Health Effects of Air Pollution:Health Effects of Air Pollution:

Asthma and Cardiovascular OutcomesAsthma and Cardiovascular Outcomes

Ralph J. Delfino, MD, PhD Ralph J. Delfino, MD, PhD Epidemiology Division, Dept. Medicine,Epidemiology Division, Dept. Medicine,

& Genetic Epidemiology Research Institute & Genetic Epidemiology Research Institute University of California, IrvineUniversity of California, Irvine

Asthma PhenotypeAsthma Phenotype

• Intermittent and reversible airway obstruction (usually measured with FEV1);

• Airway hyperresponsiveness to contractile stimuli;

• Airway inflammation: infiltration of inflammatory cells releasing cytokines, chemokines & chemical mediators.

– increasingly measured with exhaled NO (eNO)

• Allergic and non-allergic asthma

Acute asthma outcomes linked to air pollution

Experimental studies:

• Increased bronchial hyperresponsiveness;

Experimental and Epidemiological studies:

• Decreased lung function;

• Increased airway inflammation;

• Increased allergic responses;

• Increased asthma symptoms & as-needed medication use;

Epidemiological studies:

• Increased asthma morbidity from respiratory infections;

• Hospital admissions and ED visits.

Experimental Data on Polycyclic Aromatic Hydrocarbons (PAH) / DEP

• PAH and other components from fossil fuel combustion (e.g., diesel exhaust particles) may contribute to:

– worsening respiratory allergic responses (enhanced specific IgE & cytokine responses to allergen challenge)

– induction of the initial clinical expression of atopy (allergic sensitization to neoantigens)

Evidence from the Air Pollution Evidence from the Air Pollution Epidemiology LiteratureEpidemiology Literature

• Ambient Air Pollution– Time series studies (acute severe asthma

morbidity requiring medical staff intervention)

• Ambient, Outdoor Home and Personal Air Pollution– Panel studies (acute asthma outcomes)– Cohort studies (asthma onset)

Time series analyses of asthma Time series analyses of asthma hospital admissions and ED Visitshospital admissions and ED Visits

Significant associations between ozone and admissions or ED visits for asthma found in:– Southern Ontario, Canada Environ Res. 1987;43:317-31; Environ Res

1994;65:271-90

– Atlanta Environ Res 1994;65:56-68; Am J Epidemiol 2000;151:798-810; JAMA 2001;285:897-905; Epidemiology 2005;16: 164–174.

– Seattle, WA Epidemiology 1999;10:23-30.

– Brisbane and Melbourne Australia Arch Environ Health 2001;56:37-52; Int J Environ Health Res 2005;15:11-20

– Madrid, Spain Eur Respir J 2003;22:802-8

– Paris, France Pediatr Pulmonol 2000;30:41-6

– Mexico City Am J Epidemiol 1995;141:546-53

– Saint John, New Brunswick, Canada Environ Health Perspect 104:1354-60

Optimal design to study acute effects Optimal design to study acute effects on asthma in natural settingson asthma in natural settings

• Panel study: a longitudinal study with repeated measurements of health outcomes and exposures in individuals.

• e.g., UCI Asthma Panel studies:Daily follow-up of children with persistent asthmain urban regions of Southern California with high levels of air pollution, primarily from mobile sources of fossil fuel combustion products.

Panel Studies of Acute Asthma, Particulate Air Pollution & NO2

(personal and ambient air pollutant exposures)

• Asthma symptoms: episodes of interference with daily activity.

• Lung Function: Forced expiratory volume in 1 sec (FEV1).

• Airway inflammation: as represented by daily exhaled NO (eNO).

• Markers of traffic-related air pollution: PM elemental carbon (EC), PM organic carbon (OC), and NO2

Personal Exposure MonitorsPersonal Exposure Monitors

Percent Predicted FEVPercent Predicted FEV11 in Relation to Personal PM in Relation to Personal PM

Alpine, CA Asthma Panel Study. Delfino et al. Environ Health Perspect 2004;112:932-41

Percent Predicted FEVPercent Predicted FEV11 in Relation to in Relation to PMPM2.52.5 mass mass

Riverside and Whittier, CA Asthma Panel Study

Riverside and Whittier, CA Asthma Panel Study

Relationship of asthma symptoms to lag 0 PMRelationship of asthma symptoms to lag 0 PM1010 and and

elemental and organic carbon fractions of PMelemental and organic carbon fractions of PM1010Huntington Park, CA Asthma Panel Study. Delfino et al. Environ Health Perspect 2003; 111:647-656.

Delfino et al. Environ Health Perspect, 2006;114:1736-43

Riverside and Whittier, CA Asthma Panel Study

Riverside and Whittier, CA Asthma Panel Study

Riverside and Whittier, CA Asthma Panel Study

ConclusionsConclusions eNO and FEVeNO and FEV11 are associated with personal PM are associated with personal PM2.52.5 independent of other independent of other

pollutants, possibly due to more vs. less volatile components, and bioaerosol pollutants, possibly due to more vs. less volatile components, and bioaerosol components (e.g., endotoxin);components (e.g., endotoxin);

Air pollutant associations may be missed using ambient PM mass Air pollutant associations may be missed using ambient PM mass concentrations alone because the EC and OC PM fraction, or NOconcentrations alone because the EC and OC PM fraction, or NO22, were , were

more strongly associated with asthma symptoms, eNO and FEVmore strongly associated with asthma symptoms, eNO and FEV11;;

Associations of eNO with ambient & personal EC and NOAssociations of eNO with ambient & personal EC and NO22 suggests traffic- suggests traffic-

related emission components are causally related to airway inflammation.related emission components are causally related to airway inflammation.

Products of fossil fuel combustion Bioaerosols

Traffic-related Air Pollution Traffic-related Air Pollution and Asthma Onsetand Asthma Onset

• Numerous epidemiologic studies have shown associations between traffic near the home and asthma prevalence or morbidity, and atopy. Reviewed in:– Delfino RJ. Environ Health Perspect, 2002; 110(Suppl 4):573-89.

– Heinrich and Wichmann. Curr Opin Allergy Clin Immunol, 2004;4:341-8

– Sarnat and Holguin 2007 Curr Opin Pulm Med 2007;13:63-6

• These studies provide evidence that air pollution from primary emission sources is a risk factor for the development of asthma.

Prevalence of asthma and black carbon at neighborhood schools, East Bay Children’s Respiratory Health Study

Kim et al. Am J Respir Crit Care Med 170:520–526, 2004

Prevalence of asthma in 1,330 children ages 5-7 yr by distance of residence to a major road in long-term residents, no family history of asthma. McConnell et al. Environ Health Perspect 2006;114:766–772

Cardiovascular Health and Air Pollution

• Morbidity and mortality time series: ambient air pollutant data and cause of admission or death.

• Cohort studies: ambient air pollutant data and disease onset or cause of death.

• Panel studies:ambient, home and personal air pollutant data and acute physiological or biological outcomes.

Time Series Studies: MortalityTime Series Studies: Mortality Dominici et al, 2003

National Morbidity, Mortality and Air Pollution National Morbidity, Mortality and Air Pollution study (NMMAPS) 90 U.S. citiesstudy (NMMAPS) 90 U.S. cities

0.34% increase cardiorespiratory mortality 0.34% increase cardiorespiratory mortality (95% CI: 0.1, 0.57) per 10 (95% CI: 0.1, 0.57) per 10 g/mg/m33 PM PM1010

largely independent of NOlargely independent of NO22, SO, SO22 and O and O33

Time Series Studies: MorbidityTime Series Studies: Morbidity

Associations of ambient PM mass Associations of ambient PM mass concentrations with cardiovascular hospital concentrations with cardiovascular hospital admissions found in numerous studies.admissions found in numerous studies.

14 U.S. cities 14 U.S. cities (Janssen et al. 2002)(Janssen et al. 2002): : PMPM1010 from mobile source emissions and from mobile source emissions and

from oil combustion (EPA estimates) from oil combustion (EPA estimates) showed the strongest associations with showed the strongest associations with cardiovascular admissions vs. fugitive dust, cardiovascular admissions vs. fugitive dust, wood burning, coal.wood burning, coal.

Cohort Studies: Cohort Studies: Pope et al. 2004 Pope et al. 2004 Circulation 109:71-77Circulation 109:71-77

Up to 500,000 persons in the American Up to 500,000 persons in the American Cancer Society study, with 16 years follow-Cancer Society study, with 16 years follow-up across U.S. urban areas. up across U.S. urban areas.

10 10 g/mg/m33 increase in PM increase in PM2.52.5 was associated was associated

with 8-18% increases in mortality due to with 8-18% increases in mortality due to ischemic heart disease, dysrhythmias, heart ischemic heart disease, dysrhythmias, heart failure, and cardiac arrest.failure, and cardiac arrest.

Cohort Studies: Cohort Studies: Hoek et al. 2002Hoek et al. 2002 Lancet 360:1203-09Lancet 360:1203-09 5,000 persons with 8 years follow-up in the 5,000 persons with 8 years follow-up in the

Netherlands Cohort Study on Diet and Netherlands Cohort Study on Diet and Cancer.Cancer.

Cardiopulmonary mortality was more strongly Cardiopulmonary mortality was more strongly associated with:associated with:

living near high traffic density (100 m to freeway living near high traffic density (100 m to freeway or 50 m to major urban road) or 50 m to major urban road) RR 1.95 (95% CI: 1.09, 3.52) vs.RR 1.95 (95% CI: 1.09, 3.52) vs.

Est. ambient background black smoke:Est. ambient background black smoke:RR 1.34 (0.68-2.64)RR 1.34 (0.68-2.64)

Questions regarding cardiovascular Questions regarding cardiovascular M&M associations with air pollutionM&M associations with air pollution

Causal pollutant components and sources?Causal pollutant components and sources? Biological mechanisms? Biological mechanisms?

AirwayAirway inflammation,inflammation, oxidative stress, and oxidative stress, and activation of leukocytes activation of leukocytes systemic effects; systemic effects;

Autonomic dysfunctionAutonomic dysfunction (decreased HRV, (decreased HRV, arrhythmias);arrhythmias);

SystemicSystemic oxidative stress & inflammation oxidative stress & inflammation & & platelet activation / coagulation / thrombosisplatelet activation / coagulation / thrombosis; ; (coronary artery obstruction, stroke)(coronary artery obstruction, stroke)

Endothelial dysfunctionEndothelial dysfunction (with increased blood (with increased blood pressure and above)pressure and above)

Vascular smooth muscle cell migration

Foam-cellformation

Adherence andaggregation of

platelets

Adherence andentry of white blood

cells

Inflammatory cell activation

PM-induced myocardial infarctionPM-induced myocardial infarction ROS & RNS from PM ROS & RNS from PM acute systemic inflammation, oxidative stress, acute systemic inflammation, oxidative stress,

platelet and endothelial cell activation, platelet-leukocyte adhesion and platelet and endothelial cell activation, platelet-leukocyte adhesion and leukocyte transmigration leukocyte transmigration atherosclerotic plaque in atherosclerotic plaque instability and rupture. and rupture.

Chronically– atherosclerosis.Chronically– atherosclerosis.

Cardiovascular Health and Air Pollution Study (CHAPS)Cardiovascular Health and Air Pollution Study (CHAPS)air monitoring trailer and mobile biospecimen labair monitoring trailer and mobile biospecimen lab

Funding: NIH, CARB & AQMD, EPA So. Cal. Particle Center

Causal pollutant components & sources?Causal pollutant components & sources?

Problems with ambient exposure data:Problems with ambient exposure data: Exposure error: Exposure error:

data often measured at great distance from subjects;data often measured at great distance from subjects;

Reliance on PMReliance on PM2.52.5 or PM or PM1010 mass alone: mass alone:

components & size distributions vary over space & time.components & size distributions vary over space & time.

Solutions in CHAPS are to measure: Solutions in CHAPS are to measure: MicroenvironmentalMicroenvironmental PM exposures PM exposures

((indoor exposure to PM of outdoor origin)indoor exposure to PM of outdoor origin); ;

Size-fractionated PM & particle no. concSize-fractionated PM & particle no. conc;;

PM sources & components using PM sources & components using tracer methodstracer methods (SOA (SOA and primary OC) & and primary OC) & surrogates (e.g., EC).surrogates (e.g., EC).

HypothesesHypotheses Biomarkers of inflammation, thrombosis and Biomarkers of inflammation, thrombosis and

oxidative stress/antioxidant activity in subjects with oxidative stress/antioxidant activity in subjects with CAD will be associated with outdoor home PM CAD will be associated with outdoor home PM mass and number concentration.mass and number concentration.

These associations will be supported and clarified These associations will be supported and clarified by models based on:by models based on:

indoor PM exposures of outdoor origin, indoor PM exposures of outdoor origin,

ultrafine vs. larger size fractions, andultrafine vs. larger size fractions, and

exposure markers of traffic-related primary or exposure markers of traffic-related primary or secondary PM sources and components. secondary PM sources and components.

Population and Design Population and Design (year 1 of 2)(year 1 of 2)

30 nonsmoking subjects age 30 nonsmoking subjects age 65 yr, 65 yr, confirmed diagnosis of coronary artery confirmed diagnosis of coronary artery disease; disease;

Two Retirement Communities (independent Two Retirement Communities (independent living) in east and west San Gabriel Valley; living) in east and west San Gabriel Valley;

12 weekly repeated blood draws for 12 weekly repeated blood draws for biomarkers in each subject.biomarkers in each subject.

ConclusionsConclusions Positive associations of biomarkers of Positive associations of biomarkers of

systemic inflammation with PM are largely systemic inflammation with PM are largely driven by markers of driven by markers of primary combustion primary combustion sourcessources (EC, BC, primary OC); (EC, BC, primary OC);

Outdoor PM associations are supported by Outdoor PM associations are supported by associations for associations for indoor exposures to PM of indoor exposures to PM of outdoor originoutdoor origin;;

PN and quasi-ultrafine conc. are more PN and quasi-ultrafine conc. are more strongly associated with biomarkers than strongly associated with biomarkers than accumulation mode PM & SOA supporting accumulation mode PM & SOA supporting hypotheses regarding hypotheses regarding UFP (translocation?)UFP (translocation?);;

ConclusionsConclusions Inverse associations of biomarkers of Inverse associations of biomarkers of

antioxidant activity (SOD and GPx) with PM antioxidant activity (SOD and GPx) with PM are also largely driven by markers of are also largely driven by markers of primary primary combustion sourcescombustion sources (EC, BC, primary OC); (EC, BC, primary OC);

Inactivation of antioxidant enzymesInactivation of antioxidant enzymes (SOD, (SOD, GPx-1) by ROS, RNS or electrophiles may GPx-1) by ROS, RNS or electrophiles may be one mechanism of pollutant-induced be one mechanism of pollutant-induced systemic inflammation and thrombosis.systemic inflammation and thrombosis.

These findings are consistent with the view These findings are consistent with the view that oxidative stress and inflammation may that oxidative stress and inflammation may underlie the underlie the morbidity and mortality findingsmorbidity and mortality findings..

Thank-youThank-you