Health effects of ambient combustion-related fine and ultrafine particulate air

pollution: recent epidemiological evidence

C. Arden Pope III, PhDBrigham Young University

9th ETH-Conference on Combustion Generated NanoparticlesZurich, Switzerland August 15-17, 2005

Outline of epidemiologic evidence that exposure to combustion-related fine PM is a risk factor for cardiopulmonary disease:

I. Episode studies--Increases in both respiratory and cardiovascular morbidity and mortality during and immediately following pollution episodes.

II. Daily time-series studies--Day-to-day changes in PM associated with cardiopulmonary disease, deaths, and hospitalizations.

III. Population and cohort studies of long-term exposure--Increased risk of cardiopulmonary mortality associated with spatial differences in PM.

IV. Studies of specific physiologic endpoints--suggestive of general pathophysiological mechanisms or pathways that link PM and cardio-respiratory morbidity and mortality.

Note: Daily time series studies have now been conducted in 100+ cities throughout the world.

Estimates of daily mortality effects of an increase in exposure to PM by broad cause-of-death categories.

Cause of Death % of total deaths

Cause-specific percent increase per 50 µg/m3 increase in

PM2.5

% of excess deaths due to PM

exposure

All cause 100 7.0 100

Respiratory 8 25.0 28

Cardiovascular 45 11.0 69

Other 47 0.4 3

Source: Pope. Environmental Perspectives 108(suppl4):713-723(2000)

A large prospective cohort study of PM and mortality originally motivated by the Harvard Six-cities study (Dockery et al. NEJM 1993)

JAMA, 2002

IV. Studies exploring mechanistic pathways linking PM exposure and mortality

The epidemiological studies provide compelling evidence of a statistical association between combustion-related fine PM and cardiopulmonary disease and mortality but . . .

. . . what are the mechanistic pathways linking exposure, disease, and mortality?

Four Hypothesized General Pathophysiologic pathways:

1. Accelerated Progression of COPD and related disease

2. Altered Cardiac Autonomic Function

3. Pulmonary/Systemic Oxidative Stress Inflammation/Accelerated Atherosclerosis

4. Modulated host defenses and immunity

1. Accelerated Progression of COPDSupported by evidence that exposure to PM is associated with:

Reduced lung function and lung function growth in children(Note recent results from So. Cal. Children’s Health Study, Gauderman et al. NEJM 2004).

Increased symptoms of obstructive airway disease

2. Altered Cardiac Autonomic Function

Supported by evidence that exposure to PM is associated with:Changes in:Heart Rate (Peters et al. 1999; Pope et al. 1999)

HRV(Liao et al 1999; Pope et al 1999, 2004; Gold et al. 2000)

Blood pressure (Ibald-Muli et al. 2001, 2004)

Arrythmiasindicated by ICD discharges (Peters, et al. 2001)

Example 2a: Pope, Verrier, Lovett et al. Am Heart J 1999Basic methods: Repeated 24-hr AECG monitoring was

conducted on 7 subjects before, during, and after PM pollution episodes.

Basic results: After controlling for individual fixed effects a 100 µg/m3 increase in PM10 was associated with about an 18 ms decrease in SDNN (a measure of overall HRV).

PM10 (µg/m3)

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24-h

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Twenty-four hour SDNN (ms) plotted over PM10 withplots of individual regression lines.

PM

10 (u

g/m

3 )

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Plot of daily PM10 during data collection period.Larger dots represent days with ambulatory ECGmonitoring. Individuals being monitored areidentified by their corresponding subject numbers.

Example 2b: Pope, Eatough, Gold et al. EHP 2001AECG monitoring over 8 hrs while subjects alternated 2 hrs in

nonsmoking and smoking areas of the SLC airport.ETS-related PM exposure (being in the smoking lounge) was

associated with an average 10 ms decrease in SDNN.

Time in hours (10:15-18:15, Dec. 22, 1999)

Mea

n nu

mbe

r of l

it ci

gare

ttes

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-hr S

DN

N (m

s)

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Nonsmoking areaNicotine = 0 µg/m3

RSP = 43 µg/m3

Smoking areaNicotine = 23 µg/m3

RSP = 166 µg/m3

Nonsmoking areaNicotine = 2 µg/m3

RSP = 26 µg/m3

Smoking areaNicotine = 38 µg/m3

RSP = 57 µg/m3

Time in hours (9:45-17:45, Jan. 4, 2000)

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RSP = 18 µg/m3

Smoking areaNicotine = 21µg/m3

RSP = 41 µg/m3

Nonsmoking areaNicotine = 0 µg/m3

RSP = 12 µg/m3

Smoking areaNicotine = 53 µg/m3

RSP = 48 µg/m3

Hawthorne Winter(1999/2000)

Nov 29 Dec 19 Jan 8 Jan 28 Feb 17 Mar 8 Mar 28

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f Obs

erva

tions

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5 (µg

/m3 )

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Hawthorne Summer(2000)

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/m3 )

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Figure 1.

Example 2c: Pope, Hansen,Long, et al. EHP 2004

Methods: Multiple 24-hr AECG monitoring and collection of blood markers of inflammation in a panel of 88 elderly subjects from three communities along the Wasatch Front in Utah.

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Figure 3.

Example 2c: Pope, Hansen,Long, et al. EHP 2004--continued

Results: A 100-µg/m3

increase in PM2.5 was associated with:

35 (SE=8) msec decline in SDNN

0.81 (SE=0.17) mg/dl increase in CRP

3. Inflammation/Accelerated AtherosclerosisAtherosclerosis is a progressive disease characterized by the buildup of fatty plaques in artery walls. Atherosclerotic plaques are encased in a fibrous cap. They have different sizes, shapes and vulnerability to rupture and blood clots.

Atherosclerotic plaques in the coronary arteries result in coronary artery disease (CAD) and varying degrees of restricted flow of blood and oxygen (ischemia). This ischemia may cause chest pain (angina), change in cardiac function, and/or damage to the heart.

Histopathological view of artery

Plaque rupture and clot formation can often completely block an already narrowed artery. This is what happens in most heart attacks (myocardial infarctions) and strokes.

So, what is the hypothesized link between PM air pollution and atherosclerosis?

Much evidence suggests that inhaling PM can provoke low-grade pulmonary/systemic inflammation.

Over the last few decades research has linked inflammation along with blood lipid levels to atherosclerosis (Libby, Ridker, Maseri. Circulation 2002).

Inflammation contributes to the initiation and progression of atherosclerosis.

Inflammation also contributes to acute thrombotic complications, making plaques more vulnerable to rupture, clotting, and precipitating acute cardiovascular or cerebrovascular events (heart attacks and strokes).

C-reactive protein (CRP), a marker of low-grade chronic inflammation, has been shown to serve as a predictor of risk of atherosclerosis related cardiovascular disease.

Example 3a: Souza, Saldiva, Pope, Luiza. Chest 1998Basic methods: Lung tissue samples were collected during

necropsies of individuals who died due to violent causes and wholived in relatively clean and polluted areas near Sao Paulo, Brazil.

Basic results: Those who lived in more polluted areas had histopathologic evidence of sub-clinical chronic inflammatory lung injury.

Inflammation/Accelerated Atherosclerosis is supported by evidence that PM exposure is associated with:

C-reactive protein (CRP) (Peters et al. 1997; Pope et al 2004)

Blood plasma viscosity (Peters et al 1997)

Bone marrow and blood cell responses (Tan et al. 2000)

Proinflammatory cytokines (Van Eeden et al. 2001)

Inflammatory lung injury (Ghio, Devlin 2001; Souza et al 1998)

Endothelial dysfunction and brachial arteryvasoconstriction (Brook et al. 2002)

Triggering of Myocardial Infarction(Peters et al. 2001)Increased CIMT (carotid intima-media thickness)(Kunzli et al)Accelerated atherosclerosis (in rabbits)(Suwa et al. 2002)

Circulation. 2004;109:71-77.

Methods:General pathophysiological pathways linking long-term PM

exposure with mortality and expected patterns of PM-mortality with specific causes of death were proposed a priori.

Vital status, risk factor, and cause-of-death data from ACS CPS-II were linked with pollution data.

Estimate PM-mortality associations for specific causes of deaths controlling for other risk factors (using similar statistical modeling described in the previous ACS analysis)

Table 1. Expected patterns of PM-mortality associations for specific causes ofcardiopulmonary deaths based on three hypothesized general pathophysiologicalpathways.

Cause of Death

AcceleratedProgression

of COPD

Inflammation/Accelerated

Atherosclerosis

Altered Cardiac

AutonomicFunction

All cardiovascular diseases plus diabetes Ischemic heart disease Dysrhythmnias, heart failure, cardiac arrest Hypertensive disease Other atherosclerosis, aortic aneurysms Cerebrovascular disease Diabetes All other cardiovascular diseasesDiseases of the respiratory system COPD and allied conditions Pneumonia and influenza All other respiratory

RR

(95%

CI)

0.650.700.750.800.850.900.951.001.051.101.151.201.251.301.351.40

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Figure 1. Adjusted relative risk ratios for cardiovascular and respiratory mortality associated witha 10 µg/m3 change in PM2.5 for 1979-1983, 1999-2000, and the average of the two periods.(Relative size of the dots correspond to the relative number of deaths for each cause.)

Modulation of host defenses and immunity is suggested by the increase in pneumonia and influenza deaths, but not COPD deaths, associated with long-term PM exposure. Other reports of pollution associations with pediatric respiratory hospitalizations and bronchitis and pneumonia related symptoms are also suggestive .

General scheme illustrating potential mechanistic pathways.

From:AHA Scientific Statement--Brook RD, et al. Circulation 2004

What is the role of ultrafine (or nanoparticles) versus other combustion-related fine particles?

Ambient air is constantly being polluted by fresh emissions of ultrafineparticles that have short lives (minutes to hours) and rapidly grow (through coagulation and/or condensation) to form complex aggregates

Magnification of urban soot depicting aggregates of individual particles (www.defra.gov.uk/environment/airquality/aqs/air_measure/03.htm)

Magnified ambient particles from the industrial city of Port Talbot, England.(www.nasa.gov/vision/earth/environment)

Epidemiology is limited in its ability to elucidate the role of ultrafine (or nanoparticles) versus other combustion-related fine particles (in the accumulation mode because of the complex and ever changing nature of these particles.

Nevertheless, there is clear evidence that both fine and ultrafine particles can have adverse effects on cardiorespiratory health.

Idealized particle size distribution of urban aerosols.

From: Whitby K. Atmospheric Environment 1978

Aerodynamic Particle Diameter, µm0.1 0.2 0.3 0.5 1 2.5 5 10 20 50 100

Vol

ume

20

40

60

Figure 1. Stylized distributions of fine and course ambient particualte matter. The distribution is truncated at 0.1 µm, excluding the ultrafine fraction. Source: Adapted from Wilson and Suh (1997).

Total Suspended Particles (TSP)PM10

PM2.5 PM10-2.5

Fine Particles Coarse Particles

Primary sources: Combustion of fossil fuels. High tempera- ture processes such as smelters, steel mills. Atmos- pheric transformationproducts includingsulfates and nitrates.

Primary sources: Suspension or resuspension of dust, soil or other crustal materials from roads, farming, mining, wind storms, volcanos, etc.Also sea salts, pollen, moldspores, plant parts, etc.

Lifetimes: Days to WeeksTravel Dist: 100s -1000s K.

Lifetimes: Minutes to hoursTravel Dist: 1 -10s K.