Grantee Research Project Results
Final Report: Mechanism of PM-Induced Acute Health Effects
EPA Grant Number: R826244Title: Mechanism of PM-Induced Acute Health Effects
Investigators:
Institution: New York University Medical Center
EPA Project Officer: Chung, Serena
Project Period: January 23, 1998 through January 22, 2001
Project Amount: $600,799
RFA: Health Effects and Exposures to Particulate Matter and Associated Air Pollutants (1997) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air , Human Health
Objective:
The objective of this research project was to determine the biological mechanism for the systemic effects associated with acute exposure to ambient particulate matter (PM). We hypothesized that: (1) inhaled PM causes immediate effects on the autonomic regulation of the cardiovascular system, resulting in a stress response; and (2) the biological changes associated with this response can explain a substantial portion of the mortality associated with acute exposure to PM. We studied whether environmentally relevant concentrations of PM can cause a stress response and whether there is a threshold concentration below which PM does not cause acute cardiovascular changes. Moreover, because of epidemiologic evidence that PM-associated adverse effects may occur in those individuals with pre-existing illness, we also examined whether concentrated ambient PM will produce these systemic effects at lower concentrations in an animal model of compromised health. Because of the confounding effects of gaseous copollutants on estimates of relative risk of morbidity and mortality attributable to PM exposure, we also studied whether ambient gases can produce cardiovascular changes.
Summary/Accomplishments (Outputs/Outcomes):
Heart Rate Studies. The major focus of this research project was to compare the cardiac effects of concentrated ambient PM versus common gaseous air pollutants. In these experiments, we observed differences in the response of animals to environmentally relevant concentrations of concentrated ambient PM versus nitrogen dioxide, carbon monoxide, or sulfur dioxide. As in our previous work, we observed day-to-day variation in heart rate effects after exposure of young and old normal rats to concentrated ambient PM.
Concentrated ambient PM is a realistic surrogate for particulate air pollution for use in controlled animal and human exposures. However, concentrated ambient PM is not enriched in ultrafine particles or copollutant gases. Therefore, we conducted a series of cross-over experiments comparing the effects of concentrated ambient PM and SO2 in normal and aged rats. These studies were performed to determine whether the effects of any of these exposures are similar to cardiac health effects reported in panel and epidemiology studies of particulate air pollution. We exposed young and aged rats to concentrated ambient PM for 4 hours with electrocardiogram monitoring before, during, and up to 48 hours post-exposure. Effects of PM exposure on heart rate are shown below in Table 1.
Rat Age |
PM Conc. (µg/m3) |
Effect on Heart Rate |
Time Course of Effect |
Young I |
215 |
Decrease |
6-23 hours postexposure |
Young II |
60 |
Increase |
1-24 hours postexposure |
Old I |
200 |
Increase |
18-25 hours postexposure |
Old II |
161 |
Decrease |
22-31 hours postexposure |
Significant effects on heart rate were seen in each of the individual concentrated ambient PM exposures, but the direction of the effect was variable on the 2 days of the cross-over study design. Heart rate effects occurred within the first 24 hours after exposure in young animals and lasted for up to 24 hours. When the data from each of the exposures were combined, there was no significant change in heart rate in either the young or old rats, thus suggesting that concentrated ambient PM has no effect on normal, healthy rats. Exposure to SO2 at a concentration far above ambient levels (1 ppm) also had no significant effect on heart rate. These SO2 exposures were repeated twice in young rats and four times in old rats (using a cross-over design).
The next series of studies compared the effects of concentrated ambient PM, laboratory-generated ultrafine carbon particles in young versus old normal rats (see Table 2). Exposure to ultrafine carbon was generated by pyrolysis of acetylene at high temperature under reducing conditions. Target concentrations of 500 and 1,500 µg/m3 significantly decreased heart rate in young rats and increased heart rate in old rats with a time course of effects similar to that for the concentrated ambient PM exposures (i.e., later effects for the older rats). Thus, the ultrafine carbon particles, at concentrations higher than the concentrated ambient PM exposures, produced consistent changes in beats per minute (bpm).
Rat Age |
Carbon Conc. (µg/m3) |
Effect on Heart Rate |
Time Course of Effect |
Young I |
576 |
5 bpm Decrease |
7-28 hrs postexposure |
Young II |
1666 |
8 bpm Decrease |
6-32 hrs postexposure |
Old I |
497 |
9 bpm Increase |
26-30 hrs postexposure |
Old II |
1279 |
16 bpm Increase |
25-37 hrs postexposure |
We also examined the effect of particles on heart rate in a rat model of high blood pressure. Unlike the variable changes seen in young and old rats exposed to concentrated ambient PM, we observed a consistent increase in heart rate following a single 4-hr exposure of 12-month-old spontaneously hypertensive rats (SHR) (see Table 3). This increase in heart rate was not observed in old, SHR exposed to 25 ppm carbon monoxide or 1 ppm nitrogen dioxide. These findings suggest that ambient particles have a more significant effect on the cardiovascular system of aged, SHR at these exposure concentrations.
Rat age |
PM Conc. (µg/m3) |
Effect on Heart Rate |
Time Course of Effect |
SHR I |
165 |
Increase |
26-34 hours postexposure |
SHR II |
178 |
Increase |
12-29 hours postexposure |
SHR I + II* |
172 |
Increase |
8-55 hours postexposure |
CO* |
25 |
No change |
Not applicable |
NO2* |
1 |
No change |
Not applicable |
* SHR I + II, CO, and NO2 are the combined results of two cross-over exposures. |
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Pulmonary Function. Guinea pigs are particularly sensitive to the pulmonary effects of inhaled particles and our laboratory has used this animal model extensively in examining the pulmonary effects of acid-coated particles. Therefore, we used guinea pigs as a potentially sensitive model of the response of human subjects to test the effect of concentrated ambient PM on pulmonary function. Lung volumes and diffusing capacity for carbon monoxide (DLco) were measured in Hartley, outbred guinea pigs at 24 hours after a single 3-hour exposure to air or concentrated ambient PM. As seen in Table 4, no significant changes in pulmonary function were observed. These data confirm the lack of effects observed in previous experiments using normal and compromised rats and hamsters.
AIR n = 6 |
PM n = 5 |
|
VC |
19.8 ± 0.8 |
19.2 ± 0.8 |
TLC |
23.7 ± 1.3 |
22.2 ± 0.7 |
RV |
3.9 ± 0.9 |
2.9 ± 0.3 |
FRC |
8.8 ± 1.0 |
7.4 ± 0.3 |
DLco |
0.31 ± 0.02 |
0.28 ± 0.01 |
DLco/VA |
0.01 ± 0.001 |
0.01 ± 0.001 |
a All data
are expressed as mean ± SE. |
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Genetic Susceptibility. In a collaboration with Dr. Mossman (University of Vermont), we studied whether different strains of mice were more susceptible to the inflammatory effects of inhaled PM. Using nose-only restrainers, male C3H/HeJ and C57/BL6 mice (22 to 34 g) were exposed to PM2.5 at the New York University Medical Center in Manhattan, NY. These two inbred mouse strains were chosen because of their differential inflammatory responses to ozone. Mice were exposed to concentrated ambient PM2.5 for 6 hours (250 µg/m3) and were studied at 0 and 24 hours post-exposure. Sham control mice were identically treated, but exposed to filtered clean air. At both time points, the lungs of sham and PM2.5-exposed mice were lavaged to determine total and differential cell counts and the lung tissue was frozen immediately in liquid nitrogen for isolation of RNA.
At 24 hours post-exposure, an overall trend analysis indicated that significant
increases (p < 0.05) in steady-state messenger RNA (mRNA) levels of TNF-,
TNF-ß, IL-6, INF-
, and TGF-ß2 occurred in lung homogenates of
PM2.5-exposed mice in comparison with sham controls. No changes in gene expression
were observed at the end of the 6-hour exposure. Surprisingly, the response
to PM2.5 was similar for both strains of mice. Neither strain exhibited increases
in total cell numbers or neutrophils after exposure. Thus, despite a lack
of a measureable cellular response, modest but significant increases in mRNA
for several inflammatory cytokines were observed.
Journal Articles on this Report : 4 Displayed | Download in RIS Format
| Other project views: | All 9 publications | 4 publications in selected types | All 4 journal articles |
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Gordon T, Gerber H, Fang CP, Chen LC. A centrifugal particle concentrator for use in inhalation toxicology. Inhalation Toxicology 1999;11(1):71-87. |
R826244 (2000) R826244 (Final) R825268 (Final) |
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Gordon T, Reibman J. Cardiovascular toxicity of inhaled ambient particulate matter. Toxicological Sciences 2000;56(1):2-4. |
R826244 (1999) R826244 (2000) R826244 (Final) R827351 (Final) R827351C004 (2002) R827351C004 (Final) |
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Shukla A, Timblin C, BeruBe K, Gordon T, McKinney W, Driscoll K, Vacek P, Mossman BT. Inhaled particulate matter causes expression of nuclear factor (NF)-κB–related genes and oxidant-dependent NF-κB activation in vitro. American Journal of Respiratory Cell and Molecular Biology 2000;23(2):182-187. |
R826244 (1999) R826244 (2000) R826244 (Final) |
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Timblin C, BeruBe K, Churg A, Driscoll K, Gordon T, Hemenway D, Walsh E, Cummins AB, Vacek P, Mossman B. Ambient particulate matter causes activation of the c-jun kinase/stress-activated protein kinase cascade and DNA synthesis in lung epithelial cells. Cancer Research 1998;58(20):4543-4547. |
R826244 (1999) R826244 (Final) |
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Supplemental Keywords:
particles, metals, ambient air, animal, mechanisms, mammalian., RFA, Scientific Discipline, Health, Air, particulate matter, Toxicology, Health Risk Assessment, Risk Assessments, Environmental Monitoring, Biochemistry, Atmospheric Sciences, co-factors, copollutant exposures, cardiopulmonary responses, inhalability, morbidity, cardiovascular vulnerability, dose response, air pollution, air sampling, biological mechanisms, cardiopulmonary mechanisms, chronic health effects, particulate exposure, Acute health effects, mortalityProgress and Final Reports:
Original AbstractThe 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.