2009 Progress Report: Epidemiological Studies on Extra Pulmonary Effects of Fresh and Aged Urban Aerosols from Different Sources

EPA Grant Number: R832415C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R832415
(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: Epidemiological Studies on Extra Pulmonary Effects of Fresh and Aged Urban Aerosols from Different Sources
Investigators: Peters, Annette , Breitner, Susanne , Henneberger, Alexandra , Phipps, Richard , Rückerl, Regina , Stoelzel, M , Utell, Mark J. , Wichmann, Heinz-Erich , Zareba, Wojciech
Institution: GSF-National Research Center for Environment and Health , University of Rochester
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2012)
Project Period Covered by this Report: July 1, 2008 through June 30,2009
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

The objective of the epidemiological study is to examine the effect of fine and ultrafine particles on systemic responses, endothelial and cardiac function. The study was conducted in Augsburg, Germany, between March 19, 2007, and December 17, 2008.

The specific aims of the study are to:

Aim #1:   Determine the effect of ambient fine and ultrafine particles on an acute phase reaction in the blood of subjects with type 2 diabetes mellitus (T2DM), impaired glucose tolerance (IGT), and potential genetic susceptibility (gen. susc.).

Aim #2:   Determine the effect of ambient fine and ultrafine particles on pro-thrombotic states of the blood in the above subject panels.

Aim #3:   Determine the effect of ambient fine and ultrafine particles on endothelial dysfunction as a key element of coronary vulnerability in a subset of the above subject panels.

Aim #4:   Determine the effect of ultrafine particles on cardiac function as characterized by ECG measures of autonomic function and repolarization in a subset of the above subject panels.

The objectives have not been altered during this reporting period.

Progress Summary:

Figure 1 shows an overview of the study design. We examined 276 participants consisting of 1) 84 participants with T2DM, 2) 104 participants with IGT and 3) 88 participants with potential gen. susc. All individuals were invited to participate in seven repeated examinations, scheduled every 4-6 weeks on the same weekday and at the same time of the day. At each visit (base program) a blood withdrawal was conducted. Air pollution was measured at a central measurement site in Augsburg throughout the complete study period. In addition (add-on program), for a subgroup of 112 participants personal measurements of ultrafine particles using a portable condensation particle counter (CPC) as well as temperature, humidity and noise were conducted in up to four visits. Furthermore, endothelial function as a key element of coronary vulnerability as well as cardiac function characterized by ECG measures (including a resting ECG for 20 minutes) were assessed in this subset.

Figure 1. Study design.

Exclusions and drop outs, validity of examinations

Figure 2 shows the recruitment and progress status of the study. Nine participants were excluded after the first visit, five of them because of rheumatoid arthritis, three because of arthropathic psoriasis, polyarthritis and Crohn’s disease, respectively, and one individual turned out to be a regular smoker. Six persons dropped out of the study after the baseline examination. 276 participants were included into the study and 1799 visits were conducted. We considered only those participants for analysis who had at least either two blood withdrawals or one ECG-measurement or two endothelial function (ED) measurements. Therefore, we excluded one participant with two visits since he did not meet this criterion. Further 17 visits, which were part of the base program, were not considered due to invalid blood draws. In total, we included 275 participants and 1780 visits in the analysis. 163 of 275 subjects (59.3%) with 1051 valid visits (59.0%) exclusively participated in the base program.222 participants (80.7%) have completed at least 7 visits.

112 volunteers (40.7%), who participated in the add-on program, completed 729 valid visits (41.0%) including 385 visits with personal measurements and 344 visits only with blood withdrawal.

 

Figure 2. Flow diagram of recruitment and accomplishment.

1Refused: persons refused participation because of their negative attitude to research in general.
2Impeded: participation was not possible because of illness or having not enough time, but person had a positive attitude to research.
3One participant had a myocardial infarction between the fifth and sixth visit.

Table 1 shows the different sample sizes for the three outcomes (Blood, ECG, ED).

  • Out of 1799 visits 23 blood draws (1.3%) could not be conducted due to an acute inflammatory disease of the participants. These 23 blood draws include the 17 excluded visits mentioned above. For the remaining six visits without blood withdrawal the ECG or ED measurement is available. One blood sample was missing.
  • Out of 385 intended ECG measurements, three (0.8%) could not be conducted because no empty flash card was available at the time of the visit. In 16 of 382 conducted measurements (4.2%) the flash card remained empty or was unreadable. Incorrect data were recorded for three ECG measurements (0.8%) so that 363 of 382 ECG recordings (95.0%) were valid. In order to analyse A) the 5min or 1h segments of the ECG parameters at least one ECG recording has to be available per participant. For the analysis of B) the 20 min. resting ECG in supine position and the average of the complete long-term ECG, at least two ECG measurements are required per patient for the statistical analysis. Nine participants ended up with only one valid ECG recording each and thus, were excluded for part B) of the analysis.
  • Out of 385 intended ED measurements, 371 were carried out (96.4%). Three ED measurements could not be conducted because of technical problems and five participants refused the measurement in eleven visits. Out of the 371 conducted measurements, nine ED recordings (2.4%) had to be excluded because of inadequate quality. Additionally, eight  participants (2.2%) with only one ED measurement were excluded as at least two ED measurements per participant are required for data analysis. Thus, 354 of 371 ED measurements (95.4%) of 100 participants are available.

For 327 of 385 visits (84.9%), all three outcome measures were valid for analysis.

Table 1. Numbers of blood draws, ECG and ED measurements

<> 

Not conducted

Conducted

 

In total

missing/
incorrect data

excluded (not valid for analysis)

available

<>Blood

 

23

1776

1

1a

1774

ECG

<>5min/1h segments

3

382

19

0

363

resting ECG / overall mean

9b

355

<>ED

 

14

371

9

8c

354

aFor one participant only 1 blood withdrawal was available. bFor 9 participants only 1 ECG-measurement was available. cFor 8 participants only 1 ED-measurement was available.

Participant characteristics

The baseline characteristics of the study population are shown in Table 2.

Table 2. Baseline characteristics of the study population

Characteristic

All

(N=275)

T2DM
(N=83)

IGT
(N=104)

Gen. susc.

(N=88)

p-value for heterogeneity between panels

Male (%)

157 (57.1)

49 (59.0)

59 (56.7)

49 (55.7)

0.93c

Age [yrs]a

63.5

(32.8-82.3)

68.0
(50.0-80.2)

66.1
(44.3-82.3)

56.4
(32.8-79.1)

<.0001d

BMI [kg/m2]a

29.3

(19.9-56.0)

31.6 b
(22.4-43.3)

29.6
(20.0-56.0)

26.9
(19.9-46.7)

<.0001d

a mean (range); b for one participant the value for the bmi is missing; c chi-square test; d ANOVA

Genetic information

Table 3 shows the frequencies of selected SNPs (CRP rs1205; Fibrinogen rs1800790; GSTM1) within the study population and within the KORA-Survey 2000. The study population was recruited out of the KORA-Survey 2000 and the KORA F4 (Follow up of KORA-Survey 2000). Table 4 shows the frequencies of selected SNPs (CRP rs1205; Fibrinogen rs1800790; GSTM1) within the study population. Study subjects with potential genetic susceptibility were recruited to have GSTM1 00 and (rs1205 CC or rs 1800790 AA/AG).

Table 3. Frequencies of selected SNPs (CRP rs1205; Fibrinogen rs1800790; GSTM1) within the study population (Study pop) and within the KORA-Survey 2000 (KORA Survey).

rs1205

rs1800790

GSTM1

n
%

Study pop

KORA Survey

n
%

Study pop

KORA Survey

n
%

Study pop

KORA Survey

CC

 

129

46.9

1698

43.6

AA

 

18

6.6

192

4.7

00

 

161

58.6

1755

42.5

CT

 

98

35.6

1757

45.1

AG

 

104

37.8

1323

32.1

01 or 11

 

92

33.5

1999

48.4

TT

 

26

9.5

442

11.3

GG

 

139

50.6

2356

57.1

 

 

 

Missing

 

22

8.0

230

5.6

Missing

 

14

5.1

256

6.2

Missing

 

22

8.0

373

9.0

Total

275

4127

Total

275

4127

Total

275

4127

Table 4. Frequencies of selected SNPs (CRP rs1205; Fibrinogen rs1800790; GSTM1) within the study population.

rs1205

 

Total

n
%

T2DM

IGT

Gen.susc.

 

CC

23

31.9

47

50.5

59

67.1

129

51.0

CT

40

55.6

33

35.5

25

28.4

98

38.7

TT

9

12.5

13

14.0

4

4.6

26

10.3

 

 

 

 

253

100%

rs1800790

 

Total

n
%

T2DM

IGT

Gen.susc.

 

AA

2

2.6

13

13.4

3

3.5

18

6.9

AG

27

35.1

35

36.1

42

48.3

104

39.8

GG

48

62.3

49

50.5

42

48.3

139

53.3

 

 

 

 

261

100%

GSTM1

 

Total

n
%

T2DM

IGT

Gen.susc.

 

00

33

44.6

40

44.0

88

100.0

161

63.6

01 or 11

41

55.4

51

56.0

0

0.0

93

36.4

 

 

 

 

253

100%

Blood measurements

In total, 1774 valid blood samples were available. The collected blood samples were transferred to the Helmholtz Zentrum München and stored for future analyses or sent out to cooperating laboratories. One set (one sample of each visit of each patient) of the EDTA plasma NUNC tubes was sent to the laboratory of Prof. Koenig in Ulm for the determination of fibrinogen. Two sets of citrate plasma NUNC tubes were sent to the EPA laboratory of Dr. Devlin in Chapel Hill for the determination of C-reactive protein (CRP), interleukin-6 (IL-6), myeloperoxidase (MPO) and plasminogen activator inhibitor-1 (PAI-1). One set of citrate plasma NUNC tubes was sent to the laboratory of Dr. Phipps in Rochester for the determination of sCD40L. All samples arrived safely and deep frozen. The analysis of fibrinogen and sCD40 Ligand has already been completed (for descriptive statistics see Table 5) while the other analyses are still ongoing. Laboratories will keep the remaining plasma for further analyses.

Table 5. Descriptive statistics of fibrinogen

 

All

T2DM

IGT

Gen.susc.

 

 

N

mean

SD

N

mean

SD

N

mean

SD

N

mean

SD

p-valuea

Fibrinogen

1773b

3.6

0.7

521

3.7

0.8

675

3.7

0.6

577

3.3

0.5

<0.0001

sCD40 Ligand

1173b

860.3

628.1

522

764.4

532.4

675

797.1

488

576

1021.2

800.6

<0.0001

F-Test; b one measurement is missing

ECG

In total, 363 valid ECG measurements were available. The duration of each recording was longer than four hours. Several time domain (e.g., normalized RR intervals, RMSSD, PNN50) and frequency domain (e.g., high and low frequency)  characteristics of heart rate variability, repolarization parameters (e.g., Bazett-corrected QT interval, T-wave amplitude), and variables regarding ST-segment changes were calculated and are available in intervals of five minutes. Additionally, the parameters were calculated as hourly means, as means for the 20min. resting ECG and as an overall mean comprising the complete ECG measurement.

The data was analysed in Rochester by the cardiac facility core (Dr. Zareba) and is currently checked for plausibility.

Endothelial function

In total, 354 valid ED measurements were available. The description of the ED parameters is shown in Table 6.

Table 6. Description of ED parameters

 

All

T2DM

IGT

Gen.susc.

 

 

N

mean

SD

N

mean

SD

N

mean

SD

N

mean

SD

p-valuea

Reactive hyperemia

354

2.0

0.6

106

1.9

0.6

102

2.0

0.5

146

2.1

0.6

0.3221

Augmentation index

354

7.8

12.9

106

5.8

8.8

102

9.8

13.4

146

7.8

14.8

0.5426

Point in time 1. peak – point in time 2. peak

354

91.7

22.9

106

85.9

19.4

102

88.2

22.6

146

98.4

23.9

0.0109

aF-Test

Only the augmentation index and the point in time 1. - 2. peak showed a strong correlation of 0.92 (median of patient-specific Spearman correlation coefficients).

According to the recommendation of the manufacturer, room temperatures during ED measurements should vary between 21 and 24°C. In 18 cases, the room temperature exceeded the upper limit in the beginning and/or in the end of an ED measurement with a maximum of 1.2 °C. During one measurement the temperature was below 21°C. In 1 and 47 cases, the room temperature was missing in the beginning and end of an examination, respectively. The quality of all these measurements was assessed as good. ED parameters measured at temperatures beyond the required ranges did not differ significantly from ED parameters measured under normal temperature conditions.

Air pollution and meteorological measurements at a central monitoring site

Particulate and gaseous air pollutants were measured at a central monitoring site between March 14, 2007 and December 17, 2008. The examinations only started on March19; however, as lag times of up to 5 days will be taken into account for the analyses, air pollution measurements started earlier. Among others, mass and number concentrations with different size fractions as well as nitrogen dioxide, carbon monoxide, air temperature, relative humidity, and air pressure are available. The data are still preliminary and are currently checked for plausibility. Table 7 shows the description of 24h-averages of particulate air pollutants and meteorological variables.

Table 7. Daily concentration of air pollutants and meteorological variables between March 14, 2007, and December 17, 2008.

 

N

Mean

SD

Min

Q1

Median

Q3

Max

IQR

PM10 [µg/m³]

639

19.3

13.7

5.0

8.9

16.5

25.5

86.3

16.6

PM2.5 [µg/m³]

637

15.4

11.4

5.0

6.4

12.2

19.7

82.5

13.3

ACP [N/cm³]

563

2434

1727

172

1188

1990

3349

10786

2161

UFP [N/cm³]

610

10550

6487

1359

5160

9132

14596

48966

9436

Air temperature [°C]

644

9.4

6.9

-7.0

4.1

9.7

14.9

24.4

10.9

Relative humidity [%]

644

83.3

13.2

33.6

73.9

85.8

94.6

100.0

20.8

Air pressure [mbar]

644

961.5

7.9

931.7

957.2

961.6

966.1

985.3

8.9

ACP, accumulation mode particles; PM2.5, mass concentration of particles less than 2.5 µm in diameter; PM10, mass concentration of particles less than 10 µm in diameter; UFP, ultrafine particles less than 0.1 in diameter.

Personal particle, meteorological and noise measurements

341 of 385 CPC (88.6%) and 343 of 385 noise measurements (89.1%) were available for analysis. 31 CPC and 41 noise measurements were missing. 13 and one, respectively, had measurement durations of less than one hour and will not be considered for analysis. Measurements of air temperature and relative humidity were missing only in one and two cases, respectively. All other measurements lasted longer than four hours. Missing values occurred due to technical difficulties of the devices. The data is currently checked for plausibility. Figure 3 shows the frequency of CPC and noise measurement durations. Figure 4 shows the preliminary relative distribution of Leq(A), the equivalent continuous sound level (A-weighted), in total and depending on where the participant was staying. Since the activity diaries have not been completely entered into a database yet, the figure includes only the data of 197 visits of 93 different participants so far.

 

Figure 3. Frequency of measurement durations split by panel.

Figure 4. Relative distribution of LEQ, in total and depending on where the participant was staying.

Actibelt

Between September and December 2008 individuals participating in the add-on program were equipped with a special belt called ActiBelt[1]. Its high-tech buckle carries high precision 3D-acceleration sensors that allow for a continuous, unobtrusive long-term monitoring of physical activity in daily life. 39 visits of 20 participants were available. Figure 5 shows exemplarily the pie chart of the different movements for one person. The number of steps for this patient was 1077.

Figure 6 shows the physical activity for the same individual, measured through “activity count”, which describes the filtered average acceleration as time series (one mean per minute). As unit the acceleration of gravity (g, 9.81m/s2) is used. The “activity unit” (AU, 1/100g) describes the physical activity as one value for the whole measurement period. A value below 16.37 indicates low activity, from 16.37 to 74.40 medium activity and above 74.40 high activity.

Figure 5. Exemplary pie chart for different movements of a person visiting the study center on Nov 14th, 2008.

Text Box: Activity Count [g]Text Box: 0Text Box: 0.2Text Box: 0.4Text Box: 0.6Text Box: 0.8Text Box: 1Text Box: 1.2

Figure 6. Exemplary report of physical activity for a person visiting the study center on Nov 14th, 2008.

Currently, all data from different sources are being checked and datasets are being prepared for analyses. An analysis plan for the analyses of ECG has already been drawn up. ECG data will be averaged over five minute segments. Mixed models with random patient intercepts will be used to accommodate repeated measures and to account for unobserved heterogeneity of the data. This will be done within the framework of (generalized) additive mixed models to allow for non-linear confounder adjustment. Separate confounder models will be built for each ECG parameter. Five minute-particle number concentration lags calculated for the concurrent five minutes and the hour preceding the respective ECG measurements (lag 0: average of 0-4 minutes up to lag 11: 55-59 minutes) will be calculated. In addition, sixty-minute averages will be calculated and related to air pollution mass and number concentration measurements.

An analysis plan for markers of blood and endothelial dysfunction is currently being set up.

Quality assurance measures and quality control during the study can be found in the appendix.

Future Activities:

For the upcoming year, the following activities are planned:

  1. Genetic analysis with Affymetrix 1000k chip
  2. Complete data cleaning and preparation of datasets
  3. Statistical analyses
  4. Preparation of publication manuscripts


Journal Articles on this Report : 2 Displayed | Download in RIS Format

Other subproject views: All 19 publications 18 publications in selected types All 18 journal articles
Other center views: All 190 publications 156 publications in selected types All 143 journal articles
Type Citation Sub Project Document Sources
Journal Article Hildebrandt K, Ruckerl R, Koenig W, Schneider A, Pitz M, Heinrich J, Marder V, Frampton M, Oberdorster G, Wichmann HE, Peters A. Short-term effects of air pollution: a panel study of blood markers in patients with chronic pulmonary disease. Particle and Fibre Toxicology 2009;6:25. R832415 (2009)
R832415 (2010)
R832415 (2011)
R832415 (Final)
R832415C002 (2009)
R832415C002 (2010)
R832415C002 (2011)
R832415C003 (2010)
R832415C003 (2011)
R832415C004 (2010)
R832415C004 (2011)
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  • Journal Article Peters A, Greven S, Heid IM, Baldari F, Breitner S, Bellander T, Chrysohoou C, Illig T, Jacquemin B, Koenig W, Lanki T, Nyberg F, Pekkanen J, Pistelli R, Ruckerl R, Stefanadis C, Schneider A, Sunyer J, Wichmann HE, AIRGENE Study Group. Fibrinogen genes modify the fibrinogen response to ambient particulate matter. American Journal of Respiratory and Critical Care Medicine 2009;179(6):484-491. R832415 (2009)
    R832415 (2010)
    R832415 (Final)
    R832415C002 (2009)
    R832415C002 (2010)
    R832415C002 (2011)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, particulate matter, Health Risk Assessment, Epidemiology, Risk Assessments, Physical Processes, atmospheric particulate matter, atmospheric particles, long term exposure, acute cardiovascular effects, airway disease, exposure, human exposure, ambient particle health effects, atmospheric aerosol particles, PM, aersol particles, cardiovascular disease

    Progress and Final Reports:

    Original Abstract
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008 Progress Report
  • 2010 Progress Report
  • 2011 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R832415    Rochester PM Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832415C001 Characterization and Source Apportionment
    R832415C002 Epidemiological Studies on Extra Pulmonary Effects of Fresh and Aged Urban Aerosols from Different Sources
    R832415C003 Human Clinical Studies of Concentrated Ambient Ultrafine and Fine Particles
    R832415C004 Animal models: Cardiovascular Disease, CNS Injury and Ultrafine Particle Biokinetics
    R832415C005 Ultrafine Particle Cell Interactions In Vitro: Molecular Mechanisms Leading To Altered Gene Expression in Relation to Particle Composition