Can Timing of Exposure Predispose Older Adults to Disease?

Douglas W. Dockery

Effects of Air Pollution on Health of Older AdultsJune 14-15, 2005

Mickey Leland National Urban Air Toxics Research Center

Loss of Function with Age

Leap, Scientific American; 1973

Brain Weight (92%)

Nerve Conduction Velocity (90%)

Basal Metabolism (84%)

Cardiac Output (70%)

Kidney Filtration Rate (69%)

Maximum Breathing Capacity (43%)

Death (Harvesting)

And so from hour to hour We ripe and ripe,

And from hour to hourWe rot and rot.

Shakespeare

As You like It

Rapid Decline

Childhood Experience

Early Childhood ExperienceP

reN

atal

Gen

etic

Just as a twig is bent the tree inclines.

Alexander Pope

Moral Essays

Chronic Obstructive Lung Disease

• Cumulative loss of function (FEV1) from environmental insults during adulthood

• Maximum attained function determined by growth (development) during childhood– Cumulative effects of environmental insults on growth

retardation– Early childhood effects during lung development

• Pre-natal or genetic factors define track (growth curve)

Six Cities Mortality Study

• 8111 adults followed up from 1974 to 1989• Mortality risk ratios

– Adjustment• Age, Sex• Cigarette Smoking• Occupational Exposure, Education• Body Mass Index• Chronic Disease

• Compared to city-specific average PM2.5 (1979-86)

Six Cities Cohort Mortality

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

0 5 10 15 20 25 30 35

PM2.5 (mg/m3)

Mor

talit

y Ri

sk R

atio

Steubenville

TopekaWatertown

Kingston

St. Louis

Portage

Six Cities Mortality Follow-up

• 1974 to 1989 follow-up– Annual returned

postcards and National Death Index

– 1,364 deaths in 104,243 person years

– PM2.5 measurements 1979-1986

• 1990 to 1998 follow-up

– National Death Index search

– 1,368 deaths in 54,735 person years

– PM2.5 estimated from PM10 1990-1998

Six Cities Cohort Follow-up

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

0 5 10 15 20 25 30 35

PM2.5 (mg/m3)

Mor

talit

y Ri

sk R

atio

Steubenville

Topeka

Watertown

KingstonSt. Louis

Portage

Dublin Coal Ban

• Sept 1, 1990:marketing, sale, and distribution of bituminous coals banned within city of Dublin.

• Effect was an immediate and permanent reduction in average particulate concentrations.

• Average black smoke concentrations declined by 35.6 mg/m3 (70%) after the ban on coal sales.

Dublin Coal Ban

• Total (non-trauma) death rates decreased by 5·7% (p<0·0001)

• Cardiovascular deaths by 10·3% (p<0·0001)

• Respiratory deaths by 15·5% (p<0·0001)

• Effects seen within the same season

Clancy et al, Lancet, 2002

Dublin County Borough

0

200

400

600

800

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31

January 1982

Bla

ck S

mok

e (u

g/m

3)

15

20

25

30

35

40

Dea

thsDeaths

Black Smoke

Dublin 1980-1990

9

10

11

12

13

14

15

16

17

0 100 200 300 400

3 Day Mean Black Smoke (ug/m3)

Dea

ths

per

Day

Mean of 20 consecutive points

Reversible Decline

Chronic Obstructive Lung Disease

• Cumulative loss of function (FEV1) from environmental insults during adulthood

• Maximum attained function determined by growth (development) during childhood– Cumulative effects of environmental insults on growth

retardation– Early childhood effects during lung development

• Pre-natal or genetic factors define track (growth curve)• Death more likely from acute events

– Pneumonia– Acute cardiac event

Coronary Heart Disease

• Atherosclerosis– Plaque builds up in arteries

over time– Can signficantly reduce blood

flow• Carotid intima-media thickness

(CIMT) – Ultrasound measure of

atherosclerosis in carotid artery

– Correlates well with coronary artery atherosclerosis

– Associated with age and sex– Associated with long-term

exposures to smoking and passive smoking

Men Women

IMT by age in patients with heterozygous familial hypercholesterolaemia (FH) and low-risk controls. Each dot represents the average IMT of 10 carotid and femoral IMTs of a subject.

Kastelein et al,Atherosclerosis Suppl 4; 2003: 31-6

Ambient Air Pollution and Atherosclerosis in Los Angeles Kuenzli et al, EHP 2005

•798 participants in 2 clinical trials•Carotid intima-media thickness (CIMT) subclinical atherosclerosis. •Geocoded resident to assign annual mean PM2.5.

•10 mg/m3 increase in mean PM2.5

associated with 5.9% (p=0.018) increase in CIMT•Stronger associations in Women and Older subjects

Linkage of Atheroschlerotic Plaques and Acute Myocardial Infarction

Determinants of MI Onset StudyPeters et al, Circulation 2001

• 833 patients with confirmed myocardial infarction interviewed in the greater Boston area between 1995 and 1996.

• Hourly PM2.5 data available during this period (24h-average: 12.1 µg/m3; max: 47.4 µg/m3).

PM2.5 and Onset of Myocardial Infarction

24 Hr PM2.5

0.8

1.0

1.2

1.4

1.6

1.8

1.6-6.4 6.5-8.6 8.7-11.5 11.6-16.2 16.3-52.2

PM2.5 (mg/m3)

OR

fo

r M

I On

set

Coronary Heart Disease

• Cumulative build-up of plague in coronary arteries during adulthood– CIMT associatd with long term environmental exposures

(active and passive smoking, air pollution)– Developing evidence that plague buildup begins in

childhood

• Pre-natal or genetic factors may define track (growth curve)

• Death more likely from acute events– Plaque rupture, myocardial infarction, ischemic stroke

Implantable Cardioverter Defibrillators (ICD) Devices

• Implanted under skin with electrodes and leads attached to heart

• Monitor cardiac rhythm abnormalities

• On detecting potentially fatal arrhythmia, triggers cardioverter shock

• Records date and time of all detected arrhythmias and therapies

Air Pollution and Incidence of Cardiac ArrhythmiasDockery et al, EHP June 2005

• 203 patients with Implanted Cardioverter Defibrillators (ICDs)

• Lived within I-495 in eastern Massachusetts

• Followed 1995-2002, average 3.2 years

• Abstracted ICD detected ventricular arrhythmias

• Confirmed by cardiac electrophysiologist

• Daily air pollution measurements

– PM2.5, Black Carbon, SO4

– CO, O3, NO2 and SO2

• Weather

– Temperature and humidity

• Regression of cardiac arrhythmias against air pollution

Air Pollution and Incidence of Cardiac Arrhythmias Dockery et al, EHP June 2005

• ICD detected ventricular arrhythmias (VA) in 203 patients in Boston

• Increased risk of VA with 2-day mean PM2.5, Black Carbon, CO and NO2 for patients with a recent, previous arrhythmia

• Air pollution is acute trigger of potentially life-thratening VA among patients with electrically unstable cardiac substrate

Prior VA

No Prior VA

Environmental Effects on the Elderly

• Compromised Substrate– Cumulative loss of function in adults– Compromise begins during childhood– Prenatal (genes) define growth curve (track)

• Acute Trigger– Environmental exposures can also trigger

acute response– With compromised substrate (inadequate

reserve), pushed over edge

Timing of Air Pollution Exposures

• Acute exposures (hours to days) can trigger adverse events, particularly in the presence of compromised substrate

• Medium term exposures (weeks to months) also can trigger adverse events

• Long-term exposures (years to decades) can contribute to compormised substrate or loss of physiologic reserve

• Early life exposures (perinatal and childhood) can define track for development of chronic condidtions