Environmental Pollution 181 (2013) 1e6

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Environmental Pollution
journal homepage: www.elsevier.com/locate/envpol

A ve-year study of particulate matter (PM2.5) and cerebrovascular

diseases
Manuel A. Leiva G a, *, Daniela A. Santibaez a, Sergio Ibarra E b, Patricia Matus C b,
Rodrigo Seguel b
a
b

Centro de Ciencias Ambientales and Departamento de Qumica, Facultad de Ciencias, Universidad de Chile, Casilla 653, Santiago, Chile
Centro Nacional del Medio Ambiente, Avenida Larran 9975, La Reina, Santiago, Chile

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 5 March 2013
Received in revised form
17 May 2013
Accepted 21 May 2013

Cerebrovascular accidents, or strokes, are the second leading cause of mortality and the leading cause of
morbidity in both Chile and the rest of the world. However, the relationship between particulate matter
pollution and strokes is not well characterized. The association between ne particle concentration and
stroke admissions was studied. Data on hospital admissions due to cerebrovascular accidents were
collected from the Ministry of Health. Air quality and meteorological data were taken from the Air
Quality database of the Santiago Metropolitan Area. Santiago reported 33,624 stroke admissions between
January 1, 2002 and December 30, 2006. PM2.5 concentration was markedly seasonal, increasing during
the winter. This study found an association between PM2.5 exposure and hospital admissions for stroke;
for every PM2.5 concentration increase of 10 mg m
3, the risk of emergency hospital admissions for
cerebrovascular causes increased by 1.29% (95% CI 0.552%e2.03%).
2013 Elsevier Ltd. All rights reserved.

Keywords:
Air pollution
Epidemiology
Particulate matter
Negative binomial regression
Cerebrovascular disease

1. Introduction
Currently, most cities worldwide are dealing with environmental issues related to air quality deterioration and its effect on
the departure of residents, and Chiles main urban areas are not
excluded from this trend (Bell et al., 2011; Moreno et al., 2010; Dales
et al., 2010; Cakmak et al., 2010; Kavouras et al., 2001).
The atmosphere of Santiago, Chile, is heavily polluted with
particulate matter (PM) due to the anthropogenic of the almost 6
million people located in an abrupt topographical valley on the
west side of the Andes mountain range. PM pollution is particularly heavy during autumn and winter because of the Pacic
anticyclone route (Leiva et al., 2005). Due to these environmental
conditions, airborne PM has been recognized as the major
pollutant, and the city was declared PM-saturated by CONAMA
(Environmental National Commission, now the Environment
Ministry) in 2004. The PM pollution involves both coarse and ne
particulates, which are between 2.5 and 10 mm in diameter
(PM10-2.5) and less than 2.5 mm in diameter (PM2.5), respectively; their concentrations have an approximately 1:1 ratio
(Morales et al., 2009).

* Corresponding author.
E-mail addresses: manleiva@uchile.cl, manleiva@me.com (M.A. Leiva G).
0269-7491/$ e see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.envpol.2013.05.057

Airborne PM contribution to health problems (i.e., cerebrovascular, respiratory and cardiovascular diseases) in different population groups, and their effect on morbidity and mortality are not well
understood (Zeller et al., 2006; Chan et al., 2006; Wong et al., 2002;
Moolgavkar, 2000). The damage performed by PM10 and PM2.5 to
human health is manifested as mortality due to cardiac and respiratory causes, a decrease in lung capacity in children and asthmatic adults and an increase in chronic obstructive pulmonary
diseases (Zeller et al., 2006; Chan et al., 2006; Moolgavkar, 2000;
Lisabeth et al., 2008a; Chan et al., 2008; Peel et al., 2007;
Neuberger et al., 2007; Miller et al., 2007; Dominici et al., 2006;
Aga et al., 2003; Hoek et al., 2001). The negative health effects
caused by particle concentrations in the air depend on the pollutant
(i.e., its physical-chemical composition) and its concentration (the
level and time of exposure) (Upadhyay et al., 2011; Sicard et al.,
2011; Schafer et al., 2011).
Many epidemiologic studies have shown that airborne pollution
causes signicant damage to human health (Moolgavkar, 2000;
Ding et al., 2011; Nicolescu et al., 2010; Green and Armstrong,
2003). The mechanism by which ne particles cause death and
disease is unknown. It has been suggested that particles retained
deep in the lungs cause inammation, which, in turn, releases
bioactive substances into the bloodstream, causing coagulation.
Most of these studies examine time series from a specic
geographical area. Typically, a series of daily counts (i.e., of deaths

M.A. Leiva G et al. / Environmental Pollution 181 (2013) 1e6

or hospital admissions) is linked by a regression model with the

pollution levels from the previous day(s) while controlling for such
confounding factors as seasonality and meteorological conditions
(Wong et al., 2002; Moolgavkar, 2000; Aga et al., 2003; Wordley
et al., 1997). These studies allow estimating the acute effects
caused by daily variations in exposure. The results suggest that
stroke mortality and hospital admissions should be higher in the
areas with elevated outdoor air pollution levels because of the
combined acute and chronic exposure effects of air pollution on
stroke risk.
To protect human health from the known effects of PM, organizations such as the World Health Organization (WHO), the United
States Environmental Protection Agency (US-EPA), European Union
Directive (EU-D) and Environmental Ministry of Chile (MMA) have
established safety thresholds for environmental concentrations of
PM10 and PM2.5 (USEPA, 2008; WHO, 2005; MMA, 2011; UE,
2008). The annual PM10 standards or guidelines specify
20 mg m
3 (WHO), 40 mg m
3 (EU-D), and 50 mg m
3 (US-EPA and
MMA). The 24-hr mobile averages are 50 mg m
3 (WHO) and
150 mg m
3 (US-EPA and MMA). In the case of PM2.5, the annual
standards are 10 mg m
3 (WHO), 12 mg m
3 (US-EPA), 25 mg m
3
(EU-D) and 20 mg m
3 (EU-D and MMA). The 24-hr mobile averages
are 25 mg m
3 (WHO), 35 mg m
3 (US-EPA), and 50 mg m
3 (EU-D
and MMA). Note that the WHO guidelines have more stringent
values because they consider only the health risks, while the other
established standards also consider cost-benet considerations.
Chile follows the US-EPA standards.
The relative estimated risk based on the EPA Criteria Documents
review of PM10 studies suggests an increased all-age mortality of
2.5e5.0% for each 1 mg m
3 increase in the PM10 concentration or
25 mg m
3 increase in the PM 2.5 concentration. The effect on
elderly individuals is 1.5e3 times greater than that on the general
population (USEPA, 2008).
A study of 152 U.S. metropolitan areas conrmed that there is
a clear relationship between ne-particle air pollution and human deaths (Omaye and Yang, 2009). This study examined the
race, gender, weight, height and lifestyle habits of 552,138 adults
in relation to mortality. This study ruled out tobacco smoking,
passive tobacco smoke exposure, occupational exposure to ne
particles, temperature and alcohol use as a cause cerebrovascular
hospital admissions but found that ne-particle pollution was
related to at least a 15% difference in death rates between the
least polluted cities and the most polluted cities. Additionally,
the percentage increase in the number of daily deaths in 30
European cities was less than 1% for each 10 mg m
3 increase in
PM10.
These studies have provided evidence of air pollutions effects
on mortality, but there is still a shortage of studies on the effects of
air pollutants on strokes. In Korea, a time series study found relationships between air pollution and cerebrovascular ischemic
stroke. One interquartile range increase in the 6-day cumulative
mean of PM10 (43.12 mg m
3) was associated with a 6.3% increase in
non-accidental deaths due to stroke (95% condence interval (CI):
2.3, 10.5) (Kim et al., 2003). The results suggest that stroke mortality and hospital admissions should be higher in areas with
elevated outdoor air pollution levels because of the combined acute
and chronic exposure effects of air pollution on stroke risk. In the
case of Latin American cities, there is even less information about
possible links.
The aim of our study was to quantitatively analyze the effects
of short-term exposure to PM2.5 on cerebrovascular stroke in the
exposed population and to study the association between
airborne pollution and hospital admissions for cerebrovascular
causes over the 5-year period from 2002 to 2006 in the city of
Santiago, Chile.

2. Materials and methods

2.1. Description of the study area
Santiago (33.5 S, 70.6 W) is located between the Maipo and Mapocho rivers in
a valley of the Chiles central zone. The city covers approximately 1400 square kilometers, is 500 m above sea level, and is surrounded by a ring of hills belonging to
the Andes and Coastal mountain ranges (Fig. 1). (Rutllant and Garreaud, 1995)
Santiago has a persistent valley-mountain breeze system with a predominant
low-speed wind from the southwest that often is less than 2.0 m/s in autumn and
winter. The thermal inversion subsidence layer lies approximately 400 m above the
ground during the winter and autumn and 1000 m above the ground during the
spring and summer. Vertical ventilation is largely precluded during these thermal
inversion periods, and air pollution increases dramatically as a mass of cold air
becomes trapped below warmer air. Consequently, the geography and climate of the
Santiago basin are generally unfavorable for dispersing air pollutants. Extreme air
pollution events frequently occur during the high pollution season, which extends
from April to August. Moreover, the urban area is growing rapidly. As a result, most
new services, housing, industry, and vehicle use are more concentrated in the basin,
which reinforces the pollution problem.
2.2. Health database
The data on hospital admissions due to encephalic vascular accidents, which
were dened according to the International Classication of Diseases (I60eI69),
were collected from the Death and Hospital Discharges National Database of the
Statistics and Information Department from Chiles Ministry of Health. This database
includes information from all public and private hospitals on age, gender, identication number, occupation, diagnostic code, residence address and primary diagnosis that by law must be completed, without exception. The legal requirement
ensures the validity and representativeness of the data. The health authorities
removed patient names, exact addresses, and other potential identiers from the
information provided for this study, in compliance with national privacy provisions.
2.3. Meteorological and pollutant concentration measurement
The air quality and meteorological data were taken from the air quality database
of the Santiago metropolitan area. We used the PM2.5 concentration and considered
temperature and relative humidity, meteorological factors that are monitored by
MACAM, an automatic air quality and meteorology-monitoring network. The PM2.5
concentrations were determined using a tapered element oscillating microbalance
(TEOM) (Thermos Co., USA), which provides data every 5 min at 50  C. The 2002 to
2006 data had been previously validated to x vacancies, duplicated entries and
gaps by the National Committee for Environment at the Metropolitan Region.
2.4. Time series method
We used negative binomial regression (NBR) for the time series study. NBR is an
extension of Poisson regression and is used with data that display over-dispersion.

Fig. 1. The regional topography of Santiago, Chile (with 10-km grid lines). The gray
area is the urban region, and the black lines represent the main routes and streets. The
white dots indicate the air quality monitoring stations of the MACAM-2 network (M:
Las Condes; B: Providencia; F: La Paz; N: Parque OHiggins; L: La Florida; O: Pudahuel;
P: Cerrillos; Q: El Bosque).

M.A. Leiva G et al. / Environmental Pollution 181 (2013) 1e6

Poisson regression is used in the Air Pollution and Health: A European Approach
(APHEA) protocol because it establishes a short-term association between air
pollution and epidemiologic data variation while considering the structural correlation as a function of seasonality and the trends in the response and meteorological
variables. The correlation between hospital admissions due to stroke and airborne
PM2.5 during the period from 2002 to 2006 in Santiago, Chile, was analyzed in this
study. The analysis considered time (in days) and the number of hospital admissions
for stroke as the dependent variables; seasons; trends and pollutants as the regressor variables; and meteorological data as the confounding variables. The process
consisted of stepwise NBR of the time and season against the stroke variable. The
meteorological variables and, nally, the air pollutant variables were added to the
model afterward.
Thus, the general equation that describes the correlation is
log EYi b0

Xn

b
i1 i

 Xi

(1)

exhibited a steady seasonal decrease during the spring and

summer and increased during the winter and autumn. The rate of
stroke admissions increased as the study progressed (Fig. 2). The
number of cases increased during the study period. Men represented 49.7% of the cases, and women represented 50.3% of the
cases. The majority (60.9%) were over 65 years old; 30.2% were
between 45 and 65 years old, and only 8.9% were between 15 and
45 years old (Fig. 3).
The day-of-the-week trend showed a weekend effects for
stroke-related admissions, so the nal risk model considered only
Monday through Friday as statistically signicant days in the model
(Fig. 4).

where E(Yi) is the expected number of strokes, is a constant, and is the coefcient for each regressor variable Xi. Further we examined the effect of air pollutants
with different lag (L) structures of single day lag (distributed lag; from L0 to L3) and
multi-day lag (moving average lag; L01 and L02). Here a lag of 0 day (L0) corresponds
to the current-day pollution, and a lag of 1 day refer to the previous-day concentration. In multi-day lag models, L02 corresponds to 3-day moving average of
pollutant concentration of the current and previous 2 days. Here, the meteorological
factors used in the lag models (distributed lag model, moving average model) were
the current day data. Seasonality was differentiated on the basis of warm and cold
seasons. The warm season is October through March in Santiago. The cold season,
April though September, is characterized by additional pollutant emissions from
heating sources. Examination of dependence on day of the week (DOW) was also
performed. The model related the daily hospital admissions due to cerebrovascular
accidents with the regressor variables related to the disease and the pathophysiological background.
Thus, based on the pollutant coefcient values, it is possible to determine the
odds ratio (OR). The OR can be dened as OR ebp Xp , where Xp 1 refers to the
unit of pollutant measurement. By assigning values to this variable, we obtain the
relative risk from a change in concentration. Therefore, it is possible to obtain the
increased risk of stroke due to the increased PM pollution level. The software used
for all of the statistical calculations was Stata.

The PM2.5 concentration presented a markedly seasonal

behavior (Fig. 5), with an increase in the atmospheric concentration
during the cool season and a decline during the warm season. The
average annual PM2.5 concentration for the period in question was
31 mg m
3, which exceeds the US-EPA, UE-D, WHO and MMA
standards. The annual averages for the years in question were 35.1,
33.8, 29.3, 29.7 and 31.3 mg m
3 from 2002to 2006, respectively.
The temperature (T) and relative humidity (RH) were considered
in this study. Both of these variables also presented a markedly
seasonal pattern (not showed here). In general, the temperature
negatively correlated with the PM2.5 concentration, with the
highest concentration being found in winter. By contrast, RH
showed a positive relationship with the PM2.5 concentration. The
statistical analysis showed that temperature was the only signicant meteorological variable in this model.

3. Results and discussion

3.3. Time series analysis

3.1. Cerebrovascular hospital admission analysis

The associations between the PM2.5 concentrations and cerebrovascular admissions were evaluated with the NBR model. The
model that considered temperature was statistically signicant,
whereas RH and weekday/weekend status were not (results not
shown). The coefcients obtained in the model are shown in
Table 1.

There were 33,624 cerebrovascular disease (I60-I69) admissions in Santiago between January 1, 2002 and December 30,
2006 (Fig. 2). There was an average of 19 daily stroke admissions
in Santiago during the study period. The stroke admissions

3.2. Pollutant concentration and meteorological analysis

Fig. 2. The daily stroke admissions in Santiago during the study period.

M.A. Leiva G et al. / Environmental Pollution 181 (2013) 1e6

Fig. 5. The daily time series trend for PM2.5 during the study period.

Fig. 3. The population subgroups used to determine whether PM2.5 affects patient
admissions.

Because variance in the data was greater than average for this
model, we used NBR. The over-dispersion parameter (alpha) was
greater than zero, which is consistent with NBR and implies that
the model was applicable. By contrast, the alpha value was small
because the cerebrovascular accidents were more specically
related to the regressor variables. This result was in contrast to
those of typical morbidity studies, in which a higher value of alpha
is expected.
Based on the above data, the risk was calculated using the coefcients from Table 1. For the single-pollutant model, a positive
association was observed between stroke admissions and the
PM2.5 level with a 0-day lag (OR 1.013; 95% CI: 0.823, 1.203). The
analysis of the delayed and accumulated effects did not nd a
relationship between the PM2.5 level and stroke admissions.
Finally, the association between stroke admissions and PM2.5
indicated a 1.28% increase (95% CI: 0.78, 1.78) in risk per 10 mg m
3
increase in the same-day PM2.5. For the annual mean, the increase
in risk per 31 mg m
3 showed a 4.17% increase (95% CI: 1.77, 6.59).
For the winter, the increase in the PM2.5 concentration was
48.0 mg m
3, which was associated with a stroke admission increase of 6.34 (95% CI: 2.68, 10.1).
In general, our results suggest the PM2.5 urban air pollutant was
associated with emergency admissions for cerebrovascular diseases

in a single-pollutant model. These results are consistent with the

dangers of air pollutants reported in previous studies. For example,
hospital admissions for cerebrovascular diseases are reportedly
associated with PM2.5 in the United States, Finland and Denmark.
Studies have found respective increased risks of 1.78% (95% CI: 0.96,
2.62) (Zanobetti and Schwartz, 2009), 1.04% (95% CI: 1.01, 1.07)
(Yorifuji et al., 2011) and 1.56% (95% CI: 0.42, 2.70) (Lisabeth et al.,
2008b) per 10 mg m
3 increase the in the same-day PM2.5.
To our knowledge, this is the rst study to evaluate the association between PM2.5 and cerebrovascular diseases in Santiago,
Chile. The importance of this study lies both in the demonstrated
statistical relationship between PM2.5 air pollution and cerebrovascular disease and in the demonstration of a model capable of
quantifying this association. These results are of great relevance to
prevention and to developing public health activities, such as
environmental surveillance systems.

Table 1
The results of the negative binomial regression for the association between PM2.5
and cerebrovascular admissions according to Equation (1).
Regressor
variables
(Xi)a

Parameter
estimates
(bi)b

Day
0.000210
Temperature
0.0110
Monday
0.236
Tuesday
0.203
Wednesday
0.197
Thursday
0.181
Friday
0.144
PM2.5
0.00128
2.71
Constant (bo)

5.05
Log-ALPHAf
0.00639
ALPHAg
a

Z (P>jzj)d

Condence interval
(95% CI)e

0.0000110 19.02 (0)

0.000188
0.000232
0.00128

8.57(0)

0.0135

0.00849
0.0186
12.6(0)
0.199
0.272
0.0188
10.8(0)
0.166
0.240
0.0188
10.5(0)
0.160
0.234
0.0189001
9.58(0)
0.144
0.218
0.0191
7.51(0)
0.106
0.181
0.000371
3.44(0.001)
0.000550
0.00200
0.0319
85.1(0)
2.65
2.78
0.316

5.67

4.43
0.00202
0.00344
0.0119

This is the response variable in the negative binomial regression.

These are the estimated negative binomial regression coefcients for the model.
c
These are the standard errors for the regression coefcients and dispersion
parameter for the model.
d
These are the test statistic z and p-value, respectively, that the null hypothesis
that an individual predictors regression coefcient is zero, given that the rest of the
predictors are in the model.
e
This is the condence interval (CI) of an individual negative binomial regression
coefcient, given the other predictors are in the model.
f
This is the estimate of the log of the dispersion parameter, alpha, given on the
next line (g).
g
This is the estimate of the dispersion parameter. The dispersion parameter alpha
can be obtained by exponentiating/log-alpha. (more details in Institute for Digital
Research and Education, UCLA, LA, CA, USA; http://www.ats.ucla.edu/stat/stata/
output/stata_nbreg_output.htm).
b

Fig. 4. The day-of-the-week trend in stroke-related admissions.

Standard
error (si)c

M.A. Leiva G et al. / Environmental Pollution 181 (2013) 1e6

In our study, a positive association between PM2.5 and hospital

admissions on the same day was observed. The PM2.5 levels 1 or 3
days before admission were not associated with increased risk. The
observed association between PM10 and hospital admission was
limited to exposures occurring on the day of admission. This nding
supports the hypothesis that recent exposure to PM2.5 may specically increase the risk for acute ischemic cerebrovascular events.
Similarly, Dominici and colleagues have reported an approximately
1% change in hospital admissions for any cerebrovascular disease
per 10 mg m
3 increase in the same-day PM2.5. Their study was
conducted in 204 US counties (Dominici et al., 2006).
It has been suggested that the PM2.5 air pollution can induce an
alveolar inammation response and increase blood coagulation and
systemic oxidant stress (Brook et al., 2002; Urch et al., 2005; Peters
et al., 1997). These responses can increase blood clotting and
thrombosis, impair vascular function and blood ow, elevate blood
pressure, and disrupt proper cardiac electrical activity, which may
ultimately provoke heart attacks, strokes, or even death. All of these
physiological responses could explain the association between air
pollutants and cerebrovascular diseases.
We examined subgroups of the population to determine
whether their PM2.5-associated encephalic vascular accidents
differed from those of the overall population. Our observation of a
statistically signicant difference in the estimated effects for the
subjects 65 years and older suggests that the elderly are more
susceptible to increases in PM2.5 and the resultant effects on cerebrovascular disease.
A few limitations of our study should be noted. First, diagnostic
and coding errors can lead to misclassication. These errors are
probably unrelated to the ambient particle levels, however, and
their presence would likely lead us to underestimate the relative
risk. Second, we used the ambient air pollution measured at xed
outdoor monitoring sites. Outdoor measures provide a reasonable
estimate of exposure to ambient PM concentrations, and exposure
to ambient concentrations is highly correlated to outdoor air
monitors which should mitigate this limitation. Third, we used a
single-pollutant model, and some studies of atmospheric chemistry
have demonstrated that the composition and toxicity of PM2.5 are
altered by interactions with gases. However, our study does provide
a rst evidence for estimating these effects.
4. Conclusions
This study shows an association between PM2.5 exposure and
hospital admissions for stroke. We found that when the PM2.5
concentration increases by 10 mg m
3, the risk of emergency hospital admissions for cerebrovascular causes increases by 1.29% (95%
CI: 0.55, 2.03). This estimated risk is similar in magnitude to the
risks found in similar international studies.
In conclusion, despite this studys limitations, we can safely
conclude that urban PM2.5 air pollution is associated increased
emergency room admissions for cerebrovascular diseases in Santiago. Because few individuals survive a stroke without hospital
care and others are left with permanent sequel, air pollution control may provide a means of decreasing cardiovascular mortality.
Nonetheless, the health impacts identied in this study occurred
despite numerous advisories by public health agencies and the
media to avoid outdoor activities, combined with a partial restriction on vehicular eet and industrial operations. Consequently,
reducing risk will require enacting additional preventive measures
and systematically evaluating future critical pollution periods (as
indicated by epidemiological variables) when deciding to implement them.
Epidemiological and toxicological studies are necessary to
elucidate the pathogenic cerebrovascular processes that are

induced by urban air pollution. Additionally, a more direct measure

of vehicular eet and industry emissions (i.e., elemental and
organic carbon concentrations, particle numbers and chemical
speciation [organic and inorganic fractions]), which are the major
sources of PM2.5, is still required to conrm the contributions of
different urban air pollution components to increased cerebrovascular disease admissions in Santiago. There is also an urgent need to
gather nationwide scientic evidence on the health effects of
PM2.5.
Acknowledgments
The nancial support of The Chilean Environmental Ministry
(Ministerio del Medio Ambiente, MMA) is gratefully acknowledged.
This study was conducted under collaboration agreement MMACENMA 2008-2010. The authors are also grateful to Dr. Ral G.E.
Morales S. and Dr. Richard Toro for their helpful discussions and
comments. The authors greatly appreciate the time and effort given
by anonymous reviewers and by the editors of Environmental
Pollution in evaluating our manuscript.
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