Nickel-magnesium interactions in carcinogenesis: dose effects and involvement of natural killer cells

Abstract

The effects of magnesium carbonate (MgCarb) on carcinogenesis and natural killer (NK) cell modulation by nickel subsulfide (Ni3S2) were studied. Male Fischer F344/NCr rats, 50-90 g body wt, 20 rats per group, received single i.m. injections into both thigh muscles of 2.5 mg Ni3S2 alone or combined with different proportions of MgCarb; the Mg/Ni molar ratio ranged from 0.25 to 4.0. Control rats received i.m. injections of normal saline or magnesium acetate (MgAcet), or s.c. MgCarb at a site distant from Ni3S2. The animals were observed over 79 weeks for the development of tumors. The NK cell activity was determined over the first 3 weeks of the experiment in separate groups of rats treated as above, with the use of the 51Cr/YAC-1 release assay for blood and spleen cells and the peroxidase localization of Ox-8-immunoreactive lymphocytes at the injection site. I.m. administration of MgCarb mixed with Ni3S2 up to the Mg/Ni molar ratio of 1.0 inhibited the carcinogenicity of Ni3S2 in a dose-related manner; final incidence of sarcomas decreased from 100 to 55% and the appearance of first tumors was delayed from 25 to 39 weeks. Higher doses of MgCarb did not exert further effect. Distant s.c. injection of MgCarb or local i.m. application of MgAcet did not change the carcinogenic potency of i.m. Ni3S2. MgCarb or saline alone did not produce any tumors. I.m. Ni3S2 had no significant influence on the activity of NK cells in blood and spleen, while i.m. MgCarb alone did not affect the NK activity in blood but doubled it transiently in the spleen 24 h after injection. In the injected muscle, Ox-8-positive cells became abundant around MgCarb but could not be found close to Ni3S2. This inhibitory effect of Ni3S2 was partially reversed by MgCarb. Also, numerous multinucleated giant cells infiltrated the sites of injection of MgCarb alone and MgCarb + Ni3S2 but not Ni3S2 alone. The results indicate a dose-dependent and strictly local character of the inhibition by MgCarb of Ni3S2 carcinogenesis, as well as a possible involvement of NK and phagocytic cells in this inhibition.

Epidemiological and experimental aspects of metal carcinogenesis: physicochemical properties, kinetics, and the active species.

“…The 30% excess ofcancer incidence over the general population was mainly caused by lung cancer. Thus, compared with the general population of Sweden, the SMR for cancer incidence at all sites was 124 and for lung cancer was 232. SMRs relative to the county population were 133 and 355, respectively.…”

“…When injected intramuscularly together with nickel subsulfide in the same suspension, magnesium carbonate (but not acetate) inhibited (233) and zinc salts slowed down (233) the carcinogenic process. The protective effect of carbonate may have been mediated through the involvement of natural killer and phagocytic cells (232).…”

Nickel Toxicity and Carcinogenesis

“…Macrophage function was not markedly affected, but the cytotoxic activity of natural killer (NK) cells was diminished [129,130]. The acute thymic involution [131] and suppression of NK cells was also observed in rats given parenteral injections of nickel chloride and nickel subsulfi de [132,133] or intratracheal instillation of nickel sulfate [134]. NK cells' suppression by nickel was also observed in monkey cells in vitro [135].…”

Impaired Natural Killer Cell Activity Associates with Increased Susceptibility to Inflammation Induced by Herpesvirus Infection in Patients with Nickel Hypersensitivity

“…Finally, our data allow to hypothesize alternative therapeutic strategies in patients with Ni allergy and in patients with HSV recurrences or vaginitis by Candida albicans. In particular we refer to the possibility, in addition to avoid the intake of Ni, of favouring or supplementing the dietary intake of Zinc and Manganese, two elements capable of potentiating NK cell activity and to counteract the immunosuppressive effects ofNi (18)(19)(20)(21)(22)(23).…”