Carcinogenicity of Metal Compounds - Toxicology of Metals - page 189

metals, such as nickel compounds and chromate,
are associated with exposure to other environmental
carcinogens such as cigarette smoking (Gibb et al. ,
2000; Grimsrud et al. , 2002b; 2003). Recent success in
inducing cancers with arsenite and chromate in mice
was associated with the use of hairless mice exposed
to both UV and these carcinogenic metals through
their drinking water (Davidson et al. , 2004; Ross-
man et al. , 2001; 2004). Thus, in general, carcinogenic
metals have strong interactions with carcinogens,
such as PAH, UV, and the many carcinogens that
are present in cigarette smoke. Some carcinogenic
metals such as nickel compounds are able to induce
cancers in animals exposed to these metals alone,
although nickel also has a strong interaction with
other organic carcinogens such as benzo(a)pyrene
and UV (Schwerdtle et al. , 2002; Waalkes et al. , 2004;
Wozniak and Blasiak, 2004).

in vitro with a chromium (VI) reduction system with
glutathione or cells containing the shuttle plasmid
yielded mutations predominantly at GC sites (Liu et
al. , 1999). Chromium (VI) is known to have a prefer-
ence for binding to the phosphate backbone of DNA
and with positively charged N7 of guanine (Huang et
al. , 1995; Voitkun et al. , 1998; Zhitkovich, 2005). Chro-
mium (VI) is also synergistic with other organic car-
cinogens, such as those present in cigarette smoke. One
possible mechanism for these effects involves the inhi-
bition of the repair of benzo(a)pyrene DNA adducts
(Feng et al. , 2003; Hu et al. , 2004a). Chromate exposure
has been shown to induce oxidative stress in cells, and
these effects are greater with some insoluble chromium
compounds (Leonard et al. , 2004; Martin et al. , 1998; Shi
and Dalal, 1994). The oxidative stress, the reduction of
chromium (VI) to chromium (III), and the binding of
chromium (III) to DNA are thought to be involved in
its mutagenesis and genotoxicity. The binding of chro-
mium (III) to the DNA can yield a wide variety of DNA
lesions, including ternary complexes of chromium
(III) with its reducer (ascorbic acid or GSH), as well as
DNA-DNA crosslinks, DNA-protein crosslinks, sin-
gle-strand breaks, and formation of alkaline labile sites
(Coogan et al. , 1991; Costa, 1993a; Huang et al. , 1995;
Zhitkovich, 2005). It has been shown that lead chro-
mate induced morphological and neoplastic transfor-
mation in C3H/10T1/2 Cl 8 mouse embryo cells, and
chromium (VI) compounds induced mutation to 6-thio-
guanine resistance in cultured normal human diploid
fi broblasts (Biedermann and Landolph, 1990; Patierno
et al. , 1988).

2.1 Nickel
Nickel compounds are not very mutagenic in most
of the tested assay systems (Coogan et al. , 1989; Costa,
1993b; 2002). However, some studies have shown that
nickel compounds induce oxidative stress, genomic
instability, and chromosome damage (Biggart and
Costa, 1986; Conway and Costa, 1989; Costa, 2002;
Kargacin et al. , 1993; Kasprzak et al. , 2003; Lin et al. ,
1991; Sen and Costa, 1985). The Landolph labora-
tory has also shown that nickel compounds induce
morphological cell transformation, but no mutation
to ouabain resistance in C3H/10T1/2 cells (Miura et
al. , 1989). Perhaps one of the most important effects
of nickel in terms of effecting DNA is its ability to
silence genes through DNA methylation and other
epigenetic effects (Klein and Costa, 1997; Klein et al. ,
1991). The epigenetic effects of nickel compounds
are more potent with the water-insoluble forms of
nickel compounds such as Ni 3 S 2 , but this effect is
also evident when cells are exposed to soluble nickel
compounds for long periods of time (Lee et al. , 1995).
Nickel compounds can also induce oxidative stress
in vivo (Coogan et al. , 1989; Doreswamy et al. , 2004;
Kasprzak, 1995).

2.3 Arsenic
In general, arsenic compounds show poor geno-
toxicity and mutagenicity. Some studies have found
evidence of DNA damage by arsenite such as micro-
nuclei formation (Liu and Huang, 1997; Schaumloffel
and Gebel, 1998) and DNA protein crosslinks (Gebel,
1998), but others did not fi nd DNA protein crosslink
formation by arsenite (Costa et al. , 1997). Arsenic has
been found not to be mutagenic in bacteria and cul-
tured mammalian cells (Rossman et al. , 1980). How-
ever, a very consistent effect of arsenic compounds is
being a comutagen, possibly by inhibiting the repair
of DNA lesions produced by genotoxic agents such
as UV (Rossman, 1981a; 1981b; Rossman et al ., 1977;
1986). Additional studies that support the comuta-
genic effects of arsenic are those studies showing that
it is also a cocarcinogen (Rossman et al. , 2001; 2004). In
addition, arsenic has been shown to inhibit the ligation
step of DNA repair and thus can interact with many
genotoxic insults (Hu et al. , 1998).

2.2 Chromium
Water-soluble chromate (chromium VI) compounds
were tested for cell transformation, mutagenicity, and
chromosomal damage and were found to be very active
(Bianchi et al. , 1983). Analysis of the nature of mutations
in a 104-base pair segment of the HPGRT gene exon 3
showed selectivity in substitutions for GC base pairs
(Chen and Thilly, 1994). Treatment of a shuttle plasmid