Science of the Total Environment 750 (2021) 141635

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Science of the Total Environment
journal homepage: www.elsevier.com/locate/scitotenv

Association between sum of volatile organic compounds and occurrenceof building-related symptoms in humans: A study in real full-scalelaboratory houses
Norimichi Suzuki a,⁎, Hiroko Nakaoka a,b, Yoshitake Nakayama a, Kayo Tsumura a,c, Kohki Takaguchi a,
Kazunari Takaya d, Akifumi Eguchi a, Masamichi Hanazato a, Emiko Todaka a,b, Chisato Mori a,baCenter for Preventive Medical Sciences, Chiba University, 6-2-1 Kashiwanoha, Kashiwa, Chiba 277-0882, Japan
Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japanc
Graduate School of Medical and Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japand
National Institute of Occupational Safety and Health, 6-21-1 Nagao, Tama-ku, Kawasaki 214-8585, Japanb

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• The median VOC levels of LHs A and B
were 3629 μg/m3 and 55 μg/m3, respectively.
• BRSs occurred 6.89 times more in thosestaying in LH-A than those staying in
LH-B.
• BRSs also more occurred in people witha history of allergy.
• BRSs were more frequent in people sensitive to chemicals.

a r t i c l e

i n f oArticle history:
Received 15 June 2020
Received in revised form 3 August 2020
Accepted 9 August 2020
Available online 15 August 2020
Editor: Henner Hollert
Keywords:
Indoor air quality
Allergy
Chemiless Town Project
Human health, laboratory housesa b s t r a c t
It is well known that the indoor environment, particularly indoor air quality (IAQ), has signiﬁcant effects onbuilding-related symptoms (BRSs) in humans, such as irritation of mucosal membranes, headaches, and allergies,
such as asthma and atopic dermatitis. In 2017, Chiba University launched the “Chemiless Town Project Phase 3”
to investigate the relationship between IAQ and human health. Two laboratory houses (LHs) were built on a university campus in which the interiors and exteriors were similar, but the levels of indoor air volatile organic compounds (VOCs) were different. A total of 141 participants evaluated IAQ using their sensory perception. There
was a signiﬁcant relationship between differences in VOC levels and BRSs occurrence (OR: 6.89, 95% CI:
1.40–33.98). It was suggested that people with a medical history of allergies (OR: 5.73, 95% CI: 1.12–29.32)
and those with a high sensitivity to chemicals (OR: 8.82, 95% CI: 1.16–67.16) tended to experience BRSs. Thus,
when buildings are constructed, people with a history of allergies or with a sensitivity to chemicals may be athigh risk to BRSs, and it is important to pay attention to IAQ to prevent BRSs.
© 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Abbreviations: BRSs, Building-related symptoms; EPM, Environmental preventive medicine; IAQ, Indoor air quality; ISAAC, International Study of Asthma and Allergies in Childhood;
JSPS, Japan Society for the Promotion of Science; LH, Laboratory houses; MVOC, Microbial volatile organic compounds; QEESI, Quick Environmental Exposure and Sensitivity Inventory;
SBS, Sick building syndrome; SD, Standard deviation; VOCs, Volatile organic compounds; WHO, World health organization.
⁎ Corresponding author.
E-mail addresses: suzu-nori@chiba-u.jp (N. Suzuki), hnakaoka@faculty.chiba-u.jp (H. Nakaoka), seiken@chiba-u.jp (Y. Nakayama), tsumu-kayo@chiba-u.jp (K. Tsumura),k.takaguchi@chiba-u.jp (K. Takaguchi), takaya-k@h.jniosh.johas.go.jp (K. Takaya), a_eguchi@chiba-u.jp (A. Eguchi), hanazato@chiba-u.jp (M. Hanazato), todakae@faculty.chiba-u.jp(E. Todaka), cmori@faculty.chiba-u.jp (C. Mori).

https://doi.org/10.1016/j.scitotenv.2020.141635
0048-9697/© 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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N. Suzuki et al. / Science of the Total Environment 750 (2021) 141635

1. Introduction
It has been well recognized that the indoor environment has asigniﬁcant impact on human health (Sundell, 2004; Holst et al., 2016;
Mitchell et al., 2007), but the complexity of the indoor environment,
which comprises of chemical, biological, physical, social and mental factors, makes dissecting the issue challenging. Several epidemiologicalstudies have suggested that indoor airborne chemicals and molds
could cause building-related symptoms (BRSs), as sick building syndrome (SBS), such as irritation of mucosal membranes, headaches anddizziness, and allergic symptoms such as asthma, atopic dermatitis,
and allergic rhinitis (Sahlberg et al., 2013; Kim et al., 2007; Oh et al.,2019; Mendell, 2007). However, BRSs have been reported in indoor
environments with low concentrations of chemical substances.
Thus, research should focus not only on volatile organic compounds (VOCs) but also on other factors such as odor, thermal comfort, and socioeconomic and mental aspects (Lukcso et al., 2016;
Rautiainen et al., 2019; Choi and Dongwoo, 2019; Vakalis et al.,2019) As there are various types of VOCs, and their compositions
differ depending on the indoor air in buildings or rooms, Veenas
et al. (2020) attempted to distinguish the effects of individual
VOCs or patterns of VOCs on BRSs. However, few studies haveinvestigated the actual effects of differences in the concentrationsof VOCs in indoor air on BRSs under the same environmental conditions. Additionally, it was recently suggested that increased prevalence of allergic symptoms such as asthma and atopic dermatitis
was due to increased exposure to environmental chemical pollutants (Choi et al., 2010; Elberling et al., 2005; Billionnet et al.,2011; Kim et al., 2016). People with allergies are more likely to develop symptoms when exposed to building-related environmental
factors (Claeson et al., 2016), and Bönisch et al. reported that theallergic symptoms were associated with the exposure to VOCs
using an experimental mouse model (Bönisch et al., 2012). The environmental chemical substances do not seem to have antigenic effects themselves, but they may stimulate the immune response andexert adjuvant effects (Bernstein et al., 2008). Thus, BRSs have been
linked to an umbrella condition called autoimmune inﬂammatory
syndrome induced by adjuvants (ASIA) (Shoenfeld and AgmonLevin, 2011; Israeli and Pardo, 2011; Perricone et al., 2013). People
in modern society are thought to be susceptible to allergic symptoms when exposed to chemicals in the environment (Riedl, 2008).
The Center for Preventive Medical Sciences of Chiba University(Chiba, Japan) started the “Chemiless Town Project” in 2007 to investigate the adverse health effects caused by the exposure to indoor
air VOCs (Nakaoka et al., 2011). The underlying context of thisproject is based on environmental preventive medicine (EPM),
which endeavors to prevent diseases caused by environmental
pollutants by improving the environment as a whole (Mori andTodaka, 2011). “Chemiless Town” is a small model town on the university campus wherein experiments are performed to apply EPM
principles in a practical setting. We developed a method to assess
the effect of indoor air on human health based on the sum of VOCs(Σ VOCs) and odors.
The evaluation revealed that the building materials, construction
methods, furniture, and housewares primarily contributed to the chemical concentrations in the indoor air. If the concentrations of Σ VOCs andodor were sufﬁciently low, there was a decreased number of individuals
suffering from BRSs (Nakaoka et al., 2014; Nakaoka et al., 2018).
However, there were some limitations in this project. The measurementof the indoor environment, including air sampling, and the evaluation
test by the participants were not conducted at the same time. Since indoor air quality (IAQ) varies depending on ventilation, temperature, andhumidity, it is important to accurately grasp IAQ when the symptoms
appear. Another limitation was the different appearances of the experimental sites; the resulting psychological effects thus could not be excluded. Additionally, the relationship between allergies and BRSs was

not considered because the participants were not asked about their allergic history.
The new project, “Chemiless Town Project Phase 3”, was launched in2017. The aim of this project was to investigate the relationship between
VOC levels and the occurrence of BRSs by conducting the evaluation test
using human sensory perception and measurement of chemicals on thesame day. The experimental sites were built with the same interior tominimize psychological effects. In addition, we investigated if people
sensitive to chemicals or if people with a history of allergy were athigher risk for BRSs.
2. Material and methods
2.1. Test locations
Two laboratory houses (LHs) were built in Chemiless Town in
November 2017. Their interiors and exteriors were similar (Fig. 1).
The Σ VOCs of the LHs were distinct due to differences in construction structure and the building materials. LH-A is a wooden house,and LH-B was constructed of light-gage steel. Almost all the building
materials of LH-B were previously measured for emission rates
using a small chamber test, and lower emitted materials were carefully selected to use (Suzuki et al., 2020). There are two bedrooms
and a living room in each LH, and all the bedrooms were used as
the test sites.
2.2. Subjects and study design
Overall, 169 healthy volunteers were recruited to evaluate the IAQ of
the LHs from May to October 2018. All participants were ordinary people such as university students, ofﬁce workers, or housewives, and they
were considered untrained panels. Among those, 141 participants (78females and 63 males) completed all the questionnaires, and theirdata were analyzed. Before participation, the aims of the study and thetest procedures were explained to the participants, and their writtenconsents were obtained. Then, health checks were performed: thebody temperature, systolic/diastolic blood pressures, and the pulse ofeach participant were measured before the test for two reasons. Firstly,
to exclude those with fever or high blood pressure, and secondly, ourstudy deﬁned BRSs as symptoms claimed by participants who did nothave any symptom before entering the LHs and showed some symptoms during their stay in the LHs. Thus, we needed to conﬁrm thatthey were in good health before performing the sensory test. The healthcheck revealed that all the participants were in good physical condition.
The participants were randomly assigned to a bedroom in the LHs,
where they remained for approximately 90 min. Almost all of the experiments were conducted with four participants simultaneously, one per
bedroom. During the stay in LHs, the participants were requested torelax and sense the air in the room. Then, after about 90 min, and before
leaving the LHs, they were asked sit in front of a personal computer andcomplete self-reported questionnaires on BRSs, odor, sensitivity to chemical substances as screened by QEESI (Quick Environmental Exposure andSensitivity Inventory) (Miller and Prihoda, 1999a; Miller and Prihoda,
1999b), and their impressions of the test sites. All tests were conducted
and tabulated according to the guideline video shown on the monitor.
In order to avoid psychological bias, the test was performed using ablind method, that is, the participants were not informed which LH had
higher Σ VOCs. The furniture, such as beds, desks, and chairs in both LHs
were the same, and indoor environmental factors such as room temperature, relative humidity, noise, and illumination were similarly controlled between the LHs. Both LHs were equipped with mechanicalventilation systems designed to ventilate 0.5 times per hour.
The Research Ethics Committee of the Graduate School of Medicine,
Chiba University approved this study (Approval No. 2737). Approvaldate: September 21, 2017. Written informed consent obtained from allparticipants.

N. Suzuki et al. / Science of the Total Environment 750 (2021) 141635

3

Fig. 1. Evaluation tests conducted in the LHs. Upper left: LH-A (typical Japanese wooden house), upper right: LH-B (light-gage steel structure), bottom left: house plan of LHs, and bottom
right: an LH bedroom.

2.3. Collection of indoor air samples and analysis
We measured the VOCs in the indoor air of each LH before each evaluation test performed by the subjects. Before air sampling, the windows
and the doors remained open for 30 min to allow for ventilation, after
which they were shut for at least 5 h (Fig. 2). Starting at 13:00, the indoor
air samples were collected for 30 min via active sampling pumps (Shibata
MP-Σ30N and MP-Σ100HN, Shibata Scientiﬁc Technology Ltd. Saitama,
Japan) at a height of 1.2 m in the middle of two bedrooms of each LH. Environmental factors (e.g., temperature, humidity, CO2 levels, noise, illumination, and air pressure) were simultaneously recorded during the
90 min of the participants' stay in the LHs, and the averages were calculated. Temperature and humidity were measured and recorded with an
SK-L200TH Iiα datalogger (Sato Keiryoki Mfg. Co., Ltd., Tokyo, Japan),noise and illumination with an LM-8102 environmental monitor (SatoKeiryoki Mfg. Co., Ltd), air pressure with an aneroid barometer (Isuzu
Seisakusho Co. Ltd., Niigata, Japan), and CO2 concentration with a TES1370 CO2 densiometer (Satoshoji Digital, Kanagawa, Japan).
A total of 63 VOCs and 16 carbonyl compounds were identiﬁed andanalyzed (Supplementary Material, Table S1). Mechanical ventilation
systems operated during sampling. Measurements were conductedusing the standard air sampling methods issued by the Ministry of
Health, Labor, and Welfare of Japan (Japanese Ministry of Health,
Labor and Welfare). A Tenax TA thermal desorption tube (Supelco,
Sigma-Aldrich Co. LLC, MO, United States) was used for VOC capture,
and a 2,4-dinitrophenylhydrazine (DNPH) active gas tube (Shibata
Scientiﬁc Technology Ltd. Saitama, Japan) was used for carbonyl compound collection. Air was passed through the Tenax TA and DNPH samplers at ﬂow rates of 100 mL/min and 1000 mL/min, respectively.
VOCs were extracted via thermal desorption and analyzed via gas
chromatography–mass spectrometry. Regarding the carbonyl compounds, the gas tubes were eluted with acetonitrile, and high-performance liquid chromatography analyses were conducted. VOC
and carbonyl compound analyses were performed as previously described (Suzuki et al., 2019). The quantiﬁcation limit for each chemical
was 1.0 μg/m3. Target compounds in the samples were identiﬁed bycomparing the retention times to reference compounds, and positive
conﬁrmation was obtained by determining the peak area ratio of themonitor ions in the samples and comparing this with known standards.
Herein, Σ VOCs was calculated by summing the amounts of all identiﬁed
VOCs and carbonyl compounds.
2.4. Statistical analysis
The statistical software package SPSS, version 25.0 for WIN (SPSS Inc.,
Chicago, IL, USA), was used for all the analyses. The Mann-Whitney U test
was conducted to determine whether there were differences in indoor
environmental factors such as temperature, relative humidity, noise, illumination, air pressure, CO2 concentration, and VOC levels between LHs.
To investigate the relationship between the differences in Σ VOCs in LHA and LH-B and the occurrence of BRSs, a logistic regression analysis
was conducted, and odds ratios and 95% conﬁdence intervals were
calculated.
The participants' gender, age, sensitivity to chemical substances,
physical condition on the day of the evaluation test, medical historiesof allergies, and current smoking status were covariates. Furthermore,stratiﬁcations were performed based on participants' sensitivity tochemicals, and the relationship between the differences of Σ VOCs forthe two LHs and BRSs was examined by logistic regression analysis
after adjusting the covariates. The BRSs occurrence questionnaire
asked about the severity of symptoms on a scale of 1–5: 1, no symptoms; 2, faint symptoms; 3, weak symptoms; 4, moderate symptoms;
and 5, strong symptoms. Participants who answered as 1 or 2 were deﬁned as not having BRSs (“No”), and participants who answered as

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N. Suzuki et al. / Science of the Total Environment 750 (2021) 141635

Fig. 2. The evaluation test procedure.

either 3, 4, or 5 were deﬁned as having BRSs (“Yes”). In order to classify
participants' sensitivity to chemicals, the QEESI questionnaire was usedas outlined in Hojo et al. (2009). The participants were requested toscore their health status on the day of the evaluation test on a scale of
1–4: 1, very good; 2, good; 3, not good; or 4, bad. We deﬁned 1 and 2
as “good” and 3 and 4 as “bad.” Participants were asked to indicate if
they had been diagnosed by a physician with any of the following:
asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, foodallergy, or urticaria. If participants selected at least one condition, a
medical history of allergies was noted. Participants were asked about
their smoking status on a scale of 1–4: 1, never smoked; 2, stopped
smoking more than 5 years ago; 3, stopped smoking within 4 years; 4,or still smoking. Participants who indicated 4 were designated as current smokers.
3. Results
Table 1 shows the study participants' characteristics and demographical data stratiﬁed for both LHs. A total of 70 participants (42 females and 28 males) assessed the IAQ for LH-A, and 71 participants(36 females and 35 males) assessed the IAQ of LH-B. The mean ± standard deviation of participant age for LH-A was 31.4 ± 11.6 years and32.8 ± 12.6 years for LH-B. A total of 23 participants (32.9%) for LH-A
and 39 participants (54.9%) for LH-B were more sensitive to chemicals
based on the QEESI questionnaire. The difference in the number of subjects in the highly sensitive group was signiﬁcant between LH-B and LHA. However, the number of people with symptoms was more in LH-A
than in LH-B (10 in LH-A, 14.3%, 3 in LH-B, 4.2%). Thus, the differencein the number subjects in the sensitive groups did not affect the results.
Thirty-four (48.6%) participants for LH-A and 34 participants (47.9%)
for LH-B answered that they had been diagnosed with any allergic
symptoms. Additionally, 11 and 17 people (15.7% and 23.9%) for LH-A
and LH-B respectively were current smokers. No differences were
found between the LHs for participant gender, age, sensitivity tochemicals, medical history of allergic symptoms, and current smoking

status. The IAQ data for the LHs are shown in Table 2. The mean concentrations of Σ VOCs were 3629 μg/m3 in LH-A and 55 μg/m3 in LH-B,
which were signiﬁcantly different. The top ﬁve abundant substances
Table 1
Study participants' characteristics stratiﬁed for LHs (n = 141).

GenderMale
Female
Age
20–29
30–39
40–49
≥50
Sensitivity to chemicals (QEESI)aLow
High
Physical conditionb
Good
Not good
Medical history of allergyc
No
Yes
Current smoking statusd
No
Yes
Occurrence of BRSs symptomse
No
Yes

LH-A (n = 70)

LH-B (n = 71)

n

%

n

T

28
42

40
60

35
36

49.3
50.7

41
13
10
6

58.6
18.6
14.3
8.6

38
13
10
10

53.5
18.3
14.1
14.1

47
23

67.1
32.9

32
39

45.1
54.9

64
6

91.4
8.6

65
6

91.5
8.5

36
34

51.4
48.6

37
34

52.1
47.9

59
11

84.3
15.7

54
17

76.1
23.9

60
10

85.7
14.3

68
3

95.8
4.2

a
In order to classify participants' sensitivity to chemicals, the QEESI questionnaire wasused in accordance with Hojo et al.
bParticipants' physical conditions were divided into two groups: good and bad.
c
If participants were diagnosed with at least one allergic symptom, it was deﬁned “yes”.
dCurrent smoking status was divided into two groups: “no” (never smoked, stopped
smoking more than 5 years ago, and stopped smoking within 4 years) and “yes” (stillsmoking).
e
The occurrence of BRSs was deﬁned as “no” if participants did not experience any
symptoms and as “yes” if they experienced any symptoms.

N. Suzuki et al. / Science of the Total Environment 750 (2021) 141635
Table 2
Indoor environment conditions.
LH-A
Mean
Temperature
Humidity
Noise
Illumination
Air pressure
CO2
Σ VOCs

°C
%
dB
Lx
hPa
ppm
μg/m3

23.9
54.8
46.4
172
1010
701
3629

LH-B
SD (±)
1.3
13.4
6.9
95
6
142
1832

Mean
23.7
56.3
46.8
202
1009
547
55

P valueQEESI Low
0.439
0.218
0.409
0.263
0.298
<0.001<0.001detected were dichloromethane, α-pinene, texanol, 2-butoxyethanol,and 3-carene in LH-A, and pentane, acetone, ethyl acetate, 2-ethyl-1hexanol, and undecane in LH-B. The VOC concentration in both LHs decreased over time, but the difference in the concentration of Σ VOCs between the LHs did not change. The mean CO2 levels were 701 ppm in
LH-A and 547 ppm in LH-B, which was signiﬁcantly different. All theCO2 levels in this study were less than the level of the Management
Standard of Environmental Sanitation for Buildings of the Japanese Ministry of Health, Labor and Welfare (1000 ppm). However, there was asigniﬁcant difference in CO2 levels between the two LHs, so we divided
the CO2 level into two groups at the median value (625 ppm) and tried
to adjust it as a covariant in the logistic regression analysis. Regarding
temperature, relative humidity, noise, illumination, and air pressure,there were no signiﬁcant differences between LHs.
Multiple logistic regressions were used to examine the associations
between the occurrence of BRSs and differences in the two LHs as explanatory variables and personal and environmental risk factors as covariates (Table 3). The variables for each LH and the medical history ofallergies were found to have associations with BRSs occurrence. BRSs
occurred in participants who stayed in LH-A 6.89 times (95% CI,
1.40–33.98) higher than those who stayed in LH-B. BRSs also occurredin participants with a medical history of allergies 5.73 times (95% CI,
1.12–29.32) higher than those without a history of allergies. Furthermore, in the stratiﬁed analysis for participants either sensitive or not
to chemicals as screened by the QEESI questionnaire, BRSs occurrence

Table 3
Logistic regression analysis of BRSs occurrence and personal and environmental factors.

GenderMale
Female
Age
20–29
30–39
40–49
≥50
Sensitivity to chemicals (QEESI)
Low
High
Physical conditionGood
Not good
Medical history of allergy
No
Yes
Current smoking status
No
Yes
CO2 level≤624≥625
Laboratory house
LH-B
LH-A

P valueOR

95% CI

0.619

Ref
1.48

0.32

–

6.82

0.963
0.836
0.971
0.600

Ref
1.19
1.04
1.66

0.23
0.16
0.25

–
–
–

6.04
6.90
11.07

0.203

Ref
2.33

0.63

–

8.61

0.942

Ref
1.09

0.10

–

11.78

0.036

Ref
5.73

1.12

–

29.32

0.475

Ref
2.39

0.22

–

25.88

0.478

Ref
0.59

0.14

–

2.50

0.018

Ref
6.89

1.40

–

33.98

Note: Boldface indicates statistical signiﬁcance (P < .05).

Table 4
Logistic regression analysis of the association between BRSs and LHs stratiﬁed for the sensitivity to chemicals (QEESI questionnaire).

SD (±)
1.3
12.9
5.9
94
5
90
30

5

P
value
Laboratory house
(LH)
LH-B
LH-A

OR

QEESI High
95% CI

P
value

OR

95% CI

Ref
Ref
0.267 6.25 0.25 – 58.82 0.035 8.82 1.16 – 67.16

Note: Boldface indicates statistical signiﬁcance (P < .05).
Adjusted for participants' gender, age, physical condition, medical history of allergy, current smoking status, and CO2 levels in the LHs.

for sensitive participants was 8.82 times higher (95% CI, 1.16–67.16)
in LH-A than in LH-B (Table 4).
4. Discussion
Two LHs were used as the test sites in the present study, which weresimilar in appearance. The VOCs in each LH were signiﬁcantly different
due to distinguished construction methods and building materials between the LHs. In our previous study, designing houses with low ΣVOCs was possible even right after the completion, by carefully choosing low-emission methods and materials (Suzuki et al., 2019). In thisstudy, we assessed differences in human health effects of two indoor
air environments with high and low Σ VOCs concentration levels.
The number of the participants who claimed any BRSs during theirstay at either LH was 13 (9.2%) (10 in LH-A, 14.3%, 3 in LH-B, 4.2%). According to the results of a 2017 web survey of 1500 Japanese citizens,
the prevalence of having experienced BRSs was 18.8% (Nakayama
et al., 2019). The prevalence in this study was lower compared to thesurvey. The observed low prevalence of this study is probably due tothe fact that the exposure time was as short as 90 min, and the participants answered the questionnaires during their stay at test sites. Thus,
any health effects that might appear after leaving the sites were not included in our analysis.
Regarding the relationship between the occurrence of BRSs andbuilding differences, a multiple logistic regression analysis, in which
participants' characteristics and environmental factors were introduced
as covariates, were examined. The results showed positive and signiﬁcant correlations between BRSs occurrences and a medical history of allergies and the differences of the LHs. The factors related to allergic
symptoms, which have increased in recent years (Linneberg, 2011;
Umetsu et al., 2002), are living, food, and sanitary environments(Benedé et al., 2016; Subbarao et al., 2009). Especially in relation to
the indoor environment, dust mites and mold, which are allergens, areconsidered to be the main causes (WHO, 2009; Walker et al., 2003;
Weinmayr et al., 2013). Allergy is also considered to be induced bychemical substances such as MVOCs (microbial volatile organic compounds) derived from microorganisms (Choi et al., 2017) and tobaccosmoke (Von Mutius, 2002). Additionally, indoor VOCs may develop or
exacerbate allergies through an adjuvant effect (Bernstein et al., 2008;
Fraga et al., 2008), and most of these substances implicated in BRSs
may be regarded as environmental adjuvants (Perricone et al., 2013).
Animal studies demonstrated that VOC exposure could inﬂuence theimmune responses (Fujimaki et al., 2007) and might cause airway inﬂammation when exposed through the respiratory tract (Ichinose
et al., 2008; Steerenberg et al., 2004). The animal studies in the reference literature show that exposure to high concentrations of VOCs,
from several to 100 times higher than the standard indoor air quality,
causes inﬂammation. There were no epidemiological studies showing
the adverse effects of VOC exposure in ordinary indoor environments
as adjuvants in allergic inﬂammation. However, Kwon et al. (2018) indicated that VOC exposure in everyday life can cause airway inﬂammation. Further studies are necessary to determine the effects of indoor

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N. Suzuki et al. / Science of the Total Environment 750 (2021) 141635

air VOC exposure on human health. On the other hand, some reports indicated that indoor VOCs are not a major determinant of risk of allergies(Venn et al., 2003) and evidence of the effects of indoor VOCs on humanallergic symptoms is of poor quality and inconsistent (Nurmatov et al.,2015; Tagiyeva and Sheikh, 2014; Woong et al., 2009). The present
study revealed that people with a history of allergies experienced
BRSs once they were exposed to indoor VOCs. Christine and Apte
(2004) also reported that the certain health conditions, such as allergy,
confer increased susceptibility to BRSs.
Although there is insufﬁcient evidence regarding the role of VOCs in
the etiology or development of BRSs, people with a history of allergies
may be susceptible to indoor airborne chemicals. It is better for themto avoid indoor air with high VOCs to prevent BRSs occurrence. Regarding susceptibility to chemicals, the participants were divided into twogroups, high and low sensitivity, based on the QEESI questionnaire. According to the results of a previous survey by Azuma et al., the high susceptibility group in Japan was approximately 24.1% (Azuma et al.,2015), but in this study, it was 45.5%. The reason why the ratio of thehigh sensitivity group increased in this study could be due to participants' motivation. While recruiting participants of this study, we explained that this evaluation test was on IAQ. Lu et al. (2018) reported
that individuals with chemical sensitivity and migraine were atincreased risk of lower respiratory. In our previous study, the high sensitivity group was also signiﬁcantly associated with symptom development when exposed to high indoor VOCs (Nakaoka et al., 2014).
Despite the higher proportion of sensitive people in this study, the prevalence of BRSs occurrence was lower than in other studies, and our logistic regression analysis showed no signiﬁcant association between
susceptibility to chemicals and claims of BRSs. Then, we investigated theassociation with symptom development by stratifying the high and low
susceptibility group. As a result, it was found that if the sensitivity of theparticipant was “low”, it was not associated with BRSs occurrence during
a short-time stay. It was suggested, however, that when the susceptibility
was “high”, entering the LH with higher Σ VOCs increased BRSs risk (OR:8.82, 95% CI: 1.16–67.17). It is necessary to keep in mind that people whoare highly sensitive to chemicals should avoid exposure to high VOCs toprevent the development of BRSs.
Since there are some reports that the complaints of BRSs were related to psychiatric components (Azuma et al., 2017; Kinman and
Grifﬁn, 2008), the participants were asked if they had a medical historyof mental illness to adjust for psychiatric factors. Since no participants
had a medical history of mental illness, the psychiatric components
could not be added as covariates in the analysis of this study.
Regarding the difference between the results of our previous study
and this one, the former revealed the baseline of Σ VOCs level that cancause BRSs, while the latter showed that actual building materials andconstruction methods may prevent the occurrence of BRSs.
The sensory evaluation test used in the LHs for short-time periods
had several advantages. First, the two LHs were similar in appearance
and indoor environments (e.g., temperature, humidity, etc.), so
psychological-related biases based on these aspects were minimized.
Secondly, since participants focused on IAQ during a short stay of
90 min, they could clearly recognize whether they showed the symptoms during the stay. In addition, the indoor air samples werecollected just before all the evaluation tests and analyzed for VOCs andcarbonyl compounds; thus, the relationship between VOCs and BRSs occurrences could be dissected in more detail.
However, there were some limitations. In this study, it was not possible to evaluate the long-term effects of IAQ. We do not know which effects occur upon long-term exposure, even at low concentrations.
Additionally, the evaluation tests were carried out during the daytime
on weekdays, and almost all the participants were university students
and of a younger age group. Regarding the role of psychological effects,
participants who may have a medical history of mental illness might
have hesitated to answer as such, and our sample size and participants'
demographics made it difﬁcult to adjust for psychosocial aspects.

5. Conclusions
To the best of our knowledge, ours is the ﬁrst study examining theassociation between the occurrence of BRSs and differences in VOCs
under the same environmental conditions. The results of this study
found a signiﬁcant relationship between BRSs occurrence and VOC concentration after adjusting for gender, age, chemical sensitivity, current
smoking status, and CO2 concentration levels. Furthermore, the probability of developing BRSs in indoor air with low VOCs was signiﬁcantly
lower compared to indoor air with high VOCs. Our ﬁndings also revealed that we could create an indoor air environment that prevents
the occurrence of BRSs by carefully selecting the building and structural
materials. People highly sensitive to chemicals and those with a historyof allergies tended to develop BRSs. Thus, these groups may be at highrisk for BRSs, and it is important to pay attention to IAQ to prevent
BRSs occurrence and development.
Funding
This research was funded by Sekisui House Ltd. and Japan Society for
the Promotion of Science (JSPS) Grants-in-Aid for Scientiﬁc Research(C) Grant Number (19K12455, 18K13885). This work was supported by
JST OPERA Program Grant Number JPMJOP1831, Japan. The sponsor had
no control over the interpretation, writing, or publication of this work.
CRediT authorship contribution statement
Conceptualization, N.S., H.N. and Y.N.; Methodology, N.S., K.T. (Kohki
Takaguchi), K.T. (Kazunari Takaya) and H.N.; investigation, N.S. and H.N.
Formal analysis and interpretation of data, N.S., H.N., A.E., Y.N., K.T.
(Kayo Tsumura), K.T. (Kohki Takaguchi), K.T. (Kazunari Takaya), E.T.
and M.H.; Data curation, N.S., H.N., Y.N., K.T. (Kazunari Takaya), K.T.
(Kayo Tsumura), K.T. (Kohki Takaguchi), M.H., E.T. and C.M.; Writing—original draft preparation, N.S.; Writing—review and editing, C.M.
All authors have read and agreed to the published version of themanuscript.
Declaration of competing interest
The authors declare that they have no known competing ﬁnancial
interests or personal relationships that could have appeared to inﬂuence the work reported in this paper.
Acknowledgements
The authors would like to thank Enago (www.enago.jp) for the English Language review.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.scitotenv.2020.141635.
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