Grantee Research Project Results
1999 Progress 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:
Current Investigators: Oberdörster, Günter , Elder, Alison C.P.
Institution:
Current Institution: University of Rochester
EPA Project Officer:
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
Project Period Covered by this Report: June 1, 1999 through May 31, 2000
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air
Objective:
Earlier studies in our laboratory and others have shown that ultrafine particles elicit significantly greater pulmonary inflammatory responses than larger particles of the size of the accumulation mode when administered at the same mass to the respiratory tract. Normal background levels of atmospheric ultrafine particles are very low, about 1-2 µg/m3, although their number concentration at these background levels is high, up to 2-4 x 104 particles/cm3. Episodic increases as high as 5 x 105 particles/cm3 and 1 x 106 particles/cm3 have been observed. Our hypothesis is that ultrafine particles in the urban atmosphere contribute to the adverse health effects associated with PM. The objectives of the animal studies are to evaluate pulmonary and cardiovascular effects of inhaled laboratory-generated ultrafine and fine carbon particles using animal models of increased susceptibility and to obtain data on the deposition and subsequent fate of inhaled ultrafine particles.
In recent studies, we have developed a model of respiratory tract priming in rats and mice using very low doses of inhaled LPS. This model should mimic the early stages of a respiratory infection with gram-negative bacteria, and we continue using this model in combination with host factors such as old age and cardiovascular conditions. With respect to the latter, spontaneously hypertensive rats (SHR) and hypertensive rats that are prone to heart failure at 10-12 months of age (SHHF) are commercially available for use in our studies.
Very few data on the deposition of inhaled ultrafine particles in the respiratory tract of experimental animals have been reported. Preliminary data from our laboratory and others using inhaled ultrafine metal particles in rats indicated some translocation to the liver. However, solubilization of ultrafine metal particles, even those of very poorly soluble platinum and iridium, cannot be excluded and may have accounted for distribution of the metal to extrapulmonary sites. Because elemental carbon is insoluble, we have developed a technique to generate ultrafine pure 13C particles for use in these studies.
Progress Summary:
In collaboration with Drs. Zareba and Couderc of the cardiac core of our Center, we have established radiotelemetry monitoring of ECG, body temperature, and most recently blood pressure in normal young and old rats as well as SHR rats. We are using peritoneally implanted radiotelemetry transmitters and computerized monitoring to assess electrocardiograms from rats. To establish techniques by which ECG waveforms could be analyzed, we injected atropine and propanolol intraperitoneally (5 mg/kg) and then collected waveform data. Compared to baseline (no drug), we observed the expected changes in heart rate as well as decreases in heart rate variability in the time (SDNN) and frequency (HF peak energy) domains. In addition to these receptor-targeted agents, we also exposed rats to endotoxin via inhalation and monitored the ECG waveforms for 24 hours (a total of 12 hours of recorded data). The data show that HR decreased and respiratory rate increased, as evidenced by a shift in the high frequency peak to a higher frequency after exposure. In addition, in two out of three rats, the respiratory (HF) peak as well as total spectral energy decreased, suggesting a decrease in heart rate variability.
We compared in a study the pulmonary inflammatory response to inhaled ultrafine and fine carbon particles using the LPS inhalation-priming model in 22-month-old Fischer 344 rats. Both particle sizes were generated with the electric spark discharge system (PALAS generator); for the fine particles, the output of the generator was increased maximally and the generated larger particles were aged for 5 minutes to achieve further aggregation to larger particles with a count median diameter of approximately 280 nm. To achieve the same lung burden as is deposited by 100 µg/m3 of ultrafine carbon (CMD = 30 nm), the exposure concentration of the aged carbon was increased to 270 g/m3. The aged carbon induced a slightly greater pulmonary inflammatory cell response. A concurrently performed analysis of the surface area of both particle sizes by Dr. Kreyling at the GSF showed that the aged carbon paradoxically had a 3.7-fold greater surface area than the ultrafine carbon, which could explain the result. We presently are assessing other possibilities to generate the larger accumulation mode particles.
Evaluation of the utility of 13C particle to determine ultrafine particles deposition and clearance in the respiratory tract of rodents gave encouraging results. To test the sensitivity of the method, a preliminary study in mice was performed using a 30-minute and 6-hour inhalation of 13C ultrafine particles (CMD=30 nm, ~100 µg/m3). Lung lobes and trachea were analyzed for 13C by Dr. Z. Sharp (University of New Mexico, Albuquerque, NM), and the results are consistent with a very rapid clearance of these particles from the lung: only approximately 2.5-fold more 13C was retained in the lungs of the 6-hour exposed compared to the 30-minute exposed animals, despite the 12-fold difference in exposure time. A subsequent 6-hour 13C inhalation study in rats with analysis of 13C in lung lobes and extrapulmonary organs at 30-minutes, 18-hours, and 24-hours postexposure showed a very rapid early translocation of a large fraction of 13C to the liver.
Future Activities:
We will continue to assess other possibilities to generate larger accumulation mode particles. We will continue to conduct animal studies to evaluate pulmonary and cardiovascular effects of inhaled laboratory-generated ultrafine and fine carbon particles using animal models of increased susceptibility and to obtain data on the deposition and subsequent fate of inhaled ultrafine particles.
Journal Articles:
No journal articles submitted with this report: View all 33 publications for this subprojectSupplemental Keywords:
pollution prevention, atmosphere, particulates, metals, sensitive population., 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:
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
- Final Report
- 2004 Progress Report
- 2003 Progress Report
- 2002 Progress Report
- 2001 Progress Report
- 2000 Progress Report
- Original Abstract
27 journal articles for this subproject
Main Center: R827354
106 publications for this center
91 journal articles for this center