PHAGOCYTOSIS, CELLULAR-DISTRIBUTION, AND CARCINOGENIC ACTIVITY OF PARTICULATE NICKEL COMPOUNDS IN TISSUE-CULTURE

Abstract

The uptake, toxicity and morphological transformation efficacy of water-insoluble Ni compounds were examined in tissue culture. Particles (2.2-4.8 .mu.m) of crystalline Ni3S2, crystalline NiS and crystalline Ni3Se2 were actively phagocytized, as determined by light microscopy and EM. Particles of similar size consisting of amorphous NiS and metallic Ni 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, as a phagocytized particle or in a solubilized form, while the other 2 crystalline Ni compounds were actively taken up. Cells treated with amorphous NiS contained Ni levels generally < 10% of the Ni levels in whole cells and in cytoplasmic fractions, or nuclear fractions of cells treated with crystalline NiS or crystalline Ni3S2. The phagocytized Ni particles were always observed in the cytoplasm with light microscopy and EM but substantial Ni levels were measured in the nuclear fraction. Apparently, the Ni particles were broken down in the cytoplasm to a size range no longer detectable with EM and then entered the nucleus. Control experiments suggest that at least 20% of the Ni 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 Ni associated with the nuclear fraction coprecipitated with trichloroacetic acid-insoluble material, suggesting that Ni binds strongly to cellular macromolecules. The phagocytized particulate Ni 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 Ni compounds which were not phagocytized. Manganese dust inhibited the morphological transformation induced by Ni3S2 and reduced the phagocytosis of Ni3S2 particles. [Ni and its compounds have been implicated as causes of human cancer.].