Nickel carcinogenesis

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Increased incidences of cancers of the lung, nasal sinus, larynx, and possibly kidney have occurred among workers in nickel refineries: the identity of the nickel compounds that produce cancers in nickel workers remains uncertain, although principal attention is focused on (a) insoluble dusts of nickel subsulfide (Ni 3S 2 and nickel oxide (NiO), (b) the vapor of nickel carbonyl (Ni(CO) 4), and (c) soluble aerosols of nickel sulfate (NiSO 4) or nickel chloride (NiCl 2). Cancers have been induced in experimental animals by several nickel compounds by a variety of routes, including (a) lung cancers by inhalation of Ni(CO) 4 and Ni 3S 2 in rats, (b) sinus cancers by implantation of Ni 3S 2 in cats, (c) renal cancers by implantation of Ni 3S 2 in rats, and (d) sarcomas by im injection of Ni 3S 2 in mice, rats, hamsters, and rabbits. In the author's laboratory, 18 nickel compounds have been tested for carcinogenicity in male Fischer rats by a single im injection at equivalent dosages (14 mg Ni/rat). Within two years, the following incidences of sarcomas developed at the injection site: Ni 3S 2, 100%; crystalline NiS, 100%; Ni 4FeS 4, 100%; NiO, 93%; Ni 3Se 2, 91%; NiAsS, 88%; NiS 2, 86%; Ni 5As 2, 85%; Ni dust, 65%; NiSb, 59%; NiTe, 54%; NiSe, 50%; Ni 11As 8, 50%; amorphous NiS, 12%; NiCrO 4, 6%; NiAs, 0%; NiFe alloy, 0%; NiTiO 3, 0%, vehicle controls (N = 84), 0%. Distant metastases were found in 109 of 180 sarcoma-bearing rats (61%). The histological classification of the nickel-induced sarcomas included rhabdomyosarcoma, 52%, fibrosarcoma, 18%, undifferentiated sarcoma, 13%, osteosarcoma, 8%, and miscellaneous sarcomas, 9%. Relative carcinogenic activities of the compounds were not significantly correlated with dissolution half-times in rat serum or phagocytic indices by rat peritoneal macrophages in vitro. The relative carcinogenic activities were correlated (P<0.001) with potencies of the compounds to stimulate erythropoiesis in rats after intrarenal injection. The mechanism of nickel carcinogenesis may involve binding of nickel to nucleoproteins, with inhibition of nucleic acid synthesis, formation of DNA-proteins cross-links, impaired fidelity of DNA replication, and induction of chromosomal aberrations, including sister-chromatid exchanges and karyotypic anomalies. Manganese antagonism of nickel carcinogenesis may indicate competition of Mn(II) and Ni(II) for binding to specific loci on nucleoproteins or DNA polymerases.