Science of the Total Environment 616–617 (2018) 855–862

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Science of the Total Environment

journal homepage: www.elsevier.com/locate/scitotenv

Association of high-level humidifier disinfectant exposure with lung

injury in preschool children
Dong-Uk Park a, Seung-Hun Ryu b, Hyun-Suk Roh c, Eun Lee d, Hyun-Ju Cho e, Jisun Yoon f, So-Yeon Lee f,
Young Ah. Cho g, Kyung-Hyun Do g, Soo-Jong Hong f,⁎
a
Department of Environmental Health, Korea National Open University, Seoul, Republic of Korea
b
Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
c
Tiny Labs, Incheon, Republic of Korea
d
Department of Pediatrics, Chonnam National University Hospital, Gwangju, Republic of Korea
e
Department of Pediatrics, Mediplex Sejong Hospital, Incheon, Republic of Korea
f
Department of Pediatrics, Childhood Asthma and Atopy Center, Environmental Health Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
g
Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

H I G H L I G H T S G R A P H I C A L A B S T R A C T

• Risk of humidifier disinfectant-

associated lung injury (HDLI) increased
in a dose-dependent manner.
• Risk of HDLI increased ≥ two-fold in the
lower duration of usage.
• Exposure to high levels of HD within a
short period in early life affected HDLI
in preschool children.

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

Article history: Background: Children aged ≤6 years reportedly account for 52% of victims of humidifier disinfectant-associated
Received 25 August 2017 lung injuries.
Received in revised form 22 October 2017 Objectives: To evaluate the association of humidifier disinfectants with lung injury risk among children aged
Accepted 22 October 2017 ≤6 years.
Available online 7 November 2017
Methods: Patients with humidifier disinfectant-associated lung injuries (n = 214) who were clinically evaluated
Editor: Yolanda Picó
to have a definite (n = 108), probable (n = 49), or possible (n = 57) association with humidifier disinfectants as
well as control patients (n = 123) with lung injury deemed unlikely to be associated with humidifier disinfectant
Keywords: use were evaluated to determine factors associated with increased risk of humidifier disinfectant-associated lung
Exposure to household products injury using unconditional multiple logistic regression analysis.
PHMG Results: For estimated airborne humidifier disinfectant concentrations, risk of humidifier disinfectant-associated
PGH lung injury increased ≥two-fold in a dose-dependent manner in the highest quartile (Q4, 135–1443 μg/m3) com-
CMIT pared with that in the lowest quartile (Q1, ≤33 μg/m3). Registered patients using more than two humidifier dis-
MIT infectant brands were at an increased risk of humidifier disinfectant-associated lung injury (adjusted OR, 2.2; 95%
Humidifier disinfectants
confidence interval, 1.3–3.8) compared with those using only one brand. With respect to the duration of humid-
Humidifier disinfectant-associated lung injury
ifier disinfectant use, risk of humidifier disinfectant-associated lung injury increased ≥two-fold in the lowest

⁎ Corresponding author at: Department of Pediatrics, Childhood Asthma and Atopy Center, Environmental Health Center, Asan Medical Center, University of Ulsan College of Medicine,
88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
E-mail address: sjhong@amc.seoul.kr (S.-J. Hong).

https://doi.org/10.1016/j.scitotenv.2017.10.237
0048-9697/© 2017 Elsevier B.V. All rights reserved.
856 D.-U. Park et al. / Science of the Total Environment 616–617 (2018) 855–862
quartile (≤5 months) compared with that in the highest quartile (≥14 months; adjusted OR 0.3; 95% confidence
interval, 0.2–0.6).
Conclusions: Younger children are more vulnerable to HDLI when exposed to HD chemicals within short period in
early life.
1. Introduction
In 2006, an unidentified fatal interstitial lung disease was observed
among children in South Korea (Cheon et al., 2008; Kim et al., 2009). Af-
fected patients complained of rapidly progressing respiratory difficulty,
which was associated with high mortality (Lee et al., 2013). Subsequent
comprehensive epidemiological and experimental studies have demon-
strated chemical disinfectants in humidifiers as the cause of this disease
in both children and adults (Deterding and White, 2014; Yang et al.,
2013). To our knowledge, no similar fatal health problem due to the
use of household products, especially among children, has been
reported.
Several types of chemical disinfectants were widely used in humid-
ifiers since 1994 to prevent microbial contamination; they remained in
use until 2011 when certain humidifier disinfectant (HD) brands were
banned because of an outbreak of HD-associated lung injury (HDLI)
(Korean Society of Environmental Health, 2012). In South Korea, a
Humidifier-associated with Lung Injury Investigation and Decision
Committee (HLIIDC) has been operational since July 2011 to clinically
evaluate registered patients with lung injuries who were predicted to
have developed lung injuries due to HD use as well as to determine
whether the injuries were clinically associated with HD use (Korean
Centers for Disease Control and Prevention, 2011b; Park et al., 2017).
HDLI patients who were clinically confirmed to be affected by HD use
included victims from all age groups, ranging from fetuses, preschool
children, pregnant women, and elderly patients aged N80 years. The
third round of the investigation covering the period from September
2015 to August 2017 is currently underway to identify and collect
data on HDLI victims.
A previous study has revealed that 75.6% of HDLI patients use hu-
midifiers and that 31.1% of them are children (Jeon and Park, 2012). In
that study, although the percentage of patients using HDs was high,
only a subset exhibited signs of HDLI based on pathological evaluation,
chest imaging studies, or clinical manifestations. Differences in HDLI
susceptibility or other currently undetermined factors might impact
HDLI development. Since the reporting of the first fatal HDLI case, no
study has examined HD use characteristics that might affect HDLI risk.
This study aimed to determine HD exposure-related risk factors for
HDLI among children aged ≤6 years.
2. Methods
2.1. Study subjects
In total, 699 patients registered in the third round of the HLIIDC
(361, 169, and 169 subjects in the first, second, and third rounds, respec-
tively) were clinically evaluated to assess associations between HD use
and lung injury. HD exposure assessment and clinical examination of
registered subjects were conducted in a blinded and independent fash-
ion. In this study, among 343 identified children aged ≤ 6 years, 337
were selected after excluding six children, including those with indeter-
minate diagnosis due to lack of clinical information (n = 4), premature
birth (n = 1), and fetal death (n = 1). Children aged ≤6 years (n = 343)
were included in this study as they accounted for 52% of the main cohort
(n = 699) who were included in all three rounds of the national pro-
gram conducted from July 2013 to July 2016 and as their sensitivity to
HDs was assumed to be comparable to that of other age groups. Study
© 2017 Elsevier B.V. All rights reserved.
flow chart showing the selection of study subjects aged ≤ 6 years (n
= 337) is shown in Fig. 1.
2.2. Field investigation into HD use
Methods employed to evaluate HD use characteristics, which were
based on personal interviews and home investigations, have been de-
scribed elsewhere (Park et al., 2015a; Park et al., 2015b). We developed
a systematic and transparent approach to assess potential HD exposure,
which was consistently followed through all three phases of the nation-
al program. Trained environmental health scientists visited the resi-
dences of registered subjects to complete detailed questionnaires and
checklists and recorded the following information related to HD use:
type of HD brand/s used; HD volume added to the humidifier, frequency
of HD addition, and time spent in room/s with the humidifier; duration
of HD use in the household in average months/year, weeks/month, and
days/week; average sleeping hours in a room with an operating humid-
ifier containing a disinfectant; number of HD brands used and type of
HD; average distance of the bed from the humidifier in meters.
HD brands that were determined to cause lung injury included
polyhexamethylene guanidine phosphate (PHMG, CAS # 89697-78-9),
oligo(2-(2-ethoxy)ethoxyethyl guanidinium (PGH, CAS # 374572-91-
5), and a mixture of chloromethylisothiazolinone (CMIT, CAS #
26172-55-4) and methylisothiazolinone (MIT, CAS # 2682-20-4). The
exposure assessment team was blinded to the clinical diagnostic infor-
mation related to the lung injury in study subjects.
2.3. Clinical examination
All registered subjects were clinically examined by a committee
comprising two pediatric pulmonologists, two adult pulmonologists,
two pediatric radiologists, two chest radiologists, and two pathologists
to diagnose and confirm HDLI and determine its severity. Clinical confir-
mation of HDLI was based on a combination of clinical manifestations,
natural disease course, and radiological and pathological findings in
subjects whose lung specimens were available (Kim K.W. et al., 2014;
Lee et al., 2013). Registered lung injury cases were classified into five
groups, including definite, probable, possible, unlikely, and indetermi-
nate. Cases were considered definite when all of the following criteria
were met: 1) typical symptoms of HDLI, such as cough, dyspnea, and
chest wall retraction, followed by rapidly progressive respiratory dis-
tress; 2) focal patchy consolidation with subpleural sparing in early
phase and diffuse centrilobular nodules with ground glass opacities in
combination with air leak syndrome on chest computed tomography;
3) centrilobular distribution of diffuse alveolar damage in early phase
and/or diffuse alveolar damage in the later phase of disease in subjects
whose biopsy specimens were available; and 4) absence of other factors
that might cause lung injury. Probable cases included subjects with the
abovementioned symptoms and chest computed tomography and/or
pathologic findings compatible with HDLI in whom infectious, autoim-
mune, and/or other interstitial lung diseases could not be ruled out. Sub-
jects with strong infectious, autoimmune, and/or other features of
interstitial lung disease and those with weak or incomplete clinical fea-
tures and radiological and pathological findings of HDLI were classified
as possible HDLI cases and were recommended to undergo clinical ex-
amination for further assessment of HD use as an etiology. The final
group, classified as unlikely to have developed lung injury due to HDs,
 D.-U. Park et al. / Science of the Total Environment 616–617 (2018) 855–862 857

N= 699 patients who registered with the national

investigation program to evaluate the association of lung
injury with the use of humidifier disinfectant (HD)
1st round = 361(Jul 2013-Apr 2014)
2nd round=169(Jul 2014-Apr 2015)
3rd round=169(Aug 2015-Jul 2016)

N=356 patients were excluded for this study

N= 8 aged 7 and 8 years old
N= 14 aged > 8 and 18 years old
N= 332 aged > 18 years old
including pregnant women
N=2 refusal of investigation
N = 343 pre-school children aged ≤ 6years old

N= 6 patients were excluded for this study

N= 4 for lack of clinical
information
N= 1 for premature birth
N= 1 for fetal death

N=337 clinically examined to evaluate the association of

lung injury complained with the use of HD

N=108 N=49 N=57 N=123

Definite association Probable association Possible association Unlikely association
Control group

N=214
HD exposure-associated lung
injury patient group

Fig. 1. Study flowchart for selection of subjects aged ≤6 years (n = 337).

was defined as subjects presenting with strong infectious, autoimmune,
or other typical features of interstitial lung disease based on clinical
manifestation and radiological and/or pathological findings (Hong
et al., 2014; Kim H.J. et al., 2014; Kim K.W. et al., 2014; Lee et al.,
2013; Paek et al., 2015).
2.4. Data analysis
Four subject groups of clinically classified lung injury, which were
used as dependent variables, were categorized into HDLI (n = 214)
and control (n = 123) groups based on the association between HD
usage and lung injury. Three groups, including definite, probable, and
possible, based on the association of lung injury with HD use comprised
the HDLI group. The remaining group with lung injury that was unlikely
to be associated with HD use comprised the control group. Several HD
use characteristics that were employed as independent variables possi-
bly related to HDLI development were as follows. Period of exposure
was categorized as only during pregnancy, both during pregnancy and
after birth, and only after birth. Quantitative HD exposure-related vari-
ables included total time of HD use in months, average use in hours/day,
and average hours of sleeping in a room with an operating humidifier
containing HDs, airborne HD exposure intensity, and airborne disinfec-
tant exposure level. Quantitative variables were classified into quartiles
(b25th, 25–50th, 51st–75th, and N 75th) based on their distribution to
aggregate similar exposure levels. The lowest quartile was used as the
reference group. Airborne HD exposure intensity was estimated based
on the disinfectant concentration in the specific brand (Park et al.,
2015b), total HD volume used/day(mL), size of the room (m3) where
HD was used, and average HD use (hours/day); the ventilation rate
was predicted as 0.5 times/h. Qualitative variables, including chemical
functional group of HD [non-guanidine (reference) or guanidine chem-
ical groups], disinfectant type [CMIT/MIT mixture (reference), PGH, or
PHMG], average distance of the bed from the humidifier [≥1 m (refer-
ence), 0.5–1 m, or b0.5 m], and number of HD brands used [1 (refer-
ence), 2, or ≥3] were categorized arbitrarily.
Tests for trends were conducted by modeling ordinal terms for cate-
gories of quantitative variables. Various HD exposure-related metrics
were assessed alone or in combination to evaluate HDLI risk. Differences
in the distribution of descriptive variables and their association with HD
use characteristics were tested among the four groups using the chi-
square test for categorical variables. Each HD-related exposure metric
was evaluated individually in models that were adjusted for potential
covariates, including sex and age at diagnosis. Only HD-related expo-
sure variables with p values of b0.05 were included in the multi-
nominal logistic regression analysis. Stepwise multiple logistic regres-
sion was used to identify HD exposure-associated factors that were sig-
nificant risk factors for HDLI, and odds ratios (ORs) were estimated with
95% confidence intervals (CIs). All statistical analyses were performed
using STATA ver. 12 (STATA Corp, College Station, Texas, USA).
3. Results
3.1. Demographic characteristics of subjects
The demographic characteristics of registered subjects were com-
pared among the four clinical examination groups. Lung injury in
858 D.-U. Park et al. / Science of the Total Environment 616–617 (2018) 855–862

Table 1 definite and probable HDLI cases declined, whereas the numbers of pos-
Demographic characteristics of children aged ≤6 years according to the extent of the asso- sible and unlikely HDLI cases increased (Fig. 1).
ciation of lung injury with the use of HDs.

Demographic characteristic Definite Probable Possible Unlikely Total 3.2. HD exposure-related risk factors
Sex
Male 63 23 29 65 180 Most HD use characteristics were significantly different among the
Female 45 26 28 58 157 four groups. Most registered subjects stated that they not only used
p value⁎ NS
HD daily but also during sleeping at home (Table 2).
Age at diagnosis
0 0 5 20 38 63 A univariate analysis revealed that HD exposure-related factors, in-
1 21 11 13 34 79 cluding the duration of HD use (months), average days of HD use, num-
2 40 13 8 17 78 ber of HD brands used, estimated airborne HD concentration (μg/m3),
3 24 7 9 18 58 and HD type (non-guanidine vs guanidine chemical groups) were sig-
4 15 6 6 8 35
nificantly associated with HDLI risk, after adjusting for age at diagnosis
5 7 4 0 4 15
6 1 3 1 4 9 and sex (p b 0.05, Table 3). Only the estimated airborne HD concentra-
p value⁎ b0.0001 tion, number of HD brands used, and duration of HD use remained sig-
Presence of HDLI in other family nificant in the final model (Table 4). Specifically, HDLI risk increased ≥
membersa
two-fold in the highest quartile (Q4, 135–1443 μg/m3) compared with
No 72 27 37 104 240
Yes 36 22 20 18 96 that in the lowest quartile (Q1, ≤33 μg/m3) in a dose-response manner
p value⁎ b0.0001 (Q2: adjusted OR, 2.3; 95% CI, 1.1–4.6; Q3: adjusted OR, 2.4; 95% CI,
Status 1.2–4.9; Q4: adjusted OR, 2.7; 95% CI, 1.3–5.4). Total HD use (months)
Deceased 58 15 2 12 87 was negatively associated with HDLI risk. HDLI risk increased ≥ two-
Alive 50 34 55 111 250
fold in the lowest quartile [≤ 5 months (reference)] compared with
p value⁎ b0.0001
Total 108 49 57 123 337 that in the highest quartile (≥ 14 months; adjusted OR, 0.3; 95% CI,
0.2–0.6). HDLI patients who were exposed to the lowest airborne HD
Abbreviations: HD, humidifier disinfectant; HDLI, humidifier disinfectant-associated lung
injury. concentrations (≤ 33 μg/m3) were more common in children aged
a
Family member with definite or probable HDLI diagnosis. 2 years than N3 years (Fig. 2), indicating that they are far more sensitive
⁎ p values were determined using the chi-squared test. to HD for lung injury, compared to older ages Registered children who
were exposed to N two HD brands showed an increased HDLI risk (ad-
study subjects was clinically evaluated to have a definite (n = 108), justed OR, 2.2; 95% CI, 1.3–3.8) compared with those exposed to one
probable (n = 49), possible (n = 57), or unlikely (n = 123) association brand. A b1-year duration of HD use was prevalent in HDLI patients
with HD use. Young children aged b 3 years accounted for 77.1% (n = b3 years old, indicating a negative association (Fig. 3). Our results indi-
131) of the HDLI cases (n = 157) and 82.5% (n = 278) of the registered cated that relative low HD concentration (≤33 μg/m3) and HD use dura-
children in this cohort (n = 337, Table 1). In particular, the number of tion (b 1 year) can cause fatal lung injury for children younger than
HDLI patients who were exposed to the lowest HD concentrations 3 years, compared to children ≥3 years old.
(≤ 33 μg/m3) were more commonly aged ≤ 3 years (b 1 year, n = 6;
1–2 years, n = 13; 2–3 years, n = 15) than aged 4 (n = 2), 5 (n = 1), 4. Discussion
and 6 years (n = 1) (Fig. 2). Totally, 36.9% (n = 58) HDLI cases had
one or more family members with HDLI who were determined as defi- We found that several HD use characteristics were associated with
nite or probable cases of HDLI-. As the round was run, the number of an increased HDLI risk among children aged ≤6 years, after adjusting

Fig. 2. Comparison of number of humidifier disinfectant (HD)-associated lung injury (HDLI) patients according to estimated airborne HD concentration (μg/m3) and age at diagnosis. HDLI
includes definite, probable, and possible association of lung injury with the use of HD.
 D.-U. Park et al. / Science of the Total Environment 616–617 (2018) 855–862 859

for age at diagnosis and sex (Tables 1, 2). The estimated airborne HD 0.557), emphasizing the impact of the number of HDs used on HDLI
concentration, duration of HD use, and number of HD brands used risk (data not shown). Those who used ≥two HD brands might be ex-
were significantly associated with HDLI risk (Table 4). The dose- posed to different chemical disinfectant components as well as different
dependent concentrations of airborne HD particles, intense HD use in disinfectant levels, leading to potential combined of various toxic
confined rooms during short periods, and number of HD brands used chemicals in HDs, which might lead to be more susceptible to lung inju-
were key factors associated with HDLI risk among preschool children. ry. Further investigation is necessary to compare the combined health
These findings suggested that children exposed to high HD concentra- effects of HD brands containing different chemical disinfectants on spe-
tions in a period b 6 months, especially in early life, were at high HDLI cific age groups, including preschool children and adults.
risk.
First, estimated airborne HD concentration was significantly associ-
ated with HDLI risk in a dose-dependent manner after age, sex, and Table 2
other HD exposure-related factors were adjusted. Inhaled HD concen- Comparison of humidifier disinfectant use characteristics among four clinical groups to as-
tration (μg/m3) was estimated using several variables, including aver- sess the association of HD use with HDLI.
age HD amount and hours of HD use/day (mL), room size (m3), HD exposure-related variable Definite Probable Possible Unlikely Totala
concentrations of toxic chemicals in the specific HD brand used, and
Duration used
predicted ventilation rate of air change/hour (Park et al., 2015b), all of
Only after birth 97 35 31 81 244
which reflected substantial characteristics related to HD use. We further Only during pregnancy 0 2 7 6 15
examined the association of estimated airborne concentration of HD From pregnancy until after birth 11 12 19 36 78
and total duration of HD use with HDLI risk based on age range at diag- p value b0.001
nosis. HDLI patients who were exposed to the lowest airborne HD con- Location of HD use
centrations (≤ 33 μg/m3) were more commonly aged ≤ 2 years than Hospital 0 0 0 1 1
N3 years (Fig. 2). The duration of HD use was negatively associated Postpartum care center 0 0 1 0 1
with age at diagnosis. For two age groups among patients aged Home 108 49 56 122 335

b3 years at the time of diagnosis (b 1 year, n = 127; 2–3 years, n = Total HD use duration after birth, months⁎
133), more HDLI cases were significantly distributed in HD use groups, 1–5 41 11 13 29 94
such as ≤ 5 months and between ≥ 6 months and ≤ 13 months (Chi- 6–13 40 19 22 33 114
14–108 27 16 16 52 111
square test, p b 0.017) (Fig. 3). However, among children aged p value 0.033
4–6 years (n = 59), no significant association between the total dura-
tion of HD use and HDLI risk was observed (data not shown). These dif- Days used per week
≤3 1 2 5 11 19
ferences in associations between the estimated airborne HD 4–5 2 2 8 16 28
concentration (μg/m3), duration of HD use, and HDLI development ac- Every day 105 44 45 93 287
cording to the exposure period might be partially explained by the in- NI 0 0 0 2 2
creased susceptibility of the developing, immature lungs to insults. p value 0.015
The results of the current study suggested that younger children are Use of HD during sleep
more vulnerable to lung damage when exposed to toxic chemicals in Yes 104 45 57 116 322
HDs. Intensive and consecutive use of HDs during brief periods of b 5 No 0 1 0 3 4
NI 4 2 1 3 10
or 6 months from the end of fall until early spring can precipitate fatal
p value NS
lung injury. Specifically, most HDLI patients who were exposed to HDs
for b 6 months (n = 65; 41, 11, and 13 definite, probable, and possible Hours used during sleep
1.5–b8 37 15 11 23 86
cases, respectively) were estimated to have limited compensation of
8–13 71 33 46 94 244
lung injuries or respiratory health problems caused by daily inhaled NI 0 0 0 1 1
HDs. The duration of HD use has a negative association with the risk p value 0.041
while the concentration of HD shows the risk in a dose-dependent man-
Average hours used per day
ner. The cumulative HD inhalation exposure level derived from the mul- 4–10 22 15 23 30 90
tiplication of the airborne exposure concentration and cumulative 11–13 63 14 16 36 129
actual HD use hours (cumulative HD exposure level, unit-less = actual 14–24 23 19 19 53 114
HD use duration, months ∗ weeks used per month ∗ days used per p value b0.0001

week ∗ hours used per day) showed no significant association with Average distance of the bed from the humidifier (m)
HDLI risk after adjusting for both sex and age at diagnosis (data not b0.5 6 3 8 14 31
shown). The cumulative HD inhalation exposure level could not be 0.5–1 39 15 17 40 111
1–2 42 18 22 55 137
employed as HD exposure estimates because of the irregular HD use N2 21 12 10 8 51
patterns among users—consecutive HD use during one season and in- No information 0 0 1 5 6
termittent HD use for several season or years. The typical duration for p value 0.033
consecutive of HD use is about five or six months from late fall through
Average total HD volume used per day(mL)
early spring (September–March). Final multiple logistic regression 1.34–b10 19 9 19 28 75
model adjusted the HDLI risks by both HD use duration and HD expo- 10–b15 54 18 22 49 143
sure concentration (Table 4). ≥15 35 21 15 43 114
p value 0.176
Our results concluded that daily intensive use of HD in the room
without sufficient ventilation can cause fatal lung injury to pre-school Air concentration (μg/m3)
children, especially b 3 years old. Q1 (0.2–33) 12 11 18 40 81
Q2 (34–71) 29 13 12 28 82
Second, children exposed to ≥ two HD brands (total = 131; two
Q3 (72–134) 32 13 12 24 81
brands, n = 90; three brands, n = 36; four brands, n = 5) were at a sig- Q4 (135–1443) 35 12 12 24 83
nificantly increased HDLI risk compared with those exposed to only one p value 0.028
brand containing one HD chemical (n = 201). The association between Abbreviations: HD, humidifier disinfectant; HDLI, humidifier disinfectant-associated lung
the number of HDs used and estimated airborne HD concentrations in injury; NS, not significant; NI, no information.
the HDLI group (n = 214) was not significant (Chi-square test, p = a
337 registered subjects with no information were excluded.
860 D.-U. Park et al. / Science of the Total Environment 616–617 (2018) 855–862

Table 3
Association between HD exposure-related characteristics and HDLI risk in children ≤6 years.

HD Cases Controls Crude OR Adjusted ORb

exposure-related (n = 214)a (n = 123)
variable
n % n % 95% CI 95% CI

Time exposed
Only after birth 162 75.7 82 66.7 Reference
Only during pregnancy (maternal exposure) 9 4.2 5 4.1 0.7 0.3 2.1 1.3 0.4 4.1
From pregnancy until after birth 43 20.1 36 29.3 0.6 0.3 1.0 0.8 0.4 138
Total HD use duration (month)
1–5 65 31.7 29 25.4 Reference
6–13 81 39.5 33 28.9 1.1 0.6 2.0 1.0 0.6 1.9
14–108 59 28.8 52 45.6 0.5 0.3 0.9 0.4 0.2 0.8
Average days used (days)
≤3 8 3.7 11 9.0 Reference
4–5 12 5.6 16 13.1 1.1 0.4 3.6 0.9 0.3 3.8
6–7 194 90.7 93 76.2 3.1 1.2 7.9 3.2 1.2 8.4
Average hours of use
4–10 60 28.0 30 25.2 Reference
11–13 93 43.5 36 30.3 1.3 0.7 2.3 1.3 0.7 2.3
14–24 61 28.5 53 44.5 0.6 0.3 1.0 0.6 0.3 1.1
Average hours of use during sleep
1.5–7 63 29.6 23 19.7 Reference
8–13 150 70.4 94 80.3 0.6 0.3 1.0 0.7 0.4 1.3
Use of HD during sleep
No 1 0.5 3 2.5 Reference
Yes 206 99.5 116 97.5 3.6 0.3 40.6 2.4 0.2 27.4
Total volume used per day (mL)
1.3–9 47 22.2 28 23.3 Reference
10–14 93 43.9 47 39.2 1.1 0.6 2.0 1.1 0.6 2.0
N15 72 34.0 45 37.5 1.0 0.5 1.8 1.0 0.5 1.8
Air concentration (μg/m3)
Q1 (0.2–33) 38 18.0 40 34.5 Reference
Q2 (34–71) 52 24.6 27 23.3 1.9 1.0 3.5 1.8 1.0 3.5
Q3 (72–134) 62 29.4 25 21.6 2.3 1.2 4.4 2.2 1.1 4.2
Q4 (135–1443) 59 28.0 24 20.7 2.4 1.3 4.6 2.4 1.2 4.6
Type of HD
Only CMIT/MIT 13 8.9 13 14.3 Reference
Only PGH 16 11.0 4 4.4 4.0 1.0 15.3 4.1 1.0 16.0
Only PHMG 117 80.1 74 81.3 1.6 0.7 3.6 1.5 0.7 3.6
Type of HD (non-guanidine vs guanidine)c
Non-guanidine 13 8.9 13 14.3 Reference
Guanidine 133 91.1 78 85.7 1.7 0.8 3.9 1.7 0.7 3.9
Average distance of the bed from the humidifier (m)
b1 88 41.3 54 46.2 Reference
1–2 82 38.5 55 47.0 0.9 0.6 1.5 0.9 0.6 1.5
N2 43 20.2 8 6.8 3.3 1.4 7.5 3.0 1.3 7.0
Number of HD brands used
1 117 54.9 84 70.6 Reference
2–4 96 45.1 35 29.4 2.0 1.2 3.2 1.9 1.2 3.1

Abbreviations: HD, humidifier disinfectant; HDLI, humidifier disinfectant-associated lung injury; OR, odds ratio; CI, confidence interval; PHMG, polyhexamethylene guanidine phosphate;
PGH, oligo (2-(2-ethoxy) ethoxyethyl guanidinium; CMIT, chloromethylisothiazolinone; MIT, methylisothiazolinone; DDAC, didecyldimethylammonium chloride.
a
Includes definite, probable, and possible cases associated with HD use.
b
Adjusted for age at diagnosis and sex.
c
Guanidine-containing, PHMG and PGH; non-guanidine-containing, CMIT and MIT.

HDLI can develop in various age groups, ranging from fetuses, in- Table 4
fants, pregnant women, and normal adults to the elderly up to the age Significant HD exposure-related characteristics influencing the risk of HDLI in children
≤6 years.
of 80 years, with a wide array of susceptibilities (Park et al., 2016). Sus-
ceptibility as well as the chemical composition of HDs and their use var- HD exposure-related variables Crude OR 95% CI Adjusted ORa 95% CI
ied widely among people using HDs. It is difficult to identify HD Total HD use duration, month
exposure or use characteristics that influence their risk to health, in- 1–5 Reference
cluding their association with HDLI during evaluation of victims with a 6–13 1.1 0.6 2.0 1.0 0.5 1.9
wide range of susceptibilities. Children aged ≤6 years are generally sen- 14–108 0.4 0.2 0.7 0.3 0.2 0.6
Air concentration (μg/m3)
sitive to external pollutants, including chemicals. Preschool children
Q1 (0.2–33) Reference
spend most of their time at home with their mothers. The numbers of Q2 (34–71) 2.4 1.2 4.7 2.3 1.1 4.6
definite and probable HDLI cases were 91 (58.0%), 51 (32.5%), and 15 Q3 (72–134) 2.6 1.3 5.2 2.4 1.2 4.9
(10%) among patients aged ≤2 years, 3–4 years, and 5–6 years, respec- Q4 (135–1443) 2.8 1.4 5.6 2.7 1.3 5.4
Number of HD brands used
tively (Table 1). HDLI victims were largely distributed to younger age
1 Reference
groups. Preschool children, in particular infants, were exposed to HDs 2–4 2.2 1.3 3.8 2.2 1.3 3.8
intensively during early infancy, a time when their lung development
Abbreviations: HD, humidifier disinfectant; HDLI, humidifier disinfectant-associated lung
is not completed (Brandlistuen et al., 2013). Further, 73 (46%) of the injury; OR, odds ratio; CI, confidence interval.
definite and probable HDLI patients (n = 158) died (Table 1). Most a
Adjusted for age at diagnosis and sex.
 D.-U. Park et al. / Science of the Total Environment 616–617 (2018) 855–862
Fig. 3. Comparison of number of humidifier disinfectant (HD)-associated lung injury (HDLI) patients according to the duration of HD used and age at diagnosis. HDLI is categorized as
definite, probable, and possible association of lung injury with the use of HD.
victims were reported to have used HDs for N10 h/day, including
sleeping in a room with low or absent ventilation during winter.
These characteristics of preschool children's HD exposure, especially in
infants, are likely different from those of adults and school-age children.
Preschool children, especially infants, are highly likely to be exposed to
HDs at a higher level at home than other family members as they spend
most of their time at home. Furthermore, infants and young children
are suspected to be at a higher risk because they inhale more contami-
nants, such as HDs, relative to their body size than adults and have partic-
ularly vulnerable physiologies (Park et al., 2015a). Intense HD use in
confined rooms during short periods among preschool children, especial-
ly among those aged ≤3 years, might be a key reason why 48% (n = 337)
of the registered patients (n = 699) were preschool children (Fig. 1).
The development of HDLI is associated with inhalational exposure to
HD in humidifier water via nebulized air. The Korea Center for Disease
Control have reported that the average size of HD aerosols disperse
into air ranges from 30 nm to 80 nm chamber using an ultrasonic hu-
midifier (Korean Centers for Disease Control and Prevention, 2011a;
Korean Centers for Disease Control and Prevention, 2011b). Ultrasonic
humidifiers used by most patients readily disperse aerosol water drop-
lets ranging from 0.5 to 3 μm in size (Shiue et al., 1990; Suda et al.,
1995), which can easily penetrate into alveoli with the inhaled HD
dose. Submicron particles (b 1 μm) and nanoparticles (b 100 nm) with
the smallest size distribution will penetrate deeply into the alveolar re-
gion where removal mechanisms may be insufficient
(Lehman-McKeeman, 2013; Siegmann et al., 1998; Witschi et al.,
2010). The deeper the particles are deposited, the longer it is to remove
them from the lungs and higher is the probability of adverse health ef-
fects due to particle–tissue and particle–cell interactions (Blank et al.,
2009). The most prevalent mechanism for solid particle clearance in al-
veoli involves phagocytosis of deposited particles by alveolar macro-
phages (Oberdorster et al., 2005; Warheit et al., 1988). Retention half-
time of solid particles in the alveolar region based on the clearance
mechanism is approximately 70 days in rats and up to 700 days in
humans. In effect, approximately 80% of the ultrafine particles (≤ 0.1
μm) and 20% for the larger particles (N0.5 μm) are retained in the
lavaged lung tissue after exhaustive lavage (Ferin et al., 1991). During
infancy, chest walls are highly compliable, and respiratory rates are
higher than those in other age groups. The frequency of augmented
breaths is increased to improve lung compliance, and expiratory time
constants are prolonged to increase the amount of air remaining in
the lungs at end-expiration and prevent lung collapse. HD use charac-
teristics in children might not allow for sufficient time to compensate
861
for or eliminate the chemicals inhaled every day into alveoli, especially
during critically susceptible periods.
The major limitation in our approach to estimate HD-related expo-
sure characteristics was that most of the important variables related
to HD use characteristics, including duration and intensity, were pre-
dominantly obtained from direct reports provided by study subjects
and were heavily dependent on their memories. We minimized recall
bias by showing photographs of containers for each HD brand; asked
additional questions that might be specific to respective HD brand
types, such as shape and color; and collected additional information
by visiting their home (Park et al., 2015a). We could not statistically
compare HDLI risk rates between guanidine (PHMG and PGH)- and
non-guanidine-containing HD chemicals (CMIT/MIT mixture) because
HD products featuring CMIT/MIT mixtures were used in a small number
of HDLI cases (definite, n = 2; probable, n = 2; possible, n = 9). The
type of HD (PGH), number of HD brands used, and distance of the bed
from the humidifier were associated with increased HDLI risk
(Table 3). Although significant differences in the prevalence of HDLI ac-
cording to the type of HD (PHMG, PGH, or CMIT/MIT mixture) or the
presence of guanidine (PHMG or PGH) and non-guanidine chemical
groups (CMIT, MIT, or others) might still exist, such potentially signifi-
cant associations disappeared in the final multiple logistic model be-
cause of a few number of HDLI patients who used CMIT/MIT mixture.
In conclusion, airborne HD intensity, duration of HD use, and num-
ber of HD products used were major risk factors for HDLI among chil-
dren aged b 6 years. Specifically, a significant dose-dependent
association between airborne HD concentration and HDLI risk was
found, raising the possibility that HDLI risk in children is dependent
on HD exposure dose, especially during infancy.
Acknowledgments
The authors would like to thank all study subjects who participated in
this study for their cooperation. In particular, we would like to thank for
the clinical examination results and comments provided by the Environ-
mental Health Center for Hazardous Chemical Exposure at Asan Medical
Center, funded by the Ministry of Environment, Republic of Korea.
Funding
This work was supported by the Environmental Health Center for
Hazardous Chemical Exposure funded by the Ministry of Environment
of the Republic of Korea (2017).
862 D.-U. Park et al. / Science of the Total Environment 616–617 (2018) 855–862
Competing financial interests declaration
The authors declare they have no actual or potential competing fi-
nancial interests.
Author contributions
All authors reviewed and approved the final manuscript. Drs. D-U
Park and S-J Hong contributed to the entire editing process including
data collection, statistical analysis, data interpretation, and manuscript
delineation. Mr. S-H Ryu contributed to subject interviews and prepara-
tion of the questionnaires. Drs. E Lee, H-J Cho, J Yoon, S-Y Lee, YA Cho, K-
H Do, and S-J Hong contributed to the collection and the interpretation
of the clinical data.
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