Inhalation Exposure: Metallic Nickel

With respect to inhalation, the only significant health effects seen in workers occupationally exposed to metallic nickel occur in the respiratory system. The two potential effects of greatest concern with respect to metallic nickel exposures are non-malignant respiratory effects (including asthma and fibrosis) and respiratory cancer. Factors that can influence these effects include: the presence of particles on the bronchio-alveolar surface of lung tissue, mechanisms of lung clearance (dependent on solubility), mechanisms of cellular uptake (dependent on particle size, particle surface area, and particle charge) and, the release of Ni (II) ion to the target tissue (of importance to both carcinogenicity and Type I immune reactions leading to asthma).

In the case of respiratory cancer, studies of past exposures and cancer mortality reveal that respiratory tumors have not been consistently associated with all chemical species of nickel. Metallic nickel is one of the species for which this is true. Indeed, epidemiological data generally indicate that metallic nickel is not carcinogenic to humans. Over 40,000 workers from various nickel- using industry sectors (nickel alloy manufacturing, stainless steel manufacturing, and the manufacturing of barrier material for use in uranium enrichment) have been examined for evidence of carcinogenic risk due to exposure to metallic nickel and, in some instances, accompanying oxidic nickel compounds and nickel alloys (Cox et al.,1981; Polednak, 1981; Enterline and Marsh, 1982; Cragle et al., 1984; Arena et al., 1998; Moulin et al., 2000). No nickel-related excess respiratory cancer risks have been found in any of these workers.

Of particular importance are the studies of Cragle et al. (1984) and Arena et al. (1998). The former study of 813 barrier manufacturing workers is important because of what it reveals specifically about metallic nickel. There was no evidence of excess respiratory cancer risks in this group of workers exposed solely to metallic nickel. The latter study is important because of its size (>31,000 nickel alloy workers) and, hence, its power to detect increased respiratory cancer risks. Exposures in these workers were mainly to oxidic and metallic nickel. Only a very modest relative risk of lung cancer (RR, 1.13; 95% CI 1.05-1.21) was seen in these workers when compared to the overall U.S. population. Relative risk of lung cancer was even lower (RR, 1.02; 95% CI 0.96-1.10) in comparison to local populations, the risk being statistically insignificant. The lack of a significant excess risk of lung cancer relative to local populations, combined with a lack of an observed dose response with duration of employment regardless of the comparison population used, suggests that other non-occupational factors associated with geographic residence or cigarette smoking may explain the modest elevation of lung cancer risk observed in this cohort (Arena et al., 1998).

While occupational exposures to metallic nickel in the nickel-using industry have historically been low (<0.5 mg Ni/m3), certain subgroups of workers, such as those in powder metallurgy, have been exposed to higher concentrations of metallic nickel (around 1.5 mg Ni/m3) (Arena et al., 1998). Such subgroups, albeit small in size, have shown no nickel-related excess cancer risks.

In studies of nickel-producing workers (over 6,000 workers) where exposures to metallic nickel have, in certain instances, greatly exceeded those found in the nickel-using industry, evidence of a consistent association between metallic nickel and respiratory cancer is lacking. For one of these cohorts, the International Committee on Nickel Carcinogenesis in Man (ICNCM, 1990) did not find an association between excess mortality risk for respiratory cancers and metallic nickel workers, whereas another group of researchers (Easton et al., 1992) found a significant association using a multivariate regression model. However, the Easton et al. (1992) model substantially overpredicted cancer risks in long-term workers (>10 years) who were employed between the years 1930-1939. This led the researchers to conclude that they may have “overestimated the risks for metallic (and possibly soluble) nickel and underestimated those for sulfides and/or oxides” (Easton et al., 1992). A recent update of hydrometallurgical workers with relatively high metallic nickel exposures confirms the lack of excess respiratory cancer risk associated with exposures to elemental nickel during refining (Egedahl et al., 2001).

Animal data on carcinogenicity are largely in agreement with the human data. Early studies on the inhalation of metallic nickel powder, although somewhat limited with respect to experimental design, are essentially negative for carcinogenicity (Hueper, 1958; Hueper and Payne, 1962). While intratracheal instillation of nickel powder has been shown to produce tumors in the lungs or mediastinum of animals (Pott et al., 1987; Ivankovic et al., 1988), the relevance of such studies in the etiology of lung cancer in humans is questionable. This is because normal defense systems and clearance mechanisms operative via inhalation are by-passed in intratracheal studies. Moreover, high mortality in one of the studies (Ivankovic et al., 1988) suggests that toxicity could have confounded the carcinogenic finding in this study. Recently, Driscoll et al. (2000) have cautioned that, in the case of intratracheal instillation studies, care must be taken to avoid doses that are excessive and may result in immediate toxic effects to the lung due to a large bolus delivery.

To address the lack of proper inhalation studies with nickel metal powders and regulatory requests from the European Union and Germany, an inhalation carcinogenicity study was initiated by the Nickel Producers Environmental Research Association in 2004. This study was preceded by a 13-week inhalation study (Kirkpatrick, 2004) and a 4-week toxicity study (Kirkpatrick, 2002). The toxicity data from the 13-week study with nickel metal powder were used to select the exposure range in the carcinogenicity study.

The results of the definitive animal carcinogenicity study with inhalable nickel metal powder (~1.6 µMMAD) by inhalation in male and female Wistar rats was conducted using a 2-year regimen of exposure at 0, 0.1, 0.4, and 1 mg/m3. Toxicity and lethality required the termination of the 1 mg/m3. Nevertheless, the 0.4 mg/m3 group established the required Maximum Tolerated Dose (MTD) for inhalation of nickel metal powder and hence, was valid for the determination of carcinogenicity. This study did not show an association between nickel metal powder exposure and respiratory tumors.

These data, in concert with the most recent epidemiological findings and a separate negative oral carcinogenicity study of water soluble nickel salts, strongly indicates that nickel metal powder is not likely to be a human carcinogen by any relevant route of exposure.

With respect to non-malignant respiratory disease, various cases of asthma, fibrosis, and decrements in pulmonary function have been reported in workers with some metallic nickel exposures. In the case of asthma, exposure to fine dust containing nickel has only infrequently been reported in anecdotal publications as a possible cause of occupational asthma (Block and Yeung, 1982; Estlander et al., 1993; Shirakawa et al., 1990). Such dust exposures, however, have almost certainly included other confounding agents. Furthermore, no quantitative relationship has been readily established between the concentration of nickel cations in aqueous solution in bronchial challenge tests and equipotent metallic nickel in the occupational environment. In a U.S. study of welders (exposed to fumes containing some metallic nickel as well as complex spinels and other metals) at a nuclear facility in Oak Ridge, Tennessee, no increased mortality due to asthma was found among the workers studied (Polednak, 1981). Collectively, therefore, the overall data for metallic nickel being a respiratory sensitizer are not compelling, although a definitive study is lacking. In addition to the very small number of anecdotal case-reports regarding asthma, a few other respiratory effects due to metallic nickel exposures have also been reported. Data relating to respiratory effects associated with short-term exposure to metallic nickel are very limited. One report of a fatality involved a man spraying nickel using a thermal arc process (Rendall et al., 1994). This man was exposed to very fine particles or fumes, likely consisting of metallic nickel or oxidic nickel. He died 13 days after exposure, having developed pneumonia, with post mortem showing of shock lung. However, the relevance of this case to normal daily occupational exposures is questionable given the reported extremely high exposure (382 mg Ni/m3) to relatively fine nickel particles.

A few recent studies have investigated the effects of nickel exposure on pulmonary function and fibrosis. With respect to pulmonary function, the most relevant study to metallic nickel was that of Kilburn et al. (1990) who examined cross-shift and chronic pulmonary effects in a group of stainless steel welders (with some metallic nickel exposure). No differences in pulmonary function were observed in test subjects versus controls during cross-shift or short-term exposures. Although some reduced vital capacities were observed in long-term workers, the authors noted little evidence of chronic effects on pulmonary function caused by nickel. Conversely, in recent studies of stainless steel and mild steel welders, short-term, cross-shift effects were noted in stainless steel workers (reduced FEV1:FVC2 ratio), but no long-term effects in lung function were noted in workers with up to 20 years of welding activity (Sobaszek et al., 1998; 2000). A generalized decrease in lung function, however, was seen in workers with the longest histories (over 25 years) of stainless steel welding. This was attributed to the high concentrations of mixed pollutants (i.e., dust, metals, and gasses) to which these welders were exposed. A higher prevalence of bronchial irritative symptoms, such as cough, was also reported.

With respect to fibrosis, a recent study on nickel refinery workers in Norway has shown some evidence of an increased risk of X-ray abnormalities (ILO =1/0) (Berge and Skyberg, 2001). Associations of radiologically-defined fibrosis with soluble and sulfidic nickel (but, also, possibly metallic nickel) were observed. However, it(2) Forced Expiratory Volume (FEV1) is the amount of air that you can forcibly blow out in one second, measured in litres. Forced vital capacity (FVC) is the amount of air that can be maximally forced out of the lungs after a maximal inspiration. The FEV to FVC ratio reflects the severity of pulmonary impairment in obstruction (healthy adults should be between 75-89%). was noted that the associations were based on a small number of cases that were relatively mild in nature. Undetected confounders may have been present. Without further study of other nickel workers, the role of metallic nickel to induce pulmonary fibrosis remains unclear.

Animal studies on the non-carcinogenic respiratory effects of metallic nickel are few. The early studies by Heuper and Payne (1962) suggest that inflammatory changes in the lung can be observed in rats and hamsters administered nickel powder via inhalation. However, lack of details within the studies preclude drawing any conclusions with respect to the significance of the findings. More recent studies on the effects of ultrafine metallic nickel powder (mean diameter of 20 nm) administered intratracheally or via short-term inhalation in rats showed significant inflammation, cytotoxicity, and/or increased epithelial permeability of lung tissue (Zhang et al., 1998; Serita et al., 1999). While ultrafine metallic nickel powders are not widely produced or used at this time, their high level of surface energy, high magnetism, and low melting point are likely to make ultrafine metallic nickel powders desirable for future use in magnetic tape, conduction paste, chemical catalysts, electronic applications, and sintering promoters (Kyono et al., 1992). Hence, the results of the above studies bear further watching. It should be noted that occupational exposures to metallic nickel are usually to larger size particles (“inhalable” size aerosol fraction, =100 µm particle diameter). In certain specific operations involving the manufacturing and packaging of finely divided elemental nickel powders (“respirable” size particles, =10 µm particle diameter) or ultrafine powders (<1 µm particle diameter) exposures to finer particles may occur. In these operations, special precautions to reduce inhalation exposure to fine and ultrafine metallic nickel powders should be taken.

Collectively, the above findings present a mixed picture with respect to the potential risk of nonmalignant respiratory disease from metallic nick- el exposures. There is an extensive body of literature demonstrating that past exposures to metallic nickel have not resulted in excess mortality from such diseases (Cox et al., 1981; Polednak, 1981; Enterline and Marsh, 1982; Cragle et al., 1984; Egedhal et al., 1993; 2001; Arena et al., 1998; Moulin et al., 2000). However, additional studies on such effects, particularly with respect to ultrafine nickel powders, would be useful.