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Aberrant CpG island methylation of the p16(INK4a) and estrogen receptor genes in rat lung tumors induced by particulate carcinogens.

Recent studies by our laboratory indicate that the p16(INK4a) gene is frequently methylated in lung tumors induced by genotoxic carcinogens and that the frequency for methylation of the estrogen receptor alpha (ER) gene varies as a function of carcinogenic exposure. The purpose of the current investigation was to define the role of these two genes in lung tumors induced by the particulate carcinogens carbon black (CB), diesel exhaust (DE) or beryllium metal. Methylation of p16 was observed in 59 and 46% of DE and CB tumors, respectively. In contrast, the ER gene was inactivated in only 15% of DE or CB tumors. Methylation of the p16 and ER genes was very common (80 and 50%, respectively) in beryllium-induced lung tumors; both genes were methylated in 40% of the tumors. Bisulfite sequencing revealed dense methylation throughout exon 1 of the ER gene. The inhibitory effect of methylation on gene transcription was confirmed through RT-PCR expression studies in which p16 gene expression was 30-60-fold lower in methylated than unmethylated tumors. Residual expression in methylated tumors was consistent with contamination by stromal and inflammatory cells. Results indicate that tumors induced by these particulate carcinogens arise, in part, through inactivation of the p16 and ER genes. Furthermore, the inactivation of the p16 gene by these carcinogenic exposures supports a possible role for oxidative stress and inflammation in the etiology of human lung cancer.

Animals↗

Overview of analysis of carcinogenic and/or mutagenic metals in biological and environmental samples. I. Arsenic, beryllium, cadmium, chromium and selenium.

One of the most dangerous and pernicious forms of pollution arises from the potential mobilization of a spectrum of toxic trace metals and metalloids in our environment. Among the most important elements in this regard are arsenic, beryllium, cadmium, chromium and selenium whose adverse toxic effects are now well recognized including their carcinogenicity and/or mutagenicity. These agents (and their derivatives) can be widely dispersed throughout the environment as a result of fossil fuel combustion, industrial and agricultural processes and natural processes. The trend for the immediate future appears to be of greater exposure to these metals not only as a result of generally increased usage patterns but also because of prospective enhanced use of fossil fuels for space heating and electricity generation. In order to more readily evaluate trends of human exposure as well as the toxicity, bioavailability, bioaccumulation and transport of these elements, sensitive analytical procedures are required for the determination of their various oxidation states (as well as their organic derivatives) in complex matrices such as those found in both environmental and biological samples. Hence, the principal objective of this overview is to highlight the more recent trends and state-of-the-art methodologies for the determination of arsenic, beryllium, cadmium, chromium and selenium (in their various forms) in environmental compartments such as air, water, soil and in human tissues (primarily blood, urine, and milk). Techniques to be discussed primarily include atomic absorption spectrometry, neutron activation analysis, gas chromatography, differential pulse polarography and electrochemical analysis. The importance of quality control and differentiation according to speciation will also be stressed.

Air↗

Metal carcinogenesis: mechanistic implications.

Cancer epidemiology has identified several metal compounds as human carcinogens. Recent evidence suggests that carcinogenic metals induce genotoxicity in a multiplicity of ways, either alone or by enhancing the effects of other agents. This review summarizes current information on the genotoxicity of arsenic, chromium, nickel, beryllium and cadmium compounds and their possible roles in carcinogenesis. Each of these metals is distinct in its primary modes of action; yet there are several mechanisms induced by more than one metal, including: the induction of cellular immunity and oxidative stress, the inhibition of DNA metabolism and repair and the formation of DNA- and/or protein-crosslinks.

Animals↗

Localization of metallic ions with gingival fibroblast subcellular fractions.

Nickel-based alloys have been in use since the 1930s; however, there are concerns regarding the release of metal ions (Be(+2), Cr(+6), Cr(+3), Ni(+2), Mo(+6)) from these alloys into surrounding tissues. Therefore, the objective of this study was to determine the cellular location and accumulation of ions using atomic absorption spectroscopy and correlate location with the cytotoxic, morphologic, and ultrastructural evaluations reported previously. Human gingival fibroblasts were exposed to the metal ions for 72 h. Controlled atomic absorption spectroscopy studies were used to determine the intracellular location of these ions reported as parts per million metal ions per milligram protein. Enzymatic markers were shown to correspond to the appropriate fraction indicating success in fractionation of the gingival fibroblasts. These results correspond with the cytotoxic, morphologic, and ultrastructural alterations reported previously for fibroblasts exposed to these ions. The highest concentration of beryllium ions occurred in the low-density molecule fraction, where lipofuscin granules were found, which has been shown to contain metal ions. The highest concentrations of hexavalent chromium ions occurred in the plasma membrane and nuclear fractions followed by the mitochondria fraction, which is supported by the ions' ability to oxidize to trivalent chromium accumulating at the membrane as well as the alterations in nuclear and mitochondrial function. For trivalent chromium, the highest concentrations occurred in the low-density molecule and the plasma membrane fractions, which correlates with the ions' inability to readily cross membranes. The highest concentration of molybdenum ions occurred in the plasma membrane fraction correlating with alterations in membrane morphology and increased numbers of myelin figures. The highest concentration of nickel ions was associated with the cytosol fraction where lipid droplets seen in the transmission electron micrographs were located. The current study demonstrates that a successful subcellular fractionation was obtained on gingival fibroblasts and that the location of metallic ions within the fractions correlated with cellular alterations reported previously.

Beryllium↗

Interstitial lung disease induced by exogenous agents: factors governing susceptibility.

The purpose of this review is to describe the present state of knowledge regarding host susceptibility factors that may determine the occurrence, development and severity of interstitial lung disease (ILD) caused by exogenous agents. First, host susceptibility may pertain to differences in the delivery and/or persistence of the noxious agent in the lung. The deposition and clearance of inhaled particles or fibres may vary depending on innate anatomical or physiological characteristics, and on acquired changes, such as nasal disease or smoking-induced alterations. Genetically- or environmentally-induced interindividual differences in the expression of pulmonary biotransformation enzymes may form the basis for, or contribute to the risk of, drug-induced interstitial lung disease. Secondly, there are genetic and acquired variations in various enzymatic and nonenzymatic defence systems that protect cells and tissues against oxidative stress, which is often involved in the pathogenesis of interstitial lung disease caused by particles, fibres, metals, organic agents and drugs. Thirdly, the occurrence of immunological sensitization is dependent on both genetic and environmental factors. This has been demonstrated in chronic beryllium lung disease and in hypersensitivity pneumonitis. Fourthly, the propensity of individuals to develop particular types of inflammation, such as granulomas, is probably under genetic control. The regulation and resolution of inflammation and fibrogenesis caused by dust particles are also partly determined by genetic factors, involving cytokine networks and growth factors. In conclusion, although the issue of genetics pervades the entire discussion of host susceptibility, genes are not the only determinants of health and disease. Environmental factors may be equally important in shaping host susceptibility. Therefore, research must be focused on both the genetic bases and the environmental determinants of interstitial lung disease, in order to provide mechanism-based prevention strategies, early detection of, and improved therapy for these conditions.

Air Pollutants↗

Carcinogenicity of trace elements with reference to evaluations made by the International Agency for Research on Cancer.

The monograph program of the International Agency for Research of on Cancer has evaluated many trace elements for their carcinogenicity to humans. Five groups of compounds were considered human carcinogens: arsenic and arsenic compounds, beryllium and beryllium compounds, cadmium and cadmium compounds, hexavalent chromium compounds, and nickel compounds. Antimony trioxide, cobalt and cobalt compounds, lead and inorganic lead compounds, methylmercury compounds, and metallic nickel were considered possibly carcinogenic to humans. Antimony trisulfide, trivalent chromium compounds, metallic chromium, ferric oxide, organolead compounds, metallic mercury, inorganic mercury compounds, selenium and selenium compounds, and titanium dioxide were not classifiable. Trace elements studied to a limited extent include copper, manganese, tin, vanadium, and zinc. Among the problems are the lack of relevant data, the definition of active species, the extrapolation of the results of experimental studies to humans, the methodological problems of epidemiologic studies, and the possible anticarcinogenic activity of some trace elements.

Humans↗

Shear bond strength of composite resin to microetched metal with five newer-generation bonding agents.

The purpose of this study was to determine the shear bond strength of a hybrid composite resin to a nickel-chrome-beryllium (Ni-Cr-Be) alloy, using five of the newer-generation bonding agents: Optibond, All-Bond 2, Prisma Universal Bond 3, Restobond 4, and Amalgambond Plus with HPA. For each bonding system 10 samples of metal were microetched with 50-micron aluminum oxide prior to the placement of the bonding agent and resin. The shear bond strength was tested, and the results showed that Amalgambond Plus with HPA developed the strongest bond at 18.81 +/- 3.924 MPa, followed by All-Bond 2 at 14.33 +/- 3.408, Optibond at 13.97 +/- 1.508, Prisma Universal Bond 3 at 12.51 +/- 1.845, and Restobond 4 at 10.29 +/- 1.407.

Aluminum Oxide↗

Effect of adhesives on bond strength of porcelain veneer to base metal alloy.

OBJECTIVE: The purpose of this in vitro study was to evaluate the bond strength of porcelain veneer to base metal alloy using different adhesive systems. METHOD AND MATERIALS: Eighty cylindrical models were cast in a nickel-chromium-beryllium base metal alloy. After they were mounted in self-cured acrylic resin, the surfaces of the specimens were air abraded. Specimens were divided into four groups of 20. Control porcelain disks were baked on the base metal. For the experimental groups, 60 porcelain disks were made. After 50-microm aluminum oxide sandblasting, a silane coupling agent was applied to the surface of the porcelain. The experimental groups were based on the type of adhesive used to bond porcelain to metal: Scotchbond Multipurpose and Duo Cement; One Coat Bond and Duo Cement; or Panavia 21 Ex. After 500 thermal cycles, the bonded porcelain specimens were placed under a continuous shear load of 2 mm/min until fracture occurred. RESULTS: Mean values for bond strength were 25.39 (control), 19.10 (Panavia 21 Ex), 15.81 (Scotchbond Multipurpose), and 13.69 MPa (One Coat Bond). Statistically significant differences in bond strength were noted between the control group and all the experimental groups. A statistically significant difference was observed between Panavia 21 Ex specimens and One Coat Bond specimens. CONCLUSION: Panavia 21 Ex provided an effective bond strength between a porcelain veneer and a base metal alloy, the closest of all the experimental groups to that of the control group.

Acrylic Resins↗

The effect of oxidation heat treatment of porcelain bond strength in selected base metal alloys.

Base metal alloys have been widely used for fixed partial dentures in the past decade. The oxidation heat treatment (degassing) of these alloys is a controversial step to prepare the metal surface for bonding porcelain. This study evaluated the effect of oxidation heat treatment on the porcelain bond strength of base metal alloys and investigated composition changes that may have occurred during this process.

Analysis of Variance↗

Ferritin: an iron storage protein with diverse functions.

Ferritin is the major protein for iron storage and iron detoxification. Since non-ferrous metals, such as aluminum, beryllium and zinc, are bound both in vivo and in vitro, ferritin is implicated as a general metal ion donor and detoxicant. The role of ferritin in Al and Be toxicity is discussed. During iron release ferritin produces free radicals which are involved in phosphoprotein inactivation, lipid peroxidation and, possibly, the general aging process. Conversely, during iron loading oxidative energy in the form of electrons and protons is given off. The different subunit compositions of ferritin, termed isoferritins, are, at least in part, involved with the multifunctionality of this protein.

Aluminum↗

Tensile bond strength of a composite resin cement for bonded prosthesis to various dental alloys.

The development of composite resin cements that chemically bond to dental alloys has improved the construction of resin-bonded prostheses. Composite resins can be selected for various situations, but specific clinical situations may require different alloys. This study evaluated the ability of a composite resin cement to bond to various dental alloys of different compositions. Ten pairs of disks for each alloy (two NiCr, two NiCrBe, one CuAl, one gold type IV, and one gold for metal ceramic) were bonded to a composite resin cement after air abrasion was performed with aluminum oxide. The disks were then rinsed in tap water and were ultrasonically cleaned in distilled water for 2 minutes. The tensile tests exhibited greater values for alloys ultrasonically cleaned, and the best results were recorded by NiCr and NiCrBe alloys.

Aluminum↗

Clinical approach to chronic beryllium disease and other nonpneumoconiotic interstitial lung diseases.

Exposures in the workplace result in a diverse set of diseases ranging from the pneumoconiosis to other interstitial lung diseases to acute lung injury. Physician awareness of the potential disease manifestations associated with specific exposures is important in defining these diseases and in preventing additional disease. Most occupational diseases mimic other forms of lung disease, including pulmonary fibrosis, sarcoidosis, adult respiratory distress syndrome (ARDS), and bronchiolitis. A "sarcoidosis"-like syndrome, usually limited to the lungs, may result from exposure to bioaerosols and a number of metals. Exposure to beryllium in the workplace produces a granulomatous lung disease clinically indistinguishable from sarcoidosis, chronic beryllium disease (CBD). Beryllium's ability to produce a beryllium-specific immune response is used in the beryllium lymphocyte proliferation tests to confirm a diagnosis of CBD and exclude sarcoidosis. Exposure to other metals must also be considered in the differential diagnosis of sarcoidosis. When an individual presents acutely with ARDS or acute lung injury, an acute inhalational exposure must be considered. Exposure to a number of irritant substances at high levels may cause a "chemical pneumonitis" or acute lung injury, depending on the solubility and physicochemical properties of the substance. Some of the most notable agents include nitrogen and sulfur oxides, phosgene, and smoke breakdown products. Ingestion of paraquat may also result in an ARDS syndrome, with pulmonary fibrosis eventually resulting. Bronchiolitis is a rare manifestation of inhalational exposures but must also be considered in the clinical evaluation of inhalational exposure.

Adult↗

Comparison of shear bond strengths of two resin luting systems for a base and a high noble metal alloy bonded to enamel.

Researchers are investigating the use of noble metals for the fabrication of resin-bonded prostheses because of concerns about health hazards of nickel and beryllium in base metal alloys. Tin-plating has been advocated to improve the bond of resin luting agents to noble metal alloys. Some manufacturers have suggested that tin-plating is unnecessary to bond noble metal alloys to etched enamel with their products. In this study, Rexillium base metal and Olympia noble metal alloy specimens were bonded to extracted human teeth with the use of two resin luting agents (F21 and Panavia OP). One third of the noble metal specimens were tin-plated, one third were oxidized, and one third were oxidized and sandblasted. Each of the bonded specimens were thermocycled and subjected to a shear force until bond failure. The base metal specimens bonded with Panavia OP luting agent exhibited the greatest mean shear bond strengths. The tin-plating surface treatment significantly increased the mean shear bond strengths of Olympia noble metal specimens.

Adhesives↗

Pulmonary responses to oil fly ash particles in the rat differ by virtue of their specific soluble metals.

Occupational exposure to residual oil fly ash (ROFA) particulate has been associated with adverse respiratory health effects in humans. We hypothesized that ROFA collected at different sites within an oil burning power plant, by virtue of its differing metal and sulfate composition, will induce differential lung injury. Ten ROFA samples collected at various sites within a power plant were analyzed for water- and 1.0 M HCl-leachable arsenic (As), beryllium (Be), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), vanadium (V), zinc (Zn), and sulfur by inductively coupled plasma-atomic emission spectroscopy. All ROFA samples contained variable amounts of leachable (water-extractable) and 1.0 M HCl-extractable Fe, V, and/or Ni. All other metals, except Zn (ROFA No. 1 contained 3.43 and No. 3, 6.35 micrograms/mg Zn), were present in negligible quantities (< 1.0 microgram/mg) in the water extract. In vivo pulmonary injury from exposure to whole saline suspensions of these ROFA was evaluated. Male, SD rats (60 days old) were intratracheally instilled with either saline or saline suspension of whole ROFA (< 3.0 mass median aerodynamic diameter) at three concentrations (0.833, 3.33, or 8.33 mg/kg). After 24 h, lungs were lavaged and bronchoalveolar lavage fluid (BALF) was analyzed for cellular influx and protein content as well as lactate dehydrogenase (LDH) and N-acetyl glucosaminidase (NAG) activity and total hemoglobin as indicators of lung injury. ROFA-induced increases in BALF protein and LDH, but not neutrophilic inflammation, were associated with its water-leachable total metal, Ni, Fe, and sulfate content. However, the neutrophilic response following ROFA exposure was positively correlated with its water-leachable V content. Modest lung injury was observed with the ROFA samples which contained the smallest amounts of water-leachable metals. The ability of ROFA to induce oxidative burst in alveolar macrophage (AM) was determined in vitro using a chemiluminescence (CL) assay. AM CL signals in vitro were greatest with ROFA containing primarily soluble V and were less with ROFA containing Ni plus V. In summary, ROFA-induced in vivo acute pulmonary inflammation appears to be associated with its water-leachable V content; however, protein leakage appears to be associated with its water-leachable Ni content. ROFA-induced in vitro activation of AM was highest with ROFA containing leachable V but not with Ni plus V, suggesting that the potency and the mechanism of pulmonary injury will differ between emissions containing V and Ni.

Animals↗

A comparison of 3 alloy surface treatments for resin-bonded prostheses.

PURPOSE: The most frequent cause of clinical failure of resin-bonded fixed partial dentures is a debonding at the metal-cement interface. The purpose of this in vitro study was to compare the tensile bond strengths of 3 different alloy-surface treatments when cemented to human enamel with a resin cement. MATERIALS AND METHODS: Cylinders of a nickel-chromium-beryllium (Ni-Cr-Be) and a gold-palladium (Au-Pd) alloy were fabricated and assigned to different surface treatment groups as follows: Group 1: Ni-Cr-Be, chemically etched; Group 2: Au-Pd, airborne particle-abraded and tin-plated; and Group 3: Au-Pd, airborne particle-abraded and treated with the Alloy Primer (Kuraray Co, LTD, Osaka, Japan). The cylinders were bonded to the enamel surfaces of extracted, human third molars and stored in normal saline at 37 degrees C for 48 hours. The tensile bond strength of 21 specimens from each group was measured on a Universal Testing Machine (Instron, Canton, MA). Three failed specimens of each group were evaluated using scanning electron microscopy and energy dispersive spectroscopy. RESULTS: Statistically significant differences (p <.05) were found between all 3 treatment groups. The mean tensile bond strengths (+/- the standard error of mean) recorded as follows: Group 1: 10.6 MPa (+/-1.3), Group 2: 0.9 MPa (+/-0.2), and Group 3: 13.4 MPa (+/-1.0). Specimens from groups 1 and 3 revealed a trend towards mixture of cohesive, within the resin cement, and adhesive failures at the metal-cement interface. Group 2 specimens exhibited primarily adhesive failures at the metal-cement interface. CONCLUSIONS: The tensile bond strength of Au-Pd alloy specimens was significantly increased with the Alloy Primer.

Acid Etching, Dental↗