Inhalation Toxicity of Humidifier Disinfectants as a Risk Factor of Children’s Interstitial Lung Disease in Korea: A Case-Control Study
et al. (2013) Inhalation Toxicity of Humidifier Disinfectants as a Risk Factor of Children's Interstitial Lung Disease
in Korea: A Case-Control Study. PLoS ONE 8(6): e64430. doi:10.1371/journal.pone.0064430
Inhalation Toxicity of Humidifier Disinfectants as a Risk Factor of Children's Interstitial Lung Disease in Korea: A Case-Control Study
Hyeon-Jong Yang 0
Hwa-Jung Kim 0
Jinho Yu 0
Eun Lee 0
Young-Ho Jung 0
Hyung-Young Kim 0
Ju- Hee Seo 0
Geun-Yong Kwon 0
Ji-Hyuk Park 0
Jin Gwack 0
Seung-Ki Youn 0
Jun-Wook Kwon 0
Byung- Yool Jun 0
Kyung Won Kim 0
Kangmo Ahn 0
Soo-Young Lee 0
June-Dong Park 0
Ji-Won Kwon 0
Byoung-Ju Kim 0
Moo-Song Lee 0
Kyung-Hyun Do 0
Se-Jin Jang 0
Bok-Yang Pyun 0
Jong Hong 0
Thomas H. Thatcher, University of Rochester Medical Center, United States of America
0 1 Department of Pediatrics, Pediatric Allergy and Respiratory Center, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine , Seoul , Korea , 2 Department of Clinical Epidemiology and Biostatistics, Asan Cancer Center, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Korea , 3 Department of Pediatrics, Childhood Asthma Atopy Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine , Seoul , Korea , 4 Research Center for Standardization of Allergic Diseases, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine , Seoul , Korea , 5 Department of Pediatrics, Korean Cancer Center Hospital , Seoul , Korea , 6 Division of Epidemic Intelligence Service, Korea Centers for Disease Control and Prevention, Osong, Korea, 7 Center for Infectious Disease Surveillance and Response, Korea Centers for Disease Control and Prevention, Osong, Korea, 8 Department of Pediatrics and Institute of Allergy, Biomolecule Secretion Research Center, Yonsei University College of Medicine , Seoul , Korea , 9 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea , 10 Department of Pediatrics, Ajou University Hospital, Ajou University School of Medicine , Suwon , Korea , 11 Department of Pediatrics, Seoul National University Children's Hospital, Seoul University College of Medicine , Seoul , Korea , 12 Department of Pediatrics, Seoul National University Bundang Hospital, Seoul University College of Medicine , Seungnam , Korea , 13 Department of Pediatrics, Inje University Haeundae Paik Hospital, University of Inje College of Medicine , Busan , Korea , 14 Department of Preventive Medicine, Asan Cancer Center, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Korea , 15 Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Korea , 16 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine , Seoul , Korea
Background: The occurrence of numerous cases of interstitial lung disease in children (chILD) every spring in Korea starting in 2006 raised suspicion about a causal relationship with the use of humidifier disinfectants (HDs). The aim of this study was to evaluate the association between HD use and the risk of chILD. Methods: This retrospective, 1:3 matched case-control study consisted of 16 cases of chILD that had developed between 2010 and 2011. The three groups of parallel controls (patients with acute lobar pneumonia, asthma, and healthy children) were matched by age, gender, and index date. Indoor/outdoor environmental risk factors, including HD use, were investigated by asking the guardians to complete a questionnaire. Results: The median age of the affected children (43.8% male) was 26 months (18.25-36.25). The chILD group did not differ significantly from the control groups with respect to socio-demographic and clinical variables. Indoor and outdoor environmental factors were not associated with a risk of chILD. However, the previous use of HDs (OR; 2.73. 95% CI; 1.415.90, P = 0.00) were independently associated with an increased risk. Conclusions: This study showed that HDs, which are widely used in South Korea in the winter season, independently increased the risk of chILD in spring. Therefore, continuous monitoring and, if needed, changes in policy are essential to prevent and control pediatric diseases caused by toxic chemicals.
. These authors contributed equally to this work.
Childrens interstitial lung disease (chILD) refers to a diverse
spectrum of rare and diffuse lung pathologies that are associated
with high morbidity and mortality.  Various causes of chILD
including infection, environmental agents, radiation, medications,
genetic predisposition, metabolic storage diseases, and
autoimmune diseases have been identified. However, a considerable
number of ChILD cases are still idiopathic. .
Recently, we reported several cases of unclassified interstitial
pneumonia with fibrosis, describing it as a new entity of chILD. 
Briefly, these cases were the young children and parents of two
families who coincidentally developed the disease in spring. In
each of these cases, the same clinico-radiologic-pathological
findings were noted, including a clinically rapid progression to
respiratory failure. The histopathological findings showed a
centrilobular distribution of alveolar damage with sparing of the
peripheral lung parenchyma. While the rapid progression and
radiological findings were similar to what is seen in hypersensitivity
pneumonitis, the pathological findings and clinical course (poor
response to the treatment and a poor prognosis) were quite
different. Interestingly, causative microorganisms were not
detected, despite the spring-time occurrence of the disease. Thus,
the cause was suspected to be either an inflammatory process
interacting with an altered immune response against an
appropriate genetic background, or as-yet unidentified environmental
factors which the household members were evenly exposed at the
same time, particularly in winter. At our institution, a total 51
children were diagnosed between 2006 and 2011 with a similar
type of chILD, namely, chILD characterized by rapid progression
and a poor prognosis, as indicated by the high mortality (43.13%)
(unpublished data). Sporadic epidemics of similar cases in spring
have also been repeatedly reported throughout Korea since 2006.
On May 11, 2011, an article entitled Dozens of pregnant or
postpartum women have simultaneously developed interstitial
lung disease of unknown cause and died made headlines in
major a newspaper in South Korea. This article and subsequent
reports described the high prevalence of this disease in pregnant
and postpartum women and their children, and its 100%
mortality rate (all cases who did not undergo lung
transplantation died). These serial reports alerted the Korea Centers for
Disease Control and Prevention (KCDC), which initiated
investigations to identify the cause of the disease and ways to
prevent it. On August 31, KCDC announced to the media
including all major TV, radio networks, and newspapers, that
their preliminary epidemiological analyses of acute lung injury
with unknown causes in adult cases revealed that while these
cases were not associated with microorganisms, a strong
association with the use of humidifier disinfectants (HDs) (OR,
47.3) had been observed. .
Several gene mutations (such as in the ATP-binding cassette
transporter A3 or surfactant protein C) have been reported to be
risk factors for chILD.  However, although a genetic association
cannot be excluded, genetics alone cannot fully explain the
pathogenesis of chILD, because family members of different ages
are affected at the same time. It seems more likely that chILD is
the result of environmental factors to which household members,
regardless of their genetic predisposition, are evenly exposed.
Because HDs are often used in Korea during the winter, it was
suspected that they may play a key role in the subsequent
development of chILD during the spring. To date, HDs have
never been investigated as a risk factor of chILD. Thus, the aim of
this hospital-based, case-control study was to evaluate whether
there was indeed an association between the use of HDs and the
pathogenesis of chILD.
Materials and Methods
A case-control study designed to compare the environmental
exposures of chILD patients with those of their matched controls
was conducted at the Department of Pediatrics, Asan Medical
Center (a tertiary medical center in Seoul, Korea). The study
protocol was approved by the Institutional Review Boards of Asan
Medical Center, University of Ulsan College of Medicine, and
written informed consent was obtained from the parents or
guardians at enrollment.
Study Subjects: Case Ascertainment
In total 51 cases were diagnosed with chILD of an unknown
cause in our institution between January 1, 2006 and June 30,
2011. Of these, the 16 subjects who were diagnosed between April
1, 2010 and June 30, 2011 were included in the study. These cases
were confirmed using clinico-radiologic-pathologic ascertainment
criteria (Figure 1). The definite inclusion criteria consisted of all of
the following: (1) age less than 18 years at the time of diagnosis; (2)
rapid progression to acute respiratory distress; (3) chest
tomography findings of ground-glass opacities with a centrilobular
distribution, evidence of air leakage in the lung parenchyma,
and sparing of the peripheral lung parenchyma; (4)
histopathological findings of interstitial thickening and fibrosis with a
centrilobular distribution and relative sparing of the subpleural
parenchyma; and (5) chILD occurrence in the spring (i.e., from
March 1 through to May 31).
The electronic medical records of all patients were reviewed
comprehensively, and additional information, including exposure
status to environmental factors, was obtained by administering a
questionnaire (the interview process and questionnaire contents
are detailed in the supplementary text). In addition, to confirm the
diagnosis and to better assess the clinical features of each case, the
medical records of the patients were reviewed manually by a
committee composed of pediatric pulmonologists, radiologists,
pathologists, and epidemiologists.
Exclusion criteria were as follows: (1) other types of ILD, such as
those due to lung growth abnormalities, storage diseases, or
surfactant dysfunction, as identified by histopathological findings;
(2) patients with underlying conditions that could be associated
with ILD (e.g., chromosomal defects, collagen-vascular diseases,
congenital heart diseases, congenital metabolic disorders,
congenital lung diseases, immunodeficiency, malignancy, and
posttransplantation) and that were present before the index date; (3)
ILD in which the cause was established after the index date based
on a review of the individuals medical records; or (4) the absence
of written informed consent.
Selection of the Controls
In this 1:3 matched case-control study, each chILD patient was
matched with three controls randomly selected from the following
entities: acute lobar pneumonia, which is representative acute
respiratory disease; asthma, which is representative chronic
respiratory disease; and healthy subjects. All controls were paired
with their matched chILD patient by age (within 6 months),
gender, and index date. The chILD index date was defined as the
date of the initial diagnosis of the disease (within one month). The
informed consent was requested for all controls at the time of
enrollment. The exclusion criteria were the same as described
above for the chILD cases.
HD Exposure Ascertainment
To determine the exposure status to HDs prior to the index
date, a questionnaire that included the questions Did you ever
use a humidifier in the 1 year before the index date? and Did
you ever use a humidifier disinfectant in the 1 year before the
index date? was developed. To reduce recall bias, the
colorprinted questionnaire included pictures of common
on2/offmarket HDs (see supplementary material).
Data on pertinent variables that could act as covariates or
confounders were also collected as follows: (1) personal
characteristics, including ethnicity, birth mode, personal history in the 12
months prior to the index date (e.g., passive smoking, overseas trip,
medications including oriental medicine, health supplements, pet
ownership); (2) familial characteristics, including family history of
ILD in the 6 months prior to or after the index date, chronic
respiratory/allergic diseases, and socioeconomic status
(educational levels of parents); (3) comorbid conditions in the 6 months prior
to the index date, including chronic respiratory diseases, chronic
liver disease, diabetes mellitus, neurological disease with
immobility, chronic renal insufficiency, and autoimmune diseases; (4)
factors altering the immune response, including
immunosuppressive therapy, general anesthesia, major surgery, and transfusion in
the 6 months prior to the index date; (5) indoor environmental
factors, including housing, storey of residence, type of heating
system, type of drinking water, recent history of house renovation
or new furniture, use of air cleanser, air conditioner, air freshener,
water purifier, or hair spray in the 12 months prior to the index
date; and (6) outdoor environmental factors, including region of
residence and presence of particular outside facilities within 2 km
(e.g., garbage incinerator, sewage treatment plants, factory,
chemical treatment area, plants, farm/orchard, cattle shed/pigsty,
or power station). Information from the illustrated questionnaire,
which also contained photographs of on2/off-market air
cleansers, air conditioners, water purifiers, humidifiers, air fresheners,
and hair sprays used in Korea as well as the above-described HDs,
was also collected.
The primary goal of the data analysis was to determine the odds
ratio (OR) of HD exposure status for cases and controls. Nominal
variables were analyzed by using a chi-square or Fishers exact test.
Univariate analyses using conditional logistic regression analysis
were conducted to identify all pertinent covariates and
confounders, and to assess the comparability of the cases and controls.
Depending upon the results of these univariate analyses, we
determined factors that need to be adjusted for in all analyses. The
OR for the association of chILD with HD exposure was calculated
with a 95% confidence interval. All calculated P values were
twosided and P,0.05 was considered to be statistically significant.
The analyses were performed by using SAS software package (SAS
Institute, Cary, NC).
One of the controls, a patient with acute lobar pneumonia,
withdrew at the end of study. Thus, the results of 16 cases and 47
controls (16 healthy subjects, 15 subjects with acute lobar
pneumonia, and 16 subjects with asthma) were ultimately
The ethnicity of all subjects was the same (Korean). The median
age of the children in the cases group (43.8% male) was 26 months
(18.2536.25 months; min, 16 months; max, 60 months). Due to
the matched study design, the cases did not differ significantly
from the matched control groups in terms of age and sex
distribution. None of the subjects had a familial history of
idiopathic interstitial pneumonia within the previous 6 months
(Table 1). Other socio-demographic and clinical characteristics are
described in Table 1. Overall, the cases did not differ significantly
from the controls except in terms of day-care center attendance
(P = 0.04) and a family history of asthma (P = 0.01).
Indoor/outdoor environmental factors as risk factors for chILD.
The cases and controls did not differ significantly with respect to
indoor environmental factors, namely, housing (P = 0.64), storey of
residence (P = 0.75), age of the residence (P = 0.66), number of
rooms (P = 0.77), or presence of visible mold indoors (P = 0.58).
Cases and controls also did not differ with respect to prominent
sources of chemical compounds (heating system: P = 0.99, house
renovation: P = 0.64, new furniture: P = 0.42, air cleanser:
P = 0.22, air conditioner: P = 0.54, air conditioner mold cleanser:
P = 0.37, water purifier: P = 0.81, and mosquitocide: P = 0.23), but
did differ for exposure to use of hair spray (P = 0.00). Significant
differences were observed with respect to the use of humidifiers
and HDs in the 12 months before the index date. In fact, a
humidifier was used by the families of all chILD before the index
date; by contrast, only 75.0% of the healthy controls, 73.3% of
acute lobar pneumonia, and 56.3% of asthma used humidifiers
(P = 0.02). Moreover, the chILD families reported that all had used
HDs in the 12 months before the index date; this frequency was
significantly higher than that of the controls (P = 0.00) (Table 2).
By contrast, outdoor environmental factors, including living region
and outside facilities within 2 km, were not significantly different
among the study subjects (Table 3).
Univariate analysis of the association between the use of HDs
and the risk of chILD.
In conditional regression models, none of the
socio-demographic, personal, or indoor/outdoor variables were associated with risk
of chILD but the risk associated with the previous use of HDs was
significant (OR, 2.73; 1.415.90, P = 0.00) (Table 4). Attendance
in day-care center and previous use of hair spray were not
associated with risk of chILD in the conditional regression model
(0.69; 0.361.30, P = 0.25, 0.83; 0.431.61, P = 0.59).
In the present study, HD use, but not humidifier use, was
independently associated with an increased risk of chILD. Other
indoor/outdoor environmental factors, including other sources of
chemicals, did not show similar associations. To our knowledge,
this is the first case-control study that has investigated the
relationship between HD use and the risk of chILD.
Humidifiers are commonly used at home and in offices to
relieve respiratory symptoms and skin dryness, particularly in
young children and pregnant women. The MOCEH birth cohort
in Korea reported that 28.2% of the pregnant women surveyed
used humidifiers, and a rate that increased to over 45% in winter.
 This wide-spread use of humidifiers has raised concerns about
associated lung diseases, such as complicated bacterial or fungal
In Korea, HDs were originally introduced as industrial products
but they were quickly adopted for private use to prevent or
suppress the growth of molds, bacteria, or algae in water tanks,
albeit without warnings or risk assessments.  A cross-sectional
study conducted in Korea reported that of the humidifier users,
18.1% also used HDs, and that this frequency increased to over
30% in winter. .
HDs contain oligo [2-(2-ethoxy) ethoxyethyl] guanidium
chloride (PGH), polyhexamethyleneguanidine (PHMG) and
didecyldimethylammonium chloride (DDAC). [9,11] Their manufacturers
recommend their dilution, typically 5 mL of HD in 3 L of distilled
water. PHMG and PGH are well-known disinfectants for the
treatment of various medical conditions, and their use dates back
to the late 19th century. They have been classified as nontoxic
crystalline compounds for oral intake or skin application. 
Polyhexamethylene biguanidine (PBMB), a polymer of PHMG, is
a broad-spectrum antimicrobial agent that induces membrane
damage and genomic alterations in microorganisms.  It is very
stable in water, even after 60 days,  and is a common
ingredient in various consumer products (e.g., shampoo, skin
antiseptics, and sanitizers of water systems and swimming pools)
due to its reported safety by the oral or skin routes of exposure.
 It has also been investigated as a stabilizing ligand for the
synthesis of silver nanoparticles (Ag NPs).  There is only scant
information on the toxicity of PHMG. The US Environmental
Protection Agency (EPA) has never approved the use of PHMG in
diluted form to prevent humidifier-associated lung disease. Rather,
the agency has reported that the acute and chronic dietary risks of
PBMB are below the level of concern.  However, there are
reports that PHMG, as an alcohol surrogate, induces disorders of
lipid metabolism and may lead to permanent, even fatal, liver
injury, as was the case in several Russians who consumed illegally
produced alcohol.  In addition, the acute cardiovascular
toxicity of HDs in Zebrafish was reported recently: in this model,
exposure to PHMG and PGH, even at normal doses, causes severe
atherosclerotic changes, has a cytotoxic effect on human dermal
cells, and induces severe vascular fibrosis, inflammation, and
embryonic toxicity.  This report may support our findings that
suggesting pulmonary fibrosis was caused by inhalation toxicity of
DDAC, as a broad-spectrum microbial agent, is used in many
applications (e.g. water systems and swimming pools, medical and
surgical sterilization, humidifiers, and commercial aerosol sprays).
Cases (n = 16)
pneumonia (n = 15)
 The toxicity of DDAC has been well evaluated and seems to
be dose dependent. Animal studies have demonstrated that oral
intake causes skeletal alterations, Moreover, humans and animals
can develop contact dermatitis after topical use. The EPA has
reported that inhalation toxicity, although still not fully
understood, appears to be dose dependent.  Recently, acute
pulmonary injury was induced in a mouse model after the
doseand time-dependent administration of DDAC.  In that study,
Cases (n = 16)
pneumonia (n = 15)
Asthma (n = 16) P
Air freshener, n (%)
Hair spray, n (%)
Aromatic candle, n (%)
Mosquitocide, n (%)
Type of mosquitocide, n (%)
Herbicide, n (%)
Living region, n (%)
Urban area, residential district
Urban area, business district
Outside facilities within 2 km, n (%)
Sewage treatment plants
Chemical treatment plants
aVariables in the previous 1 year.
when DDAC was administered by the intratracheal route at a
sublethal dose (150 mg/kg), it exhibited cytotoxic,
proinflammatory, and profibrogenic properties, and was lethal to alveolar
macrophages and parenchymal cells.
During their lifetime, humans are exposed to tens of thousands
of synthetic chemicals, many of them recently developed, which
are used in countless applications. While the benefit or risk to
human health of some chemicals has either been proven or an
association has been established, in most cases, their effects on
human health have been scarcely evaluated and thus are only
poorly understood.  This has raised concern; given that
children have shown parallel increases in the incidences of asthma,
neuro-developmental diseases, preterm birth, and birth defects.
The EPA has identified 3,000 high-production-volume (HPV)
chemicals  and the European Union has established the
Registration, Evaluation, Authorization and Restriction of
Chemical substances (REACH) to protect human health and to evaluate
the hazards that are posed by synthetic chemicals.  However,
these risk assessment and the determination of toxic concentrations
are mostly defined for adults, despite the fact that children are
clearly exposed to toxic chemicals in the environment at higher
levels because of their inherent susceptibility (i.e. larger body
surface area in proportion to their weight, the critical window for
their development and growth, and their physiological
In the Magic Nano issue reported in Germany in 2006, it was
asserted that co-evaporation of nanoparticles with active
components and solvents could cause pulmonary toxicity in humans 
and animals.  Furthermore, a recent report found that the
white dust generated by humidifiers can cause lung injury in
young infants.  The small size of nanoparticles (#100 nm in
diameter) makes the respiratory system particularly vulnerable to
nanoparticle deposition. Although nanotechnology has been
Cases (n = 16)
pneumonia (n = 15)
Asthma (n = 16) P
Cases (n = 16)
pneumonia (n = 15)
Asthma (n = 16) P
Humidifier disinfectant, n (%)
Humidifier, n (%)
Passive smoking, n (%)
Health supplement, n (%)
Day-care center, n (%)
Chronic diseases d, n (%)
Heating system, n (%)
Local heating, gas
Local heating, oil
Drinking water, n (%)
Factors predisposing to infections c, n (%)
New furniture in the previous 1 year, n (%)
Indoor mold in the previous 1year, n (%)
Water purifier, n (%)
Air cleaner, n (%)
Air freshener, n (%)
Air conditioner, n (%)
Air conditioner mold cleanser, n (%)
Hair spray, n (%)
Mosquitocide, n (%)
Outside facilitiese, n (%)
Cases (n = 16)
Controls (n = 47)
Unadjusted ORb (95% CI)
applied to diverse fields, such as medicine and engineering, with
consequent increases in human prosperity and well-being, the
rapid advancement of nanotechnology is certain to raise new
safety concerns, especially with regard to the respiratory system.
 Crucially, in 2011, the KCDC reported that 3080 nm
nanoparticles consisting of PHMG or PGH are generated when
HDs are added to the distilled water used in ultrasonic humidifiers.
 These aerosolized HDs probably decompose into nano-sized
particles that are subsequently deposited in the respiratory system,
where they may cause chILD.
As a retrospective study, our study has inherent limitations: 1)
The subjects and controls do not represent the general population,
2) The retrospective, medical record-based ascertainment of cases
and controls may be subject to its own limitations; 3) The parents/
guardians of the cases and the controls were not completely
blinded to the purpose of this study when they answered the
questionnaire because this study was designed after May 11, 2011,
when the serial media reports of HDs and their relationship with
highly fatal ILD were released and brought the matter to the
attention of the entire nation. Moreover, the interviewing process
started after the KCDC announcement on August 31 2011 that
HDs may be the cause of ILD in adults. However, while the media
reports and the announcement may have raised the interest of the
caregivers of cases, which could have led to some bias (e.g. recall
or information bias), it is likely that the announcement had
equivalent effects on the caregivers of the controls. Nevertheless, to
reduce this possibility, patients with acute lobar pneumonia and
asthma were selected as non-healthy controls. The three controls
healthy controls, 20.0% in the acute lobar pneumonia group, and
31.3% in the asthma group, P = 0.75 in table 2); 4) Finally, there
was no adjustment for unmeasured confounding or potential
variables, such as environmental factors in day-care centers,
outdoor air quality, and fine dust particles in the homes. However,
becuase a prospective observational or clinical interventional study
is impossible due to ethical issues and the low incidence of chILD,
concerted efforts were made to minimize any expected selection or
information biases. A case was confirmed only when the members
of the expert committee unanimously agreed on the diagnosis,
while controls in the three groups were randomly selected from the
computerized database to reduce selection bias and to increase
comparability. The disease in both the cases and the non-healthy
controls occurred recently (20102011). Control children with
acute lobar pneumonia or asthma who had been admitted to our
institutions at the index date, were selected to avoid a lack of
information. To minimize recall bias, an illustrated questionnaire
was developed, including photographs of all indoor/outdoor
The design of the present study did not allow us to determine
the extent to which the risk of chILD depended on the amount of
HD exposure, nor could we speculate about an interaction
between a genetic predisposition and HDs. However, because the
cases were clustered in spring, likely concentrated use of HDs in
winter, and only a few of the numerous HDs users were affected by
chILD, it seems likely that either exposure dose or a genetic
predisposition plays an important role in the pathogenesis of this
disease. Although our study population is not necessarily
representative of the general population in Korea, the results
point to a strong association between HDs and the development of
chILD. Fortunately, there have been no further cases of chILD in
Korea since January 1, 2012, when the KCDC banned the sale of
HDs beginning in November, 2012 (data not shown). The
continued absence of such cases will provide indirect supporting
evidence for an association between HD use and chILD in Korea.
Taken together, our findings indicate that the use of HDs in
winter is strongly associated with an increased risk of chILD. Little
is known about the potential toxicity of HDs and other chemicals
when exposure occurs through an unexpected route and the
synergistic adverse effects due to combined exposures remain
unclear. The present study suggests that environmental chemicals
that may be potentially hazardous to human health should be
examined more closely.
In conclusion, we provide additional evidence that
environmental chemicals may pose an unanticipated hazard to human
health if their use in specific applications is not closely monitored.
Therefore, continuous monitoring and, if needed, changes in
policy are essential to prevent and control pediatric diseases caused
by toxic chemicals.
Conceptual framework and study process.
Material S2 Questionnaire evaluating the effects of
exposure to various environmental factors on human
The authors would like to thank all of the children and their parents for
their cooperation in this study.
Conceived and designed the experiments: HY H-JK BP SH KK KA SL
JDP ML KD SJ. Performed the experiments: HY HK BP SH JY EL YJ
HYK JS Ji-Won Kwon BK. Analyzed the data: BP SH GK JDP JG SY
JunWook Kwon BJ KK KA SL J-HP ML KD SJ. Contributed reagents/
materials/analysis tools: HY HK BP SH GK J-HP JG SY Jun-Wook Kwon
BJ JY EL YJ H-YK JS Ji-Won Kwon BK KK KA SL J-HP ML KD SJ.
Wrote the paper: HY SH KK KA SL JDP ML KD SJ.
1. Deterding R ( 2007 ) Evaluating infants and children with interstitial lung disease . Semin Respir Crit Care Med 28 : 333 - 341 .
2. Dishop MK ( 2011 ) Paediatric interstitial lung disease: classification and definitions . Paediatr Respir Rev 12 : 230 - 237 .
3. Lee E , Seo J , Kim H , Yu J , Song J , et al. ( 2012 ) Two series of familial cases with unclassified interstitial pneumonia with fibrosis . Allergy Asthma Immunol Res 4 : 240 - 244 .
4. Kim BJ , Kim HA , Song YH , Yu J , Kim S , et al. ( 2009 ) Nationwide surveillance of acute interstitial pneumonia in Korea . Korean J Pediatr 52 : 324 - 329 .
5. Cheon CK , Jin HS , Kang EK , Kim HB , Kim BJ , et al. ( 2008 ) Epidemic acute interstitial pneumonia in children occurred during the early 2006s . Korean J Pediatr 51 : 383 - 390 .
6. Korea Centers for Disease Control and Prevention ( 2011 ) Interim report of epidemiological investigation on lung injury with unknown cause in Korea . Public Health Wkly Rep : 820 - 829 .
7. Chang MH , Park H , Ha M , Kim Y , Hong YC , et al. ( 2012 ) Characteristics of humidifier use in Korean pregnant women: the mothers and children's environmental health (MOCEH) study . Environ Health Toxicol 27 : e2012003 .
8. Mu ller-Wening D , Koschel D , Stark W , Sennekamp HJ ( 2006 ) [Humidifierassociated disease in the general population] . Dtsch Med Wochenschr 131 : 491 - 496 .
9. Lee JH , Kim YH , JH K ( 2012 ) Fatal misuse of humidifier disinfectants in Korea: Importance of screening risk assessment and implications for management of chemicals in consumer products . Environ Sci Technol 46 : 2498 - 2500 .
10. Jeon BH , Park YJ ( 2012 ) Frequency of humidifier and humidifier disinfectant usage in gyeonggi provine . Environ Health Toxicol 27 : e2012002 .
11. Ohnuma A , Yoshida T , Horiuchi H , Fukumori J , Tomita M , et al. ( 2011 ) Altered pulmonary defense system in lung injury induced by didecyldimethylammonium chloride in mice . Inhalation Toxicology 23 : 476 - 485 .
12. Hubner NO , Kramer A ( 2010 ) Review on the efficacy, safety and clinical applications of polihexanide, a modern wound antiseptic . Skin Pharmacol Physiol 23 Suppl : 17 - 27 .
13. Allen MJ , White GF , Morby AP ( 2006 ) The response of Escherichia coli to exposure to the biocide polyhexamethylene biguanide . Microbiology 152 : 989 - 1000 .
14. Lucas AD ( 2012 ) Environmental fate of polyhexamethylene biguanide . Bull Environ Contam Toxicol 88 : 322 - 325 .
15. Fayaz AM , Balaji K , Girilal M , Yadav R , Kalaichelvan PT , et al. ( 2010 ) Biogenic synthesis of silver nanoparticles and their synergistic effect with antibiotics: a study against gram-positive and gram-negative bacteria . Nanomedicine 6 : 103 - 109 .
16. United States Environmental Protection Agency . Reregistration eligibility decision for aliphatic alkyl quaternaries (DDAC) , September 2004 . Available at http://www.epa.gov/oppsrrd1/REDs/phmb_red.pdf.
17. Solodun YV , Monakhova YB , Kuballa T , Samokhvalov AV , Rehm J , et al. ( 2011 ) Unrecorded alcohol consumption in Russia: toxic denaturants and disinfectants pose additional risks . Interdiscip Toxicol 4 : 198 - 205 .
18. Kim JY , Kim HH , Cho KH ( 2012 ) Acute Cardiovascular Toxicity of Sterilizers, PHMG, and PGH: Severe Inflammation in Human Cells and Heart Failure in Zebrafish . Cardiovasc Toxicol Dec 10 . [Epub ahead of print].
19. United States Environmental Protection Agency . Reregistration eligibility decision for aliphatic alkyl quaternaries (DDAC) , August 2006 . Available at http://www.epa.gov/oppsrrd1/REDs/ddac_red.pdf.
20. Ohnuma A , Yoshida T , Tajima H , Fukuyama T , Hayashi K , et al. ( 2010 ) Didecyldimethylammonium chloride induces pulmonary inflammation and fibrosis in mice . Exp Toxicol Pathol 62 : 643 - 651 .
21. Landrigan PJ , Goldman LR ( 2011 ) Children's vulnerability to toxic chemicals: a challenge and opportunity to strengthen health and environmental policy . Health Aff (Millwood) 30 : 842 - 850 .
22. Landrigan PJ , Miodovnik A ( 2011 ) Children's health and the environment: an overview . Mt Sinai J Med 78 : 1 - 10 .
23. Spivey A ( 2007 ) Children's health centers: past , present, and future. Environ Health Perspect 115 : A192 - 194 .
24. European Commission on the Environment . REACH. http://ec.europa.eu/ environment/chemicals/reach/reach_intro.htm. Accessed on September 28 , 2012 .
25. National Academy of Sciences Pesticides in the diets of infants and children . Washington, DC: National Academy Press ; 1993 .
26. Makri A , Goveia M , Balbus J , Parkin R ( 2004 ) Children's susceptibility to chemicals: a review by developmental stage . J Toxicol Environ Health B Crit Rev 7 : 417 - 435 .
27. Hubbs AF , Castranova V , Ma JYC , Frazer DG , Siegel PD , et al. ( 1997 ) Acute Lung Injury Induced by a Commercial Leather Conditioner . Toxicol Appl Pharmacol 143 : 37 - 46 .
28. Pauluhn J , Hahn A , Spielmann H ( 2008 ) Assessment of early acute lung injury in rats exposed to aerosols of consumer products: attempt to disentangle the ''Magic Nano'' conundrum . Inhal Toxicol 20 : 1245 - 1262 .
29. Daftary AS , Deterding RR ( 2011 ) Inhalational lung injury associated with humidifier ''White Dust'' . Pediatrics 127 : e509 - 512 .
30. Bonner JC ( 2010 ) Nanoparticles as a potential cause of pleural and interstitial lung disease . Proc Am Thorac Soc 7 : 138 - 141 .
31. Korea Centers for Disease Control and Prevention ( 2011 ) Interim report of epidemiological investigation on lung injury with unknown cause in Korea . Public Health Wkly Rep : 831 - 832 .