Grantee Research Project Results
Final Report: Animal Models: Dosimetry, and Pulmonary and Cardiovascular Events
EPA Grant Number: R827354C004Subproject: this is subproject number 004 , established and managed by the Center Director under grant R827354
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Rochester PM Center
Center Director: Oberdörster, Günter
Title: Animal Models: Dosimetry, and Pulmonary and Cardiovascular Events
Investigators: Oberdörster, Günter , Elder, Alison C.P.
Institution: University of Rochester
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
Objective:
The objective of this research project is to improve the generation system for laboratory-generated ultrafine carbon particles, specifically, to eliminate organic contaminants and set up a separate system for the generation of ultrafine organic particles and mixed ultrafine carbon/iron particles.
Summary/Accomplishments (Outputs/Outcomes):
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 μg/rat alveolar deposition), confirming their thrombogenic potential. Remarkably, subsequent inhalation studies with elemental carbon UFP (30 minutes; 70 μg/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.
References:
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.
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/ Exit ), 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.
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.
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.
Technical Report:
Full Final Technical Report (PDF, 5pp., 22.3KB, about PDF)
Journal Articles on this Report : 27 Displayed | Download in RIS Format
Other subproject views: | All 33 publications | 31 publications in selected types | All 27 journal articles |
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Other center views: | All 106 publications | 99 publications in selected types | All 91 journal articles |
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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(10):1129-1135. |
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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. |
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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. |
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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. |
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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. |
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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. |
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Elder ACP, 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. |
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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. |
R827354 (Final) R827354C003 (Final) R827354C004 (2003) R827354C004 (Final) R827354C005 (Final) R828046 (Final) R832415 (2010) R832415 (2011) R832415 (Final) R832415C003 (2011) R832415C004 (2011) R832415C005 (2011) |
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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. |
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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. |
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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. |
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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. |
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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. |
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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 Toxicology and Environmental Health-Part A 2002;65(20):1513-1530. |
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Oberdorster G. Pulmonary effects of inhaled ultrafine particles. International Archives of Occupational and Environmental Health 2001;74(1):1-8. |
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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. |
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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: Current Issues 2002;65(20):1531-1543. |
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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. |
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Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology:an emerging discipline evolving from studies of ultrafine particles. Environmental Health Perspectives 2005;113(7):823-839. |
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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. |
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Riesenfeld E, Chalupa D, Gibb FR, Oberdo G, Gelein R, Morrow PE, Utell MJ, Frampton MW. Ultrafine particle concentrations in a hospital. Inhalation Toxicology 2000;12(Suppl 2):83-94. |
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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. |
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Silva VM, 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. |
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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. |
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Su Y, Sipin MF, Spencer MT, Qin X, Moffet RC, Shields LG, Prather KA, Venkatachari P, Jeong C-H, Kim E, Hopke PK, Gelein RM, Utell MJ, Oberdorster G, Berntsen J, Devlin RB, Chen LC. Real-time characterization of the composition of individual particles emitted from ultrafine particle concentrators. Aerosol Science and Technology 2006;40(6):437-455. |
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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. |
R827354C004 (2001) 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. |
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Supplemental Keywords:
RFA, Scientific Discipline, Health, Air, Toxicology, particulate matter, Environmental Chemistry, Health Risk Assessment, air toxics, Risk Assessments, Biochemistry, Atmospheric Sciences, Molecular Biology/Genetics, ambient air quality, cytokine production, particle size, particulates, sensitive populations, biostatistics, health effects, risk assessment, cardiopulmonary responses, fine particles, human health effects, morbidity, ambient air monitoring, lung, cardiovascular vulnerability, pulmonary disease, susceptible populations, animal model, ambient air, environmental health effects, particle exposure, ambient monitoring, particulate exposure, lung inflamation, pulmonary, coronary artery disease, inhalation toxicology, tropospheric ozone, urban air pollution, mortality, urban environment, aerosol, cardiopulmonary, human health, aerosols, cardiovascular disease, ultrafine particles, pathophysiological mechanismsRelevant Websites:
Full Final Technical Report (PDF, 5pp., 22.3KB, about PDF)
http://www2.envmed.rochester.edu/envmed/PMC/indexPMC.html Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R827354 Rochester PM Center 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
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- 2004 Progress Report
- 2003 Progress Report
- 2002 Progress Report
- 2001 Progress Report
- 2000 Progress Report
- 1999 Progress Report
- Original Abstract
27 journal articles for this subproject
Main Center: R827354
106 publications for this center
91 journal articles for this center