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Biomedical subjects

F W Sunderman

Publications and source records attributed to F W Sunderman.

At least 55 records · Page 3Linked to original sources
PubMed1989

Toxicity to alveolar macrophages in rats following parenteral injection of nickel chloride.

Alveolar macrophages collected by pulmonary lavage from male Fischer-344 rats at intervals (1-72 hr) after NiCl2 injection (62-500 mumol/kg, sc) were tested by several techniques. Within 1 to 4 hr, the macrophages showed morphological and biochemical signs of activation (hypertrophy, ruffled plasma membrane, increased cyclic AMP concentration, and markedly diminished 5'-nucleotidase activity, assayed by concanavalin A inhibition). Functional impairment (reduced phagocytic activity) was first seen at 24 hr; lipid peroxidation (increased malondialdehyde concentration) was not detected until 48 hr. Dose- and time-related effects of NiCl2 on 5'-nucleotidase activity, phagocytic activity, malondialdehyde concentration, and nickel content of alveolar macrophages were observed 24 to 72 hr postinjection. Diminished cell viability occurred only at 72 hr after the highest dosage of NiCl2. In alveolar macrophages from 63NiCl2-treated rats, 63Ni was located primarily in the cytoplasm, based upon liquid scintillation counting and autoradiography; fractionations of macrophage cytosol by gel filtration chromatography showed that 63Ni was bound to several high- and low-molecular-weight constituents. This study demonstrates that sc administration of NiCl2 to rats caused nickel uptake into and activation of alveolar macrophages, followed by reduced phagocytic capacity. The alveolar macrophage was a cellular target for nickel toxicity following parenteral exposure to NiCl2.

Animals↗
PubMed1989

Effects of nickel chloride on lactating rats and their suckling pups, and the transfer of nickel through rat milk.

The excretion of nickel into rat milk following subcutaneous (sc) doses of nickel chloride (NiCl2) and the effects on the lactating rat and her suckling pups were determined. Plasma and milk Ni concentrations increased in a dose-dependent manner 4 hr after single doses of 0, 10, 50, or 100 mumol NiCl2/kg to lactating rats, giving milk/plasma Ni ratios of 0.02. Peak plasma Ni concentrations were reached 4 hr after injection, while milk Ni increased until 12 hr and remained elevated at 24 hr. Dosing for 4 days at 50 or 100 mumol NiCl2/kg/day led to higher milk/plasma Ni ratios of 0.10. These doses of NiCl2 had no effect on body weight but caused decreased food consumption, thymic atrophy, and a small increase in hepatic lipid peroxidation in the dams. Significant alterations in milk composition, which were not due to decreased food consumption as determined in pair-fed rats, included increased milk solids (42%) and lipid (110%), and decreased milk protein (29%) and lactose (61%). NiCl2 treatment also caused significant decreases in mammary RNA content and the RNA/DNA ratio compared to both ad libitum-fed and pair-fed rats, indicating that milk synthetic activity was reduced by NiCl2. Pups suckling the NiCl2-treated dams had plasma Ni concentrations of 24 and 48 micrograms/liter in the 50 and 100 mumol/kg dose groups, respectively, and had decreased liver weight but no changes in hepatic lipid peroxidation or thymus weight. The results indicate that high doses of NiCl2 led to the excretion of Ni into rat milk and changes in milk quality and production. Reductions in liver weight in the suckling pups were also observed which may have been due to nickel exposure or to changes in milk composition.

Animals↗
PubMed1989

Carcinogenicity of metal alloys in orthopedic prostheses: clinical and experimental studies.

Case reports of malignant tumors at sites of metal orthopedic implants in humans and domestic animals reviewed; results of carcinogenesis bioassays of implanted metal alloys and of nickel, chromium, cobalt, and titanium powders in rodents are summarized; mobilization of metals from implanted prostheses is discussed; and in vitro assays for morphological transformation of mammalian cells by metal compounds are surveyed. These considerations suggest that occurrence of sarcoma at the implantation site constitutes a complication, albeit rare, of implanted orthopedic prostheses. The author recommends (a) that orthopedic surgeons select prostheses with minimal susceptibility to metal corrosion and wear and, if feasible, replace implanted prostheses when there is evidence of corrosion or mechanical failure; (b) that epidemiological studies be undertaken to quantify cancer risks in patients with various types of metal implants; (c) that an international registry of implant-associated tumors be established; and (d) that research be focused on improved in vitro assays for carcinogenicity of alloys intended for use in orthopedic prostheses.

Alloys↗
PubMed1989

Nickel absorption and kinetics in human volunteers.

Mathematical modeling of the kinetics of nickel absorption, distribution, and elimination was performed in healthy human volunteers who ingested NiSO4 drinking water (Experiment 1) or added to food (Experiment 2). Nickel was analyzed by electrothermal atomic absorption spectrophotometry in serum, urine, and feces collected during 2 days before and 4 days after a specified NiSO4 dose (12 micrograms of nickel/kg, n = 4; 18 micrograms of nickel/kg, n = 4; or 50 micrograms of nickel/kg, n = 1). In Experiment 1, each of the subjects fasted 12 hr before and 3 hr after drinking one of the specified NiSO4 doses dissolved in water; in Experiment 2, the respective subjects fasted 12 hr before consuming a standard American breakfast that contained the identical dose of NiSO4 added to scrambled eggs. Kinetic analyses, using a compartmental model, provided excellent goodness-of-fit for paired data sets from all subjects. Absorbed nickel averaged 27 +/- 17% (mean +/- SD) of the dose ingested in water vs 0.7 +/- 0.4% of the same dose ingested in food (a 40-fold difference); rate constants for nickel absorption, transfer, and elimination were not significantly influenced by the oral vehicle. The elimination half-time for absorbed nickel averaged 28 +/- 9 hr. Renal clearance of nickel averaged 8.3 +/- 2.0 ml/min/1.73 m2 in Experiment 1 and 5.8 +/- 4.3 ml/min/1.73 m2 in Experiment 2. This study confirms that dietary constituents profoundly reduce the bioavailability of Ni2+ for alimentary absorption; approximately one-quarter of nickel ingested in drinking water after an over-night fast is absorbed from the human intestine and excreted in urine, compared with only 1% of nickel ingested in food. The compartmental model and kinetic parameters provided by this study will reduce the uncertainty of toxicologic risk assessments of human exposures to nickel in drinking water and food.

Adult↗
PubMed1989

Mechanisms of nickel carcinogenesis.

Recent investigations on possible mechanisms of nickel carcinogenesis are reviewed, emphasizing cellular uptake and intracellular translocation of nickel, morphological transformation of cells by nickel compounds, chromosomal damage, DNA strandbreaks and DNA-protein complexes produced by nickel compounds, mutagenic effects of nickel, influence of nickel on the helical transition of B-DNA to Z-DNA, nickel-induced infidelity of DNA synthesis, free radicals and lipid peroxidation induced by nickel exposures, nickel inhibition of DNA repair, nickel as a tumor promotor, nickel inhibition of natural-killer (NK) cell activity, manganese and magnesium antagonism of nickel carcinogenesis, and speculation that Ni2+ might replace Zn2+ in finger-loop domains of transforming proteins. The weight of evidence supports the following tentative conclusions: differences in the carcinogenic activities of nickel compounds may reflect variations in their capacities to provide nickel ions (eg, Ni2+) at critical sites within target cells; Ni2+ can initiate carcinogenesis, possibly by mutagenesis, chromosome damage, formation of Z-DNA, inhibition of DNA excision-repair or epigenetic mechanisms; Ni2+ can function as a tumor promoter; Ni2+ can enhance tumor progression by inhibiting NK cell activity; and nickel carcinogenesis can be suppressed or modified by certain other metals (eg, manganese and magnesium).

Animals↗
PubMed1989

Protein blotting method for detection of nickel-binding proteins.

A technique is described for detection of nickel-binding proteins in tissue extracts by protein blotting and autoradiography. The proteins are separated by SDS-polyacrylamide gel electrophoresis and blotted onto a nitrocellulose membrane. The membrane is incubated with 63NiCl2 in a tris-HCl buffer that contains NaCl and CaCl2 to suppress non-specific Ni-binding. The membrane is washed to remove unbound 63Ni2+ and autoradiography is performed to visualize the 63Ni-binding proteins. The technique furnishes a sensitive means to detect 63Ni-binding proteins in tissue extracts, facilitating their isolation, characterization, and identification.

Animals↗
PubMed1988

Acute nickel toxicity in electroplating workers who accidently ingested a solution of nickel sulfate and nickel chloride.

Thirty-two workers in an electroplating plant accidently drank water contaminated with nickel sulfate and chloride (1.63 g Ni/liter). Twenty workers promptly developed symptoms (e.g., nausea, vomiting, abdominal discomfort, diarrhea, giddiness, lassitude, headache, cough, shortness of breath) that typically lasted a few hours but persisted 1-2 days in 7 cases. The Ni doses in workers with symptoms were estimated to range from 0.5 to 2.5 g. In 15 exposed workers who were tested on day 1 postexposure, serum Ni concentrations ranged from 13 to 1,340 micrograms/liter and urine Ni concentrations ranged from 0.15 to 12 mg/g creatinine. Ten subjects (with initial urine Ni concentrations greater than 0.8 mg/g creatinine) were hospitalized and treated for 3 days with intravenous fluids to induce diuresis, resulting in a mean elimination half-time (T1/2) for serum Ni of 27 hours (SD +/- 7 hour), which was significantly shorter (p less than .001) than the mean T1/2 of 60 hours (SD +/- 11 hours) in 11 subjects who did not receive intravenous fluids. Laboratory tests showed transiently elevated levels of blood reticulocytes (N = 7), urine albumin (N = 3), and serum bilirubin (N = 2). All subjects recovered rapidly, without evident sequellae, and returned to work by the eighth day after exposure.

Accidents, Occupational↗
PubMed1988

Pulmonary histopathology of rats following parenteral injections of nickel chloride.

To elucidate the subacute toxic reactions to parenteral administration of Ni2+, male F-344 rats were given daily injections of NiCl2 (62.5 or 125 mumol/kg, sc) for 3 to 6 weeks. Nickel accumulation was greater in lung than in the other major organs, based upon tissue analyses by electrothermal atomic absorption spectrometry. After 5 or 6 weeks of NiCl2 treatment, severe pathological changes developed in the lungs, including a) prominent hydropic and degenerative changes of the endothelium of pulmonary arteries and veins; b) marked proliferation of alveolar lining cells, affecting Type II (granular)pneumocytes; c) thickening of alveolar walls, with proteinaceous alveolar exudate; d) hyperplasia of bronchial epithelium, with cellular atypia and mitoses; and e) focal bronchial pneumonia with intrabronchial exudates. These pulmonary responses to repeated daily injections of NiCl2 were substantially different from the pathological lesions seen 24 to 72 hours after a single sc injection of NiCl2 (500 or 750 mumol/kg), which included perivascular edema, karyorrhexis and pyknosis of mononuclear cells in focal perivascular infiltrates, and mild pulmonary congestion. This study shows that the lung is a primary site of toxicity in rats following parenteral administration of NiCl2; vascular endothelial cells, Type II pneumocytes, bronchial epithelial cells, and mononuclear cells constitute the principal cellular targets for pulmonary toxicity of Ni2+.

Animals↗
PubMed1988

Hypothermia and deranged circadian rhythm of core body temperature in nickel chloride-treated rats.

To quantify the immediate hypothermic response to an injection of NiCl2, and to delineate the ensuing derangements of circadian rhythms, the core body temperature and physical activity of rats were monitored by radiotelemetry from a thermistor probe implanted in the peritoneal cavity. The rats were housed in individual cages in a quiet room at 20 +/- 1 degrees C with 12 h light/dark cycles. After an injection of NiCl2 (e.g., 250 mumol/kg), the core body temperature diminished to a nadir at 1.5 h and returned to the baseline at 4 h; core body temperature at 1.5 h post-dose averaged 3.0 +/- 0.5 degrees C below the simultaneous value in control rats. During the period from 8 to 80 h post-dose, the mean body temperature of NiCl2-treated rats did not differ from controls, but the amplitude of the diurnal cycle of body temperature was dampened and the acrophase of the temperature cycle was delayed from 10:32 pm to 3:00 am. These parameters returned towards the control values during the period from 80 to 152 h post-dose. Physical activity of rats was reduced during the period from 8 to 80 h post-dose and the amplitude of the diurnal cycle of physical activity was dampened, but the acrophase of the activity cycle was not retarded in synchrony with the temperature cycle. This study shows that, in addition to causing prompt hypothermia that lasts 4 h, injection of NiCl2 deranges the circadian rhythm of thermoregulation during 3 days after recovery from hypothermia, causing 4.5 h delay of the temperature acrophase. Thus, the transient bout of hypothermia evidently sets back the biological clock of thermoregulation.

Animals↗
PubMed1988

Hepatic lipid peroxidation in CoCl2-treated rats, evidenced by elevated concentrations of thiobarbituric acid chromogens.

Parenteral administration of cobalt chloride (CoCl2) to male Fischer-344 rats caused hepatic lipid peroxidation, as evidenced by the thiobarbituric acid (TBA) reaction for malondialdehyde (MDA) and related chromogens in fresh liver homogenates. After a single sc injection of CoCl2 (300 mumol/kg, body wt.), hepatic concentrations of TBA-chromogens became significantly increased by 4 h and reached peak levels at 24-72 h post-injection. For example, in rats killed 48 h post-injection, hepatic TBA-chromogens (mean +/- SD, N = 7) averaged 607 +/- 141 nmol/g of tissue, wet wt., (P less than 0.01 versus 245 +/- 73 nmol/g in 19 controls). A dose-effect relationship was observed between CoCl2 dosages (100 to 450 mumol/kg, body wt.) and hepatic concentrations of TBA-chromogens in rats killed 24 h post-injection. This study indicates that hepatic lipid peroxidation develops as a consequence of acute CoCl2 toxicity in rats.

Animals↗
PubMed1987

Physicochemical and biological attributes of nickel compounds in relationship to carcinogenic activities.

Nickel compounds that possess similar elemental compositions but vary in physicochemical properties can elicit markedly different biological effects. The crystalline nickel sulfides and oxides that slowly dissolve in body fluids and readily enter cells by phagocytosis tend to be most active in producing morphological transformation of SHE cells in vitro and stimulating erythrocytosis and carcinogenesis following ir administration to rats. The capacities of particulate nickel compounds to induce erythropoietin-mediated erythrocytosis in rats are closely correlated with their carcinogenic activities; hence erythrocytosis stimulation can serve as a screening test for carcinogenicity. Although water-soluble nickel salts have not been shown to initiate carcinogenesis in rodents, the soluble nickel salts are evidently effective as cancer promotors following initiation of tumorigenesis by aromatic hydrocarbons and nitrosoamines. Growing evidence suggests that the Ni(III)/Ni(II) redox-couple facilitates oxygen free-radical reactions, which may represent one of the molecular mechanisms for genotoxicity and carcinogenicity of nickel compounds.

Animals↗
PubMed1987

Reference values for nickel concentrations in human tissues and bile.

Nickel concentrations in human tissues and gallbladder bile were determined by analysis of postmortem specimens from ten consecutive autopsies of adult persons. The tissue samples were collected and homogenized with precautions to avoid nickel contamination and were analyzed by electrothermal atomic absorption spectrophotometry with Zeemann background correction. In decreasing order of mean nickel concentrations, the following results were obtained (mean and range, microgram/kg dry weight, N = 7-10): lung 173 (71-371), thyroid 141 (41-240), adrenal 132 (53-241), kidney 62 (19-171), heart 54 (10-110), liver 50 (11-102), brain 44 (20-65), spleen 37 (9-95), and pancreas 34 (7-71). In five specimens of gallbladder bile, nickel concentrations averaged 2.3 +/- 0.8 micrograms/l (range 1.5-3.3). These data furnish reference values for use in evaluating tissue nickel concentrations in persons with occupational exposures to nickel, provide the first demonstration that nickel concentrations in thyroid and adrenal glands are approximately equal to those in lung and are higher than in other organs, and suggest that biliary excretion may be a significant route for the elimination of nickel in humans.

Adult↗
PubMed1987

Physicochemical characteristics and biological effects of nickel oxides.

Ten nickel oxides and nickel-copper oxides, which all contained NiO (bunsenite) as the predominant crystalline phase, were assayed as follows: in vitro dissolution tests in water and body fluids; in vitro phagocytosis tests in Chinese hamster ovary and C3H-10T1/2 cells; morphological transformation and cytotoxicity tests in cultured Syrian hamster embryo (SHE) cells; erythropoiesis stimulation assay by intrarenal administration to Fischer-344 rats; and scoring the renal histopathologic responses in rats killed 3 months post-injection. The test compounds differed substantially in their biological effects when tested in the various experimental systems. Based upon highly significant concordance of ranked results in the assays (P less than 0.001), six colligative biological attributes of the compounds were identified: (i) dissolution half-times in rat serum and renal cytosol; (ii) phagocytosis by C3H-10T1/2 cells; (iii) morphological transformation of SHE cells; (iv) erythropoiesis stimulation in rats; (v) induction of tubular hyperplasia in rat kidneys; and (vi) induction of arteriosclerosis in rat kidneys. Strong rank correlation (P less than 0.01) between results of the cell transformation and erythropoiesis stimulation assays is especially notable, since the compounds were tested by blind protocols in independent laboratories. The presence of high surface area and demonstrable Ni(III) were two physicochemical characteristics that were associated with the greatest biological effects of nickel oxides.

Animals↗
PubMed1987

Metal induction of heme oxygenase.

The experimental data that have been reviewed support the following conclusions regarding metal induction of microsomal heme oxygenase activity: 1. Induction of heme oxygenase in liver, kidney, and other organs of rodents is a nonspecific, toxic response to parenteral administration of numerous metal compounds. 2. The Co2+ and Cd2+ ions are especially potent for induction of heme oxygenase in rat liver; Sn2+, Ni2+, and As3+ are especially potent for induction of the enzyme in rat kidney; Hg2+ is especially potent for induction of the enzyme in rat adrenal. 3. Rat spleen, testis, and brain are relatively refractory to metal induction of heme oxygenase activity; in testicular microsomes from Cd2+-treated rats, heme oxygenase activity is markedly inhibited. 4. Metal induction of heme oxygenase requires de novo synthesis of mRNA and protein, based on 1) experiments with metabolic inhibitors (actinomycin D, puromycin, and cycloheximide) and 2) translation assays of heme oxygenase mRNA. 5. Heme oxygenase induction by metals is generally suppressed by treatments with SH compounds (for example, cysteine and glutathione) and enhanced by agents that deplete tissue SH levels (for example, diethyl maleate), suggesting that the induction mechanism may involve binding of metal ions to SH-containing regulatory molecules. 6. Administration of DDC exerts a pronounced synergistic effect on Ni2+ induction of heme oxygenase activity in rat tissues, attributable in part to enhanced cellular uptake of nickel. 7. Induction of heme oxygenase is not sustained during repeated daily treatments of rats with NiCl2, pointing to an adaptive mechanism for tolerance to the enzyme inducer. Investigations of metal induction of heme oxygenase activity have commonly involved sc or ip administration of the test compounds to rats. The paucity of studies in other species and the dearth of experiments with oral or respiratory exposures hinder extrapolations of the animal data to human environmental or occupational exposures to metal compounds.

Animals↗
PubMed1987

Increased nickel concentrations in body fluids of patients with chronic alcoholism during disulfiram therapy.

Nickel concentrations were measured by electrothermal atomic absorption spectrophotometry in body fluids of 61 patients with chronic alcoholism during disulfiram treatment (tetraethylthiuram disulfide, 250 mg/day, po). Nickel concentrations in serum, whole blood, and urine were significantly increased at 12 hours after the initial dose of disulfiram. In serum and whole blood, the Ni concentrations reached a plateau after two weeks of treatment; in urine, the Ni concentrations increased progressively during the initial four months of treatment. During the interval from four months to three years of disulfiram treatment, the median concentrations of nickel in serum, whole blood, and urine were elevated 17-, 15-, and 39-fold, respectively, compared to pretreatment values. The effects of disulfiram on nickel metabolism evidently involve chelation of dietary nickel by diethyldithiocarbamate (DDC), a disulfiram metabolite, and gastrointestinal absorption of the Ni-DDC complex. Since animal studies have demonstrated cerebral uptake of the lipophilic Ni-DDC complex, nickel may possibly accumulate in brain cells of disulfiram-treated patients; physicians should therefore be cautious in administering disulfiram to persons with nickel-containing orthopedic prostheses or occupational exposures to nickel.

Adult↗
PubMed1987

Acute thymic involution and increased lipoperoxides in thymus of nickel chloride-treated rats.

Acute thymic involution occurred in male, Fischer-344 rats following a single injection of nickel chloride (0.5 mmol/kg, sc). In nickel-treated rats, the mean thymic weight became significantly decreased at 24 h, continued to diminish at 48 h, and reached 24% of the control value at 72 h post-injection. The ratio of thymic weight to body weight (mg/g) decreased from 1.24 +/- 0.05 (SD) in control rats to 0.30 +/- 0.05 in nickel-treated rats at 72 h post-injection (p less than 0.01). Concentrations of thymic lipoperoxides were assayed by the thiobarbituric acid reaction, with HPLC separation and spectrophotometric quantitation of the malondialdehyde-thiobarbituric acid complex. The mean concentration of thymic lipoperoxides was unchanged at 24 h, increased 2-fold at 48 h, and reached 8-times the control value at 72 h after nickel chloride injection. On histological examination, sections of thymus from nickel-treated rats showed moderate to profound depletion of cortical lymphocytes at 72 h post-injection. Marked degenerative changes were noted in cortical lymphocytes, with pyknosis and karyorrhexis; swelling and vacuolation were evident in thymic reticular epithelial cells. The time-courses of the biochemical and histopathological responses suggest that the lipid peroxidation may be an end-result, rather than a cause, of thymic involution and injury to thymic lymphocytes in nickel-treated rats.

Animals↗