Is indoor environment a risk factor of building-related symptoms?

Kayo Tsumura; Hiroko Nakaoka; Norimichi Suzuki; Kohki Takaguchi; Yoshitake Nakayama; Keiichi Shimatani; Chisato Mori

doi:10.1371/journal.pone.0279757

. 2023 Jan 25;18(1):e0279757. doi: 10.1371/journal.pone.0279757

Is indoor environment a risk factor of building-related symptoms?

Kayo Tsumura ^1,², Hiroko Nakaoka ^2,³, Norimichi Suzuki ², Kohki Takaguchi ², Yoshitake Nakayama ², Keiichi Shimatani ², Chisato Mori ^2,^3,^*

Editor: Rajeev Singh⁴

PMCID: PMC9876365 PMID: 36696431

Abstract

The indoor environment, particularly indoor air quality (IAQ), is significantly associated with building-related symptoms (BRSs) in humans. In our previous studies, we demonstrated a significant relationship between BRSs and indoor chemical concentrations. In Japan, the Ministry of Health, Labor, and Welfare (MHLW) guideline recommends an air quality target of 13 volatile organic compounds (VOCs) and a provisional target of 400 μg/m³ for total VOCs (TVOC). The objective of this study was to determine the relationship between TVOC levels and the risk of BRSs using the Japanese provisional target TVOC level of 400 μg/m³. The relationship between odor intensity and BRSs while the TVOC levels were under 400 μg/m³ was also examined. The study was conducted in a laboratory house (LH) on the campus of Chiba University from 2017–2019. The study included 149 participants who spent 60 minutes in the LH. The participants were asked to evaluate the IAQ of the LH. A significant relationship between the risk of BRSs and the provisional target TVOC level was observed (odds ratio: 2.94, 95% confidence interval: 1.18–7.35). Furthermore, a significant relationship between odor intensity and risk of BRSs in spaces with TVOC levels less than 400 μg/m³ was detected (odds ratio: 6.06, 95% confidence interval: 1.21–30.44). In conclusion, the risk of BRSs is significantly lower in spaces with low TVOC levels and low odor intensity. Reducing the concentration of airborne chemicals and odor intensity may improve IAQ and prevent BRSs.

Introduction

People spend about 90% of their day indoors [1], and indoor air quality (IAQ) is closely related to human health. The United States Environmental Protection Agency defines IAQ as the quality of the air inside and around buildings and structures, especially related to the health and comfort of building occupant [2]. IAQ is mainly assessed based on the concentration of pollutants and chemicals in the air such as ambient fine particulate matter, carbon dioxide, and volatile organic compounds (VOCs). The World Health Organization (WHO) provides guidelines for VOCs commonly present in indoor air [3]. In Japan, the Ministry of Health, Labour and Welfare (MHLW) also set guideline concentration values for 13 VOCs and a provisional target value of 400 μg/m³ for total VOC (TVOC) level as measures against the effects of VOCs on the health of humans [4,5]. In our previous study, we found a significant relationship between indoor chemical concentrations and the occurrence of building-related symptoms (BRSs) [6]. The study findings suggest that individuals with a history of allergy and high sensitivity to chemicals are more likely to have BRSs. These findings indicate that human reactions to indoor air pollutants depend on the levels of airborne chemicals and on several other factors, including pre-existing medical conditions and personal sensitivity.

In previous studies, BRSs were found to be associated with odor. Odor perception is an early predictor of BRSs, and it is attributed to one or more VOCs [7]. Odor perception is affected by many different types of odor.

The type and intensity of odors are primarily evaluated based on individual olfactory responses. Measurements based on human olfactory response is the most common method of odor concentration evaluation [8], but the intensity and sensation of odors are different for each individual. People perceive odors due to one or more VOCs, and these substances are present in various concentrations in the air. Odors help with the evaluation of IAQ and avoidance of exposure to harmful substances. Some VOCs cause eye and airway or upper respiratory tract irritation and symptoms [9]. The IAQ and odor of real spaces are due to multiple chemicals. It is difficult to identify factors associated with health risk because multiple chemicals and odor substances coexist in the indoor air environment [10]. Our previous study showed that reducing the sum of VOC (ΣVOC) levels and odor intensity in indoor air promotes human relaxation [11]. The aims of this study were (1) to examine whether the Japanese provisional target TVOC level of 400 μg/m³ was effective in reducing the risks of BRSs and (2) to investigate the association between odors and human health to determine if odor can be considered a new indicator of IAQ and its human health effects.

Materials and methods

Study site

This study was conducted at a laboratory house (LH) built as a study site in November 2017 on the Kashiwa-no-ha campus of Chiba University. The LH has one living room and two bedrooms and is furnished. The structure of the LH is a typical Japanese wooden house constructed from timber. The LH was constructed mostly with F☆☆☆☆ (F-four stars) labeling. The F☆☆☆☆ rating is a classification of building materials in Japan based on the formaldehyde emission rate, which is defined by Japanese Industrial Standards (JIS), Japanese Agricultural Standards (JAS), and the Ministry of Land, Infrastructure, Transport, and Tourism of Japan. F-four-stars building materials, including boards, adhesives, insulation, and paints, can be used without limitations on the area of use. The LH was equipped with a mechanical ventilation system designed to ventilate 0.5 times per hour. The LH was also equipped with air conditioners that control the temperature and humidity, but no air purifiers were used. The rooms of the LH were not decorated with any indoor plants.

Participants and study design

This study was conducted between May and October of the years 2017 to 2019. Participants were recruited to evaluate the IAQ of the LH based on their sensory perception for a period of 60 minutes. All the participants were ordinary people such as students, workers, and housewives, and they were not previously trained for the study. They were recruited in pairs or were asked to invite a friend or acquaintance to pair with for the study. On the day of the test, the aims and the test procedure were explained to the participants, and written informed consent was obtained from all the participants. The body temperature, blood pressure, and pulse of the participants were then measured as a health check.

The test was conducted. During the 60 minutes of the experiment, two participants first stayed together in the living room for 30 minutes, and then proceeded to each spend 30 minutes separately in the bedrooms. The participants received guidance regarding the test and how to complete the questionnaires via audio announcements in each bedroom. The participants completed the online questionnaire using the Questant software (Macromill Inc., Tokyo, Japan) installed on a tablet. In each room, they first spent five minutes in the indoor environment to acclimatize to the indoor air and odor. After that, they indicated their impressions of the room air and odor by responding to the corresponding questions in the questionnaire. The participants spent 20 minutes freely in the room after answering questions regarding their characteristics and medical history in the questionnaire. Thereafter just before leaving the room, they completed a questionnaire on their physical condition and the occurrence of BRSs.

This study protocol was approved by the Research Ethics Committee of the Graduate School of Chiba University (No.2737). The study was conducted in accordance with the principles of the World Medical Association Declaration of Helsinki.

Questionnaire

During the experiment, participants were asked to complete several questionnaires. The questionnaire includes questions on odors perceived, personal characteristics, indoor environment of the building where the participants spend most of the day, indoor environments that may impact health, awareness of air quality, and BRSs. Further, the Quick Environmental Exposure and Sensitivity Inventory (QEESI) was used to determine the sensitivity of participants to chemicals [12,13]. QEESI was developed by Miller and Prihoda in the USA to determine the causal relationship between chemicals and personal sensitivity. Then, using the cut-off value for Japanese individuals reported by Hojo et al. [14], we determined the sensitivity or non-sensitivity of participants to chemicals. A participant was considered highly susceptible (i.e., with high QEESI score) if at least two of the following three criteria are observed: symptoms ≥ 20 points, chemical intolerance ≥ 40 points, and degree of daily life disturbance ≥10 points. Finally, using the questionnaire referred to in the Consultation Manual for Trace Chemicals in the Indoor Environment issued by the Japanese MHLW, participants were asked about the symptoms they experienced during the test.

Participants answered questions regarding the site of symptoms (e.g., mucous membrane of the eyes, nose, throat, or airways, or the skin, muscles, joints, or digestive tract). We diagnosed them using a questionnaire developed based on the “Consultation Manual for Trace Chemicals in the Indoor Environments“issued by the Japanese MHLW. Symptom severity was rated on a four-point scale as follows: 1. no symptoms;2. mild symptoms;3. moderate symptoms; and 4. severe symptoms. Participants were asked to rate the severity of their symptoms. Participants were considered to have BRSs (“yes”) if at least eight questions were rated 2, 3, or 4 by participants: otherwise, participants were considered to have no BRSs (“no”).

Furthermore, the participants were asked to subjectively score their health status on the day of the evaluation using 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”. We classified scores of 1 and 2 as “good” and scores of 3 and 4 as “bad.” Regarding allergies, participants were asked to indicate if they had been diagnosed by a physician with any of the following conditions: asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, food allergy, or urticaria. A medical history of allergy was noted if a participant selected at least one condition. Participants were also asked to rate their smoking status on a scale of 1 to 4 as follows: 1. never smoked;2. stopped smoking more than five years ago;3. stopped smoking within the last four years; or 4. still smoking. Participants who indicated 4 were designated as current smokers.

Collection of indoor air samples and analysis

The indoor air of the LH was sampled on the morning of each test. During air sampling, room temperature and humidity were measured using a thermo-hygrometer data logger (SK-L200THIiα; Sato Keiryoki Mfg. Co. Ltd., Tokyo, Japan). A mechanical ventilation system was installed in the LH and set to ventilate 0.5 times per hour. Standard air sampling methods issued by the Japanese MHLW (MHLW 2000) were used in this study. Before air sampling, the windows and doors of the LH were kept open for 30 minutes for ventilation. Indoor air samples were collected for 30 minutes at height of 1.2 m in the middle of the living room using active sampling pumps (Shibata MP-Σ30N and MP-Σ100HN; Shibata Scientific Technology Ltd., Saitama, Japan). VOCs were thermally desorbed from the sampled tube and analyzed using a thermal desorber (TurboMatrix650; PerkinElmer, USA) coupled with a gas chromatograph (7890B GC system; Agilent, USA)/mass spectrometer (5977A MSD GC/MS; Agilent, USA). Carbonyl compounds were eluted with acetonitrile from the gas tubes and analyzed using a high-performance liquid chromatograph (Prominence HPLC system; Shimadzu, Japan). Details of the chemical analysis were presented in our previous study [15]. The target compounds in this study were 51 VOCs and 2 carbonyl compounds. They were identified and analyzed. The limit of quantification for each chemical was 1.0 μg/m³. ΣVOC level in this study was defined as the sum of the concentrations of identified VOCs and carbonyl compounds.

Calculation of odor activity value (OAV) and the sum of OAVs (SOAV)

A method of calculating OAV [16] was used to quantify the odor of each VOC in indoor air. OAV was determined as the ratio of the measured concentration of a particular odor chemical in the air to its odor threshold concentration. In other words, OAV was calculated as the concentration of a VOC in indoor air divided by its odor threshold concentration. The odor threshold concentrations used in this study were published by the Japanese Ministry of Environment [17]. The concentration of each VOC in the air was converted to OAV using equation 1 below, and SOAV was calculated using equation 2.

OAV = concentration of each chemical (μg/m³)/odor threshold value of each chemical (μg/m³)
SOAV = sum of OAVs.

Statistical analysis

All analyses were performed using the statistical software package SPSS version 25.0 for Windows (SPSS Inc., Chicago, IL, USA). We first categorized spaces with ΣVOC levels of < 400 μg/m³ as Case 1 and spaces with ΣVOC level of > 400 μg/m³ as Case 2 to verify the provisional target TVOC level of 400 μg/m³ set by the Japanese MHLW. Then, the relationship between ΣVOC level and the occurrence of BRSs was evaluated using logistic regression analysis after adjusting for environmental factors (e.g., temperature, relative humidity) and characteristics of participants in Case 1 and Case 2. The relationship between odor (SAOV) and the occurrence of BRSs was also evaluated in Case 1. Covariates were selected based on our previous study. In addition, we determined final covariates from variables using Mann–Whitney U test. In the analysis, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and p < 0.05 was considered significant.

Results

Characteristics of the study population and symptoms

Table 1 shows the characteristics of the study participants. One hundred and twenty-five individuals (Females: 51 participants [40.8%], Males: 74 participants [59.2%]) participated, and their data are shown after grouping based on ΣVOC level into Case 1 or Case 2. Eighty-nine participants (71.2%) were in their 20s, while 19 participants (15.2%) were in their 30s (Case 1: 41 participants [87.2%] in their 20s, five [10.6%] in their 30s; Case 2: 48 participants [61.5%] in their 20s, 14 [17.9%] in their 30s). Based on the QEESI questionnaire, a total of 44 participants (35.2%) (Case 1: 16 [34.0%], Case 2: 28 [35.9%]) were sensitive to chemicals. On the day of the test, 114 participants (91.2%) (Case 1: 44 [93.6%], Case 2: 70 [89.7%]) stated that they were in a “good” state of health. Further, 73 participants (58.4%) (Case 1: 30 [63.8%], Case 2: 43 [55.1%]) had a history of allergy. Fifty-six participants (44.8%) (Case 1: 14 [29.8%], Case 2: 42 [53.8%]) had BRSs; Thus, the number of participants with BRSs was greater in Case 2 than in Case 1. Except for age, no participant characteristic was significantly different between Case 1 and Case 2.

Table 1. Characteristics of participants and indoor environment conditions.

Personal factors		Case 1		Case 2		P value
		ΣVOC level ≤ 400 μg/m³	n = 47	ΣVOC level > 400 μg/m³	n = 78
		n	%	n	%
Sex
	Male	29	61.7	45	57.7	0.660
	Female	18	38.3	33	42.3	0.660
Age (years)
	20–29	41	87.2	48	61.5	0.001	^*
	30–39	5	10.6	14	17.9
	40–49			9	11.5
	≥50	1	2.1	7	9.0
Sensitivity to chemicals (QEESI)
	Low	31	66.0	50	64.1	0.834
	High	16	34.0	28	35.9	0.834
Physical condition
	Good	44	93.6	70	89.7	0.461
	Not Good	3	6.4	8	10.3	0.461
Medical history of allergy
	No	17	36.2	35	44.9	0.341
	Yes	30	63.8	43	55.1	0.341
Current smoking
	No	36	76.6	66	84.6	0.264
	Yes	11	23.4	12	15.4	0.264
Occurrence of BRSs
	No	33	70.2	36	46.2	0.009	^*
	Yes	14	29.8	42	53.8	0.009	^*
Environmental factors		Case 1		Case 2		P value
Environmental factors		Mean	SD	Mean	SD	P value
Temperature	°C	23.02	0.82	23.77	1.26	<0.001	^*
Humidity	%	55.95	5.68	56.92	12.42	0.002	^*
ΣVOC level	μg/m³	278	52	2980	1982	<0.001	^*
SOAV		7.0	1.7	30.2	20.8	<0.001	^*

Open in a new tab

*Statistically significant (i.e., p < 0.05).

VOC: Volatile organic compound, QEESI: Quick Environmental Exposure and Sensitivity Inventory, BRSs: Building-related symptoms, SD: Standard deviation, SOAV: Sum of odor activity values.

Environmental measurements

The IAQ data (for Case 1 and Case 2, including temperature and humidity) are shown in Table 1. The environmental data of Case 1 and Case 2 were compared using Mann–Whitney U test. The results showed significant differences in temperature, humidity, ΣVOC level, and SOAV between Cases 1 and 2. S1 and S2 Tables (S1 and S2 Tables) show the substances identified and analyzed. In Case 1, 27 substances were identified, and 16 of them had a frequency of 100%. In Case 2, 47 substances were identified, and 12 of them had a frequency of 100%. The OAVs of nine substances in Case 1 and 18 substances in Case 2 were calculated.

Association between the occurrence of BRSs and ΣVOC level

In this study, 56 participants (44.8%) (Case 1: 14 [29.8%], Case 2: 42 [53.8%]) had BRSs, and there was a significant difference in the occurrence of BRSs between Case 1 and Case 2 (p < 0.01; Table 1). Table 2 shows the results of the multivariate logistic regression analysis. In the analysis, covariates were determined using Mann–Whitney U test. Since there were significant differences in temperature and humidity between Cases 1 and 2, we divided the variables into two categories based on their median values (i.e., 23.5°C and 58.8%, respectively) and included them as covariates. The results show that the occurrence of BRSs is significantly associated with ΣVOC level of >400 μg/m³ (OR: 2.94, 95% CI: 1.18–7.35).

Table 2. Logistic regression analysis of personal and environmental factors and occurrence of BRSs.

		P value		OR	95% CI
Temperature
	≤23.5			Ref
	≥23.5	0.246		1.60	0.72	―	3.53
Humidity
	≤58.75			Reference
	≥58.75	0.135		0.53	0.23	―	1.22
Age (years)
	20–29	0.819		Ref
	30–39	0.533		0.71	0.25	―	2.10
	40–49	0.536		1.61	0.38	―	7.28
	≥50	0.930		1.07	0.21	―	5.09
ΣVOC level
Case 1	≤400			Ref
Case 2	>400	0.021	^*	2.94	1.18	―	7.35

Open in a new tab

*p < 0.05. VOC: Volatile organic compound, OR: Odds ratio, CI: Confidence interval, BRSs: Building-related symptoms.

Association between odor (SAOV) and occurrence of BRSs

Fourteen participants in Case 1 (29.8%) had BRSs. These participants had BRSs even at ΣVOC level ≤ 400 μg/m³. To investigate the relationship between odor (SAOV) and the occurrence of BRSs in Case 1, SOAV in Case 1 was divided into two groups based on the median SOAV of 6.9 and added as a covariate to the multivariate logistic regression analysis. The results of the analysis are shown in Table 3. The results show that the occurrence of BRSs is significantly associated with high SOAV (OR: 6.06, 95% CI: 1.21–30.44).

Table 3. Logistic regression analysis of SOAV and occurrence of BRSs.

		P value		OR	95% CI
SOAV
Low	≤6.9			Ref
High	>6.9	0.029	^*	6.06	1.21	―	30.44

Open in a new tab

Other covariates (such as temperature, humidity, and age) were adjusted.

*p < 0.05.

SOAV: Sum of odor activity values, BRSs: Building-related symptoms, OR: Odds ratio, CI: Confidence interval.

Discussion

In this study, we examine the effectiveness of the Japanese provisional target TVOC level (400 μg/m³) in reducing the risk of BRSs. We also evaluated the impact of odor intensity on human health at low TVOC levels. The number of participants who reported BRSs during their stay at the LH was 56 (44.8%). The reported prevalence of BRSs (or sick building syndrome) in Asia-Pacific countries is 41.0% in Hong Kong [18], 26.2% in Taiwan [19], and 24.9% in Japan [20]. In our 2017 study [21], which involved a web survey of 1500 Japanese participants, we found that the prevalence of BRSs in Japan was 18.8%. The higher prevalence of BRSs reported in this study than in the above studies may be due to the inclusion of individuals with mild BRS symptoms in the eyes, nose, throat, airways, skin, muscles, joints, and digestive organs [6]. In this study, we found that ΣVOC level of <400 μg/m³ is significantly associated with a low prevalence of BRSs. Although TVOC has been used as an indicator of IAQ for over 30 years [22,23], the use of TVOC is still controversial. Shrubsole et al. concluded that individual VOC guidelines are more appropriate than the TVOC guidelines [24]. According to Salthammer, T., TVOC cannot be used for health- and odor-related issues [25]. Some investigators argue that health-related effects of air quality should be assessed using specific VOCs rather than TVOC, as TVOC does not reveal the toxicity of individual VOCs to humans [26,27]. However, the concentrations of single VOCs may not be valid measures of health risks [28]. Several studies demonstrated a positive correlation between TVOC or ΣVOCs and symptom severity and prevalence in humans [29,30]. TVOC measurement and analysis methods for research are improving [31]. The association between ΣVOC levels and the low prevalence of BRSs, shown in this study supports the use of TVOC or ΣVOCs as health-related indicators and can be viewed as practical evidence to support the provisional target TVOC level set by the Japanese MHLW. In addition, this study revealed that odor may influence the occurrence of BRSs in spaces with VOC concentration of <400 μg/m³. In this study, we used OAV to assess odor and to quantify the odor of each VOC in indoor air. OAV is used worldwide to evaluate odor pollution from various sources, such as industrial areas, piggeries, and landfill sites. It is also used to evaluate odor intensity levels and the impact of each odor [32,33]. There is a strong correlation between SOAV and ΣVOC concentration because OAV is calculated from VOC concentrations. However, the contribution of airborne chemicals to odor in indoor air may differ from the percentage of airborne chemical concentration because of differences in odor characteristics and odor threshold concentration of each substance. Some studies showed that the compositional percentage of airborne chemical concentrations may be different from the percentage of chemicals contributing to odor [34]. It follows from this report that airborne chemicals with high concentrations do not always dominate the odor profile. As shown in S1 Table, 16 VOCs were detected and identified in spaces with VOC concentrations of <400 μg/m³. Regarding OAV, acetaldehyde and nonanal were identified as the main odorous substances. The guideline value for acetaldehyde is set at 0.03 ppm (48 μg/m³) by the Japanese MHLW and at 0.17 ppm (300 μg/m³) by the WHO. In contrast, no guideline values have been provided for nonanal. Nonanal is a fragrance component of flowers and fruits (e.g., roses and citrus fruits) and is used in food and cosmetic preparations. It is a type of low-toxicity aldehyde with irritating effects on the eyes, skin, and respiratory organs [35]. In this study, the maximum concentration of acetaldehyde detected in spaces with VOC concentrations of <400 μg/m³ was 15.10 μg/m³. This means that in almost all cases, the concentration of acetaldehyde was less than the guideline value set by the Japanese MHLW. Nonanal has a lower VOC concentration and OAV than acetaldehyde. Nevertheless, acetaldehyde and nonanal may have contributed significantly to OAV and influenced the occurrence of BRSs. However, decreasing VOC concentrations may not necessarily improve IAQ.

Odor, especially unpleasant odor, is considered a warning sign or indicator of risk to human health [36]. Kjaergaard et al. and Wang et al. reported that stimulation irritation is associated with humidity and dryness [37,38]; in addition, it is associated with odor perception. A study of houses in a large Chinese city showed that odor complaints are a sign of air pollution [39], and it was reported in another study that odor perception is an early predictor of BRSs [7]. These studies show that olfactory sensation acts as a warning sign of decreased IAQ, and they suggest an association between olfactory sensation and BRSs. However, olfactory perception may be affected by adaptation to and preference for odor. We tend to perceive air quality as “clean” when we like the smells (i.e., the air smells nice). When we feel comfortable, the scent tends to reduce health risks [40,41]. However, even at low concentrations, the use of fragrances and deodorants releases chemicals into the air. These fragrances and deodorants may mask unpleasant odors, like odorant chemicals, and they could have unintended effects and risks to human health in the indoor environment. Moreover, olfactory perception is easily fatigued, and when it adapts to an odor, the odor becomes difficult to perceive. The easy fatigability of olfactory perception refers to the ease of adaptation of olfaction to a previously perceived odor. In previous studies examining odor intensity and olfactory adaptation and symptom levels, a negative linear correlation between odor acceptability and symptom levels, and a good positive linear correlation between odor intensity and symptom levels [42]. OAV compensates for these weaknesses in olfactory perception and can be used to evaluate odor intensity. Thus, OAV may be considered a new objective method of IAQ evaluation.

Regarding the evaluation tests of indoor environments including odor perception conducted in the LH, this study has several strengths. First, the study was conducted in a full-scale living environment. This was a significant advantage in odor evaluation experiments. Second, participants focused on IAQ and the occurrence of BRSs during their short stay, which may have allowed them to clearly recognize the development or change of symptoms in the environment they were exposed to for this study. This study also has some limitations. First, VOC levels in the air change constantly, and they change with seasons of the year and with daily lifestyle. Second, the results of this study may not be generalized.

The study results are based on the chemical composition of the air quality and the odor composition in the LH. Most study participants were in their 20s or 30s and included college students. The reason for this choice of participants is that the test had to be conducted during the day on a weekday. Furthermore, given that the occurrence of BRSs is based on the responses of the study participants, we cannot disregard the influence of individual differences on the evaluation of symptoms and odor. Moreover, we did not investigate the effects of long-term exposure to VOCs in the indoor environment on the study participants. Thus, we do not know the effects of VOCs, even at low concentrations, on exposed individuals for a long time. Recently, as a result of the coronavirus disease 2019 (COVID-19) pandemic, increasingly more time has been spent at home. In Japan, the time people spend indoors increased by 13.8% from before the COVID-19 pandemic [43]. There is growing concern regarding indoor air quality (IAQ) worldwide, with some studies suggesting that IAQ worsens with increased time at home due to the COVID-19 pandemic [44]. We hope that measures will be taken to prevent the IAQ from getting worse and that more studies on this topic will be conducted in the future.

Conclusions

To the best of our knowledge, this study is the first study to investigate the association between the occurrence of BRSs and differences in the levels of TVOC and the odor intensity under the same environmental conditions. The risk of BRSs is significantly lower in spaces with ΣVOC concentration of <400 μg/m³ than in spaces with ΣVOC concentration of >400 μg/m³. Furthermore, even in spaces with ΣVOC concentration of <400 μg/m³, high odor intensity increases the risk of BRSs, highlighting the need to reduce the concentration of chemicals in the air and to reduce odor intensity. The relationship between TVOC or ΣVOC concentration, and the occurrence of BRSs is complex, and it is difficult to estimate the combined risk of BRSs. In addition, the mechanism of how the odor triggers symptoms is still unclear. However, our study findings show that OAV can be considered a new method of IAQ evaluation and a new indicator for the prevention of BRSs. Studies focused on odors in indoor air, in addition to those of chemical concentrations, could help improve IAQ and prevent BRS.

Supporting information

S1 Table. VOCs and OAV (Case 1).

This table is the substances identified and analyzed in Case1.

(DOCX)

Click here for additional data file.^{(44.1KB, docx)}

S2 Table. VOCs and OAV (Case 2).

This table is the substances identified and analyzed in Case2.

(DOCX)

Click here for additional data file.^{(42.8KB, docx)}

Data Availability

Our data are unsuitable for public deposition due to ethical restrictions and the legal framework of Japan. It is prohibited by the Act on the Protection of Personal Information (Act No. 57 of 30 May 2003, amendment on 9 September 2015) to publicly deposit data containing personal information. Ethical Guidelines for Medical and Health Research Involving Human Subjects enforced by the Japan Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare also restrict the open sharing of epidemiologic data. All inquiries about access to data should be sent to: suzu-nori@chiba-u.jp or ho-cpms@office.chiba-u.jp.

Funding Statement

The study was supported by a grant from the 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, Japan (Grant Number JPMJOP1831). The sponsor had no control over the interpretation, writing, or publication of this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

1.Klepeis NE, Nelson WC, Ott WR, Robinson JP, Tsang AM, Switzer P, et al. The National Human Activity Pattern Survey (NHAPS): a resource for assessing exposure to environmental pollutants. J Expo Anal Environ Epidemiol. 2001;11(3):231–52. doi: 10.1038/sj.jea.7500165 . [DOI] [PubMed] [Google Scholar]
2.Introduction to Indoor Air Quality | US EPA. [cited 21 Jun 2022]. Available: https://www.epa.gov/indoor-air-quality-iaq/introduction-indoor-air-quality.
3.Hoffmann B, Boogaard H, de Nazelle A, Andersen ZJ, Abramson M, Brauer M, et al. WHO Air Quality Guidelines 2021–Aiming for Healthier Air for all: A Joint Statement by Medical, Public Health, Scientific Societies and Patient Representative Organisations. Int J Public Health. 2021;66: 1604465. doi: 10.3389/ijph.2021.1604465 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Ministry of Health, Labor and Welfare of Japan: Committee on Sick House Syndrome. Indoor air pollution progress report [cited Jun 27 2022]. Available from: https://www.mhlw.go.jp/houdou/2002/02/h0208-3.html.
5.Japanese Ministry of Land, Infrastructure and transport. [cited 27 Jun 2022]. Available: https://www.mlit.go.jp/jutakukentiku/build/jutakukentiku_house_tk_000043.html.
6.Suzuki N, Nakaoka H, Nakayama Y, Tsumura K, Takaguchi K, Takaya K, et al. Association between sum of volatile organic compounds and occurrence of building-related symptoms in humans: A study in real full-scale laboratory houses. Science of The Total Environment. 2021;750: 141635. doi: 10.1016/j.scitotenv.2020.141635 [DOI] [PubMed] [Google Scholar]
7.Shang Y, Li B, Baldwin AN, Ding Y, Yu W, Cheng L. Investigation of indoor air quality in shopping malls during summer in Western China using subjective survey and field measurement. Build Environ. 2016;108:1–11. doi: 10.1016/j.buildenv.2016.08.012 [DOI] [Google Scholar]
8.EN 13725:2003—Air quality—Determination of odour concentration by dynamic olfactometry. [cited 21 Jun 2022]. Available: https://standards.iteh.ai/catalog/standards/cen/96eeb1f0-43fc-452c-aad3-29a9c811c1ca/en-13725-2003.
9.Indoor Air Pollution: An Introduction for Health Professionals | US EPA. [cited 21 Jun 2022]. Available: https://www.epa.gov/indoor-air-quality-iaq/indoor-air-pollution-introduction-health-professionals#volatile.
10.Nielsen GD, Wolkoff P, Alarie Y. Sensory irritation: risk assessment approaches. Regul Toxicol Pharmacol. 2007;48: 6–18. doi: 10.1016/j.yrtph.2006.11.005 [DOI] [PubMed] [Google Scholar]
11.Nakayama Y, Suzuki N, Nakaoka H, Tsumura K, Takaguchi K, Takaya K, et al. Assessment of Personal Relaxation in Indoor-Air Environments: Study in Real Full-Scale Laboratory Houses. International Journal of Environmental Research and Public Health 2021, Vol 18, Page 10246. 2021;18: 10246. doi: 10.3390/ijerph181910246 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Miller CS, Prihoda TJ. The Environmental Exposure and Sensitivity Inventory (EESI): a standardized approach for measuring chemical intolerances for research and clinical applications. Toxicol Ind Health. 1999;15: 370–85. doi: 10.1177/074823379901500311 [DOI] [PubMed] [Google Scholar]
13.Miller CS, Prihoda TJ. A controlled comparison of symptoms and chemical intolerances reported by Gulf War veterans, implant recipients and persons with multiple chemical sensitivity. Toxicol Ind Health. 1999;15: 386–97. doi: 10.1177/074823379901500312 [DOI] [PubMed] [Google Scholar]
14.Hojo S, Sakabe K, Ishikawa S, Miyata M, Kumano H. Evaluation of subjective symptoms of Japanese patients with multiple chemical sensitivity using QEESI. Environ Health Prev Med. 2009;14: 267–275. doi: 10.1007/S12199-009-0095-8/FIGURES/4 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Suzuki N, Nakaoka H, Nakayama Y, Takaya K, Tsumura K, Hanazato M, et al. Changes in the concentration of volatile organic compounds and aldehydes in newly constructed houses over time. International Journal of Environmental Science and Technology. 2020;17: 333–342. doi: 10.1007/S13762-019-02503-3/TABLES/5 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Feilberg A, Liu D, Adamsen APS, Hansen MJ, Jonassen KEN. Odorant emissions from intensive pig production measured by online proton-transfer-reaction mass spectrometry. Environ Sci Technol. 2010;44: 5894–5900. doi: 10.1021/es100483s [DOI] [PubMed] [Google Scholar]
17.Nagata Y. Measurement of Odor Threshold by Triangle Odor Bag Method. Odor Measurement Review. 2003; 118–127. Available: https://www.semanticscholar.org/paper/Measurement-of-Odor-Threshold-by-Triangular-Odor-Yoshio-Nagata/f7137e4c565068b998fd6cf4277ca73ca965a2f7. [Google Scholar]
18.Gou Z, Siu‐Yu Lau S. Sick building syndrome in open‐plan offices. Journal of Facilities Management. 2012;10: 256–265. doi: 10.1108/14725961211265729 [DOI] [Google Scholar]
19.Lu CY, Tsai MC, Muo CH, Kuo YH, Sung FC, Wu CC. Personal, Psychosocial and Environmental Factors Related to Sick Building Syndrome in Official Employees of Taiwan. Int J Environ Res Public Health. 2017;15. doi: 10.3390/ijerph15010007 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Azuma K, Ikeda K, Kagi N, Yanagi U, Osawa H. Prevalence and risk factors associated with nonspecific building-related symptoms in office employees in Japan: relationships between work environment, Indoor Air Quality, and occupational stress. Indoor Air. 2015;25: 499–511. doi: 10.1111/ina.12158 [DOI] [PubMed] [Google Scholar]
21.Nakayama Y, Nakaoka H, Suzuki N, Tsumura K, Hanazato M, Todaka E, et al. Prevalence and risk factors of pre-sick building syndrome: characteristics of indoor environmental and individual factors. Environ Health Prev Med. 2019;24: 77. doi: 10.1186/s12199-019-0830-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Hodgson AT, Daisey JM, Grot RA. Sources and Source Strengths of Volatile Organic Compounds in a New Office Building. J Air Waste Manage Assoc. 1991;41: 1461–1468. doi: 10.1080/10473289.1991.10466944 [DOI] [Google Scholar]
23.Molhave L, Clausen G, Berglund B, Ceaurriz J, Kettrup A, Lindvall T, et al. Total Volatile Organic Compounds (TVOC) in Indoor Air Quality Investigations*. Indoor Air. 1997;7: 225–240. doi: 10.1111/j.1600-0668.1997.00002.x [DOI] [Google Scholar]
24.Shrubsole C, Dimitroulopoulou S, Foxall K, Gadeberg B, Doutsi A. IAQ guidelines for selected volatile organic compounds (VOCs) in the UK. Build Environ. 2019;165:106382. doi: 10.1016/j.buildenv.2019.106382 [DOI] [Google Scholar]
25.Salthammer T. TVOC—Revisited. Environ Int. 2022;167: 107440. doi: 10.1016/j.envint.2022.107440 [DOI] [PubMed] [Google Scholar]
26.Fromme H, Debiak M, Sagunski H, Röhl C, Kraft M, Kolossa-Gehring M. The German approach to regulate indoor air contaminants. Int J Hyg Environ Health. 2019;222: 347–354. doi: 10.1016/j.ijheh.2018.12.012 [DOI] [PubMed] [Google Scholar]
27.Sundell J. On the history of indoor air quality and health. Indoor Air. 2004;14: 51–58. doi: 10.1111/j.1600-0668.2004.00273.x [DOI] [PubMed] [Google Scholar]
28.Norbäck D. An update on sick building syndrome. Curr Opin Allergy Clin Immunol. 2009;9: 55–59. doi: 10.1097/ACI.0b013e32831f8f08 [DOI] [PubMed] [Google Scholar]
29.Nakaoka H, Suzuki N, Eguchi A, Matsuzawa D, Mori C. Impact of Exposure to Indoor Air Chemicals on Health and the Progression of Building-Related Symptoms: A Case Report. Sustainability. 2022;14: 14421. doi: 10.3390/su142114421 [DOI] [Google Scholar]
30.Sakellaris I, Saraga D, Mandin C, Kluizenaar Y, Fossati S, Spinazzè A, et al. Association of subjective health symptoms with indoor air quality in European office buildings: The OFFICAIR project. Indoor Air. 2021;31: 426–439. doi: 10.1111/ina.12749 [DOI] [PubMed] [Google Scholar]
31.Ishizaka TD, Kawashima A, Hishida N, Hamada N. Measurement of total volatile organic compound (TVOC) in indoor air using passive solvent extraction method. Air Qual Atmos Health. 2019;12: 173–187. doi: 10.1007/s11869-018-0639-4 [DOI] [Google Scholar]
32.Parker DB, Gilley J, Woodbury B, Kim K-H, Galvin G, Bartelt-Hunt SL, et al. Odorous VOC emission following land application of swine manure slurry. Atmos Environ. 2013;66: 91–100. doi: 10.1016/j.atmosenv.2012.01.001 [DOI] [Google Scholar]
33.Trabue S, Scoggin K, McConnell L, Maghirang R, Razote E, Hatfield J. Identifying and tracking key odorants from cattle feedlots. Atmos Environ. 2011;45(25):4243–51. doi: 10.1016/j.atmosenv.2011.04.081 [DOI] [Google Scholar]
34.Liu Y, Zhu X, Qin X, Wang W, Hu Y, Yuan D. Identification and characterization of odorous volatile organic compounds emitted from wood-based panels. Environ Monit Assess. 2020;192: 348. doi: 10.1007/s10661-019-7939-5 [DOI] [PubMed] [Google Scholar]
35.Workplace Safety Sites: Chemicals: 1-Nonanol [Internet]. [cited 2022 Jul 26]. Available from: https://anzeninfo.mhlw.go.jp/anzen/gmsds/143-08-8.html.
36.Schiffman SS, Williams CM. Science of Odor as a Potential Health Issue. J Environ Qual. 2005;34: 129–138. doi: 10.2134/JEQ2005.0129A [DOI] [PubMed] [Google Scholar]
37.Kjærgaard SK, Pedersen OF, Taudorf E, Mølhave L. Assessment of changes in eye redness by a photographic method and the relation to sensory eye irritation. International Archives of Occupational and Environmental Health 1990 62:2. 1990;62: 133–137. doi: 10.1007/BF00383590 [DOI] [PubMed] [Google Scholar]
38.Wang J, Li B, Yang Q, Yu W, Wang H, Norback D, et al. Odors and sensations of humidity and dryness in relation to sick building syndrome and home environment in Chongqing, China. PLOS ONE. 2013;8(8):e72385. doi: 10.1371/journal.pone.0072385 . [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Sun Y, Hou J, Cheng R, Sheng Y, Zhang X, Sundell J. Indoor air quality, ventilation and their associations with sick building syndrome in Chinese homes. Energy Build. 2019;197: 112–119. doi: 10.1016/J.ENBUILD.2019.05.046 [DOI] [Google Scholar]
40.Kim S, Senick JA, Mainelis G. Sensing the invisible: Understanding the perception of indoor air quality among children in low-income families. Int J Child Comput Interact. 2019;19: 79–88. doi: 10.1016/j.ijcci.2018.12.002 [DOI] [Google Scholar]
41.Basketter DA, Huggard J, Kimber I. Fragrance inhalation and adverse health effects: The question of causation. Regulatory Toxicology and Pharmacology. 2019;104: 151–156. doi: 10.1016/j.yrtph.2019.03.011 [DOI] [PubMed] [Google Scholar]
42.Xu L, Hu Y, Liang W. Subjective and objective sensory assessments of indoor air quality in college dormitories in Nanjing. Build Environ. 2022;212: 108802. doi: 10.1016/j.buildenv.2022.108802 [DOI] [Google Scholar]
43.Seposo X, Madaniyazi L, Ng CFS, Hashizume M, Honda Y. COVID-19 pandemic modifies temperature and heat-related illness ambulance transport association in Japan: a nationwide observational study. Environ Health. 2021;20(1):122. doi: 10.1186/s12940-021-00808-w . [DOI] [PMC free article] [PubMed] [Google Scholar]
44.Domínguez-Amarillo S, Fernández-Agüera J, Cesteros-García S, González-Lezcano RA. Bad air can also kill: residential indoor air quality and pollutant exposure risk during the COVID-19 crisis. Int J Environ Res Public Health. 2020;17(19):7183. doi: 10.3390/ijerph17197183 . [DOI] [PMC free article] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0279757.r001

Decision Letter 0

Rajeev Singh

17 Oct 2022

PONE-D-22-23122Is odor a risk factor of building-related symptoms?PLOS ONE

Dear Dr. Tsumura,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Dec 01 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Rajeev Singh

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating in your Funding Statement:

"The study was supported by a grant from the Sekisui House Ltd. and Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (C) Grant Number (19K12455, 18K13885), by JST OPERA Program Grant Number JPMJOP1831, and by JSPS KAKENHI Grant Numbers JP21H01487. The sponsor had no control over the interpretation, writing, or publication of this work."

Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

4. Thank you for stating the following financial disclosure:

Please state what role the funders took in the study. If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.""

If this statement is not correct you must amend it as needed.

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

5. Thank you for stating the following in the Competing Interests section:

"The authors of this article K.T. (Kayo Tsumura), and co-authors of this Y.N. and K.T. (Kohki Takaguchi), and K.S. are affiliated with the Endowed Chair of Sekisui House, Ltd. at the Centre for Preventive Medicine, Chiba University. The other authors declare that they have no known competing financial interests or personal relationships that would affect the research reported in this paper."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

6. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

Additional Editor Comments:

Dear Dr. Kayo Tsumura,

Thank you so much for submitting your research to PLOS ONE. In my opinion your manuscript has logical data and some innovative findings. Please find the comments from reviewers and incorporate the required changes in order to get accepted. I look forward to receive your revised manuscript soon.

Thanking You

Dr. Rajeev Singh

Editor PLoS One

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Title should be change, odor in title replace with indoor environment.

COVID-19 portion remove from manuscript as this study conducted 2017-2019. Focus only VOCs and biological agents which you have studied and data.

Please explain why authors use only 2 case study, as in both cases sample size also different (in case 2- sample size is double), for comparative conclusion, must have study with 3 or 5 cases

Line 83-85: give the detail information of study site area, have any natural air purifier (indoor plants) artificial air purifier inside the rooms and other building construction material details (if available), It also effect the indoor environment quality.

Line 89-93: specify age group, gender in text also

Line 132-135: this data only questionnaires base please justify with diagnostic based results.

Line 199-201: In which parameters used for concluding results as health is good, explain clearly.

Line 201: history of allergy- which types of reports you have for individuals motioned.

In table shown the data for personal factors, one of them physical condition most of them health and not any major health issues reported, until 50 % of them are have medical history of allergy. In pervious mentioned all individuals participate in this study are healthy explain it.

Discussion section updated with recent and more related paper; this portion need improvement.

Rewrite abstract and conclusion section.

Reviewer #2: The work described in the manuscript is based on questionnaire, air sampling and odor activity testing. Data are methodically and accurately analyzed. The conclusions are made basically reflecting to the results formulated.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Jan 25;18(1):e0279757. doi: 10.1371/journal.pone.0279757.r002

Author response to Decision Letter 0

13 Dec 2022

Reviewer ＃1

Thank you for your thorough consideration of our manuscript and for providing constructive feedback. The quality of our manuscript has certainly improved as a result of your comments.

We have highlighted all of our changes in the revised manuscript in red. A point-by-point response to the reviewers’ comments is given below.

------------------------------------------------------------------

Comment: The authors greatly appreciate your consideration of our manuscript and helpful comments. We divided your advice into a few points and have addressed each of these suggestions in the responses provided below.

------------------------------------------------------------------

Comment 1: Title should be change, odor in title replace with indoor environment.

Our reply:

Thank you for your advice. We changed the title to “Is indoor environment a risk factor for building-related symptoms?”.

------------------------------------------------------------------

Comment 2: COVID-19 portion remove from manuscript as this study conducted 2017-2019. Focus only VOCs and biological agents which you have studied and data.

Our reply:

Thank you for the comment. We removed the section about COVID-19 from the Introduction and focused only on VOCs and other factors.

------------------------------------------------------------------

Comment 3: Please explain why authors use only 2 case study, as in both cases sample size also different (in case 2- sample size is double), for comparative conclusion, must have study with 3 or 5 cases.

Our reply:

Thank you for the comment. In this study, we tried to examine the provisional target value of 400 µg/m3 set by the Japanese Ministry of Health, Labor, and Welfare. Thus, we divided the scenes into two: the scene with TVOC > 400 µg/ m3 is referred to as Case 1, and the second scene with TVOC < 400 µg/ m3 is referred to as Case 2. The number of participants was not the same as they were divided by TVOC concentration values. We revised the aim of this study in the Introduction.

------------------------------------------------------------------

Comment 4: Line 83-85: give the detail information of study site area, have any natural air purifier (indoor plants) artificial air purifier inside the rooms and other building construction material details (if available), It also effect the indoor environment quality.

Our reply:

Thank you for the comment. As you said, some devices and things affect indoor air quality. We added details of the study site in the text as follows:

“The structure of the LH is a typical Japanese wooden house constructed from timber. The LH was constructed mostly with F☆☆☆☆ (F-four stars) labeling. The F☆☆☆☆ rating is a classification of building materials in Japan based on the formaldehyde emission rate, which is defined by Japanese Industrial Standards (JIS), Japanese Agricultural Standards (JAS), and the Ministry of Land, Infrastructure, Transport, and Tourism. Four-star building materials, including boards, adhesives, insulation, and paints, can be used without limitations on the area of use.

The LH was equipped with a mechanical ventilation system designed to ventilate 0.5 times per hour. The LH was also equipped with air conditioners that control the temperature and humidity, but no air purifiers were used. The rooms of the LH were not decorated with any indoor plants.”

------------------------------------------------------------------

Comment 5: Line 89-93: specify age group, gender in text also

Our reply:

Thank you for the comment. We have specified age groups and gender in the text.

------------------------------------------------------------------

Comment 6:　Line 132-135: this data only questionnaires base please justify with diagnostic based results.

Our reply:

Thank you for your comment. Building-related symptoms (BRSs) and Sick building syndrome (SBS) are usually defined as the occurrence of nonspecific symptoms among populations in specific buildings. In epidemiological studies worldwide, BRSs and SBS are often diagnosed using questionnaires, such as the MM040 (Andersson, K., 1998). In this study, we diagnosed BRSs and SBSs using a questionnaire developed based on the “Consultation Manual for Trace Chemicals in the Indoor Environments” issued by the Japanese MHLW. We described the questionnaires in the “Questionnaire” section.

------------------------------------------------------------------

Comment 7: Line 199-201: In which parameters used for concluding results as health is good, explain clearly.

Our reply:

Thank you for the comment. Regarding the health of the day, we asked participants to judge their physical condition subjectively. We revised the “Questionnaire” section as follows:

“The participants were asked to subjectively score their health status on the day of the evaluation using 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.””

------------------------------------------------------------------

Comment 8:

Line 201: history of allergy- which types of reports you have for individuals motioned.

Our reply:

Thank you for the comment. In this study, the most common “medical history of allergy” was hay fever. Most symptoms of hay fever appear in early spring (February to May) in Japan. As this study was conducted from May to October, most participants with a history of hay fever had no symptoms at the time of the test. Thus, they may have evaluated themselves as healthy on those days. However, we changed “healthy volunteers” to “participants.”

------------------------------------------------------------------

Comment 9:

Discussion section updated with recent and more related paper; this portion need improvement.

Our reply:

Thank you for the comment. We updated the Discussion with recent and related papers.

------------------------------------------------------------------

Comment 10:

Rewrite abstract and conclusion section.

Our reply:

Thank you for the comment. We rewrote the abstract and conclusion.

Reviewer ＃２

------------------------------------------------------------------

Comment:

The work described in the manuscript is based on questionnaire, air sampling and odor activity testing. Data are methodically and accurately analyzed. The conclusions are made basically reflecting to the results formulated.

Our reply:

We sincerely appreciate your review and comments.

------------------------------------------------------------------

We would like to take this opportunity to express our sincere thanks to the reviewers who identified areas of the manuscript that needed corrections or modifications. We would also like to thank you for allowing us to resubmit a revised copy of the manuscript. We hope that the revised manuscript is acceptable for publication in PLOS ONE.

Sincerely,

Kayo Tsumura

Center for Preventive Medical Sciences, Chiba University, 1-33 Yayoi-tyou, Inage-ku, Chiba 263-8522, Japan

Tel.: +81-43-290-3878

Email Address: tsumu-kayo@chiba-u.jp

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(45.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0279757.r003

Decision Letter 1

Rajeev Singh

14 Dec 2022

Is indoor environment a risk factor for building-related symptoms?

PONE-D-22-23122R1

Dear Dr. Tsumura,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Rajeev Singh

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0279757.r004