Chemistry Reference
In-Depth Information
Database, 2004; Sanner and Dybling, 2005). However,
current evidence supporting metallic nickel as a respi-
ratory carcinogen is lacking. The International Com-
mittee on Nickel Carcinogenesis in Man (Doll
et al
.,
1990) reported that “there was no evidence that metal-
lic nickel was associated with increased lung and nasal
cancer risks.” Also in 1990, the International Agency for
Research on Cancer concluded that there was “inad-
equate evidence in humans for the carcinogenicity of
metallic nickel.” This is supported by some of the most
recent epidemiological studies in which lung cancer
risks were evaluated in nickel alloy manufacture work-
ers exposed to nickel oxide and metallic nickel or at least
5 years from 1953 to 1992 at the INCO nickel refi nery in
Clydach, South Wales (Sorahan, 2004). Despite numer-
ous previous reports of excess (more than 350 cases)
respiratory cancers among workers employed since the
1920s (Doll
et al
., 1977; Morgan, 1958; Peto
et al
., 1984),
this recent study did not identify occupational cancer
risk among the workers at this refi nery. There were no
nasal cancer deaths, and observed lung and other can-
cers were below expectations on the basis of national
mortality rates. Clemens and Landolph (2003) suggest
that this could have been partially because of changes
in the refi ning processes at this plant in the later 1920s
to exclude sulfuric acid-contaminating nickel arse-
nide (Ni
5
As
2
, orcelite), since unlike the 1920 samples of
green NiO dust from the refi nery that induced cellu-
lar transformation of C3H10T1/2 mouse embryo cells,
the 1929 samples did not induce cellular transforma-
tion. Another study of 1649 male workers who were
employed for at least 12 months during 1954-1978 at
a nickel refi nery and fertilizer plant in Alberta, Canada,
showed no associations between exposure to nickel
concentrate or metallic nickel and development of res-
piratory cancers involving the nasal cavity or paranasal
sinuses (Egedahl
et al
., 2003). In that study, measure-
ments taken in 1977 in nickel refi nery work areas docu-
mented nickel dust concentrations averaging 95 mg/m
3
(ranging from 9-239 mg/m
3
) in the concentration
sheds, 4 mg/m
3
(0.3-49 mg/m
3
) in the recovery areas,
and 2 mg/m
3
(0.3-7 mg/m
3
) in the mills and fabrica-
tion areas. A recent epidemiological study of workers
in New Caledonia, where nickel mining and refi ning is
the leading industry, also showed no signifi cant asso-
ciation of lung cancer among workers (Menvielle
et al
.,
2003). Likewise, a nested case-control study of the risk
of lung cancer mortality of French workers involved
in the production of stainless and alloyed steel from
1968 to 1992 (Moulin
et al
., 2000) also failed to detect
any relationship between lung cancer and exposure to
nickel, iron, or chromium compounds, in agreement
with previous literature for stainless steel and nickel
alloy manufacture (Cornell, 1984; Moulin
et al
., 1993).
Even with highly toxic gas nickel carbonyl, excess risks
of respiratory cancer in a cohort of 812 workers from a
modern nickel carbonyl refi nery showed only a nonsig-
nifi cant excess of lung cancer and no other cancer risks
(Sorahan and Williams, 2005).
Despite the carcinogenicity studies in rodents that
showed no effect with soluble nickel sulfate hexahy-
drate (Dunnick
et al
., 1995), recent studies of nickel
workers in Wales, Norway, and Finland indicate that
water-soluble nickel could be the more important risk
factor for excess respiratory cancer (see Andersen
et al
.,
1996; Easton
et al
., 1992; Grimsrud
et al
., 2002). Actual
measurements of soluble nickel in the 2002 Grimsrud
et al
. study indicated that 10-15% of the total nickel
in the grinding, roasting, and smelting departments
was of the soluble form, with nickel air concen-
trations ranging from 0.4-5.3 mg/m
3
. In that study,
the odds ratio for carcinogenic risk caused by water-
soluble nickel was found to be maximal at 3.8 (95%
confi dence interval), compared with odds ratios of
2.8 for sulfi dic nickel, 2.2 for nickel oxide, and 2.4 for
metallic nickel. Further support for soluble nickel car-
cinogenesis was in the most recent case-control study
of nickel refi nery workers in Norway, in which lung
cancer risk adjusted for smoking, showed a substantial
association with cumulative exposure to water-soluble
nickel (Grimsrud
et al
., 2005). However, it still cannot
be determined in this study whether coexposure to
tobacco smoke or other refi nery exposures is a prereq-
uisite for the carcinogenic effect of water-soluble nickel.
Finally, it is likely that these workers had mixed expo-
sures to both soluble and insoluble nickel compounds,
making it diffi cult to tease out the form of nickel com-
pound that was causing the cancer. Future research on
mixtures of nickel plus other metals and on nickel plus
organic carcinogens will be informative.
9 EFFECTS ON GENE EXPRESSION
AND SIGNALING PATHWAYS
Nickel can activate several cellular stress response
signaling pathways involving MAPKs, PI3K, HIF-1,
NFAT, and NF-
B (reviewed in Harris and Shi, 2003;
Lu
et al
., 2005). Although a thorough review of nickel
and other metal induction of these signaling path-
ways can also be found in Chapter 5 of this Handbook
( Davidson
et al
., 2006), a few particularly salient mech-
anisms related to nickel will be briefl y summarized
here. Nickel is now well known for its capacity to sta-
bilize and activate the HIF-1
κ
protein and to up-regu-
late a battery of hypoxia-inducible genes. Although
some signaling pathways may involve nickel-induced
ROS, the formation of ROS is not thought to be
α
