Critical ReviewNickel Carcinogenesis

In a previous report (Pedersen et al., 1973) an excess risk of respiratory cancer among Norwegian nickel workers was demonstrated. The number of cancer cases was relatively small for the study of temporal changes in exposure. In this report the number of cancer cases increased by 70% through an extended follow-up to 1979, and the results published previously were confirmed. Data on smoking habits of the employees at the nickel refinery have now become available. The interaction between smoking and occupational nickel exposure is assessed by comparing the excess risk of lung cancer caused by smoking in the study group and in a sample of the general population. It is shown that the interaction is closer to being additive than multiplicative. This observation has methodological implications for studying temporal changes in occupational exposure. These implications are discussed. No substantial reduction in occupational exposure at the nickel refinery can be observed as far as lung cancer is concerned. For nasal cancer, however, the risk is much smaller among those employed around 1960 than among those employed around 1930. The difference in trend of occupational risk for the two types of cancer cannot be explained by the data presented.

Cancer of respiratory organs among workers at a nickel refinery in Norway.

Fine particles in the air have been associated with increased mortality and morbidity. Particulate air pollution is a complex mixture which varies by region and includes a number of components including residual oil fly ash (ROFA), a byproduct of power plant and industry fuel-oil combustion. Human airway epithelial cells exposed to ROFA release inflammatory cytokines including interleukin (IL)-6, IL-8, and tumor necrosis factor. Expression of these genes is dependent upon pretranscriptional binding of cis regulatory elements, including nuclear factor kappaB (NF-kappaB). To investigate the role of NF-kappaB in the particulate-induced IL-6 response, we exposed human airway epithelial cells (BEAS-2B) to ROFA in vitro. ROFA stimulated a time- and dose-dependent increase in IL-6 messenger RNA (mRNA), which was preceded by the activation of nuclear proteins binding to the NF-kappaB sequence motif in the IL-6 promoter. Transient transfection of BEAS-2B cells with the 5' promoter region of the IL-6 gene linked to a luciferase reporter gene confirmed that NF-kappaB binding is necessary for the transcription of IL-6 mRNA. The IL-6 response was inhibited by the metal chelator deferoxamine and the free radical scavenger N-acetyl-L-cysteine, suggesting that the activation of NF-kappaB may be mediated through reactive oxygen intermediates generated by transition metals found in ROFA. Activation of NF-kappaB may therefore be a critical first step in the inflammatory cascade following exposure to particles generated by oil combustion.

Air pollution particles induce IL-6 gene expression in human airway epithelial cells via NF-kappaB activation.

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 log(e)-transformed exposure, ln[(cumulative exposure) + 1], originally given in (mg/m(3)) 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.

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Exposure to Different Forms of Nickel and Risk of Lung Cancer

Publisher Summary This chapter discusses the trace metals found in soils, plants, and animals. Metal sources in soils include: (1) metals contained natively in rocks and minerals, from which the soil was formed; (2) metals added as impurities in fertilizers and lime, as constituents of pesticides and manure or as contaminants of sewage sludge; (3) metals in debris from industrial and mining wastes, fossil fuel combustion products, wind-eroded soil particles, atomic testing, pollen, sea spray, and meteoric and volcanic material that settles or rains out; and (4) metals in soil particles displaced through water erosion or metals dissolved or suspended in the water itself. The nature of the plant, including its species, size, growth rate, extent and depth of rooting, transpiration rate, and nutritional requirements, may affect its efficiency for metal absorption from soils. Trees are especially effective, in absorbing many trace metals (including many rare earths), from great depths and translocating them to the leaves as determined by their transpiration rate. The toxicological implications of metals in water are very complex. Metals may exist in water as dissolved ions, in organic complexes, adsorbed on clay particles, as suspended precipitates, contained in decaying organisms and other forms. Heavy metals are absorbed across the entire body surface of fish as well as the gills. They may attach to proteins during this passage and may be tightly protein-bound in the blood. Absorption from the digestive tract also is important since consumed marine plants contain virtually all trace metals in amounts that reflect metal concentrations in the contacting water.

Ernest Mastromatteo

Papers

Nickel: a review of its occupational health aspects.