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MDEC 2011
Keynote RV - 1
Health CanadaSanté Canada
tle
RECENT DEVELOPMENTS IN THETOXICOLOGY OF DIESEL COMBUSTION
EMISSIONS
RECENT DEVELOPMENTS IN THETOXICOLOGY OF DIESEL COMBUSTION
EMISSIONS
Keynote PresentationMDEC Conference
Toronto, 5 October 2011
Keynote PresentationMDEC Conference
Toronto, 5 October 2011
Renaud Vincent PhD
Inhalation Toxicology LaboratoryHazard Identification Division
Environmental Health Science and Research BureauRadiation and Environmental Health Directorate
Renaud Vincent PhD
Inhalation Toxicology LaboratoryHazard Identification Division
Environmental Health Science and Research BureauRadiation and Environmental Health Directorate
Health CanadaSanté Canada
Ontario Medical AssociationOntario Medical Association
Attributable to Air Pollution
2005 2015 2026
Premature Deaths 5,829 7,436 10,061
Hospital Admissions 16,807 20,067 24,587
Emergency Room Visits 59,696 71,548 87,963
Minor illness•day 29 million 32 million 39 million
Attributable to Air Pollution
2005 2015 2026
Premature Deaths 5,829 7,436 10,061
Hospital Admissions 16,807 20,067 24,587
Emergency Room Visits 59,696 71,548 87,963
Minor illness•day 29 million 32 million 39 million
Health Direct Costs (2015)
Health care system $571 millionLoss productivity $402 million
Indirect Costs (2015)
Pain and suffering $593 millionLoss of life $8.3 billion
Annual Economic Loss
2005 $7.8 billion2015 $9.8 billion2026 $12.9 billion
Health Direct Costs (2015)
Health care system $571 millionLoss productivity $402 million
Indirect Costs (2015)
Pain and suffering $593 millionLoss of life $8.3 billion
Annual Economic Loss
2005 $7.8 billion2015 $9.8 billion2026 $12.9 billion
2005-2006 Health and Economic Damage Estimates2005-2006 Health and Economic Damage Estimates
MDEC 2011
Keynote RV - 2
Health CanadaSanté Canada
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MDEC 2011
Keynote RV - 3
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Günter Oberdörster, Eva Oberdörster, Jan Oberdörster. Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environ Health Perspect 113:823–839 (2005).Günter Oberdörster, Eva Oberdörster, Jan Oberdörster. Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environ Health Perspect 113:823–839 (2005).
Health CanadaSanté Canada
Time (hours)
4 8 12 16 20 24 4 8 12 16 20 24 4 8 12 16 20 24
Blo
od p
ress
ure
(m
mH
g)
95
100
105
110
115
120
125
130
135
140
abb
a abb
aab
b
a
Midnight NoonMidnightNoon NoonMidnightNoon
Day 0 Day 2Day 1
Time (hours)
4 8 12 16 20 24 4 8 12 16 20 24 4 8 12 16 20 24
Blo
od p
ress
ure
(mm
Hg)
95
100
105
110
115
120
125
130
135
140
abb
a abb
aab
b
a
Midnight NoonMidnightNoon NoonMidnightNoon
Day 0 Day 2Day 1
-24
-12 0 12 24 36 48 -24
-12 0 12 24 36 48 -24
-12 0 12 24 36 48
S-T
Seg
me
nt
% w
ave
form
(fo
lds)
0.0
0.5
1.0
1.5
2.0
Time (hours)
AirEHC
EHCL
B
p< 0.05
-24
-12 0 12 24 36 48 -24
-12 0 12 24 36 48 -24
-12 0 12 24 36 48
S-T
Seg
me
nt
% w
ave
form
(fo
lds)
0.0
0.5
1.0
1.5
2.0
Time (hours)
AirEHC
EHCL
B
p< 0.05
Vincent et al, Res Rep Health Effects Inst 104, 2001Vincent et al, Res Rep Health Effects Inst 104, 2001
Basal 2 24 32 48
ET
-1 (
pm
ol/m
L p
lasm
a)
0
2
4
6
8
Basal 2 24 32 48
ET
-3 (
pmo
l/mL
pla
sma)
0
10
20
30
40
50
ba*bb
b
***
B
D
Time post-exposure (hours)
Time post-exposure (hours)
Basal 2 24 32 48
ET
-1 (
pm
ol/m
L p
lasm
a)
0
2
4
6
8
Basal 2 24 32 48
ET
-3 (
pm
ol/m
L p
lasm
a)
0
10
20
30
40
50
ba*bb
b
***
B
D
Time post-exposure (hours)
Time post-exposure (hours)
Basal 2 24 32 48
ET
-1 (
pm
ol/m
L p
lasm
a)
0
2
4
6
8
Basal 2 24 32 48
ET
-3 (
pmo
l/mL
pla
sma)
0
10
20
30
40
50
ba*bb
b
***
B
D
Time post-exposure (hours)
Time post-exposure (hours)
Basal 2 24 32 48
ET
-1 (
pm
ol/m
L p
lasm
a)
0
2
4
6
8
Basal 2 24 32 48
ET
-3 (
pm
ol/m
L p
lasm
a)
0
10
20
30
40
50
ba*bb
b
***
B
D
Time post-exposure (hours)
Time post-exposure (hours)
MDEC 2011
Keynote RV - 4
Health CanadaSanté Canada
Human exposure to CAPs
Pla
sma
ET
-3 (
pmol
/mL)
0
10
20
30
40
50
0 60 150
PM2.5 (µg/m3)
Pre exp1 h post3 h post24 h post
Human exposure to CAPs
Pla
sma
ET
-3 (
pmol
/mL)
0
10
20
30
40
50
0 60 150
PM2.5 (µg/m3)
Pre exp1 h post3 h post24 h post
CAPs: concentrated ambient particlesVincent et al. Am J Resp Crit Care Med 163:A313 (2001) CAPs: concentrated ambient particlesVincent et al. Am J Resp Crit Care Med 163:A313 (2001)
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Brook et al. Circulation 105:1534-1536 (2002)Brook et al. Circulation 105:1534-1536 (2002)
-0.5-0.5
-0.4-0.4
-0.3-0.3
-0.2-0.2
-0.1-0.1
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
Bra
chia
l Art
ery
Dia
met
er C
hang
e (m
m)
Bra
chia
l Art
ery
Dia
met
er C
hang
e (m
m)
Exposure TypeExposure TypeFiltered AirFiltered Air CAP+OzoneCAP+Ozone
+0.01mm+0.01mm
-0.09mm-0.09mm
p=0.03p=0.03
Brachial Artery Diameter Change (post – pre)Human Subjects Exposed to Toronto PM2.5
(0.12 ppm ozone + 153 ug/m3 CAP, 2 hours at rest)
Brachial Artery Diameter Change (post – pre)Human Subjects Exposed to Toronto PM2.5
(0.12 ppm ozone + 153 ug/m3 CAP, 2 hours at rest)
Note: no change of blood pressure, no change of flow mediated dilationNote: no change of blood pressure, no change of flow mediated dilation
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Keynote RV - 5
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children pulm artery pressure mexico
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VasoconstrictionHemodynamic changes VasoconstrictionHemodynamic changes
Endothelin-1Sustained higher plasma ET-1Endothelin-1Sustained higher plasma ET-1
Heart electrophysiologyST-segment area depressionHeart electrophysiologyST-segment area depression
ParticlesParticles
Biological PlausibilityInhaled 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
Biological PlausibilityInhaled 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
Evidence in Animal Models and HumanEvidence in Animal Models and Human
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Vascular sources
Inflammed atheroma
Hypertensive arteries
Aortic aneurysm
Vascular sources
Inflammed atheroma
Hypertensive arteries
Aortic aneurysm
Extravascular sources
Adipose tissue Lungs
Chronic infections (gingivitis, bronchitis, etc)
Extravascular sources
Adipose tissue Lungs
Chronic infections (gingivitis, bronchitis, etc)
Primary inflammatory cytokines
Interleukin-1Tumor necrosis factor-α
etc.
Primary inflammatory cytokines
Interleukin-1Tumor necrosis factor-α
etc.
EndothelinsICAM-1sVCAM-1s-SelectinvWFtPAPAI-1
EndothelinsICAM-1sVCAM-1s-SelectinvWFtPAPAI-1
Acute phase proteins:CRPSAAFibrinogen
Acute phase proteins:CRPSAAFibrinogen
Serummarkers ofinflammationetc.
Serummarkers ofinflammationetc.
LiverLiver
Angiotensin IIAngiotensin II
Messenger cytokine
Interleukin-6
Messenger cytokine
Interleukin-6
Endothelial cellEndothelial cell
SelectinsSelectinsVCAM-1VCAM-1ICAM-1ICAM-1
CRP: C-reactive proteinN < 3 µg/mLR = 1000XStable
SAA: Serum amyloid A
CRP: C-reactive proteinN < 3 µg/mLR = 1000XStable
SAA: Serum amyloid A
Adapted from:Science 296:242-245 (2002)Adapted from:Science 296:242-245 (2002)
MDEC 2011
Keynote RV - 7
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http://www.sfn.org/index.aspx?pagename=brainbriefings_adult_neurogenesis#fullsizehttp://www.sfn.org/index.aspx?pagename=brainbriefings_adult_neurogenesis#fullsize
http://beersensoryscience.wordpress.com/tag/aroma/http://beersensoryscience.wordpress.com/tag/aroma/
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http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/http://www.yalescientific.org/2011/05/the-neural-basis-of-olfaction/
MDEC 2011
Keynote RV - 8
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Fast axonal transportFast 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; 1999. Copyright © 1999, American Society for Neurochemistry.
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; 1999. Copyright © 1999, American Society for Neurochemistry.
Slow axonal transportSlow axonal transport
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http://www.bio.davidson.edu/courses/immunology/Students/spring2006/Jameson/Rabies.htmlhttp://www.bio.davidson.edu/courses/immunology/Students/spring2006/Jameson/Rabies.html
MDEC 2011
Keynote RV - 9
Health CanadaSanté Canada
Günter Oberdörster, Eva Oberdörster, Jan Oberdörster. Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environ Health Perspect 113:823–839 (2005).Günter Oberdörster, Eva Oberdörster, Jan Oberdörster. Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environ Health Perspect 113:823–839 (2005).
Health CanadaSanté Canada
MDEC 2011
Keynote RV - 10
Health CanadaSanté Canada
Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004
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Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004
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Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004
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Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004
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ET-1 expression brain
Thomson et al Environ Res 105 224 2007Thomson et al Environ Res 105 224 2007
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Cruts et al Part Fibre Toxicol 5 4 2008Cruts et al Part Fibre Toxicol 5 4 2008
Median Power Frequency
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Keynote RV - 15
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HYPOTHESISHYPOTHESIS
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
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
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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)
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)
EXPERIMENTAL APPROACHEXPERIMENTAL APPROACH
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Positive Air Pressure Respiratory Protection SystemsPositive Air Pressure Respiratory Protection Systems
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Positive Air Pressure Respiratory System and Physiological Equipment
10 lbs – 4.6 kg
Positive Air Pressure Respiratory System and Physiological Equipment
10 lbs – 4.6 kg
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Keynote RV - 18
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STUDY SITEENVIRONMENTAL HEALTH CENTRE
STUDY SITEENVIRONMENTAL HEALTH CENTRE
EHCEHC
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SCHEDULE07:00 Fitting of equipment07:30 Rest08:00 Baseline physiology08:01 Installation of filters08:30 Baseline physiology09:00 Activity routine09:30 Daily work11:30 Lunch12:00 Daily work13:30 Rest14:00 Baseline physiology14:01 Removal of filters14:30 Baseline physiology14:31 Removal of equipment
SCHEDULE07:00 Fitting of equipment07:30 Rest08:00 Baseline physiology08:01 Installation of filters08:30 Baseline physiology09:00 Activity routine09:30 Daily work11:30 Lunch12:00 Daily work13:30 Rest14:00 Baseline physiology14:01 Removal of filters14:30 Baseline physiology14:31 Removal of equipment
DATA ACQUISITIONAir pollutants: continuous data acquisitionHolter monitor: continuous acquisition of ECG dataBP monitor: automatic measure every 30 minutesSaliva: sample recovery every 30 minutesOxygen saturation: reading every 30 minutes
DATA ACQUISITIONAir pollutants: continuous data acquisitionHolter monitor: continuous acquisition of ECG dataBP monitor: automatic measure every 30 minutesSaliva: sample recovery every 30 minutesOxygen saturation: reading every 30 minutes
STUDY DESIGNTen (10) subjectsTotal of 4 days: 2 days dummy filter and 2 days full filter (blind)Not necessarily consecutive days or on same weekWork station to volunteers at EHC Lunch and snack provided during the study
STUDY DESIGNTen (10) subjectsTotal of 4 days: 2 days dummy filter and 2 days full filter (blind)Not necessarily consecutive days or on same weekWork station to volunteers at EHC Lunch and snack provided during the study
07:0007:00 08:0008:00 09:0009:00 10:0010:00 11:0011:00 12:0012:00 13:0013:00 14:0014:00 15:0015:0007:3007:30 08:3008:30 09:3009:30 10:3010:30 11:3011:30 12:3012:30 13:3013:30 14:3014:30
RestRest
+Filter+Filter
BaseBase BaseBaseRestRest
-Filter-Filter
BaseBase BaseBase
+Equip+Equip -Equip-Equip
WorkWorkExercExerc
WorkWorkLunchLunch
WorkWork
QuestionnaireSnack
QuestionnaireSnack Questionnaire
SnackQuestionnaire
Snack
QuestionnaireSnack
QuestionnaireSnack
WorkWork
SalivaBP O2
SalivaBP O2
ArrivalArrival LeaveLeave
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CARBON MONOXIDE
0
0.2
0.4
0.6
0.8
1
0 0.2 0.4 0.6 0.8 1EHC CO (ppm)
NA
PS
CO
(pp
m)
NITRIC OXIDE
0
10
20
30
40
50
0 10 20 30 40 50EHC NO (ppb)
NA
PS
NO
(pp
b)
NITROGEN DIOXIDE
0
5
10
15
20
0 5 10 15 20EHC NO2 (ppb)
NA
PS
NO
2 (p
pb
)
OZONE
0
10
20
30
40
50
60
0 10 20 30 40 50 60EHC O3 (ppb)
NA
PS
O3
(ppb
)
PM 2.5
05
10152025303540
0 5 10 15 20 25 30 35 40EHC PM 2.5 (ug/m3)
NA
PS
PM
2.5
(ug
/m3)
AIR POLLUTANTS IN EHC BUILDINGAmbient air pollutants penetrate indoors (1:1)
AIR POLLUTANTS IN EHC BUILDINGAmbient air pollutants penetrate indoors (1:1)
MDEC 2011
Keynote RV - 20
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200200
150150
100100
5050
00
2525
7575
125125
175175
OVC/HEPAFILTER
OVC/HEPAFILTER
BLANKFILTERBLANKFILTER
SALIVARY BIG ENDOTHELIN-1
SALIVARY BIG ENDOTHELIN-1
Da
ily A
vera
ge B
ET
-1 (
pm
ole
/ml s
aliv
a)
Da
ily A
vera
ge B
ET
-1 (
pm
ole
/ml s
aliv
a)
GGGG
NNNN
HHHH
AAAA
Mean(p=0.101)
Mean(p=0.101)
BBBB
MMMM
FFFFLLLL
KKKK
JJJJ
GGGG
NNNNAAAA
HHHH
JJJJ
BBBB
MMMM
LLLL
FFFF
KKKK
150150
120120
130130
140140
125125
135135
145145
OVC/HEPAFILTER
OVC/HEPAFILTER
BLANKFILTERBLANKFILTER
SYSTOLIC BLOOD PRESSURE
SYSTOLIC BLOOD PRESSURE
Da
ily A
vera
ge S
ysto
lic B
P (
mm
Hg)
Da
ily A
vera
ge S
ysto
lic B
P (
mm
Hg)
HHHHHHHH
NNNNNNNN
GGGG
GGGG
KKKK
KKKK
AAAA
AAAA
JJJJ
JJJJFFFF
FFFFMMMM
MMMM
BBBBBBBB
LLLL
LLLL
Mean(p=0.001)
Mean(p=0.001)
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 (10 subjects)
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8:30-9:308:30-9:30
13:00-14:0013:00-14:00
HEPA-OVCHEPA-OVC
14:3014:30
Dummy FilterDummy Filter
125125
135135
8:30-9:308:30-9:30
13:00-14:0013:00-14:00
14:3014:30
Dummy FilterDummy Filter
130130
140140
Sys
tolic
BP
(m
m H
g)S
ysto
lic B
P (
mm
Hg)
Systolic Blood PressureSystolic Blood Pressure
MDEC 2011
Keynote RV - 21
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100
110
120
130
140
150
160
0
100
200
300
010
2030
40
SY
STO
LIC
BP
(m
mH
g)
BET-
1 (p
mol/m
l)
NITROGEN DIOXIDE (ppb-hr)
100
110
120
130
140
150
160
170
0
100
200
300
020
4060
80100
120
SY
ST
OLIC
BP
(m
mH
g)
BET-
1 (p
mol
/ml)
OZONE (ppb-hr)
100
110
120
130
140
150
160
170
0
100
200
300
020
4060
80100
SY
ST
OLI
C B
P (
mm
Hg)
BET-
1 (p
mol
/ml)
PM2.5 (ug/m3-hr)
DOSE-RESPONSEDose-dependent increases of systolic blood pressure and salivary bigET-1 as a function of cumulative pollutant exposures(subjects without masks)
DOSE-RESPONSEDose-dependent increases of systolic blood pressure and salivary bigET-1 as a function of cumulative pollutant exposures(subjects without masks)
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MDEC 2011
Keynote RV - 22
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