IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

days per week for four months followed by treatment with 20 μg/kg bw aflatoxin B 1, five
days per week for life. Two untreated groups (WHV-positive and -negative) served as the
controls. Woodchucks infected with WHV with or without aflatoxin B 1 treatment
developed preneoplastic foci, hepatocellular adenomas and carcinomas between 6 and 26
months after commencing the treatment. Liver tumours were observed by ultrasound at
25 months in 5/9 animals infected with WHV and at 11 months in 1/11, at 19 months in
4/10 and at 25 months in 2/5 animals that received the combined WHV/aflatoxin
treatment. No liver tumours were diagnosed in aflatoxin B 1-treated or untreated control
animals. The combined treatment resulted in earlier tumour appearance than with WHV
alone (Bannasch et al., 1995).
4. Other Data Relevant to an Evaluation of Carcinogenicity
and its Mechanisms
4.1 Absorption, distribution, metabolism and excretion
4.1.1 Humans
AFLATOXINS 215
Rigorous quantitative comparisons of dietary intakes and aflatoxin metabolites in
body fluids following absorption and distribution are lacking. As noted in the previous
monograph (IARC, 1993), aflatoxin M 1 concentrations in urine and human milk have
been correlated with dietary aflatoxin intake. However, studies of human exposure have
yielded quantitatively very different correlations between aflatoxin concentrations in
foods and either aflatoxin–protein or aflatoxin–DNA adducts in urine and sera (Hall &
Wild, 1994). Hudson et al. (1992) very carefully measured aflatoxin intake based on
plate foods in a village in The Gambia. They found intakes less than those estimated
from aflatoxin–serum and urinary adduct levels in the same individuals. In humans, as
with other species, the DNA binding and carcinogenicity of aflatoxin B 1 result from its
conversion to the 8,9-epoxide by cytochrome P450 (CYP) enzymes (Essigman et al.,
1982). There is individual variability in the rate of activation of aflatoxin, including
between children and adults, which may be material to the pharmacokinetics (Ramsdell
& Eaton, 1990; Wild et al., 1990). The pharmacokinetics of aflatoxins in humans are still
not clearly known.
Factors that explain variation in response to aflatoxin between individual humans,
animal species and strains include the proportion of aflatoxin metabolized to the 8,9epoxide
(mainly by CYP enzymes) relative to the other much less toxic metabolites and
the prevalence of pathways forming non-toxic conjugates with reduced mutagenicity and
cytotoxicity. Several excellent reviews have been published on the metabolism of
aflatoxins since the last IARC monograph on this topic (Eaton & Gallagher 1994;
McLean & Dutton 1995; Guengerich et al., 1998).