Human Clinical Studies of
Ultrafine Particles
Mark W. Frampton MD
University of Rochester Medical Center
Rochester, NY, USA
Air Pollution and Hospital
Readmissions of MI Survivors
von Klot et al. Circulation 2005
Do UFP Contribute to PM-Related
Cardiovascular Disease?
¾ Why might UFP be important in CV
disease?
¾ UFP deposition in the respiratory tract
¾ Human clinical studies of carbon UFP
Ultrafine Particles
¾ UFP: <100 nm
¾ High surface area
¾ Evade macrophage phagocytosis
¾ Predicted high pulmonary deposition
¾ May enter lung interstitium and blood
Fractional Deposition of Inhaled Particles in the Human Respiratory Tract
% Regional Deposition
(ICRP Model, 1994; Nose-breathing)
1.0
Nasal, Pharyngeal, Laryngeal
0.8
0.6
0.4
0.2
0.0
0.0001
0.001
0.01
0.1
1
10
100
10
100
10
100
Diameter (µm)
% Regional Deposition
1.0
0.8
0.6
Tracheobronchial
0.4
0.2
0.0
0.0001
0.001
0.01
0.1
1
Diameter (µm)
% Regional Deposition
1.0
Figure courtesy of J.Harkema
0.8
0.6
Alveolar
0.4
0.2
0.0
0.0001
0.001
0.01
0.1
1
Diameter (µm)
Pulmonary
Capillaries
UFP Beyond the Airways
Geiser et al., EHP 2005
Ambient Ultrafine Particles Have Oxidant Activity
Li et al., Environ Health Perspect 2003
Question: Does UFP exposure
affect the circulation?
¾ Pulmonary vs Systemic
¾ Implications for cardiac outcomes
Experimental Protocol
=
UFP or
Air
-2
0
2
Symptoms
Phlebotomy
Exhaled NO
DLCO
Spirometry
Oximetry
4
6
=
Resting HRV
Flow-mediated
dilatation
24
48
Exposure to Carbon UFP
¾ Count median diameter ~26 nm, GSD ~1.6
¾ 2 hrs by mouthpiece
¾ Intermittent exercise
Respiratory Deposition of UFP
Total Respiratory Deposition of UFP
1
Number Deposition Fraction
p<0.001
Healthy
p<0.001
Asthma
0.8
0.6
0.4
0.2
0
Rest
Exercise
Effects of Ultrafine Particles
10 to 50 µg/m3 for 2 hr
No effects on:
¾ Symptoms
¾ Lung function
¾ Airway inflammation
¾ Soluble markers of inflammation
¾ Cardiac rhythm, ST segment of ECG
A noninvasive marker of pulmonary
vascular effects:
blood leukocyte expression of
adhesion molecules
Leukocyte Recruitment in
Inflammation
Blood
Leukocytes:
Markers of
Vascular
Events
Interactions of Blood and the Pulmonary
Circulation, 2002
Change in Monocyte ICAM-1 Expression
3.5 h after Exposure
CD54 Monocytes (MESF x 103)
Frampton et al., Environ Health Persp 2006
3
ANOVA exposure effect
p=0.012
2
1
0
-1
Air
UFP
10 µg/m3
UFP
25 µg/m3
Pulmonary Diffusing
Capacity for CO (DLCO):
Sensitive to changes in pulmonary
capillary blood volume
Hypothesis:
Pulmonary vascular effects of PM--a function
of particle size and surface area?
Mass
(µg/m3)
Number
(particles/cm3)
Count Median
Diameter
(nm)
GSD
Surface Area
m2/g
UFP
55 ± 2.8
9.8x106 ±1.3
32±1.2
1.63±0.02
750
FP
114 ± 20.9
867±155
292±23.7
1.71±0.05
7
Conclusion: Carbon UFP
exposure may alter pulmonary
vascular endothelial function in
healthy subjects.
Does exposure to UFP alter
systemic endothelial function?
Systemic Endothelial Function:
Forearm Flow-Mediated Dilatation
Proposed UFP Vascular Effects
After
Exposure
AM
PM
O 2-
NO
NO
OONO-
CD11a/
CD18
TF
TF
Fibrin &
platelet deposition
Monocyte
Before
Exposure
Platelets
Summary & Speculation
¾ UFP fractional deposition high, increases with
exercise and asthma
¾ UFP may impair pulmonary & systemic
endothelial function
¾ Effects on endothelial function may underlie
diverse cardiovascular effects
¾ Likely role for reactive oxygen species & NO
¾ Relative absence of airway effects
¾ Vascular effects of ambient UFP may be greater
Acknowledgements
¾ U of R:
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Mark Utell
Günter Oberdörster
Alison Elder
Mark Taubman
Paul Morrow
Yuchau Chen
William Beckett
Tony Pietropaoli
Wojciech Zareba
Charles Francis
Carol-Lynn Petronaci
Alpa Shah
David Chalupa
Lauren Frasier
Donna Speers
Judith Stewart
Robert Gelein
¾ Clarkson:
z Philip Hopke
¾ Emory:
z Arshad Quyyumi
¾ US EPA:
z Bob Devlin
¾ Harvard:
z Petros Koutrakis
¾ Funding:
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HEI
EPA
NIEHS
EPRI
NYSERDA