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1.
J Toxicol Environ Health A ; 82(11): 645-663, 2019.
Article in English | MEDLINE | ID: mdl-31290376

ABSTRACT

Corian®, a solid-surface composite (SSC), is composed of alumina trihydrate and acrylic polymer. The aim of the present study was to examine the pulmonary toxicity attributed to exposure to SSC sawing dust. Male mice were exposed to either phosphate buffer saline (PBS, control), 62.5, 125, 250, 500, or 1000 µg of SSC dust, or 1000 µg silica (positive control) via oropharyngeal aspiration. Body weights were measured for the duration of the study. Bronchoalveolar lavage fluid (BALF) and tissues were collected for analysis at 1 and 14 days post-exposure. Enhanced-darkfield and histopathologic analysis was performed to assess particle distribution and inflammatory responses. BALF cells and inflammatory cytokines were measured. The geometric mean diameter of SSC sawing dust following suspension in PBS was 1.25 µm. BALF analysis indicated that lactate dehydrogenase (LDH) activity, inflammatory cells, and pro-inflammatory cytokines were significantly elevated in the 500 and 1000 µg SSC exposure groups at days 1 and 14, suggesting that exposure to these concentrations of SSC induced inflammatory responses, in some cases to a greater degree than the silica positive control. Histopathology indicated the presence of acute alveolitis at all doses at day 1, which was largely resolved by day 14. Alveolar particle deposition and granulomatous mass formation were observed in all exposure groups at day 14. The SSC particles were poorly cleared, with 81% remaining at the end of the observation period. These findings demonstrate that SSC sawing dust exposure induces pulmonary inflammation and damage that warrants further investigation. Abbreviations: ANOVA: Analysis of Variance; ATH: Alumina Trihydrate; BALF: Bronchoalveolar Lavage Fluid; Dpg: Geometric Mean Diameter; FE-SEM: Field Emission Scanning Electron Microscopy; IACUC: Institutional Animal Care and Use Committee; IFN-γ: Interferon Gamma; IL-1 Β: Interleukin-1 Beta; IL-10: Interleukin-10; IL-12: Interleukin-12; IL-2: Interleukin-2; IL-4: Interleukin-4; IL-5: Interleukin-5; IL-6: Interleukin-6; KC/GRO: Neutrophil-Activating Protein 3; MMAD: Mass Median Aerodynamic Diameter; PBS: Phosphate-Buffered Saline; PEL: Permissible Exposure Limit; PM: Polymorphonuclear Leukocytes; PNOR: Particles Not Otherwise Regulated; SEM/EDX: Scanning Electron Microscope/Energy-Dispersive X-Ray; SSA: Specific Surface Area; SSC: Solid Surface Composite; TNFα: Tumor Necrosis Factor-Alpha; VOC: Volatile Organic Compounds; σg: Geometric Standard Deviation.


Subject(s)
Dust , Lung Diseases/chemically induced , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Construction Materials , Cytokines/chemistry , Cytokines/metabolism , Inflammation/chemically induced , Inhalation Exposure , Male , Mice , Mice, Inbred C57BL , Specific Pathogen-Free Organisms
2.
J Hazard Mater ; 373: 630-639, 2019 07 05.
Article in English | MEDLINE | ID: mdl-30953980

ABSTRACT

Micronized copper azole (MCA) is a lumber treatment improve longevity. In this study, the in vivo response to PM2.5 sanding dust generated from MCA-treated lumber was compared to that of untreated yellow pine (UYP) or soluble copper azole-treated (CA-C) lumber to determine if the MCA was more bioactive than CA-C. Mice were exposed to doses (28, 140, or 280 µg/mouse) of UYP, MCA, or CA-C sanding dust using oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) lactate dehydrogenase activity was increased at 1 day post-exposure to 280 µg/mouse of MCA and CA-C compared to UYP. BALF polymorphonuclear cells were increased by MCA and CA-C. There were increases in BALF cytokines in MCA and CA-C-exposed groups at 1 day post-exposure. Lung histopathology indicated inflammation with infiltration of neutrophils and macrophages. Pulmonary responses were more severe in MCA and CA-C-exposed groups at 1 day post-exposure. MCA caused more severe inflammatory responses than CA-C at 1 day post-exposure. These findings suggest that the MCA and CA-C sanding dusts are more bioactive than the UYP sanding dust, and, moreover, the MCA sanding dust is more bioactive in comparison to the CA-C sanding dust. No chronic toxic effects were observed among all observed sanding dusts.


Subject(s)
Copper/toxicity , Inhalation Exposure/adverse effects , Particulate Matter/toxicity , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , Copper/analysis , L-Lactate Dehydrogenase/analysis , Lung/pathology , Mice , Toxicity Tests , Wood
3.
EBioMedicine ; 32: 102-110, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29861409

ABSTRACT

PURPOSE: This study aims to develop a multi-gene assay predictive of the clinical benefits of chemotherapy in non-small cell lung cancer (NSCLC) patients, and substantiate their protein expression as potential therapeutic targets. PATIENTS AND METHODS: The mRNA expression of 160 genes identified from microarray was analyzed in qRT-PCR assays of independent 337 snap-frozen NSCLC tumors to develop a predictive signature. A clinical trial JBR.10 was included in the validation. Hazard ratio was used to select genes, and decision-trees were used to construct the predictive model. Protein expression was quantified with AQUA in 500 FFPE NSCLC samples. RESULTS: A 7-gene signature was identified from training cohort (n = 83) with accurate patient stratification (P = 0.0043) and was validated in independent patient cohorts (n = 248, P < 0.0001) in Kaplan-Meier analyses. In the predicted benefit group, there was a significantly better disease-specific survival in patients receiving adjuvant chemotherapy in both training (P = 0.035) and validation (P = 0.0049) sets. In the predicted non-benefit group, there was no survival benefit in patients receiving chemotherapy in either set. The protein expression of ZNF71 quantified with AQUA scores produced robust patient stratification in separate training (P = 0.021) and validation (P = 0.047) NSCLC cohorts. The protein expression of CD27 quantified with ELISA had a strong correlation with its mRNA expression in NSCLC tumors (Spearman coefficient = 0.494, P < 0.0088). Multiple signature genes had concordant DNA copy number variation, mRNA and protein expression in NSCLC progression. CONCLUSIONS: This study presents a predictive multi-gene assay and prognostic protein biomarkers clinically applicable for improving NSCLC treatment, with important implications in lung cancer chemotherapy and immunotherapy.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , DNA Copy Number Variations/genetics , Prognosis , Adult , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Oligonucleotide Array Sequence Analysis , Proportional Hazards Models
4.
J Occup Med Toxicol ; 13: 12, 2018.
Article in English | MEDLINE | ID: mdl-29619075

ABSTRACT

BACKGROUND: Operating room personnel have the potential to be exposed to surgical smoke, the by-product of using electrocautery or laser surgical device, on a daily basis. Surgical smoke is made up of both biological by-products and chemical pollutants that have been shown to cause eye, skin and pulmonary irritation. METHODS: In this study, surgical smoke was collected in real time in cell culture media by using an electrocautery surgical device to cut and coagulate human breast tissues. Airborne particle number concentration and particle distribution were determined by direct reading instruments. Airborne concentration of selected volatile organic compounds (VOCs) were determined by evacuated canisters. Head space analysis was conducted to quantify dissolved VOCs in cell culture medium. Human small airway epithelial cells (SAEC) and RAW 264.7 mouse macrophages (RAW) were exposed to surgical smoke in culture media for 24 h and then assayed for cell viability, lactate dehydrogenase (LDH) and superoxide production. RESULTS: Our results demonstrated that surgical smoke-generated from human breast tissues induced cytotoxicity and LDH increases in both the SAEC and RAW. However, surgical smoke did not induce superoxide production in the SAEC or RAW. CONCLUSION: These data suggest that the surgical smoke is cytotoxic in vitro and support the previously published data that the surgical smoke may be an occupational hazard to healthcare workers.

5.
J Occup Environ Hyg ; 15(4): 311-321, 2018 04.
Article in English | MEDLINE | ID: mdl-29300681

ABSTRACT

To protect against decay and fungal invasion into the wood, the micronized copper, copper carbonate particles, has been applied in the wood treatment in recent years; however, there is little information on the health risk associated with sanding micronized copper-treated lumber. In this study, wood dust from the sanding of micronized copper azole-treated lumber (MCA) was compared to sanding dust from solubilized copper azole-treated wood (CA-C) and untreated yellow pine (UYP). The test found that sanding MCA released a much higher concentration of nanoparticles than sanding CA-C and UYP, and the particles between about 0.4-2 µm from sanding MCA had the highest percentage of copper. The percentage of copper in the airborne dust from sanding CA-C had a weak dependency on particle size and was lower than that from sanding MCA. Nanoparticles were seen in the MCA PM2.5 particles, while none were detected in the UYP or CA-C. Inductively coupled plasma mass spectrometry (ICP-MS) analysis found that the bulk lumber for MCA and CA-C had relatively equal copper content; however, the PM2.5 particles from sanding the MCA had a higher copper concentration when compared to the PM2.5 particles from sanding UYP or CA-C. The cellular toxicity assays show that exposure of RAW 264.7 macrophages (RAW) to MCA and CA-C wood dust suspensions did not induce cellular toxicity even at the concentration of 200 µg PM2.5 wood dust/mL. Since the copper from the treated wood dust can leach into the wood dust supernatant, the supernatants of MCA, CA-C and UYP wood dusts were subjected to the cellular toxicity assays. The data showed that at the higher concentrations of copper (≥5 µg/ml), both MCA and CA-C supernatants induced cellular toxicity. This study suggests that sanding MCA-treated lumber releases copper nanoparticles and both the MCA and CA-C-treated lumber can release copper, which are potentially related to the observed in vitro toxicity.


Subject(s)
Copper/analysis , Dust/analysis , Wood/chemistry , Animals , Azoles/chemistry , Copper/toxicity , Mice , Nanoparticles/chemistry , Nanoparticles/toxicity , Particle Size , RAW 264.7 Cells
6.
J Hazard Mater ; 344: 549-557, 2018 Feb 15.
Article in English | MEDLINE | ID: mdl-29102637

ABSTRACT

Electronic cigarettes (e-cigs) have fast increased in popularity but the physico-chemical properties and toxicity of the generated emission remain unclear. Reactive oxygen species (ROS) are likely present in e-cig emission and can play an important role in e-cig toxicity. However, e-cig ROS generation is poorly documented. Here, we generated e-cig exposures using a recently developed versatile exposure platform and performed systematic ROS characterization on e-cig emissions using complementary acellular and cellular techniques: 1) a novel acellular Trolox-based mass spectrometry method for total ROS and hydrogen peroxide (H2O2) detection, 2) electron spin resonance (ESR) for hydroxyl radical detection in an acellular and cellular systems and 3) in vitro ROS detection in small airway epithelial cells (SAEC) using the dihydroethidium (DHE) assay. Findings confirm ROS generation in cellular and acellular systems and is highly dependent on the e-cig brand, flavor, puffing pattern and voltage. Trolox method detected a total of 1.2-8.9nmol H2O2eq./puff; H2O2 accounted for 12-68% of total ROS. SAEC cells exposed to e-cig emissions generated up to eight times more ROS compared to control. The dependency of e-cig emission profile on e-cig features and operational parameters should be taken into consideration in toxicological studies.


Subject(s)
Electronic Nicotine Delivery Systems , Reactive Oxygen Species/chemistry , Reactive Oxygen Species/metabolism , Antioxidants/chemistry , Catalase/metabolism , Cell Line , Chromans/chemistry , Epithelial Cells/metabolism , Humans
7.
Part Fibre Toxicol ; 13(1): 42, 2016 08 15.
Article in English | MEDLINE | ID: mdl-27527840

ABSTRACT

BACKGROUND: Although classified as metal oxides, cobalt monoxide (CoO) and lanthanum oxide (La2O3) nanoparticles, as representative transition and rare earth oxides, exhibit distinct material properties that may result in different hazardous potential in the lung. The current study was undertaken to compare the pulmonary effects of aerosolized whole body inhalation of these nanoparticles in mice. RESULTS: Mice were exposed to filtered air (control) and 10 or 30 mg/m(3) of each particle type for 4 days and then examined at 1 h, 1, 7 and 56 days post-exposure. The whole lung burden 1 h after the 4 day inhalation of CoO nanoparticles was 25 % of that for La2O3 nanoparticles. At 56 days post exposure, < 1 % of CoO nanoparticles remained in the lungs; however, 22-50 % of the La2O3 nanoparticles lung burden 1 h post exposure was retained at 56 days post exposure for low and high exposures. Significant accumulation of La2O3 nanoparticles in the tracheobronchial lymph nodes was noted at 56 days post exposure. When exposed to phagolysosomal simulated fluid, La nanoparticles formed urchin-shaped LaPO4 structures, suggesting that retention of this rare earth oxide nanoparticle may be due to complexation of cellular phosphates within lysosomes. CoO nanoparticles caused greater lactate dehydrogenase release in the bronchoalveolar fluid (BALF) compared to La2O3 nanoparticles at 1 day post exposure, while BAL cell differentials indicate that La2O3 nanoparticles generated more inflammatory cell infiltration at all doses and exposure points. Histopathological analysis showed acute inflammatory changes at 1 day after inhalation of either CoO or La2O3 nanoparticles. Only the 30 mg/m(3) La2O3 nanoparticles exposure caused chronic inflammatory changes and minimal fibrosis at day 56 post exposure. This is in agreement with activation of the NRLP3 inflammasome after in vitro exposure of differentiated THP-1 macrophages to La2O3 but not after CoO nanoparticles exposure. CONCLUSION: Taken together, the inhalation studies confirmed the trend of our previous sub-acute aspiration study, which reported that CoO nanoparticles induced more acute pulmonary toxicity, while La2O3 nanoparticles caused chronic inflammatory changes and minimal fibrosis.


Subject(s)
Cobalt/toxicity , Lanthanum/toxicity , Lung/drug effects , Metal Nanoparticles/toxicity , Oxides/toxicity , Aerosols , Animals , Bronchoalveolar Lavage Fluid , Cobalt/pharmacokinetics , Cytokines/metabolism , Inhalation Exposure , Lanthanum/pharmacokinetics , Lung/metabolism , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Oxides/pharmacokinetics
8.
Toxicol Sci ; 150(2): 418-28, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26769336

ABSTRACT

Cobalt monoxide (CoO) and lanthanum oxide (La2O3) nanoparticles are 2 metal oxide nanoparticles with different redox potentials according to their semiconductor properties. By utilizing these two nanoparticles, this study sought to determine how metal oxide nanoparticle's mode of toxicological action is related to their physio-chemical properties in human small airway epithelial cells (SAEC). We investigated cellular toxicity, production of superoxide radicals and alterations in gene expression related to oxidative stress, and cellular death at 6 and 24 h following exposure to CoO and La2O3(administered doses: 0, 5, 25, and 50 µg/ml) nanoparticles. CoO nanoparticles induced gene expression related to oxidative stress at 6 h. After characterizing the nanoparticles, transmission electron microscope analysis showed SAEC engulfed CoO and La2O3nanoparticles. CoO nanoparticles were toxic after 6 and 24 h of exposure to 25.0 and 50.0 µg/ml administered doses, whereas, La2O3nanoparticles were toxic only after 24 h using the same administered doses. Based upon the Volumetric Centrifugation Methodin vivoSedimentation, Diffusion, and Dosimetry, the dose of CoO and La2O3nanoparticles delivered at 6 and 24 h were determined to be: CoO: 1.25, 6.25, and 12.5 µg/ml; La2O3: 5, 25, and 50 µg/ml and CoO: 4, 20, and 40 µg/ml; and La2O3: 5, 25, 50 µg/ml, respectively. CoO nanoparticles produced more superoxide radicals and caused greater stimulation of total tyrosine and threonine phosphorylation at both 6 and 24 h when compared with La2O3nanoparticles. Taken together, these data provide evidence that different toxicological modes of action were involved in CoO and La2O3metal oxide nanoparticle-induced cellular toxicity.


Subject(s)
Cobalt/toxicity , Epithelial Cells/drug effects , Lanthanum/toxicity , Nanoparticles/toxicity , Oxidative Stress/drug effects , Oxides/toxicity , Respiratory Mucosa , Cell Culture Techniques , Cell Survival/drug effects , Cells, Cultured , Cobalt/chemistry , Dose-Response Relationship, Drug , Epithelial Cells/metabolism , Epithelial Cells/pathology , Gene Expression/drug effects , Humans , Lanthanum/chemistry , Microscopy, Electron, Transmission , Nanoparticles/chemistry , Oxidative Stress/genetics , Oxides/chemistry , Reactive Oxygen Species/metabolism , Respiratory Mucosa/cytology , Respiratory Mucosa/drug effects , Surface Properties
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