As in the case of metallic nickel, the two effects of greatest concern for the inhalation of soluble nickel compounds are non-malignant respiratory effects (e.g., fibrosis, asthma) and respiratory cancer. Unlike metallic nickel, however, which has shown little evidence of carcinogenicity, the carcinogenic assessment of soluble nickel compounds has been somewhat controversial, with no consensus in the scientific community regarding the appropriate classification of soluble nickel as a carcinogen (ICNCM, 1990; IARC, 1990; ACGIH, 1998; BK-Tox, 1999; Haber, 2000a and b). As a result, some groups view soluble nickel as a “known” carcinogen; others view the evidence for carcinogenicity data as “not classifiable” or “indeterminable.” It should be noted that under the Existing Substances regulations in Europe water-soluble nickel compounds have been classified as “known human carcinogens” but only by the inhalation route of exposure. The problem lies both in reconciling what appears to be inconsistent human data and in interpreting the human and animal data in an integrated manner that provides a cohesive picture of the carcinogenicity of soluble nickel compounds (Oller, 2002).
Human evidence for the carcinogenicity of soluble nickel compounds comes mainly from studies of nickel refinery workers in Wales, Norway, and Finland (Peto et al., 1984; ICNCM, 1990; Easton et al., 1992; Andersen et al., 1996; Anttila et al., 1998). In these studies, workers involved in electrolyses, electrowinning, and hydrometallurgy have shown excess risks of lung and/or nasal cancer. Exposures to soluble nickel have generally been believed to be high in most of these workers (in excess of 1 mg Ni/m3), although some studies have suggested that exposures slightly lower than 1 mg Ni/m3 may have contributed to some of the cancers observed (Anttila et al., 1998; Grimsrud, 2003). In all instances, soluble nickel exposures in these workers have been confounded by concomitant exposures to other nickel compounds (notably, oxidic and sulfidic nickel compounds), other chemical agents (e.g., soluble cobalt compounds, arsenic, acid mists) or cigarette smoking- all known or believed to be potential carcinogens in and of themselves (see Sections 5.4 and 5.5). Therefore, it is unclear whether soluble nickel, alone, caused the excess cancer risks seen in these workers.
In contrast to these workers, electrolysis workers in Canada and plating workers in the U.K. have shown no increased risks of lung cancer (Roberts et al., 1989; ICNCM, 1990; Pang, et al., 1996). In the case of the Canadian electrolyses workers, their soluble nickel exposures were similar to those of the electrolysis workers in Norway. Soluble nickel exposures in the plating workers, although unknown, are presumed to have been lower. On the whole, these workers were believed to lack, or have lower exposures to, some of the confounding agents present in the work environments of the workers mentioned above. While nasal cancers were seen in a few of the Canadian electrolysis workers, these particular workers had also worked in sintering departments where exposures to sulfidic and oxidic nickel were very high (>10 mg Ni/m3). It is likely that exposures to the latter forms of nickel (albeit some of them short) may have contributed to the nasal cancers observed (see Sections 5.4 and 5.5).
Besides the epidemiological studies, the animal data also needs to be considered. The most important inhalation animal studies conducted to date are those of the U.S. National Toxicology Program. In these studies, nickel subsulfide, nickel sulfate hexahydrate, and a high-temperature nickel oxide were administered to rats and mice in two-year carcinogenicity bioassays (NTP, 1996a, 1996b, 1996c). Results from the nickel sulfate hexahydrate study (1996b) are particularly pertinent to the assessment of the carcinogenicity of soluble nickel compounds. This 2-year chronic inhalation study failed to produce any carcinogenic effects in either rats or mice at exposures to nickel sulfate hexahydrate up to 0.11 mg Ni/m3 or 0.22 mg Ni/m3, respectively (NTP, 1996b). These concentrations correspond to approximately 2 or 6 mg Ni/m3 workplace aerosols after adjusting for particle size and animal to human extrapolation (Hsieh et al., 1999; Yu et al., 2001). It is also worth noting that soluble nickel compounds administered via other relevant routes of exposure (oral) have also failed to produce tumors (Schroeder et al., 1964, 1974; Schroeder and Mitchener, 1975; Ambrose et al., 1976).
In sum, the negative animal data combined with the conflicting human data make for an uncertain picture regarding the carcinogenicity of soluble nickel alone.
As recently noted by Oller (2002), without a unifying mechanism that can both account for the discrepancies seen in the human data and integrate the results from human and animal data into a single model for nickel respiratory carcinogenesis, assessments of soluble nickel will continue to vary widely. Such a mechanism has been proposed in models for nickel-mediated induction of respiratory tumors. These models suggest that the main determinant of the respiratory carcinogenicity of a nickel species is likely to be the bioavailability of the nickel (II) ion at nuclear sites of target epithelial cells (Costa, 1991; Oller et al., 1997; Haber et al., 2000a). Only those nickel compounds that result in sufficient amounts of bioavailable nickel (II) ions at such sites (after inhalation) will be respiratory carcinogens. Because soluble nickel compounds are not phagocytized and are rapidly cleared, substantial amounts of nickel (II) ions that would cause tumor induction simply are not present.
However, at workplace-equivalent levels above 0.1 mg Ni/m3, chronic respiratory toxicity was observed in animal studies. Respiratory toxicity due to soluble nickel exposures may have enhanced the induction of tumors by less soluble nickel compounds or other inhalation carcinogens seen in refinery workers. This may account for the observed respiratory cancers seen in the Norwegian, Finnish, and Welsh refinery workers who had concomitant exposures to smoking and other inhalation carcinogens. Indeed, in its multi-analysis of many of the nickel cohorts discussed above, the International Committee on Nickel Carcinogenesis in Man (ICNCM) postulated that the effects of soluble nickel may be to enhance the carcinogenic process, as opposed to inducing it (ICNCM, 1990). Alternatively, it should be considered that none of the workers in the sulfidic ores refinery studies had pure exposures to soluble nickel compounds that did not include sulfidic or complex nickel oxides, and most of them had exposures which were confounded by smoking, exposure to arsenic, or both. Animal inhalation studies have shown various non-malignant respiratory effects on the lung following relatively short periods of exposure to relatively high levels of soluble nickel compounds (Bingham et al., 1972; Murthy et al., 1983; Berghem et al., 1987; Benson et al., 1988; Dunnick et al., 1988,1989). Effects have included marked hyperplasia, inflammation and degeneration of bronchial epithelium, increased mucus secretion, and other indicators of toxic damage to lung tissue. In a recent study where nickel sulfate was administered via a single intratracheal instillation in rats, the nickel sulfate was shown to affect pulmonary antitumoral immune defenses transiently (Goutet et al., 2000). Chronic exposures to nickel sulfate hexahydrate result in cell toxicity and inflammation (NTP, 1996b). Moreover, a recent subchronic study demonstrated that nickel sulfate hexahydrate has a steep dose-response for toxicity and mortality (Benson et al., 2001). Hence, although exposure to soluble nickel compounds, alone, may not provide the conditions necessary to cause cancer (i.e., the nickel (II) ion is not delivered to the target tissue in sufficient quantities in vivo), due to their toxicity, soluble nickel compounds may enhance the carcinogenic effect of certain other nickel compounds or cancer causing agents by increasing cell proliferation. Cell proliferation, in turn, is required to convert DNA lesions into mutations and expand the mutated cell population, resulting in carcinogenesis.
With respect to non-malignant respiratory effects in humans, the evidence for soluble nickel salts being a causative factor for occupational asthma, while not overwhelming, is more suggestive than it is for other nickel species. Such evidence arises mainly from a small number of case reports in the electroplating industry and nickel catalyst manufacturing (McConnell et al., 1973; Malo et al., 1982, 1985; Novey et al., 1983; Davies, 1986; Bright et al., 1997).
Exposure to nickel sulfate can only be inferred in some of the cases where exposures have not been explicitly stated. Many of the plating solutions and, hence, aerosols to which some of the workers were exposed may have had a low pH. This latter factor may contribute to irritant effects which are not necessarily specific to nickel. In addition, potential for exposure to other sensitizing metals, notably chromium and cobalt, may have occurred. On the basis of the studies reported, the frequency of occupational asthma cannot be assessed, let alone the dose response determined. Despite these shortcomings, however, the role of soluble nickel as a possible cause of asthma should be considered.
Aside from asthma, the only other non-carcinogenic respiratory effect reported in nickel workers is that of fibrosis. Evidence that soluble nickel may act to induce pulmonary fibrosis comes from a recent study of nickel refinery workers that showed modest abnormalities in the chest X-rays of workers (Berge and Skyberg, 2001). An association between the presence of irregular opacities (ILO =1/0) in chest X-rays and cumulative exposures to soluble nickel, sulfidic nickel, and possibly metallic nickel, was reported. The significance of these results for the clinical diagnosis of fibrosis remains to be determined.