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

J Appl Toxicol. 2023 May;43(5):734-751. doi: 10.1002/jat.4422. Epub 2022 Dec 21.


Inhalation studies with nickel (Ni) subsulfide (Ni3 S2 ) and Ni sulfate hexahydrate (NiSO4 ·6H2 O) 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 ·6H2 O or 0.44 mg Ni/m3 Ni3 S2 , 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 Ni3 S2 -exposed rats, whereas the reverse response was seen for apoptosis. Only Ni3 S2 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.

Keywords: cancer; genotoxicity; inhalation; mode of action; nickel; no/lowest observed adverse effect concentration (NOAEC/LOAEC).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA
  • DNA Damage
  • Hyperplasia / pathology
  • Lung*
  • Male
  • Nickel* / toxicity
  • Rats
  • Rats, Inbred F344


  • nickel subsulfide
  • nickel sulfate
  • Nickel
  • DNA