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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