ORIGINAL ARTICLE

Exposure to air pollution and incidence

of atopic dermatitis in the general
population: A national population-based
retrospective cohort study
Se Kwang Park, MD, Joung Soo Kim, MD, PhD, and Hyun-Min Seo, MD, PhD
Guri, Republic of Korea

Background: To date, little evidence is available to determine whether atopic dermatitis (AD) can be
caused by exposure to air pollutants, including gases and particulate matter.

Objective: We aimed to evaluate the relationship between air pollutants and incidence of AD using the
National Health Insurance Service-National Sample Cohort database.

Methods: We included 209,168 subjects from the general population previously not diagnosed with AD
between 2008 and 2013. Long-term average concentration of air pollutants before diagnosis was calculated
for each subject.

Results: For 1,030,324 person-years, incident cases of AD were observed in 3203 subjects. There was a
significant positive association between incidence of AD and long-term average concentration of
particulate matter smaller than 2.5 m in diameter (hazard ratio [HR], 1.420; 95% CI, 1.392-1.448; for
1 g/m3), particulate matter smaller than 10 m in diameter (HR, 1.333, 95% CI, 1.325-1.341; for 1 g/m3),
sulfur dioxide (HR, 1.626; 95% CI, 1.559-1.695; for 1 parts per billion), nitrogen dioxide (HR, 1.200; 95% CI,
1.187-1.212; for 1 parts per billion), and carbon monoxide (HR, 1.005; 95% CI, 1.004-1.005; for 1 parts per
billion) after adjusting for age, sex, income, comorbid diseases, and meteorologic variables.

Limitations: The National Health Insurance Service database lacks detailed information on individual
subjects.

Conclusions: This study demonstrated that long-term exposure to air pollutants, including gases and
particulate matter, is an independent risk factor for developing AD. ( J Am Acad Dermatol https://doi.org/
10.1016/j.jaad.2021.05.061.)

Key words: air pollutants; allergic comorbidities; atopic dermatitis; disease; fine particulate matter; national
health program.

INTRODUCTION to penetrate deep into the respiratory system,

Many epidemiologic studies have provided evi-
dence that exposure to air pollutants, including
ambient particulate matter (PM), is associated with
adverse health outcomes.1 PM is a mixture of solid
particles and liquid droplets found in the air. It is the
most harmful form of air pollution due to its ability
blood, brain, and skin. Fine particulate matter
smaller than 2.5 m in diameter (PM2.5) is primarily
associated with respiratory and cardiovascular dis-
eases and has been reported to increase mortality.2-5
The results of a previous systematic review and
meta-analysis suggest that black carbon and

From the Department of Dermatology, Hanyang University Guri
Hospital, College of Medicine, Hanyang University.
Funding sources: Supported by the research fund of Hanyang
University (HY-2020).
IRB approval status: Approved by the Ethics Committee of
Hanyang University Guri Hospital (GURI 2020-02-010) and
conducted in accordance with the principles of the Declaration
of Helsinki.
Accepted for publication May 25, 2021.
Reprints not available from the authors.
Correspondence to: Hyun-Min Seo, MD, PhD, Department of
Dermatology, Hanyang University Guri Hospital, 153,
Gyeongchun-ro, Guri-si, Gyeonggi-do 11923, Republic of
Korea. E-mail: blackshm@hanyang.ac.kr.
Published online July 24, 2021.
0190-9622/$36.00
Ó 2021 by the American Academy of Dermatology, Inc.
https://doi.org/10.1016/j.jaad.2021.05.061

1
2 Park, Kim, and Seo J AM ACAD DERMATOL
n 2021

organic carbon are important detrimental compo- It contains a large volume of representative informa-
nents of PM2.5.6 tion that does not require privacy regulation.
Atopic dermatitis (AD) is a chronic inflammatory Subjects who had been treated for AD or comorbid
skin disease that primarily occurs in early childhood. diseases during the screening period (2002-2007)
Exposure to air pollutants can exacerbate atopic were excluded. Age, sex, location, income, and
diseases or influence their prevalence in young diagnostic codes based on the International
children.4,7 Air pollutants are likely to aggravate AD Classification of Diseases, tenth revision, (ICD-10)
by damaging the skin barrier were retrieved. This study
or immune responses. was approved by the Ethics
Indoor and outdoor air pol- CAPSULE SUMMARY Committee of Hanyang
lutants have been considered University Guri Hospital
potential risk factors for d
Long-term exposure to air pollutants, (GURI 2020-02-010) and
exacerbating AD.8 Among including sulfur dioxide, nitrogen was conducted in accor-
these pollutants, particulate dioxide, carbon monoxide, particulate dance with the principles of
matter smaller than 10 m in matter \2.5 m in diameter (PM2.5), and the Declaration of Helsinki.
diameter (PM10) and PM2.5 particulate matter \10 m in diameter
have become a great concern (PM10), is independently associated with Study subjects and
for public health, particularly increased risk of developing atopic definition of clinical
in Asia, due to the large dermatitis (AD). outcomes
amount of anthropogenic d A 1 g/m increase in long-term PM2.5
3 Patients who had an ICD-
emissions from East Asia, and PM10 average concentration was 10 code of L20 (AD) were
including China.9 associated with a 42.0% and 33.3% identified from the NHIS-
Despite various studies re- increase in the development of AD, NSC. Comorbidities were
porting a significant associa- respectively. defined as allergic rhinitis
tion between air pollutants (ICD-10 codes J30), asthma
and AD, most previous cross- (ICD-10 codes J45), or
sectional studies have had a selection bias caused by allergic conjunctivitis (ICD-10 codes H10.1, H10.45,
misclassification because the diagnosis of AD was and H10.40). To improve the accuracy of the
based simply on reports from patients or parents.10-12 analysis, only the subjects who had at least 2
Our retrospective cohort study reported here used principal diagnostic codes for each disease were
survival models to investigate how the risk of included. The diagnosis date of a disease was used as
developing AD changes over time for covariates, the entry date for patients with disease.
including particulate and gaseous air pollution. The
aim of this study was to evaluate the association Measurements of air pollutants
between outdoor air pollutants and AD using the Ambient particulate matter (PM2.5, PM10), gaseous
National Health Insurance Service-National Sample air pollution (sulfur dioxide [SO2], nitrogen dioxide
Cohort (NHIS-NSC) database. [NO2], carbon monoxide [CO], and ozone [O3]),
temperature, and humidity were measured hourly
MATERIALS AND METHODS at the sites of the Korean Nationwide Meteorological
Study design and database Observatory by the Korean Department of
This retrospective cohort study examined approx- Environmental Protection. To assess the long-term
imately 1 million representative samples from the health effects of air pollution, the monitor nearest the
NHIS-NSC. One hundred percent of the Korean residence of each study subject was used to assess
population is covered by the NHIS, with health average pollutant concentrations for that individual.
coverage divided into 3 categories: the National To exclude the effect of exposure to air pollutants
Health Insurance program for employees, for self- after AD diagnosis, the long-term average concen-
employed, and for the medical aid system. In 2013, tration of air pollutants before diagnosis was calcu-
97.2% (n = 49,989,620) of the population was lated for each subject. For subjects who were not
covered by the National Health Insurance and 2.8% diagnosed with AD, the average concentration of
(n = 1,458,871) of the population was covered by the exposure was calculated from the entry date to the
medical aid system. end of follow-up.
Due to the large volume and lack of confidenti- A geographically based average concentration of
ality with regard to personal information in the each air pollutant was measured hourly at the 313
National Health Insurance database, the NHIS-NSC monitoring facilities The 256 residential zip codes
was constructed as a representative sample database. were matched with the nearest monitoring facilities.
J AM ACAD DERMATOL Park, Kim, and Seo 3
VOLUME jj, NUMBER j

Table I. Demographics and comorbidities of

Abbreviations used:
incident cases of atopic dermatitis (1,030,324
AD: atopic dermatitis person-years)
aOR: adjusted odds ratio
HR: hazard ratio Numbers of
ICD-10: International Classification of Dis- incident cases
eases, tenth revision Characteristics Value of AD (%)
NHIS-NSC: National Health Insurance Service-
National Sample Cohort Age, y 0 1364 (42.59)
PM: particulate matter 1-4 188 (5.87)
PM2.5: particulate matter smaller than 2.5 m 5-9 224 (6.99)
in diameter 1014 165 (5.15)
PM10: particulate matter smaller than 10 m 15-19 122 (3.81)
in diameter
ppb: parts per billion 20-24 145 (4.53)
ppm: parts per million 25-29 146 (4.56)
30-34 147 (4.59)
35-39 106 (3.31)
40-44 164 (5.12)
Subjects without data on PM2.5 exposure were 45-49 104 (3.25)
excluded. Because the nationwide measurement of 50-54 80 (2.50)
fine PM in Korea was not conducted before 2015, 55-59 83 (2.59)
limited data measured in only some areas were 60-64 77 (2.40)
during the study period. 65-69 41 (1.28)
70-74 33 (1.03)
Statistical analyses ;75 14 (0.44)
Incident cases of AD were calculated by dividing Sex Male 1487 (46.43)
Female 1716 (53.57)
the number of events by person-years at risk. The
Low income (\20%) 289 (9.02)
incidence rates were compared based on the Cox Comorbidities Allergic rhinitis 1502 (46.89)
proportional hazards model adjusted for age, sex, Asthma 877 (27.38)
income, comorbid diseases, and meteorologic vari- Allergic conjunctivitis 466 (14.55)
ables (temperature and humidity). We calculated Total 3203 (100)
unadjusted hazard ratios and additionally performed
analyses for the adjusted model 1 (adjusted for AD, Atopic dermatitis.
meteorologic variables) and the fully adjusted model
2 (adjusted for age, sex, income, comorbid diseases, rhinitis (46.89%). The demographic and clinical
and meteorologic variables). characteristics of the study population are summa-
A sensitivity analysis of long-term average con- rized in Table I.
centrations of air pollutants was performed 1 month,
2 months, and 6 months prior to AD diagnosis to Association between long-term average
determine the delayed effects of air pollution on the concentration of air pollutants and incidence
development of AD. Differences were considered of AD
statistically significant when the P value was less than In unadjusted analysis, there was a significant
.05. Data were analyzed using SAS (version 9.4; SAS association between the incidence of AD and long-
Institute) and the graph was visualized with R term average concentration of PM2.5, PM10, SO2,
software (version 3.5.2; R Project for Statistical NO2, and O3, and CO (Table II). After adjusting for
Computing). age, sex, income, comorbid diseases, and meteoro-
logic variables, a significant positive association was
RESULTS still observed between incidence of AD and long-
Baseline and clinical characteristics of incident term average concentration of PM2.5 (hazard ratio
cases of AD [HR], 1.420; 95% CI, 1.392-1.448; for 1 g/m3), PM10
This study included 209,168 subjects not previ- (HR, 1.333; 95% CI, 1.325-1.341; for 1 g/m3), SO2
ously diagnosed with AD. For a total of 1,030,324 (HR, 1.626; 95% CI, 1.559-1.695; for 1 part per billion
person-years, we identified 3203 incident cases of [ppb]), NO2 (HR, 1.200; 95% CI, 1.187-1.212; for
AD (310.9/100,000 person-year). The age group with 1 ppb), and CO (HR, 1.005; 95% CI, 1.004-1.005; for
the highest incidence of AD was 0 years (42.59%), 1 ppb).
followed by 5 to 9 years (6.99%) and 1 to 4 years On the other hand, there was a significant
(5.87). Of the patients with AD, 53.57% were girls. negative association between the incidence of AD
The most prevalent comorbid disease was allergic and long-term average concentration of O3 (HR,
4 Park, Kim, and Seo J AM ACAD DERMATOL
n 2021

Table II. Ambient particulate and gaseous air pollution and incidence of atopic dermatitis in the overall
general population (n = 209,168)
HR (95% CI) HR (95% CI) HR (95% CI)
Adjusted Adjusted
Air pollutant Unadjusted P value Model 1* P value Model 2y P value
Long-term average concentration
PM2.5z 1.713 (1.693-1.734) \.001 1.458 (1.431-1.486) \.001 1.420 (1.392-1.448) \.001
PM10z 1.395 (1.388-1.403) \.001 1.333 (1.325-1.341) \.001 1.319 (1.311-1.327) \.001
SO2x 2.171 (2.072-2.276) \.001 1.698 (1.627-1.772) \.001 1.626 (1.559-1.695) \.001
NO2x 1.296 (1.283-1.310) \.001 1.208 (1.196-1.221) \.001 1.200 (1.187-1.212) \.001
O3x 0.807 (0.792-0.822) \.001 0.822 (0.808-0.837) \.001 0.814 (0.800-0.829) \.001
COx 1.007 (1.007-1.008) \.001 1.005 (1.005-1.006) \.001 1.005 (1.004-1.005) \.001
Sensitivity analysis 1 (long-term average concentration 1 month prior to AD diagnosis)
PM2.5z 2.021 (1.985-2.057) \.001 1.457 (1.428-1.485) \.001 1.430 (1.400-1.461) \.001
PM10z 1.413 (1.406-1.421) \.001 1.346 (1.337-1.354) \.001 1.325 (1.316-1.333) \.001
SO2x 2.209 (2.116-2.305) \.001 1.774 (1.701-1.850) \.001 1.705 (1.637-1.776) \.001
NO2x 1.308 (1.294-1.322) \.001 1.216 (1.203-1.229) \.001 1.203 (1.190-1.216) \.001
O3x 0.802 (0.787-0.817) \.001 0.816 (0.802-0.831) \.001 0.807 (0.793-0.822) \.001
COx 1.008 (1.007-1.008) \.001 1.005 (1.005-1.006) \.001 1.005 (1.005-1.006) \.001
Sensitivity analysis 2 (long-term average concentration 2 month prior to AD diagnosis)
PM2.5z 1.991 (1.956-2.026) \.001 1.440 (1.412-1.468) \.001 1.387 (1.359-1.416) \.001
PM10z 1.363 (1.356-1.371) \.001 1.292 (1.285-1.299) \.001 1.298 (1.291-1.306) \.001
SO2x 2.252 (2.155-2.354) \.001 1.782 (1.708-1.859) \.001 1.677 (1.609-1.749) \.001
NO2x 1.316 (1.301-1.331) \.001 1.217 (1.204-1.230) \.001 1.200 (1.188-1.213) \.001
O3x 0.808 (0.793-0.824) \.001 0.821 (0.807-0.836) \.001 0.818 (0.803-0.832) \.001
COy 1.008 (1.007-1.008) \.001 1.005 (1.005-1.006) \.001 1.005 (1.005-1.006) \.001
Sensitivity analysis 3 (long-term average concentration 6 month prior to AD diagnosis)
PM2.5z 1.854 (1.831-1.878) \.001 1.462 (1.434-1.491) \.001 1.367 (1.339-1.395) \.001
PM10z 1.263 (1.259-1.266) \.001 1.228 (1.224-1.233) \.001 1.191 (1.186-1.196) \.001
SO2x 2.434 (2.339-2.533) \.001 1.864 (1.788-1.944) \.001 1.680 (1.614-1.749) \.001
NO2x 1.344 (1.330-1.358) \.001 1.241 (1.227-1.255) \.001 1.224 (1.211-1.238) \.001
O3x 0.853 (0.836-0.870) \.001 0.853 (0.837-0.869) \.001 0.837 (0.822-0.853) \.001
COx 1.008 (1.007-1.008) \.001 1.005 (1.005-1.006) \.001 1.005 (1.004-1.005) \.001

AD, Atopic dermatitis; CO, carbon monoxide; HR, hazard ratio; NO2, nitrogen dioxide; O3, ozone; PM2.5, particulate matter \2.5 m in
diameter; PM10, particulate matter \10 m in diameter; ppb, parts per billion; SO2, sulfur dioxide.
*Adjusted for meteorologic variables.
y
Adjusted for age, sex, income, comorbid diseases and meteorological variables.
z
By 1 g/m3 increase.
x
By 1 ppb increase.

0.814; 95% CI 0.800-0.829; for 1 ppb). The results
were consistent in the sensitivity analysis. The effects
of covariates other than air pollutants on the inci-
dence of AD are presented in Supplemental Tables I
to VI (available via Mendeley at https://data.
mendeley.com/datasets/w4rx3j7vmf/1.) Among the
covariates, age under 1 year, female sex, allergic
rhinitis, high average temperature, and low average
relative humidity independently showed an
increased risk of an incidence of AD.
We fit a Cox proportional hazards model that
included spline terms for covariates and climate
variables. The relationship between long-term
average concentration of each air pollutant and the
incidence of AD was plotted (Fig 1, A to F ). For the
long-term average concentration of each air
pollutant, thresholds at which the HR for incident
AD risk significantly increased or decreased were
24.78 g/m3 for PM2.5, 48.93 g/m3 for PM10,
0.005138 parts per million (ppm) for SO2,
0.03436 ppm for NO2, 0.02054 ppm for O3, and
0.5436 ppm for CO.
DISCUSSION
We conducted a retrospective cohort study of
209,168 subjects to investigate the causal relationship
between air pollutants and incidence of AD. The
results of the analysis demonstrated 2 important
findings.
First, long-term exposure to air pollutants was
significantly associated with an increased risk for
developing AD in the general population. A 1 g/m3
increase in the long-term average concentration of
PM2.5 and PM10 increased the incidence of AD by
J AM ACAD DERMATOL Park, Kim, and Seo 5
VOLUME jj, NUMBER j

Fig 1. Concentration-response relationships between incidence of atopic dermatitis and long-

term average exposure of air pollutants, including (A) PM2.5, (B) PM10, (C) SO2, (D) NO2, (E)
O3, and (F) CO. The hazard ratio was adjusted for age, sex, income, comorbid diseases, and
meteorologic variables. CO, Carbon monoxide; NO2, nitrogen dioxide; O3, ozone; PM2.5,
particulate matter smaller than 2.5 m in diameter; PM10, particulate matter smaller than 10 m
in diameter; SO2, sulfur dioxide.

42.0% and 33.3%, respectively. We also demon-
strated that long-term exposure to gaseous air
pollutants, including SO2, NO2, and CO, was associ-
ated with increased risk for developing AD. Second,
the relationship between PM2.5/PM10 concentration
and the risk of developing AD was significant above
24.78 and 48.93 g/m3, respectively.
Air pollution has been considered a potential risk
factor for developing AD, although the exact bio-
logic mechanism remains unclear. Air pollutants
induce oxidative stress in the skin, leading to skin
barrier dysfunction or immune dysregulation.8 In
2003, Niwa et al13 showed that increased oxidative
stress generated from environmental pollution can
induce oxidative protein damage in the stratum
corneum, disrupting the skin barrier and aggravating
AD. A recent in vitro and in vivo study using cultured
keratinocytes and tape-stripped BALB/c mice
showed PM-induced skin barrier-disruption and
inflammation by increased mRNA expression of
interleukin 8 and matrix metalloproteinase-1. In
addition, an in vivo study showed intercellular
penetration of PM in the barrier-disrupted skin.14
Another in vivo study using the Brown Norway rat
showed that the antioxidant desferrioxamine could
modulate chemically induced helper T cell type 2-
mediated autoimmunity by suppressing interleukin 4
cytokine.15 The results of these animal studies sug-
gest that oxidative stress and redox imbalances
produce or exacerbate AD by disrupting the skin
6 Park, Kim, and Seo
barrier or enhancing helper T cell type 2
polarization.8
Based on previous studies, air pollutants
including NO2, O3, and PM influence the prevalence
of AD.10,16-18 In a study of 4907 French children
(9-11 years of age) residing at their current address
for 3 years or longer, lifetime eczema was signifi-
cantly associated with average 3-year concentrations
of PM10 (adjusted odds ratio [aOR], 1.13; 95% CI,
1.01-1.24), NO2 (aOR, 1.23; 95% CI, 1.04-1.42), NOx
(aOR, 1.06; 95% CI, 1.00-1.18), and CO (aOR, 1.08;
95% CI, 1.00-1.21).10 A previous case-control study
comprising 198 cases with persistent allergic symp-
toms and 202 control subjects aged 3 to 8 years,
observed a higher median concentration of butyl
benzyl phthalate in dust was among cases (0.15 mg/g
dust) than among controls (0.15 mg/g dust).12 A
previous birth cohort study by Morgenstern et al19
showed that during the first 6 years of life, there was
a strong positive association between distance to the
nearest main road and eczema. The authors also
found that NO2 exposure was positively associated
with eczema.
The results of these studies suggest that both
indoor and outdoor air pollutants are potent risk
factors for developing AD. However, the studies
were limited by design and exposure assessment.
Ambient O3 is generally regarded as a toxic compo-
nent of the photochemical air pollution mixture. A
previous study found a positive relationship be-
tween ambient O3 concentration and hospital ad-
missions for asthma and AD in children.20 On the
other hand, O3 has been widely applied in clinics in
mechanisms of antimicrobial effect, immunoregula-
tion, epigenetic modification, biosynthesis, and
vasodilation.21 Zeng et al22 showed that topical
ozone therapy may improve AD by restoring the
microbiome diversity in AD. Further research is
needed on the conflicting results for O3. The results
of our study confirmed that there is an association
between air pollution and the development of AD in
a large retrospective cohort study.
The effects of PM on AD were investigated in
several studies. A previous study revealed that fine
particulates exacerbate AD symptoms more than do
coarse particulates.23 PM2.5, with its small size and
large number of component metals, can easily
penetrate deep into skin cells and can pose a higher
risk of AD. In a systematic review and meta-analysis,
Ngoc et al24 suggested that exposure to PM2.5 slightly
increases the incidence of skin disease compared to
exposure to PM10. They also reported that humans
were at greater risk of diseases at lower PM2.5
concentration (26.04 g/m3) than at PM10
J AM ACAD DERMATOL
n 2021
concentration (47.09 g/m3), which indicates that
PM2.5 is far more harmful to humans than is PM10.
On the other hand, ultrafine particles, which are
smaller than PM2.5 and have a diameter of less than
0.1 m, have recently been identified as a cause for
concern for human health. A previous study of 41 AD
patients aged 8 to 12 years showed that itching score
was significantly associated with the concentration
of ambient PM smaller than 0.1 m in diameter but
not of larger particles.25 The potential for PM smaller
than 0.1 m in diameter to cause harm to human
health, including skin diseases, is great, but the
precise role is unknown, and more research is
needed. Collectively, these results suggest that
PM2.5 is the factor most responsible for the occur-
rence and exacerbation of AD among outdoor air
pollutants.
The prevalence of atopic diseases has been
rapidly increasing worldwide. In 2008, Yu et al26
reported that the prevalence of AD in the 48,606,787
Korean population was 2.2% at all ages. In children
aged less than 24 months, the prevalence of AD has
increased from 19.8% to 23.8% between the years
2003 and 2008. In a recent systemic review about the
prevalence and incidence of AD, the authors showed
that the incidence of AD ranged from 10.2 to 95.6 per
1000 person-years in children. In adults, the inci-
dence of AD was 7.41 per 1000 person-years in
1968.27 To date, there is no study on the incidence of
AD in the Korean population.
Our study showed an incidence of 310.9 per
100,000 person-years in the general population.
The difference between the current and previous
studies in other countries is thought to be due mainly
to a difference in the study methods. For example, in
our study, only subjects with at least 2 major
diagnostic codes for AD were included and subjects
treated for AD during the screening period were
excluded from 2002 to 2007.
This study had several limitations. First, the effects
of air pollutants on AD were not entirely clear
because there could have been other confounding
factors that we could not analyze, such as exposure to
indoor volatile organic compounds (eg, benzene,
toluene, ethylbenzene, xylene, and formaldehyde)
as well as allergens and biologic materials (eg, pollen,
house dust mites, bacteria, and various fungal
spores). Second, it was difficult to confirm the
diagnosis of disease because it was identified based
on the NHIS claims database without reviewing
clinical charts. However, to our knowledge, this is
the first study to investigate the association between
outdoor air pollutants, particularly PM2.5 and PM10,
and the occurrence of AD in a large cohort database.
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
CONCLUSIONS
The results of this study confirmed that long-term
exposure to air pollutants significantly increases the
development of AD, especially above an average
PM2.5 and PM10 concentration of 24.78 and
48.93 g/m3, respectively.
Conflicts of interest
None disclosed.
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