Health Effects of Air PollutionHealth Effects of Air Pollution

March 17, 2010

Presented by David B. Peden, M.D., M.S.Professor of Pediatrics, Medicine &

Microbiology/ImmunologyDirector, UNC Center for Environmental Medicine,

Asthma and Lung Biology

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DisclosuresDisclosures

• CORPORATE• GlaxoSmithKline• Funxional Therapeutics

• FEDERAL• US EPA• NHLBI• NIEHS• NCCAM

Sources of Common Environmental Contaminants Which Modify Asthma

National Ambient Air Quality Standards National Ambient Air Quality Standards (NAAQS)(NAAQS)

Pollutant Primary Stds. Averaging Times

Carbon Monoxide 9 ppm (10 mg/m3) 8-hour(1)

35 ppm (40 mg/m3) 1-hour(1)

Lead 1.5 µg/m3 Quarterly Average

Nitrogen Dioxide 0.053 ppm (100 µg/m3) Annual (Arithmetic Mean)

Particulate Matter (PM10)

Revoked(2) Annual(2) (Arith. Mean)

150 µg/m3 24-hour(3)

Particulate Matter (PM2.5)

15.0 µg/m3 Annual(4) (Arith. Mean)

35 µg/m3 24-hour(5)

Ozone 0.075 ppm 8-hour(6)

0.12 ppm 1-hour(7)(Applies only in limited areas)

Sulfur Oxides 0.03 ppm Annual (Arith. Mean)

0.14 ppm 24-hour(1)

Pollutants and AsthmaPollutants and Asthma

Environmental Agents Which Induce Environmental Agents Which Induce Asthma, Allergies and Lung DiseaseAsthma, Allergies and Lung Disease

• Probable» Diesel Exhaust» ETS

• Possible» O3

» NO2

» Other Particulates

• Plausible» Low dose endotoxin (Gauderman et al NEJM,

2004, 351:1057-1067)

Environmental Agents Which Worsen Environmental Agents Which Worsen Asthma and AllergiesAsthma and Allergies

• Ozone

• SO2

• NO2

• Diesel Exhaust• Particulates• Environmental

Tobacco Smoke• Endotoxin

Burnett, RT et al. Am J Epidemiol. 2001 Mar 1;153(5):444-52

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1985 1986 1987 1988

Steel Mill Closed

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1985 1986 1987 1988

Steel Mill Closed

Impact of steel mill closing on PM 2.5 (left, Impact of steel mill closing on PM 2.5 (left, g/mg/m33) and Bronchitis admissions (right) in the ) and Bronchitis admissions (right) in the

Utah Valley (Pope, et al)Utah Valley (Pope, et al)

Endotoxin exposure is a risk factor for asthma: the Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing.national survey of endotoxin in United States housing.

Am J Respir Crit Care Med. 2005 Dec 1;172(11):1371-7Am J Respir Crit Care Med. 2005 Dec 1;172(11):1371-7

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Pollutants shown to enhance recall Pollutants shown to enhance recall response to allergenresponse to allergen

• Ozone

• NO2/SO2

• Endotoxin• Diesel Exhaust• ETS• Responses include:

» IgE» PMNs» Eosinophils» Airway Reactivity

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mean air air LPS mean LPS1.02.04.08.0

16.032.064.0

128.0256.0512.0

1024.02048.0

PC

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EV

1 m

ite

alle

rgen

(AU

/ml)

p<0.05n=14

Airway Responses of Airway Responses of Asthmatics to OzoneAsthmatics to Ozone

Copyright restrictions may apply.

Daily Levels of Ozone (Both 1-Hour Average and 8-Hour Average), Particulate Matter of 2.5 {micro}m or Less (PM2.5), and Daily Maximum Temperature, With Daily Prevalence of

Respiratory Symptoms for Users of Asthma Maintenance Medication (n = 130) for Southern New England, April 1 through September 30, 2001 Gent, J. F. et al. JAMA 2003;290:1859-1867

Granulocyte Response to OGranulocyte Response to O33

Effect of OEffect of O33 on IL-1 on IL-1 and IL-6 and IL-6

in Asthma and Normal Volunteersin Asthma and Normal Volunteers

Effect of OEffect of O33 on IL-8 and IL-10 on IL-8 and IL-10

in Asthma and Normal Volunteersin Asthma and Normal Volunteers

Ozone Enhances Markers of Innate Immunity and Antigen Ozone Enhances Markers of Innate Immunity and Antigen Presentation on Airway Monocytes in Healthy Individuals Presentation on Airway Monocytes in Healthy Individuals

J Allergy Clin Immunol. 2007 Sep;120(3):719-22J Allergy Clin Immunol. 2007 Sep;120(3):719-22

Ozone enhances response to inhaled allergens

Effect of 0.16 ppm O3 on Immediate Bronchial Responses to Inhaled Allergen

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8.0

4.0

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Mean Air Ozone MeanMean Air Ozone Mean

HD

M C

on

cen

trat

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(A

U/m

l)H

DM

Co

nce

ntr

atio

n (

AU

/ml)

House Dust MiteHouse Dust Mite

D-14

(Kehrl et al, 1999)(Kehrl et al, 1999)

Effect of 0.4 ppm O3 on NasalAllergen-Induced Eosinophil Influx

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2525

5050

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Clean AirClean Air OzoneOzone3-hr post allergen challenge3-hr post allergen challenge

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/ml N

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000

)E

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ph

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100

0)

D-15

(Peden et al, 1995)(Peden et al, 1995)

• Ozone exposure causes increased immediate allergic responses to house dust mite

• Ozone causes increased eosinophil (allergy cell) influx to the airway

• Experimentally demonstrated at levels as low as 0.12 ppm

SummarySummary• Epidemiological Studies clearly demonstrate an effect of

ambient air ozone in asthma • Ozone causes an immediate decrease in lung function• Ozone induced airway inflammation

» PMNs in all populations» Eosinophils-seen in asthmatics

• Ozone results in changes in airway cell surface markers which likely modulate immune response

• Ozone increases response to allergen

Climate Change, Pollutants and Climate Change, Pollutants and Environmental AllergensEnvironmental Allergens

Global temperature land-ocean anomaly (°C), 1880-2007, defined as the difference from the Global temperature land-ocean anomaly (°C), 1880-2007, defined as the difference from the average temperature of the base period (1951-1980). The 14 warmest years in the global average temperature of the base period (1951-1980). The 14 warmest years in the global

temperature record have all occurred since 1990. The blue points (annual means) in the box temperature record have all occurred since 1990. The blue points (annual means) in the box from 1990-2007 show the warmest years. Adapted from: NASA 2007from 1990-2007 show the warmest years. Adapted from: NASA 2007

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Predicted increase in ambient OPredicted increase in ambient O33 by 2050 by 2050

resulting from Climate Changeresulting from Climate Change

21Bell et al, Climatic Change (2007) 82:61–76 DOI 10.1007/s10584-006-9166-7

Predicted exceedance of the 1 and 8 hour OPredicted exceedance of the 1 and 8 hour O33 standard standard

by 2050 resulting from Climate Changeby 2050 resulting from Climate Change

22Bell et al, Climatic Change (2007) 82:61–76 DOI 10.1007/s10584-006-9166-7

Singer BD, Ziska LH, Frenz DA, Gebhard DE, Straka JG (2005) Increasing Amb a 1 Singer BD, Ziska LH, Frenz DA, Gebhard DE, Straka JG (2005) Increasing Amb a 1 content in common ragweed (Ambrosia artemisiifolia) pollen as a function of rising content in common ragweed (Ambrosia artemisiifolia) pollen as a function of rising

atmospheric CO2 concentration. Functional Plant Biology 32, 667–670.atmospheric CO2 concentration. Functional Plant Biology 32, 667–670.

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Increased CO2 linked to increased Ragweed Pollen and increased Amb a 1concentration/mg pollen

Effect of Urbanization on Ragweed growthEffect of Urbanization on Ragweed growthZiska LH et al JACI, 2003Ziska LH et al JACI, 2003

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Oxidant Stress and PollutantsOxidant Stress and Pollutants

A unifying concept for the impact of pollutants in asthma

Oxidant stressOxidant stress is a common theme in the is a common theme in the action of a wide variety of air pollutants in action of a wide variety of air pollutants in

inflammatory processes.inflammatory processes.• Pollutants & oxidant

stress:» Pollutants

themselves• O3, metals

» Products from pollutants

• Polyaromatic hydrocarbons & quinones from DEP and ETS

» Oxidants from macrophages and granulocytes

• Singlet oxygen, H2O2, superoxide

Cross, CE et al, American Journal of Respiratory and

Critical Care Medicine Vol 166. pp. S44-S50, (2002)

GSTM1 polymorphisms and and GSTM1 polymorphisms and and lung disease in humanslung disease in humans

ETS, DEP and O3

GSTM1GSTM1

• NRF2 nuclear transcription factor• GSTM1 Null

» Associated with increased response to ozone

» Associated with increased response to diesel exhaust

» Associated with increased response to tobacco smoke

Effect of GSTM1 null genotype on asthma Effect of GSTM1 null genotype on asthma relative to tobacco smoke exposurerelative to tobacco smoke exposure

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Relative risk for ERvisit for wheeze (Odds

Ratio)

GSTM1 + no smoking

GSTM1- no smoking

GSTM1+ smoking

GSTM1- smoking

• Effect of maternal smoking during pregnancy on asthma in

GSTM1- children (panel to the left, Gilliland et al, AJRCCM 166:457-463, 2002)

• GSTM1- children exposed to environmental tobacco smoke have a 5.5 odds ratio risk of current asthma relative to GSTM+ children (Kabesch et al, Thorax 59:569 2004)

DEP effect on the response to allergen DEP effect on the response to allergen stratified by GSTM1 genotype stratified by GSTM1 genotype

Gilliland et al, Lancet. 2004 Jan 10;363(9403):119-25 Gilliland et al, Lancet. 2004 Jan 10;363(9403):119-25

• Following DEP challenge, GSTM1 null individuals (vs. GSTM1+) have increased: » allergen-induced IgE

(right)» histamine (not shown)

Effect of GSTM1 genotype and ozone induced Effect of GSTM1 genotype and ozone induced decreases in FEF25-75 in asthmatics decreases in FEF25-75 in asthmatics

Romieu et al, Thorax 2004;59:8-10Romieu et al, Thorax 2004;59:8-10

• GSTM1 null asthmatics have increased asthma symptoms with ozone exposure than do GSTM1 sufficient persons

Effect of the GSTM1 null genotype on lung function Effect of the GSTM1 null genotype on lung function and inflammatory response to 0.4 ppm ozoneand inflammatory response to 0.4 ppm ozone

32Alexis et al, JACI 2009, available on line

Effect of the GSTM1 null genotype on Effect of the GSTM1 null genotype on airway cell function, IL-1 airway cell function, IL-1 & IL-8 post & IL-8 post

ozone challengeozone challenge

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GSTM1 did impact cell function but not

IL-1or IL-8

Alexis et al, JACI 2009, available on line

GSTM1 and ozone summaryGSTM1 and ozone summary• GSTM1 does not determine lung function repsonse to

ozone• GSTM1 null has a delayed PMN response to ozone• GSTM1 null vs.sufficient have different cell marker

changes in airway monocytes

What to do about pollutant-What to do about pollutant-induced diseaseinduced disease

Patient and societal interventions

Pollutant AvoidancePollutant Avoidance

• Decrease tobacco use• Local Environmental Control• Live away from a roadway• Societal Changes (decrease traffic, better

fuels)

Changes in Traffic PatternsChanges in Traffic Patterns

1996 Atlanta Olympics

Copyright restrictions may apply.

Friedman, M. S. et al. JAMA 2001;285:897-905.

Mean Levels of Major Pollutants Before, During, and After the 1996 Summer Olympic Games as a Percentage of the National Ambient Air Quality Standard

(NAAQS)

Friedman, M. S. et al. JAMA 2001;285:897-905.

Inhaled SteroidsInhaled Steroids

Effect on response to pollutants

Inhaled Corticosteroids and Inhaled Corticosteroids and EndotoxinEndotoxin

• Inhaled corticosteroids

» Decreases baseline eosinophilic inflammation

» Decreases CD14 expression on airway monocytes and macrophages

» Decreases PMN influx to inhaled endotoxin

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* signif icantly different than placebo (p = 0.04)

PM

N/m

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Neutrophils Monocytes Macrophages

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signif icantly different from placebo (* p=0.001, ** p = 0.04)

**m

CD

14(M

FI)

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Antioxidants and Asthma Treatment

Is this an option?

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Vitamin E + C supplementation protects asthmatics from OVitamin E + C supplementation protects asthmatics from O33--

induced changes in lung function and inflammation children induced changes in lung function and inflammation children with allergic asthmawith allergic asthma

• Combination ascorbate and alpha tocopherol:» Decrease effect of

ambient O3 exposure on FEF25-75 and PEFR

» Decrease O3 related inflammation

• Other reports:» Combination therapy

decreased lung function response to O3 challenge in normal volunteers and asthmatics

» Ascorbate may protect against exercise-induced asthma

Romieu et al, AJRCCM Vol 166. pp. 703-709, (2002) Sienra-Monge et al, Clin & Exp Immunology 138 (2), 317-322. (2004)

AcknowledgementsAcknowledgements

• Neil Alexis• Philip Bromberg• John Lay• Haibo Zhou• Michelle Hernandez• Carole Robinette• Martha Almond• Peg Herbst• Aline Kala• Lynne Newlin-Clapp• Sally Ivins• Heather Wells• Nolan Sweeney

• Madeline Dillon• Jessica Wiser• Marlowe Eldridge• Robert Roubey• Dhaval Patel• Robert Devlin• David Diaz-

Sanchez• Howard Kehrl• Martin Case• Steven Kleeberger

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