Analyses of chromium and nickel in human pulmonary tissue

After inhalative occupational exposure to certain compounds containing nickel and chromium (mostly over many years), an accumulation of these metals may occur in the lung tissue. This is of particular importance, both from a toxicological point of view and with regard to expert reports, since certain nickel and chromium compounds may induce lung cancers. In the context of this study, samples of pulmonary tissue from 34 deceased persons from the Bergen area (Norway) were analysed by atomic absorption spectrometry with regard to their content of chromium and nickel. The deceased comprised 21 men and 13 women. In 15 cases, death resulted from lung cancer; in the other 19 deceased, there was no indication of a malignant disease of the airways. The concentrations of nickel found in the lung tissue do not differ between patients with lung cancer and patients with healthy lungs. On the other hand, the concentration of chromium in the pulmonary tissue in the patients who had died of lung cancer and who had all been inhalative smokers, are higher (statistically significant) than in the nonsmokers or in those with healthy lungs. An accumulation of these two metals in the tumor matrix could not be detected. Both the average nickel and the average chromium concentrations were higher in the persons who had probably been exposed occupationally. Considering the present state of scientific knowledge, the aspects relevant to expert reports which result from the analyses of metals in the pulmonary tissue are discussed.     

Investigations on the quantitative determination of nickel and chromium in human lung tissue

Summary Nickel (Ni) and some of its relatively insoluble compounds as well as chromates may be able to induce cancer in the region of the lungs, as well as in the nose and paranasal sinuses after occupational exposure. Latency periods may amount to 20 years and more. The results of recent investigations have shown that these metals cumulate in the lung tissue after inhalation of relatively insoluble chromium and nickel compounds. The quantitative detection of these heavy metals in samples of pulmonary tissue hence permits the amount of past exposure to be estimated. To establish the normal values, samples of pulmonary tissue from 30 normal subjects were investigated for chromium and nickel content. The samples were taken from different segments and lobes of the lungs, taking topographical anatomical criteria into consideration. In addition, 15 persons who had formerly been exposed to nickel and/or chromium (11 nickel refinery workers, of whom 10 had died of lung cancer, 2 stainless steel welders, 1 foundry worker, 1 electrical technician) were also investigated. From the results of 495 tissue samples from the normal group, median chromium concentrations between 130 and 280 ng/g were calculated, with median nickel concentrations of 20–40 ng/g (wet weight). If these values are related to the nickel concentrations measured in refinery workers, values 112-5,860 times higher were found. The concentrations were about 500 times higher than normal for nickel, and about 60 times higher than normal for chromium in the stainless steel welders. For the foundry workers who died of lung cancer, chromium and nickel concentrations in the normal range were calculated, with the exception of the nickel concentrations in the upper and lower lobes of the right lung. The very high nickel concentrations found in the samples of lung tissue from former nickel refinery workers should be regarded as a guideline with regard to the appraisal of the causal relationship between lung cancer and occupational exposure to relatively insoluble nickel compounds. This result is also supported by epidemiological investigations on this subgroup and must thus be considered etiologically conclusive. For the welders, chromium and nickel concentrations were found that were markedly above normal, but as yet there is no epidemiologically reliable verification for the increased occurrence of malignancies in this occupational group. On the basis of present scientific knowledge, no indications were found of relevant chromium and/or nickel exposure of the lung tissue that might be able to induce lung cancer in either foundry workers or for electric technicians.Dedicated to Professor V. Becker on his 65th birthday     

Biomonitoring of nickel and chromium in human pulmonary tissue

Nickel (Ni) and chromium (Cr) and some of its compounds may be able to induce cancer in the lungs as well as in the nose and paranasal sinuses after occupational exposure. Latency periods amount to 20 years and more. Therefore objective exposure data are not available in the most cases and expert evaluation of the causal connection is often difficult. Recent investigations have shown, that Ni and Cr can cumulate in human lung tissue after occupational exposure. For the evaluation of normal Ni- and Cr-values a total of 495 human lung tissue samples of 30 occupationally non-exposed persons were analysed by AAS including ZEEMAN-compensation after wet oxidative digestion. Additional samples of 10 deceased persons who have been occupationally exposed to nickel in previous times by nickel-refining and welding, especially flame spraying have been investigated. The median Ni- and Cr- concentrations in the lungs of the non-exposed persons ranged between 20–40 resp. 133–277 ng/g (wet weight). In nickel refinery workers Ni- concentrations were found which exceeded the normal range about 1,000. In welders, especially flame sprayers, also values more than 100 times higher could be analysed for Ni and Cr. Partially these concentrations were found years after the end of the inhalative exposure.     

Problems in establishing norm values for nickel and chromium concentrations in human pulmonary tissue

In 15 random autopsies, nickel (Ni) and chromium (Cr) were determined quantitatively by atomic absorption spectrometry (AAS) in human lung tissue to evaluate norm values. None of the deceased persons had had an occupational exposure to Cr or Ni or their compounds. In all, 22 tissue samples were taken from each lung at specific topographical anatomical locations. The analytical procedure is described in detail. The results showed substantial variation in concentrations both within a single lung and also between individuals. Median values found were 204 ng/g for Cr and 25.6 ng/g for Ni. Topographical concentrations of Cr and Ni were 1.3-1.9 times higher in the upper lung areas. In view of the variability in metal concentration, analysis of only one part of lung tissue is not sufficient for determining the content of the entire lung. The evaluation of norm values is an important precondition for appraisal of Cr and Ni accumulation in human pulmonary tissue that may be due to occupational exposure.     

Metal concentrations in lung tissue of subjects suffering from lung cancer

Summary Concentrations of nine metals (Fe, Ca, Mg, Zn, Cu, Co, Ni, Pb and Cr) concentrations in lung tissues from 224 lung cancer cases were compared with those in other cases to achieve an understanding of their contribution to the development of lung cancer and the varieties after the development of cancer. Comparisons of metal concentrations in each cell type of lung cancer were also performed. All cases were collected from routine autopsies in Tokyo and Saitama, Japan. The copper concentration in tissue from lung cancers was significantly higher than that in other specimens, although calcium, magnesium, zinc and cobalt concentrations in lung cancers were significantly lower than those in other cases. There were no significant differences in the 99% intervals (excluding extremely high values for occupationally exposed cases) for chromium, nickel and lead concentrations between lung cancers and other cases, although these values were lower in lung cancers. However, in comparisons of men only, the chromium concentration, the degree of lung contamination and the severity of pulmonary emphysema in lung cancer cases were significantly higher than those in other specimens. Moreover, percentages of lung cancer in men at each degree of contamination and each severity of emphysema increased with increasing grades. Thus, this finding could be evidence that the exposure to contaminants other than chromium and nickel in the air had affected the development of lung cancer, except for occupationally exposed individuals. Therefore, almost all chromium and nickel in lung tissue might not deposit in carcinogenic forms such as hexavalent chromium or nickel subsulfide. Comparison of the characteristics in each cell type of lung cancer revealed that calcium and chromium concentrations in lung tissue (not including tumor) or squamous cell carcinomas were higher than those in the other cell types. In small cell carcinomas, calcium magnesium and zinc concentrations were low.     

Lung lesions after experimental combined exposure to nickel and trivalent chromium

Rabbits were exposed to a combination of 0.7 mg/m3 of Ni2+ as NiCl2 and 1.2 mg/m3 of Cr3+ as Cr(NO3)3, to 0.6 mg/m3 of Ni2+ as NiCl2, or to filtered air for 4 months (5 days/week, 6 hr/day). Light microscopy of the lung tissue showed widespread areas with nodular accumulation of macrophages in all rabbits exposed to both metals, in two rabbits exposed to nickel alone, and in none of the controls. Electron microscopy of the lung showed attenuated septa and alveoli stuffed with surfactant-like material in the group exposed to both metals. In two of these rabbits, groups of alveoli were filled with densely packed debris and type I cell borders were obscure. The reaction in the group exposed to nickel alone was less prominent. The volume density of alveolar type II cells showed a fourfold increase after exposure to both metals and a twofold increase following exposure to nickel alone compared to controls. The lung tissue content of total phospholipids and especially phosphatidylcholines and phosphatidylinositols was significantly higher in the groups exposed to both metals than in controls or in animals exposed to nickel only. In lung tissue the molar percentage of 1,2-dipalmitoylphosphatidylcholine was significantly higher in the group exposed to both metals than in the other groups. The results indicate that trivalent chromium potentiates the effect of nickel on the type II cells resulting in an increased surfactant production; in addition, trivalent chromium probably reduces the catabolism of surfactant in alveolar macrophages. Our observations raise the concern that noxious effects might occur also in humans exposed to a combination of nickel and trivalent chromium.     

Effect of iron,cobalt, and chromium dust on rabbit alveolar macrophages: A comparison with the effects of nickel dust

In a previous inhalation study, exposure of rabbits to concentrations of 0.5 to 2 mg/m³ of metallic nickel dust over a period of 4 weeks produced certain reproducible effects on their lungs. The weight and density of the lungs increased as well as the phagocytic activity and size distribution of the alveolar macrophages. Changes in the ultrastructure of the macrophages and the lung lavage fluid were also seen. In the present study, groups of four rabbits each were exposed to iron dust (0.4 and 1.4 mg/m³), cobalt dust (0.2 and 1.3 mg/m³), and chromium dust (0.6 and 3.1 mg/m³). None of these metals gave the same pattern of effects as the nickel dust. The particles, including the nickel particles, were studied with regard to morphology, surface and bulk composition, specific surface area, and solubility in fluids. The nickel on the nickel particles, together with manganese on the chromium particles were the most soluble components. Otherwise, the nickel particles did not differ substantially from the other particles.     

Metal concentrations in human lung tissue,with special reference to age,sex, cause of death,emphysema and contamination of lung tissue

Summary Nine element concentrations in the lung tissues of 2,274 autopsies were determined in Japan by atomic absorption spectrometry. The metals determined were iron, calcium, magnesium, zinc, copper, cobalt, nickel, lead, and chromium. The range, mean, standard deviation, mode and median are described for each metal. Moreover, these data were analyzed statistically, based on their sex, age, degree of lung contamination (color and the amount of particle deposition), severity of pulmonary emphysema and cause of death. Iron, calcium, magnesium, zinc, copper and cobalt concentrations in the lung tissue seemed to be affected mostly by physiological variation and the levels in the blood. On the other hand, nickel, lead and chromium concentrations might reflect environmental exposure. Chromium concentration especially increased with age and showed a significantly positive correlation with the degree of contamination and severity of emphysema.     

Determination of nickel in lung specimens of thirty-nine autopsied nickel workers

Summary Lung specimens from 39 nickel refinery workers autopsied during the period from 1978 to 1984 were analyzed for nickel. Fifteen of the workers were employed in the Roasting and Smelting Department, where exposure to nickel was predominantly in the form of nickel-copper oxides, Ni₃S₂ and metallic dust. The remaining 24 men worked in the Electrolysis Department. Exposure in this group was considered to be mostly to the water-soluble compounds, NiSO₄ and NiCl₂, but also to a lesser degree to water-insoluble nickel compounds such as nickel-copper oxides and sulphides. The arithmetic mean ± SD for nickel concentration in lung tissues expressed in gg^–1 dry wt for the 39 workers was 150 ± 280. In the workers employed in the Roasting and Smelting Department, the average nickel concentration was 330 ± 380; for those who worked in the Electrolysis Department it was 34 ± 48. Lung tissue from 16 autopsied persons not connected with the refinery had an average nickel concentration of 0.76 ± 0.39. Statistical analysis based on log-normal distributions of the measured nickel concentrations allowed three major conclusions to be formulated: (1) nickel refinery workers exhibit elevated nickel levels in lung tissues at autopsy; (2) workers of the Electrolysis Department and the Roasting Smelting Department constitute distinct groups with respect to the accumulation of nickel in lung tissue; (3) workers who were diagnosed to have lung cancer had the same lung nickel concentrations at autopsy as those who died of other causes.     

Chromium content of organs of chromate workers with lung cancer

The content of chromium was measured in organs of six chromate workers who had worked in a chromate chemical manufacturing plant, had been exposed to a considerable amount of chromium for over 10 years, and had died of lung cancer. The chromium in the lungs of workers averaged 51.5 micrograms/g (range 24.8-210 micrograms/g), while levels in the lungs of non-exposed controls were 0.07-1.01 micrograms/g. Organs other than the lungs of the workers also had more chromium than those of the controls. Moreover, it was apparent that the metal remained in the lungs long after exposure to chromate had ceased.     

Cancer mortality among arc welders exposed to fumes containing chromium and nickel. Results of a third follow-up: 1989-1995

For the historical follow-up study among arc welders exposed to chromium and nickel, which was started in 1980 in Germany, a third follow-up extending the observation period to the years 1989 through 1995 has been carried out. By 1995, of the 1213 welders and 1688 turners (control group) who were originally included in the study, 274 welders and 448 turners had died. Death certificates could be obtained for approximately 96% of the deceased. Results of the evaluation presented in this article showed that cancer mortality remains significantly increased, compared with the general population and the control group, by approximately 35%. There was an elevation of approximately 50% or 60% in mortality from cancers of the respiratory tract, which is also statistically significant. However, this increase is predominantly due to a large excess in mortality from mesothelioma, which is known to be caused chiefly by asbestos exposure. Lung cancer mortality is nonsignificantly increased by approximately 20% to 30%. An indirect assessment of asbestos-related lung cancers and total cancer indicates that the observed increase of mortality might be mainly due to asbestos exposure. Beyond that, no indication of an elevated cancer risk specifically associated with the exposure to welding fumes containing chromium and nickel could be determined.     

Stainless steel manual metal arc welding fumes in rats.

Forty two male Wistar rats were exposed to manual metal arc (MMA) stainless steel (SS) welding fumes generated by an automatic welding device for "nose-only" exposure. The exposure simulated an actual MMA/SS welding environment as closely as possible. For the retention study, the duration of exposure was one hour per workday for one, two, three, of four weeks and for the clearance study four weeks. The retention and clearance of the chromium, nickel, and iron found in MMA/SS welding fumes in the rats' lungs were studied as was the distribution of the metals to other organs. Instrumental neutron activation analysis (INAA) was used for the multi-element chemical activation analyses. The concentrations of chromium and nickel in the blood and the urine were determined by atomic absorption method (AAS). The retention of exogenous iron was determined by a magnetic measuring method. The results indicated that the lungs were the target organs of soluble hexavalent chromates. The half times of lung clearance for Cr, Ni, and Fe were 40 +/- 4 d, 20 +/- d, and 50 +/- 10 d. When the lung clearance curves are compared, the half times of Cr and Fe lung clearance are similar but nickel disappears faster. The distribution and clearance patterns of chromium to other organs differ from those obtained after single intravenous or intratracheal injections of alkaline chromates.     

Mortality study of nickel platers with special reference to cancers of the stomach and lung, 1945-93.

OBJECTIVES: To re-examine mortality patterns in a cohort of nickel platers with no history of chromium plating. METHODS: All 284 men first employed by the company in 1945-75 with a minimum employment of three months in the nickel plating department were identified. Workers who had worked in the chromium plating or nickel/chromium plating departments were excluded. Standardised mortality ratios (SMRs), P values, and 95% confidence intervals were calculated. Poisson regression was used to carry out statistical modelling of mortalities within the cohort (internal standard). Four variables were considered to have the potential to influence mortality within the cohort: attained age (age at follow up or age at death), year of starting nickel work, period of follow up (measured from the first period of work with nickel exposure), and duration of exposure to nickel. RESULTS: The only significant difference between observed and expected numbers, when investigated by site of cancer and by broad non-cancer groupings, was that for stomach cancer (observed eight, expected 2.49, SMR 322). CONCLUSIONS: The study provides only weak evidence that nickel plating is associated with an excess risk of stomach cancer. This cohort of nickel platers does not seem to have experienced any discernible risk of occupational lung cancer. Other studies of nickel platers rather than nickel/chromium platers would be useful.     

Exposure to stainless steel welding fumes and lung cancer: a meta-analysis.

Stainless steel welding is associated with exposure to metals including hexavalent chromium and nickel. This study is a meta-analysis of five studies of stainless steel welders and the occurrence of lung cancer. Asbestos exposure and smoking habits have been taken into account. The calculated pooled relative risk estimate was 1.94 with a 95% confidence interval of 1.28-2.93. This result suggests a causal relation between exposure to stainless steel welding and lung cancer.     

Lung cancer in workers in a nickel refinery

ABSTRACT This study is an analysis of the occurrence of lung cancer in nickel workers, particularly with regard to development time, histological types and tobacco smoking, in addition to specific exposure to nickel dust and fumes. It is a continuation of previous work in this field (Kreyberg, 1954a, b; 1962, 1969). The series consists of 44 cases of lung cancer occurring during the years 1948-74 in people currently or previously employed at Falconbridge nickel refinery. A seven-year period of reduced activity during the war enables lung cancer in workers who took up employment in 1927-39 to be compared with that in workers who started in or after 1946. It is confirmed that exposure to nickel dust and fumes increases the risk of developing lung cancer. However, all subjects with small cell anaplastic carcinoma and at least 25 out of 28 subjects with epidermoid carcinoma had been tobacco smokers. Four smokers and four non-smokers had Group II tumours. The mean age at diagnosis of lung cancer in the nickel workers corresponds closely with that of male subjects with lung cancer in general, in spite of the very wide differences in the development time, if this is related to the employment time in the refinery alone. The mean age at diagnosis is, however, consistent if the development time is related to the length of tobacco smoking. Tobacco smoking is an important factor in the development of lung cancer in nickel workers, and under the conditions described in this study the reduced carcinogenic influence may be attributable to reduced exposure to nickel and possibly also to tobacco.     

An analysis of chromium,copper, and zinc in organs of a chromate worker

Summary The content of chromium, copper, and zinc and the valency of chromium were measured in organs of a chromate worker who had been exposed to a considerable amount of hexavalent chromium for 30 years and died of maxillary and lung cancer 10 years after his retirement. The chromium in the lung of the worker averaged 3,555 ppb on a wet tissue weight basis, while those in the lung of five controls were 86.0–399 ppb. Organs other than the lung of the worker also had more chromium than those of the controls. The amounts of copper and zinc did not vary as widely as did chromium. The ratio of hexavalent chromium to total chromium was 29.3% in the lung of the worker and 12.9 to 38.7% in controls, and its ratio in the lung was lower than that in the other organs.     

Investigation of a lung cancer cluster in the melt shop of an Ontario steel producer

Workers' concerns about an excess of cancer in an electric arc steelmaking operation were investigated. In comparison with men who had worked elsewhere in the plant, an increased risk of lung cancer death was observed among men who had been employed in the melt shop. The hypothesis that the association might be related to occupational exposures is supported by the persistence of the association when the hypothesis-generating cases were removed from the analysis (p = 0.063) and by a significant trend in the risk of lung cancer with years of exposure in the melt shop. No air sampling had been performed in earlier years. Current environmental analyses in the melt shop found no polycyclic aromatic hydrocarbons (detection limit: 0.001 mg/m3), and silica levels were below 0.1 mg/m3. The carcinogenic metals arsenic and chromium were detected, but their concentrations in earlier years are unknown.     

Indoor radon exposure and active and passive smoking in relation to the occurrence of lung cancer

Exposure to indoor radon and radon daughters is currently attracting great interest as a possible cause of lung cancer. This concern is supported by several studies, most of them relatively small in numbers or weak in the assessment of exposure. This study encompasses 177 persons with lung cancer and 677 noncancer referents, all deceased and with 30 years or more of residency in the same house in an area with radon-leaking alum shale deposits in the central part of southern Sweden. Exposure categories based on building material, type of house, and ground conditions were created, but measurements of the indoor radon daughter concentration were also made for 142 cases and 264 referents. Active and passive smoking was ascertained through questionnaires sent to the next-of-kin. Overall, the lung cancer risk was approximately twofold with regard to the categories of assumed radon daughter exposure for the rural sector of the population but not for the same categories of the urban sector, possibly because of less precise exposure assessment and influence from other factors. Occasional and passive smokers, as well as passive smokers alone, had a particularly increased risk of lung cancer in association with the increased exposure categories.     

Increased risk of lung cancer in the melting department of a second Ontario steel manufacturer

A study of lung cancer among workers at an electric arc steel making operation was performed to follow up on the observation of a lung cancer cluster in the melt shop of another plant. The study group comprised 335 deceased men identified from plant records. Eight of thirty men who had ever worked in the pouring pit area died of lung cancer (PMR 276; p less than 0.01), but increased risk was not found elsewhere in the melting department. There was a significant trend in lung cancer risk with the length of employment in the pit area during a time window 18-30 years before death. Smoking data suggested that smoking alone could not account for the increased risk. An industrial hygiene assessment found present exposures to carcinogenic metals and silica to be within current guidelines. No polycyclic aromatic hydrocarbons were detected. This is the second steel plant for which we have found increased lung cancer risk in the pouring areas. The causative factors have not yet been identified.     

Non-fibrous dust load and smoking in dental technicians: a study using bronchoalveolar lavage.

A study was conducted with transmission electron microscopy to find whether bronchoalveolar lavage could be used to identify subjects with occupational exposure to mineral particles. Non-fibrous mineral particles in bronchoalveolar lavage (BAL) fluid from 46 dental technicians and 41 white collar controls with lung diseases but free from occupational exposure to dusts were analysed. The total particle concentration in BAL fluid was significantly higher in dental technicians than in controls (12.18 x 10(5) particles/ml of BAL fluid, v 2.03 x 10(5) particles/ml, p < 0.001). Dental technicians had significantly more crystalline silica, aluminium, and alloys containing nickel and chromium. There was a non-significant twofold increase of total particle concentration in the lungs of dental technicians who were smokers compared with non-smokers. The results strongly support the use of BAL fluid analysis to assess dust accumulation in workers in heavily exposed occupations such as dental technicians. This is a valid method to evaluate occupational exposure to non-fibrous mineral particles, and may be useful to determine the occupational aetiology of some respiratory diseases.