Carcinogenicity of Metal Compounds - Toxicology of Metals - page 175

smokers, with an interaction between two carcinogens,
as with asbestos and smoking (Kreyberg, 1978).
A long-term cohort study of 814 workers with
substantial exposure to airborne metallic nickel at a
gaseous diffusion plant showed no increase in mor-
tality from cancer of the respiratory tract (Godbold
and Tompkins, 1979). Similarly negative results were
obtained in a mortality study of 1925 men employed
for a minimum period of 5 years who were exposed
to average concentrations of metallic nickel of between
0.5 and 0.9 mg Ni/m 3 , half by weight being of respir-
able size (Cox et al. , 1981). From these studies, it seems
less likely that metallic nickel is a human carcinogen;
the active, carcinogenic agent must be a compound of
nickel, probably nickel subsulfi de.
An epidemiological report on cancer mortality in 10
cohorts of occupationally exposed workers aimed at
identifying the chemical forms of nickel responsible for
the elevated cancer risk. Mortality from lung and nasal
sinus cancer was associated with exposure to high
levels of oxidic nickel compounds, sulfi dic nickel in
combination with oxidic nickel, and exposure to water-
soluble nickel alone or together with less soluble nickel
compounds (Doll et al., 1990). In a case-control study
of Norwegian nickel-refi nery workers, Grimsrud et al.
(2002) examined dose-related association between lung
cancer and cumulative exposure to four forms of nickel:
water soluble, sulfi dic, oxidic, and metallic nickel. The
study positively correlated a dose-related association
between lung cancer and cumulative exposure to water-
soluble nickel compounds (Grimsrud et al. , 2002a).
The latent period from fi rst exposure to nickel com-
pounds to diagnosis of the cancer is long, averaging
approximately 25 years, with a range of 10-40 years.
In those cases for which information is available, epi-
thelial tumors predominated, but anaplastic and pleo-
morphic tumors have also been observed (Sunderman,
1973).
Signifi cant abnormalities have been found in nickel-
refi nery workers subjected to routine cytological screen-
ing. Nasal cancer and a high rate of epithelial dysplasia
compared with controls were found after biopsy of the
nasal mucosa. Sputum cytology has revealed epithe-
lial dysplasia, and in 16 of a group of the 583 refi nery
workers from a nickel-sinter plant, malignant cells
were found without clinical or radiological evidence of
cancer (McEwan, 1978). The routine use of such screen-
ing procedures should be considered when any risk of
nickel-induced cancer is believed to exist.

Sunderman (1973) and by the IARC (1976) (IARC,
1976; Sunderman, 1973). Carcinogenesis has been ade-
quately demonstrated in several animal species after
subcutaneous or intramuscular injection, but with the
exception of nickel subsulfi de, the results after inhala-
tional exposure have been less conclusive. Nickel sub-
sulfi de, Ni 3 S 2 , has given rise to fi brosarcomas and to
rhabdomyosarcomas in numerous experiments after
subcutaneous or intramuscular injection. Gilman (1966)
found a dose-response relationship with injections of
10 mg nickel subsulfi de giving an 80% tumor incidence
in Wistar rats (Gilman, 1966). Sunderman et al. (1975)
also found a dose-response relationship, with 7 of 30
rats developing sarcomas after a dose of 0.63 mg, ris-
ing to 28 of 30 rats developing sarcomas with a dose
of 2.5 mg nickel subsulfi de. Heath and Daniel (1964a)
injected powdered nickel suspended in fowl serum
into the thigh muscle in rats, all of which developed
rhabdomyosarcoma at the injection site within 17 to 41
weeks (Heath and Daniel, 1964a; 1964b). Tumors have
also been produced after the intrarenal and intrates-
ticular injection of nickel subsulfi de (Damjanov et al. ,
1978; Sunderman et al. , 1979).
Prolonged inhalation of nickel subsulfi de, of fi ne
particle size (70% smaller than 1

µ m diameter), at a

concentration of 1 g/m 3 , produced 14 malignant neo-

plasms of the lung in 226 exposed rats compared with
only 1 neoplasm in 241 control animals (Ottolenghi
et al. , 1975). Inhalation of nickel carbonyl resulted in
only two pulmonary adenocarcinomas in a series of
experiments on rats (Sunderman and Donnelly, 1965).
The repeated intravenous injection of nickel carbonyl
resulted in malignant tumors in 19 of 21 survivors, or
16% of the injected rats. In addition to the sarcomas,
one cholangiosarcoma, one carcinoma of the kid-
ney, one mammary carcinoma, and fi ve pulmonary
lymphomas were observed (Lau et al. , 1972).
Comparison of the relative poteny of the various
nickel compounds tested is diffi cult because of the
variation is experimental design is different studies(r)
Potenic seems to be inversel related to solubility of the
nickel compound is aqueoue media with the highly
soluble salts suce as nickel chloride having no appar-
ent carcinogeni activity(r). The carcinogenic activity
of nickel subsulfi de (

µ

~ Ni 2 S 3 ) is greater than that of
any other metallic compound so far investigated in
animal bioassay. The variety of animal species, routes
of administration, and high yield of tumors has made
nickel subsulfi de particularly useful for experimental
tumor induction. However, bacterial mutagenesis tests
for nickel compounds have been consistently negative.
Nickel subsulfi de and nickel sulfate induced dose-
related morphological transformation and enhanced
viral transformation in cultured hamster embryo cells

α

1.1.2 Animal Models

The experimental models that have been used to
study nickel carcinogenesis have been reviewed by