Comparative pulmonary and genotoxic responses to inhaled nickel subsulfide and nickel sulfate in F344 rats.

Inhalation studies with nickel (Ni) subsulfide (Ni3S2) and Ni sulfate hexahydrate (NiSO4·6H2O) investigated differences in mode of action that could explain why the former induced lung tumors in rats and the latter did not. Male rats were exposed to ≤0.22 mg Ni/m3 NiSO4·6H2O or 0.44 mg Ni/m3 Ni3S2, 6 h/day, 5 days/week for 3 and 13 weeks; subsets of the rats exposed for 13 weeks were held for an additional 13 weeks. Analyses of bronchoalveolar lavage fluid, isolated cells, and whole lung tissue were conducted to compare the extent and persistence of any induced lung effects. Histological findings were qualitatively identical for both compounds and consistent with lesions reported in earlier studies. After 13 weeks of exposure, the incidence and severity of pulmonary inflammation and epithelial cell hyperplasia were greater among Ni3S2‐exposed rats, whereas the reverse response was seen for apoptosis. Only Ni3S2 exposure significantly increased epithelial and non‐epithelial cell proliferation after 13 weeks of exposure. Both compounds induced DNA damage in isolated lung cells and DNA hypermethylation of whole lung tissue after 13 weeks of exposure at the highest exposure concentrations. Increases in cell proliferation, DNA damage, and tissue DNA hypermethylation did not persist during the 13‐week recovery period. In summary, the highest concentrations of each compound produced marked pulmonary toxicity, but the lowest concentrations produced minimal or no effects. Differences in the proliferative and apoptotic responses between the two compounds may help explain differences in carcinogenicity, whereas the identification of no observed adverse effect concentrations (NOAECs) contributes to the risk characterization for inhalation exposure to nickel compounds. A comprehensive study comparing rat responses to 3‐ and 13‐week inhalation exposure to NiSO4 and Ni3S2 indicated some differences (e.g., stronger apoptotic response for NiSO4 and a stronger effect on cell proliferation for Ni3S2); these responses did not persist after cessation of exposure. These findings add to our understanding of the mode of action for lung carcinogenicity by nickel compounds. Our study also contributes to the risk characterization for inhalation exposure to nickel compounds. [ABSTRACT FROM AUTHOR]