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Carcinogenic Sulfide Salts of Nickel and Cadmium Induce H₂O₂ Formation by Human Polymorphonuclear Leukocytes¹

Departments of Environmental Medicine [Z. Z., W. T., K. L. K., K. F.] and Pathology [K. F.], New York University Medical Center, New York, New York 10016

Some derivatives of nickel, cadmium, and cobalt are carcinogenic in humans and/or animals but their mechanisms of action are not known. We show that they are capable of stimulating human polymorphonuclear leukocytes (PMNs), as measured by H₂O₂ formation, a known tumor promoter. Most effective were the carcinogens nickel subsulfide, which caused a 550% net increase in H₂O₂ over that formed by resting PMNs, followed by cadmium sulfide, 400%, and nickel disulfide, 200%. Nickel sulfide and cobalt sulfide caused statistically nonsignificant increases of 45 and 20%, respectively. Noncarcinogenic barium and manganese sulfides, and sulfates of nickel, cadmium, and cobalt were inactive. The enhancement of H₂O₂ formation by CdS and Ni₃S₂ (1 µmol/2.5 x 10⁵ PMNs) was comparable to that mediated by the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate, used at 0.5 and 1 nM, respectively. Concurrent treatment of 12-O-tetradecanoylphorbol-13-acetate-stimulated PMNs with Ni₃S₂ or NiS caused a decrease in H₂O₂ accumulation from that expected if the effects were additive. Including catalase in the reaction mixture proved that the oxidant formed by stimulated PMNs was H₂O₂, whereas adding superoxide dismutase showed that superoxide was also present in PMN samples treated with NiS but not with Ni₃S₂. Since nickel-and cadmium-containing particulates are deposited in the lungs and cause infiltration of PMNs, the ability to activate those cells and induce H₂O₂ formation may contribute to their carcinogenicity.

¹ This work was supported in part by National Institute of Environmental Health Sciences Grants ES 04895 and ES 00260; and by Public Health Service Grant CA 37858, awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom all requests for reprints should be addressed, at Department of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016.

Received 5/15/90. Accepted 8/27/90.

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