Interactions in Metal Toxicology - Toxicology of Metals - page 120

conclusions on a causal relationship with the biochem-
ical mechanism, because the genetic variant may be
linked with the causal gene.) Another fact that stresses
the importance of suffi cient statistical power is that, in
general, genes act in concert to exert effects. Therefore,
effects on one gene may induce compensatory changes
in others. Moreover, many metabolic enzymes have
overlapping substrate specifi cities. Thus, there are
several grounds for analyzing interactions between
different gene loci, so-called gene-gene interactions.
However, only a limited number of studies have
until now examined the combined effects of two or
more genes in relation to metal toxicity. One example
is beryllium in which the combined effect of specifi c
variants of HLA DPB1 and DRB1 and tumor necrosis
alpha (TNF) have been analyzed in relation to clini-
cal severity (Maier et al. , 2001). Considering multiple
genes is more biologically relevant, but for these stud-
ies, a large number of individuals are needed. Moreo-
ver, it is necessary to formulate a strategy for handling
the problem of multiple comparisons that very quickly
arise when analyzing the effects of a large number of
polymorphisms in different exposure groups, in dif-
ferent subgroups, or for different markers of effect.
Simple corrections for multiple testing (e.g., Bonfer-
roni correction) are not very fruitful when analyzing
several hundreds of polymorphisms, rather it has been
suggested that the prior credibility of the hypothesis is
important for interpreting a set of observations. New
statistical methods for genetic association studies are
needed, and a recent article illustrates how a Bayesian
approach can be used to estimate the probability that a
positive association is false (Wacholder et al. , 2004).

(Vahter, 2000). In some areas of Taiwan, people excrete
an unusually high percentage as MMA in the urine
(20-30%), whereas certain populations in Argentina
and Chile only excrete a few percent as MMA. Support
for the idea that part of this variation is determined by
genetic causal components comes from a correlation
study for arsenic performed within families (Chung et
al. , 2002), showing that siblings have a higher correla-
tion of arsenic methylation capacity than their parents.
Moreover, there are two studies addressing intraindi-
vidual variability in arsenic methylation pattern, show-
ing that arsenic methylation pattern remains relatively
stable over time, suggesting that the predominant fac-
tors are either genetically infl uenced or associated with
long-term environmental factors, such as dietary habits
(Concha et al. , 2002; Steinmaus et al. , 2005).
Evidence for genetic effect modifi cation on arsenic
metabolism comes from studies on the methyltrans-
ferase CYT19 (also labelled AS3MT) that is believed to
catalyze the methylation of arsenic to MMA and further
to DMA. This enzyme is best characterized in rat (cyt19)
(Lin et al. , 2002; Thomas et al. , 2004) but is not well
defi ned in humans (Hayakawa et al. , 2005). Meza and
colleagues showed in a study from Mexico that CYT19
displayed three variants that were strongly associated
with the second methylation index (DMA/MMA)
among children but not in adults (Meza et al. , 2005).
This fi nding suggests a role for polymorphisms regu-
lating developmental differences in arsenic biotrans-
formation. However, there was a difference in ethnicity
between the groups: the children were to a larger degree
of Indigenous and the adults of European ancestry.
Wood et al. (2006) estimated the functional impact on
AS3MT enzyme activity of genetic variants occurring
in exons. However, for intronic polymorphisms, like
those reported in Meza et al. (2005), their function on
AS3MT activity is still completely unknown.
It is generally thought that many of the toxic
effects associated with arsenic exposure were medi-
ated through arsenic-induced oxidative stress. Thus,
Ahsan et al. analyzed whether polymorphisms in the
oxidative stress-scavenging enzyme catalase and the
phase I metabolic enzyme myeloperoxidase (MPO)
are associated with increased risks of hyperkeratosis
in a highly arsenic-exposed population in Bangladesh
(Ahsan et al. , 2003). The results indicated that the low-
activity variant of the catalase was overrepresented
among the cases of hyperkeratosis. Similarly, the vari-
ant of MPO producing an increased amount of the
reactive oxygen species hypochlorous acid was over-
represented among the cases. Ahsan and coworkers
also published data suggesting that genes involved in
DNA repair, removing oxidative stress-induced DNA
damage, may infl uence the risk of arsenic-induced

3.3 Interactions for Specifi c Metals
A review of what presently is known about gene-
environment interactions for different metals follows.
For most metals apart from a few exceptions (i.e. beryl-
lium, lead, and to some extent arsenic) there are no or
only a few reports on gene-environment interactions.
However, the literature within this fi eld is rapidly
growing.

3.3.1 Arsenic

Gene-environment interaction studies for this ele-
ment have mainly focused on genes involved in the
metabolism of inorganic arsenic. Of the total amount of
arsenic excreted through the urine, 10-30% is usually
inorganic, 10-20% monomethylated arsenic (MMA),
and 60-70% dimethylated arsenic (DMA). However,
there is a marked variability in metabolism of inor-
ganic arsenic within and between population groups