RECENT DEVELOPMENTS IN THE TOXICOLOGY OF DIESEL … · Keynote RV - 1 Health Canada Santé Canada t l e RECENT DEVELOPMENTS IN THE TOXICOLOGY OF DIESEL COMBUSTION EMISSIONS Keynote

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


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



MDEC 2011

Keynote RV - 3


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).


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)


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



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



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



MDEC 2011

Keynote RV - 4


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)


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

MDEC 2011

Keynote RV - 5


children pulm artery pressure mexico


MDEC 2011

Keynote RV - 6


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


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


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/


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


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


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


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).


MDEC 2011

Keynote RV - 10


Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004Calderon-Garciduenas et al. Toxicologic Pathology 32 1 2004



MDEC 2011

Keynote RV - 11





MDEC 2011

Keynote RV - 12



ET-1 expression brain

Thomson et al Environ Res 105 224 2007Thomson et al Environ Res 105 224 2007

MDEC 2011

Keynote RV - 13



Cruts et al Part Fibre Toxicol 5 4 2008Cruts et al Part Fibre Toxicol 5 4 2008

Median Power Frequency

MDEC 2011

Keynote RV - 14



MDEC 2011

Keynote RV - 15



MDEC 2011

Keynote RV - 16


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


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

MDEC 2011

Keynote RV - 17


Positive Air Pressure Respiratory Protection SystemsPositive Air Pressure Respiratory Protection Systems


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

MDEC 2011

Keynote RV - 18



STUDY SITEENVIRONMENTAL HEALTH CENTRE

STUDY SITEENVIRONMENTAL HEALTH CENTRE

EHCEHC

MDEC 2011

Keynote RV - 19


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


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


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)


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


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)


MDEC 2011

Keynote RV - 22


Documents

RECENT DEVELOPMENTS IN THE TOXICOLOGY OF DIESEL … · Keynote RV - 1 Health Canada Santé Canada t l e RECENT DEVELOPMENTS IN THE TOXICOLOGY OF DIESEL COMBUSTION EMISSIONS Keynote