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

The goals of this study were to (1)determine the effects ofrepeated inhalation of relatively insoluble nickel oxide (NiO)and highly soluble nickel sulfate hexahydrate (NiSO₄ 6H₂O) onlung particle clearance, (2)investigate the effects of repeatedinhalation of NiO or NiSO₄ on the pulmonary clearance of subsequentlyinhaled ⁸⁵Sr-labeled microspheres, (3)correlate the observedeffects on clearance with accumulated Ni lung burden and associatedpathological changes in the lung, and (4)compare responses inF344 rats and B6C3F₁, mice. Male F344/N rats and B6C3F₁ micewere exposed whole-body to either NiO or NiSO₄ 6H₂O 6 hr/day,5 days/week for up to 6 months. NiO exposure concentrationswere 0, 0.62, and 2.5 mg NiO/m for rats and 0, 1.25, and 5.0mg NiO/ m for mice. NiSO₄ 6H₂O/m³ exposure concentrations were0, 0.12, and 0.5 mg NiSO₄ 6H₂ for rats and 0, 0.25, and 1.0mg NiSO₄ 6H₂O/m³ for mice. After 2 and 6 months of whole-bodyexposure, groups of rats and mice were acutely exposed nose-onlyto 63 (NiO-exposed animals only), ⁶³NiSO₄ 6H₂O (Ni SO₄ 6H₂Oanimals only), or to ⁸⁵Sr-labeled polystyrene latex (PSL) microspheres(both NiO- and NiSO₄ 6H₂O-exposed animals) to evaluate lungclearance. In addition, groups of rats and mice were euthanizedafter 2 and 6 months of exposure and at 2 and 4 months afterthe whole-body exposures were completed to evaluate histopathologicalchanges in the left lung and to quantitate Ni in the right lung.Repeated inhalation of NiO results in accumulation of Ni inlungs of both rats and mice, but to a greater extent in lungsof rats. During the 4 months after the end of the whole-bodyexposures, some clearance of the accumulated Ni burden occurredfrom the lungs of rats and mice exposed to the lower, but notthe higher NiO exposure concentrations. Clearance of acutelyinhaled ⁶³NiO was also impaired in both rats and mice, withthe extent of impairment related to both exposure concentrationand duration. However, the clearance of acutely inhaled ⁸⁵SrPSL microspheres was not impaired. The repeated inhalation ofNiO resulted in alveolar macrophage (AM) hyperplasia with accumulationof NiO particles in both rats and mice, chronic alveolitis inrats, and interstitial pneumonia in mice. These lesions persistedthroughout the 4-month recovery period after the NiO whole-bodyexposures were terminated. In contrast, repeated inhalationof NiSO₄ 6H₂O did not result in accumulation of Ni in lungsof either rats or mice and did not affect the clearance of ⁶³NiSO₄6H₂Oinhaled after either 2 or 6 months of NiSO₄ 6H₂O exposure. Clearanceof the ⁸⁵Sr-labeled microspheres was significantly impairedonly in rats exposed to the microspheres after 2 months of exposureto NiSO₄ 6H₂O Histopathological changes in rats were qualitativelysimilar to those seen in NiO-exposed rats. Only minimal histopathologicalchanges were observed in NiSO₄ 6H₂O mice. These results suggestthat repeated inhalation of NiO at levels resulting in AM hyperplasiaand alveolitis may impair clearance of subsequently inhaledNiO. The potential effects of repeated inhalation of solubleNiSO₄ 6H₂O on the clear ance of subsequently inhaled poorlysoluble particles are less clear.