Diesel Exhaust Health Effects Diesel Exhaust Health Effects OverviewOverview

Diesel Exhaust Health Effects Diesel Exhaust Health Effects OverviewOverview

Eric Garshick, MD, MOHEric Garshick, MD, MOH

Associate Professor of MedicineAssociate Professor of Medicine

VA Boston Healthcare SystemVA Boston Healthcare System

Channing Laboratory, Brigham and Women’s HospitalChanning Laboratory, Brigham and Women’s Hospital

Harvard Medical SchoolHarvard Medical School

OutlineOutline Diesel exhaust – composition, lung deposition & clearanceDiesel exhaust – composition, lung deposition & clearance

Human health effectsHuman health effects Cancer – Lung, BladderCancer – Lung, Bladder Non-malignant respiratory diseaseNon-malignant respiratory disease Cardiovascular effects Cardiovascular effects Growth and developmentGrowth and development Physiologic mechanisms:Physiologic mechanisms:

• Amplification of allergic responseAmplification of allergic response• Airway and systemic inflammatory and vascular responsesAirway and systemic inflammatory and vascular responses

Future questionsFuture questions Exposure-response relationships Exposure-response relationships Is diesel exhaust unique?Is diesel exhaust unique? New dieselsNew diesels

Particulate Matter TerminologyParticulate Matter Terminology

Circulation 2004

(100 nm)

Diesel ParticleDiesel Particle

Health Effects Institute, 1995

(Polycyclic Aromatic Hydrocarbons)(PAH Compounds)

Elemental Carbon (EC)

Organic Carbon (OC)On surface

CO2 CO SO2 Nitrogen oxides

Size Determines Where Particles DepositSize Determines Where Particles Deposit

Oberdoster et al. (2005)

Typical Diesel Mass and Number Size DistributionTypical Diesel Mass and Number Size Distribution

Kittleson et al. (2003)

cooled gases

Carbonaceous PM and adsorbed materials

Gas-Diesel ComparisonGas-Diesel Comparison

Kleeman et al. (2000)

catalyst-gas 1981-19921995 medium diesel

Similar size distributionsDiesel engine: elemental carbon > organic compoundsGasoline engine: organic compounds > elemental carbonSimilar mutagenicity: Seagrave et al. 2002

Particle Clearance PathwaysOberdorster et al. (2005), Nemmar et al. (2002)

Particle Clearance PathwaysOberdorster et al. (2005), Nemmar et al. (2002)

Traditional PathwaysTraditional Pathways Particle phagocytosis within a few hoursParticle phagocytosis within a few hours Airway mucociliary clearance - <24 hrs Airway mucociliary clearance - <24 hrs Slower alveolar phase – up to 700 days with migration of Slower alveolar phase – up to 700 days with migration of

alveolar macrophages towards mucociliary escalatoralveolar macrophages towards mucociliary escalator

Non-traditional PathwaysNon-traditional Pathways Rapid translocation of particles across alveolar epitheliumRapid translocation of particles across alveolar epithelium Entry into circulation and lymphatics with systemic transportEntry into circulation and lymphatics with systemic transport Neuronal uptake (olfactory bulb) uptake and translocation to Neuronal uptake (olfactory bulb) uptake and translocation to

brainbrain Possible dermal uptake by sensory nerves in skinPossible dermal uptake by sensory nerves in skin

Alveolar RegionAlveolar Region

Fishman’s Pulmonary Diseases and Disorders, 1998, fig 2-27.

Macrophage

Relationship Between PM10, Carbon Content of Macrophages, Lung Function

Kulkarni et al. (2005)

Relationship Between PM10, Carbon Content of Macrophages, Lung Function

Kulkarni et al. (2005)

64 healthy children studied in Leicester, England

Lung Cancer RiskLung Cancer Risk Health Effects ReviewsHealth Effects Reviews

USEPA (2002), CAEPA (1998), Health Effects Institute (1995) USEPA (2002), CAEPA (1998), Health Effects Institute (1995) ~40 studies with 20%-50% elevated risk in DE associated ~40 studies with 20%-50% elevated risk in DE associated

occupationsoccupations EPA – likely to be a lung carcinogenEPA – likely to be a lung carcinogen California – Toxic Air ContaminantCalifornia – Toxic Air Contaminant Health Effects Institute – elevated risk not readily explained by Health Effects Institute – elevated risk not readily explained by

confounding or biasconfounding or bias

Newer studiesNewer studies Extension of U.S. railroad worker’s studyExtension of U.S. railroad worker’s study Trucking Industry Particle StudyTrucking Industry Particle Study Elevated risk observed in non-occupational settingsElevated risk observed in non-occupational settings

Diesel exhaust is likely to be carcinogenic to humans by inhalation and Diesel exhaust is likely to be carcinogenic to humans by inhalation and this hazard applies to environmental exposuresthis hazard applies to environmental exposures

Conclusions are based on the totality of evidence from human, animal, Conclusions are based on the totality of evidence from human, animal, and other supporting studies and other supporting studies

Epidemiologic studies were done in occupational cohorts, but Epidemiologic studies were done in occupational cohorts, but occupational and environmental levels overlap occupational and environmental levels overlap

Can’t derive confident quantitative estimate of cancer unit risk since Can’t derive confident quantitative estimate of cancer unit risk since human exposure-response data are uncertain human exposure-response data are uncertain

Compared to CAEPA 1998 report - difference of opinion regarding Compared to CAEPA 1998 report - difference of opinion regarding quantitative verses qualitative risk assessment, but not in overall quantitative verses qualitative risk assessment, but not in overall conclusionsconclusions

Lung Cancer Results In AnimalsLung Cancer Results In Animals

Early 1980’s to mid 1990’s diesel enginesEarly 1980’s to mid 1990’s diesel engines Dose related increase at high levels of diesel Dose related increase at high levels of diesel

exhaust (3.5 exhaust (3.5 mmg/mg/m33) in rats ) in rats Largely negative results in other rodent speciesLargely negative results in other rodent species Reproduced by inhalation of other insoluble Reproduced by inhalation of other insoluble

particles without organics particles without organics Mechanism: particle overload; inflammatory Mechanism: particle overload; inflammatory

changes precede the development of lung cancer changes precede the development of lung cancer Not relevant to humans occupationally exposed at Not relevant to humans occupationally exposed at

lower concentrationslower concentrations

Lung Cancer Occupational StudiesLung Cancer Occupational Studies

solid circle = smoking adjusted open circle = smoking unadjusted

Truck Drivers Railroad Workers

Decreased risk Increased risk“Null”

Decreased risk Increased risk“Null”

Health Effects Institute Special Report 1995

Exposure Methodology Used In 39 Lung Cancer Studies

Exposure Methodology Used In 39 Lung Cancer Studies

Single job title or usual job – 18 studies Single job title or usual job – 18 studies Yearly job – years of employment – 21 studies Yearly job – years of employment – 21 studies Source of informationSource of information

Self-report, census, next-of-kin, death certificate - 21 studies Self-report, census, next-of-kin, death certificate - 21 studies Union or work record – 17 studiesUnion or work record – 17 studies

Measurement of current exposure - 3 studiesMeasurement of current exposure - 3 studies Used to rank and validate exposure categories Used to rank and validate exposure categories Not used in primary analysisNot used in primary analysis

Garshick et al. Improving estimates of diesel and other emissions for epidemiologic studies. Boston: Health Effects Institute; 2003.

Percent Diesel Locomotives In Service:Transition From Steam To Diesel EnginesPercent Diesel Locomotives In Service:

Transition From Steam To Diesel Engines

%Diesel

Case-control study:deaths 1981-82Cohort study: mortality 1959-1996

Computerized history – starts in 1959

Railroad Worker Industrial Hygiene SurveyRailroad Worker Industrial Hygiene Survey

Large freight railroads did not participateLarge freight railroads did not participate

Four smaller US northern railroads agreedFour smaller US northern railroads agreed

Had older equipment (1960’s vintage)Had older equipment (1960’s vintage)

534 personal samples collected between 1981-534 personal samples collected between 1981-1983 in 39 jobs selected1983 in 39 jobs selected

Respirable particles collected (similar to PMRespirable particles collected (similar to PM2.52.5) )

Total and Adjusted Respirable Particulate (ETS Adjusted)

Geometric mean & sd

Total and Adjusted Respirable Particulate (ETS Adjusted)

Geometric mean & sd

Woskie et al. 1988

Job Group (N) Total ( ｵ g/m3) ARP

( ｵ g/m3)

Clerks (59) 99 (2.4) 17 (7.2)

Signal Maint (13) 58 (1.9) 49 (1.9)

Freight Engineer (55) 90 (2.3) 73 (2.3)

Freight Cond (62) 113 (1.6) 52 (2.2)

Yard Cond (32) 146 (2.0) 92 (2.0)

Machinist (110) 152 (2.0) 147 (2.3)

RR Worker Case-Control Study Garshick et al. 1987

RR Worker Case-Control Study Garshick et al. 1987

1,256 cases of lung cancer collected between 3/1/81 and 1,256 cases of lung cancer collected between 3/1/81 and 2/28/82 matched to controls based on age and date of death2/28/82 matched to controls based on age and date of death

Smoking history from NOKSmoking history from NOK

Exposure = years of work starting in 1959 in diesel jobsExposure = years of work starting in 1959 in diesel jobs

Case age Case age << 64 at death: 64 at death: OR = 1.41OR = 1.41 (95% CI = 1.06-1.88) for 20 years of exposure(95% CI = 1.06-1.88) for 20 years of exposure

Case age Case age >> 65 at death: 65 at death: OR = 0.91 (95% CI = 0.71-1.17) for 20 years of exposureOR = 0.91 (95% CI = 0.71-1.17) for 20 years of exposure

Railroad Worker Cohort StudyRailroad Worker Cohort Study 54,973 workers age 40-64 in 1959 with 10 to 20 years of 54,973 workers age 40-64 in 1959 with 10 to 20 years of

past railroad employment; 4,351 lung cancer deaths past railroad employment; 4,351 lung cancer deaths through 1996through 1996

Lung cancer risk in diesel exposed jobs Lung cancer risk in diesel exposed jobs ((Garshick et al. 2004)Garshick et al. 2004) 1.40 (95% CI = 1.30-1.51)1.40 (95% CI = 1.30-1.51)

Smoking adjusted Smoking adjusted (Garshick et al. 2006)(Garshick et al. 2006) 1.22 (95% CI = 1.12-1.32) 1.22 (95% CI = 1.12-1.32)

Increasing risk with years employed >=1945 Increasing risk with years employed >=1945 (Laden et al. (Laden et al. 2006)2006)

Teamsters Union Study Steenland et al. (1990)

Central States pension fund deaths 1982-83Central States pension fund deaths 1982-83

Teamster job history; smoking adjustedTeamster job history; smoking adjusted Long haul driver (diesel)Long haul driver (diesel)

>>18 years after 1959 OR=1.55 (95% CI=0.97-2.47)18 years after 1959 OR=1.55 (95% CI=0.97-2.47)

Pick-up & delivery driver (gas)Pick-up & delivery driver (gas) >>18 years after 1959 OR=1.79 (95% CI=0.94-3.42)18 years after 1959 OR=1.79 (95% CI=0.94-3.42)

Exposure MeasurementExposure Measurement

PM2.5 Cyclone PM1 Cyclone

Filter Cassettes

Exposures have decreased since the 1980’s in the trucking industry

Other Supporting StudiesOther Supporting Studies

Urban Traffic - Urban Traffic - Nyberg et al. (2000), Nafstad et al. (2003)Nyberg et al. (2000), Nafstad et al. (2003)

Exposure models in Stockholm and Oslo based on NOExposure models in Stockholm and Oslo based on NO22

Elevated lung cancer risk related to NOElevated lung cancer risk related to NO2 2 levelslevels

Air pollution - Air pollution - Pope et al. (2002), Laden et al. (2006Pope et al. (2002), Laden et al. (2006)) Relationship between Relationship between PMPM2.5 2.5 and lung cancer riskand lung cancer risk

American Cancer SocietyCohort 1982-1998

Trucking Industry Particle StudyNCI Funding 2001-2006

Trucking Industry Particle StudyNCI Funding 2001-2006

54,319 male Teamsters unionized workers employed in 198554,319 male Teamsters unionized workers employed in 1985 Lung cancer mortality assessed through 2000 Lung cancer mortality assessed through 2000 Uniform job classification and dutiesUniform job classification and duties Stable workforce with computerized recordsStable workforce with computerized records

Job titlesJob titles Terminal size and locationTerminal size and location

Comprehensive exposure assessment Comprehensive exposure assessment Develop statistical exposure modelsDevelop statistical exposure models Goal is to provide quantitative estimates of cancer riskGoal is to provide quantitative estimates of cancer risk

Bladder Cancer Bladder Cancer Meta-analysis with 35 studiesMeta-analysis with 35 studies (Boffetta and Silverman, 2001) (Boffetta and Silverman, 2001)

15 truck driver studies RR = 1.17 (95% CI=1.06 - 1.29)15 truck driver studies RR = 1.17 (95% CI=1.06 - 1.29) 10 bus driver studies RR= 1.33 (95% CI=1.22 - 1.45)10 bus driver studies RR= 1.33 (95% CI=1.22 - 1.45)

Swedish bladder cancer studySwedish bladder cancer study (Boeffetta et al. 2001)(Boeffetta et al. 2001)

Finnish bladder cancer studyFinnish bladder cancer study (Guo et al. 2004)(Guo et al. 2004) Two large population studies linking occupation with cancer Two large population studies linking occupation with cancer

registryregistry No association foundNo association found

Epidemiologic results not as consistent as for lung Epidemiologic results not as consistent as for lung cancercancer

Confounding and bias can’t be fully excludedConfounding and bias can’t be fully excluded

Nonmalignant Respiratory DiseaseChronic Obstructive Pulmonary Disease

Nonmalignant Respiratory DiseaseChronic Obstructive Pulmonary Disease

Pulmonary retention of fine PM may result in small airway remodeling and contribute to COPD (Brauer et al. 2001; Churg et al. 2003)

COPD mortality US Railroad cohort RR=1.41 (95% CI = 1.25-1.55) Case-control study (Hart et al. 2006)

• Smoking adjusted, increased risk with greater years of work in a diesel exposed job

Road Proximity Studies Road Proximity Studies Altered pulmonary function and symptoms in Altered pulmonary function and symptoms in

children related to truck trafficchildren related to truck traffic Brunekreef et al. (1997); Van Vliet et al. (1997); Venn et al. (2001); Brunekreef et al. (1997); Van Vliet et al. (1997); Venn et al. (2001);

Janssen et al. (2003)Janssen et al. (2003)

Wheeze in adults living 50 m from roadwayWheeze in adults living 50 m from roadway Garshick et al. (2003)Garshick et al. (2003)

Lower rates of childhood asthma hospitalizations, Lower rates of childhood asthma hospitalizations, Medicaid claims, emergency room utilization Medicaid claims, emergency room utilization during 1996 Atlanta Olympic games during 1996 Atlanta Olympic games Friedman et al. (2001)Friedman et al. (2001)

Growth and DevelopmentGrowth and Development

Elemental carbon exposures associated with lower Elemental carbon exposures associated with lower attained lung function in children in 12 Southern attained lung function in children in 12 Southern CA communities, 1993-2001CA communities, 1993-2001 Gauderman et al. (2004)Gauderman et al. (2004)

PAH exposures related to delayed cognitive PAH exposures related to delayed cognitive development, reduction in head circumference, development, reduction in head circumference, birth weight, respiratory symptoms (cohorts in birth weight, respiratory symptoms (cohorts in New York, Poland)New York, Poland) Perera et al. (2005, 2006); Miller et al. (2004)Perera et al. (2005, 2006); Miller et al. (2004)

Cardiovascular DiseaseCardiovascular Disease

Occupational studiesOccupational studies Most studies from StockholmMost studies from Stockholm Fewer studies than in lung cancer literature, results not as consistent Fewer studies than in lung cancer literature, results not as consistent Estimated risk increased by 20% - 60% Estimated risk increased by 20% - 60%

Tuchsen and Endahl (1999); Bigert et al. (2004); Finkelstein et al. Tuchsen and Endahl (1999); Bigert et al. (2004); Finkelstein et al. (2004), Gustavsson et al. (2001), Bigert et al. (2004)(2004), Gustavsson et al. (2001), Bigert et al. (2004)

Air pollution - Pope et al. (2004), Laden et al. (2006)Air pollution - Pope et al. (2004), Laden et al. (2006) Significant relationship between Significant relationship between PMPM2.5 2.5 and cardiovascular riskand cardiovascular risk

American Cancer Society American Cancer Society Study, mortality 1982-1998Study, mortality 1982-1998 Pope el al . (2004)Pope el al . (2004)

Effects of Traffic Effects of Traffic

Ultrafine PM and black carbon in patients with CAD related to Ultrafine PM and black carbon in patients with CAD related to ST segment depression during exercise ST segment depression during exercise Pekkanen et al. (2002); Lanki et al. (2006), Gold et al. (2005)Pekkanen et al. (2002); Lanki et al. (2006), Gold et al. (2005)

Exposure to traffic related to MI onset 1 hour later Exposure to traffic related to MI onset 1 hour later Peters et al. (2004)Peters et al. (2004)

Increases in C-reactive protein with ultrafine, traffic - PMIncreases in C-reactive protein with ultrafine, traffic - PM2.5 2.5 Ruckerl et al. (2006); Riediker et al. (2004) Ruckerl et al. (2006); Riediker et al. (2004)

Decreased heart rate variability and ventricular arrhythmiaDecreased heart rate variability and ventricular arrhythmia Schwartz et al. (2005), Peters et al. (2000); Dockery et al. (2005)Schwartz et al. (2005), Peters et al. (2000); Dockery et al. (2005)

Potential Disease PathwaysPotential Disease Pathways

1.1. Allergic response amplificationAllergic response amplification

2.2. Pulmonary inflammation Pulmonary inflammation

3. Systemic inflammation

4. Altered cardiac autonomic function

5. Alteration in vascular function

Conceptual Model:Systemic Effects of PM

Conceptual Model:Systemic Effects of PM

Bai et al.(2006)Donaldson et al. (2005)Altered cardiac autonomic function and

PM

Cardiovascular Pulmonary

Lung Disease

Future QuestionsFuture Questions Lung cancer hazard identified but limited availability of Lung cancer hazard identified but limited availability of

exposure information. Trucking Industry Particle Study exposure information. Trucking Industry Particle Study designed to designed to estimate quantitative risk.estimate quantitative risk.

What is the contribution of diesel exhaust to the non-cancer What is the contribution of diesel exhaust to the non-cancer health effects of ambient PM?health effects of ambient PM?

Is diesel exhaust unique, or are health effects due to a general Is diesel exhaust unique, or are health effects due to a general effect of combustion-related PM? Are there persons more effect of combustion-related PM? Are there persons more susceptible?susceptible?

What is the relative toxicity of other sources of exhaust?What is the relative toxicity of other sources of exhaust?

As mass emissions are reduced the role of exhaust-related As mass emissions are reduced the role of exhaust-related nanoparticles that arise from condensed organics may become nanoparticles that arise from condensed organics may become more important.more important.