.4 Other relevant data
AFLATOXINS 247
Metabolism of aflatoxin B 1 in humans has been well characterized, with activation
to aflatoxin B 1 8,9-exo-epoxide resulting in DNA adduct formation. CYP1A2, 3A4, 3A5,
3A7 and GSTM1 enzymes among others mediate metabolism in humans. The expression
of these enzymes can be modulated with chemopreventive agents, resulting in inhibition
of DNA-adduct formation and hepatocarcinogenesis in rats. Oltipraz is a chemopreventive
agent that increases glutathione conjugation and inhibits some cytochrome
P450 enzymes. Results from clinical trials in China using oltipraz are consistent with