Final Report: Pulmonary and Systemic Effects of Inhaled Ultrafine Particles in Senescent Rats with Cardiovascular Disease

EPA Grant Number: R828046
Title: Pulmonary and Systemic Effects of Inhaled Ultrafine Particles in Senescent Rats with Cardiovascular Disease
Investigators: Elder, Alison C.P. , Couderc, Jean-Philippe , Frampton, Mark W. , Oberd√∂rster, G√ľnter , Zareba, Wojciech
Institution: University of Rochester
EPA Project Officer: Chung, Serena
Project Period: March 24, 2000 through March 23, 2003 (Extended to September 23, 2003)
Project Amount: $408,859
RFA: Airborne Particulate Matter Health Effects (1999) RFA Text |  Recipients Lists
Research Category: Particulate Matter , Air , Health Effects

Objective:

Epidemiological studies associate cardiovascular- and pulmonary-related morbidity and mortality in elderly individuals with cardiopulmonary disease with particulate air pollution exposure. It is estimated that there are at least 500,000 excess deaths per year worldwide related to particulate pollution exposure. The consistent statistical link led to a hypothesis that inhaled particles can exert effects, either directly or indirectly, on the cardiovascular system. We further hypothesized that inhaled UFPs, because of their large numbers in ambient air and the failure of normal lung clearance mechanisms to remove them, are causally related to the observed adverse health effects in the human population. The objectives of this research project were to:  (1) determine the effects of systemic bacterial toxin-induced stress on the pulmonary responses to inhaled ultrafine carbon particles; (2) measure the interactions between inhaled ultrafine carbon particles and systemically delivered bacterial toxin that affect peripheral blood cell activation, coagulability, and the acute phase response; and (3) determine the effects of inhaled ultrafine particles (UFPs) on cardiac function (heart rate [HR], blood pressure [BP], and heart rate variability [HRV]) after systemic bacterial toxin delivery. All of the studies were carried out in healthy old and compromised (hypertensive) old rats. Endotoxin, a component of Gram-negative bacteria, was given intraperitoneally in these studies to simulate mild systemic infection. Ultrafine carbon particles were generated by electric spark discharge in an argon atmosphere to simulate the carbonaceous fraction of nucleation mode ambient air particulate matter.

Summary/Accomplishments (Outputs/Outcomes):

Effects of Systemic Endotoxin on the Responses to Inhaled UFPs in Old Fischer-344 Rats

One objective of this project was to characterize the interactions between inhaled ultrafine carbonaceous particles and systemically delivered endotoxin in lung and blood cells. Several pilot-type projects were performed to determine baseline levels of coagulability parameters and acute phase reactants in rats. The time course and dose-related changes in plasma fibrinogen were used to determine an optimal intraperitoneal dose for endotoxin to be used in the studies. We found that the early response (4 hours) to injected endotoxin in rats was a decrease in the plasma fibrinogen concentration; the later response (24 hours) was an increase. The dose that was chosen (2 mg/kg) produced a 50 percent decrease in fibrinogen at 4 hours and a doubling in its concentration at 24 hours. Interestingly, epidemiological studies have shown both increases and decreases in plasma fibrinogen concentration, and this disparity in findings could be related to the time between onset of effects and sampling (Peters, et al., 1997; Seaton, et al., 1999). Endotoxin did not change the body weight of exposed rats or produce inactivity or labored breathing. Higher doses (e.g., 5 mg/kg) had these latter effects and, in some cases, caused mortality. In addition, the number and percentage of neutrophils (polymorphonuclear leukocytes [PMNs]) in lavage fluid did not change, nor were there any changes in lactate dehydrogenase or β-glucuronidase activities or total protein concentration.

We then obtained healthy old F-344 rats and aged them to 23 months. Immediately before being exposed to ultrafine carbon particles (0 or 175 µg/m3, 6 hours; count median diameter [CMD] = 35 nm), rats were injected with endotoxin (0 or 2 mg/kg, intraperitoneally). Bronchoalveolar lavage (BAL) fluid, BAL cells, and blood were obtained 24 hours after exposure to examine endpoints of inflammation, oxidant stress, coagulability, and the acute phase response.

Neither systemic endotoxin or inhaled ultrafine carbon particles alone, nor the combination of the two, had an effect on the percentage of PMNs in BAL fluid. Our preliminary studies predicted this outcome for endotoxin by itself. A marginally significant decrease in BAL cell chemiluminescence (release of reactive oxygen species) was caused by intraperitoneal endotoxin, but inhaled UFPs did not alter this parameter. Ultrafine carbon particles were found to independently and significantly decrease the intracellular oxidation of a fluorescent probe (2',7'- dichlorodihydrofluorescin diacetate [DCFD]) in BAL cells. Endotoxin had the opposite effect, namely that DCFD oxidation was increased significantly. The net effect of the two exposure components was to decrease intracellular oxidation. These results are interesting in that an effect on BAL cell oxidant production was found in response to systemic endotoxin, and that interactions with inhaled UFPs occurred. This cell-specific flow cytometric analysis was made possible by combining light scattering characteristics of the cells with their staining intensity for CD45 (pan-leukocyte surface antigen).

Systemically, endotoxin was found to increase the number of circulating PMNs, increase the concentrations of fibrinogen, thrombin-antithrombin (TAT) complexes, and interleukin (IL)-6, as well as decrease the intracellular oxidation of DCFD in blood PMNs. Interestingly, inhaled UFPs were found to have independent systemic effects (i.e., significant main effects in two-way analysis of variance [ANOVA]), including a significant increase in blood PMN DCFD oxidation and a decrease in the number of circulating PMNs. Both of these effects were in the opposite direction from the effects of endotoxin. Inhaled UFPs and systemic endotoxin also interacted in the extrapulmonary compartments (number of circulating PMNs; concentrations of fibrinogen and IL-6) and, in all cases, the resultant response was increased relative to the control. We planned to perform immunohistochemical staining for tissue factor (TF) in lung and heart tissue sections from exposed rats. To validate the protocol, we injected rats with endotoxin as a positive control. This treatment has been shown to induce increased TF expression (Hara, et al., 1997; Holschermann, et al., 1999). In our hands, the antibody did not bind specifically to tissue targets and the analysis was, thus, omitted. This is only a minor point, however, because the other endpoints that were measured in peripheral blood suggested acute phase induction and inflammatory cell activation.

Effects of Systemic Endotoxin on the Responses to Inhaled UFPs in Old Spontaneously Hypertensive (SH) Rats

Another objective of this project was to investigate the impact of a compromised cardiovascular system on responses to inhaled UFPs combined with systemic endotoxin. Thus, in subsequent studies, we obtained retired breeder SH rats and aged them in-house to 11-14 months. Immediately before being exposed to ultrafine carbon particles (0 or 130 µg/m3, 6 hours; CMD=37 nm), the rats were injected with endotoxin (0 or 2 mg/kg, intraperitoneally). As with the F-344 rats, BAL fluid, BAL cells, and blood were obtained 24 hours after exposure to assess endpoints of inflammation, oxidant stress, coagulability, and the acute phase response.

Neither systemic endotoxin nor inhaled ultrafine carbon particles, alone or in combination with each other, had an effect on the percentage of PMNs in BAL fluid. Likewise, no significant exposure-related effects were observed in the phorbol myristate acetate-stimulated release of oxidants from BAL cells (chemiluminescence). These results are similar to what was observed in old F-344 rats. Unlike old F-344 rats, however, neither component, alone or in combination with each other, had an effect on the levels of intracellular oxidants in lavage macrophages (DCFD oxidation).

Systemically, endotoxin in SH rats was found to increase the number of circulating PMNs, intracellular oxidation of DCFD in blood PMNs, concentration of plasma fibrinogen, viscosity of whole blood and plasma, and unstimulated release of tumor necrosis factor (TNF)-a by whole blood cells in culture. It decreased the concentration of plasma TAT complexes and suppressed the release of TNF-α by cultured whole blood cells in response to a secondary stimulus. Interestingly, inhaled UFPs independently and significantly increased the concentration of plasma TAT complexes and the in vitro TNF-α  release of resting whole blood cells. Plasma levels of fibrinogen and IL-6, as well as the stimulated release of TNF-α by blood cells in culture, were decreased significantly by UFPs. Many of the independent effects (from two-way ANOVAs) of systemic endotoxin and inhaled UFPs went in opposite directions. UFPs and endotoxin also interacted to increase, relative to control, the oxidation of DCFD in blood PMNs and the resting blood cell release of TNF-α . They also decreased the stimulated blood cell release of TNF-α .

Summary of Effects of Inhaled UFPs in Old Rats: Comparison of the F-344 and SH Strains

The results from the studies in aged F-344 and SH rats are summarized in Table 1. Although we recognize that the genetic background of the SH strain (Wistar Kyoto, [WKY]) is not the same as F-344, and that this difference could be a source of altered sensitivity to particles and endotoxin, there were some striking differences in response between the two rat strains that are noteworthy. In F-344, we found that the effect of UFPs was suppressive in terms of BAL cell DCFD oxidation. The same trend was present in SH rats, but the comparisons did not reach statistical significance. When endotoxin and UFPs were combined in F-344, the response was further suppressed. Aside from these differences, there was a heightened BAL alveolar macrophage (AM) DCFD oxidation in SH relative to F-344 rats. This suggests that the lung cells from SH rats are at a higher level of oxidative stress, a notion that is supported by work from Schnackenberg and Wilcox (1999) and Suzuki, et al. (1995). The lack of response in SH rats to inhaled UFPs may reflect an inability to respond to secondary stimuli. Blood PMN DCFD oxidation was increased by inhaled UFP exposure, again either because of a main effect (F-344) or through an interaction with endotoxin (SH). Similar to the strain differences noted above for BAL AMs, the overall 12-fold lower PMN DCFD oxidation in SH rats may represent a compensatory response to the enhanced levels of oxidative stress in this model. This may reflect, however, alternate pathways of response to stimuli as compared to normotensive rats. As for plasma TAT complexes, we found that inhaled UFPs increased their plasma levels in both rat strains, either through a main effect (SH) or upon interaction with intraperitoneal endotoxin (F-344). The highest response was to UFPs alone in SH rats. The combination of factors in SH rats, however, still produced a higher response than in controls. For all of the exposure groups taken as a whole, the plasma TAT complex concentration in SH rats is approximately 6.5 times higher than in F-344 rats (a 5-fold difference for controls alone). Increased plasma TAT complex concentration is indicative of thrombin generation (Chaiworapongsa, et al., 2002; Ellison, et al., 2001). The latter catalyze the formation of fibrin monomers from fibrinogen. Thus, elevations in TAT complexes, fibrinogen, or both would result in increased fibrin monomer production and clot formation. Despite higher average levels of TAT complexes and fibrinogen in SH rats, average values for whole blood viscosity were not different between the two strains, and this parameter did not change with UFP exposure.

Several studies have been conducted in the past few years by scientists at the U.S. Environmental Protection Agency (EPA) on the effects of emission particles (residual oil fly ash), one showing that plasma fibrinogen was elevated in SH rats, but not WKY (Kodavanti, et al., 2002). Our results in SH rats exposed to laboratory-generated UFPs do not agree with these findings, although there are some important differences between the two studies, including the particle types, exposure concentration/duration, and the age of the rat.

Table 1. Summary of Results Following Exposure of Old Rats to Systemic Endotoxin (Lipopolysaccharide [LPS]) ± Inhaled Ultrafine Carbon Particles. Table 1 summarizes the statistically significant main effects and interactions found upon two-way ANOVA. p values are shown only for those effects that were significant. A line indicates that no such effect was found. The arrows indicate the direction of the effect relative to controls.

A. F-344 Rats:

Endpoints  
UFP
LPS
UFP + LPS
BAL Parameters Total cell number
  % PMNs
  BAL cell chemiluminescence(stimulated)
p = 0.03
  BAL cell DCFD oxidation (AMs)(stimulated)
p < 0.001
p < 0.001
p < 0.001
Blood Parameters Number of PMNs
p = 0.01
p < 0.001
p = 0.02
  Blood cell DCFD oxidation (PMNs)(stimulated)
p = 0.02
p < 0.01
  Hematocrit
  Whole blood viscosity
p < 0.01
  Plasma fibrinogen
p < 0.001
p < 0.01
  Plasma TAT complexes
p < 0.001
p < 0.001
  Plasma IL-6 concentration
p = 0.02

B. SH Rats:

Endpoints  
UFP
LPS
UFP + LPS
BAL Parameters Total cell number
  % PMNs
  BAL cell chemiluminescence(stimulated)
  BAL cell DCFD oxidation (AMs)(stimulated)
Blood Parameters Number of PMNs
p < 0.001
  Blood cell DCFD oxidation (PMNs)(stimulated)
p < 0.001
p = 0.02
  Hematocrit
  Whole blood viscosity
p < 0.01
  Plasma fibrinogen
p < 0.001
p < 0.001
  Plasma TAT complexes
p = 0.01
p < 0.01
  Plasma IL-6 concentration
ND
ND
ND

In summary, these results suggest that inhaled ultrafine carbon particles at concentrations mimicking high episodic events can independently induce systemic responses related to oxidative stress, and that interactions between these particles and systemically administered endotoxin occur in both the pulmonary and extrapulmonary compartments. One intriguing result is that plasma TAT complexes are increased by UFPs in both animal models, either through the main effect of the particles themselves or via an interaction with endotoxin. The study also highlights the heightened oxidative stress in SH rats, as shown by differences in basal levels of BAL AM and blood PMN DCFD oxidation between the strains. Results from these studies were presented, in part, at a meeting in the United Kingdom (2001), and also were published or are being published (Elder, et al., 2002; Elder, et al., in press, 2004a).

Effects of Ultrafine Highway Aerosols in Aged, Compromised Rats

In the original research proposal, we planned to compare the responses to UFPs and larger, fine-mode particles. As we have discovered, one drawback to this approach is that it is difficult to generate singlet fine-mode particles with the spark generator. An alternative, such as carbon black, could have been used, but there are uncertainties about surface structure and the amount of associated hydrocarbons and trace elements. Furthermore, the laboratory-generated surrogates represent only one portion of the ambient particulate matter profile. Thus, more valuable information can be gained by using real-world particles. The Rochester Particulate Matter Center, in collaboration with David Kittelson (University of Minnesota), undertook a series of studies using a newly designed system for exposures to on-road highway aerosols. This system allows the collection of aerosols and the enrichment of UFPs without chemical or physical modifications. Furthermore, exposures are to freshly generated real-world particles. It was possible to collaborate with the Center such that some limited studies were supported by this EPA Science To Achieve Results (STAR) grant. Given the importance and relevance of the work and the close ties to the Center, this was an opportunity that could not be overlooked. A portion of the overall study involved the systemic administration of endotoxin or saline in telemetered SH rats that were then exposed to on-road aerosols or filtered air (exposures separated by 4-5 weeks; described below).

The study was designed such that numerous parameters were measured in exposed aged F-344 rats and these results, in regard to the main effects of particles, can be compared to the results obtained in studies supported by this STAR grant. The highway aerosol size (15-20 nm; geometric standard deviation = 1.4-4.3) and number concentration (1.96-5.62 x 105/cm3) indicated the predominance of UFPs; the filtered air control was 1.40-12.00 x 103/cm3. An intriguing finding from the studies in the mobile laboratory was that plasma endothelin-2 increased in response to on-road particles. This finding suggests changes in vascular endothelial function, and it is consistent with previously published results after exposures to concentrated ambient particles (Vincent, et al., 2001). Another main effect of the gas-phase/particle mixture was an increase in plasma fibrinogen. In the studies with old F-344 rats described in this report, we did not find a main effect for laboratory-generated UFPs in regard to plasma fibrinogen; however, there was an interaction between intraperitoneal endotoxin and UFPs such that fibrinogen was elevated relative to controls. The connection of these responses with observed changes in HR and HRV needs to be studied carefully.

Analyses of HRV

One of our hypotheses is that inhaled UFPs can have effects on the heart alone or in combination with systemic endotoxin. Such effects may be observed by measuring exposure-related changes in HR, BP, and HRV. To accomplish this, we used radiotelemeters from DataSciences International (DSI) to acquire electrocardiogram (ECG) and BP signals from conscious, untethered rats. Our collaborators (Drs. Couderc and Zareba) developed custom programs to extract the DSI-formatted data and perform time and frequency domain-based analyses of HRV on the original ECG and BP data. The design and optimization of the algorithms for rat ECG and BP waveform analyses were more time consuming than we had originally predicted. Because we are the first group to do the analyses using continuous recordings from the DSI system, there were many technical hurdles to overcome. We explored several commercially available software packages for HRV analyses, but found our custom program to be superior for our needs because the commercial programs failed to recognize many of the R-peaks in the tachogram, giving erroneous estimations of variability. The most important lessons learned from our studies were: (1) greater than or equal to 1,500 consecutive beats are required to obtain stable estimations of HRV; (2) ECG lead placement significantly affects signal quality because of muscle movement; and (3) the use of BP instead of ECG signals can provide more stable measurement outcomes. These points are discussed in greater detail below.

In our preliminary analyses, we confirmed that ECG recordings obtained using the DSI system could provide reliable information about HRV in unrestrained rats. Software was designed subsequently (C++ platform; compatible with any Windows-based personal computer) to analyze HRV in short- and long-term rat ECG recordings. The program includes three different user interfaces allowing for: (1) a check of the recording quality; (2) a visual validation of the QRS signal detection; and (3) the computation of time and frequency quantifiers of HRV. The software automatically reads files from the DSI system and creates its own data format for the analyses. Accurate detection of the R peaks can be visually checked by the program user. The frequency-domain parameters are computed based on the power spectral density of the tachogram. The time-domain parameters are automatically computed. Several frequency-domain parameters were included according to reported methodology:

• The energy of the high frequency (HF) band (0.8-3 Hz in ms2) to estimate vagal control (parasympathetic tone) as well as the HF peak value (ms2/Hz) and its location (Hz);

• The low frequency band (LF) to estimate sympathetic tone (0.1-0.7 Hz in ms2) as well as the peak value (ms2/Hz) and its location (Hz); and

• The time-domain parameters are the standard deviation of the normal-to-normal relative risk (RR) intervals over a specific recording period and the root mean square of successive differences between normal-to-normal RR intervals. Both are expressed in ms.

In a preliminary study, the validity of the algorithm was validated for short-term ECGs (< 10 minutes). Because the optimal length of short-term ECG recordings had not been determined for the analysis of HRV in rats, the stability of various parameters according to the length of the ECG signal had to be determined. This analysis led to the conclusion that at least 1,500 beats are needed to obtain reliable and reproducible estimations of HRV parameters. It also was found that the stability of the HRV parameters is dependent on the average HR: a maximum of 5 percent variation between averaged HR from contiguous ECG segments is allowable to ensure reliable HRV measurements. These data are presented in a manuscript by Couderc, et al., 2002.

Effects of Systemic Endotoxin and Inhaled UFPs on HRV in Old SH Rats

Two separate experiments have been completed in which radiotelemetered SH rats were exposed to inhaled UFPs after sensitization of the respiratory tract with systemic endotoxin. The first study was conducted in aged SH rats (15-18 months) using a crossover study design, in which rats were exposed to combinations of systemic endotoxin and inhaled ultrafine iron-containing (25 percent) carbon particles. Preliminary analyses showed that the iron in these laboratory-generated UFPs is highly bioavailable. There were two rats per treatment group per period of the study, and each rat was exposed to all of the treatment combinations in a random manner over time. Some animals died, however, because of congestive heart failure in periods 3 and 4, making rigorous statistical analysis of results impossible. This same problem of age-related mortality was experienced in another crossover study in our laboratory; therefore, this was not an isolated occurrence. It was obvious from the results that intraperitoneal endotoxin decreased HRV, as expected. No striking effects of inhaled UFPs in addition to endotoxin were found. These analyses were performed using the ECG waveforms; subsequent analyses showed improved stability of HRV estimations when measurements were made using BP waveforms. Our work suggests that crossover studies in old SH rats are not ideal because of deaths and severe morbidity. These studies should be conducted with somewhat younger rats. In addition, we did not consider it wise to conduct these studies in SH rats with heart failure. Our efforts were devoted instead to the studies described below.

The second study with telemetered SH rats was conducted using the newly designed on-road exposure system described in an earlier section of this report. For this study, we used younger SH rats (7-11 months). Telemetric recordings began immediately after the on-road exposures, and HRV parameters were calculated from BP signals and analyzed for the first 16 hours post-exposure. Endotoxin significantly affected all of the parameters in a time-dependent manner, as expected. Additionally, a significant time-dependent effect of highway aerosol was found, irrespective of preexposure, which resulted in decreased HR. It was most persistent in rats that received intraperitoneal endotoxin. There also were significant highway aerosol/time interactions that led to short-term elevations in normalized LF power and HF power. These findings suggest that alterations in autonomic control of HR and BP occur as a result of exposure to normal concentrations of mixed highway UFPs/gas-phase emissions. Examples of the telemetry data (HR and HF power) before and after exposure are shown in Figure 1. These data will be presented at the upcoming American Thoracic Society Annual Meeting in May 2004, and are the subject of a manuscript that is in preparation.

Significance of Findings

The results of the experiments, supported by this grant, suggest that inhaled laboratory-generated UFPs can exert effects outside of the lung, altering blood cell oxidant production and the acute phase response. The concentration of laboratory-generated UFPs used in these studies is equivalent to approximately 85 µg/m3 inhaled by humans in terms of deposited lung dose, as derived from the International Commission on Radiological Protection model of particle deposition in humans (1994) and a rat-specific particle deposition model (RIVM, CIIT, 2002). Although ambient levels in the ultrafine range usually are on the order of a few µg/m3 averaged over an 8-hour period, recent studies have demonstrated much higher episodic increases in number and mass concentration for this size fraction (Brand, et al., 1992; Kittelson, et al., 2001; Tuch, et al., 1997). It is these episodic increases that we are modeling in our experiments. Indeed, atmospheric monitoring during the on-road exposures showed number concentrations of freshly generated particles as high as 500,000/cm3. Our findings from the telemetry studies in SH rats exposed to mixed highway aerosols also suggest that UFPs can induce alterations in the autonomic regulation of HR and BP.

 

Figure 1. HR (Left) and HF (Right) of Old SH Rats During the Baseline Period and for 16 Hours After Exposure to Highway Aerosols. Rats were injected with endotoxin immediately prior to the on-road exposures.

References:

Brand P, Ruob K, Gebhart J. Performance of a mobile aerosol spectrometer for an in situ characterization of environmental aerosols in Frankfurt City. Atmospheric Environment 1992;26A:2451-2457.

Chaiworapongsa T, Espinoza J, Yoshimatsu J, Y Kim M, Bujold E, Edwin S, Yoon BH, Romero R. Activation of coagulation system in preterm labor and preterm rupture of membranes. Journal of Maternal-Fetal and Neonatal Medicine 2002;11:368-373.

Ellison J, Thomson AJ, Conkie JA, McCall F, Walker D, Greer A. Thromboprophylaxis following caesarean section—a comparison of the antithrombotic properties of three low molecular weight heparins—dalteparin, enoxaparin, and tinzaparin. Thrombosis and Haemostasis 2001;86:1374-1378.

Hara S, Asada Y, Hatakeyama K, Marutsuka K, Sato Y, Kisanuki A, Sumiyoshi A. Expression of tissue factor and tissue factor pathway inhibitor in rat lungs with lipopolysaccharide-induced disseminated intravascular coagulation. Laboratory Investigation 1997;77:581-589.

Holschermann H, Bohle RM, Zeller H, Schmidt H, Stahl U, Fink L, Grimm H, Tillmanns H, Haberbosch W. In situ detection of tissue factor within the coronary intima in rat cardiac allograft vasculopathy. American Journal of Pathology 1999;154:211-221.

International Commission on Radiological Protection (ICRP). Human respiratory tract model for radiological protection. Report of the ICRP, Committee 2, 1994.

Kittelson DB, Watts WF, Johnson JP. Fine particles (nanoparticle) emissions on Minnesota highways. Presented at the 7th Diesel Engine Emissions Reduction (DEER) Workshop, Portsmouth, VA, August 5-9, 2001.

Kodavanti UP, Schladweiler MC, Ledbetter AD, Hauser R, Christiani DC, McGee J, Richards JR, Costa DL. Temporal association between pulmonary and systemic effects of particulate matter in healthy and cardiovascular compromised rats. Journal of Toxicology and Environmental Health 2002;65:1545-1569.

Peters A, Döring A, Wichmann H-E, Koenig W. Increased plasma viscosity during an air pollution episode: a link to mortality? Lancet 1997;349:1582-1587.

Multiple path particle dosimetry model, RIVM and CIIT , 2002.

Schnackenberg CG, Wilcox CS. Two-week administration of tempol attenuates both hypertension and renal excretion of 8-iso-prostaglandin F2-alpha. Hypertension 1999;33:424-428.

Seaton A, Soutar A, Crawford V, Elton R, McNerlan S, Cherrie J, Watt M, Agius R, Stout R. Particulate air pollution and the blood. Thorax 1999;54:1027-1032.

Suzuki H, Swei A, Zweifach BW, Schmid-Schonbein GW. In vivo evidence for microvascular oxidative stress in spontaneously hypertensive rats-hydroethidine microfluorography. Hypertension 1995;25:1083-1089.

Tuch TH, Brand P, Wichmann H-E, Heyder J. Variation of particle number and mass concentration in various size ranges of ambient aerosols in Eastern Germany. Atmospheric Environment 1997;31:4193-4197.

Vincent R, Kumarathasan P, Goegan P, Bjarnason S, Guenette J, Bérubé D, Adamson IY, Desjardins S, Burnett RT, Miller FJ, Battistiani B. Inhalation toxicology of urban ambient particulate matter: acute cardiovascular effects in rats. Research Report 104, Health Effects Institute, Boston, MA, 2001.


Journal Articles on this Report : 6 Displayed | Download in RIS Format

Other project views: All 11 publications 6 publications in selected types All 6 journal articles
Type Citation Project Document Sources
Journal Article Couderc JP, Elder ACP, Cox C, Zareba W, Oberdorster G. Limitations of power-spectrum and time-domain analysis of heart rate variability in short-term ECG recorded using telemetry in unrestrained rats. Computers in Cardiology 2002;29:589-592. R828046 (Final)
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  • Journal Article Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein J, Oberdorster G. Systemic interactions between inhaled ultrafine particles and endotoxin. Annals of Occupational Hygiene 2002;46(Suppl 1):231-234. R828046 (Final)
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  • Journal Article 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. R828046 (Final)
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  • Journal Article Elder A, Gelein R, Finkelstein J, Phipps R, Frampton M, Utell M, Kittelson DB, 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. R828046 (Final)
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  • Journal Article 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. R828046 (Final)
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  • Journal Article 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. R828046 (Final)
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    urban air quality, sensitivity, coagulation, aging, cardiotoxicity, air, health, atmospheric sciences, disease and cumulative effects, epidemiology, health risk assessment, genetic susceptibility, air toxics, particulate matter, acute health effects, aerosols, air pollution, air quality, airway disease, ambient particulates, animal inhalation study, animal model, bacteria, bacterial toxin induced stress, carbon particles, cardiopulmonary response, cardiovascular vulnerability, chronic health effects, circulating leukocytes, effects assessment, elderly, environmental hazard exposures, exposure, exposure and effects, exposure assessment, fine particles, heart rate, human exposure, human health effects, human susceptibility, inhaled particles, lung dysfunction, lung inflammation, morbidity, mortality, particles, particulate exposure, particulates, pulmonary disease, respiration, respiratory problems, senescent rats, sensitive populations, toxics, ultrafine carbon, ultrafine particulates, ultrafine particles, cardiovascular effects, health effects, sensitive populations, oxidative stress, inflammation,, RFA, Health, Scientific Discipline, Air, particulate matter, Toxicology, air toxics, Health Risk Assessment, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, genetic susceptability, Atmospheric Sciences, sensitive populations, urban air, fine particles, human health effects, morbidity, respiration, exposure and effects, cardiovascular vulnerability, exposure, pulmonary disease, animal model, air pollution, carbon particles, cardiopulmonary response, chronic health effects, lung inflammation, particulate exposure, bacterial toxin induced stress, Acute health effects, elderly, PM, cardiotoxicity, inhaled particles, mortality, senescent rats, aerosols, air quality, human health risk, ultrafine particles, ultrafine carbon, toxics, animal inhalation study

    Progress and Final Reports:

    Original Abstract
  • 2000 Progress Report
  • 2001 Progress Report
  • 2002