Phagocytosis, cellular distribution, and carcinogenic activity of particulate nickel compounds in tissue culture.

The uptake, toxicity, and morphological transformation efficacy of various water-insoluble nickel compounds were examined in tissue culture. Particles (2.2 to 4.8 micrometers) of crystalline Ni3S2, crystalline NiS, and crystalline Ni3Se2 were actively phagocytized by cultured cells as determined by light and electron microscopy. However, particles of similar size consisting of amorphous NiS and metallic nickel were not significantly phagocytized despite long exposure periods to high concentrations. X-ray fluorescence spectrometry measurements of metal levels in subcellular fractions isolated from cells treated with crystalline Ni3S2, crystalline NiS, or amorphous NiS confirmed that amorphous NiS did not significantly enter the cells, either as a phagocytized particle or in a solubilized form, while the other two crystalline nickel compounds were actively taken up. Cells treated with amorphous NiS contained nickel levels generally less than 10% of the nickel levels in whole cells and in cytoplasmic fractions, or nuclear fractions of cells treated with either crystalline NiS or crystalline Ni3S2. The phagocytized nickel particles were always observed in the cytoplasm with light and electron microscopy, but substantial nickel levels were measured in the nuclear fraction. These and other results suggest that the nickel particles were broken down in the cytoplasm to a size range no longer detectable with the electron microscope and then subsequently entered the nucleus. Control experiments suggest that at least 20% of the nickel measured in the nucleus isolated from cells treated with Ni3S2 is no longer part of a sedimentable particle with the same particle size and/or solubility properties of the parent compound. A substantial portion of the nickel associated with the nuclear fraction coprecipitated with trichloroacetic acid-insoluble material, suggesting that nickel binds strongly to cellular macromolecules. The phagocytized particulate nickel compounds were more cytotoxic as determined by reduction of cell-plating efficiency and induced more morphological transformations in the Syrian hamster embryo cell transformation assay than did the particulate nickel compounds which were not phagocytized. Manganese dust inhibited the morphological transformation induced by Ni3S2 and also reduced the phagocytosis of Ni3S2 particles.