Of all the nickel species examined in this document, a causal relationship for respiratory cancer can best be established for nickel subsulfide. The human data suggest that respiratory cancers have been primarily associated with exposures to less soluble forms of nickel (including sulfidic nickel) at concentrations in excess of 10 mg Ni/m3. Animal data unequivocally point to nickel sub- sulfide as being carcinogenic.
Relative to other nickel compounds, nickel sub- sulfide may be the most efficient at inducing the heritable changes needed for the cancer process. In vivo, nickel subsulfide is likely to be readily phagocytized and dissolved by respiratory epithelial cells resulting in efficient delivery of nickel (II) to the target site within the cell nucleus. In addition, nickel subsulfide has relatively high solubility in biological fluids. This results in the release of nickel (II) ions, with subsequent induction of cell toxicity and inflammation. Chronic cell toxicity and inflammation may enhance tumor formation by nickel subsulfide or other carcinogens (as discussed for soluble nickel compounds).
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, but has in refining workers in Wales. With the elimination of the very dusty conditions that likely brought about such effects, the risk of respiratory disease disappeared in the Welsh workers by the 1930s. 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. The significance of these results for the clinical diagnosis of fibrosis remains to be determined.
No relevant studies of dermal exposure have been conducted on workers exposed to sulfidic nickel. Likewise, no animal studies have been undertaken.