The evidence for the carcinogenicity of sulfidic compounds lies mainly in sinter workers from Canada. These workers were believed to have been exposed to some of the highest concentrations of nickel subsulfide (15-35 mg Ni/m3) found in the producing industry. They exhibited both excess lung and nasal cancers (Roberts et al., 1989a; ICNCM, 1990). Unfortunately, as noted in Section 5.4, these workers were also concomitantly exposed to high levels of oxidic nickel as well, making it difficult to distinguish between the effects caused by these two species of nickel.
Further evidence for the respiratory effects of sulfidic nickel can be gleaned from nickel refinery workers in Clydach, Wales. Specifically, workers involved in cleaning a nickel plant were exposed to some of the highest concentrations of sulfidic nickel at the refinery (18 mg Ni/m3) and demonstrated a high incidence of lung cancer after 15 years or more since their first exposure to cleaning. Analysis by cumulative exposure showed that Clydach workers with high cumulative exposures to sulfidic nickel and low level exposures to oxidic and soluble nickel exhibited higher lung cancer risks than workers who had low cumulative exposures to all three nickel species combined (ICNCM, 1990). Somewhat perplexing, however, was that the risk of developing lung or nasal cancer in this cohort was found primarily in those employed prior to 1930, although estimated levels of exposure to sulfidic nickel were not significantly reduced until 1937. This suggests that other factors (e.g., possible presence of arsenic in sulfuric acid that resulted in contaminated mattes) could have contributed to the cancer risk seen in these early workers (Duffus, 1996). In another cohort of refinery workers in Norway, increased cumulative exposures to sulfidic nickel did not appear to be related to lung cancer risk, although workers in this latter cohort were not believed to be exposed to concentrations of sulfidic nickel greater than about 2 mg Ni/m3 (ICNCM, 1990).
Because of the difficulty in separating the effects of sulfidic versus oxidic nickel in human studies, researchers have often turned to animal data for further guidance. Here, the data unequivocally point to nickel subsulfide as being carcinogenic. In the chronic inhalation bioassay conducted by the NTP (1996a), rats and mice were exposed for two years to nickel subsulfide at concentrations as low as 0.11 and 0.44 mg Ni/m3, respectively. These concentrations correspond to approximately 1.1-4.4 mg Ni/m3 workplace aerosol after accounting for particle size differences and animal-to-human extrapolation (Hsieh et al., 1999; Yu et al., 2001). After two years of expo- sure, there was clear evidence of carcinogenic activity in male and female rats, with a dose-dependent increase in lung tumor response. No evidence of carcinogenic activity was detected in male or female mice; no nasal tumors were detected in rats or mice, but various non-malignant lung effects were seen. This study was in agreement with an earlier inhalation study which also showed evidence of carcinogenic activity in rats administered nickel subsulfide (Ottolenghi et al., 1974). These studies, in conjunction with numerous other studies on nickel subsulfide (although, not all conducted by relevant routes of exposure) show nickel subsulfide to be a potent inducer of tumors in animals (NTP, 1996a).
With respect to non-carcinogenic respiratory effects, a number of animal studies have reported on the inflammatory effects of nickel subsulfide on the lung (Benson et al., 1986; Benson et al., 1987; Dunnick et al., 1988, 1989; Benson et al., 1989; NTP 1996a). These have been to both short- and long-term exposures and have included effects such as increased enzymes in lavage fluid, chronic active inflammation, focal alveolar epithelial hyperplasia, macrophage hyperplasia and fibrosis. For sulfidic nickel, the levels at which inflammatory effects in rats are seen are lower than for oxidic nickel, and similar to those required to see effects with nickel sulfate hexahydrate.
The evidence for non-malignant respiratory effects in workers exposed to sulfidic nickel has been mixed. Mortality due to non-malignant respiratory disease has not been observed in Canadian sinter workers (Roberts et al., 1989b). This is in agreement with the radiographic study by Muir et al. (1993) that showed that sinter plant workers exposed to very high levels of oxidic and sulfidic nickel compounds did not exhibit significant fibrotic responses in their lungs. In contrast (as noted in Section 5.4), excess risks of non-malignant respiratory disease did appear in refining workers in Wales with high nickel exposures to insoluble nickel (>10 mg Ni/m3). With the elimination of the very dusty conditions that likely brought about such effects, the risk of respiratory disease disappeared by the 1930s in this cohort (Peto et al., 1984). In a recent study of Norwegian nickel refinery workers, an increased risk of pulmonary fibrosis was found in workers with cumulative exposure to sulfidic and soluble nickel (Berge and Skyberg, 2001). Increased odds ratios were seen at lower cumulative exposures of sulfidic than of soluble nickel compounds.
The mechanism for the carcinogenicity of sulfidic nickel (as well as other nickel compounds) has been discussed by a number of researchers (Costa, 1991; Oller et al., 1997; Haber et al., 2000a). Relative to other nickel compounds, nickel subsulfide may be the most efficient at inducing the heritable changes needed for the cancer process. In vitro, sulfidic nickel compounds have shown a relatively high efficiency at inducing genotoxic effects such as chromosomal aberrations and cell transformation as well as epigenetic effects such as increases in DNA methylation (Costa et al., 2001). In vivo, nickel subsulfide is likely to be readily endocytized and dissolved by the target cells resulting in efficient delivery of nickel (II) to the target site within the cell nucleus (Costa and Mollenhauer, 1980a; Abbracchio et al., 1982). In addition, nickel subsulfide has relatively high solubility in biological fluids which could result in the release of the nickel (II) ion resulting in cell toxicity and inflammation. Chronic cell toxicity and inflammation may lead to a proliferation of target cells. Since nickel subsulfide is the nickel compound most likely to induce heritable changes in target cells, proliferation of cells that have been altered by nickel subsulfide may be the mechanism behind the observed carcinogenic effects (Oller et al., 1997).
Because of these effects, sulfidic nickel compounds appear to present the highest respiratory carcinogenic potential relative to other nickel compounds. The clear evidence of respiratory carcinogenicity in animals administered nickel subsulfide by inhalation, together with mechanistic considerations, indicate that the association of exposures to sulfidic nickel and lung and nasal cancer in humans is likely to be causal (Oller, 2001).