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									Diesel Exhaust Health Effects
          Overview
       Eric Garshick, MD, MOH
     Associate Professor of Medicine

          VA Boston Healthcare System
Channing Laboratory, Brigham and Women’s Hospital
             Harvard Medical School
                                    Outline
   Diesel exhaust – composition, lung deposition & clearance

   Human health effects
       Cancer – Lung, Bladder
       Non-malignant respiratory disease
       Cardiovascular effects
       Growth and development
       Physiologic mechanisms:
         •   Amplification of allergic response
         •   Airway and systemic inflammatory and vascular responses

   Future questions
       Exposure-response relationships
       Is diesel exhaust unique?
       New diesels
       Particulate Matter Terminology




                    (100 nm)

Circulation 2004
                       Diesel Particle
CO2 CO                                              Elemental
SO2 Nitrogen oxides                                 Carbon (EC)




                                                                  Organic
                                                                  Carbon
                                                                  (OC)
                                                                  On surface



(Polycyclic Aromatic Hydrocarbons)
(PAH Compounds)

                         Health Effects Institute, 1995
Size Determines Where Particles Deposit




   Oberdoster et al. (2005)
           Typical Diesel Mass and
           Number Size Distribution

             cooled gases



                            Carbonaceous PM and
                            adsorbed materials




Kittleson et al. (2003)
              Gas-Diesel Comparison
                             1995 medium diesel
 catalyst-gas 1981-1992




Kleeman et al. (2000)

Similar size distributions
Diesel engine: elemental carbon > organic compounds
Gasoline engine: organic compounds > elemental carbon
Similar mutagenicity: Seagrave et al. 2002
           Particle Clearance Pathways
             Oberdorster et al. (2005), Nemmar et al. (2002)


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

Non-traditional Pathways
   Rapid translocation of particles across alveolar epithelium
   Entry into circulation and lymphatics with systemic transport
   Neuronal uptake (olfactory bulb) uptake and translocation to
    brain
   Possible dermal uptake by sensory nerves in skin
               Alveolar Region

                                       Macrophage




Fishman’s Pulmonary Diseases and Disorders, 1998, fig 2-27.
  Relationship Between PM10, Carbon
Content of Macrophages, Lung Function
                 Kulkarni et al. (2005)




64 healthy children studied in Leicester, England
                Lung Cancer Risk
   Health Effects Reviews
      USEPA (2002), CAEPA (1998), Health Effects
       Institute (1995)
      ~40 studies with 20%-50% elevated risk in DE
       associated occupations
      EPA – likely to be a lung carcinogen
      California – Toxic Air Contaminant
      Health Effects Institute – elevated risk not readily
       explained by confounding or bias

   Newer studies
      Extension of U.S. railroad worker’s study
      Trucking Industry Particle Study
      Elevated risk observed in non-occupational settings
   Diesel exhaust is likely to be carcinogenic to humans by inhalation and
    this hazard applies to environmental exposures
   Conclusions are based on the totality of evidence from human, animal,
    and other supporting studies
   Epidemiologic studies were done in occupational cohorts, but
    occupational and environmental levels overlap
   Can’t derive confident quantitative estimate of cancer unit risk since
    human exposure-response data are uncertain
   Compared to CAEPA 1998 report - difference of opinion regarding
    quantitative verses qualitative risk assessment, but not in overall
    conclusions
     Lung Cancer Results In Animals

   Early 1980’s to mid 1990’s diesel engines
   Dose related increase at high levels of diesel
    exhaust (3.5 mg/m3) in rats
   Largely negative results in other rodent species
   Reproduced by inhalation of other insoluble
    particles without organics
   Mechanism: particle overload; inflammatory
    changes precede the development of lung cancer
   Not relevant to humans occupationally exposed at
    lower concentrations
       Lung Cancer Occupational Studies
         Truck Drivers                        Railroad Workers
           “Null”                                   “Null”
Decreased risk Increased risk            Decreased risk Increased risk




solid circle = smoking adjusted open circle = smoking unadjusted
              Health Effects Institute Special Report 1995
    Exposure Methodology Used In 39
         Lung Cancer Studies
   Single job title or usual job – 18 studies
   Yearly job – years of employment – 21 studies
   Source of information
        Self-report, census, next-of-kin, death certificate - 21 studies
        Union or work record – 17 studies
   Measurement of current exposure - 3 studies
        Used to rank and validate exposure categories
        Not 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 Engines

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




         Computerized history – starts in 1959
Railroad Worker Industrial Hygiene Survey
     Large freight railroads did not participate
     Four smaller US northern railroads agreed
     Had older equipment (1960’s vintage)
     534 personal samples collected between 1981-
      1983 in 39 jobs selected
     Respirable particles collected (similar to PM2.5)
       Total and Adjusted Respirable
        Particulate (ETS Adjusted)
                    Geometric mean & sd
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)

                        Woskie et al. 1988
      RR Worker Case-Control Study
                   Garshick et al. 1987
   1,256 cases of lung cancer collected between 3/1/81 and
    2/28/82 matched to controls based on age and date of death
   Smoking history from NOK
   Exposure = years of work starting in 1959 in diesel jobs
   Case age < 64 at death:
    OR = 1.41 (95% CI = 1.06-1.88) for 20 years of exposure
   Case age > 65 at death:
    OR = 0.91 (95% CI = 0.71-1.17) for 20 years of exposure
    Railroad Worker Cohort Study
 54,973 workers age 40-64 in 1959 with 10 to 20 years of
    past railroad employment; 4,351 lung cancer deaths
    through 1996
   Lung cancer risk in diesel exposed jobs
    (Garshick et al. 2004)
        1.40 (95% CI = 1.30-1.51)
   Smoking adjusted
    (Garshick et al. 2006)
        1.22 (95% CI = 1.12-1.32)
   Increasing risk with years employed >=1945 (Laden et al.
    2006)
              Teamsters Union Study
                Steenland et al. (1990)

   Central States pension fund deaths 1982-83
   Teamster job history; smoking adjusted
      Long haul driver (diesel)
          >18 years after 1959 OR=1.55 (95% CI=0.97-2.47)
     Pick-up   & delivery driver (gas)
          >18 years after 1959 OR=1.79 (95% CI=0.94-3.42)
                  Exposure Measurement

PM2.5 Cyclone                  PM1 Cyclone




            Filter Cassettes




Exposures have decreased since the
1980’s in the trucking industry
            Other Supporting Studies

Urban Traffic - Nyberg et al. (2000), Nafstad et al. (2003)
   Exposure models in Stockholm and Oslo based on NO2
   Elevated lung cancer risk related to NO2 levels

Air pollution - Pope et al. (2002), Laden et al. (2006)
   Relationship between PM2.5 and lung cancer risk


                                         American Cancer Society
                                         Cohort 1982-1998
      Trucking Industry Particle Study
                NCI Funding 2001-2006
   54,319 male Teamsters unionized workers
    employed in 1985
   Lung cancer mortality assessed through 2000
   Uniform job classification and duties
   Stable workforce with computerized records
      Job titles

      Terminal size and location

   Comprehensive exposure assessment
   Develop statistical exposure models
   Goal is to provide quantitative estimates of cancer risk
                      Bladder Cancer
   Meta-analysis with 35 studies (Boffetta and Silverman, 2001)
     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)

   Swedish bladder cancer study (Boeffetta et al. 2001)
   Finnish bladder cancer study (Guo et al. 2004)
     Two  large population studies linking occupation with cancer
      registry
     No association found

   Epidemiologic results not as consistent as for lung
    cancer
   Confounding and bias can’t be fully excluded
      Nonmalignant Respiratory Disease
    Chronic 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
   Altered pulmonary function and symptoms in
    children related to truck traffic
       Brunekreef et al. (1997); Van Vliet et al. (1997); Venn et al. (2001);
        Janssen et al. (2003)


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


   Lower rates of childhood asthma hospitalizations,
    Medicaid claims, emergency room utilization
    during 1996 Atlanta Olympic games
       Friedman et al. (2001)
           Growth and Development
   Elemental carbon exposures associated with lower
    attained lung function in children in 12 Southern
    CA communities, 1993-2001
       Gauderman et al. (2004)

   PAH exposures related to delayed cognitive
    development, reduction in head circumference,
    birth weight, respiratory symptoms (cohorts in
    New York, Poland)
       Perera et al. (2005, 2006); Miller et al. (2004)
                Cardiovascular Disease
Occupational studies
   Most studies from Stockholm
   Fewer studies than in lung cancer literature, results not as consistent
   Estimated risk increased by 20% - 60%
      Tuchsen and Endahl (1999); Bigert et al. (2004); Finkelstein et al.
        (2004), Gustavsson et al. (2001), Bigert et al. (2004)


Air pollution - Pope et al. (2004), Laden et al. (2006)
   Significant relationship between PM2.5 and cardiovascular risk


American Cancer Society
Study, mortality 1982-1998
Pope el al . (2004)
                         Effects of Traffic
   Ultrafine PM and black carbon in patients with CAD related to
    ST segment depression during exercise
     Pekkanen et al. (2002); Lanki et al. (2006), Gold et al. (2005)


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

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

   Decreased heart rate variability and ventricular arrhythmia
       Schwartz et al. (2005), Peters et al. (2000); Dockery et al. (2005)
     Potential Disease Pathways

1.   Allergic response amplification
2.   Pulmonary inflammation
3.   Systemic inflammation
4.   Altered cardiac autonomic function
5.   Alteration in vascular function
                  Conceptual Model:
                Systemic Effects of PM
              Cardiovascular                Pulmonary
                               PM




                                         Lung Disease


                                           Bai et al.(2006)
Altered cardiac autonomic function and     Donaldson et al. (2005)
                     Future Questions
   Lung cancer hazard identified but limited availability of
    exposure information. Trucking Industry Particle Study
    designed to estimate quantitative risk.
   What is the contribution of diesel exhaust to the non-cancer
    health effects of ambient PM?
   Is diesel exhaust unique, or are health effects due to a general
    effect of combustion-related PM? Are there persons more
    susceptible?
   What is the relative toxicity of other sources of exhaust?
   As mass emissions are reduced the role of exhaust-related
    nanoparticles that arise from condensed organics may become
    more important.

								
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