The urinary metabolites of volatile organic compounds and asthma in young children: NHANES 2011-2018

doi:10.21203/rs.3.rs-2991746/v1

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The urinary metabolites of volatile organic compounds and asthma in young children: NHANES 2011-2018

https://doi.org/10.21203/rs.3.rs-2991746/v1

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Background: Volatile organic compounds (VOCs) are synthetic chemicals that are broadly used in the production of numerous day-to-day products for residential and commercial-based applications. Evidence evaluating the prospective association between volatile organic compounds (VOCs) exposure and asthma in the U.S. children is limited. This study aimed to explore the associations between metabolites of VOCs (mVOCs) in urine, a representative of the internal exposure level of VOCs, and childhood asthma.

Methods:We conducted the cross-sectional analysis in 1559 children aged 3-12 years who participated in the National Health and Nutrition Examination Survey (NHANES) 2011-2018. In this study, we investigated the relationship between childhood asthma and urinary concentrations of five volatile organic compound metabolites, including N-Acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA), N-Acetyl-S-(3-hydroxypropyl)-L-cysteine (3HPMA), N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine (HPMMA), N-Acetyl-S-(benzyl)-L-cysteine (SBMA) and 2-Methylhippuric acid (2MHA). These metabolites correspond to the parent compounds acrolein, crotonaldehyde, toluene and xylene, respectively. Adjusted logistic regression models were used to assess the relationship between mVOCs and childhood asthma, followed by a stratified analysis.

Results: Urine measurements of mVOCs were weakly associated with an increased odds of childhood asthma, including 2MHA (OR:1.1; 95% CI:0.8, 1.6), SBMA (OR:1.2; 95% CI:0.8, 1.7), CEMA (OR:1.1; 95% CI:0.6, 1.7), 3HPMA (OR:1.1; 95% CI:0.7, 1.8), and HPMMA (OR:1.2; 95% CI:0.7, 2.0). Among female children, 2MHA in urine was significantly associated with the prevalence of asthma (OR: 1.8 95% CI: 1.1, 3.1)). Gender modified associations between urinary 2MHA, but not other urinary mVOCs concentrations, and odds of childhood asthma (gender x 2MHA interaction term p-value = 0.02). Age and race/ethnicity did not modify these associations.

Conclusion: We observed some evidence that urinary mVOCs concentrations are associated with increased asthma prevalence in US children, especially urinary 2MHA is significantly associated with the prevalence of asthma in female children. Further studies are needed to fully understand the potential role of VOCs in childhood asthma

NHANES

metabolites of volatile organic compounds

2MHA

SBMA

CEMA

3HPMA

HPMMA

Childhood Asthma

Childhood asthma, an extremely prevalent disease, poses a significant burden on children's health[1, 2]. Asthma cannot be cured, but its symptoms can be controlled[3]. The prevalence of asthma in children aged 5–14 years is 6.6%. Although the proportion of adults with asthma (8.4%) is significantly greater than that of children (5.8%), a large proportion of it is due to childhood asthma that is carried over [4]. Identification of modifiable risk factors for asthma (especially in children) could prevent the disease and reduce the associated morbidity[5]. Early exposure of children to environmental chemicals is a potentially modifiable risk factor that may have an adverse effect on the immune system, which may increase the risk of asthma[6–8].

Volatile organic compounds (VOCs) are a series of low molecular mass carbonaceous organic compounds that originate from a variety of natural and anthropogenic sources, such as industrial emissions, vehicle traffic, construction materials, and tobacco smoke[9]. However, the average annual emissions of man-made VOCs may have increased dramatically in recent decades. VOCs are mainly absorbed by the body through inhalation and dietary intake, and long-term exposure to VOCs may cause damage to the respiratory system, nervous system, digestive system and blood system[9–11]. Measurements of VOCs in the air and other environmental media cannot accurately reflect individual exposure levels due to the discrepancies in VOC sources and metabolism among individuals. The urinary metabolites of VOCs (mVOCs) are valuable biomarkers of VOC exposure given the advantages of long physiological half-lives and noninvasiveness of sampling[12–14].

This cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) to investigate the relationship between individual and multiple VOC coexposure and the development of asthma in US children, as indicated by the levels of mVOCs in urine. We also conducted stratified analyses by gender, age, and race to further explore the relationship between mVOCs concentration and childhood asthma prevalence.

Study population

NHANES is conducted biennially by the Centers for Disease Control and Prevention’s National Center for Health Statistics (NCHS) since 1999, which is a cross-sectional,

complex multistage, nationally representative survey that assesses population health and nutritional status that is representative of the non-institutionalized U.S. civilian population. The questionnaire data, physical examination data, and biospecimens from participants were collected. The NCHS Research Ethics Review Board reviewed and

approved the study, and informed written consent was obtained from all participants before they took part in the study. This study included children aged 3–12 years who had completed all urinary mVOCs measurements. Then we excluded participants with missing covariate data. Finally, a total of 1559 children were included in the analysis (Fig. 1).

Figure 1. Flowchart for participants selection.

NHANES, the National Health and Examination Survey; mVOCs, metabolite of volatile organic compounds.

Laboratory methods

In this study, five urinary mVOCs (2MHA [2-Methylhippuric acid], SBMA [N-Acetyl-S-(benzyl)-L-cysteine], CEMA [N-Acetyl-S-(2-carboxyethyl)-L-cysteine], 3PHMA [N-Acetyl-S-(3-hydroxypropyl)-L-cysteine], HPMMA [N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine]) were quantified in children aged 3–12 years participating in the NHANES 2011–2018 survey cycle (n = 1559). We list the relative parent compounds of the VOCs detected in this study and their official abbreviations (Table S1). Five mVOCs concentrations were quantified in urine samples using ultra-performance liquid chromatography coupled with electrospray tandem mass spectrometry (UPLC-ESI/MSMS)[12]. For mVOCs with analytical results below the lower limit of detection (LLOD), an imputed fill value (LLOD/√2) was replaced. Then, we excluded urinary mVOCs that had a low detection rate (≤ 50%) considering the representativeness of the data and the robustness of the results. Details of the analytical method and quality assurance/quality control procedures used are available on the NHANES website[15].

Outcome and covariables

Asthma diagnosis was determined by the medical conditions data file (MCQ) (question: “has a doctor or other health professional ever told you that study participant has asthma?”). We considered adjusting for variables associated with childhood urinary mVOCs concentrations and asthma diagnosis or believed to confound this relationship. Age (in years), gender (male or female), race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic (includes Mexican American and Other Hispanic), and Other (non-Hispanic Asian, and other race including multiracial), and income (ratio of family income to poverty (0–5)) were extracted from the demographic variables and sample weights data file (DEMO). Cutoffs for poverty were defined by the NHANES survey variable “INDFMPIR,” calculated as a ratio of individual/family income to poverty guidelines determined by the Department of Health and Human Services with a range from 0–5. Values from < 1.36 were considered “poor”, 1.36–1.86 were considered “nearly poor”, and values of ≥ 1.86 were considered “not poor” for classification.

Other variables considered included glomerular filtration rate, diet (fish consumption), history of wheezing, history of eczema, history of respiratory infections, history of breastfeeding, parental marital status, and parental medical history, which were not available in all study participants in this age group.

Statistical analyses

All data analyses were performed using Stata 17.0 and R version 4.2.1. We used published subsample weights (WTSA2YR) designed for a one-third subset of the entire survey for all effects and variance estimates to produce estimates representative of the U.S. population, as recommended by NHANES. Logarithmic transformation was performed for the 5 urine mVOCs to ensure a normal distribution, and then they were standardized for follow-up analyses. Then, we calculated geometric means (GM) for all five mVOCs and by age group (3–6 and 7–12 years), gender, race/ethnicity (Hispanic, non-Hispanic 100, non-Hispanic black, and other), and income (poor, nearly poor, not poor). We also calculated weighted Pearson correlation coefficients for all urinary mVOCs log10 concentrations.

In the unadjusted model, we estimated the odds ratio of ln-transformed urinary mVOCs concentrations per standard deviation (SD) increase for asthma by logistic regression. In the adjusted model, taking into account urinary dilution, we adjusted for child age (continuous), gender (binary), race/ethnicity (categorical), poverty to income ratio (continuous), and ln-transformed serum cotinine concentration (continuous) and estimated the odds ratio of ln-transformed creatinine-corrected mVOCs concentrations in current asthma per standard deviation (SD) increase in urine. We used Wald tests to detect differences in model coefficients for the mVOCs variable between different levels of modifiers. We also performed stratified regression analyses by age group, gender, and race/ethnicity. Given that mVOCs were measured in children with asthma after asthma diagnosis, we performed additional sensitivity analyses. We tested whether the difference between current age and age at diagnosis of asthma predicts urinary mVOCs concentrations in patients with asthma by Pearson correlation. Restricted cubic spline (RCS) was further used to identify potential nonlinearities. Four knots were set at the 5th, 35th, 65th, and 95th percentiles in the models, and the reference value was set to the median of the ln-transformed mVOCs concentration.

Of the children between 3 and 12 years old in the NHANES 2011–2018 cycle, 1559 participants were included in our analyses after excluding participants with missing data. The mean age of the children included in the analyses was 7.6 years (Table 1). Among the samples analyzed, there were 780 (weighted 52%) male children, 400 (weighted 14%) were Black, and 488 (weighted 25%) were Hispanic. There were 247 (weighted 17%) study participants with doctor-diagnosed asthma, of whom 73 were under 6 years of age (Table 1).

Table 1

The GM and IQR of urinary mVOCs concentrations (ng/mL) by demographic characteristics are shown in Table 1. We observed similar GM urinary mVOCs concentrations according to most demographic characteristics (Table 1). However, GM urinary SBMA, CEMA, 3HPMA and HPMMA concentrations were higher in White, non-Hispanics compared to the other races/ethnicities and in homes with lower incomes. All five GM urinary mVOCs concentrations were also higher in asthmatic patients than in nonasthmatic patients and in children aged 7–12 years than in 3- to 6-year-olds (Table 1). All five ln-transformed urinary mVOCs concentrations were slightly and moderately correlated with each other (r = 0.168–0.617, all p < 0.001) (Fig. 2). The strongest correlations were observed between CEMA and 3HPMA (r = 0.617).

Fig. 2. Weighted Pearson correlation coefficients for the (standardized) logarithms of urinary mVOCs concentrations (ng/mL) in children age 3–12 years (n = 1559): NHANES (2011–2018).

Abbreviations: metabolites of volatile organic compounds (mVOCs), NHANES: National Health and Nutrition Examination Survey, 2MHA (2-Methylhippuric acid), SBMA (N-Acetyl-S-(benzyl)-L-cysteine), CEMA (N-Acetyl-S-(2-carboxyethyl)-L-cysteine), 3PHMA (N-Acetyl-S-(3-hydroxypropyl)-L-cysteine), HPMMA (N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine). All p-values are less than 0.001.

After covariate adjustment, 2MHA (OR: 1.1; 95% CI: 0.8, 1.6), SBMA (OR: 1.2; 95% CI: 0.8, 1.7), CEMA (OR: 1.1; 95% CI: 0.6, 1.7), 3HPMA (OR: 1.1; 95% CI: 0.7, 1.8), and HPMMA (OR: 1.2; 95% CI: 0.7, 2.0) were not significantly associated with a increased odds of asthma (Table 2). Age and race/ethnicity did not modify the association between urinary creatinine-corrected mVOCs concentrations (interaction term p values = 0.12–0.97) (Table 2). However, gender did modify associations between urinary creatinine-corrected 2MHA concentrations and odds of asthma (age-by-PFOS interaction p value=0.02). Specifically, for every SD increase in urinary creatinine-corrected 2MHA concentrations, male children had an 80% increased odds of asthma (OR: 1.8; 95% CI: 1.1, 3.1) compared to a 20% decreased odds of asthma in female children (OR: 0.8; 95% CI: 0.5, 1.3) (Table 2). Children aged 3–6 years also had a 60% greater odds of asthma than older children with increasing urinary creatinine-corrected 2MHA concentrations (OR: 1.6; 95% CI: 0.9, 2.0 vs. 1.0; 95% CI: 0.6, 1.5); however, the age-by-2MHA interaction p value was nonsignificant (p = 0.39). Meanwhile, for every SD increase in urinary creatinine-corrected SBMA concentrations, both non-Hispanic white and black (OR: 2.0; 95% CI: 0.9, 4.3 and OR: 1.9; 95% CI: 1.0, 3.85) children had significantly increased odds of asthma compared to Hispanic and other racial/ethnic groups (OR: 0.5; 95% CI: 0.2, 1.1 and OR: 0.5; 95% CI: 0.2, 1.2), but the race-by-SBMA interaction p value was nonsignificant (p = 0.45). Hispanic, non-Hispanic white and black individuals (OR: 1.9; 95% CI: 0.7, 4.1; OR: 1.7; 95% CI: 0.6, 3.8 and OR: 1.3; 95% CI: 0.4, 3.9) also had a significantly greater odds of asthma than other races with increasing urinary creatinine-corrected HPMMA concentrations (OR: 0.5; 95% CI: 0.1, 1.6); however, the race-by-HPMMA interaction p value was nonsignificant (p = 0.34). The difference in current age and age of asthma diagnoses was not correlated with ln-transformed urinary mVOCs concentrations except CEMA (correlation coefficient: 0.17; p<0.05) (Tables S2).

Table 2

No nonlinear relationship was observed between all ln-transformed creatinine-corrected mVOCs concentrations and asthma (P for nonlinear >0.05, Fig. 3). As noted, 2MHA and CEMA had explicitly inverted U-shaped relationships with asthma, while SBMA showed a U-shaped relationship with asthma. 3HPMA showed S-shaped dose‒response curves with asthma. HPMMA had a linear plateau relationship with asthma.

Fig. 3. Association between ln-transformed urinary creatinine-corrected mVOCs concentrations and asthma.

The restricted cubic spline regression model with four knots located at the 5th, 35th, 65th, and 95th percentiles of ln-transformed urinary creatinine-corrected mVOCs concentrations. Odds ratios (red solid line) and 95 % confidence intervals (red shaded region) were estimated using the median ln-transformed urinary creatinine-corrected mVOCs concentration as the reference value. The horizontal dashed line represents to the reference odds ratio of 1.0. All of the models are adjusted for age (continuous), gender (binary), race/ethnicity (categorical), poverty to income ratio (continuous), ln-transformed serum cotinine concentration (continuous).

In this cross-sectional study, we observed some evidence that urinary mVOCs concentrations were weakly associated with increased asthma prevalence in US children between 3 and 12 years of age. Our findings indicate that gender significantly modified the associations between urinary 2MHA concentrations and asthma diagnosis. In secondary analyses, increasing urinary 2MHA concentrations were also associated with greater odds of asthma diagnosis in children aged 3–6 compared to children aged 7–12 years. Meanwhile, increasing urinary SBMA concentrations were also associated with greater odds of asthma diagnosis in non-Hispanic white and Black individuals compared to other races, and urinary HMPMA concentrations were also associated with greater odds of asthma diagnosis in Hispanic and non-Hispanic white individuals compared to other races. We did not find significant effect measure modifications of the associations between urinary mVOCs concentrations and asthma diagnosis based on age or race/ethnicity.

Of the few studies that measured urinary mVOCs levels in young children, we observed mVOCs levels in our study that were relatively similar to those reported in other studies[13, 16, 17]. Additionally, there have been relatively few studies examining the associations between mVOCs and asthma in young children[18]. A case‒control study reported that children in Guangzhou, China, with an average age of 8 years, had higher levels of VOCs exposure in their urine than healthy children, and those metabolites produced by VOCs exposure (2MHA,3HPMA and HPMMA) may be strongly associated with childhood asthma and increase the risk of childhood asthma[18]. Recently, a cross-sectional study from NHANES reported that urinary volatile organic compound metabolites of acrolein (CEMA, 3HPMA) and crotonaldehyde (HPMMA) were associated with reduced lung function in 1342 adults >18 years of age[19].

While the mechanisms by which VOCs increase asthma development are not completely elucidated, there is limited evidence to suggest that early-life exposure to VOCs could cause abnormal activation or overactivation of immune cells and further lead to autoimmune activation[20, 21]. Acrolein, the parent compound of CEMA and HPMMA, is a common toxic compound in smoke, is significantly associated with respiratory damage, and can cause smoke inhalation-induced pulmonary edema alone[22]. Additionally, acrolein exposure leads to high levels of mast cell toxicity and activation of calcium-dependent degranulation pathways in mast cells, while mast cell-derived histamine, leukotrienes and cytokines are key components of allergic inflammation and asthma[23]. Xylene, the parent compound of 2MHA, induces a type 2 helper T-cell (Th2) immune response by increasing the production of IL-4, IL-5, IL-13 and total IgE[24]. Th2 cell dominance is consistent with immune response patterns found in type 1 hypersensitivity disorders such as asthma[25]. However, a study also found no association between urinary 2MHA and SBMA concentrations and reduced lung function[19].

There were some limitations of this study. First, this study could not conclude the causal association between mVOCs and asthma due to the natural properties of the cross-sectional design. Because only some mVOCs were included in NHANES, the relationship between some mVOCs and childhood asthma in this study does not generalize the potential role of all mVOCs in the prevalence of childhood asthma. Second, not all mVOCs originated from environmental exposure. Thus, the extent of environmental exposure could not be assessed due to the lack of ambient VOC data. Although we observed evidence of an association between 2MHA, SBMA and HPMMA and odds of asthma in some races, there was also a large variability in the number of people per race, which resulted in less precise effect estimates compared to each race. Meanwhile, we observed evidence of an association between 2MHA and odds of asthma in children ages 3–6 years; there were relatively fewer children with asthma in this age category, which resulted in larger standard errors and less precise effect estimates compared to 7-12-year-old children. This study relied on parent-reported questionnaires to identify asthma in children, which may result in misclassification of the outcome, thus potentially attenuating these results. Due to limitations in the survey design of NHANES, there are many potential confounders that we did not have available for model adjustment, such as glomerular filtration rate, parental history of asthma and breastfeeding duration; therefore, there is potential residual confounding from unmeasured or unknown factors. Finally, NHANES is a cross-sectional survey that limits the ability to establish the temporality of the exposure and outcome sequence. Urinary mVOCs can persist in the body for years, and we cannot discern whether exposure to VOCs occurred before or after asthma development.

There are substantial gaps in our knowledge regarding the relationship between mVOCs and asthma risk in children. Although we did not observe an overall significant association between urinary mVOCs concentrations and childhood asthma, we did find an association between 2MHA and HPMMA and asthma in female children, and the association between the five mVOCs and asthma varied by race, such that SBMA was associated with asthma in non-Hispanic whites and blacks; in Hispanic and non-Hispanic whites, HPMMA was also associated with the development of asthma. Given the ubiquitous exposure observed in US children, this association warrants further investigation. Future studies could use prospective cohorts to examine links of repeated mVOCs measurements from early infancy into adolescence with immune markers and allergy- and asthma-related health outcomes. This would help determine if there are periods of heightened susceptibility to VOCs exposure for asthma risk and enhance our knowledge of the role VOCs exposure may play in immune and asthma development and morbidity in children.

A cross-sectional analysis of a representative sample of US children aged 3-12 years found that urinary VOC metabolites of acrolein (CEMA and 3PHMA), crotonaldehyde (HPMMA), toluene (SBMA), and xylene (2MHA) were associated with childhood asthma, and in particular, 2MHA was significantly associated with the prevalence of asthma in female children. Future studies should include prospective studies of repeated exposures to confirm these associations and examine the underlying mechanisms. Studies should also examine whether reducing children's exposure to VOCs helps prevent the asthma associated with VOCs found in this study.

2MHA: 2-Methylhippuric acid; 3HPMA: N-Acetyl-S-(3-hydroxypropyl)-L-cysteine; CDC: Centers for Disease Control and Prevention; CEMA: N-Acetyl-S-(2-carboxyethyl)-L-cysteine; GM: Geometric means; HPMMA: N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine; IQR: Interquartile range; LLOD: Lower limit of detection; NCHS: National Center for Health Statistics; NCHS: National Center for Health Statistics; NHANES: National Health and Nutrition Examination Surveys; mVOCs: Metabolites of VOCs; OR: Odds ratio; RCS: Restricted cubic spline; SBMA: N-Acetyl-S-(benzyl)-L-cysteine; SD: Standard deviation; VOCs: Volatile organic compounds

Acknowledgements

We thank the staff and participants of the NHANES for their contributions to this work.

Funding

This study was supported by grants from the Key Research and Development Program of Sichuan Province (2022YFS0132), the National Natural Science Foundation of China (81970715), and Yunnan Provincial Cardiovascular Disease Clinical Medical Center Project (No. FZX2019-06-01, 2022YFKY078).

Availability of data and materials

The datasets generated and analyzed during the current study are available in the NHANES repository, https://wwwn.cdc.gov/nchs/nhanes/Default.aspx.

Authors’ contributions

YX analyzed and interpreted the data, and was a major contributor in writing the manuscript. TL made substantial contributions to the concept and design, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The consent form was signed by participants in the survey, and participants consented to storing specimens of their blood for future research. The CDC/NCHS Ethics Review Board (ERB) approved the NHANES study and gave approval for public dissemination.

Consent for publication

Not applicable.

Competing interest

The authors declare that they have no competing interests.

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Table 1 Geometric mean (IQR) urine mVOCs concentrations (ng/mL) in children aged 3–12 years according to demographic characteristics (N = 1559): NHANES 2011–2018.

Characteristics	N (weighted%)	2MHA GM (IQR)	SBMA GM (IQR)	CEMA GM (IQR)	3PHMA GM (IQR)	HPMMA GM (IQR)
Overall	1559	19.8 (9.1, 36.6)	5.9 (3.3, 11.3)	68.3 (39.0, 135.0)	187.9 (103.0, 391.0)	176.8 (98.9, 319.0)
Asthmatics	247 (17)	22.0 (10.5, 37.5)	6.8 (3.2, 12.9)	75.6 (44.6, 139.0)	214.3 (113.0, 392.0)	197.9 (104.0, 338.0)
Non-asthmatics	1312 (83)	19.4 (9.0, 36.2)	5.7 (3.3, 11.2)	67.0 (38.3, 134.0)	183.1 (100.3, 389.8)	172.9 (97.5, 312.0)
Age, years (mean ± sd)	7.6 ± 0.1
3-6	600 (24)	18.6 (8.4, 34.9)	5.7 (3.1, 10.5)	59.4 (32.5, 119.8)	180.9 (92.3, 362.0)	175.0 (90.1, 306.8)
7-12	959 (76)	20.2 (9.5, 37.5)	6.0 (3.5, 11.8)	71.4 (42.8, 145.0)	190.2 (112.0, 404.0)	177.4 (98.5, 304.2)
Gender
Male	780 (52)	20.6 (9.7, 37.4)	5.8 (3.2, 10.3)	69.8 (41.1, 139.0)	192.2 (108.0, 389.0)	183.6 (106.5, 322.5)
Female	779 (48)	18.9 (8.8, 36.0)	6.0 (3.4, 12.4)	66.8 (37.4, 132.0)	183.5 (99.9, 393.0)	169.8 (91.1, 315.0)
Race/Ethnicity
Hispanic	488 (25)	17.2 (8.3, 33.7)	5.9 (3.0, 10.0)	68.7 (36.0, 123.0)	191.7 (100.0, 359.5)	175.7 (89.9, 317.3)
White, non-Hispanic	418 (50)	20.5 (10.0, 39.4)	5.1 (2.7, 9.5)	60.6 (36.1, 107.0)	162.5 (93.9, 309.0)	165.3 (96.2, 295.5)
Black, non-Hispanic	400 (14)	22.5 (10.7, 39.1)	9.9 (5.0, 17.2)	106.6 (55.7, 182.8)	258.6 (121.8, 455.8)	216.1 (122.3, 341.0)
Other	253 (10)	19.8 (7.9, 32.0)	5.9 (3.1, 10.4)	65.3 (30.9, 118.5)	234.3 (108.0, 454.0)	189.2 (91.2, 324.5)
Poverty:Income^a
Poor	739 (36)	20.3 (9.1, 37.7)	6.7 (3.4, 12.4)	76.0 (40.2, 150.0)	206.4 (105.0, 416.0)	189.0 (98.3, 335.0)
Nearly poor	201 (13)	16.7 (8.0, 31.9)	5.8 (3.1, 9.8)	70.7 (36.3, 131.0)	189.7 (94.8, 375.5)	173.5 (89.0, 301.0)
Not poor	619 (51)	20.3 (9.6, 35.4)	5.4 (3.3, 10.8)	62.9 (38.3, 123.0)	175.6 (103.0, 362.0)	169.6 (101.0, 303.0)

Abbreviations: NHANES: National Health and Nutrition Examination Survey, IQR: interquartile range, GM: geometric mean, VOC: volatile organic compound, 2MHA: 2-Methylhippuric acid, SBMA: N-Acetyl-S-(benzyl)-L-cysteine, CEMA: N-Acetyl-S-(2-carboxyethyl)-L-cysteine, 3HPMA: N-Acetyl-S-(3-hydroxypropyl)-L-cysteine, and HPMMA: N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine, SD: standard deviation.

^a Ratio of family income to poverty.

Table 2 Unadjusted and adjusted ORs for parent-reported asthma diagnosis among children aged 3–12 years per SD increase in ln-transformed urinary creatinine-corrected mVOCs concentrations (n = 1559): NHANES (2011–2018).

	2MHA	p	SBMA	p	CEMA	p	3HPMA	p	HPMMA	p
Unadjusted	1.3 (0.9, 1.7)		1.2 (0.9, 1.7)		1.3 (0.9, 1.8)		1.3 (0.9, 1.8)		1.3 (0.9, 1.8)
Multipollutant^a	1.2 (0.8, 1.6)		1.1 (0.7, 1.6)		1.1 (0.6, 2.0)		1.0 (0.5, 2.0)		1.1 (0.6, 1.8)
Adjusted^b	1.1 (0.8, 1.6)		1.2 (0.8, 1.7)		1.1 (0.6, 1.7)		1.1 (0.7, 1.8)		1.2 (0.7, 2.0)
Multipollutant	1.1 (0.8, 1.6)		1.1 (0.7, 1.7)		0.9 (0.5, 1.7)		1.0 (0.5, 2.0)		1.2 (0.6, 2.1)
Age		0.39		0.48		0.57		0.97		0.58
Age2-6	1.6 (0.9, 2.0)		1.0 (0.4, 1.9)		0.7 (0.3, 1.9)		1.3 (0.5, 3.1)		1.0 (0.4, 2.4)
Age7-12	1.0 (0.6, 1.5)		1.2 (0.7, 1.9)		1.1 (0.6, 2.0)		0.9 (0.5, 1.7)		1.1 (0.6, 2.1)
Gender		*0.02*		0.63		0.33		0.54		0.23
Male	0.8 (0.5, 1.3)		1.1 (0.6, 1.8)		0.8 (0.4, 1.7)		1.3 (0.7, 2.5)		0.9 (0.4, 1.7)
Female	1.8 (1.1, 3.1)		1.2 (0.7, 2.2)		1.2 (0.6, 2.8)		0.9 (0.4, 1.9)		1.9 (0.8, 4.4)
Race/Ethnicity		0.12		0.45		0.31		0.95		0.34
Hispanic	0.9 (0.5, 1.8)		0.5 (0.2, 1.1)		0.8 (0.3, 2.2)		0.9 (0.4, 2.5)		1.9 (0.7, 4.1)
White, non-Hispanic	0.8 (0.4, 1.6)		2.0 (0.9, 4.3)		1.0 (0.3, 2.6)		1.6 (0.5, 3.4)		1.7 (0.6, 3.8)
Black, non-Hispanic	1.7 (0.9, 3.1)		1.9 (1.0, 3.8)		0.8 (0.3, 2.2)		1.3 (0.5, 3.2)		1.3 (0.4, 3.9)
Other	1.5 (0.7, 3.4)		0.5 (0.2, 1.2)		1.6 (0.5, 3.2)		0.8 (0.2, 2.2)		0.5 (0.1, 1.6)

Abbreviations: OR: odds ratio, mVOCs: metabolites of volatile organic compounds, NHANES: National Health and Nutrition Examination Survey, SD: standard deviation, 2MHA: 2-Methylhippuric acid, SBMA: N-Acetyl-S-(benzyl)-L-cysteine, CEMA: N-Acetyl-S-(2-carboxyethyl)-L-cysteine, 3HPMA: N-Acetyl-S-(3-hydroxypropyl)-L-cysteine, and HPMMA: N-Acetyl-S-(3-hydroxypropyl-1-methyl)-L-cysteine,

p: age, gender, and race/ethnicity-mVOCs interaction p-value.

Total sample size n = 1509.

^a Regression models adjusted for other serum VOC concentrations.

^b Regression models adjusted for gender, age, race/ethnicity, poverty to income ratio, and serum cotinine.

No competing interests reported.

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The urinary metabolites of volatile organic compounds and asthma in young children: NHANES 2011-2018

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