Exposure to Different Forms of Nickel and Risk of Lung Cancer

Tom K. Grimsrud1,, Steinar R. Berge2, Tor Haldorsen1 and Aage Andersen1

1 Cancer Registry of Norway, Institute of Population-based Cancer Research, N-0310 Oslo, Norway.
2 Environment, Health, and Safety Department, Falconbridge Nikkelverk A/S, N-4606 Kristiansand, Norway.

Received for publication January 24, 2002; accepted for publication June 5, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The International Agency for Research on Cancer has classified nickel compounds as carcinogenic to humans, but it is still not known with certainty which forms of nickel pose the risk. In a case-control study of Norwegian nickel-refinery workers, the authors examined dose-related associations between lung cancer and cumulative exposure to four forms of nickel: water-soluble, sulfidic, oxidic, and metallic. A job-exposure matrix was based on personal measurements of total nickel in air and quantification of the four forms of nickel in dusts and aerosols. Data on smoking habits were collected for 213 cases identified in the Cancer Registry of Norway between 1952 and 1995 and 525 age-matched controls (94% participation rate). The nickel exposures were moderately to highly correlated. A clear dose-related effect was seen for water-soluble nickel (odds ratio = 1.7 per unit in the loge-transformed exposure, ln[(cumulative exposure) + 1], originally given in (mg/m3) x years (95% confidence interval: 1.3, 2.2)). A general rise in risk from other types of nickel could not be excluded, but no further dose-dependent increase was seen. Smoking was a weak to moderate confounder. The study suggests an important role of water-soluble nickel species in nickel-related cancer.

case-control studies; inhalation exposure; lung neoplasms; nickel; occupational exposure; smoking

Abbreviations: Abbreviation: CI, confidence interval.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In 1990, a working group of the International Agency for Research on Cancer evaluated epidemiologic and experimental studies of nickel-related cancer and concluded that nickel compounds were carcinogenic to humans (1). The same year, a large epidemiologic report on cancer mortality in 10 cohorts of occupationally exposed workers was published (2). The report, prepared by the International Committee on Nickel Carcinogenesis in Man, aimed at identifying the chemical forms of nickel that were responsible for the elevated risk. Mortality from cancers of the lung and nasal sinuses was associated with exposure to high levels of oxidic nickel compounds, exposure to sulfidic nickel in combination with oxidic nickel, and exposure to water-soluble nickel, alone or together with less soluble compounds (2).

In 1992 and 1996, new findings on cancer risk in two high-risk cohorts from southern Wales and Norway were published (3, 4). Analyses with quantitative exposure estimates indicated that water-soluble nickel was the most important risk factor, a conclusion that was later supported by a Finnish study (5). However, results from recent inhalation experiments in rodents seem to conflict with epidemiologic findings, since no carcinogenic activity was found in either rats or mice that had been breathing water-soluble nickel for 2 years (nickel sulfate hexahydrate) (6). Furthermore, sulfidic nickel (nickel subsulfide) alone produced a clear carcinogenic response in rats, while the effect from oxidic nickel (nickel oxide) was less clear. The high toxicity of nickel sulfate strongly limited the lung burdens that could be obtained in the rodents (6), a fact that may reduce the relevance of this experiment. On the other hand, many of the epidemiologic studies have suffered from sparse data on nickel exposures (2, 3). Moreover, several authors have called for better information on tobacco smoking (2, 7), as such data have been lacking in the exposed cohorts, except for the Norwegian workers, who were categorized as ever or never smokers (4, 8). In a recent evaluation of the carcinogenic properties of water-soluble nickel, the issue was judged impossible to settle (7), and the classification was left open.

The aim of the present study was to explore the dose-related association between cumulative exposure to nickel and lung cancer, with optimal adjustment for smoking, according to the four forms of nickel conventionally addressed: water-soluble, sulfidic, oxidic, and metallic. Another aim was to evaluate the effect of joint exposure to nickel and tobacco smoking.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study group, cases, and controls
Our study group included men who had been employed at the nickel refinery in Kristiansand, Norway, for a minimum of 12 months from the start of the works in 1910 through 1994, and who were under observation for cancer by the Cancer Registry of Norway between December 1952 and August 1995. The Cancer Registry of Norway is based on compulsory reporting of new cases of cancer by doctors and pathology laboratories (9). The cohort was somewhat extended in comparison with earlier studies, since some names were added according to payrolls and employment lists from the years between 1917 and 1940. In all, we had a cohort of 5,389 men with 227 incident cases of lung cancer. The distribution of data with respect to year of birth, year of first employment, year of diagnosis, and age at diagnosis is shown in table 1 for persons included in the analyses.


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TABLE 1. Characteristics of 213 patients with lung cancer diagnosed between 1952 and 1995 and 525 controls among Norwegian nickel-refinery workers
 
For cases diagnosed from 1970 onwards, three controls per case were randomly drawn among cohort members who were at risk at the time of diagnosis (incidence density sampling). The controls were free of lung cancer and had been born within 24 months from the case’s date of birth. Because of economic limitations and the assumed practical problems of acquiring information on the oldest members of the cohort, we chose to draw controls in a 1:1 ratio for cases diagnosed before 1970. To avoid loss of power, we had to draw new controls for three of the cases diagnosed before 1970, since no relatives were accessible for interview for the controls originally selected.

Collection of data
Cases and controls or their closest relatives were contacted by interviewers who were blind to the case/control status of the person in question. Information was sought by questionnaire on all occupations held for 1 year or more, dates of employment and dismissal, type of work, type of employer, and education. Information on smoking history was requested, including type of tobacco smoked (cigarettes, pipes, cigars, or cigarillos), daily amount smoked, and starting and stopping dates for all periods of smoking.

For 13 cases, we did not succeed in obtaining an interview. An additional case was excluded because the corresponding control, due to an error, did not match the case with respect to birth date. Thus, 213 cases, or 94 percent of those originally identified, were included in the analyses. Data were collected for 525 controls, representing 94 percent of the 559 controls matched to the participating cases.

For 46 individuals, age at onset of smoking was unknown. These missing values were replaced by the median onset age among smokers with a known value (16 and 17 years among cases and controls, respectively). Nineteen missing values for daily amount smoked were replaced by the median consumption among all smokers who used the same combination of types of tobacco. We computed the cumulative amount of tobacco smoked in kilograms up to the case’s date of diagnosis within each set of case and controls. Furthermore, we counted the total number of years as a smoker, calculated the corresponding average daily tobacco consumption in grams per day, and, for former smokers, calculated the number of years between smoking cessation and the date of diagnosis. A description of participants’ smoking habits is given in table 2, together with estimates of relative risk for lung cancer.


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TABLE 2. Smoking habits of patients with lung cancer and age-matched controls in a study of Norwegian nickel-refinery workers observed from 1952 to 1995
 
Exposures
Nickel exposures at the refinery had recently been reassessed and summarized in a job-exposure matrix (10). Nickel concentrations in air were based on 5,900 personal measurements of total nickel taken regularly between 1973 and 1994. From an earlier study, we knew that a cancer hazard was present at the refinery until the 1970s (4), so there was an overlap between the carcinogenic exposures and the personal monitoring. The relative concentrations of four forms of nickel were estimated on the basis of speciation analyses of refinery dusts and aerosols conducted during the 1990s. These analyses were performed with a sequential leaching (extraction) technique (11), and some measurements were verified with x-ray diffraction and scanning electron microscopy (12). Nickel appeared to be present in several forms at the refinery wherever the element was found (1214) (see table 3). The most prevalent form of water-soluble nickel was nickel sulfate until 1952, when nickel chloride became the predominating soluble form in some departments (15, 16). Oxidic and sulfidic nickel have been present as mixtures of several variants of the compounds. Time- and department-specific concentrations were estimated for the entire production period from 1910 through 1994. For the years prior to 1973, levels for each department were computed through backwards calculation with multiplication factors, which were based on important changes in production technology or chemistry or improvements in the work environment (10).


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TABLE 3. Nickel levels in air and distributions of different forms of nickel as a proportion (by weight) of total nickel in selected departments and time periods at a nickel refinery in Norway*
 
In two respects, the new exposure matrix differed substantially from the estimates developed approximately 15 years earlier through a semiquantitative approach for the International Committee on Nickel Carcinogenesis in Man study (2, 10). Firstly, in the new matrix, 10–15 percent by weight of total nickel was taken to be water-soluble in the grinding, roasting, and smelting departments (table 3), which previously were thought to be practically devoid of water-soluble species (2). Secondly, in the electrolysis departments, the new estimates of total nickel concentration were considerably lower than the old ones (2, 10).

The historical personnel files at the refinery contained the work histories of all employees, including shifts between departments. Cumulative exposures were computed throughout each man’s career as the sum of the products of concentration (in mg/m3) and corresponding duration (in years). Only 10 percent of the controls and 4.2 percent of the cases were unexposed to nickel. Further descriptive data on the exposures are shown in table 4. Some of the workers had been exposed to arsenic, asbestos, cobalt, or mists containing sulfuric acid, and some had also been exposed to lung carcinogens in work outside the refinery. Pairwise correlations between the continuous nickel variables were computed, revealing a medium to high degree of correlation (table 4).


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TABLE 4. Cumulative nickel exposures and correlations among lung cancer patients and their age-matched controls employed between 1910 and 1994 at a nickel refinery in Norway
 
Data analysis
Relative risks were estimated as odds ratios and 95 percent confidence intervals derived from conditional logistic regression models using the Stata statistical package (17, 18). Graphs were created with the program S-Plus (19). Initial analyses were performed with each form of nickel exposure included separately in smoking-adjusted models, using an unexposed reference group and five categories of exposure reflecting quintiles among the exposed controls. The dose-response relations were inspected in graphs where the logarithm of risk was plotted by the median exposure value within each category. When more than one form of nickel was included in the models, we used one or more variables in their continuous form in order to avoid numerical instability. Models were fitted with combinations of categorical, continuous log-linear, continuous log-transformed, and dichotomous (ever/never) exposure variables. The effect of a variable or group of variables adjusted for smoking was tested by likelihood ratio test. A 5 percent level of significance was used.

To allow for a possible late-stage effect from nickel, our primary approach was to perform analyses without lagging of exposure. Secondarily, we explored the effect of applying a 10 and 20 years’ lag, that is, disregarding nickel exposure during the last 10 and 20 years, respectively, before the case’s date of diagnosis. Adjustment for smoking was achieved through introduction of a variable with five categories: never smoker, former smoker for 5 years or more before the date of diagnosis, and three levels of mean daily tobacco consumption among current smokers (table 2). Potential effect modification between smoking and nickel exposure was investigated, and population attributable fractions were calculated on the basis of mutually adjusted relative risks and proportions of exposed cases (20).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The models with categorical nickel variables included separately produced elevated risks in all exposure categories for all forms of nickel (table 5). The strongest effect was found for water-soluble nickel, with a maximum odds ratio in the highest exposure category of 3.8 (95 percent confidence interval (CI): 1.6, 9.0) and a significant improvement in goodness of fit (p = 0.002). The plot of the log risk by median exposure in each category displayed a strictly monotonic dose-response curve for water-soluble nickel (figure 1, part a), suggesting a curvilinear relation. The trends were not equally clear for the other forms of nickel (figure 1, parts bd).


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TABLE 5. Smoking-adjusted* odds ratios for lung cancer by cumulative exposure to four different forms of nickel in a nested case-control study of Norwegian nickel-refinery workers observed between 1952 and 1995
 


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FIGURE 1. Smoking-adjusted odds ratios for lung cancer by cumulative exposure to four forms of nickel in a nested case-control study of Norwegian nickel-refinery workers observed between 1952 and 1995. The graphs show odds ratios for exposure variables categorized by quintiles among exposed controls. Odds ratios are plotted according to the median exposure value among cases and controls within each category. Each graph shows the odds ratio on a logarithmic scale unadjusted for the other forms of nickel. The vertical bars show 95% confidence intervals.

 
We fitted a model with the risk described as a function of the logarithmic transformation of exposure to water-soluble nickel. The risk at zero exposure was allowed to differ from this general relation by inclusion of a dichotomous term, which took the same value for all exposed individuals. The model may be written

ln(OR) = ß0 x EEw-s Ni + ß1 x ln(CEw-s Ni + 1), (1)

where ln denotes the natural logarithm (loge); OR denotes the odds ratio; EEw-s Ni denotes a dichotomous variable taking the value 1 when an individual is ever exposed to water-soluble nickel and zero otherwise; CEw-s Ni denotes cumulative exposure to water-soluble nickel in (mg/m3) x years; and ß0 and ß1 are coefficients to be estimated. The resulting estimates corresponded to a rise in odds ratio of 1.5 (95 percent CI: 0.6, 3.5) in exposed individuals compared with the unexposed, multiplied with 1.7 (95 percent CI: 1.3, 2.2) per unit in the natural log-transformed exposure originally given in (mg/m3) x years. These terms were highly significant (p = 0.0001). The curve predicted on the basis of the results gave a satisfactory fit to the odds ratios in the categorized variable (figure 2). We used this model (equation 1) in the subsequent analyses to adjust for water-soluble nickel when the effects from less soluble forms were investigated. However, because of problems with collinearity, we left out the dichotomous term whenever a categorized nickel variable was included in the model.



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FIGURE 2. Smoking-adjusted odds ratios for lung cancer by cumulative exposure to water-soluble nickel in a nested case-control study of Norwegian nickel-refinery workers observed between 1952 and 1995. The graph shows the observed risk for an exposure variable categorized by quintiles among exposed controls. Odds ratios are plotted on a logarithmic scale by the median exposure value among cases and controls. The area of the circles is proportional to the corresponding number of cases. The vertical bars show 95% confidence intervals. The solid line depicts risk predicted from a fitted model with the equation OR = 1.5ever exposed x 1.7ln(cumulative exposure + 1), where "ever exposed" takes the value 1 when the individual is exposed, zero otherwise; and "ln" is the natural logarithm.

 
With adjustment for smoking and water-soluble nickel, the categorized variable for sulfidic nickel showed elevated odds ratios at all levels, still without any clear dose-related trend (table 6). A continuous log-linear variable representing exposure to sulfidic nickel produced a negative slope (not shown). A similar pattern was found for oxidic nickel (table 6). For metallic nickel, the estimates were close to unity in the categorized variable (table 6), and even here a negative log-linear trend was found. We also included the three less soluble forms of nickel as three log-linear variables simultaneously in a model adjusted for smoking and water-soluble nickel. The log-linear variables showed no dose-related increase in risk, with odds ratios varying between 0.9 and 1.0 per unit of exposure in (mg/m3) x years.


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TABLE 6. Adjusted* odds ratios for lung cancer by exposure to sulfidic, oxidic, or metallic nickel in a nested case-control study of Norwegian nickel-refinery workers observed between 1952 and 1995
 
The lack of a dose-dependent risk from the less soluble types of nickel suggested that their effect could be represented by a dichotomous variable. However, the high degree of covariation between all four dichotomous nickel variables made it impossible to identify separate effects. In fact, exposure to water-soluble nickel occurred whenever nickel was present, so the term "ever exposed to water-soluble nickel" (EEw-s Ni in equation 1) would be equivalent to "ever exposed to nickel in any form" (EENi). Throughout the analyses with two or more forms of nickel, the natural log-transformed water-soluble nickel showed a highly significant odds ratio varying between 1.6 and 2.2. According to this, our best suggestion of the true relation between nickel exposure and lung cancer risk would be expressed in equation 1, where the dichotomous term would represent exposure to nickel in any form (EENi replacing EEw-s Ni).

This final model was explored for interaction between the smoking variable and the natural log-transformed water-soluble nickel variable, and a deviation towards a submultiplicative pattern was suggested. However, the interaction terms were not statistically significant. None of the nonsmoking cases were unexposed to nickel, so no completely unexposed reference group could be established. In table 7, the relative risks are shown according to two levels of total nickel exposure and three categories of smoking habits.


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TABLE 7. Odds ratios for lung cancer by joint exposure to smoking and total nickel in a nested case-control study of Norwegian nickel-refinery workers observed between 1952 and 1995
 
The fraction of cancer cases attributed to nickel and thus thought to be preventable by elimination of this exposure was 54.0 percent (95 percent CI: 43.6, 62.5), while 89.7 percent (95 percent CI: 82.4, 94.0) was attributed to smoking, under the presumption in each case that the other exposure would remain unchanged.

The general risk patterns were rather similar when we explored the effect of applying 10- and 20-year lags to the exposure data. With a 10-year lag, there were signs of a better fit and higher odds ratios in the categorized variables as well as in the final model. With a lag of 20 years, the association appeared less close than the associations found with the other two procedures. The results obtained from the final model with these three approaches are shown in table 8.


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TABLE 8. Odds ratios for lung cancer with lagging of nickel exposure in a nested case-control study of Norwegian nickel-refinery workers observed between 1952 and 1995
 
As a check for potential residual confounding, we included in the final model continuous variables for total amount smoked, duration of smoking, and number of years as a former smoker. The inclusion of these variables led to negligible changes in the main effect estimates. Furthermore, the results did not change when we controlled for exposure to arsenic, asbestos, cobalt, and sulfuric acid mists at the refinery and for possible occupational carcinogens outside the refinery. In general, the degree of confounding from smoking was weak to moderate, with a less than 25 percent change in the estimates in the final model.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The main purpose of this study was to obtain a better understanding of the relation between exposure to nickel and human lung cancer risk. Incident cancers were identified in a cancer registry of high quality, and vital status in controls was verified from Statistics Norway. The exposure matrix was based on personal measurements of total nickel, covering in part the period with a known carcinogenic exposure. Speciation analyses performed on dusts and aerosols from the same refinery were used to estimate the relative amounts of four forms of nickel. The participation rate in the interviews was well above 90 percent among both cases and controls.

The study provided evidence of a dose-related association between lung cancer and exposure to water-soluble nickel. The less soluble forms possibly contributed to an elevated risk, but we were not able to identify separate effects, and no dose-dependent risk was observed. With respect to water-soluble nickel, our findings support the conclusions from earlier cohort studies (25). There was a low to moderate degree of confounding from smoking.

The pronounced retrospective nature of the study, with cases and controls being sampled from a period of more than 40 years, and the high mortality among lung cancer patients could easily have led to information bias in the interviews and thus could have compromised the data on smoking. Smoking constituted the principal potential confounder and effect modifier in the study. The observed relative risks and the attributable fraction for tobacco were similar to what has been reported in other studies with firsthand information on smoking (21, 22), which suggests that the quality of our data was satisfactory.

Some nondifferential misclassification must be expected to exist in the exposure data, since no personal monitoring was performed until 1973. Besides, it was not possible to differentiate between exposure levels according to job tasks within the departments. Even the personnel files carried some degree of uncertainty, especially concerning the earliest decades of the refinery’s history. Underestimation of exposures incurred during those years, which are known to entail a high risk of cancer (4, 8, 23), could lead to an overestimation of the risk at low levels of cumulative exposure. Under extreme circumstances, such misclassification could flatten or even reverse the direction of a dose-response curve. The concentrations of the four forms of nickel, however, were computed as proportions of the total nickel values, and therefore a possible underestimation of exposure would have tended to affect all nickel species to the same degree. An overestimation of exposure levels might result from a tendency of workers to hold their breath in peak exposure situations or from the use of respirators, which became mandatory (and possibly more frequent) after 1973 in areas where the nickel threshold limit value was exceeded.

Easton et al. (3) estimated the relative potencies of the four forms of nickel in a regression analysis of the southern Wales refinery data. The best-fitting model suggested risks associated with exposure to water-soluble nickel and metallic nickel. Much less risk, if any, was found for oxides or sulfides (3). As regards chemical and technical conditions, there were several similarities between parts of the Welsh refinery before 1930 and the Norwegian plant before 1978, particularly concerning the raw material and some of the initial preparation and separation steps. Still, taking notice of the differences in epidemiologic approach, as well as the uncertain exposure estimates at the Welsh plant, we find the results from the two studies to be rather consistent. A recent Finnish study (5) also offered support for our findings. It demonstrated a higher incidence of lung cancer in refinery workers who were exposed mainly to water-soluble nickel compared with colleagues exposed to sulfidic compounds.

It has been claimed that the cancer pattern at another nickel refinery conflicts with the Norwegian findings (2, 7). Between 1926 and 1984, the refinery at Port Colborne, Canada, was conducting an electrolytic process similar to the Norwegian nickel electrolysis before 1978 (2, 24). However, no clear sign of lung cancer risk has been reported from working in the nickel tankhouse at the Canadian refinery (2, 25). The discrepancy has tentatively been ascribed to a more extensive handling of insoluble nickel species in the Norwegian electrolysis departments (2, 7). Another possible explanation could be the differences regarding exposure to water-soluble nickel.

The Norwegian plant conducted copper electrolysis that constantly produced aerosols from an electrolyte that carried approximately 60–70 g of nickel per liter. The same high nickel concentration was found in the dilute sulfuric acid recycled for copper extraction (copper leaching). In fact, the highest exposures among the Norwegian electrolysis workers were recorded in the stirring, filtering, and drying activities connected with the copper leaching and electrolyte purification steps (10), and a high proportion of water-soluble nickel has indeed been reported in exposures from electrolyte purification activities (26). At Port Colborne, however, no copper leaching or copper electrolysis was performed, since most of the copper had already been taken out during preparation of the raw material (2, 27). The low copper contents also resulted in a nickel electrolyte that did not require the same extensive purification as the Norwegian one.

Differences in exposure conditions could also possibly explain the contrasts between the epidemiologic studies and the animal inhalation studies. In a refinery, contrary to animal experiments, concomitant exposures may influence the distribution, uptake, and excretion patterns of water-soluble nickel. In general, results from experimental studies can always be questioned when it comes to their relevance to humans. Even within rodents—that is, between rats and mice and between male and female mice—there seem to be differences with respect to carcinogenic activity from inhalation of nickel (6).

The mass and size of aerosol particles influence distribution and deposition in human airways. The filter specimens on which our exposure matrix was based were collected with traditional 37-mm "total aerosol" samplers, which leave out more of the large particles than the new "inhalable aerosol" samplers do (28). A causal inference of the associations found in our study would depend on the presumption that the proportions of nickel species found in aerosols were similar also for the small particle fractions, and that the distribution of particle size was fairly consistent across departments and periods. Of course, this need not be correct, and some variation in particle size and nickel species distribution was certainly found recently between different departments in a Russian refinery that conducts an electrolytic process similar to the Norwegian process prior to 1978 (29).

To our knowledge, only a few investigations have addressed particle size and speciation simultaneously, and the amount of information is too scanty to be of any great help in the elaboration of an exposure matrix. Interestingly, measurements at the Norwegian refinery in the 1990s demonstrated an increasing proportion of water-soluble nickel with decreasing particle size in aerosols from the roasting and smelting departments (13). In the respiratory fraction, consisting of the small particles penetrating to the alveoli, as much as 72 percent by weight of the total nickel was water-soluble. In the Russian refinery mentioned above, the highest level of water-soluble nickel was found on top of the roasters, not in the hydrometallurgical departments (29). However, the Norwegian roasters after 1978, as well as the Russian ones, were both of a fluidized-bed type, which is technically quite different from the mechanically rabbled, multiple hearth roasters used in Norway between 1915 and 1978. Although fine particles constitute only a small part of the total aerosol (14), the high proportion of water-soluble nickel may be important for lung cancer risk

The estimated population attributable fraction of 54 percent suggested that nickel exposure could explain most of the excess lung cancer in the cohort compared with the general population, since a reduction to unity of the reported overall standardized incidence ratio of 3.0 (4) would require the prevention of two thirds of the cases.

Conclusions
Our results demonstrated a dose-related association between lung cancer and cumulative exposure to water-soluble nickel compounds. An additional increase in risk irrespective of dose also seemed to be present, but the effect could not be assigned to any specific form of nickel. There was low to moderate confounding from smoking. The results suggest that the role of water-soluble species in nickel carcinogenesis may be more important than previously recognized.


    ACKNOWLEDGMENTS
 
This study was performed with funding from the Norwegian Cancer Society, the Confederation of Norwegian Business and Industry Working Environment Fund, Falconbridge Nikkelverk A/S, and the Cancer Registry of Norway.

The authors thank Kirsten Boldt, Åse Lona, and Borghild Løver for collection of data by interview, Geir Helland-Hansen and Jan Ivar Martinsen for data management and programming, and Odd Magnussen for quality control of personnel files.


    NOTES
 
Reprint requests to Dr. Tom K. Grimsrud, Cancer Registry of Norway, Institute of Population-based Cancer Research, Montebello, N-0310 Oslo, Norway (e-mail: tom.k.grimsrud{at}kreftregisteret.no). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. International Agency for Research on Cancer. Chromium, nickel and welding. Lyon, France: International Agency for Research on Cancer, 1990:257–445. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 49).
  2. Doll R, Andersen A, Cooper WC, et al. Report of the International Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health 1990;16:1–82.[ISI][Medline]
  3. Easton DF, Peto J, Morgan LG, et al. Respiratory cancer mortality in Welsh nickel refiners: which nickel compounds are responsible? In: Nieboer E, Nrigau JO, eds. Nickel and human health: current perspectives. Advances in environmental sciences and technology. New York, NY: John Wiley and Sons, Inc, 1992:603–19.
  4. Andersen A, Engeland A, Berge SR, et al. Exposure to nickel compounds and smoking in relation to incidence of lung and nasal cancer among nickel refinery workers. Occup Environ Med 1996;53:708–13.[Abstract]
  5. Anttila A, Pukkala E, Aitio A, et al. Update of cancer incidence among workers at a copper/nickel smelter and nickel refinery. Int Arch Occup Environ Health 1998;71:245–50.[ISI][Medline]
  6. Dunnick JK, Elwell MR, Radovsky AE, et al. Comparative carcinogenic effects of nickel subsulfide, nickel oxide, or nickel sulfate hexahydrate chronic exposures in the lung. Cancer Res 1995;55:5251–6.[Abstract]
  7. Haber LT, Erdreicht L, Diamond GL, et al. Hazard identification and dose response of inhaled nickel-soluble salts. Regul Toxicol Pharmacol 2000;31:210–30.[ISI][Medline]
  8. Magnus K, Andersen A, Høgetveit AC. Cancer of respiratory organs among workers at a nickel refinery in Norway. Int J Cancer 1982;30:681–5.[ISI][Medline]
  9. Association of Nordic Cancer Registries. Survey of Nordic Cancer Registries. Copenhagen, Denmark: Danish Cancer Society, 2001:7–18. (World Wide Web URL: http://www.cancer.dk/ANCR/).
  10. Grimsrud TK, Berge SR, Norseth T, et al. Assessment of historical exposures in a nickel refinery in Norway. Scand J Work Environ Health 2000;26:338–45.[ISI][Medline]
  11. Zatka VJ, Warner JS, Maskery D. Chemical speciation of nickel in airborne dusts: analytical method and results of an interlaboratory test program. Environ Sci Technol 1992;26:138–44.[ISI]
  12. Andersen I, Berge SR, Resmann F. Speciation of airborne dust from a nickel refinery roasting operation. Analyst 1998;123:687–9.[ISI][Medline]
  13. Aitken RJ, Cherrie B, Donaldson R, et al. Development of health related sampling instrumentation for assessing workers exposure to aerosols in the nickel industry. (Report to the Nickel Producers Environmental Research Association (phase 3 report)). Edinburgh, United Kingdom: Institute of Occupational Medicine, 1998:1–100.
  14. Werner MA, Thomassen Y, Hetland S, et al. Correlation of urinary nickel excretion with observed "total" and inhalable aerosol exposures of nickel refinery workers. J Environ Monit 1999;1:557–62.[ISI][Medline]
  15. Archibald FR. The Kristiansand nickel refinery. J Met [New York] 1962;14:648–52.
  16. Stensholt EO, Zachariasen H, Lund JH. Falconbridge chlorine leach process. Trans Inst Min Metall 1986;5:C10–16.
  17. Breslow NE, Day NE. Statistical methods in cancer research. Vol 1. The analysis of case-control studies. Lyon, France: International Agency for Research on Cancer, 1980. (IARC scientific publication no. 32).
  18. Stata Corporation. Stata statistical software, release 7.0. College Station, TX: Stata Corporation, 2001.
  19. Insightful Corporation. S-Plus 2000 Professional, release 2. Seattle, WA: Insightful Corporation, 1999.
  20. Rothman KJ, Greenland S. Modern epidemiology. 2nd ed. New York, NY: Lippincott Williams and Wilkins, 1998.
  21. Kjuus H, Langård S, Skjærven R, et al. A case-referent study of lung cancer, occupational exposures and smoking. III. Etiologic fraction of occupational exposures. Scand J Work Environ Health 1986;12:193–202.[ISI][Medline]
  22. Doll R, Peto R, Wheatley K, et al. Mortality in relation to smoking: 40 years’ observations on male British doctors. BMJ 1994;309:901–11.[Abstract/Free Full Text]
  23. Pedersen E, Høgetveit AC, Andersen A. Cancer of respiratory organs among workers at a nickel refinery in Norway. Int J Cancer 1973;12:32–41.[ISI][Medline]
  24. International Nickel Company of Canada. Metallurgical improvements in the treatment of copper-nickel ores. Trans Can Inst Mining Met 1948;51:187–98.
  25. Mastromatteo E. Nickel: a review of its occupational health aspects. J Occup Med 1967;9:127–36.[ISI][Medline]
  26. Warner JS. Occupational exposure to airborne nickel in producing and using primary nickel products. In: Sunderman FW, Aitio A, Berlin A, et al, eds. Nickel in the human environment. Proceedings of a joint symposium held by the International Agency for Research on Cancer, Lyon, France, 8–11 March, 1983. Lyon, France: International Agency for Research on Cancer, 1984:419–37.
  27. Walter HW. Nickel, its history, refining, and uses. Can Chem 1931;15:185–94.
  28. Tsai PJ, Vincent JH, Wahl G, et al. Occupational exposure to inhalable and total aerosol in the primary nickel production industry. Occup Environ Med 1995;52:793–9.[Abstract]
  29. Thomassen Y, Nieboer E, Ellingsen D, et al. Characterisation of workers’ exposure in a Russian nickel refinery. J Environ Monit 1999;1:15–22.[ISI][Medline]