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Nanomaterials are frontier technological products used in different manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNT) are finding numerous applications in electronics, aerospace devices, computers, and chemical, polymer, and pharmaceutical industries. SWCNT are relatively recently discovered members of the carbon allotropes that are similar in structure to fullerenes and graphite. Previously, we (47) have reported that pharyngeal aspiration of purified SWCNT by C57BL/6 mice caused dose-dependent granulomatous pneumonia, oxidative stress, acute inflammatory/cytokine responses, fibrosis, and decrease in pulmonary function. To avoid potential artifactual effects due to instillation/agglomeration associated with SWCNT, we conducted inhalation exposures using stable and uniform SWCNT dispersions obtained by a newly developed aerosolization technique (2). The inhalation of nonpurified SWCNT (iron content of 17.7% by weight) at 5 mg/[m.sup.3], 5 h/day for 4 days was compared with pharyngeal aspiration of varying doses (5-20 [micro]g per mouse) of the same SWCNT. The chain of pathological events in both exposure routes was realized through synergized interactions of early inflammatory response and oxidative stress culminating in the development of multifocal granulomatous pneumonia and interstitial fibrosis. SWCNT inhalation was more effective than aspiration in causing inflammatory response, oxidative stress, collagen deposition, and fibrosis as well as mutations of K-ras gene locus in the lung of C57BL/6 mice. nanoparticles; lung disease

Nanoparticles have a fundamental dimension of < 100 nm. However, on suspension in media, agglomerates of nanoparticles are the more common structure. This is particularly evident in prior intratracheal instillation or aspiration studies of single-walled carbon nanotubes (SWCNT), in which granulomatous lesions encased by epithelioid macrophages were produced by large agglomerates. In this study, we tested the hypothesis of whether exposure to more dispersed SWCNT structures would alter pulmonary distribution and response. A dispersed preparation of single-walled carbon nanotubes (DSWCNT) with a mean diameter of 0.69 [micro]m was given by pharyngeal aspiration to C57BL/6 mice. Electron microscopy demonstrated a highly dispersed, interstitial distribution of DSWCNT deposits by 1 day postexposure. Deposits were generally < 1 [micro]m. Macrophage phagocytosis of DSWCNT was rarely observed at any time point. Lung responses were studied by lavage and morphometry at 1 h, 1 day, 7 day, and 1 mo after a single DSWCNT exposure of 10 [micro]g/mouse. Lung sections and lavage cells demonstrated an early, transient neutrophilic and inflammatory phase that rapidly resolved and was similar to that observed with large agglomerates. No granulomatous lesions or epithelioid macrophages were detected. Morphometric measurement of Sirius red staining was used to assess the connective tissue response. The average thickness of connective tissue in alveolar regions was 0.10 [+ or -] 0.02, 0.09 [+ or -] 0.02, 0.10 [+ or -] 0.01, 0.48 [+ or -] 0.04, and 0.88 [+ or -] 0.19 [micro]m for PBS and 1-h, 1-day, 7-day, and 1-mo postexposure groups, respectively. The results demonstrate that dispersed SWCNT are rapidly incorporated into the alveolar interstitium and that they produce an increase in collagen deposition. toxicology; nanoparticles; particulates; emerging technologies; lung injury

Human and animal studies have confirmed that inhalation of particles from ambient air or occupational settings not only causes pathophysiological changes in the respiratory system, but causes cardiovascular effects as well. At an equal mass lung burden, nanoparticles are more potent in causing systemic microvascular dysfunction than fine particles of similar composition. Thus, accumulated evidence from animal studies has led to heightened concerns about the potential short- and long-term deleterious effects of inhalation of engineered nanoparticles on the cardiovascular system. This review highlights the new observations from animal studies, which document the adverse effects of pulmonary exposure to engineered nanoparticles on the cardiovascular system and elucidate the potential mechanisms involved in regulation of cardiovascular function, in particular, how the neuronal system plays a role and reacts to pulmonary nanoparticle exposure based on both in vivo and in vitro studies. In addition, this review also discusses the possible influence of altered autonomic nervous activity on preexisting cardiovascular conditions. Whether engineered nanoparticle exposure serves as a risk factor in the development of cardiovascular diseases warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: The integration of engineered nanomaterials (ENM) is well-established and widespread in clinical, commercial, and domestic applications. Cardiovascular dysfunctions have been reported in adult populations after exposure to a variety of ENM. As the diversity of these exposures continues to increase, the fetal ramifications of maternal exposures have yet to be determined. We, and others, have explored the consequences of ENM inhalation during gestation and identified many cardiovascular and metabolic outcomes in the F1 generation. The purpose of these studies was to identify genetic alterations in the F1 generation of Sprague-Dawley rats that result from maternal ENM inhalation during gestation. Pregnant dams were exposed to nano-titanium dioxide (nano-TiO2) aerosols (10 ± 0. 5 mg/m3) for 7-8 days (calculated, cumulative lung deposition = 217 ± 1 μg) and on GD (gestational day) 20 fetal hearts were isolated. DNA was extracted and immunoprecipitated with modified chromatin marks histone 3 lysine 4 tri-methylation (H3K4me3) and histone 3 lysine 27 tri-methylation (H3K27me3). Following chromatin immunoprecipitation (ChIP), DNA fragments were sequenced. RNA from fetal hearts was purified and prepared for RNA sequencing and transcriptomic analysis. Ingenuity Pathway Analysis (IPA) was then used to identify pathways most modified by gestational ENM exposure. Results: The results of the sequencing experiments provide initial evidence that significant epigenetic and transcriptomic changes occur in the cardiac tissue of maternal nano-TiO2 exposed progeny. The most notable alterations in major biologic systems included immune adaptation and organismal growth. Changes in normal physiology were linked with other tissues, including liver and kidneys. Conclusions: These results are the first evidence that maternal ENM inhalation impacts the fetal epigenome. [ABSTRACT FROM AUTHOR]

Background: Heart rate and cardiovascular function are regulated by the autonomic nervous system. Heart rate variability (HRV) as a marker reflects the activity of autonomic nervous system. The prognostic significance of HRV in cardiovascular disease has been reported in clinical and epidemiological studies. The present study focused on the influence of inhaled multi-walled carbon nanotubes (MWCNTs) on autonomic nervous system by HRV analysis. Methods: Male Sprague-Dawley rats were pre-implanted with a telemetry device and kept in the individual cages for recovery. At week four after device implantation, rats were exposed to MWCNTs for 5 h at a concentration of 5 mg/m³. The real-time EKGs were recorded by a telemetry system at pre-exposure, during exposure, 1 day and 7 days post-exposure. HRV was measured by root mean square of successive differences (RMSSD); the standard deviation of inter-beat (RR) interval (SDNN); the percentage of successive RR interval differences greater than 5 ms (pNN5) and 10 ms (pNN10); low frequency (LF) and high frequency (HF). Results: Exposure to MWCNTs increased the percentage of differences between adjacent R-R intervals over 10 ms (pNN10) (p < 0.01), RMSSD (p < 0.01), LF (p < 0.05) and HF (p < 0.01). Conclusions: Inhalation of MWCNTs significantly alters the balance between sympathetic and parasympathetic nervous system. Whether such transient alterations in autonomic nervous performance would alter cardiovascular function and raise the risk of cardiovascular events in people with pre-existing cardiovascular conditions warrants further study. [ABSTRACT FROM AUTHOR]

Anecdotal reports in the press and epidemiological studies suggest that deployment to Iraq and Afghanistan may be associated with respiratory diseases and symptoms in U.S. military personnel and veterans. Exposures during military operations were complex, but virtually all service members were exposed to high levels of respirable, geogenic dust. Inhalation of other dusts has been shown to be associated with adverse health effects, but the pulmonary toxicity of ambient dust from Iraq has not been previously studied. The relative toxicity of Camp Victory dust was evaluated by comparing it to particulate matter from northern Kuwait, a standard U.S. urban dust, and crystalline silica using a single intratracheal instillation in rats. Lung histology, protein levels, and cell counts were evaluated in the bronchoalveolar lavage fluid 1–150 d later. The Iraq dust provoked an early significant, acute inflammatory response. However, the level of inflammation in response to the Iraq dust, U.S. urban dust, and Kuwait dust rapidly declined and was nearly at control levels by the end of the study At later times, animals exposed to the Iraq, U.S. urban, or Kuwait dusts showed increased small airway remodeling and emphysema compared to silica-exposed and control animals without evidence of fibrosis or premalignant changes. The severity and persistence of pulmonary toxicity of these three dusts from the Middle East resemble those of a U.S. urban dust and are less than those of silica. Therefore, Iraq dust exposure is not highly toxic, but similar to other poorly soluble low-toxicity dusts. [ABSTRACT FROM AUTHOR]

Our laboratory has previously demonstrated that application of an antimicrobial spray product containing titanium dioxide (TiO2) generates an aerosol of titanium dioxide in the breathing zone of the applicator. The present report describes the design of an automated spray system and the characterization of the aerosol delivered to a whole body inhalation chamber. This system produced stable airborne levels of TiO2 particles with a median count size diameter of 110 nm. Rats were exposed to 314 mg/m3 min (low dose), 826 mg/m3 min (medium dose), and 3638 mg/m3 min (high dose) of TiO2 under the following conditions: 2.62 mg/m3 for 2 h, 1.72 mg/m3 4 h/day for 2 days, and 3.79 mg/m3 4 h/day for 4 days, respectively. Pulmonary (breathing rate, specific airway resistance, inflammation, and lung damage) and cardiovascular (the responsiveness of the tail artery to constrictor or dilatory agents) endpoints were monitored 24 h post-exposure. No significant pulmonary or cardiovascular changes were noted at low and middle dose levels. However, the high dose caused significant increases in breathing rate, pulmonary inflammation, and lung cell injury. Results suggest that occasional consumer use of this antimicrobial spray product should not be a hazard. However, extended exposure of workers routinely applying this product to surfaces should be avoided. During application, care should be taken to minimize exposure by working under well ventilated conditions and by employing respiratory protection as needed. It would be prudent to avoid exposure to children or those with pre-existing respiratory disease. [ABSTRACT FROM AUTHOR]

Multiwalled carbon nanotubes (MWCNT) have elicited great interest in biomedical applications due to their extraordinary physical, chemical, and optical properties. Intravenous administration of MWCNT-based medical imaging agents and drugs in animal models was utilized. However, the potential harmful health effects of MWCNT administration in humans have not yet been elucidated. Furthermore, to date, there are no apparent reports regarding the precise mechanisms of translocation of MWCNT into target tissues and organs from blood circulation. This study demonstrates that exposure to MWCNT leads to an increase in cell permeability in human microvascular endothelial cells (HMVEC). The results obtained from this study also showed that the MWCNT-induced rise in endothelial permeability is mediated by reactive oxygen species (ROS) production and actin filament remodeling. In addition, it was found that MWCNT promoted cell migration in HMVEC. Mechanistically, MWCNT exposure elevated the levels of monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) in HMVEC. Taken together, these results provide new insights into the bioreactivity of MWCNT, which may have implications in the biomedical application of MWCNT in vascular targeting, imaging, and drug delivery. The results generated from this study also elucidate the potential adverse effects of MWCNT exposure on humans at the cellular level. [ABSTRACT FROM PUBLISHER]

Exposure to fine particulate matter (PM, mean aerodynamic diameter ≤2.5 μm) has been shown to be a risk factor for cardiovascular disease mortality and may contribute to acute coronary events such as myocardial infarction (MI). There is sufficient reason to believe that smaller particles, such as nanoparticles, might be even more detrimental than larger sized particles due to their increased surface area and higher pulmonary deposition. Our laboratory showed that nanoparticle inhalation impairs endothelium-dependent arteriolar vasodilation in skeletal muscle. However, it is not known whether coronary microvascular endothelial function is affected in a similar manner. Rats were exposed to filtered air (control) or TiO2 nanoparticles (primary particle diameter, ∼21 nm) via inhalation at concentrations that produced measured depositions (10 μg) relevant to ambient air pollution. Subepicardial arterioles (∼150 μm in diameter) were isolated and responses to transmural pressure, flow-induced dilation (FID), acetylcholine (ACh), the Ca2+ ionophore A23187, and sodium nitroprusside (SNP) were assessed. Myogenic responsiveness was preserved between groups. In addition, there was no difference in the vasodilation to SNP, signifying that smooth muscle sensitivity to nitric oxide (NO) is unaffected by nano-TiO2 exposure. However, inhalation of nano-TiO2 produced an increase in spontaneous tone in coronary arterioles and also impaired endothelium-dependent FID. In addition, ACh-induced and A23187-induced vasodilation was also blunted in arterioles after inhalation of nano-TiO2. Data showed that nanoparticle exposure significantly impairs endothelium-dependent vasodilation in subepicardial arterioles. Such disturbances in coronary microvascular function are consistent with the cardiac events associated with particle pollution exposure. [ABSTRACT FROM AUTHOR]

BACKGROUND: Single-wall carbon nanotubes (SWCNTs), with their unique physicochemical and mechanical properties, have many potential new applications in medicine and industry. There has been great concern subsequent to preliminary investigations of the toxicity, biopersistence, pathogenicity, and ability of SWCNTs to translocate to subpleural areas. These results compel studies of potential interactions of SWCNTs with mesothelial cells. OBJECTIVE: Exposure to asbestos is the primary cause of malignant mesothelioma in 80--90% of individuals who develop the disease. Because the mesothelial cells are the primary target cells of asbestos-induced molecular changes mediated through an oxidant-linked mechanism, we used normal mesothelial and malignant mesothelial cells to investigate alterations in molecular signaling in response to a commercially manufactured SWCNT. METHODS: In the present study, we exposed mesothelial cells to SWCNTs and investigated reactive oxygen species (ROS) generation, cell viability, DNA damage, histone H2AX phosphorylation, activation of poly(ADP-ribose) polymerase 1 (PARP-1), stimulation of extracellular signal-regulated kinase (ERKs), Jun N-terminal kinases (JNKs), protein p38, and activation of activator protein-1 (AP-1), nuclear factor [kappa]B (NF-[kappa]B), and protein serine-threonine kinase (Akt). RESULTS: Exposure to SWCNTs induced ROS generation, increased cell death, enhanced DNA damage and H2AX phosphorylation, and activated PARP, AP-1, NF-[kappa]B, p38, and Akt in a dose-dependent manner. These events recapitulate some of the key molecular events involved in mesothelioma development associated with asbestos exposure. CONCLUSIONS: The cellular and molecular findings reported here do suggest that SWCNTs can cause potentially adverse cellular responses in mesothelial cells through activation of molecular signaling associated with oxidative stress, which is of sufficient significance to warrant in vivo animal exposure studies. [ABSTRACT FROM AUTHOR]

The article presents the evidence of NEMO, a regulatory subunit of IKK complex by K63-linked polyubiquitin chain. The discovery of NEMO binding to the K63-linked polyubiquitin chain leading to the activation of IKK and conjugation to RIP and TRAF proteins is presented. The article also presents the ubiquitination in NF-kB signaling.

Risk assessment of occupational exposure to nanomaterials is needed. Human data are limited, but quantitative data are available from rodent studies. To use these data in risk assessment, a scientifically reasonable approach for extrapolating the rodent data to humans is required. One approach is allometric adjustment for species differences in the relationship between airborne exposure and internal dose. Another approach is lung dosimetry modeling, which provides a biologically-based, mechanistic method to extrapolate doses from animals to humans. However, current mass-based lung dosimetry models may not fully account for differences in the clearance and translocation of nanoparticles. In this article, key steps in quantitative risk assessment are illustrated, using dose-response data in rats chronically exposed to either fine or ultrafine titanium dioxide (TiO 2 ), carbon black (CB), or diesel exhaust particulate (DEP). The rat-based estimates of the working lifetime airborne concentrations associated with 0.1% excess risk of lung cancer are approximately 0.07 to 0.3 mg/m 3 for ultrafine TiO 2 , CB, or DEP, and 0.7 to 1.3 mg/m 3 for fine TiO 2 . Comparison of observed versus model-predicted lung burdens in rats shows that the dosimetry models predict reasonably well the retained mass lung burdens of fine or ultrafine poorly soluble particles in rats exposed by chronic inhalation. Additional model validation is needed for nanoparticles of varying characteristics, as well as extension of these models to include particle translocation to organs beyond the lungs. Such analyses would provide improved prediction of nanoparticle dose for risk assessment. [ABSTRACT FROM AUTHOR]

Clinical detection of silicosis is currently dependent on radiological and lung function abnormalities, both late manifestations of disease. Markers of prediction and early detection of pneumoconiosis are imperative for the implementation of timely intervention strategies. Understanding the underlying mechanisms of the etiology of coal workers pneumoconiosis (CWP) and silicosis was essential in proposing numerous biomarkers that have been evaluated to assess effects following exposure to crystalline silica and/or coal mine dust. Human validation studies have substantiated some of these proposed biomarkers and argued in favor of their use as biomarkers for crystalline silica- and CWP-induced pneumoconiosis. A number of “ideal” biological markers of effect were identified, namely, Clara cell protein-16 (CC16) (serum), tumor necrosis factor-α (TNF-α) (monocyte release), interleukin-8 (IL-8) (monocyte release), reactive oxygen species (ROS) measurement by chemiluminescence (neutrophil release), 8-isoprostanes (serum), total antioxidant levels measured by total equivalent antioxidant capacity (TEAC), glutathione, glutathione peroxidase activity, glutathione S-transferase activity, and platelet-derived growth factor (PDGF) (serum). TNF-α polymorphism (blood cellular DNA) was identified as a biomarker of susceptibility. Further studies are planned to test the validity and feasibility of these biomarkers to detect either high exposure to crystalline silica and early silicosis or susceptibility to silicosis in gold miners in South Africa. [ABSTRACT FROM AUTHOR]

Intercellular communications between alveolar macrophages (AM) and alveolar epithelial type II (TII) cells have been suggested to be important in cellular responses. The main objective of this study was to improve our understanding of the interactions between AM and TII cells that might occur in the lung. In the present investigation, this interaction was studied under different interaction conditions (transwell or mixed coculture) and different exposure conditions (basal, lipopolysaccharide [LPS] exposure, or silica exposure). Studies also attempted different approaches to identify specific mediator(s) involved in this interaction. The following findings were made: (1) Surfactant released from TII cells appears to exert an inhibitory effect on AM activity. (2) Basal transwell coculture conditions are better than mixed coculture conditions to study AM/TII cell interactions, since the inhibitory effect of the surfactant in the transwell coculture is minimized. (3) AM/TII cell interaction is dependent on cell culture (transwell vs mixed) and exposure conditions. (4) Oxidants, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, prostaglandins, and leukotrienes probably do not independently affect the AM/TII intercellular interaction; instead, they appear to indirectly modulate the complex pathways of AM/TII communication. [ABSTRACT FROM AUTHOR]

Rationale: Oxidative stress is believed to play a key role in the development of welding-induced disease.Objectives: This study investigated the effects of welding fume exposure on correlates of oxidative stress in the serum of asymptomatic shipyard welders.Methods: Blood samples from 197 male welders and 150 unexposed male office workers were analyzed for manganese and lead. Serum was assayed for protein, albumin, total antioxidant status (TAS), manganese superoxide dismutase (Mn-SOD), aconitase, glutathione peroxidase (GPx), heat shock protein 70, isoprostane, and reactive oxygen species, using electron spin resonance and chemiluminescence. Comparisons between welders and control subjects on biomarkers of oxidative stress were made, and evaluated for the effects of age and smoking. Associations between blood levels of manganese and lead and biomarkers were also explored.Results: Welding was associated with increases in serum protein, GPx, aconitase, TAS, and isoprostane levels compared with control subjects. These group differences were not altered by age or smoking. In welders and control subjects, age was significantly associated with changes in albumin, TAS, chemiluminescence, GPx, and Mn-SOD. In welders and control subjects, smoking resulted in a decrease in GPx, and in a significant interaction between smoking and chemiluminescence. There were significant correlations between manganese levels in welders' blood and chemiluminescence, GPx, and Mn-SOD, and between lead levels and albumin, TAS, GPx, and Mn-SOD.Conclusions: These results document that exposure to welding can cause changes in serum biomarkers of oxidative stress that may be valuable in clinical monitoring of disease development and in assessing whether further reduction of worker exposures is needed. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha (TNF-α) is produced by alveolar macrophages (AM) in response to bleomycin (BLM) exposure. This cytokine has been linked to BLM-induced pulmonary inflammation, an early drug effect, and to lung fibrosis, the ultimate toxic effect of BLM. The present study was carried out to study the time dependence of apoptotic signaling pathways and the potential roles of TNF receptors in BLM-induced AM apoptosis. Male Sprague-Dawley rats were exposed to saline or BLM (1 mg/kg) by intratracheal instillation. At 1, 3, or 7 d postexposure, AM were isolated by bronchoalveolar (BAL) lavage and evaluated for apoptosis by ELISA. The release of cytochrome c from mitochrondria, the activation of caspase-3, -8, and -9, the cleavage of nuclear poly(ADP-ribose) polymerase (PARP), and the expression of TNF receptors (TNF-R1/p55 and TNF-R2/p75), TNF-R-associated factor 2 (TRAF2), and cellular inhibitor of apoptosis 1 (c-IAP1) were determined by immunoblotting. The results showed that BLM exposure induced AM apoptosis, with the highest apoptotic effect occurring at 1 d after exposure and gradually decreasing at 3 and 7 d postexposure, but still remaining significantly above the control level. The maximal translocation of cytochromec from mitochondria into the cytosol was observed at 1 d postexposure, whereas the activation of caspase-9 and caspase-3 and caspase-3-dependent cleavage of PARP was found to reach a peak level at 3 d postexposure. BLM exposure had no marked effect on AM expression of TNF-R1 or caspase-8 activation, but significantly increased the expression of TNF-R2 that was accompanied by a rise in c-IAP1 and a decrease in TRAF2. This induction of TNF-R2 by BLM was significant on d 1 and increased with greater exposure time. In vitro studies showed that pretreatment of naive AM with a TNF-R2 antibody significantly inhibited BLM-induced caspase-3 activity and apoptosis. These results suggest that BLM-induced apoptosis involves multiple pathways in a time-dependent manner. Since maximal BLM-induced AM apoptosis (1 d postexposure) preceded maximal changes in caspase-9 and -3 (3 d postexposure), it is possible that a caspase-independent mechanism is involved in this initial response. These results indicate that the sustained expression of TNF-R2 in AM by BLM exposure may sensitize these cells to TNF-α-mediated toxicity. [ABSTRACT FROM AUTHOR]

Although diesel exhaust particles (DEP) are known to produce pulmonary disorders, the xenobiotic metabolic pathways associated with DEP detoxification and bioactivation remain unclear. In this study, the effect of acute exposure of DEP on phase I and phase II enzymes of rat lung was investigated. Intratracheal administration of DEP produced an induction of cytochrome P-450 (CYP) 1A1 enzyme protein and activity at 1 d postexposure, with the enzyme level returning to control at 5 d postexposure. On the other hand, carbon black (CB), a particle control, did not show any induction of CYP1A1 protein or enzyme activity. However, both DEP and CB significantly decreased CYP2B1 protein and enzyme activity at 1 d postexposure. The decrease in CYP2B1 enzyme protein and activity by DEP or CB treatment was observed up to 7 d postexposure. DEP and CB treatments also significantly attenuated glutathione S-transferase (GST)-π protein at 1 d postexposure. Both DEP and CB at 35 mg/kg significantly decreased the activities of GST and catalase at 1 and 7 d postexposure. DEP, but not CB, significantly induced quinone reductase (QR) activity at 7 d postexposure. This study suggests that DEP may induce CYP1A1 and QR enzymes via a chemical effect, while the carbonaceous core may be involved in the attenuation of CYP2B1, GST, and catalase proteins and enzyme activities. [ABSTRACT FROM AUTHOR]

Exposure to asphalt fumes is a health concern due to the presence of polycyclic aromatic compounds (PACs) in asphalt. Bioactivation of many PACs requires metabolism by the cytochrome P-450 (P-450) system. The objective of this study was to evaluate the effects of exposure of rats to asphalt fume condensate (AFC), collected at the top of a paving asphalt storage tank, on the pulmonary microsomal P-450 system and to determine the genotoxic effects of such exposure. Male Sprague-Dawley rats were intratracheally instilled with saline or with 0.45, 2.22, or 8.88 mg/kg AFC for 3 consecutive days and sacrificed the following day. Lung microsomes were isolated by differential centrifugation of lung homogenates. Microsomal protein level, NADPH cytochrome c reductase activity, and the activities and protein levels of cytochrome P-450 isozymes CYP1A1 and CYP2B1 were monitored to assess the effects of AFC exposure on pulmonary P-450. The activities of CYP2B1 and CYP1A1 were determined by monitoring xenobiotic metabolism of 7-pentoxyresorufin and 7-ethoxyresorufin, respectively. CYP2B1 and CYP1A1 levels were determined by immunochemical analysis. Micronucleus (MN) formation in bone-marrow polychromatic erythrocytes (PCEs) was determined to assess the genotoxic effects of AFC exposure. The results showed that exposure of rats to AFC did not significantly affect total cytochrome P-450 content or cytochrome c reductase activity in the lung. CYP2B1 levels and enzyme activity were not significantly affected by AFC exposure. In contrast, CYP1A1 levels and activity were significantly increased in microsomes isolated from AFC-exposed lungs. Increased MN formation was observed only in high-dose AFC-exposed bone marrow PCEs. These results demonstrate that AFC exposure induced CYP1A1 activity and increased the enzyme levels of CYP1A1 in lung microsomes, suggesting that AFC exposure may alter metabolism of PACs by the cytochrome P-450 system in the lung. Alteration of cytochrome P-450 metabolism of PACs may contribute to the AFC-induced genotoxic effects demonstrated as MN formation. [ABSTRACT FROM AUTHOR]

The objectives of this study were: (i) to construct a physiologically based mathematical model to describe the retention and clearance of respirable crystalline silica (MIN-U-SIL 5), the inflammatory reaction and the development of fibrosis; (ii) to calibrate/validate the model using animal data from inhalation experiments with MIN-U-SIL 5. A physiologically based mathematical model was constructed with the following features: compartments to describe the retention and clearance of silica, critical lung burdens for initiation of inflammation and fibrosis and recruitment of neutrophils and alveolar macrophages. Data were available from two recent NIOSH studies of rats exposed by inhalation to respirable crystalline silica. Data from the first study were used to estimate the model parameters not obtainable from the earlier studies, using a numerical method combining non-linear least squares analysis and integration of differential equations. The second study was used for model validation by comparing the model predictions with the data. Once validated, the model was used to predict the outcome of a 2 yr inhalation experiment with DQ-12 quartz. Finally, the model was extended to describe the dose-response relationships, including oxidant dose, antioxidant reactions, transcription factor switching, cell damage and fibrosis. A good fit of the model to the data was obtained. The critical doses of MIN-U-SIL 5 were calculated for both inflammation and fibrosis. The model was able to simulate the retention and clearance of DQ-12 quartz. The model was also extended to describe the time course of NF-B initiation, lipid peroxidation and superoxide dismutase expression. This model has provided a means to relate the inhaled silica dose to inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Study Objectives: To study the effects of extracts of brewery dust on isolated guinea pig tracheal smooth muscle in vitro.Design: Parallel pharmacologic intervention on guinea pig tracheal rings that were obtained from the same animal.Setting: Mount Sinai School of Medicine, Department of Pulmonary Medicine.Material: The isolated guinea pig tracheal tissue of 18 guinea pigs.Interventions: Pretreatment of guinea pig rings by mediator-modifying agents before challenge with the brewery dust extracts.Measurements and Results: The effect of brewery dust extracts on isolated guinea pig tracheal smooth muscle was studied using water-soluble extracts of dust obtained from brewery materials, including hops, barley, and brewery yeast. Dust extracts were prepared as a 1:10 (wt/vol) aqueous solution. Dose-related contractions of nonsensitized guinea pig tracheas were demonstrated using these extracts. The dust extracts contained significant quantities of bacterial components (eg, endotoxin and n-formyl-methionyl-leucyl-phenylalanine), but these agents were not thought to contribute directly to the constrictor effect of the dusts. Pharmacologic studies were performed by pretreating guinea pig tracheal tissue with the following drugs known to modulate smooth muscle contraction: atropine; indomethacin; pyrilamine; LY171883; nordihydroguaiaretic acid; captopril; thiorphan; verapamil; and TMB8. The constrictor effects of the dust extracts were inhibited by a wide variety of agents, the patterns of which depended on the dust extract. Atropine consistently and strikingly reduced the contractile effects of these extracts. These observations may suggest an interaction of the extracts with parasympathetic nerves or, more directly, with muscarinic receptors. The inhibition of contraction by the blocking of other mediators was less effective and varied with the dust extract.Conclusions: We suggest that brewery dust extracts cause a dose-related airway smooth muscle constriction by nonimmunologic mechanisms involving a variety of airway mediators and, possibly, cholinergic receptors. This effect is not dependent on presensitization of the guinea pigs. [ABSTRACT FROM AUTHOR]

Metal working fluids (MWFs) are widely used in industry for metal cutting, drilling, shaping, lubricating, and milling. Potential for dermal exposure to MWFs exists for a large number of men and women via aerosols and splashing during the machining operations. It has been reported earlier that occupational exposure to MWFs causes allergic and irritant contact dermatitis. Previously, we showed that dermal exposure of female and male B6C3F1 mice to 5% MWFs for 3 months resulted in accumulation of mast cells and elevation of histamine in the skin. Topical exposure to MWF also resulted in elevated oxidative stress in the liver of both sexes and the testes in males. The goal of this study was to evaluate the interaction between oxidative stress in the skin and topical application of MWF. Oxidative stress in skin of B6C3F1 mice of both sexes was generated by intradermal injection of the hydrogen peroxide (H[sub 2]O[sub 2])-producing enzyme, glucose oxidase with polyethylene glycol (GOD+PEG). In mice given GOD+PEG, topical treatment with MWF (200 μl, 30%, for 1, 3, or 7 days) resulted in a mixed inflammatory cell response, accumulation of peroxidative products, and reduction of GSH content in the skin. Such changes were not observed with MWF treatment alone. These data indicate that oxidative stress can enhance dermal inflammation caused by occupational exposure to MWF. Toxicology and Industrial Health (2000) 16, 267–276. [ABSTRACT FROM AUTHOR]