5. TOXICITY OF NICKEL COMPOUNDS
The major routes of nickel exposure that have toxicological relevance to the workplace are inhalation and dermal exposures. Oral exposures can also occur (e.g., hand to mouth contact), but the institution of good industrial hygiene practices (e.g., washing hands before eating) can greatly help to minimize such exposures. Therefore, this chapter mainly focuses on the target systems affected by the former routes (i.e., the respiratory system and the skin). To the extent that other routes (such as oral exposures) may play a role in the overall toxicity of nickel and its compounds, these routes are also briefly mentioned. Focus is on the individual nickel species most relevant to the workplace, namely, metallic nickel and nickel alloys, oxidic, sulfidic and soluble nickel compounds, and nickel carbonyl.
5.1 METALLIC NICKEL
Occupational exposure to metallic nickel can occur through a variety of sources. Most notable of these sources are metallurgical operations, including stainless steel manufacturing, nickel alloy production, and related powder metallurgy operations. Other sources of potential occupational exposure to metallic nickel include nickel-cadmium battery manufacturing, chemical and catalyst production, plating, and miscellaneous applications such as coin production. In nearly all cases, metallic nickel exposures include concomitant exposures to other nickel compounds (most notably oxidic nickel, but other nickel compounds as well), and can be confounded with exposure to toxic non-nickel materials. Therefore, it is important to summarize those health effects which can most reasonably and reliably be considered relevant to metallic nickel in occupational settings, despite the fact that other nickel and non-nickel compounds may be present.
5.1.1 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, 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 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.
In summary, human and animal data by the most relevant route of occupational exposure (inhalation) suggest a lack of carcinogenicity for metallic nickel dust.
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 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 occasional 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 and FVC), 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 ³ 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 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 non-malignant respiratory disease from metallic nickel 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.
5.1.2 Dermal Exposure: Metallic Nickel
Dermal exposure to metallic nickel is possible wherever nickel powders are handled, such as powder metallurgy, and in the production of nickel-containing batteries, chemicals, and catalysts. Occasional contact with massive forms of metallic nickel could occur during nickel plating (anodes) and coin manufacturing (nickel alloys).
Skin sensitization to nickel metal can occur wherever there is sufficient leaching of nickel ions from articles containing nickel onto exposed skin (Hemingway and Molokhita, 1987; Emmet et al., 1988). However, cutaneous allergy (allergic contact dermatitis) to nickel occurs mainly as the result of non-occupational exposures. Indeed, in recent years, the evidence for occupationally-induced dermal nickel allergy is sparse (Mathur, 1984; Schubert et al., 1987; Fischer, 1989).
Sensitization and subsequent allergic reactions to nickel require direct and prolonged contact with nickel-containing solutions or nickel-releasing items that are non-resistant to sweat corrosion (see further discussion under Sections 5.2 and 5.4). The nickel ion must be released from a nickel-containing article in intimate contact with skin to elicit a response. Evidence suggests that humid environments are more likely to favor the release of the nickel ion from metallic nickel and nickel alloys, whereas dry, clean operations with moderate or even intense contact to nickel objects will seldom, alone, provoke dermatitis (Fischer, 1989). In some occupations for which nickel dermatitis has been reported in higher proportion than the general populace (e.g., cleaning, hairdressing and hospital wet work), the wet work is, in and of itself, irritating and decreases the barrier function of the skin. Often it is the combination of irritant dermatitis and compromised skin barrier that produces the allergic reaction (Fischer, 1989). The role of nickel in the manifestation of irritant dermatitis in metal manufacturing, cement and construction industries, and coin handling has been debated. It has been suggested by some researchers that nickel probably does not elicit dermatitis in workers from such industries unless the worker is already strongly allergic to nickel (Fischer, 1989). There are some reports that oral ingestion of high nickel levels (above 1.25 mg/day) can trigger a dermatitis response in susceptible nickel-sensitized individuals (see section 5.3.3).
5.2 NICKEL ALLOYS
Often there is a misconception that exposure to nickel-containing alloys is synonymous with exposure to metallic nickel. This is not true. Each type of nickel-containing alloy is a unique substance with its own special physico-chemical and biological properties that differ from those of its individual metal constituents. The potential toxicity of a nickel alloy (including carcinogenic effects) must, therefore, be evaluated separately from the potential toxicity of nickel metal itself and other nickel-containing alloys. While there are hundreds of different nickel-containing alloys in different product categories, the major product categories are stainless steel (containing Fe, Cr and up to 34% Ni) and high nickel content alloys. Occupational exposures to these and other forms of nickel alloys (e.g., superalloys, cast-irons) can occur wherever alloys are produced (metallurgical operations) or in the processing of alloys (such as welding, grinding, cutting, polishing, and forming). Like metallic nickel, occupational exposures to nickel-containing alloys will mainly be via the skin or through inhalation. However, in the case of certain nickel alloys that are used in prosthetic devices, localized exposures can occur. Because such exposures are not of specific concern to occupational settings, they are not discussed in this Guide. However, a comprehensive review of information pertaining to prosthetic devises can be found in McGregor et al. (2000).
5.2.1 Inhalation Exposure: Nickel Alloys
There are no studies of nickel workers exposed solely to nickel alloys in the absence of metallic or oxidic nickel. Clearly, however, workers in alloy and stainless steel manufacturing and processing will likely have some low level exposure to nickel alloys. In general, most studies on stainless steel and nickel alloy workers have shown no significant occupationally-related excess risks of respiratory cancer (Cox et al., 1981; Polednak, 1981; Cornell, 1984; Svensson et al., 1989; Moulin et al., 1993, 2000; Hansen et al., 1996; Jakobsson et al., 1997; Arena et al., 1998). There have been some exceptions, however, in certain groups of stainless steel welders (Gerin et al., 1984; Kjuus et al., 1986) where excess lung tumors were detected. Further analyses of these and other stainless steel workers as part of a large international study on welders (> 11,000 workers) failed to show any association between increased lung cancer mortality and cumulative exposure to nickel (Siminato et al., 1991). A later analysis of this same cohort (Gerin et al., 1993) showed no trend for lung cancer risk for three categories of nickel exposure. Likewise, no nickel-related tumors were observed in a group of German arc welders exposed to fumes containing chromium and nickel (Becker, 1999). As noted above and in the discussion on metallic nickel, some of these studies involved thousands of workers (Arena et al., 1998; Siminato et al., 1991). Hence, these studies suggest an absence of nickel-related excess cancer risks in workers exposed to nickel-containing alloys.
Limited data are available to evaluate respiratory carcinogenicity of nickel alloys in animals. One intratracheal instillation study looked at two types of stainless steel grinding dust. An austenitic stainless steel (6.8% nickel) and a chromium ferritic steel (0.5% nickel) were negative in hamsters after repeated instillations (Muhle et al., 1992). In another study, grinding dust from an austenitic stainless steel (26.8% nickel) instilled in hamsters was also negative (Ivankovic et al., 1988). In this same study, an alloy containing 66.5% nickel, 12.8% chromium, and 6.5% iron showed some evidence of carcinogenic potential at the higher doses tested. A significant shortening in survival time in one of the high dose groups compared to untreated controls, however, raises the question of toxicity and its possible confounding effect on tumor formation. As noted in the discussion of metallic nickel, intratracheal instillation studies must be carefully interpreted in light of their artificial delivery of unusually large and potentially toxic doses of chemical agents to the lung (Driscoll et al., 2000).
In total, there is little evidence to suggest that nickel alloys act as respiratory carcinogens. For many alloys, this may be due to their corrosion resistance which results in reduced release of metal ions to target tissues.
With respect to non-carcinogenic respiratory effects, no animal data are available for determining such effects, and the human studies that have looked at such endpoints have generally shown no increased mortality due to non-malignant respiratory disease (Polednak, 1981; Cox et al., 1981; Simonato et al., 1991; Moulin et al., 1993, 2000; Arena et al., 1998).
5.2.2 Dermal Exposure: Nickel Alloys
Because alloys are specifically formulated to meet the need for manufactured products that are durable and corrosion resistant, an important property of all alloys and metals is that they are insoluble in aqueous solutions. They can, however, react (corrode) in the presence of other media, such as air or biological fluids, to form new metal-containing species that may or may not be water soluble. The extent to which alloys react is governed by their corrosion resistance in a particular medium and this resistance is dependent on the nature of the metals, the proportion of the metals present in the alloy, and the process by which the alloy was made.
Of particular importance to dermal exposures are the potential of individual alloys to corrode in sweat. As noted under the discussion of metallic nickel, sensitization and subsequent allergic reactions to nickel require direct and prolonged contact with nickel-containing solutions or materials that are non-resistant to sweat corrosion. It is the release of the nickel (II) ion, not the nickel content of an alloy, that will determine whether a response is elicited. Occupational dermal exposures to nickel alloys are possible wherever nickel alloy powders are handled, such as in powder metallurgy or catalyst production. While exposures to massive forms of nickel alloys are also possible in occupational settings, these exposures do not tend to be prolonged, and, hence, are not of greatest concern with respect to contact dermatitis. Dermal contact with nickel-copper alloys in coinage production can also occur. The potential for nickel alloys to elicit an allergic reaction in occupational settings, therefore, will depend on both the sweat resistant properties of the alloy and the amount of time that a worker is in direct and prolonged contact with an alloy.
The European Union has adopted a Directive (94/27/EC) that is designed to protect most consumers against the development of dermal nickel sensitization through direct and prolonged contact with nickel-containing articles (EC, 1999). With the exception of ear-piercing materials, which are limited to <0.05% nickel content, other nickel-containing articles are regulated based upon the amount of nickel released into "artificial sweat." Only metals and alloys that release less than 0.5 micrograms of nickel per square centimeter per week are allowed to be used in such articles. While determination of individual nickel alloys to meet this standard requires testing on a case-by-case basis, it is worth noting that recent studies of nickel release from stainless steels (AISI 303, 304, 304L, 316, 316L, 310S, 430) in artificial sweat medium have shown that the only grade of stainless steel for which the nickel release rates were close to or exceeded the 0.5 µg/cm2/week limit is type 303 (a special stainless steel type with elevated sulfur content to aid machinability). All other grades of stainless steel demonstrated negligible nickel release, in all cases less than 0.3 µg Ni/cm2/week (Haudrechy et al., 1994). Although the EU Nickel Directive aims at preventing dermatitis in most nickel sensitized patients, there are some extremely sensitive subjects that have shown positive patch test results with nickel alloys (non-stainless steels) that release 0.5 µg Ni/cm2/week or less (Gawkrodger, 1996). With these few exceptions, the use of 0.5 µg Ni/cm2/week seems to be protective for the majority of nickel-allergic patients.
While the EU Nickel Directive is geared toward protecting the general public from exposures to nickel contained in consumer items, it may also provide some guidance in occupational settings where exposures to nickel alloys are direct and prolonged. It should be noted, however, that alloys that release greater than 0.5 ug/cm2/week of nickel may not be harmful in an occupational or commercial setting. They may be used safely when not in direct and prolonged contact with the skin or where ample protective clothing is provided. A recent comprehensive review of the health effects associated with the manufacture, processing, and use of stainless steel can be found in Cross et al. (1999).
5.3 SOLUBLE NICKEL
Exposure to readily water soluble nickel salts occurs mainly during the electrolytic refining of nickel (producing industries) and in electroplating (using industries). Depending upon the processes used, exposures are usually to hydrated nickel (II) sulfate or nickel chloride in solution. Like the previously mentioned nickel species, the routes of exposure of toxicological relevance to the workplace are inhalation and dermal exposures. However, unlike other nickel species, soluble nickel occurs in food and water; thus, oral exposures are briefly mentioned below.
5.3.1 Inhalation Exposure: Soluble Nickel
Like 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." 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, 2001). 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, or whether it acted in conjunction with other carcinogenic agents to enhance the risks of respiratory cancer.
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., 1989a; 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).
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 transiently affect pulmonary antitumoral immune defenses (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.
5.3.2 Dermal Exposure: Soluble Nickel
Historically, risks for allergic contact nickel dermatitis have been elevated in workplaces where exposures to soluble nickel have been high. For example, nickel dermatitis was common in the past among nickel platers. However, due to improved industrial and personal hygiene practices, more recent reports of nickel sensitivity in workplaces such as the electroplating industry have been sparse (Mathur, 1984; Fischer, 1989). Schubert et al., (1987) found only two nickel sensitive platers among 176 nickel sensitive individuals studied. A number of studies have shown nickel sulfate to be a skin sensitizer in animals, particularly in guinea pigs (Lammintausta et al., 1985; Zissu et al., 1987; Rohold et al., 1991; Nielsen et al., 1992). Dermal studies in animals suggest that sensitization to soluble nickel (nickel sulfate) may result in cross sensitization to cobalt (Cavelier et al., 1989) and that oral supplementation with zinc may lessen the sensitivity reaction of NiSO4-induced allergic dermatitis (Warner et al., 1988). Five percent nickel sulfate in petrolatum is typically used in patch tests as the threshold for elicitation of a positive skin reaction, although individual thresholds may vary (Uter et al., 1995). Soluble nickel compounds should be considered skin sensitizers in humans and care should be taken to avoid prolonged contact with nickel solutions in the workplace.
5.3.3 Other Exposures: Soluble Nickel
Unlike other species of nickel, oral exposure to soluble nickel occurs from drinking water and food. Data from both human and animal studies show that absorption of nickel from food and water is generally low (1-30%), depending on the fasting state of the subject, with most of the nickel excreted in feces (Diamond et al., 1998). In humans, effects of greatest concern for ingested nickel are those produced in the kidney, possible reproductive effects, and the potential for soluble nickel to exacerbate nickel dermatitis following oral provocation.
Several researchers have examined the evidence of nephrotoxicity related to long-term exposures of soluble nickel in electroplating, electrorefining and chemical workers (Wall and Calnan, 1980; Sunderman and Horak, 1981; Sanford and Nieboer, 1992; Vyskocil et al., 1994). These workers not only would have been exposed to soluble nickel in their food and water, but also in the workplace air which they breathed. Wall and Calnan (1980) found no evidence of renal dysfunction among 17 workers in an electroplating plant. Likewise, Sanford and Nieboer (1992), in a study of 26 workers in electrolytic refining plants, concluded that nickel, at best, might be classified as a mild nephrotoxin. In the Sunderman and Horak study (1981) and the Vyskocil et al., study (1994), elevated markers of renal toxicity (e.g., ß2 microglobulin) were observed, but only spot urinary nickel samples were taken. The chronic significance of these effects is uncertain. In addition, nickel exposures were quite high in these workers (up to 13 mg Ni/m3 in one instance), and certainly not typical of most current occupational exposures to soluble nickel. Severe proteinuria and other markers of significant renal disease that have been associated with other nephrotoxicants (e.g., cadmium) have not been reported in nickel workers, despite years of biological monitoring and observation (Nieboer et al., 1984).
In regard to reproductive effects, there is some evidence in humans to indicate that absorbed nickel may be able to move across the placenta into fetal tissue (Creason et al., 1976; Casey and Robinson, 1978; Chen and Lin, 1998; Haber et al., 2000b). Because of this, the preliminary results from a study of Russian nickel refinery workers that showed evidence of spontaneous abortions, stillbirths, and structural malformations in babies born to female workers at this refinery deserve careful attention (Chashschin et al., 1994). Concerns about the reliability of this study have been expressed and include lack of information on confounders that may have contributed to the effects observed and lack of proper controls. Therefore, a more thorough and well-conducted epidemiology study is currently being undertaken on this group of workers to determine whether the effects observed in this cohort are really due to their workplace nickel exposures or to other confounders in the workplace and/or ambient environment.
With respect to animal studies, a variety of developmental, reproductive, and teratogenic effects have been reported in animals exposed mainly to soluble nickel via oral and parenteral administration (Haber et al., 2000b). However, factors such as high doses, relevance of routes of exposure, avoidance of food and water, lack of statistical significance, and parental mortality have confounded the interpretation of many of the results (Nieboer, 1997; Haber et al., 2000b). In the most recent and reliable reproductive study conducted to date, rats were exposed to various concentrations of nickel sulfate hexahydrate by gavage. In the 1-generation range finding study, evaluation of post-implantation/perinatal lethality among the offspring of the treated parental rats (i.e., number of pups conceived minus the number of live pups at birth) showed statistically significant increases at the 6.6 mg Ni/kg/day exposure level and questionable increases at the 2.2 and 4.4 mg Ni/kg/day levels. The definitive 2-generation study demonstrated that these effects were not evident at concentrations up to 2.2 mg Ni/kg/day soluble nickel. No nickel effects on fertility, sperm quality, estrous cycle and sexual maturation were found in these studies (NiPERA, 2000).
With respect to oral provocations of nickel dermatitis, it should be noted that nickel dermatitis via oral exposures only occurs in individuals already sensitized to nickel via dermal contact. The literature is conflicting with respect to the nickel concentration required to elicit a flare. However, collectively, studies suggest that only a minor number of nickel sensitive patients react to oral doses below 1.25 mg of nickel (about 0.02 mg Ni/kg) (Menné and Maibach, 1987; Haber et al., 2000b). These doses are in addition to normal dietary nickel intake (about 170 µg Ni/day).
Conversely, oral exposure to nickel in non-nickel-sensitized individuals has been shown to provide tolerance to future dermal nickel sensitization. Observations first made in animal experiments (Vreeburg et al., 1984) and correlations obtained from studies of human cohorts (van der Burg et al., 1986) led to the hypothesis that nickel hypersensitivity reactions may be prevented by prior oral exposure to nickel if long-term, low-level antigenic contact occurs in the non-sensitized organism. Studies that followed van der Burg's initial observation of induced nickel tolerance in humans have repeatedly confirmed the occurrence of this phenomenon both in humans (Kerosuo et al., 1996; Todd and Burrows, 1989; van Hoogstraten et al, 1991a; van Hoogstraten et al., 1989; van Hoogstraten et al., 1991b) and animals (van Hoogstraten et al., 1992; van Hoogstraten et al., 1993). Suppression of dermal nickel allergic reactions can also be achieved in sensitized individuals (Sjövall et al., 1987).
5.4 OXIDIC NICKEL
The term "oxidic nickel" includes nickel (II) oxides, nickel (III) oxides, possibly nickel (IV) oxides and other non-stochiometric entities, complex nickel oxides (including spinels in which other metals such as copper, chromium, or iron are present), silicate oxides (garnierite), hydrated oxides, hydroxides, and, possibly, carbonates or basic carbonates which are subject to various degrees of hydration. Therefore, for the purposes of this document they will be considered together.
Oxidic nickel is used in many industrial applications and will be present in virtually every major nickel industry sector (NiPERA, 1996). Nickel oxide sinter is often the end product in the roasting of nickel sulfide concentrates. It is used as charge to produce wrought stainless steel and other alloy materials. It is also used in cast stainless steel and nickel-based alloys. Commercially available nickel oxide powders are used in the electroplating industry, for catalysis preparation, and for other chemical applications. Black nickel oxide and hydroxide are used in the production of electrodes for nickel-cadmium batteries utilized in domestic markets and also in large power units. Complex nickel oxides are used in oil refining and ceramic magnets (Thornhill, 2000; Van Vlack, 1980).
Like the previously discussed nickel species, inhalation of oxidic nickel compounds is the route of exposure of greatest concern in occupational settings. Unlike the former species of nickel, however, dermal exposures to oxidic nickel are believed to be of little consequence to nickel workers. While no data are directly available on the effects of oxidic nickel compounds on skin, due to their low water solubility, very low absorption of nickel through the skin is expected.
5.4.1 Inhalation Exposure: Oxidic Nickel
The critical health effect of interest in relation to occupational exposure to oxidic nickel is, again, respiratory cancer. Unlike metallic nickel, which does not appear to be carcinogenic, and soluble nickel, whose carcinogenic potential is likely to be promotional in nature, the evidence for the carcinogenicity of certain oxidic nickel compounds is more compelling. That said, there is still some uncertainty regarding the forms of oxidic nickel that induce tumorigenic effects. Although oxidic nickel is present in most major industry sectors, it is of interest to note that epidemiological studies have not consistently implicated all sectors as being associated with respiratory cancer. Indeed, excess respiratory cancers have been observed only in refining operations in which nickel oxides were produced during the refining of sulfidic ores and where exposures to oxidic nickel were relatively high (> 5 mg Ni/m3) (ICNCM, 1990; Grimsrud et al., 2000). At various stages in this process, nickel-copper oxides may have been formed. In contrast, no excess respiratory cancer risks have been observed in workers exposed to lower levels (< 2 Ni/m3) of oxidic nickel free of copper during the refining of lateritic ores or in the nickel-using industry.
Specific operations where oxidic nickel was present and showed evidence of excess respiratory cancer risk include refineries in Kristiansand, Norway, Clydach, Wales, and Copper Cliff and Port Colborne, Ontario, Canada. In all instances, workers were exposed to various combinations of sulfidic, oxidic, and soluble nickel compounds. Nevertheless, conclusions regarding the carcinogenic potential of oxidic nickel compounds have been gleaned by examining those workers predominantly exposed to oxidic nickel.
In the case of Kristiansand, this has been done by examining workers in the roasting, smelting and calcining department (ICNCM, 1990) and by examining all workers by cumulative exposure to oxidic nickel (ICNCM, 1990; Andersen et al., 1996). In the overall cohort, there was evidence to suggest that long-term exposure (>15 years) to oxidic nickel (mainly nickel-copper oxides at concentrations of 5 mg Ni/m3 or higher) was related to an excess of lung cancer. There was also some evidence that exposure to soluble nickel played a role in increasing cancer risks in these workers (see Section 5.3). The effect of cigarette smoking has also been examined in these workers (Andersen et al., 1996; Grimsrud, 2001), with the former study showing a multiplicative effect (i.e., interaction) between cigarette smoking and exposure to nickel. Evidence of excess nasal cancers in this group of workers has been confined to those employed prior to 1955. This evidence suggests that oxidic nickel has been a stronger hazard for nasal cancer than soluble nickel, as 12 cases (0.27 expected) out of 32 occurred among workers exposed mostly to nickel oxides.
In the Welsh and Canadian refineries, workers exposed to some of the highest levels (10 mg Ni/m3 or higher) of oxidic nickel included those working in the linear calciners and copper and nickel plants (Wales) and those involved in sintering operations in Canada. In Wales, oxidic nickel exposures were mainly to nickel-copper oxides or impure nickel oxide; in Canada, exposures were mainly to high-temperature nickel oxide with lesser exposure to nickel-copper oxides. Unfortunately, in the latter case, oxidic exposures were completely confounded by sulfidic nickel exposures, making it difficult to distinguish between the effects caused by these two species of nickel. Both excess lung and nasal cancer risks were seen in the Welsh and Canadian workers (Peto et al., 1984; Roberts et al., 1989a; ICNCM, 1990).
In contrast to the above refinery studies, studies of workers mining and smelting lateritic ores (where oxidic nickel exposures would have been primarily to silicate oxides and complex nickel oxides free of copper) have shown no evidence of nickel-related respiratory cancer risks. Studies by Goldberg et al. (1987; 1992) of smelter workers in New Caledonia showed no evidence of increased risk of lung or nasal cancer at estimated exposures of 2 mg Ni/m3 or less. Likewise, in another study of smelter workers in Oregon there was no evidence of excess nasal cancers (Cooper and Wong, 1981; ICNCM, 1990). While there were excess lung cancers, these occurred only in short-term workers, not long-term workers. Hence, there was no evidence to suggest that the lung cancers observed were related to the low concentrations (< 1 mg Ni/m3) of oxidic nickel to which the men were exposed (ICNCM, 1990).
In nickel-using industries, the evidence for respiratory cancers has also largely been negative. As noted in previous sections (Sections 5.1 and 5.2), most studies on stainless steel and nickel alloy workers that would have experienced some level of exposure to oxidic nickel have shown no significant nickel-related excess risks of respiratory cancer (Polednak, 1981; Cox et al., 1981; Cornell, 1984; Moulin et al., 1993, 2000; Svensson et al., 1989; Simonato et al., 1991; Gerin et al., 1993; Hansen et al., 1996; Jakobsson et al., 1997; Arena et al., 1998). In Swedish nickel-cadmium battery workers, there is some evidence of an increased incidence of nasal cancers, but it is not clear whether this is due to exposure to nickel hydroxide, cadmium oxide, or a combination of both (Jarup et al, 1998). In addition, little is known about the previous employment history of these workers. It is, therefore, not clear whether past exposures to other potential nasal carcinogens may have contributed to the nasal cancers observed in these workers. In contrast, no nickel-related increased risk for lung cancer has been found in these or other nickel-cadmium battery workers (Kjellström et al, 1979; Sorahan and Waterhouse, 1983; Andersson et al., 1984; Sorahan, 1987; Jarup et al., 1998).
From the overall epidemiological evidence, it is possible to speculate that the composition of oxidic nickel associated with an increase of lung or nasal cancer may primarily be nickel-copper oxides produced during the roasting and electrorefining of sulfidic nickel-copper mattes. However, careful scrutiny of the human data also reveals that high respiratory cancer risks occurred in sintering operations-where exposures to nickel-copper oxides would have been relatively low-and, possibly, in nickel-cadmium battery workers, where oxidic exposures would predominantly have been to nickel hydroxide. In addition to the type of oxidic nickel, the level to which nickel workers were exposed must also be taken into consideration. Concentrations of oxidic nickel in the high-risk cohorts (those in Wales, Norway, and Port Colborne and Copper Cliff, Canada) were considerably higher than those found in New Caledonia, Oregon, and most nickel-using industries. In the case of the nickel-cadmium battery workers, the early exposures that would have been critical to the induction of nasal cancers of long latency were believed to have been relatively high (> 2 mg Ni/m3). Hence, it may be that there are two variables-the physicochemical nature of the oxide and the exposure level-that contribute to the differences seen among the various cohorts studied.
Animal data shed some light on the matter. In the previously mentioned NTP studies, nickel oxide was administered to rats and mice in a two-year carcinogenicity bioassay (NTP, 1996c). The nickel oxide used was a green, high-temperature nickel oxide calcined at 1,350°C; it was administered to both rats and mice for 6 hours/day, 5 days/week for 2 years. Rats were exposed to concentrations of 0, 0.5, 1.0, or 2.0 mg Ni/m3. These concentrations are equivalent to over 5.0 to 20 mg Ni/m3 workplace aerosol after adjusting for particle size differences and animal to human extrapolation (Hsieh et al., 1999; Yu et al., 2001). After two years, no increased incidence of tumors was observed at the lowest exposure level in rats. At the intermediate and high concentrations, 12 out of 106 rats and 9 out of 106 rats, respectively, presented with either adenomas or carcinomas. On the basis of these results, the NTP concluded that there was some evidence of carcinogenic activity in rats. In contrast, there was no evidence of treatment-related tumors in male mice at any of the doses administered (1.0, 2.0 and 4.0 mg Ni/m3) and only equivocal evidence in female mice exposed to 1.0 but not 2.0 or 4.0 mg Ni/m3.
Carcinogenic evidence for other oxidic nickel compounds comes from animal studies using routes of exposure that are not necessarily relevant to man (i.e. intratracheal instillation, injection). In these studies, nickel-copper oxides appear to be as potent as nickel subsulfide in inducing tumors at injection sites (Sunderman et al., 1990). There is, however, no strong evidence to indicate that black (low temperature) and green (high temperature) nickel oxides differ substantially with regard to tumor-producing potency. Some forms of both green and black nickel oxide produce carcinogenic responses, while other forms have tested negative in injection and intratracheal studies (Kasprzak et al., 1983; Sunderman, 1984; Sunderman et al., 1984; Berry et al., 1985; Pott et al., 1987, 1992; Judde et al., 1987; Sunderman et al., 1990).
On the whole, comparisons between human and animal data suggest that certain oxidic nickel compounds at high concentrations may increase respiratory cancer risks and that these risks are not necessarily confined to nickel-copper oxides. However, there is no single unifying physical characteristic that differentiates oxidic nickel compounds with respect to biological reactivity or carcinogenic potential. Some general physical characteristics which may be related to carcinogenicity include: particle size < 5 µm, a relatively large particle surface area, presence of metallic or other impurities and/or amount of Ni (III). Phagocytosis appears to be a necessary, but not sufficient condition for carcinogenesis. Solubility in biological fluids will also affect how much nickel ion is delivered to target sites (i.e., cell nucleus) (Oller et al., 1997). The ability of particles to generate oxygen radicals may also contribute to their carcinogenic potential (Kawanishi et al., 2001).
With respect to non-malignant respiratory effects, oxidic nickel compounds do not appear to be respiratory sensitizers. Based upon numerous epidemiological studies of nickel-producing workers, nickel alloy workers, and stainless steel workers, there is little indication that exposure to oxidic nickel results in excess mortality from chronic respiratory disease (Polednak, 1981; Cox et al., 1981; Enterline and Marsh, 1982; Roberts et al., 1989b; Simonato et al., 1991; Moulin et al., 1993, 2000; Arena et al., 1998). In the few instances where excess risks of non-malignant respiratory disease did appear-for example, in refining workers in Wales-the excesses were seen only in workers with high nickel exposures (> 10 mg Ni/m3), in areas that were reported to be very dusty. With the elimination of these dusty conditions, the risk that existed in these areas seems largely to have disappeared by the 1930s (Peto et al., 1984).
In a study using radiographs of nickel sinter plant workers exposed to very high levels of oxidic and sulfidic nickel compounds (up to 100 mg Ni/m3), no evidence that oxidic or sulfidic nickel dusts caused a significant fibrotic response in workers was reported (Muir et al., 1993). 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, but not oxidic nickel (Berge and Skyberg, 2001). The previously mentioned Kilburn et al. (1990) and Sobaszek et al. (2000) studies (see Section 5.1.1) showed mixed evidence of chronic effects on pulmonary function in stainless steel welders. Broder et al. (1989) showed no differences in pulmonary function of nickel smelter workers versus controls in workers examined for short periods of time (1 week); however, there were some indicators of a healthy worker effect in this cohort which may have resulted in the negative findings. Anosmia (loss of smell) has been reported in nickel-cadmium battery workers, but most researchers attribute this to cadmium toxicity (Sunderman, 2001).
Animal studies have shown various effects on the lung following relatively short periods of exposure to high levels of nickel oxide aerosols (Bingham et al., 1972; Murthy et al., 1983; Dunnick et al., 1988; Benson et al., 1989; Dunnick et al., 1989). Effects have included increases in lung weights, increases in alveolar macrophages, fibrosis, and enzymatic changes in alveolar macrophages and lavage fluid. Studies of repeated inhalation exposures to nickel oxide (ranging from two to six months) have shown that exposure to nickel oxide may impair particle lung clearance (Benson et al., 1995; Oberdörster et al., 1995). Chronic exposures to a high-temperature nickel oxide resulted in statistically significant inflammatory changes in lungs of rats and mice at 0.5 mg Ni/m3 and 1.0 mg Ni/m3, respectively (NTP, 1996c). These values correspond to workplace exposures above 5-10 mg Ni/m3. At present, the significance of impaired clearance seen in nickel oxide-exposed rats and its relationship to carcinogenicity is unclear (Oller et al., 1997).
5.5 SULFIDIC NICKEL
Data relevant to characterizing the adverse health effects of nickel "sulfides" in humans arises almost exclusively from processes in the refining of nickel. Exposures in the refining sector should not be confused with those in mining, where the predominant mineral from sulfidic ores is pentlandite [(Ni, Fe)9S8]. Pentlandite is very different from the nickel subsulfides and sulfides found in refining. Although a modest lung cancer excess has been found in some miners (ICNCM, 1990), this excess has been consistent with that observed for other hard-rock miners of non-nickel ores (Muller et al., 1983). This, coupled with the fact that millers have not presented with statistically significant excess respiratory cancer risks, suggests that the lung cancer seen in miners is not nickel-related (ICNCM, 1990). Further, pentlandite has not been shown to be carcinogenic in rodents intratracheally instilled with the mineral over their lifetimes (Muhle et al., 1992). Therefore, for purposes of this document, it should be understood that any critical health effects discussed relative to "sulfidic nickel" pertains mainly to nickel sulfides (NiS) and subsulfide (Ni3S2).
Like oxidic nickel, inhalation of sulfidic nickel compounds is the route of exposure of greatest concern in occupational settings. No relevant studies of dermal exposure have been conducted on workers exposed to sulfidic nickel. Because exposures to sulfidic and oxidic nickel compounds have often overlapped in refinery studies, it has sometimes been difficult to separate the effects of these two nickel species from each other. Overwhelming evidence of carcinogenicity from animal studies, however, has resulted in the consistent classification of sulfidic nickel as a "known carcinogen" by many scientific bodies (IARC, 1990; ACGIH, 1998; NTP, 1998). This evidence is discussed below.
5.5.1 Inhalation Exposure: Sulfidic Nickel
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.
F
urther 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 suggested 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 exposure, 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).
5.6 NICKEL CARBONYL
Unlike other nickel species, nickel tetracarbonyl (commonly referred to as nickel carbonyl) can be found as a gas or as a volatile liquid. It is mainly found as an intermediate in the carbonyl process of refining. By virtue of its toxicokinetics, it is the one nickel compound for which short-term inhalation exposures are the most critical. With respect to dermal exposures, although biologically possible, absorption through the skin has not been demonstrated in humans, nor have any dermal studies on animals been conducted. The discussion, below, therefore, focuses on inhalation exposures.
5.6.1 Inhalation Exposure: Nickel Carbonyl
Nickel carbonyl delivers nickel atoms to the target organ (lung) in a manner that is probably different from that of other nickel species. After nickel carbonyl inhalation, removal of nickel from the lungs occurs by extensive absorption and clearance. The alveolar cells are covered by a phospholipid layer, and it is the lipid solubility of nickel carbonyl vapor that is of importance in its penetration of the alveolar membrane. Extensive absorption of nickel carbonyl after respiratory exposure has been demonstrated. Highest nickel tissue concentrations after inhalation of nickel carbonyl have been found in the lungs, with lower concentrations in the kidneys, liver, and brain. Urinary excretion of nickel increases in direct relationship to exposure to nickel carbonyl (Sunderman et al., 1986).
Acute toxicity is of paramount importance in controlling risks associated with exposure to nickel carbonyl. The severe toxic effects of exposure to nickel carbonyl by inhalation have been recognized for many years. The clinical course of nickel carbonyl poisoning involves two stages. The initial stages are characterized by headache, chest pain, weakness, dizziness, nausea, irritability, and a metallic taste in the mouth (Morgan, 1992; Vuopala et al., 1970; Sunderman and Kincaid, 1954). There is then generally a remission lasting 8-24 hours followed by a second phase characterized by a chemical pneumonitis but with evidence, in severe cases, of cerebral poisoning. Common clinical signs in severe cases include tachypnoea, cyanosis, tachycardia, and hyperemia of the throat (Shi, 1986). Hematological results include leukocytosis. Chest x-rays in some severe cases are consistent with pulmonary edema or pneumonitis, with elevation of the right hemidiaphragm. Shi reported three patients with ECG changes of toxic myocarditis.
The second stage reaches its greatest severity in about four days, but convalescence is often protracted. In ten patients with nickel carbonyl poisoning, there were initial changes in pulmonary function tests consistent with acute interstitial lung disease (Vuopala et al., 1970). However, these results returned to normal after several months.
The mechanism of the toxic action of nickel carbonyl has never been adequately explained, and the literature on the topic is dated (Sunderman and Kincaid, 1954). Some researchers have held the view that nickel carbonyl passes through the pulmonary epithelium unchanged (Amor, 1932). However, as nickel carbonyl is known to be reactive to a wide variety of nitrogen and phosphorous compounds, as well as oxidizing agents, it is not unreasonable to assume that it is probably reactive with biological materials (Sunderman and Kincaid, 1954). It is known to inhibit the utilization of adenosine triphosphate (ATP) in liver cells and brain capillaries (Joo, 1969; Sunderman, 1971). Following acute exposure to nickel carbonyl, sections of lung and liver tissue have been shown to contain a granular, brownish-black, noniron-staining pigment (Sunderman et al., 1959). It has not been established, however, whether these dark granules represent metallic nickel or the compound, itself. Sunderman et al. (1959) proposed that nickel carbonyl may dissociate in the lung to yield metallic nickel and carbon monoxide, each of which may act singly, or in combination with each other, to induce toxicity.
Evidence of chronic effects at levels of exposure below those which produce symptomatic acute toxicity is difficult to find. The only epidemiological study specifically investigating the possible carcinogenic effect of nickel carbonyl (Morgan, 1992) was limited in power and confounding factors-such as exposures to certain oxidic and sulfidic nickel species-thereby clouding any interpretation regarding the contribution of nickel carbonyl, per se, to the carcinogenic risk.
Like humans, the lung is the primary target organ from exposure to nickel carbonyl in animals, regardless of route of administration, and effects in animals are similar to those observed in cases of human exposure. Experimental nickel carbonyl poisoning in animals has shown that the most severe pathological reactions are in the lungs with effects in brain and adrenal glands as well. Acute toxicity is of greatest concern. The LD50 in rats is 0.20 mg Ni/liter of air for 15 minutes or 0.12 mg/rat. Effects on the lung include severe pulmonary inflammation, alveolar cell hyperplasia and hypertrophy, and foci of adenomatous change.
With respect to carcinogenic effects, studies on the carcinogenicity of nickel carbonyl were performed prior to present day standardized testing protocols, but because of the extreme toxicity of this material, more recent studies are not likely to be conducted. Studies by Sunderman et al., (1959) and Sunderman and Donnelly (1965) have linked nickel carbonyl to respiratory cancer, but high rates of early mortality in these studies preclude a definitive evaluation. It would be desirable to have additional studies with less toxic levels of exposure permitting a higher proportion of the animals to survive. This would provide a more complete understanding of the spectrum of lung pathology produced by nickel carbonyl. Nevertheless, the deficiencies in these early studies preclude reaching any definitive conclusions regarding the carcinogenicity of nickel carbonyl via inhalation. Possible developmental toxicity effects are also of concern for nickel carbonyl. In a series of studies, Sunderman et al. (1979, 1980,1983) demonstrated that nickel carbonyl, administered by inhalation (160-300 mg Ni/m3) or injection (before or a few days after implantation) produced various types of fetal malformations in hamsters and rats.
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