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Welding fumes are a Group 1 (carcinogenic to humans) carcinogen as classified by the International Agency for Research on Cancer. The process of welding creates inhalable fumes rich in iron (Fe) that may also contain known carcinogenic metals such as chromium (Cr) and nickel (Ni). Epidemiological evidence has shown that both mild-steel (Fe-rich) and stainless steel (Fe-rich + Cr + Ni) welding fume exposure increase lung cancer risk, and experimental animal data support these findings. Copper-nickel (CuNi) welding processes have not been investigated in the context of lung cancer. Cu is intriguing, however, given the role of Cu in carcinogenesis and cancer therapeutics. This study examines the potential for a CuNi fume to induce mechanistic key characteristics of carcinogenesis in vitro and to promote lung tumorigenesis, using a two-stage mouse bioassay, in vivo. Male A/J mice, initiated with 3-methylcholanthrene (MCA; 10 µg/g), were exposed to CuNi fumes or air by whole-body inhalation for nine weeks (low-deposition-LD and high deposition-HD) then sacrificed at 30 weeks. In BEAS-2B cells, the CuNi fume induced micronuclei and caused DNA damage as measured by γ-H2AX. The fume exhibited high reactivity and a dose response in cytotoxicity and oxidative stress. In vivo, MCA/CuNi HD and LD significantly decreased lung tumor size and adenomas. MCA/CuNi HD exposure significantly decreased gross-evaluated tumor number. In summary, the CuNi fume in vitro exhibited characteristics of a carcinogen, but in vivo the exposure resulted in smaller tumors, fewer adenomas, less hyperplasia severity, and with the HD exposure, less overall lung lesion/tumors.
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The toxicity of boron nitride nanotubes (BNNTs) has been the subject of conflicting reports, likely due to differences in the residuals and impurities that can make up to 30-60% of the material produced based on the manufacturing processes and purification employed. Four BNNTs manufactured by induction thermal plasma process with a gradient of BNNT purity levels achieved through sequential gas purification, water and solvent washing, allowed assessing the influence of these residuals/impurities on the toxicity profile of BNNTs. Extensive characterization including infrared and X-ray spectroscopy, thermogravimetric analysis, size, charge, surface area, and density captured the alteration in physicochemical properties as the material went through sequential purification. The material from each step is screened using acellular and in vitro assays for evaluating general toxicity, mechanisms of toxicity, and macrophage function. As the material increased in purity, there are more high-aspect-ratio particulates and a corresponding distinct increase in cytotoxicity, nuclear factor-κB transcription, and inflammasome activation. There is no alteration in macrophage function after BNNT exposure with all purity grades. The cytotoxicity and mechanism of screening clustered with the purity grade of BNNTs, illustrating that greater purity of BNNT corresponds to greater toxicity.
Assuntos
Compostos de Boro , Nanotubos , Compostos de Boro/toxicidade , Compostos de Boro/química , Macrófagos , Nanotubos/toxicidade , Nanotubos/químicaRESUMO
Thermal spray coating is an industrial process in which molten metal is sprayed at high velocity onto a surface as a protective coating. An automated electric arc wire thermal spray coating aerosol generator and inhalation exposure system was developed to simulate an occupational exposure and, using this system, male Sprague-Dawley rats were exposed to stainless steel PMET720 aerosols at 25 mg/m3 × 4 h/day × 9 day. Lung injury, inflammation, and cytokine alteration were determined. Resolution was assessed by evaluating these parameters at 1, 7, 14 and 28 d after exposure. The aerosols generated were also collected and characterized. Macrophages were exposed in vitro over a wide dose range (0-200 µg/ml) to determine cytotoxicity and to screen for known mechanisms of toxicity. Welding fumes were used as comparative particulate controls. In vivo lung damage, inflammation and alteration in cytokines were observed 1 day post exposure and this response resolved by day 7. Alveolar macrophages retained the particulates even after 28 day post-exposure. In line with the pulmonary toxicity findings, in vitro cytotoxicity and membrane damage in macrophages were observed only at the higher doses. Electron paramagnetic resonance showed in an acellular environment the particulate generated free radicals and a dose-dependent increase in intracellular oxidative stress and NF-kB/AP-1 activity was observed. PMET720 particles were internalized via clathrin and caveolar mediated endocytosis as well as actin-dependent pinocytosis/phagocytosis. The results suggest that compared to stainless steel welding fumes, the PMET 720 aerosols were not as overtly toxic, and the animals recovered from the acute pulmonary injury by 7 days.
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Poluentes Ocupacionais do Ar , Soldagem , Ratos , Animais , Masculino , Aço Inoxidável/toxicidade , Poluentes Ocupacionais do Ar/toxicidade , NF-kappa B , Actinas , Fator de Transcrição AP-1 , Ratos Sprague-Dawley , Aerossóis e Gotículas Respiratórios , Soldagem/métodos , Exposição por Inalação/efeitos adversos , Pulmão , Poeira , Inflamação/patologia , Citocinas , Clatrina/farmacologiaRESUMO
Cultured murine macrophages (RAW 264.7) were used to investigate the effects of fracking sand dust (FSD) for its pro-inflammatory activity, in order to gain insight into the potential toxicity to workers associated with inhalation of FSD during hydraulic fracturing. While the role of respirable crystalline silica in the development of silicosis is well documented, nothing is known about the toxicity of inhaled FSD. The FSD (FSD 8) used in these studies was from an unconventional gas well drilling site. FSD 8was prepared as a 10 mg/ml stock solution in sterile PBS, vortexed for 15 s, and allowed to sit at room temperature for 30 min before applying the suspension to RAW 264.7cells. Compared to PBS controls, cellular viability was significantly decreased after a 24 h exposure to FSD. Intracellular reactive oxygen species (ROS) production and the production of IL-6, TNFα, and endothelin-1 (ET-1) were up-regulated as a result of the exposure, whereas the hydroxyl radical (.OH) was only detected in an acellular system. Immunofluorescent staining of cells against TNFα revealed that FSD 8 caused cellular blebbing, and engulfment of FSD 8 by macrophages was observed with enhanced dark-field microscopy. The observed changes in cellular viability, cellular morphology, free radical generation and cytokine production all confirm that FSD 8 is cytotoxic to RAW 264.7 cells and warrants future studies into the specific pathways and mechanisms by which these toxicities occur.
Assuntos
Poeira , Fraturamento Hidráulico , Areia , Animais , Sobrevivência Celular , Ensaio Cometa , Inflamação , Interleucina-6 , Camundongos , Células RAW 264.7 , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfaRESUMO
Hydraulic fracturing ("fracking") is used in unconventional gas drilling to allow for the free flow of natural gas from rock. Sand in fracking fluid is pumped into the well bore under high pressure to enter and stabilize fissures in the rock. In the process of manipulating the sand on site, respirable dust (fracking sand dust, FSD) is generated. Inhalation of FSD is a potential hazard to workers inasmuch as respirable crystalline silica causes silicosis, and levels of FSD at drilling work sites have exceeded occupational exposure limits set by OSHA. In the absence of any information about its potential toxicity, a comprehensive rat animal model was designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems (Fedan, J.S., Toxicol Appl Pharmacol. 00, 000-000, 2020). The present report, part of the larger investigation, describes: 1) a comparison of the physico-chemical properties of nine FSDs, collected at drilling sites, and MIN-U-SIL® 5, a reference silica dust, and 2) a comparison of the pulmonary inflammatory responses to intratracheal instillation of the nine FSDs and MIN-U-SIL® 5. Our findings indicate that, in many respects, the physico-chemical characteristics, and the biological effects of the FSDs and MIN-U-SIL® 5 after intratracheal instillation, have distinct differences.
Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Areia/química , Silicose/etiologia , Traqueia/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Poeira , Fraturamento Hidráulico/métodos , Masculino , Exposição Ocupacional/efeitos adversos , Pneumonia/induzido quimicamente , Quartzo/efeitos adversos , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/efeitos adversosRESUMO
Engineered water nanostructures (EWNS) synthesized utilizing electrospray and ionization of water, have been, recently, shown to be an effective, green, antimicrobial platform for surface and air disinfection, where reactive oxygen species (ROS), generated and encapsulated within the particles during synthesis, were found to be the main inactivation mechanism. Herein, the antimicrobial potency of the EWNS was further enhanced by integrating electrolysis, electrospray and ionization of de-ionized water in the EWNS synthesis process. Detailed physicochemical characterization of these enhanced EWNS (eEWNS) was performed using state-of-the-art analytical methods and has shown that, while both size and charge remain similar to the EWNS (mean diameter of 13 nm and charge of 13 electrons), they possess a three times higher ROS content. The increase of the ROS content as a result of the addition of the electrolysis step before electrospray and ionization led to an increased antimicrobial ability as verified by E. coli inactivation studies using stainless steel coupons. It was shown that a 45-minute exposure to eEWNS resulted in a 4-log reduction as opposed to a 1.9-log reduction when exposed to EWNS. In addition, the eEWNS were assessed for their potency to inactivate natural microbiota (total viable and yeast and mold counts), as well as, inoculated E.coli on the surface of fresh organic blackberries. The results showed a 97% (1.5-log) inactivation of the total viable count, a 99% (2-log) reduction in the yeast and mold count and a 2.5-log reduction of the inoculated E.coli after 45 minutes of exposure, without any visual changes to the fruit. This enhanced antimicrobial activity further underpins the EWNS platform as an effective, dry and chemical free approach suitable for a variety of food safety applications and could be ideal for delicate fresh produce that cannot withstand the classical, wet disinfection treatments.
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Indium-tin oxide (ITO) is used to produce flat panel displays and several other technology products. Composed of 90% indium oxide (In2O3) and 10% tin oxide (SnO2) by weight, ITO is synthesized under conditions of high heat via a process known as sintering. Indium lung disease, a recently recognized occupational illness, is characterized by pulmonary alveolar proteinosis, fibrosis, and emphysema. Murine macrophage (RAW 264.7) and epidermal (JB6) cells stably transfected with AP-1 to study tumor promoting potential, were used to differentiate between the toxicological profiles of sintered ITO (SITO) and unsintered mixture (UITO). We hypothesized that sintering would play a key role in free radical generation and cytotoxicity. Exposure of cells to both UITO and SITO caused a time and dose dependent decrease of the viability of cells. Intracellular ROS generation was inversely related to the dose of both UITO and SITO, a direct reflection of the decreased number of viable RAW 264.7 and JB6/AP-1 cells observed at higher concentrations. Electron spin resonance showed significantly increased hydroxyl radical (OH) generation in cells exposed to UITO compared to SITO. This is different from LDH release, which showed that SITO caused significantly increased damage to the cell membrane compared to UITO. Lastly, the JB6/AP-1 cell line did not show activation of the AP-1 pathway. Our results highlight both the differences in the mechanisms of cytotoxicity and the consistent adverse effects associated with UITO and SITO exposure.
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Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Compostos de Estanho/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/fisiologia , Dano ao DNA/fisiologia , Relação Dose-Resposta a Droga , Epiderme/metabolismo , Macrófagos/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Graphene, a monolayer of carbon, is an engineered nanomaterial (ENM) with physical and chemical properties that may offer application advantages over other carbonaceous ENMs, such as carbon nanotubes (CNT). The goal of this study was to comparatively assess pulmonary and systemic toxicity of graphite nanoplates, a member of the graphene-based nanomaterial family, with respect to nanoplate size. METHODS: Three sizes of graphite nanoplates [20 µm lateral (Gr20), 5 µm lateral (Gr5), and <2 µm lateral (Gr1)] ranging from 8-25 nm in thickness were characterized for difference in surface area, structure,, zeta potential, and agglomeration in dispersion medium, the vehicle for in vivo studies. Mice were exposed by pharyngeal aspiration to these 3 sizes of graphite nanoplates at doses of 4 or 40 µg/mouse, or to carbon black (CB) as a carbonaceous control material. At 4 h, 1 day, 7 days, 1 month, and 2 months post-exposure, bronchoalveolar lavage was performed to collect fluid and cells for analysis of lung injury and inflammation. Particle clearance, histopathology and gene expression in lung tissue were evaluated. In addition, protein levels and gene expression were measured in blood, heart, aorta and liver to assess systemic responses. RESULTS: All Gr samples were found to be similarly composed of two graphite structures and agglomerated to varying degrees in DM in proportion to the lateral dimension. Surface area for Gr1 was approximately 7-fold greater than Gr5 and Gr20, but was less reactive reactive per m(2). At the low dose, none of the Gr materials induced toxicity. At the high dose, Gr20 and Gr5 exposure increased indices of lung inflammation and injury in lavage fluid and tissue gene expression to a greater degree and duration than Gr1 and CB. Gr5 and Gr20 showed no or minimal lung epithelial hypertrophy and hyperplasia, and no development of fibrosis by 2 months post-exposure. In addition, the aorta and liver inflammatory and acute phase genes were transiently elevated in Gr5 and Gr20, relative to Gr1. CONCLUSIONS: Pulmonary and systemic toxicity of graphite nanoplates may be dependent on lateral size and/or surface reactivity, with the graphite nanoplates > 5 µm laterally inducing greater toxicity which peaked at the early time points post-exposure relative to the 1-2 µm graphite nanoplate.
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Grafite/toxicidade , Pulmão/efeitos dos fármacos , Nanopartículas , Nanoestruturas/toxicidade , Animais , Líquido da Lavagem Broncoalveolar , Pulmão/metabolismo , Camundongos , Microscopia Eletrônica de Varredura , RNA Mensageiro/metabolismoRESUMO
Incomplete understanding of the contributions of dispersants and engineered nanoparticles/materials (ENM) agglomeration state to biological outcomes presents an obstacle for toxicological studies. Although reactive oxygen species (ROS) production is often regarded as the primary indicator of ENM bioactivity and toxicity, it remains unclear whether ENM produce ROS or whether ROS is an outcome of ENM-induced cell injury. Phagolysosomal disruption and cathepsin B release also promote bioactivity through inflammasome activation. Therefore, specific particle parameters, i.e. preexposure dispersion status and particle surface area, of two ENM (NiO and CeO2) were used to evaluate the role of ROS generation and cathepsin B release during ENM-induced toxicity. Male C57BL/6J mice were exposed to 0, 20, 40, or 80 µg of poorly or well-dispersed NiO-NP or CeO2-NP in four types of dispersion media. At 1- and 7-day postexposure, lung lavage fluid was collected to assess inflammation, cytotoxicity, and inflammasome activation. Results showed that preexposure dispersion status correlated with postexposure pulmonary bioactivity. The differences in bioactivity of NiO-NP and CeO2-NP are likely due to NiO-NP facilitating the release of cathepsin B and in turn inflammasome activation generating proinflammatory cytokines. Further, both metal oxides acted as free radical scavengers. Depending on the pH, CeO2-NP acted as a free radical scavenger in an acidic environment (an environment mimicking the lysosome) while the NiO-NP acted as a scavenger in a physiological pH (an environment that mimics the cytosol of the cell). Therefore, results from this study suggest that ENM-induced ROS is not likely a mechanism of inflammasome activation.
Assuntos
Catepsina B/metabolismo , Cério/toxicidade , Inflamassomos/metabolismo , Nanopartículas Metálicas/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Níquel/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Cério/química , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , L-Lactato Desidrogenase/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Nanopartículas Metálicas/química , Camundongos Endogâmicos C57BL , Níquel/química , Propriedades de SuperfícieRESUMO
Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. Occupational exposures to potentially toxic particles generated during ITO production have increased in recent years as the demand for consumer electronics continues to rise. Previous studies have demonstrated cytotoxicity in vitro and animal models have shown pulmonary inflammation and injury in response to various indium-containing particles. In humans, pulmonary alveolar proteinosis (PAP) and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which indium materials or specific processes in the workplace may be the most toxic to workers is unknown. Here we examined the pulmonary toxicity of three different particle samples that represent real-life worker exposures, as they were collected at various production stages throughout an ITO facility. Indium oxide (In2O3), sintered ITO (SITO) and ventilation dust (VD) particles each caused pulmonary inflammation and damage in rats over a time course (1, 7 and 90 days post-intratracheal instillation), but SITO and VD appeared to induce greater toxicity in rat lungs than In2O3 at a dose of 1 mg per rat. Downstream pathological changes such as PAP and fibrosis were observed in response to all three particles 90 days after treatment, with a trend towards greatest severity in animals exposed to VD when comparing animals that received the same dose. These findings may inform workplace exposure reduction efforts and provide a better understanding of the pathogenesis of an emerging occupational health issue.
Assuntos
Poluentes Atmosféricos/toxicidade , Pneumonia/patologia , Compostos de Estanho/toxicidade , Animais , Lavagem Broncoalveolar , Relação Dose-Resposta a Droga , Poeira , Concentração de Íons de Hidrogênio , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Fagocitose , Pneumonia/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Occupational exposure to indium compound particles has recently been associated with lung disease among workers in the indium-tin oxide (ITO) industry. Previous studies suggested that excessive alveolar surfactant and reactive oxygen species (ROS) may play a role in the development of pulmonary lesions following exposure to indium compounds. However, toxicity at the cellular level has not been comprehensively evaluated. Thus, the aim of this study was to assess which, if any, compounds encountered during ITO production are toxic to cultured cells and ultimately contribute to the pathogenesis of indium lung disease. The compounds used in this study were collected from eight different processing stages at an ITO production facility. Enhanced dark field imaging showed 5 of the compounds significantly associated with cells within 1 h, suggesting that cellular reactions to the compound particles may be occurring rapidly. To examine the potential cytotoxic effects of these associations, ROS generation, cell viability, and apoptosis were evaluated following exposures in RAW 264.7 mouse monocyte macrophage and BEAS-2B human bronchial epithelial cell lines. Both exhibited reduced viability with exposures, while apoptosis only occurred in RAW 264.7 cells. Our results suggested that excessive ROS production is likely not the predominant mechanism underlying indium-induced lung disease. However, the effects on cell viability reveal that several of the compounds are cytotoxic, and therefore, exposures need to be carefully monitored in the industrial setting.
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Pneumopatias/patologia , Pulmão/efeitos dos fármacos , Exposição Ocupacional/análise , Compostos de Estanho/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Pulmão/citologia , Pulmão/patologia , Pneumopatias/induzido quimicamente , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Metalurgia , Camundongos , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismoRESUMO
Due to their unique size, surface area, and chemical characteristics, nanoparticles' use in consumer products has increased. However, the toxicity of nanoparticle (NP) exposure during the manufacturing process has not been fully assessed. Tungstate NP are used in numerous products, including but not limited to scintillator detectors and fluorescent lighting. As with many NP, no apparent toxicity studies have been completed with tungstate NP. The hypothesis that tungstate NP in vitro exposure results in reactive oxygen species (ROS) formation and cytotoxicity was examined. Differences in toxicity based on tungstate NP size, shape (sphere vs. wire), and chemical characteristics were determined. RAW 264.7 mouse monocyte macrophages were exposed to tungstate NP, and ROS formation was assessed via electron spin resonance (ESR), and several assays including hydrogen peroxide, intracellular ROS, and Comet. Results showed ROS production induced by tungstate nanowire exposure, but this exposure did not result in oxidative DNA damage. Nanospheres showed neither ROS nor DNA damage following cellular exposure. Cells were exposed over 72 h to assess cytotoxicity using an MTT (tetrazolium compound) assay. Results showed that differences in cell death between wires and spheres occurred at 24 h but were minimal at both 48 and 72 h. The present results indicate that tungstate nanowires are more reactive and produce cell death within 24 h of exposure, whereas nanospheres are less reactive and did not produce cell death. Results suggest that differences in shape may affect reactivity. However, regardless of the differences in reactivity, in general both shapes produced mild ROS and resulted in minimal cell death at 48 and 72 h in RAW 264.7 cells.
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Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Nanopartículas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Compostos de Tungstênio/toxicidade , Animais , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Linhagem Celular , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Espectroscopia de Ressonância de Spin Eletrônica , Peróxido de Hidrogênio/metabolismo , Macrófagos/citologia , Camundongos , Monócitos/metabolismo , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Compostos de Tungstênio/químicaRESUMO
Abstract The potential applications of cellulose nanomaterials in advanced composites and biomedicine makes it imperative to understand their pulmonary exposure to human health. Here, we report the results on the biodurability of three cellulose nanocrystal (CNC), two cellulose nanofibril (CNF) and a benchmark cellulose microcrystal (CMC) when exposed to artificial lung airway lining fluid (SUF, pH 7.3) for up to 7 days and alveolar macrophage phagolysosomal fluid (PSF, pH 4.5) for up to 9 months. X-ray diffraction analysis was used to monitor biodurability and thermogravimetry, surface area, hydrodynamic diameter, zeta potential and free radical generation capacity of the samples were determined (in vitro cell-free and RAW 264.7 cell line models). The CMC showed no measurable changes in crystallinity (x(CR)) or crystallite size D in either SUF or PSF. For one CNC, a slight decrease in x(CR) and D in SUF was observed. In acidic PSF, a slight increase in x(CR) with exposure time was observed, possibly due to dissolution of the amorphous component. In a cell-free reaction with H2O2, radicals were observed; the CNCs and a CNF generated significantly more ·OH radicals than the CMC (p < 0.05). The ·OH radical production correlates with particle decomposition temperature and is explained by the higher surface area to volume ratio of the CNCs. Based on their biodurability, mechanical clearance would be the primary mechanism for lung clearance of cellulose materials. The production of ·OH radicals indicates the need for additional studies to characterize the potential inhalation hazards of cellulose.
Assuntos
Celulose/toxicidade , Radicais Livres/metabolismo , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Modelos Biológicos , Nanoestruturas/toxicidade , Mucosa Respiratória/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/química , Linhagem Celular Transformada , Celulose/química , Celulose/metabolismo , Celulose/ultraestrutura , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Depuração Mucociliar/efeitos dos fármacos , Nanofibras/química , Nanofibras/toxicidade , Nanofibras/ultraestrutura , Nanopartículas/química , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Fagocitose/efeitos dos fármacos , Eliminação Pulmonar/efeitos dos fármacos , Explosão Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Propriedades de SuperfícieRESUMO
Respiratory problems are common among wildland firefighters. However, there are few studies directly linking occupational exposures to respiratory effects in this population. Our objective was to characterize wildland fire fighting occupational exposures and assess their associations with cross-shift changes in lung function. We studied 17 members of the Alpine Interagency Hotshot Crew with environmental sampling and pulmonary function testing during a large wildfire. We characterized particles by examining size distribution and mass concentration, and conducting elemental and morphological analyses. We examined associations between cross-shift lung function change and various analytes, including levoglucosan, an indicator of wood smoke from burning biomass. The levoglucosan component of the wildfire aerosol showed a predominantly bimodal size distribution: a coarse particle mode with a mass median aerodynamic diameter about 12 µm and a fine particle mode with a mass median aerodynamic diameter < 0.5 µm. Levoglucosan was found mainly in the respirable fraction and its concentration was higher for fire line construction operations than for mop-up operations. Larger cross-shift declines in forced expiratory volume in one second were associated with exposure to higher concentrations of respirable levoglucosan (p < 0.05). Paired analyses of real-time personal air sampling measurements indicated that higher carbon monoxide (CO) concentrations were correlated with higher particulate concentrations when examined by mean values, but not by individual data points. However, low CO concentrations did not provide reliable assurance of concomitantly low particulate concentrations. We conclude that inhalation of fine smoke particles is associated with acute lung function decline in some wildland firefighters. Based on short-term findings, it appears important to address possible long-term respiratory health issues for wildland firefighters. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resources: a file containing additional information on historical studies of wildland fire exposures, a file containing the daily-exposure-severity questionnaire completed by wildland firefighter participants at the end of each day, and a file containing additional details of the investigation of correlations between carbon monoxide concentrations and other measured exposure factors in the current study.].
Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Bombeiros , Exposição por Inalação/efeitos adversos , Pulmão/fisiopatologia , Exposição Ocupacional/efeitos adversos , Fumaça/efeitos adversos , Adulto , Aerossóis/efeitos adversos , Aerossóis/análise , Aerossóis/química , Poluentes Ocupacionais do Ar/análise , Poluentes Ocupacionais do Ar/química , Biomarcadores/análise , Testes Respiratórios , Carbono/efeitos adversos , Carbono/análise , Monóxido de Carbono/efeitos adversos , Monóxido de Carbono/análise , Feminino , Volume Expiratório Forçado , Glucose/efeitos adversos , Glucose/análogos & derivados , Glucose/análise , Glucose/química , Humanos , Exposição por Inalação/análise , Masculino , Exposição Ocupacional/análise , Tamanho da Partícula , Dióxido de Silício/efeitos adversos , Dióxido de Silício/análise , Fumaça/análise , Espirometria , Inquéritos e QuestionáriosRESUMO
Double-walled carbon nanotubes (DWCNT) are a rather new and unexplored variety of carbon nanotubes. Previously conducted studies established that exposure to a variety of carbon nanotubes produced lung inflammation and fibrosis in mice after pharyngeal aspiration. However, the bioactivity of double-walled carbon nanotubes (DWCNT) has not been determined. In this study, the hypothesis that DWCNT would induce pulmonary toxicity was explored by analyzing the pulmonary bioactivity of DWCNT. To test this hypothesis, C57Bl/6 mice were exposed to DWCNT by pharyngeal aspiration. Mice underwent whole-lung lavage (WLL) to assess pulmonary inflammation and injury, and lung tissue was examined histologically for development of pulmonary disease as a function of dose and time. The results showed that DWCNT exposure produced a dose-dependent increase in WLL polymorphonuclear leukocytes (PMN), indicating that DWCNT exposure initiated pulmonary inflammation. DWCNT exposure also produced a dose-dependent rise in lactate dehydrogenase (LDH) activity, as well as albumin levels, in WLL fluid, indicating that DWCNT exposure promoted cytotoxicity as well as decreases in the integrity of the blood-gas barrier in the lung, respectively. In addition, at 7 and 56 d postexposure, the presence of significant alveolitis and fibrosis was noted in mice exposed to 40 µg/mouse DWCNT. In conclusion, this study provides insight into previously uninvestigated pulmonary bioactivity of DWCNT exposure. Data indicate that DWCNT exposure promotes inflammation, injury, and fibrosis in the lung.
Assuntos
Barreira Alveolocapilar/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Fibrose Pulmonar/induzido quimicamente , Animais , Barreira Alveolocapilar/patologia , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Relação Dose-Resposta a Droga , Exposição por Inalação/efeitos adversos , L-Lactato Desidrogenase/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologiaRESUMO
Thermal spray coating is a process in which molten metal is sprayed onto a surface. Little is known about the health effects associated with these aerosols. Sprague-Dawley rats were exposed to aerosols (25 mg/m3 × 4 hr/d × 4 d) generated during thermal spray coating using different consumables [i.e. stainless-steel wire (PMET731), Ni-based wire (PMET885), Zn-based wire (PMET540)]. Control animals received air. Bronchoalveolar lavage was performed at 4 and 30 d post-exposure to assess lung toxicity. The particles were chain-like agglomerates and similar in size (310-378 nm). Inhalation of PMET885 aerosol caused a significant increase in lung injury and inflammation at both time points. Inhalation of PMET540 aerosol caused a slight but significant increase in lung toxicity at 4 but not 30 d. Exposure to PMET731 aerosol had no effect on lung toxicity. Overall, the lung responses were in the order: PMET885â«PMET540 >PMT731. Following a shorter exposure (25 mg/m3 × 4 h/d × 1d), lung burdens of metals from the different aerosols were determined by ICP-AES at 0, 1, 4 and 30 d post-exposure. Zn was cleared from the lungs at the fastest rate with complete clearance by 4 d post-exposure. Ni, Cr, and Mn had similar rates of clearance as nearly half of the deposited metal was cleared by 4 d. A small but significant percentage of each of these metals persisted in the lungs at 30 d. The pulmonary clearance of Fe was difficult to assess because of inherently high levels of Fe in control lungs.
Assuntos
Pulmão , Aerossóis e Gotículas Respiratórios , Ratos , Animais , Ratos Sprague-Dawley , Administração por Inalação , Metais/toxicidade , Aerossóis , Exposição por Inalação , Líquido da Lavagem Broncoalveolar , Tamanho da PartículaRESUMO
The Phase 2 drug metabolism of busulfan yields a glutathione conjugate that undergoes a ß-elimination reaction. The elimination product is an electrophilic metabolite that is a dehydroalanine-containing tripeptide, γ-glutamyldehydroalanylglycine (EdAG). In the process, glutathione lacks thiol-related redox properties and gains a radical scavenging dehydroalanine group. EdAG scavenged hydroxyl radical generated in the Fenton reaction in a concentration-dependent manner was monitored by electron paramagnetic resonance (EPR) spectroscopy. The apparent rate of hydroxyl radical scavenging was in the same range as published values for known antioxidants, including N-acyl dehydroalanines. A captodatively stabilized carbon-centered radical intermediate was spin trapped in the reaction of EdAG with hydroxyl radical. The proposed structure of a stable product in the Fenton reaction with EdAG was consistent with that of a γ-glutamylserylglycyl dimer. Observation of the hydroxyl trapping properties of EdAG suggests that the busulfan metabolite EdAG may contribute to or mitigate redox-related cytotoxicity associated with the therapeutic use of busulfan, and reaffirms indicators that support a role in free radical biology for dehydroalanine-containing peptides and proteins.
Assuntos
Alanina/análogos & derivados , Bussulfano/metabolismo , Glutationa/metabolismo , Radical Hidroxila/metabolismo , Alanina/metabolismo , Antioxidantes/metabolismo , Biocatálise , Bussulfano/química , Cromatografia Líquida , Óxidos N-Cíclicos/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Glutationa Transferase/metabolismo , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Ferro/química , Cinética , Oxirredução , Piridinas/metabolismo , Espectrometria de Massas em TandemRESUMO
Induction of massive apoptosis of hair follicle cells by chemotherapy has been implicated in the pathogenesis of chemotherapy-induced alopecia (CIA), but the underlying mechanisms of regulation are not well understood. The present study investigated the apoptotic effect of cisplatin in human hair follicle dermal papilla cells and HaCaT keratinocytes, and determined the identity and role of specific reactive oxygen species (ROS) involved in the process. Treatment of the cells with cisplatin induced ROS generation and a parallel increase in caspase activation and apoptotic cell death. Inhibition of ROS generation by antioxidants inhibited the apoptotic effect of cisplatin, indicating the role of ROS in the process. Studies using specific ROS scavengers further showed that hydroxyl radical, but not hydrogen peroxide or superoxide anion, is the primary oxidative species responsible for the apoptotic effect of cisplatin. Electron spin resonance studies confirmed the formation of hydroxyl radicals induced by cisplatin. The mechanism by which hydroxyl radical mediates the apoptotic effect of cisplatin was shown to involve down-regulation of the anti-apoptotic protein Bcl-2 through ubiquitin-proteasomal degradation. Bcl-2 was also shown to have a negative regulatory role on hydroxyl radical. Together, our results indicate an essential role of hydroxyl radical in cisplatin-induced cell death of hair follicle cells through Bcl-2 regulation. Since CIA is a major side effect of cisplatin and many other chemotherapeutic agents with no known effective treatments, the knowledge gained from this study could be useful in the design of preventive treatment strategies for CIA through localized therapy without compromising the chemotherapy efficacy.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Folículo Piloso/citologia , Radical Hidroxila/metabolismo , Queratinócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Acetilcisteína/farmacologia , Alopecia/induzido quimicamente , Alopecia/prevenção & controle , Antineoplásicos/efeitos adversos , Antioxidantes/farmacologia , Caspase 3/metabolismo , Catalase/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/efeitos adversos , Formiatos/farmacologia , Folículo Piloso/efeitos dos fármacos , Humanos , Metaloporfirinas/farmacologia , Ubiquitinação , Proteína X Associada a bcl-2/metabolismoRESUMO
Fine- and coarse-sized titanium dioxide (TiO2) particles are considered to be relatively inert when inhaled. The goal of this study was to assess potential lung toxicity associated with well-characterized, non-dispersed rutile TiO2 nanorods (10 × 40 nm). In vitro bioreactivity of TiO2 nanorods was determined by electron spin resonance (ESR) to measure free radical production. To assess pulmonary effects in vivo, Sprague-Dawley rats were intratracheally instilled with saline, silica, or TiO2 nanorods (10 µg, 100 µg, or 1 mg/rat). On d 1, 3, and 6 posttreatment, left lungs were preserved for microscopy and histopathology, and lung lavage was performed on right lungs. Additional rats were treated with saline or TiO2 nanorods (100 µg or 1 mg/rat) on d 0, intratracheally inoculated with 5 × 10(5) Listeria monocytogenes on d 3, and bacterial clearance was assessed. ESR showed a significant concentration-dependent generation of hydroxyl radicals by TiO2 nanorods in the presence and absence of macrophages; however, the hydroxyl radical signals from TiO2 samples were low compared to silica. Rats exposed to 1 mg of TiO2 nanorods had significantly elevated levels of lung injury, inflammation, and lavage fluid monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-2 on d 1 and 3 that subsided by d 6, unlike the silica response that persisted. Immune cytokine secretion in the lung and bacterial clearance were not affected by preexposure to TiO2 nanorods. To summarize, non-dispersed TiO2 nanorods were found to induce radical formation and cellular oxidant production, and to generate transient and reversible pneumotoxic effects, and to not markedly alter pulmonary immune function.
Assuntos
Exposição por Inalação , Pulmão/efeitos dos fármacos , Nanoestruturas/toxicidade , Titânio/toxicidade , Administração por Inalação , Animais , Relação Dose-Resposta a Droga , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/crescimento & desenvolvimento , Listeria monocytogenes/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Nanoestruturas/química , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/toxicidadeRESUMO
Electronic cigarettes (e-cigarettes) were introduced in the United States in 2007 and by 2014 they were the most popular tobacco product amongst youth and had overtaken use of regular tobacco cigarettes. E-cigarettes are used to aerosolize a liquid (e-liquid) that the user inhales. Flavorings in e-liquids is a primary reason for youth to initiate use of e-cigarettes. Evidence is growing in the scientific literature that inhalation of some flavorings is not without risk of harm. In this review, 67 original articles (primarily cellular in vitro) on the toxicity of flavored e-liquids were identified in the PubMed and Scopus databases and evaluated critically. At least 65 individual flavoring ingredients in e-liquids or aerosols from e-cigarettes induced toxicity in the respiratory tract, cardiovascular and circulatory systems, skeletal system, and skin. Cinnamaldehyde was most frequently reported to be cytotoxic, followed by vanillin, menthol, ethyl maltol, ethyl vanillin, benzaldehyde and linalool. Additionally, modern e-cigarettes can be modified to aerosolize cannabis as dried plant material or a concentrated extract. The U.S. experienced an outbreak of lung injuries, termed e-cigarette, or vaping, product use-associated lung injury (EVALI) that began in 2019; among 2,022 hospitalized patients who had data on substance use (as of January 14, 2020), 82% reported using a delta-9-tetrahydrocannabinol (main psychoactive component in cannabis) containing e-cigarette, or vaping, product. Our literature search identified 33 articles related to EVALI. Vitamin E acetate, a diluent and thickening agent in cannabis-based products, was strongly linked to the EVALI outbreak in epidemiologic and laboratory studies; however, e-liquid chemistry is highly complex, and more than one mechanism of lung injury, ingredient, or thermal breakdown product may be responsible for toxicity. More research is needed, particularly with regard to e-cigarettes (generation, power settings, etc.), e-liquids (composition, bulk or vaped form), modeled systems (cell type, culture type, and dosimetry metrics), biological monitoring, secondhand exposures and contact with residues that contain nicotine and flavorings, and causative agents and mechanisms of EVALI toxicity.