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Biomedical subjects

F W Sunderman

Publications and source records attributed to F W Sunderman.

At least 91 records · Page 5Linked to original sources
PubMed1983

Effects of manganese compounds on carcinogenicity of nickel subsulfide in rats.

The effects of manganese compounds upon the carcinogenicity of alpha Ni3S2 were tested in male Fischer rats. In Experiment I, rats were given i.m. injections of alpha Ni3S2 (2.5 mg) and Mn dust (2.0 mg), singly or in combination. By 100 weeks, sarcomas occurred at the injection site in 0 of 24 rats in the vehicle control group, in 0 of 24 rats that received Mn dust alone, and in 23 of 24 rats that received alpha Ni3S2 alone. Combined administration of alpha Ni3S2 plus Mn dust as a single i.m. injection resulted in sarcomas in 14 of 23 rats (p less than 0.05 versus alpha Ni3S2 alone). In rats that received injections of alpha Ni3S2 in one thigh and Mn dust in the opposite thigh, the sarcoma incidence at the site of alpha Ni3S2 injection was 24 of 24 rats. In Experiment II, rats were given i.m. injections of alpha Ni3S2 (1.2 mg) and Mn compounds (MnS, Mn2O3, MnO2 or MN2(CO)10, in dosages equivalent to 1.0 mg of Mn), singly or in combination. No sarcomas occurred at the injection site in rats that received the vehicle or any of the manganese compounds alone. Sarcomas occurred in 13 of 27 rats that received alpha Ni3S2 alone; this sarcoma incidence was not reduced by admixture of any of the Mn compounds. The median tumor latent period and the median survival period were significantly longer (p less than 0.05) in rats that received MnS plus alpha Ni3S2, compared with rats that received alpha Ni3S2 alone, suggesting that MnS may have weak anticarcinogenic effect. These experiments demonstrate that inhibition of alpha Ni3S2-carcinogenesis by Mn dust is a local rather than a systemic effect, and that, with the possible exception of MnS, the other manganese compounds that were tested are ineffective as inhibitors of alpha Ni3S2-carcinogenesis.

Animals↗
PubMed1983

Carcinogenesis tests of nickel arsenides, nickel antimonide, and nickel telluride in rats.

Carcinogenicity of nickel arsenides (NiAs, Ni11As8, Ni5As2, NiAsS), nickel antimonide (NiSb), and nickel telluride (NiTe) was tested by IM administration to male Fischer rats (14 mg Ni/rat). Three negative control groups received similar IM injections of glycerol vehicle, ferronickel alloy (NiFe), or nickel titanate (NiTiO3); two positive control groups received nickel oxide (NiO) or ferronickel sulfide (Ni4FeS4) at equivalent dosages (14 mg Ni/rat). Within 2 years, the incidences of sarcomas at the injection site were: 0/20 (0%) in NiAs-treated rats, 8/16 (50%) in Ni11As8-treated rats; 17/20 (85%) in Ni5As2-treated rats; 14/16 (85%) in NiAsS-treated rats; 17/29 (59%) in NiSb-treated rats; and 14/26 (54%) in NiTe-treated rats. No local sarcomas occurred in the negative control groups, including 40 glycerol-treated rats, 16 NiFe-treated rats, and 20 NiTiO3-treated rats; in the positive control groups, local sarcomas occurred in 14/15 (93%) of NiO-treated rats and 15/15 (100%) of Ni4FeS4-treated rats. The 99 sarcomas that were induced by the various nickel compounds included 67 rhabdomyosarcomas, 11 fibrosarcomas, 15 osteosarcomas, 1 fibrous histiocytic sarcoma, and 5 undifferentiated sarcomas; metastases were found in 57 sarcoma-bearing rats. This study demonstrates that Ni11As8, Ni5As2, NiAsS, NiSb, and NiTe are carcinogenic for rats. Since Ni11As8, Ni5As2, and NiAsS are likely to be formed during oil shale retorting, environmental contamination by nickel arsenides in spent shale products could conceivably pose a carcinogenic hazard if large-scale production of petroleum from oil share is established.

Animals↗
PubMed1983

High-performance size-exclusion chromatography of 63Ni-constituents in renal cytosol and microsomes from 63NiCl2-treated rats.

Fractionations of 63Ni-constituents were performed by high-performance size-exclusion chromatography upon samples of renal cytosol and washed renal microsomes from rats that were killed 1 h after an im injection of 63NiCl2 (50 or 125 mumol/kg body wt). The kidney homogenates contained 2.0 +/- 0.4% of the total dose of 63Ni. Renal cytosol contained 55 +/- 5% and washed microsomes contained 5.4 +/- 1.2% of 63Ni that was present in the kidney homogenates. Chromatography of renal cytosol on TSK-GEL SW-2000 and SW-3000 separated 63Ni into six fractions. The largest component (Fraction F) contained approximately 80% of cytosolic 63Ni. Since Fraction F was eluted near the total permeation volume of SW-2000 columns and beyond the total permeation volume of SW-3000 columns, its molecular weight could not be reliably estimated. The other components, which comprised collectively the remaining 20% of cytosolic 63Ni, had apparent molecular weights of 168,000 (Fraction A), 84,000 (Fraction B), 51,000 (Fraction C), 24,000 (Fraction D), and approximately 10,000 (Fraction E). Solubilized washed microsomes from kidneys of 63NiCl2-treated rats contained 63Ni in five components with elution profiles and 63Ni-contents that resembled Fractions A, B, D, E, and F of renal cytosol, based upon chromatography on SW-3000 columns. The solubilized microsomes also contained a 63Ni-component with high molecular weight (Fraction M, greater than 700,000 daltons), which accounted for 3% of microsomal 63Ni. This study provides a rapid, convenient, and reproducible technique to fractionate 63Ni-components in tissue extracts, and it demonstrates in vivo binding of 63Ni to several constituents of renal cytosol and microsomes from 63NiCl2-treated rats.

Animals↗
PubMed1982

Erythrocytosis, glomerulomegaly, mesangial hyperplasia, sialyl hyperplasia, and arteriosclerosis induced in rats by nickel subsulfide.

Histopathological examinations were performed upon groups of male Fischer rats killed at intervals from 1 h to 18 weeks after unilateral intrarenal (ir) injection of nickel subsulfide (2.5 or 5 mg of Ni3S2/rat). Consistent with previous findings, erythroid hyperplasia of bone marrow and spleen occurred from 2 to 18 weeks after Ni3S2-treatment, resulting in pronounced erythrocytosis. Hitherto unreported effects of Ni3S2-treatment include: (a) marked glomerulomegaly and hyperplasia of mesangial cells in both kidneys; (b) hyperplasia of submandibular salivary glands, and (c) widespread arteriosclerotic lesions. The present study suggests that mesangial cells of renal glomeruli produce erythropoietin. Discovery that ir injection of Ni3S2 induces arteriosclerotic lesions in rats furnishes a new experimental model to investigate the pathogenesis of arteriosclerosis.

Animals↗
PubMed1982

Effects of unilateral nephrectomy on erythrocytosis and arteriosclerosis induced in rats by intrarenal injection of nickel subsulfide.

Administration of Ni3S2 to rats by unilateral inrarenal (ir) injection (5 mg/rat) caused erythrocytosis, arteriosclerosis, and abnormal plasma concentrations of asparagine, glycine, histidine, and lysine. Resection of the ipsilateral (Ni3S2-treated) kidney on the fourth day after the ir injection prevented erythrocytosis, amino acid disturbances, and severe arteriosclerotic lesions (fibrous intimal plaques and focal medial necrosis), but did not prevent early arteriosclerotic lesions (subintimal oedema with splitting of elastica). The early arteriosclerotic lesions appear to be initiated by vascular dissemination of Ni3S2 particles immediately post-injection, whereas the erythrocytosis, amino acid disturbances, and advanced arteriosclerotic lesions depend upon continued presence of the Ni3S2-injected kidney. Resection of the contralateral (non-injected) kidney has no effect upon Ni3S2-induced erythrocytosis, arteriosclerosis, or amino acid disturbances. Glomerulomegaly and mesangial hyperplasia developed in control rats following unilateral nephrectomy, owing to compensatory renal hypertrophy. Glomerulomegaly was more pronounced in Ni3S2-treated rats following contralateral nephrectomy than following ipsilateral nephrectomy, suggesting that erythrocytosis and compensatory renal hypertrophy act synergistically to enhance glomerulomegaly.

Animals↗
PubMed1982

Dissolution half-times of nickel compounds in water, rat serum, and renal cytosol.

Seventeen nickel compounds were incubated in water, rat serum, and rat renal cytosol for 72 hr at 37 degrees C. Concentrations of dissolved nickel were analyzed by electrothermal atomic absorption spectrophotometry, and dissolution half-times (T50) were computed by the Weibull equation. Eleven of the nickel compounds (Ni, beta NiS, amorphous NiS, alpha Ni3S2, NiSe, Ni3Se2, NiTe, NiAs, Ni11As8, Ni5As2, and NiFeS4) dissolved more rapidly in serum or cytosol than in water. Four of the compounds (NiO, NiSb, NiFe alloy, and NiTiO3) had no detectable dissolution in any of the media (i.e., T50 greater than 11 yr). One compound (NiAsS) had approximately equal T50 values in the three media; the T50 value of one compound (NiS2) could not be determined in serum or cytosol owing to precipitation. T50 value of 34 and 21 days for dissolution of alpha Ni3S2 in serum and cytosol, respectively, agree closely with the excretion half-time of 24 days derived from previously reported data for excretion of 63Ni in urine and feces of rats after intramuscular injection of alpha 63Ni3S2. These findings suggest that in vitro dissolution half-times of nickel compounds may be used to predict their in vivo excretion half-times, since the dissolution process is rate-limiting to their metabolism and excretion.

Animals↗
PubMed1982

Phagocytosis of particulate nickel compounds by rat peritoneal macrophages in vitro.

Phagocytic indices of 17 nickel compounds were measured in vitro in monolayer cultures of rat peritoneal macrophages. The macrophages were exposed for 1 h at 37 degrees C to particles (1.5 micrometer median diameter) of the nickel compounds, at concentrations of 10 microgram/ml of medium (2 microgram/cm2 of monolayer). Phagocytic induces (i.e., the percentages of macrophages with one or more engulfed particles) ranged from 69% (NiO) to 3% (amorphous NiS). In order to decreasing phagocytic indices, the 17 nickel compounds were ranked as follows: NiO greater than Ni4FeS4 greater than NiTiO3 greater than NiSe greater than alpha Ni3S2 greater than Ni greater than Ni5As2 greater than NiS2 greater than NiFe alloy greater than NiSb greater than Ni11As8 greater Ni3-Se2 greater than beta NiS greater than NiTe greater than NiAs greater than NiAsS greater than amorphous NiS. Rank-correlation (P less than 0.03) was observed between the phagocytic indices of the nickel compounds and their dissolution half-times in rat serum. Nickel subsulfide, alpha Ni3S2, was a notable exception to the general concordance between phagocytic indices and dissolution half-times: alpha Ni3S2 was avidly phagocytized by macrophages, yet it had one or the shortest dissolution half-times. Preliminary results of carcinogenesis tests of 14 of the nickel compounds do not indicate significant rank-correlation between the phagocytic indices of the nickel compounds and the sarcoma incidences at 1 yr after i.m. administration of the compounds to rats.

Animals↗
PubMed1982

Gas-chromatographic assay for heme oxygenase activity.

We have developed an improved assay for microsomal heme oxygenase activity, based on the enzymic release of CO from the alpha-methene bridge of hemin and the quantitation of CO by gas chromatography. The within-run coefficient of variation (CV) of heme oxygenase assays in microsomes from rat tissues (liver, kidney) averaged 8%; the between-run CV averaged 15%. The detection limit for heme oxygenase activity was approximately 1 nmol/h per milligram of microsomal protein. Gas-chromatographic assays of heme oxygenase activities in rat tissues correlated well (r = 0.94) with results by a spectrophotometric assay based on bilirubin production. In untreated rats, heme oxygenase activity averaged 7 +/- 3 nmol/h per milligram of protein (n = 36) in kidney microsomes and 14 +/- 5 nmol/h per milligram of protein (n = 17) in liver microsomes. Heme oxygenase activity was increased 10-fold in kidney microsomes and threefold in liver microsomes from rats killed 17 h after subcutaneous injection of NiCl2 (0.5 mmol/kg body wt). These findings illustrate the efficacy of the gas-chromatographic assay for measuring xenobiotic effects on heme oxygenase activity.

Animals↗
PubMed1982

Induction of ocular neoplasms in Fischer rats by intraocular injection of nickel subsulfide.

Nickel subsulfide, alpha Ni3S2, was administered to albino Fischer rats by a single injection into the vitreous body of the right eye (0.5 mg alpha Ni3S2/rat, suspended in 20 microliter of NaCl vehicle). Control rats received a similar injection of the vehicle. Malignant tumors developed in the injected eyes of 14/15 alpha Ni3S2-treated rats by 8 months (vs. 0/11 controls, p less than 0.001). Five of the injected eyes of alpha Ni3S2-treated rats contained multiple tumors. The 21 eye tumors that were induced by alpha Ni3S2 included 11 melanomas, four retinoblastomas, three gliomas, and three unclassified malignant neoplasms. Three of the melanomas developed extraocular extensions; one of the melanomas metastasized to lungs and brain. Although the melanomas arose from amelanotic uveal melanocytes, melanosomes were observed in electron micrographs of the tumor cells. This study provides a new experimental model for chemical induction of ocular neoplasms. As a procedure to test the carcinogenicity of nickel compounds, intraocular injection has the advantages of short latency period, high tumor incidence, and ease of tumor detection.

Animals↗
PubMed1981

Recent research on nickel carcinogenesis.

Research on nickel carcinogenesis from 1975 to March 1980 is reviewed. Epidemiological studies have strengthened the evidence that workers in nickel refineries have increased risks of cancers of the nasal cavities and lungs. Clinical investigations have resulted in improved diagnosis, classification, and management of cancers of respiratory organs in nickel refinery workers. Carcinogenicity tests have demonstrated the carcinogenicity of nickel subsulfide (alpha-Ni3S2) in rodents following administration by a variety of parenteral routes. Radiotracer studies and x-ray diffractometry have clarified the metabolism of alpha-Ni3S2 in rodents. In vitro exposures of mammalian cells to certain nickel compounds have been shown to inhibit cellular uptake of thymidine-3H, and to induce chromosomal aberrations, somatic mutations, and morphological transformation. Mutagenicity tests of nickel compounds in bacterial systems have consistently been negative. Ni(II) has beeb reported to impair the fidelity of viral and bacterial DNA polymerases for in vitro replication of synthetic nucleotide templates.

Administration, Oral↗
PubMed1981

Spectrophotometric assay for urinary N-acetyl-beta-D-glucosaminidase activity.

An improved assay for N-acetyl-beta-D-glucosaminidase activity in urine is described that involves (a) gel filtration to separate the enzyme from inhibitors in urine, (b) enzymic hydrolysis of p-nitrophenyl-N-acetyl-beta-D-glucosaminide at pH 4.4, and (c) spectrophotometry of the liberated p-nitrophenylate. Measurements of activity of the enzyme in 58 urine specimens correlated closely (r = 0.9998) with results by an established procedure. The within-run coefficient of variation (CV) was 3.7%; the between-run CV averaged 6.8%. Reference values for the activity were established by assays of urine specimens from 135 healthy persons, age two weeks to 52 years. Efficacy of the assay for detection of nephrotoxicity was demonstrated in rats after experimental induction of reversible renal insufficiency by intraperitoneal injection of nickel chloride. Clinical application of the assay in approximately 1000 patients corroborated its utility for detection and monitoring of renal disorders.

Acetylglucosaminidase↗
PubMed1981

Negative test for transplacental carcinogenicity of nickel subsulfide in Fischer rats.

Transplacental carcinogenicity of nickel subsulfide (Ni3S2) was tested by im administration of Ni3S2 (20 mg) to 8 pregnant Fischer rats on day 6 of gestation. Control dams received a similar injection of the vehicle. The progeny at risk for tumor development comprised 50 offspring (17 males, 33 females) of Ni3S2-treated dams and 53 offspring (29 males, 24 females) of control dams. Body weights of progeny of Ni3S2 treated dams were lower than progeny of control dams, but sex-specific cumulative mortality rates in the two groups did not differ significantly. By age 26 months, 2 malignant and 2 benign tumors developed in progeny of Ni3S2-treated dams, versus 3 malignant and 2 benign tumors in progeny of control dams. Hence, administration of Ni3S2 to pregnant rats had no significant effect upon tumor incidence in the progeny.

Animals↗
PubMed1980

Nickel concentrations in plasma and urine of shipyard workers.

Nickel concentrations were analyzed by electrothermal atomic absorption spectrophotometry in plasma from workers at a repair shipyard and a construction shipyard. Four groups of workers were studied: (a) 62 welders, (b) 31 painters, (c) 27 riggers/carpenters, and (d) 21 shipfitters/pipefitters. Controls were 15 hospital workers and 28 retirees at the repair shipyard. In the combined groups of all tested workers at the repair shipyard, increased plasma Ni concentrations (greater than 5.2 micrograms/liter) occurred in 32 of 82 subjects (39%): (p less than .05 vs increased plasma Ni concentrations in 13 of 59 workers at the construction shipyard [22%], and p less than .001 vs increased plasma Ni concentrations in 1 of 43 controls [2%]). At both shipyards, plasma Ni concentrations were higher in the groups of painters and shipfitters/pipefitters than in the groups of welders and riggers/carpenters. In random urine specimens from workers at the construction shipyard. Ni concentrations exceeded 5.2 micrograms/liter in 9 of 24 welders [38%], (p less than .01 vs increased urine Ni concentrations in 1 of 15 controls [hospital workers]). The ratios of plasma/urine nickel concentrations were higher in painters (p less than .05) and lower in welders (p less than .05) than in other workers at the construction shipyard. Increased concentrations of nickel in body fluids of shipyard workers are attributed to exposures to nickel compounds and alloys in the working environment.

Adult↗
PubMed1980

Teratogenicity and embryotoxicity of nickel carbonyl in Syrian hamsters.

Nickel carbonyl was administered to groups of pregnant hamsters by inhalation (0.06 mg Ni(CO)4/liter/15 min) on days 4, 5, 6, 7, or 8 of gestation. The dams were killed on day 15 of gestation, and the fetuses were examined for malformations. Exposure to Ni(CO)4 on days 4 or 5 of gestation resulted in malformations in 5.5% (8/146) and 5.8% (10/171) of the progeny, respectively (P less than 0.05, versus 0/95 in controls). The proportions of litters with malformed fetuses were 33% (4/12) and 24% (4/17) in dams exposed to Ni(CO)4 on days 4 and 5 of gestation (P less than 0.05, versus 0/9 in litters of control dams). Progeny of dams exposed to Ni(CO)4 on days 4 and 5 included 9 fetuses with cystic lungs, 7 fetuses with exencephaly, 1 fetus with exencephaly plus fused rib, and 1 fetus with anophthalmia plus cleft palate. Hemorrhages into serous cavities were found in 18% (26/146) and 25% (42/171) of fetuses of dams exposed to Ni(CO)4 on days 4 or 5 of gestation. Such hemorrhages were not observed in controls. In progeny of dams exposed to Ni(CO)4 on days 6 or 7 of gestation, there was 1 fetus with fused ribs and there were 2 fetuses with hydronephrosis. In another experiment, pregnant hamsters were exposed to inhalation of Ni(CO)4 (0.06 mg/liter/15 min) on day 5 of gestation; these dams were permitted to deliver their litters and to nurse their pups. On the day of delivery, there was no significant difference in the average number of live pups in the Ni(CO)4-exposed litters compared to control litters. Neonatal mortality was increased in Ni(CO)4-exposed litters; by day 4 postpartum, the number of live pups averaged 7.6 +/- 1.5 in Ni(CO)4-exposed litters (P less than 0.01 versus 9.6 +/- 1.8 pups in control litters). This study demonstrates that Ni(CO)4 is teratogenic and embryotoxic in Syrian hamsters.

Abnormalities, Drug-Induced↗
PubMed1980

Effects of nickel compounds on incorporation of [3H] thymidine into DNA in rat liver and kidney.

In vivo incorporation of [3H] thymidine into DNA was determined in rats at 28 h after partial hepatectomy. Administration of nickel carbonyl (Ni(CO)4) at 2 or 4 h before sacrifice inhibited [3H] thymidine uptake into liver and kidney DNA. For example, in rats killed 4 h after i.v. injection of Ni(CO)4 (2 mg Ni/100 g), [3H]-labelling of liver DNA averaged 54 (SE +/- 10)% of controls (p less than 0.05), and [3H]-labelling of kidney DNA averaged 53 (SE +/- 6)% of controls (p less than 0.01). Injection of NiCl2 (2 mg Ni/100 g, i.m.) 4 h before death did not significantly affect [3H] thymidine uptake into liver DNA, but did inhibit [3H] thymidine uptake into kidney DNA (65 +/- 6%, p less than 0.02). Binding of 63Ni to DNA in liver and kidney of rats killed 4 h after injection of 63Ni(CO)4 or 63NiCl2 ranged from 0.3 to 2.2 mol 63Ni/mol of DNA nucleotides. Ultracentrifugation of DNA on alkaline sucrose gradients did not reveal any differences between sedimentation profiles of hepatic DNA from Ni(CO)4-treated rats versus paired control rats.

Animals↗
PubMed1980

Manganese inhibition of sarcoma induction by benzo[a]pyrene in rats.

The effects of Mn and Cr dusts upon carcinogenesis by polycyclic aromatic hydrocarbons were tested in male Fischer 344 rats. In Experiment I, rats were given i.m. injections of benzo[a]pyrene (BP, 1.2 mg), Mn dust (4.4 mg), and Cr dust (4.4 mg), alone, and in various combinations. By 100 weeks, sarcomas occurred at the injection site in 17/20 rats that received BP alone, versus 10/19 rats that received BP plus Mn dust (P < 0.05). The sarcoma incidences were 0/20 in 3 control groups that received the vehicle, Mn dust alone, or Cr dust alone, and 20/20 in rats that received BP plus Cr dust. In Experiment II, rats were given i.m. injections of BP (0.6 mg), 7,12-dimethylbenz[a]anthracene (DMBA, 0.6 mg), Mn dust (4.4 mg), and Cr dust (4.4 mg), alone, and in various combinations. Local sarcomas occurred in 17/20 rats that received BP alone, versus 5/17 rats that received BP plus Mn dust (P < 0.001). Sarcoma induction was not inhibited when BP was injected in the right thigh and Mn dust in the left thigh (sarcoma incidence = 16/20). The sarcoma incidences were 0/19 in a vehicle control group; 0/18 in 2 control groups that received Mn dust or Cr dust alone; 18/20 in rats that received BP plus Cr dust; 14/20 in rats that received DMBA alone; 17/19 in rats that received DMBA plus Mn dust; and 13/18 in rats that received DMBA plus Cr dust. These experiments show that Mn dust inhibits the carcinogenicity of BP when the Mn dust and BP are administered to rats by a single i.m. injection. Under identical conditions, Mn dust does not affect the carcinogenicity of DMBA; Cr dust does not affect the carcinogenicity of BP or DMBA.

9,10-Dimethyl-1,2-benzanthracene↗