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EVALUATION OF RESPIRATORY CARCINOGENICITY OF NICKEL AND NICKEL COMPOUNDS

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Executive Summary

Examination of the in vitro, animal, and epidemiologic data pertaining to four classes of nickel compounds1 indicates that these compounds have very different biological behaviors, particularly with regard to respiratory carcinogenicity. Nickel subsulfide is likely to be carcinogenic to humans. Soluble nickel compounds, by themselves, are not likely to be carcinogenic to humans, although an enhancing (promoter) effect on other carcinogens is possible. High concentrations of Ni-Cu oxides, mixed with low-temperature (black) and high- (green) temperature NiO, appear to be carcinogenic to humans. Exposures to nickel silicates-oxides and complex nickel oxides devoid of copper have not resulted in excess cancer risks in other human cohorts. Finally, exposure to metallic nickel particles does not appear to pose a respiratory carcinogenic risk for humans.

 

Introduction

Historically, inhalation exposure to very high concentrations of certain nickel compounds in the nickel producing industry has been associated with an excess of respiratory cancer. To understand the risks associated with these exposures, consideration should be given to the respiratory carcinogenic potential of the individual nickel species and the influence of particle size and mixed exposures.

A brief review of the epidemiologic, animal and in vitro data pertinent to the understanding of the inhalation carcinogenicity of nickel and its compounds is presented in this report. Based on these data, a possible mechanistic model for the carcinogenicity of nickel compounds is discussed (1). The carcinogenic potential of nickel subsulfide, oxidic nickel compounds (with particular emphasis on high-temperature [green] nickel oxide), nickel sulfate hexahydrate, and metallic nickel is considered within the framework provided by this model.

(1)The four classes of nickel compounds discussed in this paper are: metallic nickel, oxidic nickel (including nickel oxides, hydroxides, silicates, carbonates, and complex nickel oxides), sulfidic nickel (including nickel sulfide and subsulfide) and water soluble nickel compounds (including nickel acetate, sulfate, chloride, etc.). Metallic, oxidic and sulfidic nickel compounds are insoluble in water.

 

Epidemiologic Data

Epidemiologic data from nickel workers are difficult to interpret because of mixed exposures to not only different nickel compounds but also to other inorganic compounds (arsenic, strong acid mists) and to organic combustion products (2). In addition, exposure measurements are sparse, very little chemical speciation and particle size information is available, and the confounding effects of cigarette smoking on respiratory cancers have not been adequately studied. Nevertheless, with the continued acquisition of new epidemiologic data, a clearer picture is emerging with respect to the likely role that different nickel species play in human respiratory carcinogenesis. In later sections, it will be noted that this picture is largely in agreement with what is known about these compounds from animal and in vitro studies.

Studies of past exposures and cancer mortality reveal that only respiratory tumors have been consistently associated with inhalation exposure to certain nickel compounds. Data from ten different cohorts were presented in the report of the International Committee on Nickel Carcinogenesis in Man (ICNCM) (2). These cohorts included approximately 80,000 workers involved in nickel operations (mostly mining, smelting, and refining, but some nickel alloy production and miscellaneous applications as well) located in the United States, Canada, England, Wales, Norway, Finland and New Caledonia.

Of the examined workers, less than 10% had clear excess respiratory cancer risks. The excess risks were confined to workers in certain types of refining operations. Only slightly elevated risks of respiratory cancer were seen in some (but not all) smelting and mining workers; these appeared to be attributable to other causes (3,4). There was no evidence of risk for workers in the manufacturing of barrier material for gaseous diffusion (uranium enrichment process), nor in workers involved in alloy production. An additional 50,000 workers in nickel-using industries and applications (stainless steel and nickel alloy production, welding, and plating) have given no evidence of excess respiratory cancer risks from exposures to metallic and/or complex nickel oxides largely free of copper (5-9).

Thus, of the large number of nickel-exposed workers comprising a variety of occupations, only a small proportion have shown excess respiratory cancer risks. Nickel-related cancer risks appear to have been confined to certain types of refining operations, most of which are no longer in existence today. No nickel-related excess respiratory cancer risks have been found in any nickel-using industry workers.

Sulfidic and Oxidic Nickel. The ICNCM report (2) concluded that much of the excess respiratory cancer risk in workers involved in certain types of nickel refining operations appeared to be associated with exposure to a mixture of sulfidic and oxidic nickel compounds at high concentrations (>10 mg Ni/m3). In the case of sulfidic nickel, both lung and nasal cancers were associated with exposure to this nickel compound in Canadian sinter plant workers. In refinery workers in Clydach, Wales excess lung cancers were associated with high cumulative exposures to sulfidic nickel and low-level exposures to other nickel compounds. It should be noted that the risks of developing respiratory cancers in this cohort dramatically dropped after 1930 despite the continued presence of some high levels of sulfidic nickel into the late 1930s, suggesting that other factors (e.g., possible presence of arsenic) could have contributed to the cancer risks seen in these workers. However, clear evidence of respiratory carcinogenicity in animals administered nickel subsulfide (see below) indicates that the association of exposures to sulfidic nickel and lung and nasal cancer in humans is likely to be causal.

With respect to oxidic nickel, excess lung and nasal cancers reported in refinery workers in Clydach and in Kristiansand, Norway who were exposed to high concentrations of oxidic nickel (mainly as nickel copper oxides, but with the possible presence of both high-temperature and low-temperature NiO as well), strongly suggests that these forms of oxidic nickel are likely human respiratory carcinogens 2. Conversely, in nickel-using industry workers exposed to metallic nickel and/or complex nickel oxides free of copper, with no exposure to sulfidic nickel, there have been no nickel-related excess risks of respiratory cancer. Likewise, nickel production workers involved in the mining and smelting of lateritic ores have shown no nickel-related excess respiratory cancer risks. The oxidic nickel to which these workers were exposed would have mainly been nickel silicates-oxides and complex nickel oxides devoid of copper. It should be mentioned that oxidic nickel exposures in the latter groups were considerably lower than those experienced by workers in certain types of nickel refining operations. It is uncertain, therefore, whether the lack of increased respiratory cancer risk in these workers was due to the low concentrations of oxidic nickel to which they were exposed and/or to the physico-chemical properties (including particle size) of the particular oxidic nickel compounds present.

2 It should be noted that these workers were also exposed to various levels of metallic, sulfidic and/or soluble nickel compounds, since no workplace in the producing industry had "pure" exposure to any individual nickel compound.

Soluble Nickel. The role of soluble nickel in respiratory carcinogenesis is less evident than that of sulfidic and certain oxidic nickel compounds. Comparisons of electrolysis workers at Port Colborne, Canada and Kristiansand, Norway reveal that only Kristiansand workers had excess lung cancers. Because of differences in processes, the Kristiansand workers were thought to be exposed to slightly higher levels of soluble nickel and also to handle approximately seven times more insoluble nickel (per unit of soluble nickel) than those at Port Colborne. In addition, basic nickel carbonate (water insoluble) was included in the soluble compounds category at Kristiansand, whereas it was classified as insoluble at Port Colborne. While the amounts involved were not large, they would have exaggerated the differences in exposure to soluble compounds between the two operations. In another cohort of hydro-metallurgical workers at Clydach that had high cumulative exposure to soluble forms of nickel but low exposures to oxidic and sulfidic forms of nickel, there was no evidence of increased risks of respiratory cancer. From these studies, the ICNCM Report concluded that, while there was evidence that soluble nickel exposure (> 1 mg Ni/m3) could increase the risk of respiratory cancers, the effect might be one of enhancing risks associated with co-exposure to less soluble forms of nickel or other non-nickel compounds.

Recent studies have provided supportive evidence for the possible role of soluble nickel as a promoter of carcinogenicity. In particular, in a recent study of the Kristiansand cohort that has updated cancer morbidity, newly available information on the smoking characteristics of the workers has been included (10). A synergistic lung cancer response between smoking and exposure to a mixture of soluble and insoluble nickel compounds was observed. In the small number of nickel-exposed workers who did not smoke, there was no evidence that nickel exposure increased the risk for lung cancer. A similar lack of excess respiratory cancers was noted in a 1996 cancer mortality study in a relatively small population of nickel platers exposed solely to nickel chloride and sulfate mists (9). The results from these two studies are consistent with those of the ICNCM Report.

In a 1998 study of Finnish refinery workers exposed predominantly to soluble nickel three nasal cancer cases were identified and a 2-fold increase in lung cancer risk was found in nickel workers with more than 20 years employment (11). Unfortunately, smoking data are unavailable for these workers. As indicated in the above study on Norwegian electrolysis workers, such data would be helpful in interpreting the significance of the lung cancers seen in these workers. In the case of the observed nasal cancers, even though the Finnish workers were predominantly exposed to soluble nickel during their employment at the refinery, their previous job experiences, as well as concomitant exposures to insoluble nickel compounds and acid mists, make the establishment of a causal association with soluble nickel compounds difficult.

Taken together, the epidemiologic results from all the above studies are most consistent with soluble nickel compounds enhancing, rather than initiating, cancer. The animal data on soluble nickel compounds strongly support this interpretation (see next section).

Metallic Nickel. The ICNCM Report found no evidence that exposure to metallic nickel in industrial plants increased respiratory cancer risk. The lack of excess respiratory cancer risks in workers at a gas diffusion barrier manufacturing plant was particularly notable as these workers were exposed solely to metallic nickel. Likewise, in a recent update of a study on 715 hydrometallurgical workers in Canada, no excess lung or nasal cancers was reported (12). Although the size of the cohort was small, exposures in this plant were solely to nickel concentrates and metallic nickel. In a recent study of nickel alloy workers, Redmond and coworkers updated the cancer mortality data from more than 30,000 people employed in 13 nickel alloy plants in the U.S.A. Exposures were primarily to metallic nickel and complex nickel oxides devoid of copper. No excess mortality rates were observed for respiratory cancers in these workers when compared to local population rates (5,6). Examination of the available data shows that, even in the past, exposures to metallic nickel have generally been low (<</u> 1 mg Ni/m3) compared to exposures to other nickel compounds found in certain types of nickel refining operations. Lack of epidemiologic carcinogenic evidence for metallic nickel could be due to the combination of low-dose exposures, the particle size of the metallic nickel found in the workplace, and the bioavailability of the nickel ion from nickel metal itself. It is clear then, that under past and current industrial practices, exposure to metallic nickel does not appear to pose a respiratory carcinogenic risk for humans.

 

Animal Data

Animal data are often useful in helping to elucidate mechanisms of carcinogenesis. As noted above, this is particularly true in the case of nickel and its compounds where the animal data are in good agreement with the human lung carcinogenicity data. The ICNCM Report, recognizing the limitations of human studies involving mixed exposures, pointed out the importance of the results of animal carcinogenesis studies (using inhalation as the route of exposure) to help understand the human health risks associated with individual nickel compounds. It should be noted that under the conditions used in the studies, none of the rodent species showed evidence of nasal tumors after inhalation exposure to any one of the nickel compounds tested. The animal data are reviewed herein.

Nickel Subsulfide. In a 1974 study, inhalation of nickel subsulfide (Ni3S2) resulted in the induction of lung tumors in rats (13). The U.S. National Toxicology Program (NTP) recently completed two-year inhalation cancer bioassays in rats and mice with three nickel compounds, including nickel subsulfide (14,15). In the nickel subsulfide study, rats were exposed to 0, 0.1 or 0.7 mg Ni/m3; mice were exposed to 0, 0.4, or 0.8 mg Ni/m3. 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.

Oxidic Nickel. In the case of oxidic nickel, few properly designed chronic inhalation studies had been performed prior to the NTP studies (14,16). The first inhalation studies that were carried out on hamsters and rats with different nickel oxides were either negative or inconclusive due to high mortality at toxic concentrations (17-22).

In the recently completed NTP study (14,16), rats were exposed to high temperature, green NiO (calcined at 1,350 oC) at concentrations of 0, 0.5, 1.0, or 2.0 mg Ni/m3. 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. These numbers were not statistically different from those seen both in the control and low dose groups, but were statistically significant compared to historical controls (cancer incidence in ~200 control rats per sex used in previous NTP studies). Therefore, the NTP concluded that there was some evidence of carcinogenic activity in rats. NTP also found equivocal evidence of carcinogenicity in female mice based on excess tumors found in animals exposed to 1 but not 2 or 4 mg Ni/m3. Other findings in rodents included inflammation and pigmentation in the lung and lymphoid hyperplasia and pigmentation in the bronchial lymph nodes. No nasal tumors were observed in rats or mice.

Two clearance studies of high temperature, green NiO particles from the respiratory tract of rats and mice showed impaired clearance of NiO after two to six months exposure to the same concentrations used in the NTP studies (23-25). These results indicate that impairment of lung clearance was likely present in the NTP rats at the concentrations at which tumors were found.

It has been shown in rats that prolonged exposures to high concentrations of particles of low toxicity can result in lung tumors independent of the composition of the particles (26,27). The mechanism for tumor induction involves an impairment of lung clearance that leads to chronic inflammation. Chronic inflammation can result in enhanced cell proliferation, and, indirectly, in increases in mutations through the action of oxygen radicals produced by the activated inflammatory cells (28-31). The tumors found in rats exposed to high concentrations of high temperature green nickel oxide in the NTP studies could have been the result of the indirect particle effect described above, rather than resulting from the direct genotoxic effects of Ni2 . It is uncertain at present, whether the induction of tumors secondary to a particle effect observed in rats could occur in humans, since no excess tumor incidence has been observed in workers exposed to very high concentrations of low solubility and low toxicity dusts (32).

In evaluating the carcinogenicity of oxidic nickel compounds, it is important to consider the concentration and physicochemical characteristics of the particles (including particle size). The physicochemical characteristics of oxidic nickel produced by different processes as well as the presence of other metals (e.g., Ni-Cu oxides) may result in different biological activities. For example, a nickel oxide produced at lower calcining temperatures than the green NiO may have increased solubility resulting, perhaps, in enhanced toxicity as well as clearance. Depending on the balance of these effects, the ultimate result may be an increase or decrease in the respiratory carcinogenic potential of the various oxidic nickel compounds relative to high temperature, green nickel oxide.

Soluble Nickel. No inhalation studies with soluble nickel compounds had been conducted prior to the NTP studies. Soluble nickel compounds gave consistent negative results by oral (33-36) and intramuscular (37-40) routes of exposure; only intraperitoneal injection studies gave positive results with nickel acetate (41-44). Injection studies are not appropriate to evaluate hazards for predicting human risk from inhalation exposures. This is due to the fact that injection bypasses natural protective mechanisms and causes unrealistically high spikes of exposure to occur in various organ systems.

In the recently conducted NTP inhalation study (15,45), rats were exposed to NiSO4·6H2O at concentrations up to 0.11 mg Ni/m3; mice were exposed to up to 0.22 mg Ni/m3. These concentrations were chosen based on the toxicity observed in the 13-week studies and corresponded to the maximum tolerated doses (MTD). After two years of continuous exposure, there was no evidence of lung or nasal carcinogenic activity in mice or rats. Various combinations of non-carcinogenic lung effects were seen in both sexes in rats and mice. Overall, the non-carcinogenic effects were similar to those seen with the other two nickel compounds.

Metallic Nickel. A limited number of animal inhalation studies with elemental nickel powder have not indicated carcinogenicity in rats or hamsters (46). In one intratracheal instillation study, 9 mg Ni/rat of nickel powder (unspecified particle size) produced malignant lung tumors in rats (47). However, the relevance of such a route of administration for humans is highly questionable, given that the lung burden by intratracheal instillation is massive, potentially overloading lung clearance mechanisms and affecting the animal's ability to eliminate the material. Intratracheal instillation of 10 mg Ni did not induce tumors in hamsters (48).

In Vitro Studies

In vitro, the Ni2 ion does not behave like a typical mutagen; it does not show high affinity for DNA and lacks mutagenicity in most bacterial and mammalian assays (49-56). Only chromosomal aberration assays (indicative of chromosomal damage) have been positive with nickel compounds in vitro (57-64) and in vivo (65-70).

However, in vitro cell transformation assays have been positive with soluble and insoluble nickel compounds (51,52,71-74). It was shown that endocytosis by target cells was likely to play an important role in the in vivo transforming potential of nickel compounds (74). Endocytized particles release Ni2 ions and are transported to the nuclear membrane where the endocytic vesicles deliver Ni2 ions in close proximity to the chromosomes (75). Some of the characteristics of insoluble nickel compounds that increase their ability to be endocytized include: crystalline nature, negative surface charge, 2-4 µm range particle size, and low solubility in biological fluids (76-78). Even though water soluble nickel compounds are not endocytized, they are positive in in vitro transformation assays due to the persistent high concentration of Ni2 ions that can be achieved in the cell culture medium. The high nickel gradient in the medium allows Ni2 ions to concentrate at the nuclear target sites. However, in vivo, Ni2 ions from soluble compounds are unlikely to be bioavailable due to their rapid clearance from the lung and excretion in urine (t½ in rats of ~ 2-3 days (23)).

The Ni2 ion has been shown in vitro to bind to proteins within heterochromatin regions of DNA (79-81). This binding may enhance DNA condensation and methylation in nearby regions (82-84) and may result in nickel-mediated induction of oxidative DNA damage (43,79, 85-89). These actions could have similar effects on senescence or tumor suppressor genes; the former, by diminishing gene expression, the latter by resulting in deletion of these genes (83,84,90-93).

 

Mechanistic Model Related to the Carcinogenicity of Nickel Compounds

There are two components that may contribute to the development of lung tumors by certain nickel compounds (1): (1) heritable changes in gene expression and (2) cell proliferation. Heritable changes in gene expression can be the result of: (i) genetic changes such as mutations (changes in DNA sequence) or chromosomal aberrations (changes at the chromosome level), and (ii) epigenetic changes that affect gene expression without altering DNA sequences. Nickel compounds have not been shown to directly induce mutations, but some nickel compounds are able to cause heritable chromosomal aberrations and epigenetic changes through methylation. These direct effects could be specific for Ni2 ions and dependent on its bioavailability (the delivery of the nickel ion to sites within the nuclei of the target cells). In addition, some nickel compounds may have indirect effects as a consequence of an inflammatory response. The indirect effects could be attributed to DNA damage caused by oxygen radicals and are not specific to nickel.

Cell proliferation is required to convert DNA lesions into mutations and is also involved in clonal expansion of the initiated cell population, a factor that increases the probability of occurrence of a second mutating event. Only sustained increases in cell proliferation, as seen in chronic exposures, are likely to be significant in carcinogenesis (94). Expression of pro-inflammatory cytokines was found to be increased in lungs of rats and mice after subchronic exposure to Ni3S2 (25). Cell proliferative responses in alveolar epithelial cells from rats and mice exposed to high temperature green NiO, paralleled the inflammatory responses (25). Collectively, these studies suggest that some nickel compounds can stimulate cell proliferation in vivo. Again, this effect may not be specific for nickel compounds, and it could be similar for other substances that can induce proliferative responses. Both components: heritable changes in gene expression and cell proliferation, are needed for tumor development.

 

Carcinogenic Assessment of Individual Nickel Compounds

Sulfidic Nickel (nickel subsulfide). The human data provide evidence of an association of excess respiratory cancer risk with inhalation of aerosols containing high concentrations of sulfidic nickel (>10 mg Ni/m3). Positive animal carcinogenicity results from inhalation exposure to nickel subsulfide have been found in rats (with evidence of dose-response).

Nickel subsulfide particles need to be oxidized to release Ni2 ions. Ni3S2 is quite insoluble in water, but shows enhanced release of Ni2 ions in biological fluids. In vivo, since Ni3S2 is likely to be readily endocytized by the target cells, this compound is likely to affect both components of the carcinogenic process (induction of heritable changes and increases in cell proliferation). Because of its enhanced "solubility" in biological fluids, efficient delivery of Ni2 ions to the target site within the cell nucleus is likely. The release of Ni2 ions on the alveolar surface can result in cell toxicity and directly induce inflammation and proliferation of initiated cells.

With regard to carcinogenicity assessment, because Ni subsulfide may efficiently affect both components of the carcinogenic process, this compound appears to present the highest respiratory carcinogenic potential relative to other nickel compounds.

Oxidic Nickel (high-temperature green nickel oxide). Historical human data indicate that inhalation exposure to high concentrations (>10 mg Ni/m3) of oxidic nickel (consisting of Ni-Cu oxides mixed with high and low temperature NiO), was associated with respiratory carcinogenicity. Conversely, exposures to approximately <</u> 1 mg Ni/m3 of silicate oxides and complex Ni oxides (largely free of Cu) did not result in any nickel-related respiratory cancer risk.

The animal data suggest that high temperature green NiO is a weakly positive carcinogen in rats by inhalation, with negative or equivocal evidence of carcinogenicity in mice. It is possible that the lung tumors seen in rats exposed to high temperature (green) NiO may have been generated by an inflammatory/proliferative response that results from the impaired function and chronic activation of macrophages, rather than by a direct heritable effect of Ni2 ions. At present, it is not known if this high-concentration, low-solubility particle effect can occur in humans. With regard to carcinogenicity assessment, compared to nickel subsulfide, high temperature, green NiO may pose a lower risk for respiratory carcinogenicity.

The relative carcinogenic potential of other nickel oxides (NiO) and complex oxides will likely depend on their concentration, solubility and ease of phagocytosis/endocytosis.

Soluble Nickel (Ni sulfate hexahydrate). The human evidence of soluble Ni compounds acting as complete respiratory carcinogens is unclear. In the ICNCM Report (2), there were no cohorts where exposure was solely to soluble nickel compounds. While the Report concluded that exposures to soluble nickel compounds (predominantly in excess of 1 mg Ni/m3) were associated with excess respiratory cancers, the authors suggested the possibility that the role of soluble nickel may be one of enhancement, since the evidence for soluble nickel compounds being carcinogenic was inconsistent across cohorts. The recent negative rodent NTP inhalation studies with concentrations of Ni sulfate hexahydrate at and below the MTD (45), appear to confirm that soluble nickel compounds, by themselves, are not likely to cause respiratory tumors.

The relevance of the animal data for human extrapolation has been questioned on the grounds that the highest concentration to which rats were exposed was 0.1 mg Ni/m3 while workers in some of the cohorts studied by the ICNCM experienced soluble nickel exposures > 1 mg Ni/m3. It should be noted that the aerosol used in the NTP studies (mist) had an average size of 2-3 µm while the particle size of the aerosols in the workplace has a much larger distribution with aerosols of 2-3 µm comprising less than 5% of the total. Preliminary results from an animal to human extrapolation study based on deposition/clearance models for rat and human lungs, indicate that after accounting for particle size distribution, the exposures experienced by the rats in the NTP studies appear equivalent (in terms of nickel lung burden) to those experienced by workers in the epidemiologic nickel refinery studies (95).

In the lung, soluble nickel compounds are not endocytized; rather, they dissociate to release nickel ions and are rapidly cleared from the lungs. Ni2 ions may cross the cell membrane using the Mg2 ion transport system, as has been seen in microorganisms (96). Because Mg2 ions are present in cells at mM levels, high concentrations of Ni2 ions are needed to compete with Mg2 ions for their uptake (97). It is possible to speculate that if the dose were sufficiently high (as happens in in vitro assays) enough Ni2 ions could reach the nucleus to have an effect. This is unlikely in vivo since the toxic effects of soluble nickel compounds (45) would be evident long before a sufficiently high concentration of Ni2 ions in the nucleus could be achieved.

The solubility of nickel sulfate hexahydrate in biological fluids results in release of Ni2 ions at the bronchioalveolar surface, causing cell toxicity and some inflammation. Proliferation rates are enhanced, but given that the background (spontaneous) number of initiated cells is presumed to be very low, and many of these cells could be killed by the toxic effects of Ni2 ions, no tumors are expected to develop. Because soluble nickel compounds may stimulate cell proliferation (the second component of the cancer process), they may act as enhancers of other compounds that are able to induce heritable changes. Furthermore, the presence of soluble nickel compounds could adversely affect the macrophage-mediated clearance of more insoluble nickel compounds (76).

With regard to carcinogenicity assessment, because soluble nickel compounds (such as hydrated nickel sulfate and nickel chloride) may affect only one of the components of the carcinogenic process (cell proliferation), they should present negligible risk of carcinogenicity as single agents at non-overtly toxic concentrations. However, in evaluating the workplace risk associated with chronic inhalation exposure to soluble Ni compounds, the presence of other compounds (especially those that can cause heritable changes such as tobacco smoke) should be considered.

Metallic Nickel (elemental nickel and nickel alloys). Epidemiologic studies have not shown an association between the relatively low (<</u> 1 mg Ni/m3) metallic nickel exposure found in industrial settings and respiratory carcinogenesis. Animal evidence regarding the potential carcinogenicity of metallic nickel by a relevant route of exposure is limited but suggests the absence of respiratory carcinogenic risk.

For metallic nickel, as for nickel subsulfide, the release of Ni2 ion is not based on solubility. Rather, deposited or endocytized particles need to be oxidized to release Ni2 ions. The particle size and the presence of oxidants in the lung surface and inside the cells could influence the kinetics of this reaction. Small size particles are expected to have a higher release of Ni2 ion resulting in greater toxicity but faster lung and renal clearance than larger particles.

In addition, the presence of other metals in Ni-containing alloys may increase or decrease the rates of oxidation and release of Ni2 ions. Therefore, more research is needed to determine the relative rates of nickel corrosion from elemental nickel and individual alloys under biologically relevant conditions.

With regard to respiratory carcinogenicity assessment, past and current exposures to metallic nickel particles in occupational settings do not appear to pose a risk for humans.

 

Gaps in Knowledge

The role of soluble nickel compounds as possible enhancers of the respiratory carcinogenic potential of insoluble nickel compounds and other substances should be investigated. Larger epidemiologic studies in cohorts exclusively exposed to soluble nickel compounds are desirable (e.g., platers). In addition, it is important to characterize the effect of inhaled nickel compounds on nasal and pulmonary target cell proliferation and to determine if there is a threshold for the enhancing (i.e., promoting) effects.

Interestingly, the biological properties of "oxidic" and "sulfidic" compounds depend strongly on the metallurgical history of the compound and on the presence of other metals (e.g., Ni-Cu oxides). For example, differences in biological effects between NiO calcined at different temperatures (<650 to 1,045 oC) have been clearly demonstrated (78). The lack of carcinogenicity of amorphous versus crystalline Ni monosulfide has also been shown (98). Based on the model described above, the potential for nickel oxides to directly cause heritable changes will depend on the bioavailability of Ni2 ion at the critical nuclear sites of epithelial cells. The bioavailability of Ni2 ion will likely depend on their concentration and the degree to which these compounds are endocytized, solubilized and delivered to the target site. Some of the factors that can affect endocytosis include particle size, surface charge, crystalline nature, and chemical composition of the particle, all factors that may vary among nickel oxides. Comparative in vitro and in vivo studies with the same compounds could be useful to evaluate the ability of the in vitro measurements to predict the behavior in vivo.

To clarify the influence of particle size, in vitro and inhalation animal studies that address the influence of particle size on cell transformation, clearance and inflammatory/proliferative responses would be useful. For example, smaller size particles may result in enhanced release of the Ni2 ion, increasing either the bioavailability of Ni2 ion at nuclear sites or conversely its elimination from the lung.

Finally, there are a number of nickel alloys for which there is not enough information available to reliably predict how they would fit within the model presented in this paper. Further research could be directed towards selecting a set of in vitro assays that could be used to characterize a broader array of nickel alloys and to predict their relative potential for in vivo carcinogenesis. These studies could help prioritize nickel compounds and alloys for further animal testing.

 

Conclusions

Examination of the in vitro, animal and epidemiologic data indicates that speciation is of paramount importance for assessing the respiratory carcinogenicity of individual nickel compounds. The concentration as well as the ability of nickel compounds to be phagocytized/endocytized and their in vivo solubility may be the most important factors in determining the bioavailability of Ni2 ion at target sites in the nucleus of respiratory tract cells, and hence, the respiratory carcinogenic potential of these compounds.

The four examples of classes of nickel compounds discussed in this paper have very different biological behaviors:

  • Nickel subsulfide is likely to be a human respiratory carcinogen;
  • Nickel sulfate hexahydrate, and other equally soluble nickel compounds by themselves, are not likely to be carcinogenic to humans. However, their possible enhancing effects on respiratory carcinogenicity require further study;
  • High temperature, green nickel oxide (NiO formed at temperatures above 1,000 oC) appears to induce lung tumors in rats only at high concentrations that result in chronic inflammation/cell proliferation. It is possible that the tumors seen in rats exposed to this compound were generated as a consequence of a particle effect rather than by a direct effect of Ni2 ion. At present, it is not known if this particle effect can occur in humans. However, there does appear to be an association of human respiratory cancer risk with exposures to certain oxidic nickel compounds (mainly as Ni-Cu oxides, but with the possible presence of both high-temperature and low-temperature NiO). Exposures to silicate oxides and complex nickel oxides (devoid of copper) showed no increased risks. Therefore, the carcinogenic potential of individual nickel oxides may depend on their concentration, manufacturing history, and solubility.
  • Exposure to metallic nickel particles in occupational settings does not appear to pose a respiratory carcinogenic risk for humans. Given the paucity of animal and in vitro data, additional studies on individual nickel alloys would be useful.

     

 

References

 1. Oller, A. R., Costa, M., and Oberdörster, G. (1997). Carcinogenicity assessment of selected nickel compounds. Toxicol. Appl. Pharmacol., 143, 152-166.

 2. ICNCM Report. (1990). Report of the International Committtee on Nickel Carcinogenesis in Man. Scand. J. Work Environ. Health 16(1), 1-82.

 3. Verma, D. K., Julian, J. A., Roberts, R. S., Muir, D. C. F., Jadon, N., and Shaw, D. S. (1991). Polycyclic aromatic hydrocarbons (PAHs): A possible cause of lung cancer mortality among nickel/copper smelter and refinery workers. Am. Ind. Hyg. Assoc. J., 7, 277-294.

 4. Muller, J., Wheeler, W. C., Gentleman, J. F., Suranyi, G., and Kusiak, R. A. (1983). Study of the mortality of Ontario miner, 1955-1977: Part 1. Toronto, Canada: Atomic energy Control Board of Canada, Ontario Workmen's Compensation Board, Ontario Ministry of Labour.

 5. Redmond, C. K., Arena, V. C., Costantino, J. P., Trauth, J. M., Bass, G., and LeGasse, A. A. (1994). High nickel alloys workers study update. University of Pittsburgh. Final report to NiPERA.

 6. Redmond, C. K., Sussman, N. B., Arena, V. C., and Costantino, J. P.(1996). Supplemental analysis of high nickel alloys workers. University of Pittsburgh. Final report to NiPERA.

 7. Simonato, L., Fletcher, A. C., Andersen, A., Andersen, K., Becker, N., Chang-Claude, J., Ferro, G., Gérin, M., Gray, C. N., Hansen, K. S., Kalliomäki, P.-L., Kurppa, K., Långard, S., Merló, F., Moulin, J. J., Newhouse, M. L., Peto, J., Pukkala, E., Sjögren, B., Wild, P., Winkelmann, R., and Saracci, R. (1991). A historical prospective study of European stainless steel, mild steel, and shipyard welders. Br. J. Ind. Med., 48, 145-154.

 8. Moulin, J. J., Mantout, B., Portefaix, P., Wild, P., Fournier-Betz, M., Mur, J. M. , and Smagghe, G. (1992). Etude épidémiologique de mortalité dans deux aciéries d'acier inoxydable. [Historical prospective mortality study in two stainless steel factories]. Arch. Mal. Prof. Med. Trav. Secur. Soc., 53, 157-166.

 9. Pang, D., Burges, D. C., and Sorahan, T. (1996). Mortality study of nickel platers with special reference to cancers of the stomach and lung, 1945-93. Occup. Environ. Med., 53, 714-717.

 10. Andersen, A., Engeland, A.; Berge, S.R., and Norseth, T. (1996). Exposure to nickel compounds and smoking in relation to incidence of lung and nasal cancer among nickel refinery workers. Occup. Environ. Med., 53, 708-713.

 11. Anttila, A., Pukkala, E., Aitio, A., Rantanen,T., and Karjalainen, S. (1998). Update of cancer incidence among workers at a copper/nickel smelter and nickel refinery. Int. Arch. Occup. Environ. Health, 71, 245-250.

 12. Egedahl, R. D., Carpenter, M., and Homik, R. (1993). An update of an epidemiological study at a hydrometallurgical nickel refinery in Fort Saskatchewan, Alberta. Health Reports, 5, 291-302.

 13. Ottolenghi, A. D., Haseman, J.K., Payne, W. W., Falk, H. J., and MacFarland, H. N. (1974). Inhalation studies of nickel sulfide in pulmonary carcinogenesis in rats. J. Natl. Cancer Inst., 54, 1165-1172.

 14. Dunnick, J. K., Elwell, M. R., Radovsky, A. E., Benson, J. M., Hahn, F. F., Nikula, K. J., Barr, E. B., and Hobbs, C. H. (1995). Comparative carcinogenic effects of nickel subsulfide, nickel oxide, or nickel sulfate hexahydrate on chronic exposures in the lung. Cancer Res., 55, 5251-5256.

 15. NTP (National Toxicology Program) Draft Technical Report (1994a). Toxicology and carcinogenesis studies of nickel subsulfide in F344/N rats and B6C3F1 mice. NTP TR 453, NIH publication No. 94-3369.

 16. NTP (National Toxicology Program) Draft Technical Report (1994b). Toxicology and carcinogenesis studies of nickel oxide in F344/N rats and B6C3F1 mice. NTP TR 451, NIH publication No. 94-3363.

 17. Tanaka, I, Horie, A., Haratake, J., Kodama, Y., and Tsuchiya, K. (1988). Lung burden of green nickel oxide aerosol and histopathological findings in rats after continuous inhalation. Biol. Trace Elem. Res., 16, 19-26.

 18. Takenaka, S., Hochreiner, D., and Oldiges, H. (1985). Alveolar proteinosis induced in rats by long-term inhalation of nickel oxide. In Progress in Nickel Toxicology (S.S. Brown and F. W. Sunderman Jr. Eds.), pp. 89-92. Blackwell Scientific Publications, Oxford.

 19. Horie, A., Haratake, J., Tanaka, I., Kodama, Y., and Tsuchiya, K. (1985). Electron microscopical findings with special reference to cancer in rats caused by inhalation of nickel oxide. Biol. Trace Elem. Res., 7, 223-239.

 20. Glaser, U., Hochrainer, D., Oldiges, H., and Takenaka, S. (1986). Long-term inhalation studies with NiO and As2O3 aerosols in Wistar rats. In Health hazards and biological effects of welding fumes and gases: Proceedings of the international conference; February 1985; (R. M. Stern, A. Berlin, A. C. Fletcher, J. Jarvisalo, Eds.) pp. 325-328. The Netherlands: Excerpta medica (International Congress series No. 676). Amsterdam, Copenhagen, Denmark.

 21. Wehner, A. P, Busch, R. H., Olson, R. J., and Craig, D. K. (1975). Chronic inhalation of nickel oxide and cigarette smoke by hamsters. Am. Indust. Hyg. Assoc. J., 36, 801-810.

 22. Wehner, A. P., Dagle, G. E., and Busch, R. H. (1984). Pathogenicity of inhaled nickel compounds in hamsters. In Nickel in the human environment: Proceedings of a joint symposium: March 1983 (Sunderman, F. W. Jr., Ed.), pp. 143-151. International Agency for Research on Cancer, (IARC scientific publications no. 53). Lyon, France.

 23. Benson, J. M., Chang, I.-Y., Cheng, Y. S., Hahn, F. F., Kennedy, C. H., Barr, E. B., Maples, K. R., and Snipes, M. B. (1995). Particle clearance and histopathology in lungs of F344/N rats and B6C3F1 mice inhaling nickel oxide or nickel sulfate. Fundamental and Applied Toxicology, 28, 232-244.

 24. Benson, J. M., Barr, E. B., Bechtold, W. E., Cheng, Y. S., Dunnick, J. K., Eastin, W. E., Hobbs, C.H., Kennedy, C. H., and Maples, K. R. (1994). Fate of inhaled nickel oxide and nickel subsulfide in F344/N rats. Inhalation Toxicology 6, 167-183.

 25. Oberdörster, G., Baggs, R. B., and Finkelstein, J. (1995). Pulmonary retention and effects of inhaled NiO and Ni3S2 in rats and mice: indicators of maximum tolerated dose? Annals of Clinical and Laboratory Sciences, 25, pp. 441, abstract 101.

 26. Mauderly, J. L. (1994). Non-cancer pulmonary effects in chronic inhalation exposure of animals to solid particles. In Toxic and Carcinogenic Effects of Solid Particles in the Respiratory Tract (U. Mohr, D. L. Dungworth, J. L. Mauderly, and G. Oberdörster, Eds.), pp.43-55. ILSI Monographs ILSI Press, Washington, DC.

 27. Mauderly, J. L., Burton Snipes, M., Barr, E. D., Belinsky, S. A., Bond, J. A., Brooks, A. L., Chang, I-Y, Cheng, Y. S., Gillet, N.A., Griffith, W. C., Henderson, R. F., Mitchell, C. E., Nikula, K. J., and Thomassen, D. G. (1994). Pulmonary toxicity of inhaled diesel exhaust and carbon black in chronically exposed rats. Part I: neoplastic and nonneoplastic lung lesions. Health Effects Institute (HEI). HEI Research report No. 68. Montpelier, VT: Capital City Press.

 28. Cerutti, P.A. (1985). Pro-oxidant states and tumor promotion Science, 227, 375-381.

 29. Driscoll, K. E., Carter, J. M., Howard, B. W., and Hassenbein, D. G. (1994). Mutagenesis in rat lung epithelial cells after in vivo silica exposure or ex vivo exposure to inflammatory cells. A. J. Respir. Crt. Care Med,. 149, A553.

 30. Driscoll, K. E., Carter, J. M., Howard, B. W., and Hassenbein, D. G., Pepelko, W., Baggs, R. B., Oberdörster G. (1996). Pulmonary inflammatory, chemokines and mutagenic responses in rats after subchronic inhalation of carbon black. Tox. Appl. Pharmacol., 136, 372-380.

 31. Oberdörster, G. (1995). Lung particle overload: implications for occupational exposures to particles. Reg. Toxicol. and Pharmacol., 21, 123-135.

 32. Snipes, M. B. (1996) Current information on lung overload in nonrodent mammals: contrast with rats. Inh. Toxicol., 8(suppl), 91-109.

 33. Schroeder, H. A., Balassa, J. J., and Vinton, W. H. (1964). Chromium, lead, cadmium, nickel and titanium in mice: effect on mortality, tumors and tissue levels. J. Nutr., 83, 239-250.

 34. Schroeder, H.A., Mitchener, M., and Nason, A.P. (1974). Life-term effects of nickel in rats: survival, tumors, interactions with trace elements and tissue levels. J. Nutr., 104, 239-243.

 35. Schroeder, H. A. and Mitchener, M. (1975). Life-term effects of mercury, methyl mercury, and nine other trace metals on mice. J. Nutr., 105, 452-458.

 36. Ambrose, A. M., Larson, P. S., Borzelleca, J. F., and Hennigar, G. R. Jr. (1976). Long term toxicologic assessment of nickel in rats and dogs. J. Food Sci. Technol., 13, 181-187.

 37. Gilman, J. P. W. (1962). Metal Carcinogenesis. II. A study of the carcinogenic activity of cobalt, copper, iron and nickel compounds. Cancer Res., 22, 158-162.

 38. Payne, W. W. (1964). Carcinogenicity of nickel compounds on experimental animals. Proc. Am. Assoc. Cancer Res., 5, 50.

 39. Kasprzak, K. S., Gabryel, P., and Jarczewska, K. (1983). Carcinogenicity of nickel (II) hydroxides and nickel(II) sulfate in Wistar rats and its relation to the in vitro dissolution rates. Carcinogenesis, 4, 275-279.

 40. Kasprzak, K. S. (1994). Lack of carcinogenic activity of promptly soluble (hydrated) and sparingly soluble (anhydrous) commercial preparations of nickel (II) sulfate in the skeletal muscle of male F334/NCR rats. Toxicologist, 14, 239.

 41. Stoner, G. D., Shimkin, M. D., Troxell, M. C., Thompson, T. L., and Terry, L. S. (1976). Test for carcinogenicity of metallic compounds by the pulmonary tumor response in Strain A mice. Cancer Res., 36, 1744-1747.

 42. Poirier, L. A., Theiss, J. C., Arnold, L. J., and Shimkin, M. B. (1984). Inhibition by magnesium and calcium acetates, of lead subacetate- and nickel acetate-induced lung tumors in strain A mice. Cancer Res., 44, 1520-1522.

 43. Kasprzak, K. S., Diwan, B. A., Konishi, N., Misra, M., and Rice, J. M. (1990). Initiation by nickel acetate and promotion by sodium barbital of renal cortical epithelial tumors in male F344 rats. Carcinogenesis, 11(4), 647-652.

 44. Pott, F., Rippe, R. M., Roller, M., Csicsaky, M., Rosenbruch, M., and Huth, F. (1992). Carcinogenicity of nickel compounds and nickel alloys in rats by intraperitoneal injection. In Nickel in human health: current perspectives (E. Nieboer, and J. O. Nriagu, Eds.) pp. 491-502. John Wiley and Sons, Inc., New York, NY.

 45. NTP (National Toxicology Program) Draft Technical Report (1994c). Toxicology and carcinogenesis studies of nickel sulfate hexahydrate in F344/N rats and B6C3F1 mice. NTP TR 454, NIH publication No. 94-3370.

 46. Hueper, W. C. and Payne, W. W. (1962). Experimental studies in metal carcinogenesis. Arch. Environ. Health, 5, 445-462.

 47. Pott, F., Ziem, U., Reiffer, F. J., Huth, F. Ernst, H., and Mohr, U. (1987). Carcinogenicity studies on fibers, metal compounds, and some other dusts in rats. Exp. Pathol. 32, 129-152.

 48. Muhle, H., Bellman, B., Takenaka, S., Fuhst, R., Mohr, U., and Pott, F. Chronic effects of intratracheally instilled nickel-containing particles in hamsters. In: Nickel and Human Health: Current Perspectives. Nieboer, E.; Nriagu, N. O., eds. New York, NY: John Wiley & Sons, Inc. p. 467-479 (1992).

 49. Biggart, N. W. and Costa, M. (1986). Assessment of the uptake and mutagenicity of nickel chloride in Salmonella tester strains. Mutat. Res., 175, 209-215.

 50. Miura, T., Patierno, S. R., Sakuramoto, T., and Landolph, J. R. (1989). Morphological and neoplastic transformation of C3H/10T1/2 Cl 8 mouse embryo cells by insoluble carcinogenic nickel compounds. Environ. Mol. Mutagen., 14, 65-78.

 51. Little, J. B., Frenial, J.-M., and Coppey, J. (1988). Studies of mutagenesis and neoplastic transformation by bivalent metal ions and ionizing radiation. Terato., Carcino., Mutagen., 8, 287-292.

 52. Gurley, L. R., Valdez, J. G., Miglio, J. J., Cox, S. H., and Tobey, R. A. (1986). Biological availability of nickel arsenides: Cellular response to soluble Ni5As2. J. Toxicol. Environ. Hlth., 17, 101-117.

 53. Arrouijal, F. Z., Hildebrand, H. F., Vophi, H., and Marzin, D. (1990). Genotoxic activity of nickel subsulphide a-Ni3S2. Mutagenesis, 5(6), 583-589.

 54. Kargacin, B., Klein, C. B., and Costa, M. (1993). Mutagenic responses of nickel oxides and nickel sulfides in Chinese hamster V79 cell lines at the xanthine-guanine phosphoribosyl transferase locus. Mutat. Res., 300, 63-72.

 55. Biedermann, K. A. and Landolph, J. R. (1987). Induction of anchorage independence in human diploid foreskin fibroblasts by carcinogenic metal salts. Canc. Res., 47, 3815-3823.

 56. Skopek, ( 1995). Mutagenic potential of nickel compounds in human lymphoblastoid cells in vitro. Final report to NiPERA.

 57. Sen, P. and Costa, M. (1985). Induction of chromosomal damage in Chinese hamster ovary cells by soluble and particulate nickel compounds: Preferential fragmentation of the heterochromatic long arm of the X-chromosome by carcinogenic crystalline NiS particles. Canc. Res., 45, 2320-2325.

 58. Sen, P., Conway, K., and Costa, M. (1987). Comparison of the localization of chromosome damage induced by calcium chromate and nickel compounds. Canc. Res., 47, 2142-2147.

 59. Lin, X., Sugiyama, M., and Costa, M. (1991). Differences in the effect of vitamin E on nickel sulfide or nickel chloride-induced chromosomal aberrations in mammalian cells. Mutat. Res., 260, 159-164.

 60. Howard, W., Leonard, B., Moody, W., and Kochhar, T. S. (1991). Induction of chromosome changes by metal compounds in cultured CHO cells. Tox. Lett., 56, 179-186.

 61. Conway, K, Wang, X-W, Xu, L.-S., and Costa, M. (1987). Effect of magnesium on nickel-induced genotoxicity and cell transformation. Carcinogenesis, 8(8), 1115-1121.

 62. Christie, N. T., Sen, P., and Costa, M. (1988). Chromosomal alterations in cell lines derived from mouse rhabdomyosarcomas induced by crystalline nickel sulfide. Biol. Metals, 1, 43-50.

 63. Larramendy, M. L., Popescu, N. C., and DiPaolo, J. A. (1981). Induction by inorganic metal salts of sister chromatid exchanges and chromosome aberrations in human and Syrian hamster cell strains. Environ. Mutagen., 3, 597-606.

 64. Montaldi, A., Zentilin, L., Zordan, M., Bianchi, V., and Levis, A. G. (1987). Chromosomal effects of heavy metals (Cd, Cr, Hg, Ni and Pb) on cultured mammalian cells in the presence of nitrolotriacetic acid (NTA). Tox. Environ. Chem., 14, 183-200.

 65. Sharma, G. P., Sobti, R. C., Chaudhry, A., Ahluwalia, K. K., and Gill, R. K. (1987). Effect of some nickel compounds on the chromosome of mice and mosquitoes. La Kromosomo II, 45, 1423-1432.

 66. Mohanty, P. K. (1987). Cytotoxic effect of nickel chloride on the somatic chromosomes of swiss albino mice mus musculus. Current Sci., 56(22), 1154-1157.

 67. Chorvatovicova, D. (1983). The effect of nickel chloride on the level of chromosome aberrations in Chinese hamsters Cricetulus griseus. Biologia (Bratislava), 38(11), 1107-1112.

 68. Chorvatovicova, D. (1987). Synergic effects on chromosome aberration frequency of chromium and nickel ions in vivo. Biologia, 42(11), 1047-1052.

 69. Zhong, B.-Z., Li, Z.-Q., Ma, G.-Y., and Wang, B.-S. (1989). Study of the mutagenicity and carcinogenicity of produced nickel dust. Environ. Mol. Mutagen., 14 (Suppl. 15), Abstract no. 669.

 70. Zhong, Z., Troll, W., Koenig, K. L., and Frenkel, K. (1990). Carcinogenic sulfide salts of nickel and cadmium induce H2O2 formation by human polymorphonuclear leukocytes. Canc. Res., 50, 7564-7570.

 71. Costa, M., Abbracchio, M. P., and Simmons-Hansen, J. (1981). Factors influencing the phagocytosis, neoplastic transformation, and cytotoxicity of particulate nickel compounds in tissue culture systems. Toxicol. Appl. Pharmacol., 60, 313-323.

 72. Patierno, S. R., Dirscherl, L. A., and Xu, J. (1993). Transformation of rat tracheal epithelial cells to immortal growth variants by particulate and soluble nickel compounds. Mutat. Res., 300, 179-193

 73. DiPaolo, J. A. and Casto, B. L. C. (1979). Quantitative studies of in vitro morphological transformation of Syrian hamster cells by inorganic metal salts. Cancer Res., 39, 1008-1313.

 74. Costa, M. and Mollenhauer, H. H. (1980). Phagocytosis of nickel subsulfide particles during the early stages of neoplastic transformation in tissue culture. Canc. Res., 40, 2688-2694.

 75. Abbracchio, M. P., Simmons-Hansen, J., and Costa M. (1982a). Cytoplasmic dissolution of phagocytized crystalline nickel sulfide particles: a prerequisite for nuclear uptake of nickel. J. Toxicol. and Environ. Health, 9, 663-676.

 76. Heck, J. D. and Costa, M. (1983). Influence of surface charge and dissolution on the selective phagocytosis of potentially carcinogenic particulate metal compounds. Canc. Res., 43, 5652-5656.

 77. Costa, M. and Heck, J. D. (1984). Perspective on the mechanism of nickel carcinogenesis. In Advances in Inorganic Biochemistry, (G. L. Eichhorn and L. Marzilli, Eds.), Vol. 6, Chapter 8, pp. 285-309. Springer-Verlag, New York.

 78. Sunderman, F. W., Jr., Hopfer, S. M., Knight, J. A., McCully, K. S., Cecutti, A. G., Thornhill, P. G., Conway, K., Miller, C., Patierno, S. R., and Costa, M. (1987). Physicochemical characteristics and biological effects of nickel oxides. Carcinogenesis, 8(2), 305-313.

 79. Huang, X., Kitahara, J., Zhitkovich, A., Dowjat, K and Costa, M. (1995). Heterochromatic proteins specifically enhance nickel-induced 8-oxo-dG formation. Carcinogenesis, 16, 1753-1759.

 80. Patierno, S. R., Sugiyama, M., Basilion, J. P., and Costa, M. (1985). Preferential DNA-protein cross-linking by NiCl2 in magnesium-insoluble regions of fractionated Chinese hamster ovary cell chromatin. Can. Res., 45, 5787-5794.

 81. Sen, P. and Costa, M. (1986). Pathway of nickel uptake influences its interaction with heterochromatic DNA. Toxicol. Appl. Pharmacol., 84, 278-285.

 82. Klein, C. B., Conway, K., Wang, X. W., Bhamra, R. K., Lin, X., Cohen, M. D., Annab, L., Barrett, J. C., and Costa, M. (1991). Senescence of nickel-transformed cells by an X chromosome: possible epigenetic control. Science, 251, 796-799.

 83. Costa, M. (1991). Molecular mechanisms of nickel carcinogenesis. Ann. Rev. Pharmacol. Toxicol., 31, 321-337.

 84. Lee, Y.-W., Klein, C. B., Kargacin, B., Salnikow, K., Kitahara, J., Dowjat, K., Zhitkovich, A., Christie, N. T., and Costa, M. (1995). Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens. Mol. Cell. Biol., 15(5), 2547-2557.

 85. Kasprzak, K. S., Diwan, B. A., Rice, J. M., Misra, M., Riggs, C. W., Olinski, R., and Dizdaroglu, M. (1992). Nickel(II)-mediated oxidative DNA base damage in renal and hepatic chromatin of pregnant rats and their fetuses. Possible relevance to carcinogenesis. Chem. Res. Toxicol., 5, 809-815.

 86. Datta, A. K., Misra, M., North, S. L., and Kasprzak, K. S. (1992). Enhancement by nickel(II) and L-histidine of 2'-deoxyguanosine oxidation with hydrogen peroxide. Carcinogenesis, 13(2), 283-287.

 87. Kawanishi, S., Inoue, S., and Yamamoto, K. (1989). Site-specific DNA damage induced by nickel(II) ion in the presence of hydrogen peroxide. Carcinogenesis, 10(12), 2231-2235.

 88. Nackerdien, Z., Kasprzak, K. S., Rao, G., Halliwell, B., and Dizdaroglu, M. (1991). Nickel(II)- and Cobalt(II)-dependent damage by hydrogen peroxide to the DNA bases in isolated human chromatin. Canc. Res., 51, 5837-5842.

 89. Misra, M., Olinski, R., Dizdaroglu, M., and Kasprzak, K. S. (1993). Enhancement by L-histidine of Nickel(II)-induced DNA-protein cross-linking and oxidative DNA base damage in the rat kidney. Chem. Res. Toxicol., 6, 33-37.

 90. Trott, D. A., Cuthbert, A. P., Overell, R. W., Russo, I., and Newbold, R. F. (1995). Mechanisms involved in the immortalization of mammalian cells by ionizing radiation and chemical carcinogens. Carcinogenesis, 16, 193-204.

 91. Zhang, Q. and Barrett, J. C. (1988). Dose-response studies of nickel-induced morphological transformation of Syrian hamster embryo fibroblasts. Toxic. In Vitro, 2(4), 303-307.

 92. Wang, X. W., Lin, X., Klein, C. B., Bhamra, R. K., Lee, Y. W., and Costa, M. (1992). A conserved region in human and Chinese hamster X chromosomes can induce cellular senescence of nickel-transformed Chinese hamster cell lines. Carcinogenesis, 13, 555-561.

 93. Conway, K. and Costa, M. (1989b). Nonrandom chromosomal alterations in nickel-transformed Chinese hamster embryo cells. Canc. Res., 49, 6032-6038.

 94. Swenberg, J. A. (1995). Bioassay design and MTD setting: old methods and new approaches. Reg. Toxicol. and Pharm., 21, 44-51.

 95. Yu, C. P., Hsieh, T. H., and Oberdörster, G. (1998). Dosimetry of inhaled nickel compounds. Abstract and presentation made at the American Association for Aerosol Research Annual Meeting held June 22-26, 1998 in Cincinnati, Ohio.

 96. Hausinger, R. P. (1992). Biological utilization of nickel. In Nickel in human health: current perspectives (E. Nieboer, and J. O. Nriagu, Eds.), pp. 21-36. John Wiley and Sons, Inc. New York, NY.

 97. Abbracchio, M. P., Evans, R. M., Heck, J. D., Cantoni, O., and Costa M. (1982b). The regulation of ionic uptake and cytotoxicity by specific amino acids and serum components. Biol. Trace Element Res., 4, 289.

 98. Sunderman, F. W. Jr. and Maenza, R. M. (1976). Comparisons of carcinogenicity of nickel compounds in rats. Chem. Pathol. Pharmacol., 14, 319-330.

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