ambient particles, their toxic - us epa

Ambient Particles, Their Toxic Ambient Particles, Their Toxic Components, Sources and How Components, Sources and How

They Impact HealthThey Impact Health

John R. Froines, Ph.D.John R. Froines, Ph.D.Southern California Particle Center and Southern California Particle Center and SupersiteSupersite

EPA Particulate Matter Research Centers ProgramEPA Particulate Matter Research Centers Program

Accomplishments Reviewed in this PresentationAccomplishments Reviewed in this Presentation

Variation in source, season and atmospheric Variation in source, season and atmospheric processes influence chemical and toxicological processes influence chemical and toxicological

characteristics of particlescharacteristics of particles

•• PM sources and particle characteristicsPM sources and particle characteristics

•• Freeway/mobile source associated health effectsFreeway/mobile source associated health effects

•• PM toxicity in relation to mechanistic hypothesesPM toxicity in relation to mechanistic hypotheses

•• Oxidative stress and catalytic ROS generationOxidative stress and catalytic ROS generation

•• Cellular uptake of Cellular uptake of ultrafinesultrafines

•• Key accomplishments and future research questionsKey accomplishments and future research questions

Zone of Influence of

Emissions/Sources

Freeways

Dispersion

Urban/Downtown Los Angeles, beyond immediate zones of

influence

“Source” areas

TransformationChemical reaction

Inland-Eastern Los Angeles Basin

regions

“Receptor” areas

Studies of PM Sources and Studies of PM Sources and Atmospheric ChemistryAtmospheric Chemistry

Three Zones of PM Exposure:Three Zones of PM Exposure:Zone of influence: adjacent to primary emissions sourcesZone of influence: adjacent to primary emissions sourcesSource sites: influenced by a variety of sourcesSource sites: influenced by a variety of sourcesReceptor sites: influenced by transport and atmospheric chemistReceptor sites: influenced by transport and atmospheric chemistryry

West West East East

Prevailing winds in the Los Angeles BasinPrevailing winds in the Los Angeles Basin

Spatial Distribution of Particle Phase Spatial Distribution of Particle Phase PhenanthroquinonePhenanthroquinone in the LA Basinin the LA Basin

0.00

0.05

0.10

0.15

0.20

0.25

0.30

LOMATASM

ALCRLAHLBCALPM

RLLKESDSRIV UPL

ng/m

^3

Particle-phase

WestWest EastEast

EigurenEiguren--Fernandez A., Miguel A.H, Jaques, P. and Sioutas, C.Fernandez A., Miguel A.H, Jaques, P. and Sioutas, C. Aerosol Science and TechnologyAerosol Science and Technology, 2003, 2003

Effect of Transport on PAH Size Effect of Transport on PAH Size Distribution (Source/Receptor)Distribution (Source/Receptor)

Downey Regular MOUDI - Aug.- Oct. 2000

0.0

0.2

0.4

0.6

0.8

1.0

FLT PYR BAA CRY BBF BKF BAP DBA BGP IND

Riverside Regular MOUDI - Aug.-Oct. 2001

0.0

0.2

0.4

0.6

0.8

1.0

FLT PYR BAA CRY BBF BKF BAP DBA BGP IND

Frac

tion

by m

ass

Frac

tion

by m

ass

Frac

tion

by m

ass

Frac

tion

by m

ass

(Source)

(Receptor)

Use of Source Tracers in PM Exposure and Use of Source Tracers in PM Exposure and Toxicology ResearchToxicology Research

Fine, P.M., Chakrabarti, B, Krudysz M., Schauer J.J. and SioutasFine, P.M., Chakrabarti, B, Krudysz M., Schauer J.J. and Sioutas**, C. , C. Environmental Science and TechnologyEnvironmental Science and Technology, 2004., 2004.

Which sources pose the greatest risks to public health?Which sources pose the greatest risks to public health?

•• Characterize physical/chemical characteristics including sourcCharacterize physical/chemical characteristics including source tracerse tracers•• ConductConduct toxicological studies to differentiate toxicity toxicological studies to differentiate toxicity •• Analyze associations between toxicity and source tracers to deAnalyze associations between toxicity and source tracers to determine relative termine relative source toxicitysource toxicity

How do source contributions to ambient PM samples vary from:How do source contributions to ambient PM samples vary from:

•• Site to site?Site to site?•• Over the course of the day? Seasons?Over the course of the day? Seasons?•• Between size fractions?Between size fractions?

Approach: Evaluate concentrations/size distribution of individuApproach: Evaluate concentrations/size distribution of individual al organic compounds to trace primary and secondary sources of PM:organic compounds to trace primary and secondary sources of PM:

Markers have been developed for vehicles, cooking, wood smoke anMarkers have been developed for vehicles, cooking, wood smoke and d photochemistryphotochemistry

Mobile Source StudiesMobile Source Studies

•• Particle mass remains relatively Particle mass remains relatively constant with distance from freeway; constant with distance from freeway; size distribution changes size distribution changes considerably.considerably.

•• Concentrations of nanoparticles Concentrations of nanoparticles (<20 nm) are much higher in winter (<20 nm) are much higher in winter than summer, suggesting that these than summer, suggesting that these particles are volatile, formed by particles are volatile, formed by condensation of organic vapors after condensation of organic vapors after they leave the tailpipe. they leave the tailpipe. •• Zhu, Y., Hinds, W.C., Kim, S., Zhu, Y., Hinds, W.C., Kim, S., ShenShen, S. and Sioutas, S. and Sioutas**, , C. C. ““Aerosol Science and Technology, Aerosol Science and Technology, 38, 538, 5--13, 2004.13, 2004.

••Highway study found Highway study found ““Most of the Most of the particles consisted of volatile particles consisted of volatile material.material.””•• KittlesonKittleson et al., et al., InhalInhal. Tox.. Tox.--16, 2004:16, 2004:

Recent Studies from PM Centers and EPA:Recent Studies from PM Centers and EPA:Freeway Exposures and Mobile Source EffectsFreeway Exposures and Mobile Source Effects

Studies in mice, rats and humans have reported effects of healthStudies in mice, rats and humans have reported effects of healthendpoints in several target tissues/organ systems:endpoints in several target tissues/organ systems:

1.1. Cardiovascular effectsCardiovascular effects in aged rats (2 studies) and in humans (3 in aged rats (2 studies) and in humans (3 studies)studies)

2.2. Allergic airways responsesAllergic airways responses in sensitized micein sensitized mice3.3. ChildrenChildren’’s Health Study s Health Study asthma prevalenceasthma prevalence4.4. ChildrenChildren’’s Health Study s Health Study lung developmentlung development5.5. Traffic density study of effects on Traffic density study of effects on human fetal developmenthuman fetal development6.6. Brain inflammation responsesBrain inflammation responses in micein mice

Exposure to Traffic and Exposure to Traffic and the Onset of Myocardial Infarctionthe Onset of Myocardial Infarction

Results:Results: An association between exposure to traffic and An association between exposure to traffic and myocardial infarction onset one hour later was observed myocardial infarction onset one hour later was observed (odds ratio: 2.9; 95% confidence interval: 2.2 to 3.8, (odds ratio: 2.9; 95% confidence interval: 2.2 to 3.8, p<0.001). p<0.001).

Time spent in cars, public transport and on bicycles was Time spent in cars, public transport and on bicycles was consistently connected with an increased risk for myocardial consistently connected with an increased risk for myocardial infarction. infarction.

Conclusions:Conclusions: Transient exposure to traffic might pose a Transient exposure to traffic might pose a risk in persons vulnerable to myocardial infarctions.risk in persons vulnerable to myocardial infarctions.

Peters et al., NEJM, 2004, In pressPeters et al., NEJM, 2004, In press

Recent Studies of Recent Studies of Freeway Exposures and Mobile Source Effects:Freeway Exposures and Mobile Source Effects:

Cardiovascular effectsCardiovascular effects•• Exposures to onExposures to on--road particles road particles

produce effects on the pulmonary produce effects on the pulmonary and cardiovascular system in and cardiovascular system in compromised aged rats, including compromised aged rats, including observed acute phase response observed acute phase response and inflammatory cell activation and inflammatory cell activation (Elder et al. (Elder et al. InhInh ToxTox 2004) as well 2004) as well as as changes in heart rate and blood changes in heart rate and blood pressure (Kleinman et al. pressure (Kleinman et al. In In PreparationPreparation).).

•• Study of healthy men exposed Study of healthy men exposed during driving (the during driving (the ““Trooper Trooper StudyStudy””) noted a significant ) noted a significant association between inassociation between in-- vehicle PM vehicle PM 2.5 exposure levels and changes 2.5 exposure levels and changes in heart rate variability (HRV) and in heart rate variability (HRV) and other cardiac endpoints. (other cardiac endpoints. (RiedikerRiedikeret al., et al., AJRCCMAJRCCM 2004)2004)

•• Gong et al. have completed the first ultrafine Gong et al. have completed the first ultrafine exposures on human subjects (healthy and exposures on human subjects (healthy and asthmatic) and have seen a significant asthmatic) and have seen a significant change in heart rate variability.change in heart rate variability.

SDNN (5 min rest): Healthy (red line) & Asthmatic (blue line) Subjects

0

20

40

60

80

100

120

Pre 0 4 Pre 0 4

m/s

ecfiltered air UFP

Pre/Post Exposure (in Hrs)


Pulmonary and Allergic Airways ResponsesPulmonary and Allergic Airways Responses

Markers of Markers of allergic and inflammatory airways responsesallergic and inflammatory airways responses increased in increased in sensitized mice sensitized exposed to mobile source emissions shsensitized mice sensitized exposed to mobile source emissions short ort distances from a freeway.distances from a freeway. Kleinman et al, 2004Kleinman et al, 2004

•• Greater responses at 50m compared to 150m from the freeway Greater responses at 50m compared to 150m from the freeway

Asthma prevalenceAsthma prevalence in the Childrenin the Children’’s Health Study is associated with s Health Study is associated with residential distance to freeway, both within and across communitresidential distance to freeway, both within and across communitiesies..GaudermanGauderman et al, 2004. et al, 2004.

Current levels of air pollution associated with mobile sources hCurrent levels of air pollution associated with mobile sources have chronic, ave chronic, adverse effects on adverse effects on lung developmentlung development from the age of 10from the age of 10--18 years 18 years leading to clinically significant deficits in attained FEV1 as cleading to clinically significant deficits in attained FEV1 as children reach hildren reach adulthood.adulthood. GaudermanGauderman et al, 2004et al, 2004


ChildrenChildren’’s Health Study s Health Study -- Prevalence of Asthma by Prevalence of Asthma by Distance to the Freeway Distance to the Freeway

p=0.01p=0.01Trend Trend testtestbb

1.001.00(7.6)(7.6)2102103.0 3.0 –– 7.07.0

1.481.482.382.38

(10.8)(10.8)(15.9)(15.9)

102102138138

1.5 1.5 –– 2.02.02.0 2.0 -- 3.03.0

2.332.33(16.4)(16.4)1461461.0 1.0 –– 1.51.5

2.002.002.922.92

(13.5)(13.5)(18.9)(18.9)

104104169169

>0.5>0.50.5 0.5 –– 1.01.0

ORORaa(%)(%)NN

AsthmaAsthmaTotalTotal

All SubjectsAll SubjectsDistance to the Distance to the Nearest Freeway Nearest Freeway

(Kilometers)(Kilometers)

aa Odds ratio relative to the 3.0 Odds ratio relative to the 3.0 –– 7.0 km group, based on the combined model with 7.0 km group, based on the combined model with adjustment for sex, race, Hispanic ethnicity, and cohortadjustment for sex, race, Hispanic ethnicity, and cohort

bb Test of trend in odds ratio across distance groupsTest of trend in odds ratio across distance groups

Recent Studies of Recent Studies of Freeway Exposures and Mobile Source Effects:Freeway Exposures and Mobile Source Effects:ChildrenChildren’’s Health Study s Health Study -- Lung Development and Lung Development and

Exposure to Air PollutionExposure to Air Pollution

GaudermanGauderman, et al. 2004 New England Journal of Medicine, et al. 2004 New England Journal of Medicine

Proportion Proportion of 18of 18--year year olds with olds with FEV1 FEV1 below 80% below 80% of the of the predicted predicted valuevalue

Number of freeway trucks passing within 750 feet of a home per day

Odds Ratio (95% Cl)

≥ 13,290 trucks ≥ 8,684 heavy-duty diesel vehicles

(n=4,346; 26,606) 1.23 (1.06-1.43) 1.18 (1.02-1.37)

Model adjusted for all maternal risk factors as covariates, background air pollution concentrations and census block-group level socio-economic status

Infants born between 1997Infants born between 1997--2000 in Los Angeles County2000 in Los Angeles County

Recent Studies of Recent Studies of Freeway Exposures and Mobile Source Effects:Freeway Exposures and Mobile Source Effects:Residential Proximity to Freeway Truck Traffic Residential Proximity to Freeway Truck Traffic

and Preand Pre--term and LBW Babiesterm and LBW Babies

Distance Weighted Traffic Density and Distance Weighted Traffic Density and Preterm Birth in LA: 1994Preterm Birth in LA: 1994--19961996

(Case N=17,706; Control N=26,005)(Case N=17,706; Control N=26,005)

0.90

1.00

1.10

1 2 3 4 5

OR

(95%

CI)

All births

DWTD Quintiles

Wilhelm M, Ritz B. Residential Proximity to Traffic and Adverse Wilhelm M, Ritz B. Residential Proximity to Traffic and Adverse Birth Outcomes in Los Angeles County, California, 1994Birth Outcomes in Los Angeles County, California, 1994--1996. 1996. Environ Health Environ Health PerspectPerspect 2003 Feb;111(2):2072003 Feb;111(2):207--16.16.

0.91

1.11.2

1 2 3 4 5

Winter births

DWTD QuintilesO

R (9

5% C

l)


Central Nervous System Central Nervous System Kleinman et al., in preparation, 2004Kleinman et al., in preparation, 2004

Mechanistic Hypotheses as a Basis for Studying Mechanistic Hypotheses as a Basis for Studying PM Toxicity and Health EffectsPM Toxicity and Health Effects

PM contains proPM contains pro--oxidative chemicalsoxidative chemicals

Organic chemicals and metals located on the PM matrix are Organic chemicals and metals located on the PM matrix are responsible for toxicity responsible for toxicity

PM generates reactive oxygen species PM generates reactive oxygen species oxidative stressoxidative stress

Oxidative stress Oxidative stress propro--inflammatory effects inflammatory effects

Inflammation Inflammation adjuvant effects in asthma, cardiovascular adjuvant effects in asthma, cardiovascular disease and other endpointsdisease and other endpoints

Susceptibility to oxidative stressSusceptibility to oxidative stress--related health effects may related health effects may be modulated by antibe modulated by anti--oxidant defensesoxidant defenses

High High GSH/GSSG GSH/GSSG

RatioRatioL

evel

of

Lev

el o

f ox

idat

ive

stre

ssox

idat

ive

stre

ss

Low Low GSH/GSSG GSH/GSSG

RatioRatio

NormalNormal InflammationInflammationCell response pathway:Cell response pathway: ToxicityToxicityAntiAnti--oxidantoxidantDefenseDefense

Xiao, et al.Xiao, et al.

Dose Dose

Pathways of Oxidative StressPathways of Oxidative Stress

Compounds Capable of Catalytic Compounds Capable of Catalytic RedoxRedox Activity Activity and Oxidative Stress Productionand Oxidative Stress Production

Metal ++

Quinone

Metal ++

Quinone

Electron Metal++

Quinone

Oxygen

Superoxide

Hydrogen peroxide

Hydroxyl

Metal++

Quinone

Superoxide +

Metal+++

Quinone

Electron

Superoxide

Superoxide

Superoxide

Superoxide

Superoxide

Hydroxyl

HydroxylHydroxyl

Hydroxyl

Hydroxyl

From:From: Li, N., Li, N., HaoHao, M., Phalen, R., Hinds, W., Nel, A. (2003). "Particulate air po, M., Phalen, R., Hinds, W., Nel, A. (2003). "Particulate air pollutants and asthma: A paradigm for the llutants and asthma: A paradigm for the role of oxidative stress in PMrole of oxidative stress in PM--induced adverse health effects." induced adverse health effects." Clinical ImmunologyClinical Immunology 109: 250109: 250--265.265.

Particle Size and Composition:Particle Size and Composition:Relation to ToxicityRelation to Toxicity

(sampled at source site)

RedoxRedox Activity of Ambient PM:Activity of Ambient PM:Effect of Location and Size FractionEffect of Location and Size Fraction

Redox activity

Freeway Source Receptor0.0

0.1

0.2CF/UFUF

Red

ox a

ctiv

ity/µ g

FreewayFreeway SourceSource ReceptorReceptor

Red

oxR

edox

activ

ity/

activ

ity/ µµ

gg

Li, N., Sioutas S, Cho A, Schmitz D, Li, N., Sioutas S, Cho A, Schmitz D, MisraMisra C, C, SempfSempf J, Wang M, J, Wang M, OberlyOberly T, Froines J, Nel A (2003). "Ultrafine Particulate T, Froines J, Nel A (2003). "Ultrafine Particulate Pollutants Induce Oxidative Stress and Mitochondrial Damage." Pollutants Induce Oxidative Stress and Mitochondrial Damage." Environmental Health PerspectivesEnvironmental Health Perspectives 111(4): 455111(4): 455--460.460.

Mitochondria: An Important Mitochondria: An Important SubcellularSubcellular Target Target of PM and a Source of ROS Generationof PM and a Source of ROS Generation

Unt

reat

edU

ntre

ated

Coa

rse

Coa

rse

M

P P

M

Mag. x 6000Mag. x 6000 Mag. x 21000Mag. x 21000 Mag. x 6000Mag. x 6000 Mag. x 21000Mag. x 21000

Fine

Fine

UFPUFP

P P

PP

M

M

MMM

M

RAW 264.7RAW 264.7

Hypothesis:Hypothesis:Differential Differential CytotoxicCytotoxic Effects of Diesel Exhaust Effects of Diesel Exhaust Particulate Fractions Are Caused by Selective Particulate Fractions Are Caused by Selective

Perturbation of Mitochondrial FunctionsPerturbation of Mitochondrial Functions

DEP, ultrafine DEP, ultrafine PM fractionsPM fractions

Mitochondrial functional assaysMitochondrial functional assays Cell deathCell death

•• Potential changes in the Potential changes in the mitochondrial membrane mitochondrial membrane

•• Mitochondrial PTP opening Mitochondrial PTP opening --swellingswelling--calcium retention capacitycalcium retention capacity--oxygen uptakeoxygen uptake

Recent Findings from the PM Centers Augment the Recent Findings from the PM Centers Augment the Literature that Associates PM and Reactive Oxygen Literature that Associates PM and Reactive Oxygen

Species/Oxidative StressSpecies/Oxidative Stress

ROS activity in ambient PM samples:ROS activity in ambient PM samples:•• Vary by location and timeVary by location and time--ofof--year.year.

•• Vary by size fraction: Smaller PM fractions (10Vary by size fraction: Smaller PM fractions (10--56 nm ) had dramatically higher 56 nm ) had dramatically higher ROS concentrations. ROS concentrations. VenkatachariVenkatachari et al, et al, AtmAtm. Chem. 2004. Chem. 2004

Biological markers of ROS production:Biological markers of ROS production:•• Increased oxidative stress markers and inflammatory effects in rIncreased oxidative stress markers and inflammatory effects in rat lung after at lung after

exposure to concentrated ambient particles (exposure to concentrated ambient particles (CAPsCAPs). ). RhodenRhoden et al, et al, ToxTox SciSci 20042004

•• Oxidative damage (TBARS) was correlated with the metal content oOxidative damage (TBARS) was correlated with the metal content of f CAPsCAPs. . RhodenRhoden et al, et al, ToxTox SciSci 20042004

•• Increased ROS in heart and lung of rats with short term Increased ROS in heart and lung of rats with short term CAPsCAPs exposure. exposure. GurgueiraGurgueira et al, 2002et al, 2002

Summary of PM Center AccomplishmentsSummary of PM Center Accomplishments

•• Atmospheric chemistryAtmospheric chemistry has a significant effect on PM has a significant effect on PM composition.composition.

•• A wider range of A wider range of target tissues and health endpoints are target tissues and health endpoints are associated with PM exposureassociated with PM exposure than was known in 1997.than was known in 1997.

•• Results from diverse types of studies has strengthened the evideResults from diverse types of studies has strengthened the evidence nce that that mobile sources are highly relevantmobile sources are highly relevant to the public health to the public health risks posed by ambient PMrisks posed by ambient PM. .

•• Improved mechanistic understandingImproved mechanistic understanding of PM toxicity has of PM toxicity has evolved:evolved:•• Ultrafine particlesUltrafine particles•• MitchondrialMitchondrial uptakeuptake•• Organic compounds and metals capable of catalytically generatingOrganic compounds and metals capable of catalytically generating

oxidative stress has been shown.oxidative stress has been shown.

Key Questions for Future WorkKey Questions for Future Work

Which sources pose the greatest risks to public health?Which sources pose the greatest risks to public health?→→ Need for studies of the relationships among specific sources, inNeed for studies of the relationships among specific sources, including mobile cluding mobile

sources, atmospheric chemistry products, wood smoke, cooking andsources, atmospheric chemistry products, wood smoke, cooking and others, others, and toxicityand toxicity--health effectshealth effects

What are critical characteristics of PM in relation to toxicity?What are critical characteristics of PM in relation to toxicity?→→ Further evaluation of size fractions needed; implications for PMFurther evaluation of size fractions needed; implications for PM regulationregulation

→→ Relationship between toxic mechanisms and specific toxic compoRelationship between toxic mechanisms and specific toxic components nents

Which health effects are most sensitive to low levels of PM?Which health effects are most sensitive to low levels of PM?→→ More quantitative eMore quantitative exposurexposure--response data are neededresponse data are needed

→→ Role of susceptibility findings including geneRole of susceptibility findings including gene--environment interactions in environment interactions in determining most sensitive endpointsdetermining most sensitive endpoints

EPA Particulate Matter Research Centers ProgramEPA Particulate Matter Research Centers Program

ambient particles, their toxic - us epa

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