The carcinogenicity of nickel subsulfide (alpha Ni3S2) was studied following intrarenal (i.r.) injection in rats. Within 100 weeks after i.r. injection of 5 mg of alpha Ni3S2, renal cancers were found in 64 percent of Wistar-Lewis rats, 50 percent of NIH Black rats, 28 percent of Fischer rats and 0 percent of Long-Evans rats. These findings demonstrate significant differences in susceptibilities of the four rat strains to alpha Ni3S2-induction of renal cancers. No renal cancers were found in male Fischer rats that received i.r. injection of alpha Ni3S2 in dosages of 0.6, 1.2 or 2.5 mg. In male Fischer rats that received i.r. injection of alpha Ni3S2 in dosages of 5 or 10 mg, the incidences of renal cancers were 28 percent and 75 percent, respectively. These findings demonstrate a dose response relationship for alpha Ni3S2-induction of renal cancers. In male Fischer rats that received i.r. injection of 10 mg of alpha Ni3S2 combined with 6.9 mg of Mn dust, the incidence of renal cancers was 32 percent, which differed significantly from the corresponding incidences of 75 percent and 0 percent in rats that received i.r. injections of only alpha Ni3S2 (10 mg) or Mn dust (6.9 mg). These findings demonstrate that alpha Ni3S2-induction of renal cancers is inhibited by simultaneous administration of manganese dust. The 54 renal tumors that were found in this study were all malignant, and distant metastases were present in 69 percent of tumor-bearing rats. The histogenesis of alpha Ni3S2-induced renal tumors from epithelial or mesenchymal progenitor cells could not be definitely established.

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Preparation and delivery of a speech in medicine and allied sciences.

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Sodium diethyldithiocarbamate administration in nickel-induced malignant tumors.

Studies were undertaken to ascertain the possible antitumorigenic effectiveness of sodium diethyldithiocarbamate (dithiocarb) on the development of tumors in rats following the muscular implantations of nickel subsulfide (Ni3S2). These tumors have histologic characteristics which suggest origin from striated muscle and have been classified as rhabdomyosarcoma. Most of the tumors metastasized. In two separate studies over a period of two years, a total of 100 four-month old Fischer rats received muscular implantations of Ni3S2. Of this total, 50 rats (25 males and 25 females) were treated with dithiocarb for a period of four to six weeks. Seventy-eight percent of the untreated rats developed sarcomas as compared to 32 percent of the treated rats. Analyses of the data revealed a striking difference in the sex responsiveness to dithiocarb. Of the 25 female rats with Ni3S2 implantations and treated with dithiocarb, only 12 percent developed sarcomas; of the male rats similarly treated, 52 percent developed sarcomas. The difference in sex response is statistically significant (p = 0.005). Therapeutic implications are suggested.

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Recent advances in metal carcinogenesis.

Recent advances in metal carcinogenesis are comprehensively reviewed, including (a) epidemiological and clinical aspects, (b) carcinogenesis bioassays, (c) bacterial mutagenesis, (d) mammalian cell mutagenesis, (e) chromosomal damage, (f) mammalian cell transformation, (g) microsomal metabolism, (h) DNA strandbreaks and crosslinks, (i) DNA polymerase infidelity, (j) RNA strand initiation, and (k) helical transition of B-DNA to Z-DNA. Based upon these observations, several hypotheses are proposed for the molecular pathogenesis of carcinogenesis by metal compounds. These hypotheses are amenable to experimental test by existing techniques of molecular biology.

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Studies of the pathogenesis of arteriosclerosis induced in rats by intrarenal injection of a carcinogen, nickel subsulfide.

Widespread arteriosclerotic lesions were detected by histological examinations of rats killed at seven or nine weeks after an intrarenal (ir) injection of nickel subsulfide (Ni3S2, 5 mg per rat). Arteriosclerotic plaques were readily visualized by administering hematoporphyrin derivative (HPD) iv to rats at 24 hours before sacrifice. At necropsy, the major arteries were inspected under ultraviolet light, revealing patches of intense HPD-fluorescence in the arterial endothelium of Ni3S2-treated rats, but not in control rats. Consistent with previous reports, the Ni3S2-treated rats developed pronounced erythrocytosis; blood hematocrit values averaged 70 +/- 4 percent at seven weeks after ir injection of Ni3S2 (P less than 0.001 vs corresponding value of 49 +/- 2 percent in vehicle controls). At seven weeks, blood platelet counts averaged 17 percent lower and serum glucose concentrations averaged 23 percent lower in Ni3S2-treated rats than in controls; serum lipids, lipoproteins, non-protein nitrogen constituents, electrolytes, proteins, and enzymes were not significantly affected. Body weights and systolic blood pressures of rats at two, four, and six weeks after ir injection of Ni3S2 did not differ from corresponding values in controls. Addition of egg yolk to the diet caused mild hypercholesterolemia, but it did not enhance the incidence or severity of arterial lesions in Ni3S2-treated rats. These findings exclude hypertension and hyperlipidemia as pathogenic factors in Ni3S2-induced arteriosclerosis.

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Chelation therapy in nickel poisoning.

For the treatment of acute poisoning from the inhalation of nickel carbonyl, sodium diethyldithiocarbamate (Dithiocarb) has proved to be a specific antidote; tetraethylthiuram (Antabuse) is effective to a lesser degree; d-penicillamine and dimercaprol (BAL) have limited therapeutic value. For the treatment of nickel eczema and dermatitis, favorable response has been obtained by placing patients on a diet of low nickel content together with the oral administration of Dithiocarb or Antabuse. No specific therapy has been advanced for the treatment of nickel cancer in humans. In experimental animals, Dithiocarb has an inhibitory effect on the production of rat rhabdomyosarcomas induced by the intramuscular implantation of nickel subsulfide, and N-methyl formamide inhibits the growth of transplantable nickel fibromas in rats. It is suggested that for the treatment of tumors arising from the implantations of nickel-containing prostheses in humans, chelation therapy be considered.

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Erythropoietin-mediated erythrocytosis in rodents after intrarenal injection of nickel subsulfide.

Rats and guinea pigs developed pronounced erythrocytosis at one to four months after unilateral intrarenal (ir) injection of nickel subsulfide (Ni3S2). For example, at two months after ir administration of Ni3S2 (5 mg) to rats, blood hematocrit values averaged 70 +/- 3 percent (p less than 0.001 vs. 48 4/- 2 in controls); at two months after ir administration of Ni3S2 (20 mg) to guniea pigs, blood hematocrit values averaged 67 +/- 6 percent (p less than 0.001 vs. 49 +/- 1 percent in controls). Hamsters and gerbils did not develop erythrocytosis after ir injection of Ni3S2 (5 mg/animal). Administration of Ni3S2 to rats by intrasplenic injection did not increase blood hematocrit; splenectomy did not prevent erythrocytosis in rats that received ir injection of Ni3S2. Erythrocytosis in rats was completely blocked by excision of the Ni3S2-injected kidney but was unaffected by excision of the non-injected kidney. Partial inhibition of Ni3S2-induced erythrocytosis in rats occurred after simultaneous ir injection of Mn, Cu, or Al dusts, benzo(a)pyrene, or subcutaneous (sc) infusion of sodium diethyldithiocarbamate. Erythrocytosis induced by ir injection of Ni3S2 was augmented by ir injection of Cr dust or intramuscular (im) administration of iron-dextran. Erythrocytosis occurred in rats after ir implantation of Ni3S2 within semi-permeable cellulose tubules, indicating that phagocytosis of Ni3S2 particles is unnecessary for erythropoietic stimulation. Erythropoietin (Ep) activity in rat serum increased sixfold at two weeks after ir injection of Ni3S2 (p less than 0.001 vs. controls), but Ep activity in pooled extracts of Ni3S2-treated rat kidneys did not increase significantly. This study identifies several factors that influence erythropoietic stimulation by Ni3S2, and furnishes salient information concerning the pathogenesis of Ni3S2-induced erythrocytosis.

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Effects of nickel chloride and diethyldithiocarbamate on metallothionein in rat liver and kidney.

Effects of NiCl2 and sodium diethyldithiocarbamate (DDC) upon metallothionein (MT) concentrations were studied in liver and kidney of male Fischer rats. After injection of NiCl2 (0.75 mmol per kg, sc), hepatic MT concentration increased 2.6-fold at 6.5 hr and 8.2-fold at 17 hr; renal MT concentration increased 1.4-fold at 6.5 hr and 2.3-fold at 17 hr. Dose-related increases of MT concentrations were observed in liver and kidney of rats killed 17 hr after injection of NiCl2 (0.25 to 0.75 mmol per kg, sc). Repeated administration of NiCl2 (0.1 mmol per kg, ip) on four successive days, with sacrifice three days after the last treatment, increased MT concentrations 1.4-fold in liver and kidney, whereas CdCl2-treatment at the same dosage schedule increased MT concentration 16-fold in liver and 3.3-fold in kidney. NiCl2-Induction of MT in liver and kidney was not prevented by actinomycin D (1 mg per kg, ip), but was inhibited by cycloheximide (2 mg per kg, ip). Sodium diethyldithiocarbamate given alone (1.33 mmol per kg, im) 17 hr before death, increased MT concentration 7.6-fold in liver but did not affect MT concentration in kidney; administration of DDC prior to injection of NiCl2 did not inhibit NiCl2-induction of MT.

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Potential toxicity from nickel contamination of intravenous fluids.

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Urine nickel concentrations in nickel-exposed workers.

Electrothermal atomic absorption spectrometry was employed for analyses of nickel concentrations in urine samples from nickel-exposed workers in 10 occupational groups and from non-exposed workers in two control groups. Mean concentrations of nickel in urine were greatest in workers who were exposed to inhalation of aerosols of soluble nickel salts (e.g., workers in nickel plating operations and in an electrolytic nickel refinery). Less marked increases in urine nickel concentrations were found in groups of metal sprayers, nickel battery workers, bench mechanics and are welders. No significant increases in mean concentrations of nickel were found in urine samples from workers who performed grinding, buffing and polishing of nickel-containing alloys or workers in a coal gasification plant who employed Raney nickel as a hydrogenation catalyst. Measurements of nickel concentrations in urine are more sensitive and practical than measurements of serum nickel concentrations for evaluation of nickel exposures in industrial workers.

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