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The assessment of the carcinogenic properties of different forms of nickel represents a challenge to the scientific and regulatory groups. In 1990, the International Agency for Research on Cancer (IARC) classified all nickel compounds, inclusive of water-soluble nickel salts, as “Group 1” carcinogenic to humans based on a sufficient amount of epidemiologic evidence.1 Nearly 10 years later, the U.S. corporation Toxicology Excellence for Risk Assessment concluded that the carcinogenic properties of water-soluble nickel compounds could not be determined.2 Their rationale for the conclusion, based on guidelines proposed by the U.S. Environmental Protection Agency (EPA) in 1996,3 was that the evidence consisted of conflicting data.
The main inconsistency was claimed to lie in the lack of satisfactory adjustment for potentially confounding factors, such as insoluble forms of nickel, tobacco smoking, arsenic, and sulfuric acid mists.2 Additionally, there is an intriguing contrast between negative inhalation experiments in animals, as reported from the U.S. National Toxicology Program,4 and the epidemiologic studies from nickel refineries during the 1990s. Although no carcinogenic effect was found in rodents exposed to nickel sulfate hexahydrate, a water-soluble compound,4 recent studies among nickel workers indicate that water-soluble nickel is the most important risk factor for excess respiratory cancer.5–8
At present, the relevance for some of these objections could perhaps be questioned. The bulk of evidence for the carcinogenicity of sulfuric acid mists is linked to laryngeal cancer,9 whereas nickel is considered a lung and nasal sinus carcinogen. Data on smoking have been included in studies from a Norwegian nickel refinery for 2 decades.6,8,10,11 Multivariable analyses of lung cancer risk according to different forms of nickel were published in 1992, 1996, and 2002,5,6,8 the latter after reassessment of the exposure estimates based on personal measurements and speciation analyses.12
Still, it would be of interest to see what impact other occupational carcinogens may have had on nickel refiners, whose elevated risk of respiratory cancer has been recognized and discussed since the 1930s.1 Refinery exposures represent complex chemical mixtures. In experimental studies, combined exposure to nickel and other carcinogens have shown a striking effect at low concentrations,13,14 but the role of occupational carcinogens other than nickel has not been evaluated quantitatively in epidemiologic studies in the nickel-producing industry. The present study addressed this issue by developing exposure estimates and analyzing risk for arsenic, asbestos, sulfuric acid mists, and cobalt. Additionally, we investigated the influence from employment in high-risk occupations outside the refinery. The analyses used data from a case–control study nested in the Norwegian nickel-refinery cohort, for whom detailed information had been collected on smoking habits and occupational history.
The risk according to different forms of nickel and tobacco smoking has been reported, with the finding of strong dose-related risks of lung cancer for water-soluble nickel and for smoking, after simultaneous adjustment for the 2 exposures.8 This setting offered a unique opportunity for further exploration of the risks among nickel refinery workers because of the completeness of the Norwegian cancer registry data, the documentation of exposures and process chemistry, the knowledge of historical smoking habits, and the individual work histories at the refinery.
Since the start of production in 1910, the refinery in Norway has been treating a sulfidic nickel copper concentrate (matte), consisting of approximately 45% nickel, 25% copper, 23% sulfur, 2% cobalt, and less than 2% iron and precious metals. A combination of pyrometallurgical and hydrometallurgical methods has been applied, with crushing, roasting (calcining), smelting, extraction (leaching) with dilute sulfuric acid or chlorine, and deposition of pure metals in electrolytic tanks (electrowinning and electrorefining processes). The electrorefining method required a number of electrolyte purification steps with precipitation and filtering. Details of the production method are available elsewhere.15,16
The nickel exposures recently were reassessed, based on 5900 personal measurements of total nickel from 1973 through more than 2 decades and speciation analyses from the 1990s. A job–exposure matrix was developed for water-soluble, sulfidic, oxidic, and metallic nickel covering the period from 1910 to 1994.12 For the same period, historical personnel files were available, with data on individual employment at the department level.
Our case–control study analyzed lung cancer cases (diagnosed between December 1952 and August 1995) and controls from a cohort of workers with a minimum employment of one year. Controls were required to be free from lung cancer at the time of diagnosis of the case (incidence density sampling) and were matched according to sex and year of birth. Information on smoking habits and occupational history outside the refinery was collected by interview with cases and controls or their next of kin. We included in the analysis 213 cases (94% of those originally identified), along with 525 controls (representing 94% of the 559 controls matched to the participating cases).8 The study followed guidelines reviewed and accepted by the Norwegian Data Inspectorate and the Regional Committee for Medical Research Ethics. Participation was based on informed consent.
Refinery Exposures Other Than Nickel
Arsenic is considered to be a human carcinogen because of strong epidemiologic evidence in individuals exposed by inhalation or ingestion.17,18 Around 1930, the proportion of arsenic in the matte increased 10-fold because of importation of matte from Canada (from 0.02% to 0.2% by weight). Changes in the electrolyte purification system led to recycling and a build-up of arsenic, causing concern as to industrial hygiene and production efficiency until the mid-1950s.
Data on arsenic in the process were summarized in 1995 by a retired chief chemist from the company.19 A time- and department-specific exposure matrix was constructed from these data and from the nickel exposure matrix,12 under the presumption that the proportion of arsenic to total nickel in aerosols was equal to the ratio in the intermediates. Levels greater than 0 were estimated for 22 departments and 6 periods between 1930 and 1955, with a maximum air concentration in the roasting department of about 0.4 mg/m3 during the 1940s and early 1950s. Selected results are shown in Figure 1.
The classification of asbestos as a carcinogen relies on epidemiologic as well as experimental evidence.17 Asbestos was used at the plant for protection against heat of both the workers and the equipment. The refinery's medical unit identified departments and periods where non-negligible exposure to asbestos was likely to have occurred, including furnace areas and some maintenance departments and workshops. We used a dichotomous categorization (exposure vs. no exposure).
Sulfuric Acid Mists
Recent reviews9,20 found epidemiologic evidence for a carcinogenic effect of exposure to mists containing sulfuric acid, mainly based on larynx cancer. At the refinery we studied, sulfuric acid was used in the extraction of copper from metal oxides by leaching and filtering operations. The sulfuric acid was regained, with a simultaneous generation of oxygen, at the anodes in the copper electrolysis, resulting in aerosols containing sulfuric acid, copper sulfate, and nickel sulfate from the electrolyte. The amount of sulfuric acid in the working atmosphere was presumed to be proportional to the water-soluble nickel level described in the nickel exposure matrix,12 with a factor reflecting the relative amounts in the solution. The level of sulfuric acid was estimated to be greater than 0 for 11 of the more than 80 departments covered by the nickel matrix,12 including the copper electrolysis and associated departments, the copper leaching department, and, for a limited period, the cobalt precipitation and cobalt electrolysis. The highest estimates occurred in the copper leaching area (up to 1.4 mg/m3). For more than two-thirds of the department-period combinations with sulfuric acid exposure, the values were less than 0.5 mg/m3.
In 2003, an expert working group appointed by IARC concluded that cobalt metal (in the absence of tungsten carbide) and water-soluble cobalt salts were possibly carcinogenic to humans.21 A small amount of cobalt has probably always followed nickel in the raw materials and intermediates at the refinery. From 1952 onwards, cobalt was produced electrolytically in an electrowinning process. Relative to nickel, there is more cobalt in the process today than several decades ago, due to a rising intake of raw material rich in cobalt.
Nearly 3500 personal samples from the breathing zone were analyzed for cobalt between 1982 and 1994 and were made accessible for the present study. The measurements were part of routine sampling, as reported for the nickel measurements in an earlier work.12 We excluded cobalt values above a chosen limit of 50 mg/m3 (only 3 measurements) and calculated 8-hour time-weighted arithmetic averages for the departments in question. Thirty percent of the measurements were below the limit of detection (median limit value 3 μg/m3), and these lower-than-detection values were substituted by half the detection limit. No major change in the average levels occurred whether the substitution value was set to zero or half the detection limit, except for some low exposure departments, where the levels changed within the range of 1.2 to 3.4 μg/m3.
The ratio between cobalt and total nickel in air was computed for departments and periods with measured values. Cobalt amounted to approximately 4-15% of the total nickel, except for the cobalt electrolysis in which cobalt tripled the nickel level. Departments with no measurements were assigned a cobalt–nickel ratio of 7.1%, which was the average for all measured departments exclusive of the cobalt electrolysis. Time trends in these ratios back in time were assumed to follow the trends of the corresponding ratio in the raw materials, or the ratio between the produced amounts of the 2 metals. In a final step, the absolute concentrations of cobalt were computed for each department and time period based on the nickel exposure matrix. Examples of the estimates for cobalt and water-soluble nickel are shown in Figure 2.
Occupational Exposures Outside the Refinery
In the interviews, participants were asked to list occupations outside the refinery held for 1 year or more, with time of start and stop, type of employer, and a short description of the work. The list of occupations for all participants was evaluated later, and the types of work classified according to the first 2 or 3 digits in the Nordic Classification of Occupations of 1965.22 Subsequently, the list was compared with a listing of occupations considered to present a lung cancer hazard based on the IARC evaluations of carcinogenic risk to humans.23
The total number of jobs outside the refinery held by cases and controls amounted to more than 4,000; of which 450 were considered to present a carcinogenic risk. Altogether 82 cases and 182 controls were involved in such work. Some of these 450 jobs (8%) lacked information either on time of start, time of stop, or both. The missing dates were substituted by dates taken from the refinery's personnel files, by the 15th birthday (first job), the 64th birthday (last job), or by midpoints, assuming equal lengths when more than one job outside the refinery were in question. Further details on type of work and distribution among cases and controls are seen in Table 1.
Nickel exposure was modeled as 2 variables, as developed in the previous article,8 a dichotomous variable (ever vs. never exposed to nickel) and a continuous function of cumulative exposure to water-soluble nickel (log-transformed). We calculated cumulative exposures to arsenic, sulfuric acid mists, and cobalt for each participant as the sum of products of time- and department-specific concentrations and corresponding durations.
For asbestos exposure at the refinery and for external jobs entailing a lung cancer hazard, quantitative measures were expressed as the number of years in exposed work. The correlations between cumulative exposure to water-soluble nickel and the other exposure measures were explored (data available with the electronic version of this article). To allow the dose–response pattern to take any form, we preferred categorical variables in the analyses, with 3 levels greater than 0 according to tertiles among exposed controls. Whenever collinearity threatened the stability of the results, we included the variable in its continuous form. Trend tests were performed by replacing each categorical variable, one at the time, with the corresponding continuous variable. We also fitted a model with these exposure variables included simultaneously as continuous variables. Product terms were generated from the water-soluble nickel variable (continuous), and arsenic, asbestos, sulfuric acid mists, and cobalt, respectively, in their continuous form. Smoking was adjusted for in the analyses according to a model developed in the previous article.8
In an additional model, the risk was analyzed by duration of employment in 3 major groups of departments at the refinery: the furnace departments and associated areas (pyrometallurgical production with exposure mainly to insoluble nickel); work in electrolysis, leaching, and associated departments (hydrometallurgical production with exposure mainly to water-soluble nickel); and work in maintenance departments. Further details on this categorization were given in a recent update of lung cancer incidence in the cohort.11 The early decades at the nickel refinery were characterized by more manual work and less strict boundaries between departments, and were associated with higher risk than the subsequent decades.11 We therefore chose to include an additional variable denoting first employment before 1930. The relative risks of lung cancer were estimated with the Stata Statistical Software as odds ratios (ORs) with 95% confidence intervals (CIs), using multivariable conditional logistic regression models.24
The results from the multivariable regression analyses, including all potential risk factors described previously are presented in Table 2. For arsenic exposure, a modest 20–30% elevated lung cancer risk was suggested, but no dose-dependent increase was seen. A trend was suggested with increasing length of work in occupations presenting carcinogenic risk outside the refinery, with a 50% excess risk from exposure of 15 years or more.
Exposure to asbestos at the refinery had no detectable influence on the risk of lung cancer. No effect from sulfuric acid mists was found in the fully adjusted model. The cobalt variable, attributable to collinearity, could not be retained in the full model in its categorized form, and the dose-related effect from cobalt alone (suggested in the continuous variable), changed sign in the full model. However, all individuals who were exposed to nickel also were exposed to cobalt, and the dichotomous nickel variable (thought to represent insoluble nickel species or possibly any form of nickel8) might even represent an effect of cobalt. None of the interaction terms was statistically significant. When all occupational exposures other than nickel were included simultaneously as continuous variables, the estimates were only slightly different from the linear trends reported in Table 2.
Table 3 displays the risk estimates by duration of work in 3 large groups of departments at the refinery, duration of work in high-risk occupations outside the refinery, and first employment at the refinery before 1930. Thus, work in the 3 department groups was mutually adjusted for in the model. Strong gradients were found by length of work in the production departments, with a 5-fold increase in relative risk for 12 years or more in the electrolysis and associated departments. In the group with no experience from production or maintenance departments, the lung cancer incidence, expressed as the standardized incidence ratio, was recently shown to be close to that of the general male population.11
As seen in Table 4, the estimated ORs according to nickel exposure changed only slightly when we adjusted for known lung carcinogens (arsenic, asbestos, and experience in external occupations presenting carcinogenic risk), or, additionally, for 2 suspected carcinogens (sulfuric acid mists and cobalt).
The present study is the first to report quantitative estimates of lung cancer risk from occupational exposures other than nickel, in a cohort of nickel-refinery workers. We found only weak effects, and the strong effect of nickel was not confounded to any substantial degree. Occupational exposures other than nickel posed no threat to the validity of the risk estimates according to nickel exposure and smoking, which were presented earlier.8
Some effect was suggested from arsenic, sulfuric acid mists, and cobalt when these exposures were explored separately in smoking adjusted models. There were, however, positive correlations between these exposures and water-soluble nickel, and the effects largely disappeared in the full model. A possible effect of cobalt could not be distinguished from the one earlier ascribed to insoluble forms of nickel.8
A fundamental question for the interpretation of our study is to what extent we have succeeded in describing the exposures retrospectively. Adequate nickel measurements existed only for the last quarter of a century, while important exposures obviously have occurred through the preceding 60 years.6,11 However, a recent comparison of the nickel-related risk patterns before and after 1968 suggested that the exposure estimates for the oldest period were consistent with those from more recent periods that were largely covered by environmental monitoring.11 For other occupational exposures, no aerosol measurements were available, except for cobalt and sulfuric acid mists in more recent periods. Although most of the exposure matrices had some link to measurements of process materials, errors probably do exist in the estimated aerosol values. The effect of this bias is difficult to predict, but a flattening of the dose-response curve would be expected, provided that areas with no exposure were correctly classified.25 The participation rate and the smoking data were judged to be satisfactory and should add credibility to our results.8,11
The problem with build-up of arsenic in some of the intermediate materials has been recognized earlier,26 but even if arsenic can increase lung cancer risk at relatively low levels,27 it is not likely to explain the substantial risk in workers hired after 1955.6,11 Elevated lung cancer risk was experienced at a Swedish copper smelter where the workers operated a multiple hearth roaster of a similar type as those used at the Norwegian nickel plant from 1915 to 1978. The risk among the Swedish workers was in part ascribed to arsenic in the raw material, which reached as much as 20% by weight28 (about 4 times the maximum content in the partly recycled roaster feed at the Norwegian refinery). Smoking-adjusted odds ratios for lung cancer in the Swedish low-exposure subgroups varied in the range 0.7–1.3, which can be taken to be in line with our findings.29
Most of the epidemiologic evidence for carcinogenicity of asbestos is based on workers exposed at very high levels.30 The validity of our asbestos matrix was recently supported by another study31 in the same refinery cohort, with the finding of a strong dose-dependent relationship between duration of asbestos exposure at the plant and pleural plaques diagnosed by x-ray examination. However, only 3 cases of pleural mesothelioma have been diagnosed among the nickel workers during the period 1953–2000, giving a standardized incidence ratio of 0.9 (95% CI = 0.2–2.8).11 In contrast, the overall standardized incidence ratio of lung cancer in the same period was 2.6 (2.3–2.9), based on 267 incident cancers. Asbestos exposure can increase the risk of both these diseases and, although sufficient to produce pleural plaques, it was, presumably, too low to produce excess cancer.
There is only limited evidence of a link between exposure to sulfuric acid mists and lung cancer.9 In industries where a such a risk has been suspected, the average concentration in air has been reported to be frequently above 0.5 mg/m3.20 According to our exposure matrix, the level was below this value for most of the departments and periods where the exposure occurred. Our estimates were compared with stationary measurements from a survey conducted at the plant by the National Institute of Occupational Health in the mid-1960s,32 and with stationary measurements carried out by the company in 1969 and in the period 1984–1994. From the 1960s, the measurements showed concentrations between 0.1 and 1.1 mg/m3. An arithmetic average of 0.18 mg/m3 based on stationary measurements in the copper electrolysis around 1990 was found to be in agreement with the downward trend from 0.2 to 0.05 mg/m3 in our estimates.
The lack of increased risk according to exposure to sulfuric acid mists may result from an absent or weak causal link, possibly combined with low exposure levels. Relatively few of the workers were exposed to acid mists (14% among the controls); nonetheless, the size of the study and the distribution of the exposures would leave us with roughly a 50% chance of detecting a relative risk of 2.
It was not possible to sort out a separate effect of cobalt. A lack of effect would be in accordance with the modest risk suggested in recent occupational studies, except for workers producing hard-metal of the combined cobalt and tungsten carbide type.33,34 Our negative results for cobalt may be the result of low exposures (all concentrations below 0.15 mg/m3), a problem with correlation, and possibly only a weak association to lung cancer in humans.
Controls tend to live longer than lung cancer patients, and the interview-based data on occupational history may be affected by information or recall bias. The size of this potential bias is difficult to assess. In a population-based case–control study of lung cancer in Norway with firsthand information on occupations, a smoking-adjusted relative risk slightly above 2.0 was reported in men with more than 10 years’ work with known carcinogenic exposures.35 Our finding, with suggestions of a positive trend and a maximum relative risk of 1.5 from work lasting for 15 years or longer, is in agreement with the existence of a cancer hazard. The effect remained unaltered whether adjustment for refinery work was obtained by duration of employment or by use of exposure matrices.
The present investigation did not support the suggestion that exposures other than nickel may explain the large excess of lung cancer among Norwegian nickel-refinery workers. The water-soluble nickel salts clearly remained the strongest candidate to explain the excess risk, a conclusion that is in harmony with earlier epidemiologic studies from Wales (UK), Finland, and Norway.5–7 Additional data pointing in the same direction have been reported from the former Soviet Union.1 Exposure to water-soluble nickel may even play an important role for the risk traditionally ascribed to insoluble forms of nickel, as water-soluble compounds repeatedly have been identified in furnace departments, especially in the fine particle fractions.12,36–38
Results from 2 cohorts have suggested that water-soluble nickel is not carcinogenic. One cohort is a small group of British nickel electroplaters,39 and the other is a larger group of electrolysis workers at a Canadian nickel refinery (Port Colborne).26,40 In the most recent report from the latter cohort (a mortality study), vital status was unknown for about 40% of the workers at the end of follow-up.26,40 The number of expected deaths was calculated under the assumption that these subjects were all alive throughout the follow-up period (a maximum of 35 years).40 Thus, inflated numbers of expected deaths, combined with a recognized deficit in the observed numbers, would be expected to give an unknown degree of underestimation in the mortality rates. The electroplater study39 included fewer than 300 men, most of whom were exposed for less than one year, presumably to low levels of water-soluble nickel compounds. The negative results from these cohorts are not strong enough to counter-balance the positive findings in the studies among Welsh, Finnish, and Norwegian nickel workers.
The weak to absent effects that we report, other than for nickel and tobacco smoking, could also be brought about by misclassification of exposure involving the groups that were considered unexposed, although this explanation does not seem very likely. We cannot determine from our data whether coexposure to tobacco smoke, or to other refinery exposures, or the occurrence of spontaneous mutations, may be an essential prerequisite for the carcinogenic effect of water-soluble nickel. Still, the dose-related risk pattern for exposure to the water-soluble fraction was highly consistent, only slightly changing by adjustment for known or suspected carcinogens acting as potential confounders. The role of the less soluble forms of nickel remains somewhat unclear, but our results reinforce the epidemiologic evidence for the carcinogenicity of water-soluble nickel salts.
We 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; Hans Zachariasen and Finn Resmann for help with the exposure assessments; Odd Magnussen for quality control of personnel files; and Paolo Boffetta for useful comments on earlier versions of the manuscript. We are also grateful to the management and union at the Norwegian refinery for giving us access to data and for their positive cooperation and encouragement throughout the studies.
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