The nickel ion bioavailability model of the carcinogenic potential of nickel-containing substances in the lung

Abstract

The inhalation of nickel-containing dust has been associated with an increased risk of respiratory cancer in workplaces that process and refine sulfidic nickel mattes, where workers are exposed to mixtures of sulfidic, oxidic, water-soluble, and metallic forms of nickel. Because there is great complexity in the physical and chemical properties of nickel species, it is of interest which specific nickel forms are associated with carcinogenic risk. A bioavailability model for tumor induction by nickel has been proposed, based on the results of animal inhalation bioassays conducted on four nickel-containing substances. The nickel ion bioavailability model holds that a nickel-containing substance must release nickel ions that become bioavailable at the nucleus of epithelial respiratory cells for the substance to be carcinogenic, and that the carcinogenic potency of the substance is proportional to the degree to which the nickel ions are bioavailable at that site. This hypothesis updates the nickel ion theory, which holds that exposure to any nickel-containing substance leads to an increased cancer risk. The bioavailability of nickel ions from nickel-containing substances depends on their respiratory toxicity, clearance, intracellular uptake, and both extracellular and intracellular dissolution. Although some data gaps were identified, a weight-of-evidence evaluation indicates that the nickel ion bioavailability model may explain the existing animal and in vitro data better than the nickel ion theory. Epidemiological data are not sufficiently robust for determining which model is most appropriate, but are consistent with the nickel ion bioavailability model. Information on nickel bioavailability should be incorporated into future risk assessments.

Persistent Hepatic Structural Alterations Following Nanoceria Vascular Infusion in the Rat

“…The appearance of very fine and larger nanocrystals suggests a critical role of the phagolysosome in the metabolism of nanoceria. While the mechanisms remain to be elucidated, the clinical presentation of metal fume fever appeared to be associated with lysosomal dissolution/releasing of zinc oxide nanoparticles (Kuschner et al 1995), localized release of nickel from a presumed insoluble compound playing a role in tumor formation (Pott et al 1992), and lysosomal-induced release of nickel ions with nuclear translocation in respiratory epithelial cells, all point to the pivotal role of the phagolysosome in nanoparticle metabolism and elimination (Goodman et al 2011). Other reports on lysosomal instability, phagolysosomal membrane breakage, and appearance of finer nanoparticles (Cho et al 2011;Miyawaki et al 2009;Rossi et al 2009;Tsai et al 2012) further indicate that the stability of the nanoparticle after phagolysosome enclosure is a major determinant of cellular toxicity.…”

Nickel release and surface characteristics of fine powders of nickel metal and nickel oxide in media of relevance for inhalation and dermal contact

“…Increased incidence of respiratory cancer has been observed among some groups of nickel refinery workers exposed to sulfidic, oxidic and water soluble nickel compounds, e.g. review by Goodman et al (2011). Only respiratory tumors have been consistently associated with exposure to nickel-containing compounds (Goodman et al, 2011).…”

Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide

“…Although the precise mode of action for nickel carcinogenesis has not been elucidated, nickel ion is considered to be the ultimate carcinogen. For lung tumor induction, the in vivo intracellular delivery of Ni ions is expected to be dependent on toxicity-limited exposure levels, clearance, cellular uptake, and extra and intracellular particle dissolution (e.g., Benson et al, 1992;Costa and Mollenhauer, 1980;Costa et al, 1981;Goodman et al, 2011;Hack et al, 2007).…”

“…The two highest Ni 3 S 2 inhalation exposure concentrations selected for this evaluation (0.15 and 0.6 mg/m 3 ) were similar to those used in the cancer 2-year study (0.15 and 1.0 mg/m 3 , Dunnick et al, 1995), and two lower exposure concentrations (0.04 and 0.08 mg/m 3 ) were added to more fully explore the dose-response for genomic changes. These exposure levels are roughly equivalent to inhalable workplace exposure levels ranging from 0.2 to 3.3 mg Ni/m 3 , when differences in parameters that affect deposited daily doses per surface area of the thoracic region of the lung are considered using a dosimetric model (see Goodman et al, 2011). The exposure duration of four weeks was selected to assure that steady-state concentrations of nickel were achieved and that cellular genomic responses had stabilized.…”