RECENT DEVELOPMENTS IN THE TOXICOLOGY OF DIESEL COMBUSTION EMISSIONS. Renaud Vincent PhD

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1 t l e RECENT DEVELOPMENTS IN THE TOXICOLOGY OF DIESEL COMBUSTION EMISSIONS Renaud Vincent PhD Inhalation Toxicology Laboratory Hazard Identification Division Environmental Health Science and Research Bureau Radiation and Environmental Health Directorate Keynote Presentation MDEC Conference Toronto, 5 October 211 Ontario Medical Association Health and Economic Damage Estimates Attributable to Air Pollution Premature Deaths 5,829 7,436 1,61 Hospital Admissions 16,87 2,67 24,587 Emergency Room Visits 59,696 71,548 87,963 Minor illness day 29 million 32 million 39 million Health Direct Costs (215) Health care system $571 million Loss productivity $42 million Indirect Costs (215) Pain and suffering $593 million Loss of life $8.3 billion Annual Economic Loss 25 $7.8 billion 215 $9.8 billion 226 $12.9 billion Keynote RV - 1

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3 MDEC 211 Günter Oberdörster, Eva Oberdörster, Jan Oberdörster. Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environ Health Perspect 113: (25). ET-1 (pmol/ml plasma) B a b b * b b Basal Time post-exposure (hours) Blood pressure (mmhg) Noon Noon Midnight Noon Noon Midnight Noon Noon Midnight Noon Noon a b b ab a ab ab a b Day Day 1 Day 2 Time (hours) ET-3 (pmol/ml plasma) * * * D Basal Time post-exposure (hours) S-T Segment % waveform (folds) B p< Time (hours) Air EHC EHCL Vincent et al, Res Rep Health Effects Inst 14, 21 Keynote RV - 3

4 Plasma ET-3 (pmol/ml) Human exposure to CAPs Pre exp 1 h post 3 h post 24 h post 6 15 PM2.5 (µg/m 3 ) CAPs: concentrated ambient particles Vincent et al. Am J Resp Crit Care Med 163:A313 (21) Brachial Artery Diameter Change (post pre) Human Subjects Exposed to Toronto PM 2.5 (.12 ppm ozone ug/m 3 CAP, 2 hours at rest) Brachial Artery Diameter Change (mm) mm p=.3 Filtered Air CAP+Ozone Exposure Type Note: no change of blood pressure, no change of flow mediated dilation Brook et al. Circulation 15: (22) -.9mm Keynote RV - 4

5 children pulm artery pressure mexico Keynote RV - 5

6 Particles Biological Plausibility Inhaled urban particles cause endothelial dysfunction Elevation of circulating ET-1 Changes are sufficient to induce systemic vasoconstiction May be compensated in healthy individuals May not be compensated in individuals with heart diseases Endothelin-1 Sustained higher plasma ET-1 Vasoconstriction Hemodynamic changes Heart electrophysiology ST-segment area depression Evidence in Animal Models and Human Extravascular sources Adipose tissue Lungs Chronic infections (gingivitis, bronchitis, etc) Primary inflammatory cytokines Interleukin-1 Tumor necrosis factor-α etc. Vascular sources Inflammed atheroma Hypertensive arteries Aortic aneurysm Angiotensin II Messenger cytokine Interleukin-6 Selectins ICAM-1 VCAM-1 CRP: C-reactive protein N < 3 µg/ml R = 1X Stable Liver Endothelial cell SAA: Serum amyloid A Serum markers of inflammation etc. Acute phase proteins: CRP SAA Fibrinogen Endothelin sicam-1 svcam-1 s-selectin vwf tpa PAI-1 Adapted from: Science 296: (22) Keynote RV - 6

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8 Fast axonal transport Slow axonal transport From: Discovery and Conceptual Development of Fast and Slow Axonal Transport. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Siegel GJ, Agranoff BW, Albers RW, et al., editors. Philadelphia: Lippincott- Raven; Copyright 1999, American Society for Neurochemistry. Keynote RV - 8

9 Günter Oberdörster, Eva Oberdörster, Jan Oberdörster. Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environ Health Perspect 113: (25). Keynote RV - 9

10 Calderon-Garciduenas et al. Toxicologic Pathology Calderon-Garciduenas et al. Toxicologic Pathology Keynote RV - 1

11 Calderon-Garciduenas et al. Toxicologic Pathology Calderon-Garciduenas et al. Toxicologic Pathology Keynote RV - 11

12 ET-1 expression brain Thomson et al Environ Res Keynote RV - 12

13 Median Power Frequency Cruts et al Part Fibre Toxicol Keynote RV - 13

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16 HYPOTHESIS Cardiovascular status is affected by the presence of ambient air contaminants The cardiovasacular system is at homeostatic baseline when breathing clean air Detection of a difference in the cardiovascular status (ambient air vs clean air) will reveal physiological effects attributable to inhaled contaminants EXPERIMENTAL APPROACH Blind, randomized, crossover, placebo-controlled trials Controlled exposure of mobile subjects to air pollutants (ambient and indoor) Positive air pressure respiratory protection system (3M Breathe Easy Turbo PAPR Assembly) Selective removal of pollutants using specific filters (dummy, HEPA, OVC, OVC/HEPA, etc) Keynote RV - 16

17 Positive Air Pressure Respiratory Protection Systems Positive Air Pressure Respiratory System and Physiological Equipment 1 lbs 4.6 kg Keynote RV - 17

18 STUDY SITE ENVIRONMENTAL HEALTH CENTRE EHC Keynote RV - 18

19 Questionnaire Snack Questionnaire Snack Saliva BP O 2 Questionnaire Snack Arrival Rest +Filter Base Base Work Exerc Work Work Lunch Work Rest -Filter Base Base Leave +Equip -Equip 7: 7:3 8: 8:3 9: 9:3 1: 1:3 11: 11:3 12: 12:3 13: 13:3 14: 14:3 15: STUDY DESIGN Ten (1) subjects Total of 4 days: 2 days dummy filter and 2 days full filter (blind) Not necessarily consecutive days or on same week Work station to volunteers at EHC Lunch and snack provided during the study DATA ACQUISITION Air pollutants: continuous data acquisition Holter monitor: continuous acquisition of ECG data BP monitor: automatic measure every 3 minutes Saliva: sample recovery every 3 minutes Oxygen saturation: reading every 3 minutes SCHEDULE 7: Fitting of equipment 7:3 Rest 8: Baseline physiology 8:1 Installation of filters 8:3 Baseline physiology 9: Activity routine 9:3 Daily work 11:3 Lunch 12: Daily work 13:3 Rest 14: Baseline physiology 14:1 Removal of filters 14:3 Baseline physiology 14:31 Removal of equipment AIR POLLUTANTS IN EHC BUILDING Ambient air pollutants penetrate indoors (1:1) NAPS CO (ppm) CARBON MONOXIDE EHC CO (ppm) NAPS NO2 (ppb) NITROGEN DIOXIDE EHC NO2 (ppb) NAPS NO (ppb) NITRIC OXIDE EHC NO (ppb) NAPS O3 (ppb) OZONE EHC O3 (ppb) NAPS PM 2.5 (ug/m3) PM EHC PM 2.5 (ug/m3) Keynote RV - 19

20 SALIVARY BIG ENDOTHELIN-1 SYSTOLIC BLOOD PRESSURE Daily Average BET-1 (pmole/ml saliva) GG NN JJ HH AA BB MM FF LL KK BLANK FILTER Mean (p=.11) GG HH NN AA JJ BB MM FF LL KK OVC/HEPA FILTER Daily Average Systolic BP (mm Hg) HH NN GG KK AA JJ FF MM BB LL BLANK FILTER Mean (p=.1) HH NN KK GG JJ FF AA BB MM LL OVC/HEPA FILTER Breathing clean air reduces daily mean systolic blood pressure and salivary biget-1 Each blue dot is the mean from 28 measurements (14 measures on 2 days) Red dot is group mean (1 subjects) Systolic Blood Pressure Systolic BP (mm Hg) :- 14: 8:3-9:3 13:- 14: 14:3 8:3-9:3 14:3 Dummy Filter HEPA-OVC Dummy Filter Keynote RV - 2

21 DOSE-RESPONSE Dose-dependent increases of systolic blood pressure and salivary biget-1 as a function of cumulative pollutant exposures (subjects without masks) SYSTOLIC BP (mmhg) PM2.5 (ug/m3-hr) BET-1 (pmol/ml) SYSTOLIC BP (mmhg) 12 SYSTOLIC BP (mmhg) NITROGEN DIOXIDE (ppb-hr) BET-1 (pmol/ml) OZONE (ppb-hr) BET-1 (pmol/ml) Keynote RV - 21

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