Interactions in Metal Toxicology - Toxicology of Metals - page 121

premalignant hyperkeratotic skin lesions (Ahsan et al. ,
2003). However, in both studies the results were based
on very small study populations. Genes involved in
oxidative stress have also been shown to modify the
risk for arsenic-related cardiovascular effects (Hsueh
et al. , 2005, Wang et al. , 2006).

Hard metal disease is a pulmonary disorder associ-
ated with occupational exposure to inhalation of cobalt
ions, sintered or not to other metals. A strong associa-
tion with hard metal disease and HLA-DP sharing a
Glu at position 69 has been reported (Potolicchio et al. ,
1997, 1999). On the other hand, no infl uence of Glu 69 was
observed in relation to lung function changes among
workers from a cobalt-producing plant (Verougstraete
et al. , 2004).

3.3.2 Beryllium and Cobalt

Genetic susceptibility for beryllium-associated sen-
sitization and subsequent chronic beryllium disease
(CBD) has been described and is maybe the clear-
est example of a gene-environment interaction for
a metal. The immunopathogenesis of CBD and beryl-
lium sensitization depends on the development of
an antigen-specifi c, cell-mediated immune response
(Saltini et al. , 1989). Beryllium-specifi c CD4 + T cells
probably recognize a form of beryllium as an antigen,
acting in combination with MHC class II molecules on
antigen-presenting cells. In a key study, Richeldi et al.
(1993) reported an increased prevalence of HLA-DPB1
with glutamic acid in position 69 (Glu 69 ) in cases of
CBD (97%) compared with beryllium-exposed non-
diseased controls (30%). These results were later con-
fi rmed by further studies, although the frequency of
the Glu 69 variant was somewhat lower (Maier et al. ,
2003; Rossman et al. , 2002; Saltini et al. , 2001). The
results from these studies show that specifi c Glu 69 -con-
taining alleles and their copy number (homozygous
or heterozygous) confer the greatest susceptibility to
CBD in exposed individuals. However, because 15-
20% of CBD patients lack Glu 69 , other class II markers
are likely to be involved in the Be-specifi c response
as well. Recently, Amicosante and coworkers identi-
fi ed the HLA-DRPhebeta47 marker to be associated
with beryllium sensitivity in Glu 69 -negative subjects
( Amicosante et al. , 2005).
Beryllium antigen stimulates tumor necrosis factor
alfa (TNF

3.3.3 Cadmium

Support for genetic infl uences comes from a large
number of studies performed on different inbred strains
of rodents that differ greatly in metal susceptibility. As
an example, for cadmium-induced testicular toxicity,
more than 30 mice strains are sensitive at very low cad-
mium levels, whereas approximately 10 are resistant,
even at very high cadmium concentrations (Liu et al. ,
2001). Differences in the cadmium-binding protein met-
allothionein have generally been thought to be respon-
sible for the strain susceptibility to cadmium toxicity.
Metallothionein null mice, indeed, are more sensitive
to certain effects of cadmium (e.g., nephrotoxic or tes-
ticular injuries) (Liu et al. , 2000). However, a study
on cadmium-induced testicular damage showed that
the genetic mouse strain and not the metallothionein
genotype determined susceptibility to testicular injury
(Liu et al. , 2001). Therefore, the resistance to cadmium-
induced testicular injury among certain strains has
been sought in other factors, most probably including
genetic differences in the recently reported transporter
ZIP8, located at mouse chromosome 3 (Dalton et al. ,
2000; 2005).
Although cadmium is one of the major toxic met-
als, so far strikingly little is known about what extent
and which genetic factors infl uence its toxicity among
humans. One twin study has been performed for
quantifying the genetic infl uence of variation in blood
concentrations of cadmium and lead (Björkman et al. ,
2000). Heredity had a substantial impact on blood cad-
mium and lead levels, but a striking sex difference was
observed. Among nonsmoking women, the hereditary
impact was 65%, whereas for nonsmoking men it was
only 13%.

) from bronchoalveolar lavage cells in CBD.
Thus, functional gene polymorphisms of this gene are
suspected to modify the course of CBD. Several studies
suggest that the −308 allele in the promoter region of
TNF

α

determines susceptibility for CBD (Dotti et al. ,
2004; Gaede et al. , 2005; Maier et al. , 2001). Moreover,
the antiinfl ammatory cytokine transforming growth
factor beta (TGF

α

) is able to inhibit production of alve-
olar macrophages and monocytes, and it has recently
been demonstrated that the frequency of a polymor-
phism associated with a low TGF

β

3.3.4 Lead

3.3.4.1 ALAD
It is now 20 years since the fi rst study by Ziemsen
et al. describing differences in blood lead levels by gen-
otype of the gene

β release (labeled

TGF β 1 , codon 25) was strongly associated with CBD

(Gaede et al. , 2005). However, this phenomenon was
only seen among individuals from the United States,
suggesting that different genetic factors are important
in different populations.

-amino levulinic acid dehydratase
(ALAD) (Ziemsen et al. , 1986). Since then, there have
been a large number of studies performed focusing on

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