RESUMEN
Bisphenol A (BPA) belongs to a group of chemicals used in the production of polycarbonate, polysulfone, and polyethersulfone which are used, among other applications, in the manufacture of dialyzers. While exposure to BPA is widespread in the general population, dialysis patients represent a population with potentially chronic parenteral BPA exposures. To assess the potential risk of BPA exposure to dialysis patients through dialyzer use, exposure estimates were calculated based on BPA levels measured by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry following extractions from dialyzers manufactured by Fresenius Medical Care. Extraction conditions included both simulated-use leaching and exaggerated extractions to evaluate possible leachable and extractable BPA, respectively, from the devices. The mean BPA concentrations were 3.6 and 108.9 ppb from simulated-use and exaggerated extractions, respectively, from polycarbonate-containing dialyzers. No BPA was detected from polypropylene-containing dialyzers. Margins of Safety (MOS) were calculated to evaluate the level of risk to patients from estimated BPA exposure from the dialyzers, and the resulting MOS were 229 and 45 for simulated-use and exaggerated extractions, respectively. The findings suggest that there is an acceptable level of toxicological risk to dialysis patients exposed to BPA from use of the dialyzers tested in the current study.
Asunto(s)
Compuestos de Bencidrilo/análisis , Cromatografía Líquida de Alta Presión , Espectrometría de Masas , Membranas Artificiales , Fenoles/análisis , Cemento de Policarboxilato/análisis , Polipropilenos/análisis , Diálisis Renal/instrumentación , Pruebas de Toxicidad , Compuestos de Bencidrilo/toxicidad , Humanos , Fenoles/toxicidad , Cemento de Policarboxilato/toxicidad , Polipropilenos/toxicidad , Medición de RiesgoRESUMEN
1,3-Dichloropropene (1,3-D; CAS No. 542-75-6) is a soil fumigant used for the control of nematodes in agriculture. There is an extensive database on the genotoxicity of 1,3-D and many of the published studies are confounded by the presence of mutagenic stabilisers in the test substance. Mixed results were obtained in the in vitro assays, often due to the purity of the 1,3-D sample tested. In order to get further clarity, the mutagenic potential of 1,3-D was investigated in vivo in the transgenic Big Blue rodent models. Inhalation exposure of 150 ppm 1,3-D (×2.5 tumourigenic dose) to transgenic male B6C3F1 mice did not induce lacI mutations in either the lung (tumour target tissue) or liver. Similarly, dietary administration of 1,3-D up to 50 mg/kg/day to transgenic male Fischer 344 rats did not increase the cII mutant frequency in either the liver (tumour target) or kidney. These results, along with other available in vivo data, including the absence of DNA adducts and clastogenic/aneugenic potential, support the conclusion that 1,3-D is efficiently detoxified in vivo and, as such, does not pose a mutagenic hazard or risk.
Asunto(s)
Compuestos Alílicos/farmacología , Hidrocarburos Clorados/farmacología , Mutagénesis/efectos de los fármacos , Mutágenos/farmacología , Plaguicidas/farmacología , Compuestos Alílicos/toxicidad , Animales , Aductos de ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hidrocarburos Clorados/toxicidad , Represoras Lac/genética , Ratones , Ratones Transgénicos , Pruebas de Mutagenicidad , Mutágenos/toxicidad , Mutación/efectos de los fármacos , Plaguicidas/efectos adversos , Ratas , Ratas Endogámicas F344RESUMEN
The results of a large 2-year bisphenol A (BPA) rat study conducted by the NTP, called the CLARITY-BPA Core Study, were recently released. This study addressed some of the toxicological issues associated with BPA, including endocrine disruption and non-monotonic dose responses (NMDR). The study involved oral gavage treatment of rats to BPA at doses of 2.5-25,000 µg/kg-bw/day. To address NMDR, the 81 statistically significant findings (based on the primary statistical tests) from the Core Study were evaluated using a recently published methodology that relies upon six checkpoints to determine if there is evidence for a NMDR. Failure to meet the majority of the checkpoints indicates limited evidence of NMDR. The analysis found that only 2 of the 81 findings met at least 5 of the checkpoints: an increase in percent basophils in stop-dose females and decreased total bile acids in stop-dose males. However, these findings are not concordant or consistent with those of other BPA data. Importantly, none of the endocrine-related or reproductive endpoints fulfilled at least 5 of the checkpoints. This analysis found limited evidence for NMDR associated with BPA treatment in the study. These results are consistent with the conclusions reached in the Core Study report.
Asunto(s)
Compuestos de Bencidrilo/toxicidad , Disruptores Endocrinos/toxicidad , Fenoles/toxicidad , Animales , Basófilos/metabolismo , Ácidos y Sales Biliares/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Exposición Materna/efectos adversos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas Sprague-DawleyRESUMEN
Inhalation of indium-containing dusts is associated with the development of indium lung disease. Workers may be exposed to several different chemical forms of indium; however, their lung dosimetry is not fully understood. We characterized the physicochemical properties and measured the lung dissolution kinetics of eight indium-containing dusts. Indium dissolution rates in artificial lung fluids spanned two orders of magnitude. We used the International Commission on Radiological Protection (ICRP) human respiratory model (HRTM) to estimate pulmonary indium deposition, retention and biokinetic clearance to blood. For a two-year (median workforce tenure at facility) exposure to respirable-sized particles of the indium materials, modeled indium clearance (>99.99% removed) from the alveolar-interstitial compartment was slow for all dusts; salts would clear in 4 years, sintered indium-tin oxide (ITO) would clear in 9 years, and indium oxide would require 48 years. For this scenario, the ICRP HRTM predicted that indium translocated to blood would be present in that compartment for 3.5-18 years after cessation of exposure, depending on the chemical form. For a 40-year exposure (working lifetime), clearance from the alveolar-interstitial compartment would require 5, 10 and 60 years for indium salts, sintered ITO and indium oxide, respectively and indium would be present in blood for 5-53 years after exposure. Consideration of differences in chemical forms of indium, dissolution rates, alveolar clearance and residence time in blood should be included in exposure assessment and epidemiological studies that rely on measures of total indium in air or blood to derive risk estimates.
Asunto(s)
Polvo/análisis , Indio/química , Modelos Biológicos , Fenómenos Fisiológicos Respiratorios , Sistema Respiratorio/anatomía & histología , Líquidos Corporales , Humanos , RadiometríaRESUMEN
Cerium (Ce) is becoming a popular metal for use in electrochemical applications. When in the form of cerium oxide (CeO2), Ce can exist in both 3 + and 4 + valence states, acting as an ideal catalyst. Previous in vitro and in vivo evidence have demonstrated that CeO2 has either anti- or pro-oxidant properties, possibly due to the ability of the nanoparticles to transition between valence states. Therefore, we chose to chemically modify the nanoparticles to shift the valence state toward 3+. During the hydrothermal synthesis process, 10 mol% gadolinium (Gd) and 20 mol% Gd, were substituted into the lattice of the CeO2 nanoparticles forming a perfect solid solution with various A-site valence states. These two Gd-doped CeO2 nanoparticles were compared to pure CeO2 nanoparticles. Preliminary characteristics indicated that doping results in minimal size and zeta potential changes but alters valence state. Following characterization, male Sprague-Dawley rats were exposed to 0.5 or 1.0 mg/kg nanoparticles via a single intratracheal instillation. Animals were sacrificed and bronchoalveolar lavage fluid and various tissues were collected to determine the effect of valence state and oxygen vacancies on toxicity 1-, 7-, or 84-day post-exposure. Results indicate that damage, as measured by elevations in lactate dehydrogenase, occurred within 1-day post-exposure and was sustained 7-day post-exposure, but subsided to control levels 84-day post-exposure. Furthermore, no inflammatory signaling or lipid peroxidation occurred following exposure with any of the nanoparticles. Our results implicate that valence state has a minimal effect on CeO2 nanoparticle toxicity in vivo.
Asunto(s)
Cerio/química , Cerio/toxicidad , Pulmón/efectos de los fármacos , Nanopartículas/química , Nanopartículas/toxicidad , Animales , Líquido del Lavado Bronquioalveolar/química , Relación Dosis-Respuesta a Droga , Gadolinio/química , Instilación de Medicamentos , Peroxidación de Lípido/efectos de los fármacos , Pulmón/metabolismo , Masculino , Oxígeno/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
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.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Neumonía/patología , Compuestos de Estaño/toxicidad , Animales , Lavado Broncoalveolar , Relación Dosis-Respuesta a Droga , Polvo , Concentración de Iones de Hidrógeno , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Fagocitosis , Neumonía/inducido químicamente , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Indium-tin oxide (ITO) is used to make transparent conductive coatings for touch-screen and liquid crystal display electronics. As the demand for consumer electronics continues to increase, so does the concern for occupational exposures to particles containing these potentially toxic metal oxides. Indium-containing particles have been shown to be cytotoxic in cultured cells and pro-inflammatory in pulmonary animal models. In humans, pulmonary alveolar proteinosis and fibrotic interstitial lung disease have been observed in ITO facility workers. However, which ITO production materials may be the most toxic to workers and how they initiate pulmonary inflammation remain poorly understood. Here we examined four different particle samples collected from an ITO production facility for their ability to induce pro-inflammatory responses in vitro. Tin oxide, sintered ITO (SITO), and ventilation dust particles activated nuclear factor kappa B (NFκB) within 3 h of treatment. However, only SITO induced robust cytokine production (IL-1ß, IL-6, TNFα, and IL-8) within 24 h in both RAW 264.7 mouse macrophages and BEAS-2B human bronchial epithelial cells. Our lab and others have previously demonstrated SITO-induced cytotoxicity as well. These findings suggest that SITO particles activate the NLRP3 inflammasome, which has been implicated in several immune-mediated diseases via its ability to induce IL-1ß release and cause subsequent cell death. Inflammasome activation by SITO was confirmed, but it required the presence of endotoxin. Further, a phagocytosis assay revealed that pre-uptake of SITO or ventilation dust impaired proper macrophage phagocytosis of E. coli. Our results suggest that adverse inflammatory responses to SITO particles by both macrophage and epithelial cells may initiate and propagate indium lung disease. These findings will provide a better understanding of the molecular mechanisms behind an emerging occupational health issue.
Asunto(s)
Industria Química , Células Epiteliales/efectos de los fármacos , Inflamasomas/agonistas , Macrófagos/efectos de los fármacos , Exposición Profesional , Compuestos de Estaño/toxicidad , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Línea Celular , Endotoxinas/farmacología , Células Epiteliales/citología , Células Epiteliales/inmunología , Escherichia coli/inmunología , Regulación de la Expresión Génica , Humanos , Inflamasomas/genética , Inflamasomas/inmunología , Interleucina-1beta , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Macrófagos/citología , Macrófagos/inmunología , Ratones , FN-kappa B/genética , FN-kappa B/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR , Tamaño de la Partícula , Fagocitosis/efectos de los fármacos , Transducción de Señal , Compuestos de Estaño/química , Compuestos de Estaño/clasificación , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Epidemiology has indicated a possible increase in lung cancer among stainless steel welders. Chromium (Cr) is a primary component of stainless steel welding fume. There is an initiative to develop alternative welding consumables [nickel (Ni)- and copper (Cu)-based alloys] that do not contain Cr. No study has been performed to evaluate the toxicity of fumes generated from Ni- and Cu-based consumables. Dose-response and time-course effects on lung toxicity of a Ni- and Cu-based welding fume (Ni-Cu WF) were examined using an in vivo and in vitro bioassay, and compared with two other well-characterized welding fumes. Even though only trace amounts of Cr were present, a persistent increase in lung injury and inflammation was observed for the Ni-Cu WF compared to the other fumes. The difference in response appears to be due to a direct cytotoxic effect by the Ni-Cu WF sample on lung macrophages as opposed to an elevated production of reactive oxygen species (ROS).
RESUMEN
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.
Asunto(s)
Enfermedades Pulmonares/patología , Pulmón/efectos de los fármacos , Exposición Profesional/análisis , Compuestos de Estaño/toxicidad , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Humanos , Pulmón/citología , Pulmón/patología , Enfermedades Pulmonares/inducido químicamente , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Metalurgia , Ratones , Tamaño de la Partícula , Especies Reactivas de Oxígeno/metabolismoRESUMEN
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.
Asunto(s)
Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Nanopartículas/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Tungsteno/toxicidad , Animales , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 7/genética , Caspasa 7/metabolismo , Línea Celular , Ensayo Cometa , Daño del ADN/efectos de los fármacos , Espectroscopía de Resonancia por Spin del Electrón , Peróxido de Hidrógeno/metabolismo , Macrófagos/citología , Ratones , Monocitos/metabolismo , Nanopartículas/química , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Compuestos de Tungsteno/químicaRESUMEN
Welding processes that generate fumes containing toxic metals, such as hexavalent chromium (Cr(VI)), manganese (Mn), and nickel (Ni), have been implicated in lung injury, inflammation, and lung tumor promotion in animal models. While federal regulations have reduced permissible worker exposure limits to Cr(VI), this is not always practical considering that welders may work in confined spaces and exhaust ventilation may be ineffective. Thus, there has been a recent initiative to minimize the potentially hazardous components in welding materials by developing new consumables containing much less Cr(VI) and Mn. A new nickel (Ni) and copper (Cu)-based material (Ni-Cu WF) is being suggested as a safer alternative to stainless steel consumables; however, its adverse cellular effects have not been studied. This study compared the cytotoxic effects of the newly developed Ni-Cu WF with two well-characterized welding fumes, collected from gas metal arc welding using mild steel (GMA-MS) or stainless steel (GMA-SS) electrodes. RAW 264.7 mouse macrophages were exposed to the three welding fumes at two doses (50 µg/ml and 250 µg/ml) for up to 24 hours. Cell viability, reactive oxygen species (ROS) production, phagocytic function, and cytokine production were examined. The GMA-MS and GMA-SS samples were found to be more reactive in terms of ROS production compared to the Ni-Cu WF. However, the fumes from this new material were more cytotoxic, inducing cell death and mitochondrial dysfunction at a lower dose. Additionally, pre-treatment with Ni-Cu WF particles impaired the ability of cells to phagocytize E. coli, suggesting macrophage dysfunction. Thus, the toxic cellular responses to welding fumes are largely due to the metal composition. The results also suggest that reducing Cr(VI) and Mn in the generated fume by increasing the concentration of other metals (e.g., Ni, Cu) may not necessarily improve welder safety.
Asunto(s)
Cobre/toxicidad , Macrófagos/patología , Níquel/toxicidad , Estrés Oxidativo/efectos de los fármacos , Humo/efectos adversos , Acero Inoxidable/toxicidad , Soldadura , Animales , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/biosíntesis , Espectroscopía de Resonancia por Spin del Electrón , Metabolismo Energético , Mediadores de Inflamación/metabolismo , Exposición por Inhalación , Espacio Intracelular/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fagocitosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
One of the barriers to successful nonviral gene delivery is the crowded cytoplasm, which plasmids need to actively traverse for gene expression. Relatively little is known about how this process occurs, but our lab and others have shown that the microtubule network and motors are required for plasmid movement to the nucleus. To further investigate how plasmids exploit normal physiological processes to transfect cells, we have taken a proteomics approach to identify the proteins that comprise the plasmid-trafficking complex. We have developed a live cell DNA-protein pull-down assay to isolate complexes at certain time points post-transfection (15 minutes to 4 hours) for analysis by mass spectrometry (MS). Plasmids containing promoter sequences bound hundreds of unique proteins as early as 15 minutes post-electroporation, while a plasmid lacking any eukaryotic sequences failed to bind many of the proteins. Specific proteins included microtubule-based motor proteins (e.g., kinesin and dynein), proteins involved in protein nuclear import (e.g., importin 1, 2, 4, and 7, Crm1, RAN, and several RAN-binding proteins), a number of heterogeneous nuclear ribonucleoprotein (hnRNP)- and mRNA-binding proteins, and transcription factors. The significance of several of the proteins involved in protein nuclear localization and plasmid trafficking was determined by monitoring movement of microinjected fluorescently labeled plasmids via live cell particle tracking in cells following protein knockdown by small-interfering RNA (siRNA) or through the use of specific inhibitors. While importin ß1 was required for plasmid trafficking and subsequent nuclear import, importin α1 played no role in microtubule trafficking but was required for optimal plasmid nuclear import. Surprisingly, the nuclear export protein Crm1 also was found to complex with the transfected plasmids and was necessary for plasmid trafficking along microtubules and nuclear import. Our results show that various proteins involved in nuclear import and export influence intracellular trafficking of plasmids and subsequent nuclear accumulation.