Goal of the present analysis was to investigate the independent risks of each class of VOCs at home, controlling for the known and potential demographic correlates of both the bedroom VOC concentrations and the outcomes. In the present group of children, only PGEs in indoor air significantly increased the risks of multiple allergic symptoms/diseases (i.e. case status), asthma, rhinitis and eczema, respectively. In addition, a ln-unit PGE concentrations also increased the likelihood of IgE-sensitization among the cases while similar associations were not found for the other VOC classes. At the same time, roles of Texanol A and B require further examination due to their moderate correlation with the PGE levels, and demonstrated risks on asthma symptoms in prior investigations 
Several lines of evidence support that our findings are not due to a chance or a bias. First, concentration-dependent increases in the likelihood for all outcomes were observed per ln-unit concentration, or per quartile categories.
Second, apparently elevated likelihood of the present outcomes was not driven by propylene glycol, most abundant PGE compound. Rather, the estimated risks after excluding the propylene glycol were almost identical as those based on the original definition of the PGEs. Furthermore, mean risks of the number of the PGE compounds in given home posed comparable risks as those estimates using the PGE concentrations, shown in . This suggests that multiple compounds, rather than a single one, contribute to the observed risks.
Third, water-based cleaning does not confound the PGE-outcome associations, and, thus, does not raise potential for a reverse causality. This is supported by similarity in risks across the families with varying cleaning frequencies. In addition, limonene was neither an independent risk factor (aOR
1.15; 95% CI, 0.86 – 1.53) of the case status, nor a confounder of PGE-asthma/allergy associations. Similarly, the terpene hydrocarbons did not pose an independent risk on any of the outcomes, or confound the PGE-asthma/allergy associations. Furthermore, among the cases, a unit PGE exposure increased the likelihood of IgE-sensitization by 1.3- and 1.7-fold within the families that clean ≥ once/wk and every other week, respectively. Such independent validation of PGEs-IgE sensitization suggests that our diagnosis dependent outcomes are not merely correlated with frequent cleaning.
Fourth, a history of repainting at least one room in the house pre- or post-natal to the birth of the child was associated with a 63% increase in mean PGEs compared to those who never repainted in a group of families with higher than the median excess moisture level (≥2.158 g/m3
, p for interaction =0.03
). Thus, repainting might have provided a sustained exposure since the gestational period or shortly following the birth. This is because the information regarding the history of repainting was collected 1.5 year prior to the onset of the case-control study. Since the initial cross-sectional investigation, all parents reported that they remained in the same house and have not changed most life-style practices. To further validate this, the families that renovated their house due to flooding were excluded. This suggests that the temporal window of exposure occurred prior to the initial symptom presentation while the present cohort was critically vulnerable to these chemical compounds.
Multiple indoor sources emit PGEs. A growing body of literature suggest either the PGE sources (self-reported by the subjects), or their directly quantified concentrations exacerbate airway problems. Propylene glycol and glycol ethers are a diverse group of compounds with superior solvent and coalescent properties 
. Due to their lower volatility and higher degree of solvency, they are widely used in water-based paint, varnishes, cleaning fluids, pharmaceuticals, pesticides, cosmetics, and processed foods 
. For non-solvent purposes, they are used in PVC pipes 
, hydraulic and brake fluids, de-icing fluids for aircrafts, and artificial theatrical smoke 
. 1-methoxy-2-propanol was the most prevalent glycol ether compound in the present investigation. In a group of healthy adult volunteers, administration of 309 mg/m3
of propylene glycol, and 35 mg/m3
of glycol ethers and texanol mixture, respectively induced acute eye, nose, throat irritation and dyspnea 
. However, our observed PGE concentration range (i.e. <82 µ
) is more than 400-folds lower than the exposure ranges reported in occupational and experimental settings 
. In a prospective cohort study of house-painters from 1989 – 1991, occupational exposure to water-based paint led to a significantly higher incidence of chest tightness/wheezing, airway irritation, bronchial hyper-responsiveness, and shortness of breath 
. In a non-occupational setting, greater likelihood of asthma symptoms have been observed in adults exposed to a newly painted wood or kitchen surfaces 
, and/or synthetic material-based furniture 
. Finally, in the Avon cohort study, a household chemical exposure score was associated with late onset wheezing as well as reduced lung function in children 8.5 years of age 
While the mechanism through which glycols and glycol ethers affect the allergic responses is not well understood, it has been known for more than three decades that inhalation of vaporized propylene glycol methyl ether (PGME) induce mucous membrane irritation in nasal passage way of humans 
and rats 
. Administration of human nasal respiratory epithelial cell line from healthy individuals with 1-methoxy-2-propanol in vitro
acutely induced the transcription of TNF-α, IL-1β, and IL-6, markers of early inflammatory response, as well as Cyclooxygenase 2 (COX-2) for the following 4-hours 
. However, sustained response was observed only for COX-2, a key enzyme in the prostaglandin synthesis during inflammatory responses 
. Overall, the question of long-term airway injury from the glycol ethers and other organic solvent exposure requires clarification 
Glycol ethers as endocrine disrupting chemicals
Several glycol ether compounds join a growing list of sVOCs that are suggested to contribute to allergic diseases in humans 
. While several PGEs are well-known endocrine disruptors, very little is known whether and how they influence developing immune system. For example, 1-methoxy-2-propanol, a beta-isomer of PGME, was the most common glycol ethers in the homes of our cohort. Administration of 1-methoxy-2-propanol, during gametogenesis phase of the parent rats could induce >50% reduction of testicular and epididymal sperm counts 
. Furthermore, 1-methoxy-2-propanol exposure in the parental generation of rats significantly alter the sex ratio, the fetal loss, and birthweight reduction in two subsequent generations 
. In addition to these effects, our results suggest the PGEs may pose wider range of health effects than previously known. Considering low range of exposure in the present observation, experimental model should be developed not only to validate our results, but also to clarify the mechanism of PGE effects in developing airways and reproductive systems.
Limitations of the study
We examined whether the limitations in sampling and laboratory analysis misclassified the exposure scenarios for the children, and resulted in a biased estimates of the risks.
First, the airborne VOC levels were measured on the prevalent cases and the controls. VOC exposure characteristics during the period of the child's critical developmental window and temporal stability of the exposure traits to the present study period (at age 3 – 8) remain unknown. While the temporal reliability of the VOC concentrations could not be directly ascertained here, the parental responses from the two rounds of questionnaires suggest that the home indoor environment has not changed between the baseline and the present investigation. We also excluded families that renovated or moved their residence. In addition, while the likelihood of the outcome diagnosis as well as the severity is often positively correlated with the age of the child, we could not examine whether the age modifies the PGE risks due to the limited sample size.
Second, the possibility that the cases and the controls differ in the likelihood or in the concentration range of the missing PGE concentrations was examined. Under this scenario, the detected PGE concentration range would systematically differ between the cases and the controls, resulting in biased estimates of the risks away from the null. Proportion of the cases and controls with unknown PGE concentrations were comparable (28% vs. 37%). The interquartile ranges of the minimum of the 405 compounds were almost identical between the cases and the controls (Figure S2
). This suggests that our sampling methods and laboratory analysis are unlikely to have artificially inflated the true concentrations among the cases only. In a subset of children whose sensitization status was determined independent of the clinical diagnoses, the mean PGE levels were significantly higher for the sensitized children, compared to either the non-sensitized children. Similar association was absent for all other VOC classes. As a result, systematic difference in concentration ranges of 50 compounds between the cases and the controls were ruled out.
Third, we did not measure the frequency and extensiveness of the skin lotion use on the child as possible source for PGEs. This might have also contributed to an exposure misclassification. Transdermal exposure to PGEs has been suggested an important exposure route 
. In a group of 28 healthy male printing workers chronically exposed to 2-(2-butoxyethoxy)ethanol, urinary level of its chief metabolite, 2-(2-butoxyethoxy)ethanol butoxyethoxyacetic acid, was elevated particularly among those with skin lesion 
. Evidence of transdermal absorption was observed in all workers with erythema and scaliness of skin 
. While the children could have been exposed to PGE through skin lotion application in this study, this does not account for the present association.
Fourth, due to high mutual correlations of the PGE compounds, and their overall low concentrations, we currently cannot distinguish the risks of the individual compounds.
Internal Validity of VOC Sampling and the Laboratory Analysis
Our VOC sampling approach with adsorption/thermal desorption coupled with gas chromatography-mass spectrometry (GC/MS) has been validated as sensitive, simple, and cost-effective assessment method 
. Also, our sampling duration (60–90 min) was substantially longer than the standard protocol 
. Compared to other methods, our present approach has an advantage of higher sensitivity 
. In a number of indoor VOC investigations, which relied on Tenax TA as a general purpose adsorbent, overall very low inherent artifacts were observed 
. Known artifacts of Tenax TA do not include glycol ethers. Thus, glycol ethers are unlikely to have been introduced in this investigation as sampling artifacts 
. At the same time, no study as ever examined temporal stability of the 405 compounds in this study over time. A time period of 5 to 6 weeks between sampling and analysis could influence the artifact level and recovery rates. While this is likely to have biased the aromatic hydrocarbon level towards the null, there was no evidence that the PGEs were also influenced by the transport duration. The method used is in accordance to best laboratory practice and the recommendations given by DIN EN 14662-1 and Helmig 1996 
The prevalence and concentration the VOCs detected in the present study are strikingly concordant with those detected from other Scandinavian countries. We compared the concordance of our detected VOCs with Finnish EXPOLIS study 
. In the EXPOLIS study, air samples (2–3 L) from 183 homes were collected during the winter of 1996–1997 in Helsinki, Finland, focusing on 30 VOCs as target compounds. Extensive quality assurance and control standards were practiced. Of the 30 VOCs, 21 VOCs were also collected in our study. The prevalence (% detected in participant homes) of the VOC compounds were significantly correlated between the two studies (R2
) (Figure S3
). Also, eight VOC compounds, which were identified in ≥80% of the homes in both the studies (i.e., toluene, limonene, hexanal, p/m-xylene, benzaldehyde, octanal, undecane, and ethylbenzene), their concentrations were significantly correlated (R2
) (Figure S4
). This suggests that compounds with low prevalence are also expected to have low concentrations in both DBH and EXPOLIS. For example, 2-methyl-1-propanol, observed in 5% of the homes of DBH study was 1.96 µ
and 3.37 µ
in EXPOLIS. Striking similarities in absolute concentration and correlation of the compounds between the two studies support the validity of our sampling and analytical procedures.
Here, the present investigation demonstrates for the first time that the bedroom concentration of PGEs are significantly associated with an elevated risks of multiple allergic symptoms, rhinitis and eczema, respectively, as well as IgE-sensitization in preschool age children. Apparent risks of PGEs at such low concentrations at home raise concerns for the vulnerability of infants and young children. Our present observations warrant confirmation in a prospective cohort study. Clarification of the underlying mechanism of the PGE effects on developing human immune system is also necessary.