IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

AFLATOXINS 229
to non-HBV-infected individuals. CYP3A4 phenotype, as judged by urinary cortisol
metabolite ratios, was also not associated with adduct level. The main factors affecting
the level of aflatoxin–albumin adducts were place of residence (rural areas higher than
urban areas) and season of blood sample collection (dry season higher than wet season)
(Wild et al., 2000). Kensler et al. (1998) also found no association between aflatoxin–albumin
adducts and GSTM1 genotype in 234 adults from Qidong County, China.
The role of polymorphisms in the DNA repair enzyme, XRCC1, in influencing the
levels of aflatoxin B 1–DNA adducts in samples of placental DNA was studied in women
at a Taiwanese maternity clinic. The presence of at least one allele of polymorphism,
399Gln, was associated with a two- to three-fold higher risk of having detectable aflatoxin
B 1–DNA adducts compared with subjects homozygous for the 399Arg allele.
However, when the association between polymorphism and tertiles of adduct level was
examined, the 399Gln allele was associated with intermediate but not high adduct levels.
The authors suggested that this may reflect saturation of repair pathways (Lunn et al.,
1999).
Studies of the types of genetic alteration associated with exposure to aflatoxin in vivo
have been less extensive. In human subjects from Qidong County, China, aflatoxin exposure
was determined as high or low (dichotomized around the population mean) by aflatoxin–albumin
adduct level in serum and compared with the HPRT mutation frequency
in lymphocytes. A raised HPRT mutant frequency was observed in subjects with high
compared with low aflatoxin exposure (OR, 19; 95% CI, 2.0–183) (Wang et al., 1999b).
The levels of chromosomal aberrations, micronuclei and sister chromatid exchange
were studied in 35 Gambian adults, 32 of whom had measurable concentrations of aflatoxin–albumin
adducts. There was no correlation within this group between the
cytogenetic alterations and aflatoxin–albumin adducts in peripheral blood at the individual
level. In a further study, blood samples of 29 individuals of the same Gambian
group were tested for DNA damage in the single-cell gel electrophoresis (comet) assay
but no correlation was observed with aflatoxin–albumin adducts or GSTM1 genotype
(Anderson et al., 1999).
(b) TP53 mutations in human hepatocellular carcinoma (HCC)
Molecular analyses of human HCC have revealed a high prevalence of an AGG to
AGT (arg to ser) transversion at codon 249 of the TP53 tumour-suppressor gene (249 ser
mutation) in tumours from areas of the world with reported high aflatoxin exposure
(Montesano et al., 1997). A large number of studies have been published since 1993 on
aflatoxin exposure and TP53 mutations; two recent meta-analyses examined the
relationship between aflatoxin exposure, HBV infection and TP53 mutations in 20
(Lasky & Magder, 1997) and in 48 published studies (Stern et al., 2001). Table 15
summarizes the published data and the key findings are described below. [It is important
to note that the specificity of TP53 mutations in relation to aflatoxin exposure is associated
only with G to T transversions at the third base of codon 249, whereas the metaanalysis
by Stern et al. (2001) included a few G to T transversions in the second base of