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Final Report: Ultrafine Particles: Characterization, Health Effects and Pathophysiological Mechanisms
EPA Grant Number: R827354Center: Airborne PM - Rochester PM Center
Center Director: Oberdorster, Gunter
Title: Ultrafine Particles: Characterization, Health Effects and Pathophysiological Mechanisms
Investigators: Oberdörster, Günter , Beckett, William , Cass, Glen , Cox, Christopher , Ensor, David , Finkelstein, Jacob N. , Frampton, Mark W. , Heyder, Joachim , Looney, John , Marder, Victor J. , Morrow, P. E. , O'Reilly, Michael , Peters, Annette , Phipps, Richard , Prather, Kimberly A. , Schwarz, Edward , Sharp, Zachary , Stripp, Barry , Utell, Mark J. , Wichmann, Heinz-Erich , Yu, C. P. , Zareba, Wojciech
Institution: University of Rochester , GSF- Institute for Epidemiologie , Georgia Institute of Technology , Research Triangle Institute , University of California - Los Angeles , University of California - San Diego
EPA Project Officer: Stacey Katz/Gail Robarge,
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Amount: $8,302,447
RFA: Airborne Particulate Matter (PM) Centers (1999)
Research Category: Particulate Matter
Description:
Objective:The five Research Cores of the Rochester PM Center integrated findings from ambient particle characterization (Core 1, R827354C001), epidemiological panel studies (Core 2, R827354C002), controlled clinical studies (Core 3, R827354C003), animal studies (Core 4, R827354C004) and in vitro studies (Core 5, R827354C005) to answer key questions regarding the involvement of ultrafine particles in the PM effects on respiratory and cardiovascular systems that have been observed in previous epidemiological studies. This report summarizes results of the Rochester PM Center research, demonstrating associations between specific ambient ultrafine particles and cardiovascular endpoints, effects on blood and vascular parameters following exposures to laboratory generated ultrafine carbon particles, controlled clinical studies in human subjects and in rodents, and cellular studies.
Summary/Accomplishments (Outputs/Outcomes):Results indicate that underlying mechanisms include direct (translocation of inhaled UFP from the portal-of-entry to extrapulmonary organs) as well as indirect mechanisms (systemic acute phase response). Results from rodent studies also demonstrate that the central nervous system appears to be yet another target organ for adverse effects of inhaled UFP. Investigation of factors associated with increased susceptibility to PM, such as asthma, chronic obstructive pulmonary disease (COPD), hypertension, inflammation, and advanced age was a major part of the Rochester PM Center studies, as described in the reports of the individual Research Cores.
Characterization of the Chemical Composition of Atmospheric Ultrafine Particles (RD827354C001)
Investigators: Philip K. Hopke, Kimberly A. Prather, Glen Cass, Ann Dillner
Summary of Findings: In the early stage of this project, the state of knowledge of the composition of ultrafine particles was summarized by Cass, et al. (2000). The Cass/Dillner group collected ultrafine particle samples in field experiments in a south central U.S. city (Houston, TX) and in a west coast city (Riverside, CA). A cluster analysis was applied by Dillner, et al., (2005) using data from two sites in Houston, TX; one site surrounded by refineries, chemical plants, and vehicular and commercial shipping traffic, and the other site, 25 miles inland surrounded by residences, light industrial facilities, and vehicular traffic. Twenty-four hour size-segregated (0.056 μm < Dp (particle diameter) <1.8 μm) particulate matter samples were collected during five days in August 2000. Inductively coupled plasma mass spectrometry (ICPMS) was used to quantify 32 elements with concentrations as low as a few picograms per cubic meter. Concentrations of particulate matter mass, sulfate and organic carbon at the two sites were often not significantly different from each other and had smooth unimodal size distributions indicating the regional nature of these species. Element concentrations varied widely across events and sites and often showed sharp peaks at particle diameters between 0.1 and 0.3 μm and in the ultrafine mode (Dp <0.1 μm) that suggested the sources of these elements were local, high temperature processes. Elements were clustered to provide normalized size distributions of all elements and to yield groups of elements with similar size distributions that were attributed to sources such as automobile catalysts, fluid catalytic cracking unit catalysts, fuel oil burning, a coal-fired power plant, and high-temperature metal working. The clustered elements were generally attributed to different sources at the two sites during each sampling day indicating the diversity of local sources that impact heavy metals concentrations in the areas around the sampling sites.
Su, et al., (2004) described the development of an improved aerosol time of flight mass spectrometry (ATOFMS) instrument to measure the chemical composition of single atmospheric particles smaller than 100 nm in particle diameter. An ultrafine particle aerosol time of flight mass spectrometry instrument has been constructed incorporating an aerodynamic lens system that allows transmission of ultrafine particles into the instrument. An effective method for detecting ultrafine particles in the systems has been developed and used in a number of ambient aerosol characterization studies including studies supported by the Center and many others. Thus, the development effort supported under this Core has lead to a significant advance in ultrafine particle characterization that has broadened our understanding of their chemical composition.
To further support the field studies, Spencer and Prather (2006) used laboratory generated ultrafine particles to demonstrate the ability to quantify the amount of organic carbon (OC) on elemental carbon (EC) particles. They coated generated EC particles and developed a calibration curve that permitted the quantification of the amount of OC on EC particles. This resulting calibration curve was used to calculate the OC/EC mass fraction for particles in lab studies; field studies in Boston, San Diego, and Atlanta; and in two source studies (gasoline and diesel vehicles). In addition, this calibration curve was used to show that 30% of the additional OC coating observed in particles produced by an ultrafine concentrator were being added to ultrafine particles in the concentrator (Su, et al., 2006). This change was attributed to additional gas-particle partitioning in the humidified growth region.
A study was conducted in Riverside, CA during the summer and fall of 2005. This was a large field study focused on PM2.5 organic aerosols. In addition to standard gas, aerosol, and PM measurements, as part of this project, ultrafine particles were measured using a UF-ATOFMS for 3 weeks during both of these studies. In addition to standard ambient sampling and characterization, ambient particles were size selected using a Scanning Mobility Particle Sizer (SMPS). The aerodynamic sizes of these particles were measured in the ATOFMS. These two sizes could be used to determine the density and shape of ambient EC particles. It was determined that most of the particles in the summer had different densities on different days and times of the day. These densities were strongly dependent on the atmospheric water content. The higher the water content, the lower the particle density. This result suggested the Riverside summer aerosol was highly processed, allowing significant uptake of water (Spencer and Prather, 2007). Spencer, et al. (2006) reported the development of a procedure to make diesel lubricating oil particles and showed how similar their ATOFMS spectra were to ambient particles from diesel vehicles.
Beginning at the end of November 2001, the number concentrations of ultrafine particles have been measured at the NYS Department of Environmental Conservation (DEC) monitoring site on the central fire station in downtown Rochester, NY. Particle size distributions are being measured using an SMPS comprised of a differential mobility analyzer (DMA) and a condensation particle counter (CPC). In the diameter range of 10 to 500 nm, ambient particles are classified by a DMA (TSI 3071) and counted with a CPC (TSI 3010) every five minutes. This work was originally supported by the New York State Energy Research and Development Authority, but at the end of that support, the work was continued with Center support. We have 1.5 years of data providing information on the number distributions of particles between 10 and 500 nm. In addition, the DEC site monitors SO2, CO, PM2.5, and meteorological variables. The results of this monitoring have been reported by Jeong, et al. (2004a; 2006). More than 70% of measured total number concentration was associated with ultrafine particles (UFP, 0.011-0.050 μm). Morning nucleation events typically peaking UFP number concentrations at around 8:00 were apparent in winter months with CO increases. These particles appear to be formed following direct emissions from motor vehicles during morning rush hour. There were also often observed increases in this smaller sized range particles in the late afternoon during the afternoon rush hour particularly in winter when the mixing heights remain lower than in summer. Strong afternoon nucleation events (> 30,000 cm-3) peaking at around 13:00 were more likely to occur in spring and summer months. During the prominent nucleation events, peaks of SO2 were strongly associated with the number concentrations of UFP, whereas there were no significant correlations between these events and PM2.5 and CO. Increased SO2 concentrations were observed when the wind direction was northwesterly where three SO2 sources were located. It is hypothesized that UFP formed during the events are sulfuric acid and water from the oxidation of SO2. There was also a more limited number of nucleation events followed by particle growth up to approximately 0.1 μm over periods of up to 18 hours. The nucleation and growth events tended to be common in spring months especially in April.
As part of the Core’s effort to characterize the nature of PM2.5, measurements of particle composition were made in Rochester, Philadelphia, and New York City that have been reported by Jeong, et al. (2004b,c) and Venkatachari, et al. (2006a,b). A major contribution of this Core has been the initiation of study of particle-bound reactive oxygen species (ROS). There is currently very limited information available on particle-bound ROS and thus, measurements in Rubidoux, CA (Venkatachari, et al., 2005) and New York City (Venkatachari, et al., 2007) suggest that there can be significant concentrations of oxidant on fine particle surfaces. Studies of the effects of the particle-bound ROS are planned for the future at the University of Rochester.
Inflammatory Responses and Cardiovascular Risk Factors in Susceptible Populations (RD827354C002)
Investigators: H. Erich Wichmann, Annette Peters
Objective(s) of the Research Project: The aim of the Rochester PM Center epidemiological studies was to assess short-term health effects of fine and ultrafine particles (UFP) on vascular and cardiac function. It was hypothesized that patients with coronary artery disease (CAD) as well as chronic obstructive pulmonary disease (COPD) would be susceptible to ambient fine and ultrafine particles.
Summary of Findings: Two epidemiological studies were conducted in 61 patients with CAD and in 39 patients with COPD in Erfurt, Germany as part of the Rochester Particle Center. Twelve clinical visits including ECG measurements and blood withdrawals were scheduled for each panel. Intermediate phenotypes such as measurements of clinical parameters like blood inflammation, coagulability, and heart rate variability (HRV) were analyzed based on linear and logistic regression models considering repeated measurements for the subjects adjusting for time trend, season, and meteorological parameters. The lag structure of the association between the air pollutants and the outcomes was analyzed to evaluate the time lags between exposure and response. Additional information on source contributions was obtained to help elucidate the role of different particle properties responsible for cardiovascular disease exacerbation via different mechanisms.
Vascular Function. For CAD patients C-reactive protein (CRP), prothrombin fragments 1+2, soluble CD40 Ligand, and von Willebrand factor (vWF) showed positive associations with UFP, while Factor VII (FVII) decreased significantly. Intercellular adhesion molecule-1 (ICAM-1), serum amyloid A (SAA), and CRP increased in association with increased PM10 levels, while Factor VII, again, was negatively associated. No associations were found for fibrinogen in this study setting. Platelets and leukocytes were negatively associated with UFP (Ruckerl, et al., 2006; Ruckerl, et al., 2007). In contrast to our initial hypothesis, some markers of the clotting cascade decreased in association with air pollution. Apart from the results of FVII and fibrinogen, the significant increase in prothrombin fragments 1+2 indicates an activation of the early steps of blood coagulation. However, this activation was not associated with increased formation of fibrin, as would be detected by elevated D-dimer levels, which we did not observe.
For the COPD panel, results do not support the concept of an overall increased systemic inflammatory response as no changes in CRP, SAA, and ICAM-1 were seen. However, an increase of fibrinogen and the endothelial adhesion molecule E-selectin was observed. In the differential hemograms preliminary results suggest no effect of particulate matter on all leukocytes combined. However, an increase in neutrophilic bandform granulocytes was observed in association with PM10. Other leukocytic cell types were either unaffected or showed small decreases. These results may provide evidence for a stimulation of the bone marrow by particulate matter (Socher, et al., 2005).
Cardiac Function. In the CAD panel, the autonomic control of the heart was altered in association with PM2.5 and organic (OC) and elementary carbon (EC) concentrations of PM2.5 (Ibald-Mulli, et al., 2005). These findings highlight the importance of the carbonaceous component in particles. Furthermore, we were able to detect for the first time changes in the repolarization of the heart in association with PM2.5 (Henneberger, et al., 2005). Regarding arrhythmia, the number of supraventricular and ventricular runs showed strong effects correlated to UFP (Berger, et al., 2006). Thereby, we found the first evidence that particles also might increase cardiac vulnerability and might modify the cardiac substrate.
In patients suffering from COPD, low frequency (LF) and the ratio of low to high frequency (LF/HF) increased in association with an increase in PM10, OC, and EC during the 24 hours before the ECG measurement. Consistently, there was a significant decrease in heart rate. The analysis also showed a significant delayed increase in root mean square successive difference (RMSSD) in response to an increase in all particle concentrations. These results are contradictory to prior findings in CAD patients and our initial hypothesis. Taking both findings into account, it is conceivable that the air pollution reaction depends on the disease status of the patient and that elevated concentrations of ambient particles are associated with a disturbance of the autonomic heart control manifested by an increased HRV in patients with COPD (Bero Bedada, et al., 2005).
Interdependence of Vascular and Cardiac Function. Between ECG recordings and blood markers, repolarization parameters and acute phase response proteins showed moderate but significant associations. HRV parameters and endothelial cell activation markers were significantly but only weakly associated. The results indicate the interplay between the autonomic nervous system and myocardial substrate as well as interactions of the acute phase response with endothelial cell activation and coagulation state. While ECG parameters and blood markers seem to vary independently, there was the suggestion for a link between systemic inflammation and repolarization as well as endothelial dysfunction and HRV (Yue, et al., 2006).
Effects of Traffic on Myocardial Infarction. A complete series of 691 myocardial infarction (MI) survivors registered between 1999 and mid 2001 was interviewed to collect information on activities during the four days before MI onset. Time spent in traffic was associated with MI onset 1 hour later (OR= 2.9 (95% CI: 2.2 to 3.8). These associations were seen for times spent in cars, in public transport, and on bicycles (Peters, et al., 2004). Ambient PM2.5 concentrations at the urban background site also suggested an association with MI onset 2 days later (Peters, et al., 2005).
Source Apportionment. Sources of fine and ultrafine particles were analyzed by positive matrix factorization. Analyses were conducted in collaboration with Core 1. Five factors representing particles from airborne soil, UFP from local traffic, secondary aerosols from local fuel combustion, particles from remote traffic, and secondary aerosols from multiple sources were identified (Yue, et al., 2007a). The associations of the contributing particle fractions and gaseous pollutants with the ECG and blood biomarkers were compared to the health effects of the different sources. The results suggest that traffic-related and combustion-generated particles show stronger adverse health impact with regard to cardiac function measured by QT interval and T wave amplitude, and that different source particles may have the potential to cause an acute phase response indicated by CRP and vWF in these patients (Yue, et al., 2007b).
Clinical Studies of Ultrafine Particle Exposure In Susceptible Human Subjects (RD827354C003)
Investigators: Mark Frampton; Mark J. Utell
Objective(s) of the Research Project: Our overall objectives were to utilize controlled human exposures to examine, in healthy and potentially susceptible subjects, the role of ultrafine particles (UFP) in inducing respiratory and cardiovascular health effects. We developed a facility for experimental exposure of humans to ultrafine particles, which permits the quantitative determination of the exposure levels, respiratory intakes, and depositions of the aerosol. Our hypothesis was that inhalation of UFP alters pulmonary vascular function, circulating leukocyte activation, coagulation, and cardiac repolarization. We speculated that these alterations reflect mechanisms involved in the observed increase in cardiovascular morbidity and mortality associated with particulate air pollution.
Summary of Findings: For our initial studies, exposures were conducted in healthy subjects at rest with a relatively low concentration of elemental carbon UFP (~10 μg/m3, ~2 x 106 particles/cm3, count median diameter [CMD] 26.4 nm, GSD 2.3). The overall deposition fraction (DF) was 0.66 ± 0.12 (mean ± SD) by number, and 0.58 ± 0.14 by mass. We found no differences in respiratory symptoms, blood pressure, pulse-oximetry, spirometry, exhaled NO, blood markers of coagulation and endothelial activation, leukocyte activation, or sputum cell differential counts. There was no convincing evidence for significant effects on heart rate variability, repolarization, or arrhythmias. We concluded that exposure to 10 μg/m3 elemental carbon UFP for 2 hours at rest does not cause significant respiratory or cardiac effects in healthy nonsmokers.
We then initiated studies to examine concentration-response effects, and to incorporate exercise. Subjects received each of three exposures (air, 10, and 25 μg/m3 UFP). Analyses indicated that exercise further increased the relatively high resting deposition of UFP (number deposition fraction at rest: 0.63 ± 0.04; exercise: 0.76 ± 0.06; means ± SD). There was evidence for a concentration-related effect of UFP exposure on the percentage of blood monocytes. In addition, monocyte expression of CD54 (ICAM-1) decreased after exposure in a concentration-response pattern (p=0.001), with the greatest effect occurring at 0 and 3.5 hours after exposure, and the differences resolved at 21 hours after exposure. Overall, the findings provided evidence for effects of UFP exposure, with exercise, on blood monocyte number and leukocyte expression of surface markers. In general, surface marker expression decreased in association with UFP exposure, consistent with retention of higher expressing cells within the capillary bed. ECG recording analyses showed that the response of the parasympathetic system (measured by normalized units of high-frequency [HF] components) was blunted during recovery from exercise immediately after exposure to UFP in comparison to air exposure. These findings suggested that inhalation of UFP at both concentrations altered myocardial repolarization in healthy subjects.
We next initiated a study to confirm and extend these observations in a larger group of healthy men and women, using a higher, yet still environmentally relevant, concentration of UFP. Our hypothesis was that inhalation of UFP alters pulmonary vascular function and circulating leukocyte activation. In order to test our hypothesis, and to determine concentration-response relationships, we initiated exposures of healthy subjects to a higher concentration, 50 μg/m3 UFP, using the same protocol. In these studies, we also measured the pulmonary diffusing capacity for carbon monoxide (DLCO), which is affected by changes in pulmonary capillary blood volume in 16 subjects. We observed a significant reduction in the DLCO, 21 hours after exposure to 50 μg/m3 UFP when compared with air. There was also a significant reduction in blood NO products throughout the post-exposure period. The reduction in DLCO in these studies may be caused by mild pulmonary vasoconstriction, as a consequence of reduced NO availability, leading to a reduction in the pulmonary capillary blood volume.
In addition, we measured flow-mediated vascular dilatation of the forearm (FMD), before and at intervals up to 48 hours after exposure, using forearm plethysmography before and after ischemia, which measures the response in resistance vessels to the post ischemic increase in flow. FMD is mediated in part by endothelial NO action on vascular smooth muscle, and we hypothesized that UFP-induced reductions in vascular responsiveness would be accompanied by reduction in plasma NO reaction products. We therefore measured changes in the products of NO metabolism, nitrite, and nitrate. We did not see any significant effect of UFP exposure on total forearm blood flow, either before or after ischemia. However, UFP exposure appeared to cause a blunting of the increase in peak flow in response to exercise. Peak flow (0 minutes) after air exposure increased, representing increased flow-mediated dilatation in response to exercise, which is an expected change. However, peak flow did not increase with UFP exposure. These findings suggest that exposure to UFP reduced or delayed the exercise-induced increase in flow-mediated dilatation. Thus, inhalation of ultrafine carbon particles may have subtle vasoconstrictive effects in both the pulmonary and systemic vasculature.
Subjects with asthma may represent a group with increased susceptibility to the ultrafine particles. In asthmatics, we found that total respiratory deposition was significantly increased compared to healthy subjects at rest. Blood studies revealed a particle-related decrease in blood eosinophils, basophils, and CD4+ T-lymphocytes. Blood monocytes showed a significant reduction in CD11b expression after exposure. Exposure to even low mass concentrations of ultrafine particles altered circulating leukocyte subsets. These data are most consistent with an alteration in leukocyte retention in the pulmonary circulation.
Patients with diabetes have been identified in recent epidemiological studies as being particularly susceptible to the effects of PM exposure. We hypothesize that patients with diabetes, who are known to have underlying endothelial dysfunction, will show enhanced vascular responses to particle inhalation. Preliminary analysis showed significant reductions in forearm flow-mediated vascular dilatation in comparison with healthy subjects.
In summary, we found high deposition of UFP with vasoconstrictive effects in both the pulmonary and systemic circulations. Future studies will examine these effects in subjects with diabetes using ambient particles. Our data demonstrate that UFP contribute to PM-induced adverse cardiovascular responses.
Animal Models: Dosimetry, and Pulmonary and Cardiovascular Events (RD827354C004)
Investigators: Gunter Oberdorster, Alison Elder
Summary of Findings: Our rodent studies focused initially on the effects of inhaled laboratory generated ultrafine carbon particles—as surrogates for ambient UFP—with a count median diameter of 30-35 nm and at concentrations of 100-150 μg/m3. We have shown in these studies in rodents that inhaled UF carbon particles as well as UF/fine real-world particles can induce significant respiratory tract inflammatory mediator release and systemic effects. The laboratory-generated model UFP, i.e., elemental carbon, were either delivered alone or in combination with ozone. Age and respiratory tract health (i.e., respiratory tract priming with endotoxin or influenza) were key determinants of pulmonary and cardiovascular outcomes.
Inhaled carbon UFP were independently and significantly associated with changes in respiratory and cardiovascular endpoints related to inflammation and inflammatory cell activation (Elder, et al., 2002, 2004b). Consistent interactions between UFP, a priming agent (lipopolysaccharide [LPS]; influenza virus), ozone, and age were also noted. The effect of age was manifested in the observation that cells from old animals released more reactive oxygen species (ROS) upon stimulation than did cells from young animals, suggesting an imbalance between oxidant and antioxidant systems. Furthermore, dramatic gene expression changes related to oxidative stress were found in lung and heart tissue. These changes again reflected an oxidant/antioxidant imbalance in old animals, as pro-oxidant mediators (e.g., MIP-1α) were more greatly induced and antioxidant mediators (e.g., IL-10) were less responsive in lung and heart tissue from old as compared to young animals.
In another series of studies, rats were exposed on highways to freshly generated real-world diesel exhaust emission aerosols while riding in a mobile laboratory (MEL) designed at the University of Minnesota by Kittelson and colleagues (2004). Geriatric rats were exposed directly on highways to either the aerosol + gas phase, gas phase only, or clean (filtered, gas-denuded) air in MEL. The particle number concentration and aerosol size (1.95-5.62 x 105 particles/cm3; CMD=15-20 nm) indicated the predominance of freshly generated UFP (Elder, et al., 2004a). Main effects of on-road particles included increases in plasma endothelin-2, plasma fibrinogen, bronchoalveolar lavage (BAL) cell ROS release, and surface expression of ICAM-1 on BAL alveolar macrophages (AMs); blood neutrophil (PMN) ICAM-1 expression was marginally decreased, in agreement with data from Frampton and colleagues (2001) of our Clinical Core (see the report for R827354C003), who demonstrated a decrease in blood PMN ICAM-1 from human asthmatics exposed to the same laboratory-generated carbon UFP during intermittent exercise. Microarray analyses showed that the expression of two genes, in particular (TNF-α and TNF-α receptor I), was found to be increased consistently by ~3-fold in lung, heart, and olfactory bulb. Taken as a whole, these results suggest that acute phase reactants and peripheral inflammatory cell activation are affected by freshly generated highway aerosol exposure (Elder, et al., 2004a; Kittelson, et al., 2004).
Furthermore, the results from heart rate variability (HRV) analyses developed for use in rats by our Cardiology Core (Couderc, et al., 2002) showed that heart rate and vagosympathetic balance were decreased and high-frequency power (indicator of parasympathetic activity) was increased in spontaneously hypertensive (SH) rats in response to on-road aerosols. The results suggest that activation of the autonomic nervous system (ANS) occurs either directly or indirectly by inhaled UF on-road aerosols and that the observed effects are mediated at the level of the lung as opposed to a systemically-derived response (Elder, et al., 2007). These findings seem to be consistent with results from our Epidemiology Core (Peters, et al., 2004), which show that exposure to traffic-related PM while riding in cars, public transportation, or on bicycles is consistently and significantly associated with increased risk for myocardial infarction in susceptible populations.
One limitation of our first on-road studies was the variability in the particle number concentration due to day-to-day variations in traffic density. In order to achieve more continuous and consistent exposure levels, we performed another series of studies with MEL, this time orienting two telescoping inlet pipes on the back of the trailer so that they sampled the engine exhaust plume from MEL itself as well as those particles and gases from surrounding vehicles. The particle sizes and number concentrations again indicated the predominance of UFP, this time at twice the concentration. Results confirmed effects on cardiovascular parameters, some of which persisted up to 3 days post-exposure.
In order to study thrombus formation in vivo, we have modified an invasive thrombus model and adapted it for non-invasive use in rat ear veins (Silva, et al., 2004). We confirmed with this model that the presence of positively-charged UFP in the blood circulation significantly increased thrombus formation. We hypothesized that UFP depositing in the alveoli are taken up by blood platelets after translocation from the alveoli, which results in their activation and thrombus formation with activated (primed) endothelial cells. Our follow-up studies with the ear vein model showed that elemental carbon UFP (~30 nm, CMD) significantly increased thrombus formation when administered intratracheally (~0.2 mg/rat alveolar deposition), confirming their thrombogenic potential. Remarkably, subsequent inhalation studies with elemental carbon UFP (30 minutes; 70 mg/m3; est. alveolar deposition of only 85 ng) showed the same highly significant effect on in vivo thrombus formation.
We also found the inhaled carbon UFP translocate to the liver and CNS, supporting our hypothesis that inhaled UFP can have effects outside of the lung, the apparent sensitive targets being the cardiovascular system and potentially the CNS (Oberdorster, et al., 2002, 2004). Additional studies using poorly-soluble Mn oxide UFP (CMD=30 nm) confirmed the olfactory translocation pathway: when one naris was occluded, Mn accumulated only in the olfactory bulb of the patent naris, confirming that the inhaled Mn originated from UFP deposited on the olfactory mucosa and not from the circulation (Elder, et al., 2006). Studies with the Mn oxide particles placed in 0.9% saline showed less than 1.5% solubility over a 24-hour period. Thus, neuronal translocation of the solid UFP is the most likely mechanism for translocation from the upper respiratory tract to the central nervous system. Our studies point to the CNS as a potential target for detrimental effects of inhaled UFP. Indeed, data from the Mn oxide-exposed rats showed that TNF-α mRNA and protein levels were significantly increased in the olfactory bulb, as were MIP-2 and NCAM mRNAs.
Ultrafine Particle Cell Interactions: Molecular Mechanisms Leading to Altered Gene Expression (RD827354C005)
Investigators: Jacob Finkelstein
Objective(s) of the Research Project: A key component of our studies was to examine particle cell interactions in individual cell populations to begin to assess the role of ultrafine particles (UFP) in altering inflammatory gene expression by an oxidant-related mechanism. In our experiments, in collaboration with Core 4 (R827354C004) we were able to define susceptible populations on the basis of age as well as prior or concurrent infection.
Summary of Findings: To test the hypothesis that increased susceptibility of aged animals is due to cell intrinsic differences in oxidant sensitivity, we evaluated the effect of age on the response of cells to particles. We compared macrophage production of cytokines following lipopolysaccharide (LPS) and particles from 22-27 month old rats to cells from 10-12 week old rats. Baseline (unstimulated) production of MIP-2 (and TNF) was elevated 30-50% in these cells as well as increased response to exogenous stimulus. Increased production of prostaglandin E2 (PGE2) by alveolar macrophages from “aged” animals, an endpoint chosen to better correlate with the animal studies (Core 4) and the human clinical studies (Core 3) was observed when cultured in the presence of LPS used as a positive particle control, and LPS plus particles confirming age effects for a number of endpoints
An important development during this project was the ability to use laboratory generated ultrafine particles containing various metals. The choice of the specific metal was based on the data provided by our Chemical UFP characterization (Core 1) that iron is among the most abundant metal constituents. This material was produced by our particle generation Core. We compared macrophage production of cytokines following LPS and particles (with C/Fe) incubation with cells from 20-22 month old and 8-10 week old mice. Baseline MIP-2 and TNF was significantly elevated in cells from “old” mice. After stimulation the old mice were also found to be more responsive.
When particles and LPS were combined as a stimulus an enhanced effect is observed only in the “old” cells except at the highest dose of particles. Most significant, in the context of our investigation of age effects and the ability of particles to induce effects at low dose, was the fact that in the aged animals co-administration of particles and LPS leads to synergistic effects at the lowest dose of particles. This result is somewhat similar to results obtained in the in vivo studies in which enhanced response to combined insult was noted in aged rats.
One marker that has proven useful in assessing cellular response to PM is the production of prostaglandins (PGs). By measuring changes in PGs we could indirectly monitor activity of COX-2, the rate limiting enzyme and also determine the role of PGs in pulmonary and systemic inflammation. Stimulation of young and old cells with a combination of ultrafine C/Fe particles and LPS lead to an increase in PGE2 production. As with MIP-2 (and TNF), this was mainly observed in the cells from the old mice. This is consistent with our other age experiments and reinforces the hypothesis that age is related to increased PM susceptibility.
We also developed reagents and approaches that would allow extension of our in vitro studies to human cells while also developing a test of our oxidant stress hypothesis. We developed a human lung cell line, A549, which was stably transfected with a reporter gene that in other studies has been shown to be responsive to oxidant stress. Using this transfected A549 cell line we were able to detect changes in gene expression at particle doses below 1 μg/cm2. This clearly puts us in the realistic range of ultrafine PM mass burdens. In future studies, together with our particle generation Facility Core we will determine if this relationship will be maintained for particles of different composition or with ambient particles collected using the Harvard ultrafine particle concentrator that we have available for our use. Our initial studies comparing cytokine analysis with luciferase activity show a reasonable correlation between these two measurements.
Particle Effects on Vascular Endothelium
Recent experiments, to better bridge the experiments that are being carried out in Clinical Studies Core and Animal Exposure Core, have focused on vascular endothelial models that could be useful in assessing particle induced changes in endothelial gene expression; and that may represent aspects of endothelial dysfunction. To more accurately reflect the complex nature of endothelial interactions with particles, we have used two complementary culture models.
Many of our experiments utilize a standard monolayer culture of primary vascular endothelial cells. A second model, a bilayer epithelial/endothelial co-culture system permits study of cell-cell interactions mediated by particles.
Monolayer cultures of human umbilical vein endothelial cells (HUVEC) were established and optimized with regard to media, serum and other culture conditions. Production of IL-6 and PGE2 when endothelial cells were cultured in the presence of LPS or TNF for 24 hours was used to establish the basic parameters. Our major objective with these cultures was to establish appropriate dose and time parameters of incubation with particles so that we could begin testing with UFP of various compositions. Based on our experiments with cultured epithelial cells we began our studies using laboratory generated particles containing 25% Fe. Particles were added to the cells at concentrations ranging from 0.47 to19.0 μg/cm2 and media collected at 6 and 24 hours. Particle induced cytotoxicity was measured by LDH release. Addition of particles in the presence of a priming dose of LPS stimulated the release (production) of both IL-6 and PGE2 at both 6 and 24 hours. The PGE2 response appears to be more sensitive as it is observed at doses as low as 0.47 μg/cm2 (which converts to a total mass dose of ~1.5 μg of particle).
In this system we also assessed the response of these cells to laboratory generated carbon, similar to the material used in the human clinical studies, TiO2, and a laboratory generated Mn-oxide. In contrast to our experiments with epithelial cells, the endothelial cell cultures were moderately responsive to the carbon alone. After 24 hours of incubation, PGE2 production was increased 2-3 fold. In contrast C/Fe particles increased PGE2 by 5-6 fold. Additionally, in support of the role of oxidant stress in particle effects, pretreatment with either a soluble ( N-acetyl-cysteine) or lipophilic (BHA) antioxidant suppressed the production of PGE2 induced by PM.
Overall comparison of particle, dose, and time parameters suggest that PGE2 is the most reliable marker of endothelial activation. It was also noted that particle composition was a major response factor, with TiO2 being most active and Mn-oxide being most directly cytotoxic. We also determined if coculturing these cells with A549 pulmonary epithelial cells would alter their ability to be stimulated by LPS or by particles. Both cell types appear to be responsive to particles and LPS with apparently different concentration dependence. Using this second model we have begun to examine cytokine production in response to various stimuli, including particle and LPS. Among the cytokines we evaluated in this model were IL-6 and PGE2.
The endothelium appears to respond to lower particle mass burdens than does the epithelium. This may account for the enhanced sensitivity of the vascular endothelium in vivo. Additionally, aided by our Immunology and Vascular Core, we also measured production of prostaglandins in these culture supernatants. Since the majority of the prostaglandin was found below the membrane this would suggest it is derived from the endothelium. This is consistent with the in vivo results from Core 4 showing enhanced prostaglandin production following particle exposure in a sensitive animal model.
Our experiments have focused on a number of critical issues that relate to the overall goals of the Rochester PM Center. A key point of the studies was the emphasis on real-world particles in lieu of laboratory surrogates. The delay in the characterization of the HUCAPS concentrator in Rochester has delayed this effort somewhat. However, it has enabled us to continue mechanistic studies with defined composition particles that may ultimately be important in attributing effects seen in specific cell populations to unique sources. The one source of real world particles available for in vitro studies was the material collected as part of the MAPS, multi-Center multi-site particle collection effort begun at the end of the grant period.
Vascular endothelial cells (HUVEC) exposed to concentrated fine and ultrafine particles respond through increased production of IL-6. This cytokine was chosen as a potential sentinel as a result of experiments from the Animal and Clinical Studies Cores that suggested a possible acute phase response following particle inhalation. Interestingly, using this marker and cell type, we revealed a differential response from particles collected from certain sites. It is hypothesized that this relates to the abundance of vehicle emissions at these sites. More detailed analyses and source calculations are planned with the help of Core 1 as the compositional data are provided.
An additional important piece of data was revealed as a consequence of this study. When epithelial cells (A549 cells) were similarly exposed to these materials, no differential response based on site selection was noted. To verify this cell-specific difference and to relate this potential mechanistic difference to studies from Cores 3 and 4, we carried out a direct comparison of the response of the epithelium and vascular endothelium in a series of well characterized particles. We chose these carbon particles as they had previously been used for in vivo studies within the Center. While these studies are interesting and important, they do not necessarily address the most relevant question, that of the response of the microvascular endothelium, which is being investigated during the next project cycle.
References:
Berger A, Zareba W, Schneider A, Ruckerl R, Ibald-Mulli A, Cyrys J, Wichmann HE, Peters A. Runs of ventricular and supraventricular tachycardia triggered by air pollution in patients with coronary heart disease. Journal of Occupational and Environmental Medicine 2006;48(11):1149-1158.
Bero Bedada G, Henneberger A, Zareba W, Ruckerl R, Cyrys J, Wichmann HE, Peters A. Ambient air pollution and heart rate variability in patients with chronic obstructive pulmonary disease (COPD). Masters Thesis (not peer review published yet, 2005).
Cass GR, et al. The chemical composition of atmospheric ultrafine particles. The Philosophical Transactions of the Royal Society (Series A) 2000;358:2581-2592.
Chen LC. Real-time characterization of the composition of individual particles emitted from ultrafine particle concentrators. Aerosol Science and Technology 2006;40(No. 6):437-455.
Couderc J-P, Elder ACP, Cox C, Zareba W, Oberdorster G. Limitation of power spectrum and time-domain analysis of heart rate variability in short-term ECG recorded using telemetry in unrestrained rats. Computers in Cardiology, IEEE Computer Society Press 2002;29:589-592.
Dillner AM, Schauer JJ, Christensen WF, Cass GR. A quantitative method for clustering size distributions of elements. Atmospheric Environment 2005;39:1525–1537.
Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein JN, Oberdorster G. Systemic interactions between inhaled ultrafine particles and endotoxin. The Annals of Occupational Hygiene 2002;46(Suppl 1):231-234.
Elder ACP, Gelein R, Finkelstein J, Phipps R, Frampton M, Utell M, Kittelson DB, Watts WF, Hopke P, Jeong C-H, Liu W, Zhao W, Zhuo L, Vincent R, Kumarathasan P, Oberdorster G. On-road exposure to highway aerosols. 2. Exposures of aged, compromised rats. Inhalation Toxicology 2004a;16(Suppl. 1):41-53.
Elder ACP, Gelein R, Finkelstein J, Frampton M, Utell M, Carter J, Driscoll K, Kittelson, Watts W, Hopke P, Vincent R, Premkumari K, Oberdorster G. Effects of inhaled fine/ultrafine particles combined with other air pollutants. In: Heinrich U, ed. INIS Monographs, 9th Intl. Inhalation Symposium: Effects of Air Contaminants on the Respiratory Tract—Interpretations from Molecules to Meta Analysis, 2004b, pp. 53-68.
Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdorster G. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environmental Health Perspectives 2006;114:1172-1178 (available online: 20 April 2006 (http://dx.doi.org/), doi:10.1289/ehp.9030).
Elder A, Couderc J-P, Gelein R, Eberly S, Cox C, Xia X, Zareba W, Hopke P, Watts W, Kittelson D, Frampton M, Utell M, Oberdorster G. Effects of on-road highway aerosol exposures on autonomic responses in aged, spontaneously hypertensive rats. Inhalation Toxicology 2007;19:1-12.
Frampton MW. Systemic and cardiovascular effects of airway injury and inflammation: ultrafine particle exposure in humans. Environmental Health Perspectives 2001;109(Suppl. 4):529-532.
Henneberger A, Zareba W, Ibald-Mulli A, Ruckerl R, Cyrys J, Couderc JP, Mykins B, Woelke G, Wichmann HE, Peters A. Repolarization changes induced by air pollution in ischemic heart disease patients. Environmental Health Perspectives 2005;113(4):440-446.
Ibald-Mulli A, Zareba W, Ruckerl R, Couderc JP, Mykins B, Woelke G, Pitz M, Wichmann HE, Peters A. Heart rate variability changes induced by ambient air pollution in patients with ischemic heart disease. Ph.D. Thesis (not peer review published yet, 2005).
JeongC-H, Hopke PK, Chalupa D, Utell M. Characteristics of nucleation and growth events of ultrafine particles measured in Rochester, NY. Environmental Science & Technology 2004a;38(No.7):1933-1940.
Jeong C-H, Lee D-W, Kim E, Hopke PK. Measurement of real-time PM2.5 mass, sulfate, and carbonaceous aerosols at the multiple monitoring sites. Atmospheric Environment 2004b;38:5247-5256.
Jeong C-H, Hopke PK, Kim E, Lee D-W. The comparison between thermal-optical transmittance elemental carbon and Aethalometer black carbon measured at the multiple monitoring sites. Atmospheric Environment 2004c;38:5193-5204.
Jeong C-H, Evans GJ, Hopke PK, Chalupa D, Utell MJ. Influence of atmospheric dispersion and new particle formation events on ambient particle number concentration in Rochester, United States, and Toronto, Canada. Journal of the Air & Waste Management Association 2006;56:431-443.
Kittelson DB, Watts WF, Johnson JP, Remerowki ML, Ische EE, Oberdorster G, Gelein RM, Elder AC, Hopke PK, Kim E, Zhao W, Zhou L, Jeong C-H. On-road exposure to highway aerosols. 1. Aerosol and gas measurements. Inhalation Toxicology 2004;16(Suppl. 1):31-39.
Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, Kreyling W, Cox C. Extrapulmonary translocation of ultrafine carbon particles following inhalation exposure. Journal of Environmental Science and Health. Part A 2002;65(20):1531-1543.
Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C. Translocation of inhaled ultrafine particles to the brain. Inhalation Toxicology 2004;16(6-7):437-445.
Peters A, von Klot S, Heier M, Trentinaglia I, Hormann A, Wichmann HE, Lowel H. Exposure to traffic and the onset of myocardial infarction. New England Journal of Medicine 2004;351:1721-1730.
Peters A. Particulate matter and heart disease: evidence from epidemiological studies. Toxicology and Applied Pharmacology 2005;207(2 Suppl):477-82.
Phipps RP. Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system. Proceedings of the National Academy of Sciences of the United States of America 2000;97(13):6930-6932.
Ruckerl R, Ibald-Mulli A, Koenig W, Schneider A, Woelke G, Cyrys J, Marder V, Frampton M,Wichmann HE, Peters A. Air pollution and markers of inflammation and coagulation in patients with coronary heart disease. American Journal of Respiratory and Critical Care Medicine 2006;173(4):432-41.
Ruckerl R, Phipps RP, Schneider A, Frampton M, Cyrys J, Oberdorster G, Wichmann HE, Peters A. Ultrafine particles and platelet activation in patients with coronary heart disease–results from a prospective panel study. Particle and Fibre Toxicology 2007;4(1):1
Silva V, Corson N, Elder A, Oberdorster G. The rat ear vein model for investigating in vivo thrombogenicity of ultrafine particles (UFP). Toxicological Sciences 2005;85:983-989.
Socher M, Ruckerl R, Henneberger A, Berger A, Heinrich J, Wichmann HE, Peters A. Impact of ambient air pollution and the white blood cell count in patients with chronic obstructive pulmonary disease (COPD). Masters Thesis (not peer review published yet, 2005).
Spencer MT, Prather KA. Using ATOFMS to determine OC/EC mass fractions in particles. Aerosol Science and Technology 2006;40:585-594.
Spencer M, Prather K. Measurements of the density of atmospheric aerosols. Environmental Science & Technology 2007;41:1303-1309.
Spencer MT, Prather KA, Shields LG. Chemical analysis of used and new petroleum-based lubricants using ATOFMS. Atmospheric Environment 2006;40:5224-5235.
Su YX, Sipin MF, Furutani H, Prather KA. Development and characterization of an ATOFMS with increased detection efficiency. Analytical Chemistry 2004;76(3):712-719.
Su YX, Sipin MF, Spencer MT, Qin X, Moffet RC, Shields LG, Prather KA, Venkatachari P, Jeong CH, Kim E, Hopke PK, Gelein RM, Utell MJ, Oberdorster G, Berntsen J, Devlin RB, Yue W, Schneider A, Ruckerl R, Koenig W, Marder V, Wang S, Wichmann HE, Peters A, Zareba W. Relationship between electrocardiographic and biochemical variables in coronary artery disease. International Journal of Cardiology 2006; online.
Venkatachari P, Hopke PK, Grover BD, Eatough DJ. Measurement of particle-bound reactive oxygen species in rubidoux aerosols. Journal of Atmospheric Chemistry 2005;50:49-58.
Venkatachari P, Zhou L, Hopke PK, Schwab JJ, Demerjian KL, Weimer S, Hogrefe O, Felton D, Rattigan O. An intercomparison of measurement methods for carbonaceous aerosol in the ambient air in New York City. Aerosol Science and Technology 2006a;40:788-795.
Venkatachari P, Zhou L, Hopke PK, Felton D, Rattigan OV, Schwab JJ, Demerjian KL. Spatial and temporal variability of black carbon in New York City. Journal of Geophysical Research 2006b;111:D10S05, doi:10.1029/2005JD006314.
Venkatachari P, Hopke PK, Brune WH, Ren X, Lesher R, Mao J, Mitchell M. Characterization of wintertime reactive oxygen species concentrations in flushing, New York. Aerosol Science and Technology 2007;41:97-111.
Yue W, Stolzel M, Cyrys J, Pitz M, Heinrich J, Kreyling WG, Wichmann HE, Peters A. Source apportionment of ambient fine particle size distribution using positive matrix factorization in Erfurt, Germany. Atmospheric Chemistry and Physics. 2007a; online.
Yue W, Schneider A, Stolzel M, Ruckerl R, Cyrys J, Pan X, Zareba W, Koenig W, Wichmann HE, Peters A. Ambient source-specific particles are associated with prolonged repolarizationand increased levels of inflammation in male coronary artery disease patients. Mutation Research 2007b; online.
Technical Report:
Full Final Technical Report (PDF, 46pp., 1.08MB, about PDF)
Journal Articles: 78 Displayed | Download in RIS Format
| Other center views: | All 87 publications | 85 publications in selected types | All 78 journal articles |
| Type | Citation | ||
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Azadniv M, Torres A, Boscia J, Speers DM, Frasier LM, Utell MJ, Frampton MW. Neutrophils in lung inflammation: which reactive oxygen species are being measured? Inhalation Toxicology 2001;13(6):485-495. |
R827354 (2004) R827354 (Final) R827354C003 (2001) R827354C003 (2002) R827354C003 (Final) R826781 (2001) R826781 (Final) |
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Beckett WS, Chalupa DF, Pauly-Brown A, Speers DM, Stewart JC, Frampton MW, Utell MJ, Huang L-S, Cox C, Zareba W, Oberdorster G. Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults: a human inhalation study. American Journal of Respiratory and Critical Care Medicine 2005;171(1):1129-1135. |
R827354 (2004) R827354 (Final) R827354C003 (Final) R827354C004 (Final) |
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Berger A, ZarebaW, Schneider A, Ruckerl R, Ibald-Mulli A, Cyrys J, Wichmann HE, Peters A. Runs of ventricular and supraventricular tachycardia triggered by air pollution in patients with coronary heart disease. Journal of Occupational and Environmental Medicine 2006;48(11):1149-1158. |
R827354 (Final) R827354C003 (Final) R827354C004 (Final) |
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Cass GR, Hughes LA, Bahave P, Kleeman MJ, Allen JO, Salmon LG. The chemical composition of atmospheric ultrafine particles. The Philosophical Transactions of the Royal Society A: Mathematical, Physical, & Engineering Sciences 2000;358(1775):2581-2592. |
R827354 (2004) R827354 (Final) R827354C001 (1999) R827354C001 (2000) R827354C001 (Final) |
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Chalupa DC, Morrow PE, Oberdorster G, Utell MJ, Frampton MW. Ultrafine particle deposition in subjects with asthma. Environmental Health Perspectives 2004;112(8):879-882. |
R827354 (2004) R827354 (Final) R827354C003 (Final) R827354C004 (Final) |
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Cyrys J, Heinrich J, Peters A, Kreyling W, Wichmann HE. Emission, immission und messung feiner und ultrafeiner partikel (Emission, immission and measurement of fine and ultrafine particles). Umweltmedizin Forschung Praxis 2002;7(2):67-77. |
R827354 (2004) R827354 (Final) R827354C002 (2001) R827354C002 (2002) R827354C002 (Final) R827354C003 (Final) |
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Daigle CC, Chalupa DC, Gibb FR, Morrow PE, Oberdorster G, Utell MJ, Frampton MW. Ultrafine particle deposition in humans during rest and exercise. Inhalation Toxicology 2003;15(6):539-552. |
R827354 (2004) R827354 (Final) R827354C003 (1999) R827354C003 (2000) R827354C003 (2001) R827354C003 (2002) R827354C003 (2003) R827354C003 (2004) R827354C003 (Final) R827354C004 (Final) R826781 (2001) R826781 (Final) |
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Dillner AM, Schauer JJ, Christensen WF, Cass GR. A quantitative method for clustering size distributions of elements. Atmospheric Environment 2005;39(8):1525-1537. |
R827354 (2004) R827354 (Final) R827354C001 (Final) |
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Elder AC, Gelein R, Oberdorster G, Finkelstein J, Notter R, Wang Z. Efficient depletion of alveolar macrophages using intratracheally inhaled aerosols of liposome-encapsulated clodronate. Experimental Lung Research 2004;30(2):105-120. |
R827354 (Final) R827354C003 (Final) R827354C004 (2003) R827354C004 (Final) R827354C005 (Final) |
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Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein JN, Oberdorster G. Systemic interactions between inhaled ultrafine particles and endotoxin. Annals of Occupational Hygiene 2002;46(Suppl 1):231-234. |
R827354 (Final) R827354C003 (Final) R827354C004 (Final) R826784 (Final) |
not available |
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Elder A, Gelein R, Finkelstein J, Phipps R, Frampton M, Utell M, Kittelson D, Watts WF, Hopke P, Jeong C-H, Kim E, Liu W, Zhao W, Zhuo L, Vincent R, Kumarathasan P, Oberdorster G. On-road exposure to highway aerosols. 2. Exposures of aged, compromised rats. Inhalation Toxicology 2004;16(Suppl 1):41-53. |
R827354 (Final) R827354C003 (Final) R827354C004 (2003) R827354C004 (Final) R827354C005 (Final) R828046 (Final) |
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Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein J, Oberdorster G. Systemic effects of inhaled ultrafine particles in two compromised, aged rat strains. Inhalation Toxicology 2004;16(6-7):461-471. |
R827354 (Final) R827354C003 (Final) R827354C004 (2003) R827354C004 (Final) R827354C005 (Final) R826784 (Final) R828046 (Final) |
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Elder A, Johnston C, Gelein R, Finkelstein J, Wang Z, Notter R, Oberdorster G. Lung inflammation induced by endotoxin is enhanced in rats depleted of alveolar macrophages with aerosolized clodronate. Experimental Lung Research 2005;31(6):527-546. |
R827354 (Final) R827354C004 (Final) R827354C005 (Final) |
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Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdorster G. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environmental Health Perspectives 2006;114(8):1172-1178. |
R827354 (Final) R827354C004 (Final) R827354C005 (Final) R832415C004 (2006) R832415C005 (2006) |
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Elder A, Couderc J-P, Gelein R, Eberly S, Cox C, Xia X, Zareba W, Hopke P, Watts W, Kittelson D, Frampton M, Utell M, Oberdorster G. Effects of on-road highway aerosol exposures on autonomic responses in aged, spontaneously hypertensive rats. Inhalation Toxicology 2007;19(1):1-12. |
R827354 (Final) R827354C001 (Final) R827354C003 (Final) R827354C004 (Final) R832415C004 (2006) |
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Frampton MW. Systemic and cardiovascular effects of airway injury and inflammation: ultrafine particle exposure in humans. Environmental Health Perspectives 2001;109(S4):529-532. |
R827354 (Final) R827354C003 (2001) R827354C003 (2002) R827354C003 (Final) R826781 (2001) R826781 (Final) |
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Frampton MW, Stewart JC, Oberdorster G, Morrow PE, Chalupa D, Pietropaoli AP, Frasier LM, Speers DM, Cox C, Huang L-S, Utell MJ. Inhalation of ultrafine particles alters blood leukocyte expression of adhesion molecules in humans. Environmental Health Perspectives 2006;114(1):51-58. |
R827354 (Final) R827354C003 (Final) R827354C004 (Final) |
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Frampton MW. Does inhalation of ultrafine particles cause pulmonary vascular effects in humans? Inhalation Toxicology 2007;19(Suppl 1):75-79. |
R827354 (Final) R827354C003 (Final) |
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Henneberger A, Zareba W, Ibald-Mulli A, Ruckerl R, Cyrys J, Couderc J-P, Mykins B, Woelke G, Wichmann H-E, Peters A. Repolarization changes induced by air pollution in ischemic heart disease patients. Environmental Health Perspectives 2005;113(4):440-446. |
R827354 (Final) R827354C002 (2003) R827354C002 (Final) |
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Hopke PK, Ito K, Mar T, Christiansen WF, Eatough DJ, Henry RC, Kim E, Laden F, Lall R, Larson TV, Liu H, Neas L, Pinto J, Stölzel M, Suh H, Paatero P, Thurston GD. PM source apportionment and health effects: 1. Intercomparison of source apportionment results. Journal of Exposure Science & Environmental Epidemiology 2006;16(3):275-286. |
R827354 (Final) R827354C001 (Final) R827353 (Final) R827353C017 (Final) R827355 (Final) R827355C008 (Final) |
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Ibald-Mulli A, Wichmann H-E, Kreyling W, Peters A. Epidemiological evidence on health effects of ultrafine particles. Journal of Aerosol Medicine 2002;15(2):189-201. |
R827354 (Final) R827354C002 (2001) R827354C002 (2003) R827354C002 (Final) |
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Ito K, Christiansen WF, Eatough DJ, Henry RC, Kim E, Laden F, Lall R, Larson TV, Neas L, Hopke PK, Thurston GD. PM source apportionment and health effects: 2. An investigation of intermethod variability in associations between source-apportioned fine particle mass and daily mortality in Washington, DC. Journal of Exposure Science & Environmental Epidemiology 2006;16(4):300-310. |
R827354 (Final) R827354C001 (Final) R827351 (Final) R827351C001 (Final) R827353 (Final) R827353C015 (Final) R827355 (Final) R827355C008 (Final) R827997 (Final) |
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Jeong C-H, Hopke PK, Chalupa D, Utell M. Characteristics of nucleation and growth events of ultrafine particles measured in Rochester, NY. Environmental Science & Technology 2004;38(7):1933-1940. |
R827354 (Final) R827354C001 (2003) R827354C001 (Final) R827354C003 (Final) |
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Jeong C-H, Lee D-W, Kim E, Hopke PK. Measurement of real-time PM2.5 mass, sulfate, and carbonaceous aerosols at the multiple monitoring sites. Atmospheric Environment 2004;38(31):5247-5256. |
R827354 (Final) R827354C001 (2003) R827354C001 (Final) |
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Jeong C-H, Hopke PK, Kim E, Lee D-W. The comparison between thermal-optical transmittance elemental carbon and Aethalometer black carbon measured at multiple monitoring sites. Atmospheric Environment 2004;38(31):5193-5204. |
R827354 (Final) R827354C001 (2003) R827354C001 (Final) |
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Jeong C-H, Evans GJ, Hopke PK, Chalupa D, Utell MJ. Influence of atmospheric dispersion and new particle formation events on ambient particle number concentration in Rochester, United States, and Toronto, Canada. Journal of the Air & Waste Management Association 2006;56(4):431-443. |
R827354 (Final) R827354C001 (Final) R827354C003 (Final) |
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Kim E, Larson TV, Hopke PK, Slaughter C, Sheppard LE, Claiborn C. Source identification of PM2.5 in an arid Northwest U.S. City by positive matrix factorization. Atmospheric Research 2003;66(4):291-305. |
R827354 (Final) R827354C001 (Final) R827355 (2004) R827355 (Final) R827355C008 (2002) R827355C008 (Final) R827355C009 (2003) R828678C010 (2003) R828678C010 (2004) R828678C010 (2005) R828678C010 (2006) R828678C010 (2007) |
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Kim E, Hopke PK, Larson TV, Covert DS. Analysis of ambient particle size distributions using Unmix and positive matrix factorization. Environmental Science & Technology 2004;38(1):202-209. |
R827354 (Final) R827354C001 (Final) R827354C002 (2004) R827355 (2004) R827355 (Final) R827355C004 (2003) R827355C008 (2002) R827355C008 (2003) R827355C008 (Final) |
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Kim E, Hopke PK, Larson TV, Maykut NN, Lewtas J. Factor analysis of Seattle fine particles. Aerosol Science and Technology 2004;38(7):724-738. |
R827354 (Final) R827354C001 (Final) R827355 (2004) R827355 (Final) R827355C004 (2003) R827355C008 (2003) R827355C008 (Final) |
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Kittelson DB, Watts WF, Johnson JP, Remerowki ML, Ische EE, Oberdorster G, Gelein RM, Elder A, Hopke PK, Kim E, Zhao W, Zhou L, Jeong C-H. On-road exposure to highway aerosols. 1. Aerosol and gas measurements. Inhalation Toxicology 2004;16(Suppl 1):31-39. |
R827354 (Final) R827354C001 (Final) R827354C004 (2003) R827354C004 (Final) |
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Kreyling WG, Semmler M, Erbe F, Mayer P, Takenaka S, Schulz H, Oberdorster G, Ziesenis A. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. Journal of Environmental Science and Health. Part A 2002;65(20):1513-1530. |
R827354 (Final) R827354C004 (2001) R827354C004 (Final) |
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Lippmann M, Frampton M, Schwartz J, Dockery D, Schlesinger R, Koutrakis P, Froines J, Nel A, Finkelstein J, Godleski J, Kaufman J, Koenig J, Larson T, Luchtel D, Liu L-J S, Oberdorster G, Peters A, Sarnat J, Sioutas C, Suh H, Sullivan J, Utell M, Wichmann E, Zelikoff J. The U.S. Environmental Protection Agency Particulate Matter Health Effects Research Centers Program: a midcourse report of status, progress, and plans. Environmental Health Perspectives 2003;111(8):1074-1092. |
R827354 (Final) R827351 (2002) R827351 (Final) R827352 (Final) R827352C002 (Final) R827352C014 (Final) R827353 (Final) R827353C006 (Final) R827353C015 (Final) R827355 (Final) |
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Mar TF, Ito K, Koenig JQ, Larson TV, Eatough DJ, Henry RC, Kim E, Laden F, Lall R, Neas L, Stolzel M, Paatero P, Hopke PK, Thurston GD. PM source apportionment and health effects. 3. Investigation of inter-method variations in associations between estimated source contributions of PM2.5 and daily mortality in Phoenix, AZ. Journal of Exposure Science & Environmental Epidemiology 2006;16(4):311-320. |
R827354 (Final) R827354C001 (Final) R827351 (Final) R827353 (Final) R827353C015 (Final) R827355 (Final) R827355C002 (Final) R827355C008 (Final) |
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Moffet R, Shields L, Berntsen J, Devlin R, Prather K. Characterization of an ambient coarse particle concentrator used for human exposure studies: aerosol size distributions, chemical composition, and concentration enrichment. Aerosol Science and Technology 2004;38(11):1123-1137. |
R827354 (Final) R827354C001 (2003) R827354C001 (Final) |
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Oberdorster G. Pulmonary effects of inhaled ultrafine particles. International Archives of Occupational and Environmental Health 2001;74(1):1-8. |
R827354 (Final) R827354C004 (2000) R827354C004 (2001) R827354C004 (Final) R826784 (Final) |
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Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, Kreyling W, Cox C. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. Journal of Toxicology and Environmental Health-Part A 2002;65(20):1531-1543. |
R827354 (Final) R827354C004 (2001) R827354C004 (Final) R826784 (Final) |
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Oberdorster G, Utell MJ. Ultrafine particles in the urban air: to the respiratory tract—and beyond? Environmental Health Perspectives 2002;110(8):A440-A441. |
R827354 (Final) R827354C003 (Final) R827354C004 (Final) R826784 (Final) |
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Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C. Translocation of inhaled ultrafine particles to the brain. Inhalation Toxicology 2004;16(6-7):437-445. |
R827354 (Final) R827354C004 (2003) R827354C004 (Final) |
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Oberdorster G, Oberdorster E, Oberdorster J. Invited Review: Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environmental Health Perspectives 2005;113(7):823-839. |
R827354 (Final) R827354C004 (Final) |
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Oberdorster G, Stone V, Donaldson K. Toxicology of nanoparticles: a historical perspective. Nanotoxicology 2007;1(1):2-25. |
R827354C001 (Final) R832415 (2007) R832415C004 (2006) |
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Ogulei D, Hopke PK, Chalupa DC, Utell MJ. Modeling source contributions to submicron particle number concentrations measured in Rochester, New York. Aerosol Science and Technology 2007;41(2):179-201. |
R827354 (Final) R827354C001 (Final) R827354C003 (Final) R831078 (Final) |
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Pekkanen J, Peters A, Hoek G, Tiittanen P, Brunekreef B, de Hartog J, Heinrich J, Ibald-Mulli A, Kreyling WG, Lanki T, Timonen KL, Vanninen E. Particulate air pollution and risk of ST-segment depression during repeated submaximal exercise tests among subjects with coronary heart disease: the exposure and risk assessment for fine and ultrafine particles in ambient air (ULTRA) study. Circulation 2002;106(8):933-938. |
R827354 (Final) R827354C002 (2001) R827354C002 (2002) R827354C002 (2003) R827354C002 (Final) |
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Peters A, Heinrich J, Wichmann HE. Gesundheitliche wirkungen von feinstaub: epidemiologie der kurzzeiteffekte (Health impact of exposure to fine particles. Epidemiology of short-term effects). Umweltmedizin in Forschung und Praxis 2002;7(2):101-115. |
R827354 (Final) R827354C002 (2001) R827354C002 (2002) R827354C002 (2003) R827354C002 (Final) |
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Peters A, von Klot S, Heier M, Trentinaglia I, Hormann A, Wichmann HE, Lowel H. Exposure to traffic and the onset of myocardial infarction. New England Journal of Medicine 2004;351(17):1721-1730. |
R827354 (Final) R827354C002 (Final) |
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Peters A. Particulate matter and heart disease: Evidence from epidemiological studies. Toxicology and Applied Pharmacology 2005;207(Suppl 2):477-482. |
R827354 (Final) R827354C002 (Final) |
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Pietropaoli AP, Frampton MW, Hyde RW, Morrow PE, Oberdorster G, Cox C, Speers DM, Frasier LM, Chalupa DC, Huang L-S, Utell MJ. Pulmonary function, diffusing capacity, and inflammation in healthy and asthmatic subjects exposed to ultrafine particles. Inhalation Toxicology 2004;16(Suppl 1):59-72. |
R827354 (Final) R827354C003 (2003) R827354C003 (Final) R827354C004 (Final) R826781 (Final) |
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Riesenfeld E, Chalupa D, Gibb FR, Oberdorster G, Gelein R, Morrow PE, Utell MJ, Frampton MW. Ultrafine particle concentrations in a hospital. Inhalation Toxicology 2000;12(Suppl 2):83-94. |
R827354 (Final) R827354C003 (2000) R827354C003 (2001) R827354C003 (2002) R827354C003 (Final) R827354C004 (2000) R827354C004 (Final) R826781 (2000) R826781 (2001) R826781 (Final) |
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Ruckerl R, Ibald-Mulli A, Koenig W, Schneider A, Woelke G, Cyrys J, Heinrich J, Marder V, Frampton M, Wichmann HE, Peters A. Air pollution and markers of inflammation and coagulation in patients with coronary heart disease. American Journal of Respiratory and Critical Care Medicine 2006;173(4):432-441. |
R827354 (Final) R827354C002 (2003) R827354C002 (Final) R827354C003 (Final) R827354C004 (Final) |
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Ruckerl R, Phipps RP, Schneider A, Frampton M, Cyrys J, Oberdorster G, Wichmann HE, Peters A. Ultrafine particles and platelet activation in patients with coronary heart disease – results from a prospective panel study. Particle & Fibre Toxicology 2007;4(22 January):1. |
R827354 (Final) |
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Silva V, Corson N, Elder A, Oberdorster G. The rat ear vein model for investigating in vivo thrombogenicity of ultrafine particles (UFP). Toxicological Sciences 2005;85(2):983-989. |
R827354 (Final) R827354C004 (2003) R827354C004 (Final) |
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Singal M, Finkelstein JN. Amorphous silica particles promote inflammatory gene expression through the redox sensitive transcription factor, AP-1, in alveolar epithelial cells. Experimental Lung Research 2005;31(6):581-597. |
R827354 (Final) R827354C005 (Final) |
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Singal M, Finkelstein JN. Use of indicator cell lines for determining inflammatory gene changes and screening the inflammatory potential of particulate and nonparticulate stimuli. Inhalation Toxicology 2005;17(9):415-425. |
R827354 (Final) R827354C005 (Final) |
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Spencer MT, Shields LG, Sodeman DA, Toner SM, Prather KA. Comparison of oil and fuel particle chemical signatures with particle emissions from heavy and light duty vehicles. Atmospheric Environment 2006;40(27):5224-5235. |
R827354 (Final) R827354C001 (Final) |
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Spencer MT, Prather KA. Using ATOFMS to determine OC/EC mass fractions in particles. Aerosol Science and Technology 2006;40(8):585-594. |
R827354 (Final) R827354C001 (Final) R831083 (Final) |
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Spencer MT, Shields LG, Prather KA. Simultaneous measurement of the effective density and chemical composition of ambient aerosol particles. Environmental Science & Technology 2007;41(4):1303-1309. |
R827354 (Final) R827354C001 (Final) R831083 (Final) R832415C001 (2006) |
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Stolzel M, Breitner S, Cyrys J, Pitz M, Wolke G, Kreyling W, Heinrich J, Wichmann H-E, Peters A. Daily mortality and particulate matter in different size classes in Erfurt, Germany. Journal of Exposure Science and Environmental Epidemiology 2007;17(5):458-467. |
R827354 (Final) R827354C002 (Final) |
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Su Y, Sipin MF, Furutani H, Prather KA. Development and characterization of an aerosol time-of-flight mass spectrometer with increased detection efficiency. Analytical Chemistry 2004;76(3):712-719. |
R827354 (Final) R827354C001 (2003) R827354C001 (Final) |
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Su Y, Sipin MF, Prather KA, Gelein RM, Lunts A, Oberdorster G. ATOFMS characterization of individual model aerosol particles used for exposure studies. Aerosol Science and Technology 2005;39(5):400-407. |
R827354 (Final) R827354C001 (2003) R827354C001 (Final) R827354C004 (Final) |
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Su Y, Sipin M, Spencer M, Qin X, Moffet R, Shields L, Prather K, Venkatachari P, Jeong C-H, Kim E, Hopke P, Gelein R, Utell M, Oberdorster G, Berntsen J, Devlin R, Chen L. Real-time characterization of the composition of individual particles emitted from ultrafine particle concentrators. Aerosol Science and Technology 2006;40(6):437-455. |
R827354 (Final) R827354C001 (Final) R827354C003 (Final) R827354C004 (Final) |
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Thurston GD, Ito K, Mar T, Christensen WF, Eatough DJ, Henry RC, Kim E, Laden F, Lall R, Larson TV, Liu H, Neas L, Pinto J, Stotzel M, Suh H, Hopke PK. Workgroup report: workshop on source apportionment of particulate matter health effects--Inter-Comparison of results and implications. Environmental Health Perspectives 2005;113(12):1768-1774. |
R827354 (Final) R827354C001 (Final) R827351 (Final) R827351C001 (Final) R827353 (Final) R827353C015 (Final) R827355 (Final) R827355C008 (Final) |
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Toner SM, Shields LG, Sodeman DA, Prather KA. Using mass spectral source signatures to apportion exhaust particles from gasoline and diesel powered vehicles in a freeway study using UF-ATOFMS. Atmospheric Environment 2008;42(3):568-581. |
R827354 (Final) R827354C001 (Final) |
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Utell MJ, Frampton MW. Acute health effects of ambient air pollution: the ultrafine particle hypothesis. Journal of Aerosol Medicine 2000;13(4):355-359. |
R827354 (Final) |
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Utell MJ, Frampton MW. Toxicologic methods: controlled human exposures. Environmental Health Perspectives 2000;108(Suppl 4):605-613. |
R827354 (Final) |
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Utell MJ, Frampton MW, Zareba W, Devlin RB, Cascio WE. Cardiovascular effects associated with air pollution: potential mechanisms and methods of testing. Inhalation Toxicology 2002;14(12):1231-1247. |
R827354 (Final) R827354C003 (2001) R827354C003 (2002) R827354C003 (Final) R826781 (2001) R826781 (Final) |
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Venkatachari P, Hopke PK, Grover BD, Eatough DJ. Measurement of particle-bound reactive oxygen species in rubidoux aerosols. Journal of Atmospheric Chemistry 2005;50(1):49-58. |
R827354 (Final) R827354C001 (2003) R827354C001 (Final) |
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Venkatachari P, Zhou L, Hopke P, Schwab J, Demerjian K, Weimer S, Hogrefe O, Felton D, Rattigan O. An intercomparison of measurement methods for carbonaceous aerosol in the ambient air in New York City. Aerosol Science and Technology 2006;40(10):788-795. |
R827354 (Final) R827354C001 (Final) |
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Venkatachari P, Zhou L, Hopke PK, Felton D, Rattigan OV, Schwab JJ, Demerjian KL. Spatial and temporal variability of black carbon in New York City. Journal of Geophysical Research 2006;111:D10S05, doi:10.1029/2005JD006314. |
R827354 (Final) R827354C001 (Final) |
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Venkatachari P, Hopke PK, Brune WH, Ren X, Lesher R, Mao J, Mitchell M. Characterization of wintertime reactive oxygen species concentrations in Flushing, New York. Aerosol Science and Technology 2007;41(2):97-111. |
R827354 (Final) R827354C001 (Final) |
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Venkatachari P, Hopke PK. Characterization of products formed in the reaction of ozone with α-pinene: case for organic peroxides. Journal of Environmental Monitoring 2008;10(8):966-974. |
R827354 (Final) R827354C001 (Final) |
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Venkatachari P, Hopke PK. Development and evaluation of a particle-bound reactive oxygen species generator. Journal of Aerosol Science 2008;39(2):168-174. |
R827354 (Final) R827354C001 (Final) |
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Veranth JM, Gelein R, Oberdorster G. Vaporization–condensation generation of ultrafine hydrocarbon particulate matter for inhalation toxicology studies. Aerosol Science and Technology 2003;37(7):603-609. |
R827354 (Final) R827354C004 (2001) R827354C004 (Final) |
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von Klot S, Peters A, Aalto P, Bellander T, Berglind N, D’Ippoliti D, Elosua R, Hormann A, Kulmala M, Lanki T, Lowel H, Pekkanen J, Picciotto S, Sunyer J, Forastiere F, Health Effects of Particles on Susceptible Subpopulations (HEAPSS) Study Group. Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities. Circulation 2005;112(20):3073-3079. |
R827354 (Final) R827354C002 (Final) |
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Yue W, Schneider A, Stolzel M, Ruckerl R, Cyrys J, Pan X, Zareba W, Koenig W, Wichmann HE, Peters A. Ambient source-specific particles are associated with prolonged repolarization and increased levels of inflammation in male coronary artery disease patients. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2007;621(1-2):50-60. |
R827354 (Final) R827354C003 (Final) R827354C004 (Final) |
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Yue W, Schneider A, Ruckerl R, Koenig W, Marder V, Wang S, Wichmann HE, Peters A, Zareba W. Relationship between electrocardiographic and biochemical variables in coronary artery disease. International Journal of Cardiology 2007;119(2):185-191. |
R827354 (Final) R827354C003 (Final) R827354C004 (Final) |
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Zareba W, Nomura A, Couderc JP. Cardiovascular effects of air pollution: what to measure in ECG? Environmental Health Perspectives 2001;109(Suppl. 4):533-538. |
R827354 (Final) R827354C003 (Final) R827354C004 (Final) |
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Zhao W, Hopke PK, Qin X, Prather KA. Predicting bulk ambient aerosol compositions from ATOFMS data with ART-2a and multivariate analysis. Analytica Chimica Acta 2005;549(1-2):179-187. |
R827354 (Final) R827354C001 (Final) R831083 (Final) |
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Zhou L, Kim E, Hopke PK, Stanier C, Pandis SN. Mining airborne particulate size distribution data by positive matrix factorization. Journal of Geophysical Research 2005;110:D07S19, doi:10.1029/2004JD004707. |
R827354 (Final) R827354C001 (Final) |
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Zhou L, Hopke PK, Venkatachari P. Cluster analysis of single particle mass spectra at Flushing, NY. Analytica Chimica Acta 2006;555(1):47-56. |
R827354 (Final) R827354C001 (Final) |
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, Air, Scientific Discipline, Waste, Health, RFA, Molecular Biology/Genetics, Risk Assessments, Health Risk Assessment, Incineration/Combustion, air toxics, Children's Health, Biochemistry, particulate matter, Environmental Chemistry, tropospheric ozone, aerosols, cardiopulmonary, epidemiology, risk assessment, susceptible populations, ultrafine particles, urban environment, aerosol, ambient air quality, cardiovascular disease, cardiovascular vulnerability, coronary artery disease, health effects, mortality, lung inflamation, epidemelogy, inhalation toxicology, ambient air, fine particles, lead, environmental health effects, cardiopulmonary responses, human health risk, cytokine production, particle exposure, human health effects, particulates, PM 2.5, PM2.5, sensitive populations, combustion engines, ambient monitoring, lung, metals, stratospheric ozone, ambient air monitoring, pathophysiological mechanisms, pulmonary, urban air pollution, human health, human exposure, morbidity, particle size, pulmonary disease, animal model
Relevant Websites:
Full Final Technical Report (PDF, 46pp., 1.08MB, about PDF)
http://www2.envmed.rochester.edu/envmed/PMC/indexPMC.html
Progress and Final Reports:
2004 Progress Report
Original Abstract
Subprojects under this Center:
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R827354C001 Characterization of the Chemical Composition of Atmospheric Ultrafine Particles
R827354C002 Inflammatory Responses and Cardiovascular Risk Factors in Susceptible Populations
R827354C003 Clinical Studies of Ultrafine Particle Exposure in Susceptible Human Subjects
R827354C004 Animal Models: Dosimetry, and Pulmonary and Cardiovascular Events
R827354C005 Ultrafine Particle Cell Interactions: Molecular Mechanisms Leading to Altered Gene Expression
R827354C006 Development of an Electrodynamic Quadrupole Aerosol Concentrator
R827354C007 Kinetics of Clearance and Relocation of Insoluble Ultrafine Iridium Particles From the Rat Lung Epithelium to Extrapulmonary Organs and Tissues (Pilot Project)
R827354C008 Ultrafine Oil Aerosol Generation for Inhalation Studies