Toxicology of Industrial Compounds

162 BIOMARKERS AND RISK ASSESSMENT
Figure 12.2 Total white blood cell DNA adducts, determined by immunoassay,
HPRT and glycophorin A mutations in foundry workers, exposed to various levels
of BP (Perera et al., 1993).
in singlestrand breaks while none of the cytogenetic parameters are
elevated in the foundry workers.
Adducts and metabolic genotypes
The modulation of environmental carcinogenesis by host polymorphism in
genes for xenobiotics metabolising enzymes is currently under extensive
investigation. It was initially sparked by findings linking certain
phenotypes of drug metabolism to cancer risk (Seidegård et al., 1986;
Nebert, 1991). The enzymes of interest in the context of exposure to PAHs
include cytochrome P450 CYP1A1 and glutathione transferase GST,
involved in the activation and inactivation, respectively, of PAHs. By
restriction enzyme mapping two allelic forms, ml and m2, and two other
closely linked codons for isoleucine (Ile, linked to ml) and valine (Val,
linked to m2) can be defined, where m2 and valine represent the rare
mutant genotypes, associated with the inducibility of the enzyme activity
(Hayashi et al., 1991). Polymorphism in GST1 involves the presence or the
absence of the gene (Nakachi et al., 1992). The null genotype lacks the
enzyme completely.
Among chimney sweeps there was an association of the rare, inducible
CYP1A1 genotype ml/m2 with low adduct levels in white blood cell DNA
(Ichiba et al., 1994). In the same study an increased level of adducts was
noted in the GST1-individuals. The level of DNA adducts appeared to be
related to both the GST and CYP1A1 genotype (Figure 12.3). Analysis of
micronuclei in chimney sweeps resulted in no differences between
individuals of either CYP1A1 ml/m2, m2/m2 or Ile/Val genotypes nor of
GST1 + or − genotypes (Carstensen et al., 1993). There was however a