The relative toxicity and carcinogenicity of nickel sulfate hexahydrate (NiSO4·6H2O), nickel subsulfide (Ni3S2), and nickel oxide (NiO) were studied in F344/N rats and B6C3F1 mice after inhalation exposure for 6 h/day, 5 days/week, for 2 years. Nickel subsulfide (0.15 and 1 mg/m3) and nickel oxide (1.25 and 2.5 mg/m3) caused an exposure-related increased incidence of alveolar/bronchiolar neoplasms and adrenal medulla neoplasms in male and female rats. Nickel oxide caused an equivocal exposure-related increase in alveolar/bronchiolar neoplasms in female mice. No exposure-related neoplastic responses occurred in rats or mice exposed to nickel sulfate or in mice exposed to nickel subsulfide. These findings are consistent with results from other studies, which show that nickel subsulfide and nickel oxide reach the nucleus in greater amounts than the do water-soluble nickel compounds such as nickel sulfate. It has been proposed that the more water-insoluble particles are phagocytized, whereas the vacuoles containing nickel migrate to the nuclear membrane, where they release nickel ions that effect DNA damage. The findings from these experimental studies show that chronic exposure to nickel can cause lung neoplasms in rats, and that this response is related to exposure to specific types of nickel compounds.
This research was conducted under Interagency Agreement Y01-ES-30108 between the National Institutes of Environmental Health Sciences and the United States Department of Energy. The in-life phase of the study was conducted at the Inhalation Toxicology Research Institute which is operated for the United States Department of Energy under contract DE-AC04-76EV01013. The facilities used for this research were fully accredited by the American Association for the Accreditation of Laboratory Animal Care.