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EPIDEMIOLOGY FINDS ASSOCIATIONS BETWEEN PM AND NUMEROUS HEALTH EFFECTS

EPIDEMIOLOGY FINDS ASSOCIATIONS BETWEEN PM AND NUMEROUS HEALTH EFFECTS. Mortality (non-accidental, non-homicide deaths) Daily mortality rates (time series studies) Shortened life span (cohort studies) Morbidity (illness) Respiratory Symptoms Reduced lung function Lung inflammation

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EPIDEMIOLOGY FINDS ASSOCIATIONS BETWEEN PM AND NUMEROUS HEALTH EFFECTS

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  1. EPIDEMIOLOGY FINDS ASSOCIATIONS BETWEEN PM AND NUMEROUS HEALTH EFFECTS Mortality (non-accidental, non-homicide deaths) Daily mortality rates (time series studies) Shortened life span (cohort studies) Morbidity (illness) Respiratory Symptoms Reduced lung function Lung inflammation Exacerbation of asthma Incidence of infections Allergic sensitization Reduced rate of lung growth Medication use, physician visits and hospital admissions Cardiovascular ECG abnormalities Implanted cardioverter events Heart attacks Athersclerosis Other Premature birth Low birth weight Altered maternal hormones Developmental effects: Reduced thymus size Reproductive system CNS Inflammation Cognitive defects Metabolic Disorders The list is growing !

  2. Tools for Evaluation of Toxicity

  3. SOURCE APPORTIONMENT OF IMPACT OF PM10 ON RESPIRATORY AND CARDIOVASCULAR HOSPITAL ADMISSIONS Janssen et al., Environ. Health Perspect. 110: 43, 2002  Time series study of PM10 vs. hospital admissions in 14 U.S. cities 1985 –1994, adjusted for weather, day, season, and air conditioning  Proportional source contributions from Emission Inventory Estimates Vehicle and oil combustion-derived PM had the greatest impact % change in regression coefficient for interquartile change in PM10(*p<0.05) PM10 SourceCVDCOPDPneumonia Highway vehicles +58* +48 +61 Highway diesels +56* +47 +56 Oil combustion +38* +2 +27 Wood burning +3 +1 +2 Coal combustion +1 +0 +2 Metal processing +29* +3 +12 Fugitive dust 49*11 31 *P < .05

  4. EFFECTS OF PROXIMITY TO TRAFFIC ON LUNG FUNCTION OF CHILDREN Brunekreef et al., Epidemiology 8:298, 1997  Lung function of 877 9 yr olds and air pollution at schools in 6 locations Measured black smoke (proxy for diesel), PM10, and NO2  Traffic counts (cars & trucks), distance from motorway, & wind direction

  5. IF MOBILE SOURCE COMBUSTION IS IMPLICATED, WHAT PART OF EMISSIONS ARE MOST IMPORTANT?

  6. C57Bl6N Male Mice Exposed by Inhalation 6h/day 7 days Exposed to whole exhaust with PM range from 30-3000 µg/m3 Exhaust generated from Yanmar Genset: No 2 fuel, steady state Composition of exhaust varied by change in engine operation Group 1: Implanted with telemeters to monitor heart rate/variance Group 2: Challenged with respiratory syncytial virus at end of exposure Evaluated 4 days later for viral persistance/pathology

  7. Engine Operation Conditions Had Marked Impact on Composition

  8. High Black Carbon Content/Low Organics Led to Increased Susceptibility to Infection

  9. High Organic (Volatile and Non) had Largest Impact on Cardiovascular Physiology

  10. THE BEHAVIOR OF ULTRAFINES AND NANOPARTICLES WILL DEPEND ON THEIR COMPOSITION, AS WELL AS THEIR SIZE Solubility determines whether mass or number/surface area is the most important dose metric

  11. BOTTOM LINES • Epidemiology associations have been found with environmental • Pollution and many health outcomes 2. Mobile-Source PM appears to be especially important • Careful consideration of the composition and type of exhaust • Needs to be considered when interpreting results • Modern diesel is much different than old diesel

  12. IDENTIFYING TOXIC COMPONENTS OF ENGINE EMISSION SAMPLES • Collected PM and vapor-phase SVOCs during urban driving cycle • Analyzed composition in detail • Tested the re-combined fractions by instillation into rat lungs [Seagrave et al. Toxicol. Sci. 70: 212-226, 2002] [Zielinska et al., J. Air Waste Man. Assoc. 54: 1138-1150, 2004]

  13. SAMPLES HAD A 5-FOLD RANGE OF POTENCY Lung Inflammation (5 parameters)

  14. Laboratory Results Also Suggest SOA NOT More Toxic than Primary Sources Collected Ambient Samples Explored as Described for Motor Vehicle Study Toxicity Source Apportionment

  15. PCA/PLS Reveals Composition:Toxicity Associations SOA “Indicators” (diacids) Methods reported in McDonald et al.,2004

  16. IARC: Diesel Exhaust Carcinogenic “The Working Group found that diesel exhaust is a cause of lung cancer (sufficient evidence) and also noted a positive association (limited evidence) with an increased risk of bladder cancer (Group 1). The Working Group concluded that gasoline exhaust was possibly carcinogenic to humans (Group 2B), a finding unchanged from the previous evaluation in 1989.” IARC press release, 2012

  17. CANCER HAZARD Kotin et al., Indust. Health 11:113, 1955 (USC) Solvent extracts of diesel and gasoline emissions caused tumors in mouse skin painting assay Related to source, operating condition, and aromatic hydrocarbons Mutagenicity  Interest heightened in 1970s with application of Ames test Reverse mutations in Salmonella bacteria Many labs studied many variables through 1980s (huge literature) Biodirected fractionation pointed toward nitro-aromatic compounds Carcinogenicity  Several large-scale gasoline and diesel rodent inhalation studies U.S., Germany, Switzerland, Japan Results generally consistent across studies Extreme exposures increased lung tumors in rats No increase in mice or Syrian hamsters Gasoline studies did not cause cancer in any species  Led to recognition of “particle overload” phenomenon

  18. ORIGINAL LOVELACE DIESEL STUDY (early 1980s) Mauderly et al. Fundam. Appl. Toxicol. 9:208-221, 1987 Male & female F344 rats, n=221-230 examined for tumors/group Exposed 7 hr/day, 5 days/wk for up to 30 mo 1980 5.7L GM engines on FTP, burning certification fuel 0, 350, 3470, or 7080 µg total chamber PM/m3(control  10 µg/m3 ) High level = 30 ppm CO, 11 ppmNOx, 13 ppm HC Results: No effect on clinical signs, body weight, or survival Progressive accumulation of soot in lung at mid & high levels Progressive inflammatory and fibrotic lung disease at mid & high levels Lung tumor incidences (benign + malignant) C = 0.9%, L = 1.3%, M = 3.6%, H = 12.8% Low level (340 µg exhaust PM/m3): No progressive lung disease or increase in lung tumors No significant effects on hematology, serum chemistry, bronchoalveolarlavage, pulmonary function, lymphocyte function in bronchial lymph odes, or histopathology(except for PM in some macrophages)

  19. ORIGINAL LRRI CARCINOGENICITY STUDY Rats exposed 7 hr/day, 5 days/wk x 30 mo to whole diesel exhaust Mauderly et al. Fundam. Appl. Toxicol. 9:208-221, 1987  Some estimated risks for humans exposed at much lower levels by linear extrapolation of these data No significant carcinogenicity in CD-1 mice exposed simultaneously

  20. THE LACK OF CARCINOGENICITY FROM LOW EXPOSURES WAS TOO READILY IGNORED Mauderly, in Environmental Toxicants , Lippmann Ed., Wiley, 2000 Increased tumors resulted only from exposures that caused preceding, chronic-active inflammation and progressive epithelial hyperplasia-metaplasia

  21. RAT LUNG TUMORS IN OLD DIESEL STUDIES WERE PRIMARILY DUE TO LUNG LOADING WITH PM Nikula et al., Fundam. Appl. Toxicol. 25: 80-94, 1995 Male & Female F344 rats exposed to diesel exhaust (DE) or carbon black (CB) 16 hr/day, 5 days/wk at 2 PM concentrations 1988 6.2L GM engine on FTP burning certification fuel 2390 & 6280 µg PM/m3 exhaust PM 10 & 27 ppm CO 9.5 & 27.2 ppm NOx (0.7 & 3.8 ppm NO2) 6.5 & 8.1 ppm HC Cabot Elftex-12 2410 & 6500 µg PM/m3 CB Control 50 µg PM/m3 Lung tumor results (n = 210-213): DECB High level 17.9% 15.2% Low level 6.2% 4.7% Control 1.4%

  22. THE LUNG “OVERLOADING” CONCEPT EVOLVED Heinrich et al. Inhal. Toxicol. 7:533-556, 1995 Other poorly-soluble, respirable PM fell on the same exposure-response line Mutagen-free carbon blacks gave same result in two studies Same exposures were not tumorigenic in normal test strains of mice Patterns of particle retention in the lung differ between rats and humans Consensus evolved that results from “overloaded” rats should not be used to estimate risks to humans   Threshold  Nonspecific Not reliable for estimating human risk  Species-specific

  23. OLD DIESEL  NEW DIESEL Pre-1990

  24. NTDE: Less PM and Composition Very Different TDE NTDE [ACES, 2009] [Kittelson, 1998]

  25. Particulate Matter Composition Breakdown -99% Mass Cummins ISM 2007; Liu et al. , Aerosol Science and Technology, 43/11: 1142-52 2009 ≥0.1 g/bhp-hr 0.01 g/bhp-hr

  26. ACES Engine and Primary Dilution System

  27. CORE BIOSCREENING STUDY DESIGN Chronic Carcinogenicity Bioassay of Wistar Han Rats:  Expose 288/group 16 hr/day, 5 days/wk for 24-30 months 3 dilutions of whole emissions + clean air controls 166/group committed to carcinogenesis bioassay 122/group allocated for interim evaluations at 1, 3, 12, & 24 months Pulmonary function (3, 12, & 24 mo) Lung lavage, lung tissue & cell proliferation Hematology & serum chemistry (3, 12, & 24 mo) Histopathology

  28. Exhaust Extraction and Secondary Dilution Systems

  29. ATMOSPHERE COMPOSITION Real-time particle mass Real-time particle number

  30. Biological Response in Rats

  31. Histopathology in Rats at 3 Months: Higher Power View of Previous Slide Control Thickening of alveolar duct septae Macrophage High

  32. Histopathology in Rats at 3 and 12 Months: 3 months 12 months Enhanced epithelial hyperplasia at 12 months. Only observed at high level, but in both sexes.

  33. ACES Findings In a nutshell; we did not observe any exposure related evidence of cancer

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