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NICKEL (SOLUBLE)								Related Pages
										*OSHA comments from the January 19, 1989 Final Rule on Air Contaminants Project extracted from 54FR2332 et. seq. This rule was remanded by the U.S. Circuit Court of Appeals and the limits are not currently in force.*
**CAS:** 7440-02-0; **Chemical Formula:** Varies
The former OSHA PEL for all forms of inorganic nickel (as Ni) was 1 mg/m3 TWA. Based on the ACGIH recommendation, OSHA proposed revising this limit to 0.1 mg/m3 TWA; this limit is established in the final rule. NIOSH recommends that exposure to any form of inorganic nickel be maintained at or below 0.015 mg/m3.
A variety of toxic effects results from exposure to nickel compounds. Soluble nickel salts cause contact dermatitis in sensitized individuals and eye irritation (ACGIH 1986/Ex. 1-3, p. 422). Cases of asthmatic lung disease have been reported among nickel-plating workers (EPA 1986a/Ex. 1-1132).
OSHA’s proposal to lower the PEL for soluble nickel compounds to 0.1 mg/m3 was based primarily on evidence that exposure to soluble nickel at low levels and for relatively short durations causes pathological changes in the lungs of experimental animals. In addition, OSHA reviewed several animal and human studies designed to investigate the carcinogenic potential of soluble nickel compounds. Three soluble nickel compounds have been tested for their carcinogenic potential: nickel chloride, nickel sulfate, and nickel acetate. Some sparingly soluble compounds, nickel carbonate and nickel hydroxide, have also been studied.
The results of animal studies suggest that some soluble nickel compounds are potentially carcinogenic; however the data are derived predominately from injection studies and results are conflicting. Results from occupational studies on soluble nickel compounds are also conflicting and are confounded by the presence of several types of nickel compounds in the facilities studied.
In the proposal, OSHA made a preliminary finding that exposure to soluble nickel compounds presented a potential cancer mortality risk to workers. Since publication of the proposal, however, OSHA has reviewed all of the record evidence, including an additional epidemiologic study, and has determined that further analysis is necessary before any definitive findings can be made with regard to the carcinogenic potential of the soluble nickel compounds. OSHA wishes to emphasize, however, that this determination does not negate the evidence that exposure of experimental animals to low levels of soluble nickel causes pathological changes in the lung. Accordingly, OSHA is establishing the 0.1 mg/m3 TWA PEL in the final rule, as proposed, but is basing this limit on the respiratory toxicity of these compounds. OSHA’s findings on the evidence on soluble nickel compounds is presented below.
Bingham, Barkley, Zerwas et al. (1972/Ex. 1-204) exposed rats by inhalation to 0.1 mg/m3 nickel chloride for 12 hours per day for two weeks. Animals showed evidence of pulmonary irritation and damage in the form of marked mucous secretion, hyperplasia, and accumulations of alveolar macrophages. Fluid obtained by lung lavage appeared very cloudy and viscous due to the presence of free alveolar cells. Rats and guinea pigs exposed daily to 1.0 mg/m3 (as Ni) nickel chloride for six months showed increased lung weight, which is an indication of pulmonary damage and hyperplasia (Clary 1977, as cited in ACGIH 1986/Ex. 1-3, p. 422); exposed rats also developed signs of interstitial fibrotic lesions. Rabbits inhaling 0.3 mg/m3 (as Ni) nickel chloride aerosol for 30 days showed a doubling in alveolar cell number and volume of alveolar epithelial cells, as well as nodular accumulation of macrophages and laminated structures (Johansson, Curstedt, Robertson, and Camner 1983/Ex. 1-273). These studies clearly show that exposure at or below the former OSHA PEL of 1.0 mg/m3 for soluble nickel, even for durations considerably less than a working lifetime, is associated with increased cell turnover and pathological changes in the lung. These pathological changes, in particular the appearance of fibrotic lesions, observed in animals exposed to low levels of soluble nickel salts indicate that lung damage has occurred and suggests that significant decrements in lung function may result from prolonged exposure to these low levels. Furthermore, the appearance of hyperplasia is indicative of abnormal cell growth and suggests the presence of pre-cancerous lesions.
Nickel chloride has been reported to be mutagenic in Salmonella typhimurium and Cornebacterium, but negative in E. coli (EPA 1986a/Ex. 1-1132). The positive studies are not considered conclusive, however, because the S. typhimurium report is an abstract lacking detailed data and Cornebacterium is not the usual species used in these tests. Amacher and Paillet (1980/Ex. 1-286) reported that nickel chloride was mutagenic in mouse lymphoma cells and demonstrated a dose-response relationship for this endpoint.
Some in vitro studies using soluble nickel compounds report finding chromosomal aberrations (EPA 1986a/Ex. 1-1132). These studies do not demonstrate a dose-response relationship or statistical significance, which weakens their findings. Several in vivo studies have failed to detect chromosomal aberrations (EPA 1986a/Ex. 1-1132). However, several in vitro studies on nickel sulfate and nickel chloride have reported findings of sister chromatid exchanges (EPA 1986a/Ex. 1-1132).
Some animal studies on soluble nickel compounds suggest that these compounds are carcinogenic in animals. Strain A mice receiving intraperitoneal injections of nickel acetate had an increased rate of lung adenomas and adenocarcinomas that was statistically significant in the high-dose group (Stoner, Shimkin, Troxell et al. 1976/Ex. 1-203). The animals were injected three times per week for eight weeks at 72, 180, or 360 mg/kg.
EPA (1986a/Ex. 1-1132) reported a study in which rats were given monthly intramuscular injections of 35 mg/kg nickel acetate for four to six months (Haro, Furst, and Falk 1968/Ex. 1-1022). Twenty-two percent of the treated rats developed sarcomas. Payne (1964/Ex. 1-200) observed tumor responses in rats after intramuscular implantation of 7 mg nickel acetate, nickel sulfate, nickel chloride, or nickel carbonate. Implant-site sarcomas developed in one of 35 rats exposed to nickel acetate, one of 35 rats exposed to nickel sulfate, none of 35 rats exposed to nickel chloride, and four of 35 rats exposed to nickel carbonate.
Results of other studies on nickel sulfate have been negative. Three studies used intramuscular injection in rats and reported that no tumors developed in the treated group (Gilman 1962/Ex. 1-205; Gilman 1966, as cited in EPA 1986/Ex. 1-1132; Kasprzak, Gabryel, and Jaraczewska 1983/Ex. 1-201). An ingestion study also reported no tumors among treated rats or dogs (Ambrose, Larson, Borzelleca et al. 1976/Ex. 1-211).
Gilman (1966, as cited in EPA 1986a/Ex. 1-1132) administered 5 mg nickel hydroxide to rats by intramuscular injection in each thigh. Nineteen out of 40 injection sites developed sarcomas. Kasprzak, Gabryel, and Jaraczewska (1983/Ex. 1-201) gave rats intramuscular injections of nickel hydroxide in gel, crystalline, or colloidal form. Five out of 19 animals receiving the gel developed sarcomas (two with metastasis to the lung), three out of 20 receiving the crystalline form developed sarcomas (one with metastasis to the lung), and none of 13 rats receiving the colloid developed tumors.
Inco United States, Inc. (with its subsidiary, Inco Ltd.) (Exs. 3-915 and 167) and the Nickel Producers Environmental Research Association (NiPERA), Inc. (Ex. 3-668) discussed the limitations of the animal data. For example, both of these commenters noted that soluble nickel compounds have produced tumors in animals only by injection and that the results among studies were conflicting. In the NPRM and in the discussion above, OSHA recognized many of these limitations of the data. Although it is true, as Inco pointed out (Exs. 3-915 and 167), that EPA (1986a/Ex. 1-1132) concluded that the animal data are “too limited to support any definitive judgment regarding... [the] carcinogenic potential [of soluble nickel compounds]” (EPA 1986a/Ex. 1-1132, p. 8-229), EPA also concluded that:
The observation of pulmonary tumors in strain A mice from the administration of nickel acetate by intraperitoneal injections and the ability of nickel acetate to transform mammalian cells in culture and to inhibit RNA and DNA synthesis provides limited evidence for the carcinogenicity of nickel acetate and supports a concern for the carcinogenic potential of other soluble nickel compounds (EPA 1986a/Ex. 1-1132, p. 8-229).OSHA agrees with EPA’s assessment that, although some studies are suggestive of a carcinogenic effect and an ability of soluble nickel to transform cells, overall the animal data are too equivocal at this time to support any firm conclusions that soluble nickel compounds do or do not cause cancer in experimental animals.
In addition to the animal evidence described above, OSHA reviewed studies conducted on workers exposed to soluble nickel compounds. Electrolysis workers at a refinery in Kristiansand, Norway, experienced a higher lung cancer risk than employees from the same facility who worked in three other job categories, including roasting and smelting workers (Magnus, Andersen, and Hogetveit 1982/Ex. 1-241). Electrolysis workers were exposed to an aerosol composed predominantly of nickel sulfate, which was estimated to contain soluble nickel at a concentration of 0.2 mg/m3 (EPA 1986a/Ex. 1-1132); these workers also had higher plasma and urine levels of nickel than did roasting and smelting workers, who were predominately exposed to insoluble nickel subsulfides and oxides. However, exposure to nickel subsulfide and oxides may have occurred in the electrolysis building, and the electrolysis workers may also have worked in other process departments (Grandjean, Andersen, and Nielsen 1988/Ex. 1-207). Roasting and smelting workers were exposed to an estimated average of 0.5 mg/m3 (as Ni) of roasting dust.
The standardized mortality ratios (SMRs) for lung cancer were 550 for electrolysis workers, 390 for other process workers, and 360 for roasting and smelting workers. The pattern of SMRs for nasal cancer, which is a rare form of cancer in humans, was different among these groups: 2600 for electrolysis workers, 2000 for other process workers, and 4000 for roasting and smelting workers. The results seem consistent with studies that show that roasting and smelting workers have the highest concentrations of nickel in the nasal mucosa, presumably because of the relatively larger particles resulting from roasting. Conversely, electrolysis workers, who showed a larger lung cancer risk than roasting and smelting workers, have higher plasma and urine levels of nickel, suggesting that nickel aerosolized by this process penetrates to the deep lung (EPA 1986a/Ex. 1-1132).
In the NPRM, OSHA presented quantitative estimates of the cancer risk believed to be associated with exposure to soluble nickel; these estimates were based on the Magnus et al. (1982/Ex. 1-241) study of electrolysis workers. During the rulemaking proceeding, OSHA re-evaluated the underlying exposure data and now believes that, because the electrolysis workers may have been concurrently exposed to some insoluble forms of nickel, the data from the Magnus et al. (1982/ Ex. 1-241) study may not be appropriate to use to develop a quantitative estimate of the cancer risk associated with exposure to the soluble forms of nickel.
In contrast to the study of Norwegian nickel refinery workers, a study of 4,288 refinery workers at Port Colborne, Ontario, failed to find an increased lung or nasal cancer mortality rate among electrolysis workers (Roberts et al. 1982; Roberts et al. 1984). Excess incidences of larynx and kidney cancer deaths were reported to be elevated among electrolysis workers, but the numbers of observed deaths were small (two deaths observed for each cause of death). The Roberts et al. studies did report substantially increased incidences of lung and nasal cancer deaths among sinter plant workers exposed to insoluble forms of nickel, a finding consistent with that of Magnus et al. (1982/Ex./1-241) for the Norwegian workers and with many other studies (EPA 1986a/Ex./1-1132).
The stark contrast between these two studies is difficult to explain. According to Inco (Ex./3-915, p. 5), exposures to soluble nickel at the Ontario facility, where no excess risk was found among electrolysis workers, were probably similar to those at the Norwegian facility, where cancer mortality was increased. Exposure data taken during the late 1970s at the Ontario facility (Ex./3-915, Table 1c) indicate that, in most job categories, electrolysis workers were exposed to both soluble and insoluble forms of nickel; this is evidenced by the higher reported employee sampling results for total nickel than for soluble nickel. Thus, concurrent exposure to both soluble and insoluble forms of nickel existed at both the Ontario and Norwegian facilities. The size of the cohort at the Ontario facility was approximately twice that of the Norwegian study; thus, the Ontario study has sufficient power to detect the sizable increases in the incidences of nasal and lung cancer that were reported in the Norwegian study. It is possible, as EPA (1986a/Ex./1-1132) has suggested, that quantitative or qualitative differences in the conditions of exposure between the two cohorts accounts for the discrepant results; however, no information contained in the Ontario or Norwegian reports suggests that there were substantial differences in exposure to soluble nickel. Given the magnitude of the difference in the reported cancer mortality for these two groups of electrolysis workers, it is clear that additional investigation is required to identify the risk factors that account for the different mortality patterns observed in Ontario and Norway. Therefore, OSHA concludes that, at this time, the available human data do not permit any definitive conclusion to be made linking occupational exposure to the soluble forms of nickel with an elevated cancer mortality risk in humans.
The primary impetus to revise the PEL for soluble nickel was the finding that exposure of animals for relatively short periods of time to soluble nickel aerosols at levels equal to or below the former PEL of 1 mg/m3 produced increased cellular growth and pathological changes that reflect the lung’s defense against chemical insult; this finding is consistent across three animal studies conducted in several species (Bingham, Barkley, Zerwas et al. 1972/Ex./1-204; Clary 1977, as cited in ACGIH 1986/Ex./1-3, p. 422; Johansson, Curstedt, Robertson, and Camner 1983/Ex./1-273). Furthermore, these observations were made in animals that were exposed for as short a duration as two weeks and for no more than six months; thus, the consequences of continued, low-level exposure for a full lifetime are unknown. Both Inco (Exs. 3-915 and 167) and NiPERA, Inc. (Ex./3-668) agree that these studies provide an appropriate basis for establishing a 0.1 mg/m3 PEL for soluble nickel. NIOSH (Ex. 8-47, Table N6B) does not concur with the selection of this limit and believes that a full 6(b) rulemaking is appropriate for the soluble (or inorganic) compounds of nickel.
OSHA concludes that these studies, one of which demonstrated pathological and perhaps precancerous changes following exposure to 0.1 mg/m3, clearly demonstrate that exposure to the former PEL of 1.0 mg/m3 presents a significant risk to workers of lung irritation accompanied by pathological changes that may presage cancer. OSHA has determined that these effects constitute material impairments of health and functional capacity. OSHA also concludes that the final rule’s reduction in the PEL will substantially reduce these significant risks. Accordingly, OSHA is establishing a revised 8-hour TWA PEL of 0.1 mg/m3 (as Ni) for the soluble nickel compounds in the final rule.
										
							
								Page last reviewed:  September 28, 2011						Content source:  	National Institute for Occupational Safety and Health NIOSH
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