Environmental Pollution 246 (2019) 183e189

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

Impacts of air pollution on dry eye disease among residents in

Hangzhou, China: A case-crossover study*,**
Zhe Mo a, 1, Qiuli Fu b, c, 1, Danni Lyu b, c, Lifang Zhang b, c, Zhenwei Qin b, c,
Qiaomei Tang b, c, Houfa Yin b, c, Peiwei Xu a, Lizhi Wu a, Xiaofeng Wang a, Xiaoming Lou a,
Zhijian Chen a, *, Ke Yao b, c, **
a
Department of Environmental and Occupational Health, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang Province,
China
b
Eye Center of the 2nd Affiliated Hospital, School of Medicine, Zhejiang University, China
c
Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, Zhejiang Province, China

a r t i c l e i n f o a b s t r a c t

Article history: The purpose of this study is to investigate the potential associations between air pollution and dry eye
Received 29 January 2018 disease (DED). Data of outdoor air pollutants and meteorology as well as outpatient visits for DED were
Received in revised form collected. A time-stratified case-crossover approach was used to analyze the associations between
26 November 2018
ambient air pollutants and outpatient visits for DED. Among the 5062 DED patients studied, 65.45% were
Accepted 30 November 2018
Available online 4 December 2018
female and 34.55% were male. In the single-pollutant model, significant associations were observed
between an increase of 10 mg/m3 in the concentrations of fine-particulate matter with a median aero-
metric diameter of less than 10 mm (PM10), fine-particulate matter with a median aerometric diameter of
Keywords:
Air pollution
less than 2.5 mm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) and
Dry eye disease outpatient visits for DED. These results were consistent with those of the multipollutant model. The
Pollutants strongest associations between air pollutants and patient visits were observed during the cold season
Case-crossover study and in patients aged 21e40. The significant association between air pollutants (PM10, PM2.5, SO2, NO2,
and CO) and DED outpatient visits indicates the importance of increased environmental protection.
© 2018 Elsevier Ltd. All rights reserved.

1. Introduction keratoconjunctivitis sicca, can be caused by decreased tear pro-

Dry eye disease (DED) is a common ocular surface disorder that
results in symptoms of discomfort, visual disturbance, and tear-film
instability with potential damage to the ocular surface. DED is a
multifactorial disease and is a rising public health issue (Al-Saedi
et al., 2016; Lemp, 1995; Um et al., 2014). DED, also known as
*
This paper has been recommended for acceptance by Dr. Payam Dadvand.
**
This article has not been presented elsewhere. No conflicting relationship exists
for any author.
* Corresponding author.Department of Environmental and Occupational Health,
Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road,
Hangzhou, 310051, Zhejiang Province, China.
** Corresponding author. Eye Center of the 2nd Affiliated Hospital, Medical Col-
lege of Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province,
China.
1
E-mail addresses: zhjchen@cdc.zj.cn (Z. Chen), xlren@zju.edu.cn (K. Yao).
Z.M. and Q.F. contributed equally to this work.
duction or excessive tear evaporation, wearing of contact lenses,
LASIK surgery, etc. (National Eye Institute, 2013). Symptoms of DED
tend to increase in windy, dusty, or smoky areas and include irri-
tation, redness, discharge, and easily fatigued eyes. Evidence
showed that environmental pollution had major effects on the
occurrence of ocular surface diseases, such as DED (Pouyeh et al.,
2012; Wolkoff, 2010).
Increasing environmental pollution is a cost of industrializa-
tion seen currently in China. The Yangtze River Delta (YRD) region,
in which the city of Hangzhou is located, is one of the most so-
cioeconomically developed and rapidly urbanizing city clusters in
southeast China. People in this area benefit from the high level of
social development but suffer from the adverse health effects
associated with air pollution. Evaluations of air pollution levels as
well as its effects on human health have been conducted in several
studies in Hangzhou (Lu et al., 2017; Lu et al., 2008; Shen et al.,
2017). The seasonal variation of fine-particulate matter with a
median aerometric diameter of less than 2.5 mm (PM2.5) and its

https://doi.org/10.1016/j.envpol.2018.11.109
0269-7491/© 2018 Elsevier Ltd. All rights reserved.
184 Z. Mo et al. / Environmental Pollution 246 (2019) 183e189
bounded polycyclic aromatic hydrocarbons have been thoroughly
analyzed (Ming et al., 2017). The increase in respiratory diseases
due to severe air pollution in Hangzhou was reported by Shen
et al. (2017), indicating the potential link between air pollutants
and DED.
A few epidemiological studies have been conducted to evaluate
the relationship between air pollution and DED (Hwang et al.,
2016; Ong et al., 2016; Um et al., 2014; Versura et al., 1999). A
study by Galor et al. (2014) found that environmental factors
affected the risk of DED in a US veteran population, during which
air pollution and atmospheric pressure emerged as the most
influential predictors, while another study on the same group
revealed that DED has a seasonal pattern with the highest prev-
alence of DED in winter and spring, due to higher allergen expo-
sure, and the lowest prevalence in summer (Kumar et al., 2015).
These results are consistent with the findings in South Korea that
indicate the prevalence of DED can be affected by the degree of
urbanization. This finding may link DED to air pollution and nat-
ural environmental factors, such as an area's humidity and dura-
tion of sunshine. Their results also suggested that SO2, a main air
pollutant, was associated with DED (Um et al., 2014). However,
another study investigating outdoor air pollution and DED
revealed that higher ozone levels and lower humidity were
associated with DED in the Korean population (Hwang et al.,
2016). In China, DED is a common ocular disease that is
receiving increased attention as society develops. The prevalence
of DED in China continues to increase and is currently as high as
17e21% (Liu et al., 2014). However, the potential associations be-
tween air pollutants and DED in China is far from understood.
The time-stratified case-crossover design is one of the most
used designs for analyzing the health-related effects of air pollution
(Carracedo-Martinez et al., 2010). There are two main characteris-
tics for this approach. One is that each subject serves as his or her
own control during the analysis, which is a characteristic for all
types of case-crossover studies. The other is that the control periods
most frequently used for the time are the same days of the week as
the case within the same month (Carracedo-Martinez et al., 2010).
Our previous study using the time-stratified case-crossover
method found that outpatient visits for conjunctivitis, another
common ocular surface disease, was significantly associated with
air pollutants, specifically PM10, PM2.5, SO2, and CO (Fu et al.,
2017b). So far, to our knowledge, the time-stratified case-cross-
over design has not been employed in studying the association
between air pollution and DED.
Some studies have shown that DED is frequently associated
with ocular surface cell dysfunction (Al-Saedi et al., 2016; Han
et al., 2017). Our previous study showed that PM2.5 collected in
Hangzhou significantly inhibited the viability and proliferation of
ocular surface epithelial cells (human corneal epithelial cells
(HCECs)), resulting in damage of the ocular surface cells and
imbalance of the ocular surface microenvironment (Fu et al.,
2017a). To further investigate the adverse effects of air pollut-
ants on ocular surface diseases in Hangzhou, a time-stratified
case-crossover study was performed to analyze the effects of
ambient air pollution on outpatient visits for DED. This approach
was used to compare the exposure of individual DED patients on
the day of the outpatient visits to their exposure on up to four
referent days occurring on the same day of the week during the
same month. The effects of air pollutants, including PM2.5, fine-
particulate matter with a median aerometric diameter of less
than 10 mm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2),
and carbon monoxide (CO), and meteorological factors, including
relative humidity and pressure, on DED outpatient visits were
investigated in this study.
2. Materials and methods
2.1. Study population and design
As a retrospective study, individual-level data on outpatient
visits during July 1, 2014, through June 30, 2016, at the Eye Center of
the Second Affiliated Hospital at the School of Medicine in Zhejiang
University (Hangzhou, Zhejiang Province, China), which is the
biggest ophthalmology clinic in Zhejiang Province, were obtained
from the IT Department of the Second Affiliated Hospital at the
School of Medicine in Zhejiang University (n ¼ 1,067,441). Out-
comes were defined using the International Classification of Dis-
eases, 10th Revision (ICD-10). The definition for DED was H16.208
and H11.103. Outpatient information was obtained, including pa-
tients' numbers (every patient has a unique number to differentiate
them), visit dates, ages, genders, and home addresses (including ZIP
codes). The locations of the hospital and the patients’ home are
shown in Fig. 1. Revisiting patients were excluded, and only first-
visit patients were included in this study. The research adhered
to the tenets of the Declaration of Helsinki. The Ethics Committee of
Zhejiang University approved the procedures performed in this
study. Informed consent was not required because the data came
from anonymous datasets typically used for administrative
purpose.
The case-crossover design, which was first proposed by Maclure
(1991), is characterized by the fact that each subject serves as his or
her own control. It is one of the most used designs for analyzing the
health-related effects of air pollution (Carracedo-Martinez et al.,
2010). The time-stratified case-crossover design has most often
proven to be the best in different simulations (Carracedo-Martinez
et al., 2010). Therefore, the time-stratified case-crossover design
was employed in our study. Control periods most frequently used
for the time-stratified design are all the same days of the week as
the case within the same month (Carracedo-Martinez et al., 2010).
Detailed statistical analysis is provided below.
2.2. Outdoor air pollutants and meteorology data
The daily concentrations of PM2.5, PM10, SO2, NO2, and CO as
well as the 8-h maximum value for ozone (O3) were collected by
eight fixed urban background air-quality monitors (Hemuxiaoxue
(HMXX), Xixi (XX), Yunxi (YX), Zhejiangnongda (ZJND), Binjiang
(BJ), Xiasha (XS), Wolongqiao (WLQ), and Zhaohuiwuqu (ZJWQ))
covering the main city districts of Hangzhou (Fig. 1). This work was
conducted by the Environmental Protection Department of Zhe-
jiang Province using the National Air Pollution Monitoring System
under the control of the China National Quality Control for Air
Monitoring Network (He et al., 2002). The daily average concen-
trations of PM2.5 and PM10 were measured using the method of
tapered element oscillating microbalance (TEOM). The method
based on ultraviolet fluorescence and chemiluminescence was used
to measure SO2 and NO2. An IR analyzer and nondispersive ultra-
violet fluorescence photometer were applied to measure CO and O3,
respectively. The daily mean temperature, relative humidity, and
atmospheric pressure were provided by the Meteorological
Administration of Zhejiang Province. All data were collected from
July 1, 2014, to June 30, 2016.
2.3. Statistical analysis
A time-stratified case-crossover approach, which takes the
subjects as self-control, was used to analyze the associations be-
tween ambient air pollutants and outpatient visits for DED. This
approach was used to compare exposures of individual patients on
the day of the outpatient visits to their exposures on up to four
 Z. Mo et al. / Environmental Pollution 246 (2019) 183e189 185

Fig. 1. Locations of patients, environmental monitoring stations, and the hospital in Hangzhou of Zhejiang Province, China. The red points represent each air-quality monitor;
the brown point represents the location of the hospital; the black points represent the home addresses of each patient in the study. HMXX: Hemuxiaoxue; XX: Xixi; YX: Yunxi;
ZJND: Zhejiangnongda; BJ: Binjiang; XS: Xiasha; WLQ: Wolongqiao; ZJWQ: Zhaohuiwuqu. (For interpretation of the references to colour in this figure legend, the reader is referred
to the Web version of this article.)

referent days occurring on the same day of the week during the
same month. Because each individual serves as his or her own
control, no confounding factors vary within a month (Malig et al.,
2016). Descriptive statistics and correlation coefficients were ob-
tained for the outpatients, air pollutants, and meteorological factors
using SAS 9.4 software (Cary, NC, USA).
Outpatients were divided into four age groups (0e20, 21e40,
41e60, and 65) and two gender groups (male and female). Par-
ticipants were also divided into two season groups (warm season
from April to September, and cold season from January to March
and October to December) according to the seasonal characteristics
of Hangzhou.
Here is the analyzing process of outpatient visits for DED. First,
among all DED outpatients with no missing information
(n ¼ 31,375), only the first-visit patients (n ¼ 7636), not the revis-
iting ones (n ¼ 23,739), were included in the study. Then, according
to the latitude and longitude of the patient's home addresses ob-
tained by package Baidu Map version 0.2 in R, the patients living
within the main districts of Hangzhou (n ¼ 5677), including
Shangcheng, Xiacheng, Jianggan, Xihu, Gongshu, and Binjiang,
were included. Then, the corresponding air pollution data for each
patient was obtained from the nearest air-quality monitor accord-
ing to the distance calculated between the patient's home and the
location of the monitor using SoDA version 1.0e6. Evidence showed
that the hospital's accessibility is a distance of 10 km from the
hospital (Jones and Bentham, 1997), and in our study, most of the
patients live near the hospital, as shown in Fig. 1. Therefore,
sensitivity analyses were performed to examine the stability of the
model by selecting the data of the patients (n ¼ 5.062) living within
10 km from the hospital. Characteristics of the DED outpatients
including (n ¼ 5677) or excluding (n ¼ 5062) those living 10 km
further from the hospital in the analyses were presented in
Supplemental Table 1.
A conditional logistic regression was performed using a Cox
proportional hazards regression model with survival version
2.41e3 in R to calculate the odds ratios (O'Donnell et al., 2011). The
numbers of daily DED outpatient visits were used as weights after
case controls were selected and matched by the program.
The meteorological factors that can lead to the exacerbation of
DED and the air pollutant levels were viewed as covariates in the
model:
ln(h(t, X)) ¼ ln(h0i(t)) þ (s(T, df) þ s(RH, df) þ s(P, df) þ C(PM10)
b1 þ C(PM2.5)b2 þ C(SO2)b3 þ C(NO2)b4 þ C(O3)b5 þ C(CO)b6)
where t refers to the day; X refers to the hospital visit; ln(h(t, X))
refers to the risk function; ln(h0i(t)) refers to the baseline risk
function; and T, RH, and P refer to the temperature, relative hu-
midity, and atmospheric pressure, respectively. s() indicated
smoother based on penalized smoothing spline, which were used
to adjust for nonlinear effects of meteorological factors. The degree
of freedom (df) was selected based on the preliminary analysis. The
strategy for the selection of the df was first to fit the Cox model with
some df values (we chose the df from 2 to 4 (2, 2.5, 3, 3.5, 4, 4.5, and
5)) and, then, select the df with the lowest p-value for each mete-
orological factor as the analysis df. C(PM10), C(PM2.5), C(SO2),
C(NO2), C(O3), and C(CO) are the corresponding concentrations of
pollutants, and b refers to the coefficient for each variate. Results
are expressed as changes in the percentage and 95% confidence
interval (CI) of outpatient visits per 10 mg/m3 increase in pollutants.
The acute effects of air pollution were analyzed with both
single-day lags (lag 0 to lag 7) and successive-day lags (lag 0e1 to
lag 0e7). Same-day exposure was defined as lag 0, and daily
exposure was reviewed for up to seven days prior to the outpatient
visits. In lag models, the best lag periods were obtained according
to the maximum values of odds ratios and the minimum values of p.
A p-value less than 0.05 was considered significant in the statistical
analysis.
186 Z. Mo et al. / Environmental Pollution 246 (2019) 183e189
3. Results
Of the patients that visited the Eye Center of the Second Affili-
ated Hospital at the School of Medicine in Zhejiang University from
July 1, 2014, to June 30, 2016, a total of 5677 were recruited for this
study. Detailed demographic information is provided in Table 1. We
observed that the number of female patients (n ¼ 3,711, 65.4%) was
almost twice that of the number of male patients (n ¼ 1,966, 34.6%),
a finding consistent with previous studies (Rapoport et al., 2016;
Versura et al., 1999). Most patients (n ¼ 4,743, 83.6%) ranged from
21 to 40 (n ¼ 2,794, 49.2%) to 41e60 (n ¼ 1949, 34.3%) years old. No
significant difference was observed in the number of patients be-
tween the warm and cold seasons.
The concentrations of the ambient pollutants (SO2, NO2, CO, O3,
and PM) fluctuated dynamically during the study period. The
weekly average concentrations are presented in Supplemental
Fig. 1A. Meteorological factors (temperature, relative humidity,
and pressure) were collected from the Meteorological Adminis-
tration of Zhejiang Province. The weekly averages for these factors
are presented in Supplemental Fig. 1B.
The association of air pollutants and DED outpatient visits was
first analyzed using the single pollutant model. As shown in Table 2,
significant associations were observed between an increase of
10 mg/m3 in the concentration of PM10, PM2.5, SO2, NO2, and CO and
outpatient visits for DED. Significant associations were observed
with PM10 lags of 0, 0e1, 0e2, and 0e3 days, with PM2.5 lags of 0,
0e1 and 0e2 days, with SO2 lags of 0, 1, 0e1, 0e2, 0e3, 0e4, 0e5,
0e6, and 0e7 days, with NO2 lags of 0, 1, 2, 3, 0e1, 0e2, 0e3, 0e4,
0e5, 0e6, and 0e7 days, and with CO lags of 0, 0e1, 0e2, and 0e3
days. Consecutive exposure to these air pollutants may have
increased the number of DED outpatient visits, as the results
showed for lags of 0e1, 0e2, 0e3, 0e4, 0e5, 0e6, and 0e7 days.
There was no evidence indicating the relationship between DED
outpatient visits and O3 in the single-pollutant model.
As there are unavoidable interactions between air pollutants,
the multipollutant model was also employed for analysis. PM2.5 and
PM10 were shown to be highly correlated (Fu et al., 2017b). Because
the OR of PM2.5 for DED outpatient visits was higher than that of
PM10, as observed during the single-pollutant model analysis, PM2.5
was selected for the multipollutant model. The meteorological
variables served as control variables and the levels of pollutants in
the best lags were chosen to be used in this model. Both NO2 and
SO2 were strongly associated with DED outpatient visits, even after
adjusting for the other factors. The number of DED outpatient visits
was also associated with the pollutants PM10, PM2.5, and CO after
adjusting for a certain pollutant. The pollutant O3 was not signifi-
cantly associated with the number of DED outpatient visits, a
finding which was consistent with the results of the single-
pollutant model (Table 3).
Table 1
Characteristics of outpatient for DED in eye center of the 2nd affiliated hospital of
Zhejiang university school of medicine (7/1/2014 to 6/30/2016).
Characteristics Number of patients Percentage (%)
Sex
Male 1966 34.6
Female 3711 65.4
Age (years)
0e20 233 4.1
21e40 2794 49.2
41e60 1949 34.3
61- 701 12.4
Season
Warm season 2816 49.6
Cold season 2861 50.4
Total patients 5677 100.0
The relationship between each pollutant and DED outpatient
visits among different demographic groups was also investigated.
Consistent with the results using both the single-pollutant and
multipollutant models, PM10, PM2.5, SO2, NO2, and CO were strongly
associated with DED outpatient visits, while O3 was not. The pa-
tients who were most susceptible were those aged 21e40. The re-
sults showed strong seasonal dependence between the pollutants
and DED outpatient visits, as the strong association was only pre-
sent during the cold season (Table 4).
Previous studies concluded that meteorological factors, such as
relative humidity and pressure, may affect the morbidity of DED
(Galor et al., 2014; Kumar et al., 2015). Therefore, the association of
meteorological factors and DED outpatient visits was also analyzed.
The results showed that relative humidity was negatively associ-
ated with the number of DED outpatient visits, a finding which is
consistent with previous studies (Supplemental Fig. 2) (Galor et al.,
2014; Kumar et al., 2015).
As evidence showed that the hospital's accessibility is a distance
of 10 km from the hospital (Jones and Bentham, 1997), we per-
formed sensitivity analyses by excluding those participants living
further than 10 km from the hospital. We found that the results
from the analyses including (Tables 2e4) or excluding
(Supplemental Table 2, 3 and 4) the participants living further than
10 km from the hospital were comparable.
4. Discussion
Significant associations between air pollutants (PM10, PM2.5,
SO2, NO2, and CO) and DED outpatient visits were revealed during
this study. The most susceptible populations were those aged
21e40 (49.2% of total study patients). The association between air
pollutants and the number of DED outpatient visits was stronger in
the cold season than it was in the warm season.
Several studies suggested that outdoor air pollution could pro-
mote the occurrence of DED. Galor et al. (2014) found that air
pollution measured by aerosols optical depth (which is an indicator
of the concentration of aerosols, including all solid and liquid par-
ticles suspended in the air) played an important role in DED.
However, only a few studies have focused on the exact pollutants
that may contribute to this situation. Hwang et al. (2016) investi-
gated the association of DED and several outdoor air pollution
measurements (humidity, PM10, O3, and NO2) using a population-
based cross-sectional study. They found that only O3 and humidi-
ty were associated with DED in the Korean population, while PM10
and NO2 did not contribute to DED. Another study from South
Korea investigated the association between DED and air pollutants,
including SO2, NO2, O3, CO, and PM10, and they found that only SO2
was associated with DED (Um et al., 2014). In the present study, the
effects of multiple air pollutants, including PM10, PM2.5, SO2, NO2,
and CO, on DED were investigated in both single-pollutant and
multipollutant models, and we found significant associations be-
tween DED and air pollutants PM10, PM2.5, SO2, NO2, and CO, which
differed from the findings of other studies. These differences may
be explained by two reasons. First, these two regions (South Korea
and Hanghzou) differ greatly in climate and environment, which
may cause divergent outcomes of each air pollutant on DED. Sec-
ond, as the time-stratified case-crossover design where each pa-
tient served as his or her own control was applied in the present
study, the bias of the patients’ socioeconomic status, educational
level, living conditions, and systemic health conditions could be
avoided during the analysis, therefore, resulting in the difference in
the association of each air pollutant on DED. Altogether, our find-
ings at least further prove that air pollution is partially responsible
for the increasing cases of DED.
Because of its powerful oxidizing properties, O3 is a primary
 Z. Mo et al. / Environmental Pollution 246 (2019) 183e189 187

Table 2
Correlation of air pollutants and outpatients for DED: Single-pollutant model.

Lag PM10 PM2.5 SO2 NO2 O3 CO

0 1.0106(1.0029e1.0183)** 1.0222(1.0097e1.0348)** 1.0628(1.0149e1.1130)* 1.0324(1.0127e1.0525)** 0.9884(0.9745e1.0026) 1.0020(1.0007e1.0032)**

1 1.0062(0.9990e1.0136)
2 1.0032(0.9960e1.0105)
3 1.0033(0.9962e1.0104)
4 0.9986(0.9915e1.0058)
5 0.9977(0.9907e1.0049)
6 1.0029(0.9960e1.0099)
7 1.0012(0.9941e1.0083)
0e1 1.0115(1.0027e1.0204)*
0e2 1.0117(1.0018e1.0218)*
0e3 1.0124(1.0016e1.0233)*
0e4 1.0108(0.9991e1.0226)
0e5 1.0091(0.9967e1.0217)
0e6 1.0103(0.9971e1.0237)
0e7 1.0109(0.9967e1.0252)
1.0115(0.9999e1.0232) 1.0690(1.0245e1.1155)** 1.0466(1.0259e1.0677)** 0.9928(0.9805e1.0052) 1.0009(0.9997e1.0021)
0.9991(0.9875e1.0108) 1.0437(0.9992e1.0901) 1.0356(1.0160e1.0556)** 0.9919(0.9799e1.0041) 1.0002(0.9990e1.0013)
0.9986(0.9870e1.0103) 1.0665(1.0214e1.1137) 1.0321(1.0128e1.0517)** 1.0032(0.9912e1.0154) 0.9994(0.9982e1.0006)
0.9942(0.9827e1.0058) 1.0059(0.9628e1.0510) 1.0044(0.9853e1.0239) 1.0009(0.9887e1.0134) 0.9991(0.9980e1.0002)
0.9966(0.9851e1.0083) 0.9788(0.9366e1.0228) 1.0113(0.9920e1.0309) 0.9921(0.9799e1.0043) 0.9999(0.9988e1.0010)
1.0027(0.9914e1.0141) 1.0105(0.9679e1.0550) 1.0141(0.9946e1.0340) 0.9965(0.9846e1.0086) 0.9998(0.9987e1.0009)
1.0001(0.9885e1.0118) 0.9906(0.9489e1.0342) 1.0105(0.9911e1.0302) 0.9976(0.9856e1.0097) 1.0000(0.9988e1.0011)
1.0222(1.0082e1.0364)** 1.0998(1.0420e1.1608)** 1.0539(1.0300e1.0782)** 0.9859(0.9696e1.0023) 1.0022(1.0008e1.0035)**
1.0178(1.0023e1.0337)* 1.1159(1.0496e1.1864)** 1.0682(1.0409e1.0962)** 0.9831(0.9655e1.0009) 1.0021(1.0006e1.0035)**
1.0151(0.9982e1.0323) 1.1461(1.0720e1.2253)** 1.0806(1.0504e1.1117)** 0.9869(0.9679e1.0062) 1.0017(1.0001e1.0033)*
1.0110(0.9930e1.0294) 1.1377(1.0587e1.2225)** 1.0773(1.0447e1.1109)** 0.9884(0.9678e1.0094) 1.0012(0.9995e1.0029)
1.0087(0.9897e1.0282) 1.1187(1.0358e1.2082)** 1.0787(1.0440e1.1145)** 0.9847(0.9627e1.0072) 1.0009(0.9992e1.0027)
1.0095(0.9893e1.0301) 1.1198(1.0322e1.2150)** 1.0830(1.0460e1.1213)** 0.9835(0.9601e1.0074) 1.0007(0.9989e1.0026)
1.0094(0.9879e1.0313) 1.1134(1.0209e1.2143)* 1.0872(1.0477e1.1281)** 0.9823(0.9577e1.0076) 1.0007(0.9988e1.0027)

*P < 0.05, **P < 0.01.

PM10, fine particulate matter with a median aerometric diameter of less than 10 mm; PM2.5, fine particulate matter with a median aerometric diameter of less than 2.5 mm; SO2,
sulfur dioxide; NO2, nitrogen dioxide; CO, carbon monoxide; O3, ozone.

Table 3
Correlation of air pollutants and outpatients for DED: Multipollutant model.

PM10 PM2.5 SO2 NO2 O3 CO

Adjusted for PM10 e e 1.0583(1.0130 1.0420(1.0201 0.9875(0.9735 1.0016(1.0001

e1.1057)* e1.0643)** e1.0017) e1.0031)*
Adjusted for PM2.5 e e 1.0535(1.0082 1.0387(1.0168 0.9860(0.9720 1.0012(0.9997
e1.1008)* e1.0611)** e1.0002) e1.0026)
Adjusted for SO2 1.0083(1.0004 1.0186(1.0057 e 1.0400(1.0170 0.9894(0.9754 1.0018(1.0006
e1.0162)* e1.0316)** e1.0635)** e1.0036) e1.0031)**
Adjusted for NO2 1.0052(0.9971 1.0136(1.0003 1.0304(0.9823 e 0.9891(0.9750 1.0015(1.0002
e1.0134) e1.0271)* e1.0808) e1.0033) e1.0028)*
Adjusted for O3 1.0108(1.0031 1.0231(1.0105 1.0676(1.0230 1.0465(1.0258 e 1.0019(1.0006
e1.0186)** e1.0359)** e1.1142)** e1.0676)** e1.0031)**
Adjusted for CO 1.0045(0.9954 1.0149(0.9999 1.0578(1.0133 1.0384(1.0173 0.9908(0.9767 e
e1.0138) e1.0300) e1.1044)* e1.0599)** e1.0050)
Adjusted for the other 4 0.9999(0.9903 1.0084(0.9927 1.0233(0.9748 1.0295(1.0055 0.9909(0.9767 1.0010(0.9995
pollutants e1.0096) e1.0243) e1.0742) e1.0540)* e1.0054) e1.0025)

*P < 0.05, **P < 0.01.

PM10, fine particulate matter with a median aerometric diameter of less than 10 mm; PM2.5, fine particulate matter with a median aerometric diameter of less than 2.5 mm; SO2,
sulfur dioxide; NO2, nitrogen dioxide; CO, carbon monoxide; O3, ozone.

Table 4
Correlation of air pollutants and outpatients for DED, and effect modification through stratified analyses by patients characteristics.

Characteristics PM10 PM2.5 SO2 NO2 O3 CO

Sex
Male 1.0219(1.0091e1.0349) 1.0378(1.0168e1.0591) 1.1240(1.0461e1.2077) 1.058(1.0233e1.0939)** 0.9861(0.9624 1.0028(1.0006e1.0049)*
** ** ** e1.0105)
Female 1.0044(0.9948e1.0140) 1.0137(0.9982e1.0295) 1.0394(0.9858e1.0960) 1.0407(1.015e1.0670)** 0.9897(0.9725 1.0015(0.9999e1.0031)
e1.0073)
Age (years)
0-20 1.0469(1.0044e1.0911)* 1.0473(0.9771e1.1225) 0.9119(0.7312e1.1371) 0.9838(0.8905e1.0869)
0.9860(0.9172 1.0050(0.9983e1.0118)
e1.0599)
21-40 1.0113(1.0006e1.0221)* 1.0279(1.0104e1.0457) 1.0773(1.0151e1.1434)* 1.0544(1.0253e1.0844) 0.9934(0.9737 1.0020(1.0002e1.0037)*
** ** e1.0135)
61-60 1.0074(0.9942e1.0207) 1.0192(0.9979e1.0410) 1.0777(1.0011e1.1602)* 1.0389(1.0036e1.0755)* 0.9790(0.9548 1.0017(0.9995e1.0038)
e1.0037)
61- 1.0076(0.9847e1.0311) 0.9989(0.9631e1.0360) 1.0679(0.9410e1.2120) 1.0518(0.9913e1.1160) 0.9926(0.9532 1.0019(0.9983e1.0056)
e1.0336)
Season
Warm 0.9892(0.9739e1.0047) 0.9881(0.9639e1.0128) 0.9640(0.8882e1.0463) 0.9955(0.9579e1.0345) 0.9921(0.9755 1.0004(0.9982e1.0026)
season e1.0090)
Cold season 1.0158(1.0068e1.0249) 1.0311(1.0161e1.0463) 1.1044(1.0498e1.1619) 1.0645(1.0395e1.0901) 0.9863(0.9584 1.0024(1.0009e1.0040)
** ** ** ** e1.0150) **

*P < 0.05, **P < 0.01.

PM10, fine particulate matter with a median aerometric diameter of less than 10 mm; PM2.5, fine particulate matter with a median aerometric diameter of less than 2.5 mm; SO2,
sulfur dioxide; NO2, nitrogen dioxide; CO, carbon monoxide; O3, ozone.
188 Z. Mo et al. / Environmental Pollution 246 (2019) 183e189
irritant, affecting especially the eye, respiratory system, and skin.
Direct exposure to environmental O3 can be hazardous, even at low
concentrations. A large-scale population-based study from South
Korea demonstrated that higher O3 levels were strongly associated
with occurrence of DED (Hwang et al., 2016). However, the asso-
ciation between O3 and DED outpatient visits was not observed in
either a single-pollutant or multipollutant model, even adjusting
for the other five pollutants. Since China's air quality is generally
regarded as much poorer than that of South Korea, the lack of a
strong O3 and DED association is puzzling. However, the adverse
effects of air pollutants are complicated, especially when multiple
factors work together. One possible explanation may involve the
high levels of the other air pollutants seen in Hangzhou, all of
which showed a strong association with the number of DED
outpatient visits but made the effect of O3 less apparent. Another
possible explanation is that the short analysis period for O3 and
DED, like the several days seen in this study, may not be long
enough to reveal the association, as O3 effects may take longer to
present. Future studies should focus on the relationship between
O3 and DED, and investigations in a longer period are needed to
explain their relationship in Hangzhou.
It was hypothesized that air pollutants could alter the pre-
corneal tear film (PTF), causing ocular discomfort, such as burning,
dry, and itchy eyes, resulting in a diagnosis of DED in most cases
(Wolkoff, 2010). One possible mechanism for this alteration is that
the PTF structure is disturbed by environmental pollutants, such
asPM10 and PM2.5. In this study, PM10 and PM2.5 were strongly
associated with DED outpatient visits in both single-pollutant and
multipollutant models, consistent with the above hypothesis.
Another possible mechanism is that the structural composition of
the outermost lipid layer of the PTF is altered by aggressive aerosols
and combustion products (SO2, NO2, and CO). The results of this
study showed that a 10 mg/m3 increase in SO2, NO2, and CO con-
centrations was associated with increased outpatient visits for DED
on the same day or on subsequent lag days. Further experiments
are needed to investigate the exact effects of each air pollutant on
ocular surface cells.
One strength of this study is the use of the time-stratified case-
crossover design, a method which has been rarely used in previous
studies on DED and air pollution. In this study, each patient served
as his or her own control to avoid the bias effects of the patients’
socioeconomic status, educational level, living conditions, and
systemic health conditions.
In addition to the Eye Center of the Second Affiliated Hospital at
the School of Medicine in Zhejiang University, there are several
other general hospitals in Hangzhou that are qualified for the
treatment of eye diseases. Although a large number of patients with
eye diseases in Hangzhou visit the Eye Center of the Second Affil-
iated Hospital at the School of Medicine in Zhejiang University,
there were still patients visiting other qualified general hospitals.
Therefore, one limitation of this study is that the data on patients in
other clinics or hospitals were not included. Another limitation of
this study is that the subtypes of DED were not considered during
the analyses. Although only a tiny part of the DED patients were
caused or combined with other diseases such as concomitant eye
comorbidities glaucoma meds, Sjogren's syndrome and etc, they
should also be excluded in future study.
Recently, the Department of Environmental and Occupational
Health, Zhejiang Provincial Center for Disease Control and Pre-
vention introduced an individual backpack system for data gath-
ering that involves fixing a monitor to a study participant to collect
direct dynamic data on air pollution, location, and meteorology. In
future studies on the association of environmental factors and DED,
bioinformatic analysis will be performed using this backpack sys-
tem to collect more accurate environmental data. Various factors
such as satellite remote sensing and land-use parameters, meteo-
rological data, geographical information, traffic distribution, and
population travel patterns will be combined in future studies to
estimate the air pollution data corresponding to each patient as the
basis of big data analysis. These two new methods will help un-
cover how air pollution contributes to the development of DED.
5. Conclusions
The present study provided robust evidence that outpatient
visits for DED were significantly associated with air pollutants
(PM10, PM2.5, SO2, NO2, and CO) in Hangzhou, China, using a time-
stratified case-crossover study. In addition, this association showed
age and season dependence, as the strong association was only
present during the cold season and the most susceptible were aged
21e40. Additionally, relative humidity was found to be negatively
associated with DED. Finally, the significant association between air
pollution and DED indicates the urgency to accelerate the envi-
ronmental governance through policies and laws.
Acknowledgements
This work has been supported by National Natural Science
Foundation of China (81371001, 81300641, 81502786, 81570822,
81670833), Project of National Clinical Key Discipline of Chinese
Ministry of Health, Zhejiang Key Laboratory Fund of China
(2011E10006), Zhejiang Province Key Research and Development
Program (2015C03042), Program of Zhejiang Medical technology
(2015KYA109, 2016KYB062, 2017KY288), Science and Technology
Program of Zhejiang (2014C03025), Natural Science Foundation of
Zhejiang Province (LQ14H260003).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.envpol.2018.11.109.
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