Showing papers in "Inhalation Toxicology in 2010"

Exposure assessment of carbon nanotube manufacturing workplaces

Abstract: Seven CNT (carbon nanotube) handling workplaces were investigated for exposure assessment. Personal sampling, area sampling, and real-time monitoring using an SMPS (scanning mobility particle sizer), dust monitor, and aethalometer were performed to characterize the mass exposure, particle size distribution, and particle number exposure. No workplace was found to exceed the current ACGIH (American Conference of Governmental Industrial Hygienists) TLVs (threshold limit values) and OELs (occupational exposure levels) set by the Korean Ministry of Labor for carbon black (3.5 mg/m 3 ), PNOS (particles not otherwise specified; 3 mg/m 3 ), and asbestos (0.1 fiber/cc). Nanoparticles and fine particles were most frequently released after opening the CVD (chemical vapor deposition) cover, followed by catalyst preparation. Other work processes that prompted nanoparticle release included spraying, CNT preparation, ultrasonic dispersion, wafer heating, and opening the water bath cover. All these operation processes could be effectively controlled with the implementation of exposure mitigation, such as engineering control, except at one workplace where only natural ventilation was used.

Cytotoxic and proinflammatory effects of ambient and source-related particulate matter (PM) in relation to the production of reactive oxygen species (ROS) and cytokine adsorption by particles

Abstract: The composition of airborne particulate matter (PM) varies widely depending on its source, and recent studies have suggested that particle-associated adverse health effects are related to particle

Is the air pollution health research community prepared to support a multipollutant air quality management framework

Abstract: Ambient air pollution is always encountered as a complex mixture, but past regulatory and research strategies largely focused on single pollutants, pollutant classes, and sources one-at-a-time. There is a trend toward managing air quality in a progressively “multipollutant” manner, with the idealized goal of controlling as many air contaminants as possible in an integrated manner to achieve the greatest total reduction of adverse health and environmental impacts. This commentary considers the current ability of the environmental air pollution exposure and health research communities to provide evidence to inform the development of multipollutant air quality management strategies and assess their effectiveness. The commentary is not a literature review, but a summary of key issues and information gaps, strategies for filling the gaps, and realistic expectations for progress that could be made during the next decade. The greatest need is for researchers and sponsors to address air quality health impacts fro...

Inflammation and tissue damage in mouse lung by single and repeated dosing of urban air coarse and fine particles collected from six European cities

Abstract: The authors have previously demonstrated heterogeneities in the inflammatory activities of urban air fine (PM(2.5-0.2)) and coarse (PM(10-2.5)) particulate samples collected from six European cities with contrasting air pollution situations. The same samples (10 mg/kg) were intratracheally instilled to healthy C57BL/6J mice either once or repeatedly on days 1, 3, and 6 of the study week. The lungs were lavaged 24 h after the single dose or after the last repeated dosing. In both size ranges, repeated dosing of particles increased the total cell number in bronchoalveolar lavage fluid (BALF) more than the respective single dose, whereas cytokine concentrations were lower after repeated dosing. The lactate dehydrogenase (LDH) responses increased up to 2-fold after repeated dosing of PM(2.5-0.2) samples and up to 6-fold after repeated dosing of PM(10-2.5) samples. PM(10-2.5) samples evoked a more extensive interstitial inflammation in the mouse lungs. The constituents with major contributions to the inflammatory responses were oxidized organic compounds and transition metals in PM(2.5-0.2) samples, Cu and soil minerals in PM(10-2.5) samples, and Zn in both size ranges. In contrast, poor biomass and coal combustion were associated with elevated levels of polycyclic aromatic hydrocarbons (PAHs) and a consistent inhibitory effect on the inflammatory activity of PM(2.5-0.2) samples. In conclusion, repeated intratracheal instillation of both fine and coarse particulate samples evoked enhanced pulmonary inflammation and cytotoxicity compared to single-dose administration. The sources and constituents of urban air particles responsible for these effects appear to be similar to those encountered in the authors' previous single-dose study.

Direct measurement of toxicants inhaled by water pipe users in the natural environment using a real-time in situ sampling technique.

Abstract: While narghile water pipe smoking has become a global phenomenon, knowledge regarding its toxicant content and delivery, addictive properties, and health consequences is sorely lagging. One challenge in measuring toxicant content of the smoke in the laboratory is the large number of simplifying assumptions that must be made to model a "typical" smoking session using a smoking machine, resulting in uncertainty over the obtained toxicant yields. In this study, we develop an alternative approach in which smoke generated by a human water pipe user is sampled directly during the smoking session. The method, dubbed real-time in situ sampling (RINS), required developing a self-powered portable instrument capable of automatically sampling a fixed fraction of the smoke generated by the user. Instrument performance was validated in the laboratory, and the instrument was deployed in a field study involving 43 ad libitum water pipe use sessions in Beirut area cafes in which we measured inhaled nicotine, carbon monoxide (CO), and water pipe ma'ssel-derived "tar." We found that users drew a mean of 119 L of smoke containing 150 mg of CO, 4 mg of nicotine, and 602 mg of ma'ssel-derived "tar" during a single use session (mean duration = 61 min). These first direct measurements of toxicant delivery demonstrate that ordinary water pipe use involves inhaling large quantities of CO, nicotine, and dry particulate matter. Results are compared with those obtained using the Beirut method smoking machine protocol.

Comparative effects of inhaled diesel exhaust and ambient fine particles on inflammation, atherosclerosis, and vascular dysfunction.

Abstract: Ambient air PM2.5 (particulate matter less than 2.5 μm in diameter) has been associated with cardiovascular diseases (CVDs), but the underlying mechanisms affecting CVDs are unknown. The authors investigated whether subchronic inhalation of concentrated ambient PM2.5 (CAPs), whole diesel exhaust (WDE), or diesel exhaust gases (DEGs) led to exacerbation of atherosclerosis, pulmonary and systemic inflammation, and vascular dysfunction; and whether DEG interactions with CAPs alter cardiovascular effects. ApoE−/− mice were simultaneously exposed via inhalation for 5 hours/day, 4 days/week, for up to 5 months to one of five different exposure atmospheres: (1) filtered air (FA); (2) CAPs (105 μg/m3); (3) WDE (DEP = 436 μg/m3); (4) DEG (equivalent to gas levels in WDE group); and (5) CAPs+DEG (PM2.5: 113 μg/m3; with DEG equivalent to WDE group). After 3 and 5 months, lung lavage fluid and blood sera were analyzed, and atherosclerotic plaques were quantified by ultrasound imaging, hematoxylin and eosin (H&E stain...

Subchronic effects of nasally instilled diesel exhaust particulates on the nasal and airway epithelia in mice

Abstract: Diesel exhaust is the major source of ultrafine particles released during traffic-related pollution. Subjects with chronic respiratory diseases are at greater risk for exacerbations during exposure to air pollution. This study evaluated the effects of subchronic exposure to a low-dose of diesel exhaust particles (DEP). Sixty male BALB/c mice were divided into two groups: (a) Saline: nasal instillation of saline (n = 30); and (b) DEP: nasal instillation of 30 microg of DEP/10 microl of saline (n = 30). Nasal instillations were performed 5 days a week, over 30 and 60 days. Animals were anesthetized with pentobarbital sodium (50 mg/kg intraperitoneal [i.p.]) and sacrificed by exsanguination. Bronchoalveolar lavage (BAL) fluid was performed to evaluate the inflammatory cell count and the concentrations of the interleukin (IL)-4, IL-10, and IL-13 by enzyme-linked immunosorbent assay (ELISA). The gene expression of oligomeric mucus/gel-forming (Muc5ac) was evaluated by real-time polymerase chain reaction (PCR). Histological analysis in the nasal septum and bronchioles was used to evaluate the bronchial and nasal epithelium thickness as well as the acidic and neutral nasal mucus content. The saline group (30 and 60 days) did not show any changes in any of the parameters. However, the instillation of DEP over 60 days increased the expression of Muc5ac in the lungs and the acid mucus content in the nose compared with the 30-day treatment, and it increased the total leukocytes in the BAL and the nasal epithelium thickness compared with saline for 60 days. Cytokines concentrations in the BAL were detectable, with no differences among the groups. Our data suggest that a low-dose of DEP over 60 days induces respiratory tract inflammation.

Toxicological effects of emission particles from fossil- and biodiesel-fueled diesel engine with and without DOC/POC catalytic converter

Abstract: There is increasing demand for renewable energy and the use of biodiesel in traffic is a major option when implying this increment. We investigated the toxicological activities of particulate emissions from a nonroad diesel engine, operated with conventional diesel fuel (EN590), and two biodiesels: rapeseed methyl ester (RME) and hydrotreated fresh vegetable oil (HVO). The engine was operated with all fuels either with or without catalyst (DOC/POC). The particulate matter (PM1) samples were collected from the dilution tunnel with a high-volume cascade impactor (HVCI). These samples were characterized for ions, elements, and polycyclic aromatic hydrocarbon (PAH) compounds. Mouse RAW264.7 macrophages were exposed to the PM samples for 24 h. Inflammatory mediators, (TNF-α and MIP-2), cytotoxicity, genotoxicity, and oxidative stress (reactive oxygen species [ROS]) were measured. All the samples displayed mostly dose-dependent toxicological activity. EN590 and HVO emission particles had larger inflammatory res...

Acute pulmonary response of mice to multi-wall carbon nanotubes.

Abstract: Widespread use of carbon nanotubes is predicted for future and concerns have been raised about their potential health effects. The present study determined the pulmonary response of mice to multi-w...

Inhalability of micron particles through the nose and mouth.

Abstract: Aspiration efficiencies from nose and mouth inhalations are investigated at low and high inhalation rates by using the commercial Computational Fluid Dynamics (CFD) software CFX 11. A realistic human head with detailed facial features was constructed. Facial features were matched to represent the 50th percentile of a human male, aged between 20 and 65 years old, based on anthropometric data. The constant freestream velocity was 0.2 ms(-1), normal to the face, and inhalation rates through the mouth and nose were 15 liters per minute (LPM) for light breathing and 40 LPM for heavy breathing. It was found that the flow field in the near breathing region exhibited vertical direction caused by the presence of the torso where the airstream diverges as it flows around and over the body. The critical area concept was used as a tool to determine the aspiration efficiency of particles. Comparisons between critical areas for the nose and mouth inhalations show similar geometric properties such as the area's shape, and its vertical distance location on the x-z plane located at y = 80 cm upstream. The critical area sizes were found to be slightly larger for the mouth inhalation mainly due to the larger mouth area and also the aligned orientation of the mouth to the upstream flow, whereas the nose is perpendicular to the upstream flow. This study was undertaken to establish the flow field in the near breathing region that will help to characterize the flow and particle field for initial boundary conditions leading to a more holistic modeling approach of respiration through the internal nasal cavity and mouth.

Changing the dose metric for inhalation toxicity studies: Short-term study in rats with engineered aerosolized amorphous silica nanoparticles

Abstract: Inhalation toxicity and exposure assessment studies for nonfibrous particulates have traditionally been conducted using particle mass measurements as the preferred dose metric (i.e., mg or μg/m3). However, currently there is a debate regarding the appropriate dose metric for nanoparticle exposure assessment studies in the workplace. The objectives of this study were to characterize aerosol exposures and toxicity in rats of freshly generated amorphous silica (AS) nanoparticles using particle number dose metrics (3.7 × 107 or 1.8 × 108 particles/cm3) for 1- or 3-day exposures. In addition, the role of particle size (d50 = 37 or 83 nm) on pulmonary toxicity and genotoxicity endpoints was assessed at several postexposure time points. A nanoparticle reactor capable of producing, de novo synthesized, aerosolized amorphous silica nanoparticles for inhalation toxicity studies was developed for this study. SiO2 aerosol nanoparticle synthesis occurred via thermal decomposition of tetraethylorthosilicate (TEOS). The...

Diesel exhaust particulate (DEP) and nanoparticle exposures: What do DEP human clinical studies tell us about potential human health hazards of nanoparticles?

Abstract: Engineered nanoparticles (ENPs) are increasingly tested in cellular and laboratory-animal experiments for hazard potential, but there is a lack of health effects data for humans exposed to ENPs. However, human data for another source of nanoparticle (NP) exposure are available, notably for the NPs contained in diesel exhaust particulate (DEP). Studies of human volunteers exposed to diesel exhaust (DE) in research settings report DEP-NP number concentrations (i.e., >10(6) particles/cm(3)) that exceed number concentrations reported for worst-case exposure conditions for workers manufacturing and handling ENPs. Recent human DE exposure studies, using sensitive physiological instrumentation and well-characterized exposure concentrations and durations, suggest that elevated DE exposures from pre-2007 engines may trigger short-term changes in, for example, lung and systemic inflammation, thrombogenesis, vascular function, and brain activity. Considerable uncertainty remains both as to which DE constituents underlie the observed responses (i.e., DEP NPs, DEP mass, DE gases), and as to the implications of the observed short-term changes for the development of disease. Even so, these DE human clinical data do not give evidence of a unique toxicity for NPs as compared to other small particles. Of course, physicochemical properties of toxicological relevance may differ between DEP NPs and other NPs, yet overall, the DE human clinical data do not support the idea that elevated levels of NPs per se (at least in the DEP context) must be acutely toxic by virtue of their nano-sized nature alone.

Exposure to nitrogen dioxide is not associated with vascular dysfunction in man

Abstract: Background: Exposure to air pollution is associated with increased cardiorespiratory morbidity and mortality. It is unclear whether these effects are mediated through combustion-derived particulate ...

Malondialdehyde and superoxide dismutase correlate with FEV1 in patients with COPD associated with wood smoke exposure and tobacco smoking.

Abstract: Tobacco smoking is the primary risk factor for chronic obstructive pulmonary disease (COPD). However, recent epidemiological studies have established domestic exposure to wood smoke and other biomass fuels as additional important risk factors, characteristic in developing countries. Oxidative stress is one of the mechanisms concerned with pathogenesis of COPD. However, the molecular mechanisms involved in the onset and progress of COPD associated with biomass and specifically that derived from wood smoke exposure remain unknown. We analyzed the relationship between forced expiratory volume in first second (FEV(1)) with plasma malondialdehyde (MDA) concentration and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) in COPD patients associated with wood smoke (WSG; n = 30), tobacco smoking (TSG; n = 30), and healthy control subjects (HCG; n = 30). Differences between FEV(1) from WSG and TSG (58 +/- 22% and 51 +/- 24%, respectively) with HCG (100 +/- 6%) were observed (P < 0.01). Plasma MDA concentration was higher in both WSG and TSG (1.87 +/- 0.81 and 1.68 +/- 0.82 nmol/mL, respectively) compared with HCG (0.42 +/- 0.17 nmol/mL; P < 0.01). SOD activity showed a significant increase in both WSG and TSG (0.36 +/- 0.12 and 0.37 +/- 0.13 U/mL) compared with HCG (0.19 +/- 0.04 U/mL; P < 0.01). No differences were shown regarding GPx, GR, and GST activities between COPD and control groups. Inverse correlations were founded between MDA and SOD with FEV(1) in both COPD patients and control subjects (P < 0.001). These results indicate a role for oxidative stress in COPD associated with wood smoke similar to that observed with tobacco smoking in subjects who ceased at least 10 years previous to this study.

Development and characterization of a Versatile Engineered Nanomaterial Generation System (VENGES) suitable for toxicological studies

Abstract: A novel system for generation of engineered nanomaterials (ENMs) suitable for in situ toxicological characterization within biological matrices was developed. This Versatile Engineered Nanomaterial Generation System (VENGES) is based on industry-relevant, flame spray pyrolysis aerosol reactors that can scaleably produce ENMs with controlled primary and aggregate particle size, crystallinity, and morphology. ENMs are produced continuously in the gas phase, allowing their continuous transfer to inhalation chambers, without altering their state of agglomeration. Freshly generated ENMs are also collected on Teflon filters for subsequent physicochemical and morphological characterization and for in vitro toxicological studies. The ability of the VENGES system to generate families of ENMs of pure and selected mixtures of iron oxide, silica, and nanosilver with controlled physicochemical properties was demonstrated using a range of state-of-the-art-techniques. Specific surface area was measured by nitrogen adsor...

Low-level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans.

Abstract: The effects of low-level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known; however, much less is known about the inflammatory and immunomodulatory effects of low-level ozone in the airways. Techniques such as induced sputum and flow cytometry make it possible to examine airways inflammatory responses and changes in immune cell surface phenotypes following low-level ozone exposure. The purpose of this study was to determine if exposure to 0.08 parts per million ozone for 6.6 h induces inflammation and modifies immune cell surface phenotypes in the airways of healthy adult subjects. Fifteen normal volunteers underwent an established 0.08 part per million ozone exposure protocol to characterize the effect of ozone on airways inflammation and immune cell surface phenotypes. Induced sputum and flow cytometry were used to assess these endpoints 24 h before and 18 h after exposure. The results showed that exposure to 0.08 ppm ozone for 6.6 h induced increased airway neutrophils, monocytes, and dendritic cells and modified the expression of CD14, HLA-DR, CD80, and CD86 on monocytes 18 h following exposure. Exposure to 0.08 parts per million ozone is associated with increased airways inflammation and promotion of antigen-presenting cell phenotypes 18 hours following exposure. These findings need to be replicated in a similar experiment that includes a control air exposure.

N-acetylcysteine attenuates phosgene-induced acute lung injury via up-regulation of Nrf2 expression

Abstract: Previous studies indicated that oxidative stress was involved in phosgene-induced acute lung injury (ALI) and many antioxidants had been used to prevent ALI. N-acetylcysteine (NAC) had been used to protect ALI induced by various types of oxidative stress. Considering the limited information of NAC on phosgene-induced ALI, the purpose of this study was to elucidate the molecular mechanisms of phosgene-induced ALI and the protective effects of NAC. This study discovered that intraperitoneal administration of NAC significantly alleviated phosgene-induced pulmonary edema, as confirmed by decreased lung wet to dry weight ratio and oxidative stress markers. The content of l-gamma-glutamyl-l-cysteinyl-glycine (glutathione; GSH) and the ratio of the reduced and disulfide forms (GSH/GSSG), significant indicators of the antioxidative ability, were apparently inhibited by phosgene exposure. However, both indicators could be reversed by NAC administration, indicating that dysregulation of redox status of glutathione might be the cause of phosgene-induced ALI. The nuclear factor (NF)-E2-related factor 2 (Nrf2), which has been proven to up-regulate the expression of glutathione reductase (GR), was obviously decreased by phosgene exposure. However, NAC administration elevated Nrf2 expression significantly. In conclusion, these data provided the first evidences showing that it was the transcriptional factor Nrf2 that connected phosgene-induced ALI with GSH metabolism. NAC protected against oxidative stress through acting on this newly disclosed Nrf2/GR/GSH pathway, by which NAC elevated the biosynthesis of protective GSH to repair and reconstitute the defense system destroyed by phosgene.

Lung antioxidant and cytokine responses to coarse and fine particulate matter from the great California wildfires of 2008

Abstract: The authors have previously demonstrated that wildfire-derived coarse or fine particulate matter (PM) intrat racheally instilled into lungs of mice induce a strong inflammatory response. In the current study, the authors demonstrate that wildfire PM simultaneously cause major increases in oxidative stress in the mouse lungs as measured by decreased antioxidant content of the lung lavage supernatant fluid 6 and 24 h after PM administration. Concentrations of neutrophil chemokines/cytokines and of tumor necrosis factor (TNF)-α were elevated in the lung lavage fluid obtained 6 and 24 h after PM instillation, consistent with the strong neutrophilic inflammatory response observed in the lungs 24 h after PM administration, suggesting a relationship between the proinflammatory activity of the PM and the measured level of antioxidant capacity in the lung lavage fluid. Chemical analysis shows relatively low levels of polycyclic aromatic hydrocarbons compared to published results from typical urban PM. Coarse PM fraction is more active (proinflammatory activity and oxidative stress) on an equaldose basis than the fine PM despite its lower content of polycyclic aromatic hydrocarbons. There does not seem to be any correlation between the content of any specific polycyclic aromatic hydrocarbon (or of total polycyclic aromatic hydrocarbon content) in the PM fraction and its toxicity. However, the concentrations of the oxidation products of phenanthrene and anthracene, phenanthraquinone and anthraquinone, were several-fold higher in the coarse PM than the fine fraction, suggesting a significant role for atmospheric photochemistry in the formation of secondary pollutants in the wildfire PM and the possibility that such secondary pollutants could be significant sources of toxicity in the wildfire PM.

Impact of ambient air pollution on the differential white blood cell count in patients with chronic pulmonary disease

Abstract: Epidemiologic studies report associations between particulate air pollution and increased mortality from pulmonary diseases. This study was performed to examine whether the exposure to ambient gaseous and particulate air pollution leads to an alteration of the differential white blood cell count in patients with chronic pulmonary diseases like chronic bronchitis, chronic obstructive pulmonary disease, and asthma. A prospective panel study was conducted in Erfurt, Eastern Germany, with 12 repeated differential white blood cell counts in 38 males with chronic pulmonary diseases. Hourly particulate and gaseous air pollutants and meteorological data were acquired. Mixed models with a random intercept adjusting for trend, meteorology, weekday, and other risk variables were used. In this explorative analysis, we found an immediate decrease of polymorphonuclear leukocytes in response to an increase of most gaseous and particulate pollutants. Lymphocytes increased within 24 h in association with all gaseous pollutants but showed only minor effects in regard to particulate air pollution. Monocytes showed an increase associated with ultrafine particles, and nitrogen monoxide. The effect had two peaks in time, one 0-23 h before blood withdrawal and a second one with a time lag of 48-71 h. The increase of particulate and gaseous air pollution was associated with multiple changes in the differential white blood cell count in patients with chronic pulmonary diseases.

Comparative airway inflammatory response of normal volunteers to ozone and lipopolysaccharide challenge.

Abstract: Ozone and lipopolysaccharide (LPS) are environmental pollutants with adverse health effects noted in both healthy and asthmatic individuals. The authors and others have shown that inhalation of ozone and LPS both induce airway neutrophilia. Based on these similarities, the authors tested the hypothesis that common biological factors determine response to these two different agents. Fifteen healthy, nonasthmatic volunteers underwent a 0.4 part per million ozone exposure for 2 h while performing intermittent moderate exercise. These same subjects underwent an inhaled LPS challenge with 20,000 LPS units of Clinical Center Reference LPS, with a minimum of 1 month separating these two challenge sessions. Induced sputum was obtained 24 h before and 4-6 h after each exposure session. Sputum was assessed for total and differential cell counts and expression of cell surface proteins as measured by flow cytometry. Sputum supernatants were assayed for cytokine concentration. Both ozone and LPS challenge augmented sputum neutrophils and subjects' responses were significantly correlated (R = .73) with each other. Ozone had greater overall influence on cell surface proteins by modifying both monocytes (CD14, human leukocyte antigen [HLA]-DR, CD11b) and macrophages (CD11b, HLA-DR) versus LPS where CD14 and HLA-DR were modified only on monocytes. However, LPS significantly increased interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, with no significant increases seen after ozone challenge. Ozone and LPS exposure in healthy volunteers induce similar neutrophil responses in the airways; however, downstream activation of innate immune responses differ, suggesting that oxidant versus bacterial air pollutants may be mediated by different mechanisms.

Association of size-resolved number concentrations of particulate matter with cardiovascular and respiratory hospital admissions and mortality in Prague, Czech Republic

Abstract: We analyzed the association of particle number and PM(2.5) concentrations with mortality and cardiorespiratory hospital admissions in Prague. Number concentrations of submicron particles in the range of 15-487 nm were measured continuously at a central site in 2006. The particle number concentrations were integrated into four groups with count median diameters of 31 (NC(31)), 128 (NC(128)), and 346 nm (NC(346)). The total number concentration of submicron particles 15-487 nm (NC(tot)) was also constructed. The studied health outcomes were the daily hospital admissions due to cardiovascular and respiratory diseases and daily cardiovascular and respiratory mortality and the total mortality. The Poisson regression was used for data analysis. The strongest association was found for the accumulation mode particles (NC(346)) (RR 1.164, 95% CI: 1.052-1.287 for cardiovascular and 1.334, 95% CI: 1.126-1.579 for respiratory admissions for a 7-day moving average for 1000 particles per 1 cm(3) increase). Reasonable association between both the cardiovascular and respiratory admissions and NC(346) was also found for lag 0, lag 1, lag 2 (not for respiratory admissions), and the 4-day moving average. For NC(128) and NC(tot), the association was also significant for both cardiovascular and respiratory admissions at lag 0, lag 1, and lag 2 (not for respiratory admissions) for the 4-day and 7-day moving average. The association between the PM(2.5) and daily cardiovascular hospital admissions was significant at 2-day lag and for a 4-day average. Positive association with respiratory admissions was significant only for a 7-day average. No association was found between the studied air pollution variables and daily mortality.

Pulmonary toxicity and extrapulmonary tissue distribution of metals after repeated exposure to different welding fumes

Abstract: Welders are exposed to fumes with different metal profiles. The goals of this study were to compare lung responses in rats after treatment with chemically different welding fumes and to examine the extrapulmonary fate of metals after deposition in the lungs. Rats were treated by intratracheal instillation (0.5 mg/rat, once a week for 7 weeks) with gas metal arc-mild steel (GMAW-MS) or manual metal arc-hardsurfacing (MMAW-HS) welding fumes. Controls were treated with saline. At 1, 4, 35, and 105 days after the last treatment, lung injury and inflammation were measured, and elemental analysis of different organs was determined to assess metal clearance. The MMAW-HS fume was highly water-soluble and chemically more complex with higher levels of soluble Mn and Cr compared to the GMAW-MS fume. Treatments with the GMAW-MS fume had no effect on toxicity when compared with controls. The MMAW-HS fume induced significant lung damage early after treatment that remained elevated until 35 days. Metals associated with each fume sample was cleared at different rates from the lungs. Mn was cleared from the lungs at a faster rate and to a greater extent compared to the other metals over the 105-day recovery period. Mn and Cr in the MMAW-HS fume translocated from the respiratory tract and deposited in other organs. Importantly, increased deposition of Mn, but not other metals, was observed in discrete brain regions, including dopamine-rich areas (e.g., striatum and midbrain).

New developments in aerosol dosimetry

Abstract: Dosimetry provides information linking environmental exposures to sites of deposition, removal from these sites, and translocation of deposited materials. Dosimetry also aids in extrapolating laboratory animal and in vitro data to humans. Recent progress has shed light on: properties of particles in relation to their fates in the body; influence of age, gender, body size, and lung diseases on inhaled particle doses; particle movement to the brain via the olfactory nerves; and particle deposition hot spots in the respiratory tract. Ultrafine size has emerged as an important dosimetric characteristic. Particle count, composition, and surface properties are recognized as potentially important toxicology-related considerations. Differences in body size influence airway sizes, inhaled particle deposition, specific ventilation, and specific doses (e.g. per unit body mass). Related to body size, age, gender, species, and strain are also dosimetric considerations. Diseases, such as chronic obstructive pulmonary disease (COPD) and bronchitis, produce uneven doses within the respiratory tract. Traditional concepts of the translocation and clearance of deposited particles have been challenged. Ultrafine particles can translocate to the brain via olfactory nerves, and from the lung to other organs. The clearance rates of particles from tracheobronchial airways are slowed by respiratory tract infections, but newer evidence implies that slow particle clearance from this region also exists in healthy lungs. Finally, hot spots of particle deposition are seen in hollow models, lung tissue, and dosimetric simulations. Local doses to groups of epithelial cells can be much greater than those to surrounding cells. The new insights challenge dosimetry scientists.

Associations between asthma emergency visits and particulate matter sources, including diesel emissions from stationary generators in Tacoma, Washington

Abstract: The objective of this research was to evaluate the effect of particulate matter air pollution, including emissions from diesel generators, on visits to emergency departments for asthma. Daily asthma case data from participating hospitals in the greater Tacoma, Washington area were obtained. Daily asthma emergency room visit data were available from six Tacoma hospitals from January 3, 1998 to May 30, 2002. Only emergency visits where the primary discharge diagnosis was asthma were included in the analysis. Air pollution, daily temperature and relative humidity data were obtained from the Puget Sound Clean Air Agency. An association between daily PM2.5 and emergency department (ED) visits for asthma at lag days 2 and 3 was observed. The relative risk for lag day 2 was 1.04 (95% confidence interval[CI]: 1.01, 1.07) and for lag day 3 was 1.03 (1.0, 1.06). A significant association between ED visits for asthma and increased use of diesel generators was not detected. The use of low-sulfur diesel oil may have mitigated potential adverse health effects. These data indicate that air pollution in a medium-sized coastal city may be sufficient to have a public health impact on asthma.

Cigarette smoke-induced effects on bone marrow B-cell subsets and CD4+:CD8+ T-cell ratios are reversed by smoking cessation: influence of bone mass on immune cell response to and recovery from smoke exposure.

Abstract: Cigarette smoking adversely affects the immune system, and is a risk factor for developing osteoporosis. How smoking contributes to osteoporosis is unclear, but since lymphocytes help maintain bone homeostasis and lymphocyte depletion results in bone loss, one potential mechanism for how smoke exposure promotes osteoporosis is by reducing bone marrow lymphocytes. Since the risk for developing osteoporosis is reportedly greater in smokers with polymorphisms in LRP5, a gene involved in canonical Wnt signaling that regulates bone metabolism, smoking-induced effects on lymphocytes may be influenced by Lrp5 functionality. To test these possibilities, we examined how the duration and cessation of cigarette smoke exposure affects lymphocyte distribution and function in normal mice and mice predisposed to low or high bone mass due to disruption or mutation of Lrp5. We find that, independent of genotype, mice exposed to cigarette smoke for 3-12 weeks showed a significant reduction in bone marrow B220(+)CD43(-) B cells and splenic transitional T1 B cells, and exhibited a splenic CD4(+):CD8(+) T-cell ratio that was skewed toward CD8(+) T cells. Smoke exposure had little or no effect on other lymphocyte subsets or on lymphocyte function ex vivo. Interestingly, these differences were no longer apparent after 6 weeks without smoke exposure, except in mice with high bone mass where bone marrow B220(+)CD43(-) B cells failed to fully recover. These data provide the first evidence that smoke exposure reduces bone marrow B cells, providing a plausible mechanism for how smoking contributes to osteoporosis.

Nanoparticles-containing spray can aerosol: characterization, exposure assessment, and generator design

Abstract: This is the first report demonstrating that a commercially available household consumer product produces nanoparticles in a respirable range. This report describes a method developed to characterize nanoparticles that were produced under typical exposure conditions when using a consumer spray product. A well-controlled indoor environment was simulated for conducting spray applications approximating a human exposure scenario. Results indicated that, while aerosol droplets were large with a count median diameter of 22 µm during spraying, the final aerosol contained primarily solid TiO(2) particles with a diameter of 75 nm. This size reduction was due to the surface deposition of the droplets and the rapid evaporation of the aerosol propellant. In the breathing zone, the aerosol, containing primarily individual particles (>90%), had a mass concentration of 3.4 mg/m(3), or 1.6 × 10(5) particles/cm(3), with a nanoparticle fraction limited to 170 µg/m(3), or 1.2 × 10(5) particles/cm(3). The results were used to estimate the pulmonary dose in an average human (0.075 µg TiO(2) per m(2) alveolar epithelium per minute) and rat (0.03 µg TiO(2)) and, consequently, this information was used to design an inhalation exposure system. The system consisted of a computer-controlled solenoid ''finger'' for generating constant concentrations of spray can aerosols inside a chamber. Test results demonstrated great similarity between the solenoid ''finger''-dispersed aerosol compared to human-generated aerosol. Future investigations will include an inhalation study to obtain information on dose-response relationships in rats and to use it to establish a No Effect Exposure Level for setting guidelines for this consumer product.

Exposure of mice to concentrated ambient particulate matter results in platelet and systemic cytokine activation

Abstract: Increasingly, evidence suggests a role for a systemic procoagulant state in the pathogenesis of cardiac dysfunction subsequent to inhalation of airborne particulate matter. The authors evaluated blood cell parameters and markers of platelet activation in mice exposed to concentrated ambient particulate matter (CAPs) from the San Joaquin Valley of California, a region with severe particulate matter (PM) pollution episodes. The authors exposed mice to an average of 88.5 microg/m(3) of CAPs in a size range less than 2.5 microm for 6 h/day for 5 days per week for 2 weeks. Platelets were analyzed by flow cytometry for relative size, shape, aggregation, fibrinogen binding, P-selectin, and lysosomal-associated membrane protein-1 (LAMP-1) expression. Serum cytokines were analyzed by bead-based immunologic assays. CAPs-exposed mice had elevations in macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNFalpha), macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor (PDGF)-bb, and RANTES (regulated upon activation, normally T-expressed, and presumably secreted). Platelets were the only peripheral blood cells that were significantly elevated in number in CAPs-exposed mice. Flow cytometric analysis of unstimulated platelets from CAPs-exposed mice indicated size and shape changes, and platelets from CAPs-exposed animals had a 54% increase in fibrinogen binding indicative of platelet priming. Stimulation of platelets by thrombin resulted in up-regulation of LAMP-1 expression in CAPs-exposed animals and an increased microparticle population relative to control animals. These findings demonstrate a systemic proinflammatory and procoagulant response to inhalation of environmentally derived fine and ultrafine PM and suggests a role for platelet activation in the cardiovascular and respiratory effects of particulate air pollution.

Exposure to inhaled nickel nanoparticles causes a reduction in number and function of bone marrow endothelial progenitor cells.

Abstract: Introduction: Particulate matter (PM), specifically nickel (Ni) found on or in PM, has been associated with an increased risk of mortality in human population studies and significant increases in vascular inflammation, gen- eration of reactive oxygen species, altered vasomotor tone, and potentiated atherosclerosis in murine exposures. Recently, murine inhalation of Ni nanoparticles have been shown to cause pulmonary inflammation that affects cardiovascular tissue and potentiates atherosclerosis. These adverse cardiovascular outcomes may be due to the effects of Ni on endothelial progenitor cells (EPCs), endogenous semi-pluripotent stem cells that aid in endothelial repair. Thus, we hypothesize that Ni nanoparticle exposures decrease cell count and cause impairments in function that may ultimately have significant effects on various cardiovascular diseases, such as, atherosclerosis. Methods: Experiments involving inhaled Ni nanoparticle exposures (2 days/5 h/day at ∼1200 µg/m 3 , 3 days/5 h/ day at ∼700 µg/m 3 , and 5 days/5 h/day at ∼100 µg/m 3 ), were performed in order to quantify bone marrow resident EPCs using flow cytometry in C57BL/6 mice. Plasma levels of human stromal cell-derived factor 1α (SDF-1α) and vascular endothelial growth factor (VEGF) were assessed by enzyme-linked immunosorbent assay and in vitro functional assessments of cultured EPCs were conducted. Results and conclusions: Significant EPC count differences between exposure and control groups for Ni nanopar - ticle exposures were observed. Differences in EPC tube formation and chemotaxis were also observed for the Ni nanoparticle exposed group. Plasma VEGF and SDF-1α differences were not statistically significant. In conclusion, this study shows that inhalation of Ni nanoparticles results in functionally impaired EPCs and reduced number in the bone marrow, which may lead to enhanced progression of atherosclerosis.

Particulate matter inhalation exacerbates cardiopulmonary injury in a rat model of isoproterenol-induced cardiomyopathy

Abstract: Ambient particulate matter (PM) exposure is linked to cardiovascular events and death, especially among individuals with heart disease. A model of toxic cardiomyopathy was developed in Spontaneously Hypertensive Heart Failure (SHHF) rats to explore potential mechanisms. Rats were infused with isoproterenol (ISO; 2.5 mg/kg/day subcutaneous [sc]), a beta-adrenergic agonist, for 28 days and subsequently exposed to PM by inhalation. ISO induced tachycardia and hypotension throughout treatment followed by postinfusion decrements in heart rate, contractility, and blood pressures (systolic, diastolic, pulse), and fibrotic cardiomyopathy. Changes in heart rate and heart rate variability (HRV) 17 days after ISO cessation indicated parasympathetic dominance with concomitantly altered ventilation. Rats were subsequently exposed to filtered air or Harvard Particle 12 (HP12) (12 mg/m(3))--a metal-rich oil combustion-derived PM--at 18 and 19 days (4 h/day) after ISO infusion via nose-only inhalation to determine if cardio-impaired rats were more responsive to the effects of PM exposure. Inhalation of PM among ISO-pretreated rats significantly increased pulmonary lactate dehydrogenase, serum high-density lipoprotein (HDL) cholesterol, and heart-to-body mass ratio. PM exposure increased the number of ISO-pretreated rats that experienced bradyarrhythmic events, which occurred concomitantly with acute alterations of HRV. PM, however, did not significantly affect mean HRV in the ISO- or saline-pretreated groups. In summary, subchronic ISO treatment elicited some pathophysiologic and histopathological features of heart failure, including cardiomyopathy. The enhanced sensitivity to PM exposure in SHHF rats with ISO-accelerated cardiomyopathy suggests that this model may be useful for elucidating the mechanisms by which PM exposure exacerbates heart disease.

Seasonal variation in chemical composition of size-segregated urban air particles and the inflammatory activity in the mouse lung.

Abstract: We investigated the seasonal variations in the chemical composition and in vivo inflammatory activity of urban air particulate samples in four size ranges (PM10–2.5, PM2.5–1, PM1–0.2, and PM0.2). The samples were collected in Helsinki using a high-volume cascade impactor (HVCI). Healthy C57BL/6J mice were intratracheally instilled with a single dose (10 mg/kg) of the particulate samples. The lungs were lavaged and the bronchoalveolar lavage fluid (BALF) was assayed for indicators of inflammation and tissue damage: cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-6, and keratinocyte-derived chemokine [KC]) at 4 h, and total cell number and total protein concentration at 12 h. The PM10–2.5 and PM2.5–1 samples had much higher inflammatory potency than the PM1–0.2 and PM0.2 samples. The relative inflammatory activities of the autumn samples were the highest on an equal mass basis, but when estimated for the particulate mass per cubic meter of air, the springtime samples had the highest inflammatory ...