# Presentation: 379869

## Health Effects of Air Pollution

- Michael Lipsett, M.D.
- California Office of Environmental Health Hazard Assessment,
- Oakland, California
- and
- Department of Epidemiology & Biostatistics
- UCSF School of Medicine
- San Francisco, California

## Breaking News: Air Pollution and New-onset Asthma

- 3,535 children in 12 communities in Southern California
- Over a 4-year period, playing 3 or more outdoor team sports increased risk of new asthma by 1.8 (95% CI=1.2-2.8)
**** Asthma risk observed in high ozone (4-yr mean = 59.6 ppb) communities (RR=3.3, 95% CI=1.9-5.8), but not low ozone  (4-yr mean = 40 ppb) communities

*(McConnell R et al. Lancet 2002;359:386-91)*

## Ozone and new asthma – Plausibility?

- Overall risk of asthma in high ozone communities was not increased
- Increased time spent outdoors in high ozone communities was associated with a 1.4-fold increase in  risk of asthma
- High activity sports can increase breathing rates by up to 17 times
- Risk increased linearly with the number of sports played

## Slide 4

## Overview

- Criteria pollutant exposures
-       **→** focus on particulate matter
- Particulate matter deposition and
-    retention
- Effects of acute exposure
- Chronic effects in
-     adults and children

## Particulate Matter Sizes and Composition

- Particulate Matter Sizes and Composition

**Notes:**
PM10 can also be divided into several size fractions.
Coarse particles are between 2.5 and 10 microns in diameter;
fine particles in the 0.1 to 2.5 micron range; and
particles less than 0.1 micron in diameter are referred to as ultrafine particles. 
	[These are freshly emitted from combustion sources.  They have almost no mass, but the absolute number of particles in this size category is very large.  This represents a new and growing area of research.]
Adverse health effects have been associated with all inhalable particles, PM10, as well as the PM2.5 and ultrafine sub-fractions of PM10.

## PM in the Cross-hair

**Human Hair**
**(60 **m** diameter)**

- Hair cross section (60 m)

**Notes:**
The potential for particulate matter to induce adverse health effects is related to particle size.  Particles 10 microns or less in aerodynamic diameter can be inhaled deep into the lungs where they can induce tissue damage and various adverse health effects.  Particles larger than 10 microns in diameter are generally filtered out in the nasal passages, and have a much lower likelihood of entering the lungs.  
To give you a perspective on how small these particles are, the left side of this slide shows an electron micrograph of a human hair.  On the right is a representation of the cross-section of the hair compared with two particles, one a 10 micron particle, and the other a 2.5 micron particle.
Individually these particles are not visible to the naked eye; together, however, they can cause reduced visibility often seen as haze. 

## Diesel Particles and Human Hair: One Perspective

## Particles – Does Size Matter?Or Mass? Or Number? Or What?

- Mass		Diameter       Number   Surface Area
- (g/m3)          ()             (per ml)      ( 2/ml)
-   10                 2                    1.2               24
-   10                 0.5                 153              120
-   10                 0.02               2,400,000    3016

*Adapted from Donaldson K et al. Occup Environ Med 2001;58:211-216*

**Notes:**
Donaldson et al. think that the reason that ultrafines may be more effective in inducing inflammation is the vastly larger surface area. The increased surface area of ultrafine particles may permit absorption of metals, organic chemicals or other substances either in the environment, or perhaps found in the epithelial lining fluid, such as iron, which can participate in Fenton chemistry to produce reactive oxygen species. 

## Particle Deposition

- Larger particles (greater than 1 ) tend to deposit higher in the respiratory tract
- Smaller particles tend to penetrate more deeply in the lung
- However, some of each deposit
-    throughout the respiratory tract
- Chronic lung disease **→** up to 3X
-    deposition as in healthy people

## Particle Retention

- Large numbers of particles retained in airways (@107/g dry lung tissue)
- Increasing concentrations deeper in lung : 25 - 100X more at airway branches and in respiratory bronchioles than along mainstem bronchus
- Marked inter-individual variability in particle retention (several hundred-fold)
*(Source: Churg A, Brauer M. Ultrastruct Pathol 2000; 24:353-61)*

## PM Ambient Air Quality Standards are Based on Epidemiological Studies

**Use real-world exposures and health responses**
**Can examine different segments of the population (e.g., elderly, asthmatics, children) **
**Use statistical associations to infer effects of air pollution**

## PM Epidemiological Studies – Associations with Short-term Exposures

**Studies of PM10 and mortality conducted in over 200 cities world-wide**
**Examine associations between daily concentrations of PM and daily death counts.**
**Studies account for weather extremes, seasonal effects, day of week, co-pollutants, and other factors.**

## PM Epidemiology Studies – Short-term Exposure Results

**Associations also reported between daily PM10 and many measures of illness**
**cardiorespiratory hospitalizations**
**emergency room visits**
**school absenteeism**
**asthma attacks**
**bronchitis & other respiratory symptoms  in children**
**decreased lung function **

**PM Epidemiology Studies – Short-term Exposure Results**

**Notes:**
Mortality categories include total (minus homicides and trauma), respiratory, and cardiovascular deaths, and mortality for those > 65 years of age

## Low-Level Particulate Matter and Cardiovascular Effects  - Are these Studies Believable?

- Numerous time-series studies link low-level ambient particulate matter (PM) with increased cardiac morbidity and mortality
- No good mechanistic explanations for this phenomenon until recently

**Notes:**
This is not a comprehensive review of the evidence – focus on selected aspects

## PM  & Effects on the Circulatory System

**Pulmonary inflammation and/or particles absorbed into the blood may:**
**   ****Blood viscosity**
**   ****Blood coagulability**
**   ****Blood clot formation**
**   ****Cardiac ischemic events**
***(First proposed by Seaton A et al. Lancet 1995; ******345:176-178)***

**Notes:**
Seaton et al. proposed a mechanism of alveolar inflammation, due mainly to exposure to huge numbers of ultrafine particles

Thrombus formation in coronary arteries is the key element in acute coronary events in many patients. 

## PM and Plasma Viscosity

- In German study of cardiovascular risk factors,
- analysis of blood drawn during 13-day
- air pollution episode in 1985 showed     risk
- of having blood viscosity >95th percentile
- for the whole study
* **(Peters A, Lancet  1997;349:1582- 1587)*:
- Men --      OR = 3.62, 95% CI = 1.61-8.13
- Women -- OR = 2.26, 95% CI = 0.97-5.26
- Plasma viscosity is associated with increased severity of cardiovascular disease.

**Notes:**
Odds ratios for a 100 g/m3 change in TSP were also increased, but not significantly so. 
MONICA was a large cross-sectional study of cardiovascular risk factors in southern Germany (MONICA -- MONItoring of trends and determinants in CArdiovascular disease),  Fibrinogen, one of the principal proteins involved in the determination of blood viscosity, is well established as an important independent risk factor for myocardial infarction and stroke.  However, fibrinogen was not specifically assayed in this investigation. 

## PM and Myocardial Infarction

- Boston study of 772 patients interviewed about onset of myocardial infarction symptoms
- PM10 and PM2.5 measured 2 and 24 hours before symptom onset both showed elevated odds ratios

*Source Peters A et al. Circulation 2001:103*

**Odds ratio**

**Exposure quintile**

**Notes:**
One mechanism by which myocardial infarction may develop is through disruption of an atherosclerotic plaque in one of the coronary arteries; the extent to which this becomes a site for thrombus formation depends in part on the balance of forces affecting blood coagulation in the individual’s circulation. 
Recently, Peters et al. (2001a) examined potential associations between PM concentrations and the timing of onset of symptoms in 772 patients with myocardial infarction in the greater Boston area.  They found significant associations between symptom onset and both acute (within 2 hr prior to symptom onset) and subacute (24-average PM2.5 in the previous day) exposures, after adjusting for season, weather, and day of the week.  Moreover, they found increasing risks with increasing PM2.5 concentrations.  Adjusted odds ratios for increases in PM2.5 from the 5th to the 95th percentiles in 2-hr (25 g/m3, representing the range of the 2-hr average PM2.5 distribution between the 5th and 95th percentiles) and 24-hr (20 g/m3, representing the range of the 24-hr average PM2.5 distribution between the 5th and 95th percentiles) exposures were 1.48 (95% CI=1.09-2.02) and 1.62 (95% CI=1.13-2.34), respectively.  For PM10 the comparable odds ratios for 2-hr (40 g/m3) and 24-hr (30 g/m3) averaging times were 1.51 (95% CI=1.06-2.15) and 1.66 (95% CI=1.11-2.49), respectively. In this study the mean levels of 2-hr and 24-hr average PM2.5 were both 12.1, and for PM10 the corresponding mean values were both 19.4, though in both instances the shorter averaging intervals showed greater variability.  Interestingly, the entire range of 24-hr PM2.5 concentrations in this study was lower than the U.S. EPA’s ambient air quality fine particles standard of 65 g/m3. 

## PM and Heart Rate Variability

- 3 studies in Utah (n=7) , Boston (n =21) , and Baltimore (n=26)
- Results not entirely consistent, but all found at least one measure of HRV decreased in relation to PM10 or PM2.5
- Of note, changes in HRV occurred within hours of exposure

*(Pope CA et al.,  Am Heart J 1999;138: 890-899;*
*Gold DR, et al. Circulation 2000;101: 1267-1273;*
*Liao, D et al.  Environ Health Perspect 1999;107: 521-525)*

**Notes:**
If the changes in HRV are causally related to more serious outcomes such as cardiac arrhythmias, then the short time frame involved may offer one plausible explanatory mechanism. Even if the effects on HRV are only an indicator of other more important underlying processes, the short time frame between air pollution changes and HRV changes is still relevant, as it suggests rapid effects. May provide a time-relevant explanation of cardiac effects seen same-day or with one-day lag. 

## PM and Cardiac Arrhythmias

- Among 100 patients with implantable cardioverter defibrillators, risks of >10 events (1995-1997), for 5th-95th percentile change:
-  _**Pollutant metric                  OR (95% CI)**_
-    PM10  (lag 2)                       1.68 (0.98-2.86)
-    PM2.5  (lag 2)                      1.64 (1.03-2.62)
-    Black carbon  (5-day avg)    2.16 (0.96-4.86)
-    CO (5-day avg)                    1.94 (1.01-3.75)
-    NO2 (5-day avg)                   2.13 (1.76-5.56)
*(Peters A et al. Epidemiology 2000;11:11-17)*

**Associations with black carbon, CO, and NO****2 ****suggest link with traffic generally, not just PM**

## PM Epidemiology Studies – Long-term Exposures

- Several studies report associations between mortality and long-term exposure to PM10 and/or PM2.5.
- Analysis accounts for relevant individual-level factors (e.g., smoking, weight, alcohol, occupational exposure, gender, age, and others).

## PM Epidemiology Studies – Long-term Exposure Results

- Harvard 6-cities study - RR (cardiorespiratory mortality) = 1.37 (95%CI=1.11-1.68)
- American Cancer Society study -  RR (cardiorespiratory) = 1.31 (95%CI=1.17-1.46)
- Chronic exposure to air pollution corresponding a difference of 24 g/m3 (PM2.5), might decrease average life expectancy by about 1.5 years.

## Adjusted Mortality Rate Ratios in Six Cities Study

*(Dockery DW et al., N Engl J Med 1993;329:1753-1759)*

## HEI Re-analysis of Cohort Mortality Studies

- Many sensitivity analyses confirmed basic results
- Effects seen mainly in less educated: tend to be nonsignificant for those with > high school education

## Slide 25

## Children’s Health Study

- Largest recent prospective study of air pollution’s chronic effects in children
- 3,676 schoolchildren in 12 communities followed for up to 10 years
- Avg PM10 (1994) = 34.8 g/m3 (13 Lompoc – 71 Mira Loma)

## Children’s Health Study: Results

- At study inception, no relation of PM10 or PM2.5 with respiratory illness (current asthma, bronchitis, cough or wheeze)
- 40% greater risk of bronchitis in asthmatics per 19 g/m3 change in PM10, but high correlation with other pollutants *(McConnell R et al. Environ Health Perspect 1999;107:757-60)*
- Over a 4-year period, PM10, PM2.5, coarse particles, acid vapors, and NO2 were associated with  lung growth, more pronounced with more time outdoors *(Gauderman WJ et al. Am J Respir Crit Care Med 2000;162;1383-90)*

## Some unresolved issues in PM epidemiology

- Which subfraction(s) [size/composition] most important in health effects?
- Do early-life exposures have a life-long impact?
- How do educational differences affect susceptibility to mortality?
- Common underlying mechanisms for acute health impacts?
- Are there thresholds for any of the observed effects?

## Slide 29

## Slide 30

## Ambient Particles and  Mortality in the Coachella Valley

- Desert area @ 60 miles east of L.A., where most PM10 variability (>90%) is due to the coarse fraction
- Time-series of daily mortality (8/89-10/92) found a relationship with PM10 similar to urban areas -- 4.6% increase in daily mortality/50 g/m3 PM10, with 7.3% increase in cardiovascular mortality.

## Mortality Time-Series Studies

- Method to test hypothesis about an association between dose (exposure) and response
- Attempts to explain variation in some health endpoint due to variation in some pollution exposure, controlling for other factors that may also influence endpoint
- Daily mortality = f(air pollution, age, weather, DOW, season)
- Concern for confounders: A factor that is related to both air pollution and health

## PM and fibrinogen

- In a large cross-sectional U.S. study, OR = 1.77 (95% CI = 1.26-2.49) for having fibrinogen > 95th percentile for PM10 (IQR) of 26 g/m3 *(Schwartz J. Environ Health Perspect 2001;109(suppl 3):405-409.).*
- In a 12-month cohort study (n=112) in the U.K., **suggested ** possibly    fibrinogen in relation to PM10 *(Seaton A et al. Thorax 1999; 54: 1027-1032) *
- Increased blood fibrinogen levels also reported in a human controlled exposure study and in one very high-dose animal study using ROFA particles *(Ghio et al. AJRCC 2000;981-988; Gardner SY et al. Toxicol Sci 2000;56:175-180)*

**Notes:**
Some studies have reported associations between PM exposure and   fibrinogen.
Increased fibrinogen levels represent an independent risk factor for the development of cardiovascular disease and cardiac mortality. 
In the Schwartz study, the estimated odds ratios for being in the top 90th percentile of the distribution of these blood markers for the entire NHANES population associated with an interquartile change in PM10 (26 g/m3) were 1.77 (95% CI = 1.26-2.49) for fibrinogen, 1.27 (95% CI = 0.97-1.67) for platelet counts, and 1.64 (95% CI = 1.17-2.30) for WBC counts. 

In the Seaton study, while there was no relationship with fibrinogen, the investigators found an unanticipated pattern of PM-associated changes in blood components suggesting a sequestration of red blood cells, specifically decreased levels of hemoglobin, RBCs, and packed cell volume.  In addition, there was a significant decrease in platelets in relation to personal PM exposure and a decrease in fibrinogen associated with central-city PM measurements (both of these blood components are involved in the formation of thrombi).  Finally, they observed a significant increase in CRP, consistent with the recent Peters (2001b) study discussed above.  Seaton speculated that these results might be explained by particle-associated effects on RBC adhesive properties, making these cells more likely to be involved in thrombus formation in the circulation.  The findings related to decreased RBCs, hemoglobin, platelets and fibrinogen are not entirely consistent with the results of the controlled exposure study by Ghio et al. (2000) or the cross-sectional data from Schwartz (2001b), discussed above. 

## PM and C-reactive protein

- German MONICA study found increased odds of high CRP levels associated with TSP
*(Peters A et al. Eur. Heart J 2001;22:1198-1204)*

**Odds ratio**

**TSP Metric**

- 12-month U.K. cohort study also found
-  CRP in relation to ambient PM10
-  *(Seaton A et al. Thorax 1999; 54: 1027-1032)*

## Harvard 6-cities study

- 8111 adults followed for 14-16 yr
- Used annual average of PM in each city
- Results adjusted for age, sex, smoking, occupational exposure to dust, gases or fumes, education, BMI
- RR (all cause) = 1.26 (95%CI=1.08-1.47)
- RR (cardiorespiratory) = 1.37 (95%CI=1.11-1.68)
- RR (lung cancer) = 1.37 (95% CI=0.81-2.31)

## ACS II Cohort Study

- 550,000 people from 151 cities followed for 7 years starting in 1982
- Controlled for age, sex, occupational exposure, obesity, alcohol and cigarette use, socioeconomic status
- RR (all cause) = 1.17 (95%CI=1.09-1.26)
- RR (cardiorespiratory) = 1.31 (95%CI=1.17-1.46)
- RR (lung cancer) = 1.03 (95% CI=0.80-1.33)
- RRSO4 (lung cancer) = 1.36 (95% CI=1.11-1.66)