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The risk assessment conducted by the European Food Safety Authority stated some concerns regarding the chronic exposure of the European population to nickel due to food intake. This study aimed to evaluate the extent of the Belgian population's exposure to nickel via intake of different foods/drinks available in their market. Ni concentrations were measured in selected foods consumed in Belgium, and exposures from this limited group of foods were estimated for consumers of these foods. Legumes, soy products, breakfast cereals, and chocolate spreads were responsible for 26%, 14%, 11% and 8% of the overall exposure (overall chronic exposure through consuming all the included food types in this study except tap water) of children (3-9 years) to nickel. For adolescents (10-17 years), the highest percentage of overall chronic exposure again originated from legumes (19%). This was followed by breakfast cereals (14%), soy products (11%) and chocolate spreads (11%). For adults (18-64 years), major contributors to the overall chronic daily exposure were legumes (16%), dark chocolate (15%) and breakfast cereals (10%). The aggregate exposure assessment, including the highest contaminated foods, for different sub-populations, revealed mean exposure levels of 1.02, 0.60 and 0.34 μg kg -1 b.w. day -1 for children, adolescents, and adults respectively. The mean, P75, P90 and P95 values for aggregate chronic exposure of the overall consumer's population were 0.62, 0.80, 1.5 and 210 μg kg -1 b.w. day -1 respectively. This study recommends controlling the intake of food products with elevated nickel content especially for the more vulnerable sub-population groups such as children with lower body weight and nickel sensitised individuals. It also demonstrates a shift in potential risk on human health to nickel exposure due to the transition towards a more plant-based diet.

Gastric carcinoma is one of the most lethal malignant tumors. As part of our long-term efforts on seeking effective diagnosis and therapeutic strategies of gastric cancer, we present herein novel ternary copper-based chalcogenide nanoplatform CuS-NiS 2 nanomaterials with outstanding photothermal (PT)/photodynamic (PD) property that could effectively suppress human gastric cancer in vitro and in vi vo without obvious side effects. We revealed that CuS-NiS 2 induced reactive oxygen species (ROS) generation, leading to apoptosis through Bcl-2/Bax pathway of human gastric cancer cells under 808 nm near-infrared (NIR) irradiation. In addition, we also confirmed that the combination of CuS-NiS 2 and 808 nm NIR laser treatment triggered necroptosis by regulating the novel pathway MLKL/CAPG of human gastric cancer cells. Moreover, the CuS-NiS 2 exhibited excellent contrast enhancement according to magnetic resonance imaging (MRI). Taken together, we reported new ternary copper-based chalcogenide nanomaterials CuS-NiS 2 , which could be successfully applied for MRI-guided PT/PD therapy of gastric carcinoma through mitochondria-mediated apoptosis and MLKL/CAPG-mediated necroptosis.

The health risks of inhalation exposure to engineered nanomaterials in the workplace are a major concern in recent years, and hazard assessments of these materials are being conducted. The pulmonary surfactant of lung alveoli is the first biological entity to have contact with airborne nanomaterials in inhaled air. In this study, we retrospectively evaluated the pulmonary surfactant components of rat lungs after a 4-week inhalation exposure to three different nanomaterials: fullerenes, nickel oxide (NiO) nanoparticles and multi-walled carbon nanotubes (MWCNT), with similar levels of average aerosol concentration (0.13-0.37 mg/m(3)). Bronchoalveolar lavage fluid (BALF) of the rat lungs stored after previous inhalation studies was analyzed, focusing on total protein and the surfactant components, such as phospholipids and surfactant-specific SP-D (surfactant protein D) and the BALF surface tension, which is affected by SP-B and SP-C. Compared with a control group, significant changes in the BALF surface tension and the concentrations of phospholipids, total protein and SP-D were observed in rats exposed to NiO nanoparticles, but not in those exposed to fullerenes. Surface tension and the levels of surfactant phospholipids and proteins were also significantly different in rats exposed to MWCNTs. The concentrations of phospholipids, total protein and SP-D and BALF surface tension were correlated significantly with the polymorphonuclear neutrophil counts in the BALF. These results suggest that pulmonary surfactant components can be used as measures of lung inflammation.

In order to examine whether intratracheal instillation studies can be useful for determining the harmful effect of nanoparticles, we performed inhalation and intratracheal instillation studies using samples of the same nanoparticles. Nickel oxide nanoparticles (NiO) and titanium dioxide nanoparticles (TiO2) were used as chemicals with high and low toxicities, respectively. In the intratracheal instillation study, rats were exposed to 0.2 or 1 mg of NiO or TiO2. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed from 3 days to 6 months following the single intratracheal instillation. In the inhalation study, rats were exposed to inhaled NiO or TiO2 (1.65, 1.84 mg/m(3), respectively) for 4 weeks. The same endpoints were examined from 3 days to 3 months after the end of exposure. Inhalation of NiO induced an increase in the number of neutrophils in BALF and concentrations of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2 and heme oxygenase (HO)-1. Intratracheal instillation of NiO induced persistent inflammation and upregulation of these cytokines was observed in the rats. However, inhalation of TiO2 did not induce pulmonary inflammation, and intratracheal instillation of TiO2 transiently induced an increase in the number of neutrophils in BALF and the concentrations of CINC-1, CINC-2 and HO-1. Taken together, a difference in pulmonary inflammation was observed between the high and low toxicity nanomaterials in the intratracheal instillation studies, as in the inhalation studies, suggesting that intratracheal instillation studies may be useful for ranking the harmful effects of nanoparticles.

Inhalation studies and intratracheal instillation studies using laboratory animals are commonly conducted for pulmonary toxicity tests of nanomaterials. In our study, male Wister rats were exposed to nickel oxide (NiO) particles including a nano-scale, even for aerosols and suspensions, in a 4-week inhalation and intratracheal instillation. Using polymorphonuclear neutrophils (PMNs) in bronchoalveolar lavage fluid as a biomarker of inflammation, we attempted to quantify the relationship between responses to inhalation and intratracheal instillation of the nanoparticles, based on surface area doses. Four kinds of NiO suspension samples with different specific surface areas were singly injected via the tracheas of the rats. The relationship between the instilled doses and PMN production was examined 3 days and 1 month after the instillation. In parallel, 4-week inhalation studies, using two of the suspensions, were conducted for aerosols generated by a pressurized nebulizer. NiO samples induced PMN responses 3 days after instillation according to the surface area doses, but not the mass doses, as has been reported in many studies. When the same NiO samples were tested in a 4-week inhalation and intratracheal instillation, the amount of pulmonary deposition of the sample after the 4-week inhalation, and an intratracheally instilled dose about ten-times higher, induced similar PMN responses 3 days after termination of inhalation and instillation. Using the relationship between these responses to 4-week inhalation and intratracheal instillation, it may be possible to estimate what aerosol concentrations of other nanomaterials might cause the same responses of PMN production as intratracheal instillation tests.

The aim of this study was to analyse nickel content in foods and beverages most commonly consumed by the Canary Island people to determine the dietary intake of this metal throughout the Canary Islands as a whole and in each of the seven islands. A total of 440 samples were analysed by graphite furnace atomic absorption spectrometry. Nickel concentrations ranged between 2.348 ± 1.716 mg/kg in nuts and 0.002 ± 0.002 mg/l in water. Estimated total intake of nickel was 0.093 mg/day for the Canary population, which is far below the tolerable upper intake level (UL) established for adults. Gran Canaria turned out to be the island with the highest nickel intake. Differential analysis of nickel intake by age and sex of the Canary Island community showed that values were below the UL in children as well as in adults. These outcomes were compared with data from other populations at the national and international levels.

This study determined whether nickel sulfate (Ni)-induced reproductive damage occurs via apoptosis and oxidative stress and to examine the expression of Bax and c-kit and their effects on Ni exposure. The study also explored the protective effects of grape seed proanthocyanidin extract (GSPE) against Ni toxicity in the testes. Wistar rats were treated with normal saline, Ni alone (1.25, 2.5, and 5 mg/kg/day), and Ni (2.5 mg/kg/day) plus GSPE (50 and 100 mg/kg/day). After 30 days, Ni significantly decreased sperm motility and the percentage of S-phase cells and enhanced testicular apoptosis in the 2.5 and 5 mg groups. The levels of malondialdehyde (MDA), hydrogen peroxide (H₂O₂), and nitric oxide (NO) significantly increased. The decreased activity of glutathione peroxidase and catalase in the Ni groups showed that Ni could increase oxidative stress, especially at 2.5 and 5 mg. Western blot analysis showed that the expression of Bax protein and c-kit increased in 2.5 and 5 mg Ni groups compared with controls. Conversely, these changes were partially attenuated in rats simultaneously administered GSPE, especially in the 100 mg group. These results demonstrate the following: (1) Ni exhibits reproductive toxicity in rats by decreasing sperm at concentrations of 2.5 and 5 mg; (2) intratesticular apoptosis, oxidative stress, and c-kit overexpression play pivotal roles in reproductive damage induced by Ni; and (3) GSPE enhances sperm motility by down-regulating c-kit expression and offsetting the apoptosis and oxidative stress induced by Ni by directly decreasing MDA and NO, scavenging H₂O₂, and down-regulating Bax expression.

Objective: To investigate the biocompatibility of diamond-like carbon (DLC) coated nickel-titanium shape memory alloy (NiTi SMA) in vitro and in vivo., Methods: The in vitro study was carried out by co-culturing the DLC coated and uncoated NiTi SMA with bone marrow mesenchymal stem cells (MSCs), respectively, and the in vivo study was carried out by fixing the rabbits' femoral fracture model by DLC coated and uncoated NiTi SMA embracing fixator for 4 weeks, respectively. The concentration of the cells, alkaline phosphatase (AKP), and nickel ion in culture media were detected, respectively, at the first to fifth day after co-culturing. The inorganic substance, osteocalcin, alkaline phosphatase (ALP), and tumor necrosis factor (TNF) in callus surrounding fracture and the Ni(+) in muscles surrounding fracture site, liver and brain were detected 4 weeks postoperatively., Results: The in vitro study showed that the proliferation of MSCs and the expression of AKP in the DLC-coated group were higher than the uncoated group (P < 0.05), while the uncoated group released more Ni(2+) into the culture media than that in the coated group (P < 0.05). The in vivo study revealed that the inorganic substance and AKP, osteocalcin, and TNF expression were significantly higher in the DLC coated NiTi SMA embracing fixator than that in the uncoated group (P < 0.05). Ni(2+) in liver, brain, and muscles surrounding the fracture were significantly lower in the DLC coated groups than that in the uncoated group (P < 0.05)., Conclusion: Nickel-titanium shape memory alloy coated by diamond-like carbon appears to have better biocompatibility in vitro and in vivo compared to the uncoated one.

In this pilot study, we investigated which physicochemical properties of nickel hydroxide nanoparticles (nano-NH) were mainly responsible in inducing pulmonary toxicity. First, we studied the role of nickel ions solubilized from nano-NH by comparing the toxic effects of nano-NH to those of readily soluble nickel sulfate nanoparticles (nano-NS). Additionally, to test whether there was a non-specific stress response due to particle morphology, we compared the toxicity of nano-NH with that of carbon nanoparticles (nano-C) and titanium dioxide nanoparticles (nano-Ti), both of which had similar physical properties such as particle size and shape, to nano-NH. We exposed mice to each type of nanoparticles for 4?h via a whole-body inhalation system and examined oxidative stress and inflammatory responses in the lung. We also determined the lung burden and clearance of Ni following nano-NH and nano-NS exposures. The results showed that lung deposition of nano-NH was significantly greater than that of nano-NS and nano-NH appeared to have stronger inflammogenic potential than nano-NS even when lung Ni burden taken into consideration. This suggests that the toxicity of nano-NH is not driven solely by released Ni ions from deposited nano-NH particles. However, it is unlikely that the greater toxic potential of nano-NH is attributable to a generic stress response from any nanoparticle exposure, since nano-C and nano-Ti did not elicit toxic responses similar to those of nano-NH. These results indicate that the observed pulmonary toxicity by inhaled nano-NH were chemical-specific and deposited dose and solubility are key factors to understand toxicity induced by nano-NH.

Since nanoparticles easily agglomerate to form larger particles, it is important to maintain the size of their agglomerates at the nano-level to evaluate the harmful effect of the nanoparticles. We prevented agglomeration of nickel oxide nanoparticles by ultrasound diffusion and filtration, established an acute exposure model using animals, and examined inflammation and chemokine expression. The mass median diameter of nickel oxide nanoparticle agglomerates suspended in distilled water for intratracheal instillation was 26 nm (8.41 nm weighted average surface primary diameter). Male Wistar rats received intratracheal instillation of nickel oxide nanoparticles at 0.1 mg (0.33 mg/kg) or 0.2 mg (0.66 mg/kg), and were dissected 3 days, 1 week, 1 month, 3 months, and 6 months after the instillation. The control group received intratracheal instillation of distilled water. Three chemokines (cytokine-induced neutrophil chemoattractant-1 (CINC-1), CINC-2alphabeta, and CINC-3) in the lung tissue and bronchoalveolar lavage fluid (BALF) were determined by quantitative measurement of protein by ELISA. Both CINC-1 and CINC-2alphabeta concentration was elevated from day 3 to 3 months in lung tissue and from day 3 to 6 months in BALF. On the other hand, CINC-3 was elevated on day 3 in both lung tissue and BALF, and then decreased. The total cell and neutrophil counts in BALF were increased from day 3 to 3 months. In lung tissue, infiltration of mainly neutrophils and alveolar macrophages was observed from day 3 to 6 months in alveoli. These results suggest that CINC was involved in lung injury by nickel oxide nanoparticles.

The soluble metal fraction of residual oil fly ash (ROFA) has been shown to increase the susceptibility to infection in animal models. The goal of this study was to determine which of the primary soluble metals or metal combinations in ROFA were responsible for the increased infectivity. The soluble fraction of ROFA contained Ni, Fe, Al, and Zn. On Day 0, Sprague-Dawley rats were intratracheally (IT) instilled with NiCl2 (55.7 microg/rat), FeSO4 (32.7 microg/rat), Al3(SO4)2 (46.6 microg/rat), or ZnCl2 (8.69 microg/rat), or a combination of all the metals (Total Mixture). In a separate experiment, rats were instilled with metal mixtures, including the total mixture, and mixtures without Fe (Mix--No Fe), Ni (Mix--No Ni), Al (Mix--No Al), or Zn (Mix--No Zn). At Day 3, rats were instilled with 5 x 10(4) Listeria monocytogenes. At Days 6, 8 and 10, left lungs were removed to assess bacterial clearance. Bronchoalveolar lavage (BAL) was performed on right lungs on Day 3, before infection, and on Days 6, 8 and 10 to assess lung injury and cellular activity. Prior to infection, soluble Ni and mixtures containing Ni significantly increased lung injury, inflammation, and oxidative damage to a comparable degree when compared to control. Post-infection, rats pre-treated with soluble Ni, alone or in a metal mixture, had increased bacterial lung burden on Day 6, and body weight decreased in the soluble Ni, Mix--No Fe, and Mix--No Al groups post-infection, indicating Fe and Al may act antagonistically to Ni. Ni alone and in metal mixtures increased reactive oxidants in the lung and appeared to be the most important factor in suppressing T-cell activity post-infection. Soluble Ni is likely the primary metal involved in the increased susceptibility to infection observed in rats exposed to the soluble metals of ROFA.

In order to investigate whether or not airborne nanoparticles with a minimum agglomeration could be used for exposure tests on animals, we developed a nanoparticle generation system and examined the biological effects of the particles in an inhalation study. The generation system was composed of an ultrasonic nebulizer and diffusion dryers, and 30 Wistar male rats were exposed to nickel oxide (NiO) nanoparticles for 4 wk (6 h/day). The geometric mean diameter of the particles and the daily average exposure concentration determined by a combination of a differential mobility analyzer and a condensation nucleus counter in the exposure chamber were 139 +/- 12 nm and 1.0 +/- 0.5 x 10(5) particles/cm3, respectively. At 4 days and 1 and 3 mo after the inhalation, each group of 10 rats were sacrificed and NiO nanoparticles deposited in the lung were determined by chemical analysis and the biopersistence (biological half time) was calculated. The deposited amount of NiO nanoparticles in the rat lungs at 4 days after the inhalation was 29 +/- 4 microg. The retained particle amount in the rat lungs after the inhalation exponentially decreased and the calculated biological half time was 62 days. The histopathological change was not severe just after the inhalation nor throughout the observation time. We concluded that nanoparticles with a minimum agglomeration were dispersed stably in the chamber and exposed to rats for 4 wk and that deposited amounts in the rat lungs and the biopersistence of the particles and the biological response in lung were detected.

The aim of the present study was to investigate dose- and time-dependent effects of NiCl2 on T-lymphocyte and macrophage-derived cytokine production in rats. Moreover we have determined the concentrations of nickel in the plasma that are required to elicit alterations in T-lymphocyte and macrophage function. NiCl2 suppressed T-lymphocyte proliferation and Th1 (IFN-gamma) and Th2 (IL-10) cytokine production in a dose- and time-dependent fashion. In addition, NiCl2 inhibited production of the pro-inflammatory cytokine TNF-alpha and increased production of the anti-inflammatory cytokine IL-10 from lipopolysaccharide (LPS) stimulated cultures. We have determined that the minimal plasma concentrations of nickel required to provoke immunosuppression are in the range 209-585 ng/mL. In the time-course study NiCl2 (3.3 mg/kg) provoked immunological changes that were maximal 1 h following administration, and some of these changes persisted for up to 24 h post administration. Overall these data clearly demonstrate that NiCl2 suppresses T-cell function and promotes an immunosuppressive macrophage phenotype in rats. This study also indicates that measuring T-cell proliferation is as sensitive a marker of NiCl2-induced immunotoxicity as measuring T-cell or macrophage cytokine production. Co-measurement of circulating nickel concentrations and immune parameters yields valuable information with regard to the potency of nickel to alter immune function in vivo. These data also suggest that quite a large quantity of nickel needs to reach the systemic circulation before any adverse effects on immune function are observed.

There is growing epidemiological evidence for statistical associations between increases in air pollution, especially particulate matter, and increases in cardiovascular morbidity and mortality. Laboratory studies have shown that transition metals contribute strongly to the effects of high lung doses of model particles on changes in the electrocardiograms of animals. The present study evaluated the effects of short-term inhalation exposure to respirable particles of specific oxide and sulfate forms of transition metals on heart rate and the electrocardiogram of old dogs having preexisting cardiac abnormalities. Conscious beagle dogs were exposed by oral inhalation for 3 h on each of 3 successive days to aerosols of manganese, nickel, vanadium, iron, and copper oxides, and nickel and vanadium sulfates as single compounds at concentrations of 0.05 mg/m(3). Electrocardiograms were recorded and evaluated for exposure-related changes in heart rate, heart rate variability, and abnormalities of waveforms. Although the electrocardiograms of this population of dogs having potential age and cardiovascular susceptibility factors reflected their underlying clinical abnormalities, no significant effect of exposure to the transition metal aerosols was observed.

The effects of inhaled particulate matter in the workplace and outdoor environment on sensitive subpopulations are not sufficiently investigated in human and animal models. Thus, animal models for pulmonary diseases are necessary for appropriate risk assessment of toxic materials. We studied biochemical characteristics of an acute inflammatory process induced by inhalation of nickel chloride aerosols in rats. Acute bronchiolitis was induced by inhalation of nickel chloride aerosols for 5 days in Wistar rats according to the method described by Kyono et al. (1999). Deterioration and recovery from inflammatory responses were evaluated by analyzing markers of inflammation in bronchoalveolar lavage (BAL) fluid. Experimental animals were sacrificed during and after the nickel aerosol exposure period. The number of neutrophils markedly increased to approximately 0.5 x 10(3) cells/microl BAL fluid during nickel aerosol exposure, accompanied by increase of total protein, soluble L-selectin, cytokine-induced neutrophil chemoattractant/growth-regulated gene products (CINC/GRO), elastolytic activity, trypsin inhibitory capacity, beta-glucuronidase activity, fucose, and sialic acid in BAL fluid compared with those of the control group. There was correlation between number of leukocytes and soluble L-selectin concentration. The number of pulmonary macrophages in BAL fluid decreased to approximately 15% of those of the control group on the days of nickel aerosol exposure. The level of CINC/GRO recovered to that of the control group on day 3 after cessation of the nickel aerosol exposure. However, other inflammatory markers remained at the elevated levels. Changes in the markers of inflammation during and after the nickel aerosol exposure were consistent with previously reported morphological findings. The results indicated that this animal model is potentially useful as an acute bronchiolitis model.