Particle Clearance and Histopathology in Lungs of F344/N Rats and B6C3F1 Mice Inhaling Nickel Oxide or Nickel Sulfate

Abstract

The goals of this study were to (1)determine the effects of repeated inhalation of relatively insoluble nickel oxide (NiO) and highly soluble nickel sulfate hexahydrate (NiSO4 6H2O) on lung particle clearance, (2)investigate the effects of repeated inhalation of NiO or NiSO4 on the pulmonary clearance of subsequently inhaled 85Sr-labeled microspheres, (3)correlate the observed effects on clearance with accumulated Ni lung burden and associated pathological changes in the lung, and (4)compare responses in F344 rats and B6C3F1, mice. Male F344/N rats and B6C3F1 mice were exposed whole-body to either NiO or NiSO4 6H2O 6 hr/day, 5 days/week for up to 6 months. NiO exposure concentrations were 0, 0.62, and 2.5 mg NiO/m for rats and 0, 1.25, and 5.0 mg NiO/ m for mice. NiSO4 6H2O/m3 exposure concentrations were 0, 0.12, and 0.5 mg NiSO4 6H2 for rats and 0, 0.25, and 1.0 mg NiSO4 6H2O/m3 for mice. After 2 and 6 months of whole-body exposure, groups of rats and mice were acutely exposed nose-only to 63 (NiO-exposed animals only), 63NiSO4 6H2O (Ni SO4 6H2O animals only), or to 85Sr-labeled polystyrene latex (PSL) microspheres (both NiO- and NiSO4 6H2O-exposed animals) to evaluate lung clearance. In addition, groups of rats and mice were euthanized after 2 and 6 months of exposure and at 2 and 4 months after the whole-body exposures were completed to evaluate histopathological changes in the left lung and to quantitate Ni in the right lung. Repeated inhalation of NiO results in accumulation of Ni in lungs of both rats and mice, but to a greater extent in lungs of rats. During the 4 months after the end of the whole-body exposures, some clearance of the accumulated Ni burden occurred from the lungs of rats and mice exposed to the lower, but not the higher NiO exposure concentrations. Clearance of acutely inhaled 63NiO was also impaired in both rats and mice, with the extent of impairment related to both exposure concentration and duration. However, the clearance of acutely inhaled 85Sr PSL microspheres was not impaired. The repeated inhalation of NiO resulted in alveolar macrophage (AM) hyperplasia with accumulation of NiO particles in both rats and mice, chronic alveolitis in rats, and interstitial pneumonia in mice. These lesions persisted throughout the 4-month recovery period after the NiO whole-body exposures were terminated. In contrast, repeated inhalation of NiSO4 6H2O did not result in accumulation of Ni in lungs of either rats or mice and did not affect the clearance of 63NiSO46H2O inhaled after either 2 or 6 months of NiSO4 6H2O exposure. Clearance of the 85Sr-labeled microspheres was significantly impaired only in rats exposed to the microspheres after 2 months of exposure to NiSO4 6H2O Histopathological changes in rats were qualitatively similar to those seen in NiO-exposed rats. Only minimal histopathological changes were observed in NiSO4 6H2O mice. These results suggest that repeated inhalation of NiO at levels resulting in AM hyperplasia and alveolitis may impair clearance of subsequently inhaled NiO. The potential effects of repeated inhalation of soluble NiSO4 6H2O on the clear ance of subsequently inhaled poorly soluble particles are less clear.