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. Author manuscript; available in PMC: 2024 Oct 15.
Published in final edited form as: Environ Res. 2023 Jul 5;235:116560. doi: 10.1016/j.envres.2023.116560

Exposure to Dust Organophosphate and Replacement Brominated Flame Retardants During Infancy and Risk of Subsequent Adverse Respiratory Outcomes

Angelico Mendy 1, Zana Percy 1, Joseph M Braun 2, Bruce Lanphear 3, Mark J La Guardia 4, Robert Hale 4, Kimberly Yolton 5, Aimin Chen 6
PMCID: PMC10528780  NIHMSID: NIHMS1919855  PMID: 37419195

Abstract

BACKGROUND:

Children are highly exposed to flame retardants in indoor environments, partly through inhalation. However, the associations of early life exposure to novel organophosphate (OPFRs) and replacement brominated flame retardants (RBFRs) with adverse respiratory outcomes during childhood are unclear.

METHODS:

We used a prospective birth cohort of 234 children recruited from the greater Cincinnati, Ohio metropolitan area between 2003 and 2006. OPFRs and RBFRs were analyzed in dust sampled from home’s main activity room and child bedroom floors at child age 1 year. Caregivers reported subsequent respiratory symptoms every six months until child age 5 years and we measured forced expiratory volume in 1 second as well as peak expiratory flow (PEF) at child age 5 years. We performed generalized estimating equations and linear regression modeling adjusted for covariates to examine the exposure-outcome associations.

RESULTS:

Geometric means (GMs) (standard error [SE]) for dust concentrations were 10.27 (0.63) μg/g for total OPFRs (ΣOPFRs) and 0.48 (0.04) μg/g for total RBFRs (ΣRBFRs); GMs (SE) for dust loadings were 2.82 (0.26) μg/m2 for ΣOPFRs and 0.13 (0.01) μg/m2 for ΣRBFRs. Dust ∑OPFRs concentrations at age 1 year were associated with higher subsequent risks of wheezing (relative risk [RR]: 1.68, 95% confidence interval [CI]: 1.20–2.34), respiratory infections (RR: 4.01, 95% CI: 1.95–8.24), and hay fever/allergies (RR: 1.33, 95% CI: 1.10–1.60), whereas ∑OPFRs dust loadings at age 1 year were associated with higher risks of subsequent respiratory infections (RR: 1.87, 95% CI: 1.05–3.34) and hay fever/allergies (RR: 1.34, 95% CI: 1.19–1.51). PEF (mL/min) was lower with higher ∑OPFRs dust loadings (β: −12.10, 95% CI: −21.10, −3.10) and with the RBFR bis(2-ethylhexyl) tetrabromophthalate (β: −9.05, 95% CI: −17.67, −0.43).

CONCLUSIONS:

Exposure to OPFRs and RBFRs during infancy may be a risk factor for adverse respiratory outcomes during childhood.

Keywords: Replacement Flame Retardants, Respiratory Health, Early Life Exposures

INTRODUCTION

Flame retardants are chemicals added to a wide variety of polymeric household products to reduce their flammability and minimize the risk of fire (Stapleton et al., 2009). They are commonly found in insulation, furniture, carpets, car seats, textiles, electric and electronic appliances, and other consumer products (Ospina et al., 2018). Flame retardants are not covalently bound to polymers and can leach into house dust where they accumulate due to their slow degradation; they can also be released into the air by volatilization and deposit on surfaces (Van den Eede et al., 2011). Weathering and fragmentation of polymer products expedite the release of these additives and generate small particles (microplastics) with physical dimensions that can facilitate human ingestion and inhalation (Hale et al., 2022).

Previously, polybrominated diphenyl esters (PBDEs) were used as flame retardants, but were phased out by 2013 due to their environmental persistence and association with endocrine, reproductive, neurodevelopmental, as well as carcinogenic effects in humans (Blum et al., 2019; Zuiderveen et al., 2020). Nonetheless, PBDEs still persist in the environment and may be released from long-lived household products (Hale et al., 2022). Substitutes to PBDEs include organophosphate (OPFRs) and replacement brominated flame retardants (RBFRs) (Blum et al., 2019; Zuiderveen et al., 2020). Common OPFRs are tris(2-chloroethyl) phosphate (TCEP), and tris(1-chloro-2-propyl) phosphate (TCIPP), tris(1,3-dichloroisopropyl) phosphate (TDCIPP), and triphenyl phosphate (TPHP) and these OPFRs were already in popular use prior to PBDEs phaseout (Blum et al., 2019). Common RBFRs are 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP) (Zuiderveen et al., 2020). The production of OPFRs and RBFRs has significantly increased since 2013, leading to widespread human exposure (Li et al., 2019).

Inhalation of volatile or semi-volatile compounds directly or via contaminated dust are major exposure routes to flame retardants and have raised concerns for respiratory health, especially in children (Schreder et al., 2016). Young children inhale more chemicals per body weight than adults, ingest twice as much dust as adults due to their frequent hand-to-mouth activity, and have immature respiratory as well as immune systems (Selevan et al., 2000). Additional causes for respiratory concerns associated with OPFRs and RBFRs include their potential to cause irritation, oxidative stress, bronchoconstriction through acetylcholinesterase inhibition or M2 muscarinic receptor function, endocrine disruption, and epigenetic alterations of genes associated with bronchoconstriction and airway inflammation (Canbaz et al., 2016; Chen et al., 2015a; Paul et al., 2018). Yet, the respiratory effects of RBFRs have not been previously investigated. The few existing studies on OPFRs and respiratory outcomes have mostly been cross-sectional or case-control in design and/or have not included lung function assessments (Araki et al., 2014; Araki et al., 2018; Canbaz et al., 2016; Navaranjan et al., 2021; Leijs et al., 2018). Studies on these chemicals’ content in dust have also not examined dust chemicals’ loadings, despite reports that these are better exposure predictors than dust chemical concentrations, because they combine the concentration of chemical in dust and the dust amount in the sampled area (De Voogt, 2015; Lanphear et al., 1995). Environmental exposure assessments are also immune to pharmacokinetic confounding and can be used to develop environmental standards for health effects (Weisskopf & Webster, 2017).

METHODS

Study Population

The Health Outcomes and Measures of the Environment (HOME) Study is a prospective pregnancy and birth cohort designed to determine the influence of early life environmental exposures on children’s health (Braun et al., 2017). The HOME study enrolled pregnant women between March 2003 and January 2006 from the Greater Cincinnati, Ohio metropolitan area. The expectant mothers were identified through the medical scheduling systems of nine prenatal practices affiliated with three hospitals. They were eligible for inclusion if they were 18-years or older, fluent in English, resided in the study region with no plan of moving for the next year, were less than 16 weeks pregnant, did not live in a trailer or mobile home, and were HIV negative. Additional inclusion criteria consisted of not taking medication for thyroid disease or convulsions, planning to deliver at participating clinics and hospitals, not having diabetes, bipolar disorder, schizophrenia, or cancer treated with radiotherapy or chemotherapy. The enrollment was designed to include 50% of women from the city of Cincinnati, 38% from surrounding suburbs, and 12% from rural areas; African Americans were oversampled to 31% to allow for examination of potential health disparities. A detailed description of the cohort has been published elsewhere (Braun et al., 2017). Among the 401 mother-child pairs included in the HOME Study, 234 children had complete data on dust flame retardants at age 1 year, on covariates, and on respiratory outcomes measurements during follow-up until age 5 years and were included in our analysis.

Dust OPFRs and RBFRs Measurements

Settled dust was collected from the home’s main activity room and from child bedroom floor using high volume small surface sampler when the child was age 1 year. It was stored at −20 °C before shipping to the Virginia Institute of Marine Sciences for analysis (La Guardia & Hale, 2015). Sieved dust (at 300 μm) was purified and analyzed by high-performance liquid chromatography mass spectrometry (HPLC-MS) to quantify the concentrations of the OPFRs (TCEP, TCIPP, TDCIPP, and TPHP) and RBFRs (EH-TBB and BEH-TEBP). The limit of detection (LOD) was 0.10 μg/g dust for OPFRs and 0.0002 μg/g dust for RBFRs. Quality control was performed on all batches and recovery warning limits were estimated to 100% ± 2 standard deviations of the recovery rate distribution. Exposure concentrations with recovery rates outside of the recovery warning limits were excluded (4.2%) (Percy et al., 2020). Estimates were corrected by dividing by their recovery rates, and the batches were adjusted by subtracting the blank value from the uncorrected measurements if the blank value was >0.1 μg/g. We imputed concentrations < LOD with LOD/√2 (3.1% of samples) before recovery rate adjustment and blank subtraction which resulted in some concentrations corrected with values below the LOD (Hornung & Reed, 1990).

OPFRs and RBFRs dust loadings were calculated using the formula loading = (concentration [μg/g dust]) × (sieved dust weight [g dust]) / dust sampling area (m2). Total OPFR (∑OPFR) and total RBFR (∑RBFR) concentrations and loadings were calculated as the sum of the individual congeners (Percy et al., 2020). Additional details on the analytical and quality control methods are described elsewhere (Percy et al., 2020).

Respiratory Outcomes

Caregivers completed standardized questions assessing respiratory symptoms (wheeze, respiratory infections, and hay fever or allergies) which were based on the National Health and Nutrition Examination Survey (NHANES), a national survey by the Centers for Disease Control and Prevention (CDC) designed to assess the health status of the U.S. population (Mendy & Mersha, 2022; Mendy et al., 2020). The respiratory questionnaires were administered every six months until the child reached age 5 years. During a clinic visit at age 5 years, children completed spirometry with a portable spirometer, and ≥3 acceptable measures of forced expiratory volume in one second (FEV1) and of peak expiratory flow (PEF). We used spirometry acceptability criteria defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force, as described elsewhere (Miller et al., 2005).

Covariates

Given the multiple factors that could influence the associations between chemical exposures and children’s health, the HOME Study collected extensive data on variables such as child’s sex and race/ethnicity, birth weight, gestational age, median household income at baseline, and duration of breastfeeding, previously reported to be associated with exposure and/or outcomes (Rosas-Salazar & Hartert, 2017). Child’s sex and race/ethnicity, median household income at baseline, and duration of breastfeeding were assessed using survey questionnaires, while gestational age, birth weight, and anthropometric measures were abstracted from medical records. Prenatal exposure to tobacco smoke was assessed using serum cotinine analyzed in the pregnant mothers at 16- and 26-weeks’ gestation. Anthropometry measurements including weight and height were performed annually until age 5 years. Additional variables such as cleanliness and clutter, assessed through visual inspection, were used in sensitivity analysis; we categorized cleanliness into 1) clean appearance, 2) Some evidence of housecleaning, and 3) no evidence of housecleaning and we classified clutter into low, moderate, and high (Braun et al., 2017).

Statistical Analysis

We performed descriptive analyses to examine the distribution of dust OPFRs and RBFRs concentrations and loadings overall and for different subgroups of study participants. We reported the geometric means (GMs) along with corresponding standard errors (SE) and estimated P-values for the differences in exposure levels using the Wilcoxon Rank Test. Given the skewed distribution of OPFRs and RBFRs dust concentrations and loadings, we applied log10-transformation to improve the distribution normality. We explored the intercorrelation between the dust concentrations, the dust loadings, and the dust concentrations and loadings. Generalized estimating equation (GEE) analysis was used to determine the association of dust OPFRs and RBFRs concentrations and loadings at age 1 year with the subsequent repeated reports of wheezing, respiratory infections, and hay fever or allergy. We selected a log-binomial distribution for the models, due to the longitudinal repeated measures and binary nature of the outcomes. We also specified an unstructured working matrix and robust variance estimators to calculate the β coefficients which were exponentiated to obtain the relative risks (RR) and their corresponding 95% confidence intervals (CI). We used linear regression modeling to estimate the β regression coefficients for the associations of the exposures at age 1 year with FEV1 and PEF at age 5 years. We adjusted the models for child’s birth weight, gestational age, family household income at baseline, duration of breastfeeding, prenatal exposure to tobacco measured by serum cotinine, and total dust weight, used as continuous variables as well as for child’s sex and race/ethnicity used as categorical variables. The models for the association of the exposures with lung function were additionally adjusted for the child’s height at age 5 years. In sensitivity analysis reported in the online supplement, we further adjusted for clutter and cleanliness. We performed the analyses in SAS (version 9.4, SAS Institute, Cary, NC) and generated restricted cubic splines for the dose-response relationship between the dust flame retardants and the adverse respiratory outcomes using the postrcspline package in Stata (version 17, StataCorp, College Station, TX). Two-sided P values < 0.05 were considered significant in all analyses.

RESULTS

Overall distribution of dust OPFRs and RBFRs concentrations and loadings

Among the 234 children included in the study, total OPFRs (ΣOPFRs) GMs (SE) were 10.27 (0.63) μg/g dust for dust concentrations and 2.82 (0.26) μg/m2 for dust loadings. The levels of OPFRs dust concentrations and loadings were highest for TCIPP, followed by TDCIPP, TPHP, and TCEP. Total RBFRs (ΣRBFRs) GMs (SE) were 0.48 (0.04) μg/g dust for dust concentrations and 0.13 (0.01) μg/m2 for dust loadings and the levels of RBFRs dust concentrations and loadings were higher for BEH-TEBP than EH-TBB (Table 1).

Table 1:

Distribution of replacement flame retardants in dust (N = 234)

Flame retardants Dust concentration (μg/g dust) Dust Loadings (μg/m2)
GM (SE) 5th-95th percentile GM (SE) 5th-95th percentile
∑OPFRs 10.27 (0.63) 2.35 – 47.13 2.82 (0.26) 0.29 – 30.54
 TCEP 1.07 (0.09) 0.08 – 9.26 0.30 (0.03) 0.02 – 3.77
 TCIPP 2.33 (0.21) 0.26 – 21.25 0.66 (0.08) 0.04 – 13.57
 TDCIPP 2.23 (0.16) 0.44 – 13.14 0.64 (0.07) 0.06 – 8.47
 TPHP 1.81 (0.13) 0.34 – 9.66 0.48 (0.04) 0.07 – 5.05
∑RBFRs 0.48 (0.04) 0.07 – 4.72 0.13 (0.01) 0.01 – 1.83
 EH-TBB 0.16 (0.02) 0.02 – 2.81 0.04 (0.01) 0.00 – 0.91
 BEH-TEBP 0.27 (0.02) 0.04 – 1.66 0.08 (0.01) 0.01 – 0.80
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Abbreviations: GM: geometric mean, SE: standard error, TCEP: tris(2-chloroethyl) phosphate, TCIPP: tris(1-chloro-2-propyl) phosphate, TDCIPP: tris(1,3-dichloroisopropyl) phosphate, TPHP: triphenyl phosphate, EH-TBB: 2-ethylhexyl-2,3,4,5-tetrabromobenzoate, BEH-TEBP: bis(2-ethylhexyl) tetrabromophthalate

Dust OPFRs and RBFRs by characteristics of study participants

Flame-retardants dust concentrations were higher in non-Hispanic White than non-Hispanic Black participants for TCEP and TCIPP, in those with annual household income between $50,000 and $75,000 compared to <$50,000 for TCIPP, and in participants with paternal or maternal asthma than without parental asthma for TCEP and EH-TBB. The flame retardants dust concentrations were also higher in children who were breastfed compared to those who were not for TCIPP and EH-TBB and in children with maternal serum cotinine during pregnancy <0.10 ng/mL versus 0.10 to 10 ng/mL or >10 ng/mL for TCEP, TCIPP, and BEH-TEBP. In contrast, dust OPFRs and RBFRs loadings were higher in non-Hispanic Black and/or ‘other’ race/ethnicity participants than in non-Hispanic White participants for TDCIPP, TPHP, and EH-TBB and in those with annual household income <$50,000 versus higher for TDCIPP and TPHP (Table 2).

Table 2:

Dust ORFRs and RBFRs concentrations overall and by characteristics of study participants – HOME Study (N = 234)

Characteristics Dust Flame-Retardant Concentrations (μg/g dust) Dust Flame-Retardants Loadings (μg/m2)
% OPFRs RBFRs OPFRs RBFRs
TCEP TCIPP TDCIPP TPHP EH-TBB BEH-TEBP TCEP TCIPP TDCIPP TPHP EH-TBB BEH-TEBP
Child’s sex
 Male 42.7 1.15 (0.14) 2.09 (0.25) 2.10 (0.20) 1.83 (0.17) 0.15 (0.02) 0.26 (0.02) 0.34 (0.05) 0.63 (0.09) 0.63 (0.09) 0.52 (0.06) 0.04 (0.01) 0.08 (0.01)
 Female 57.3 0.97 (0.11) 2.70 (0.36) 2.42 (0.25) 1.79 (0.19) 0.18 (0.03) 0.29 (0.04) 0.25 (0.04) 0.71 (0.13) 0.64 (0.10) 0.43 (0.07) 0.04 (0.01) 0.07 (0.01)
Race/ethnicity
 NH-White 66.2 1.37 (0.13) 2.83 (0.31) 2.37 (0.21) 1.88 (0.15) 0.16 (0.02) 0.30 (0.03) 0.30 (0.04) 0.62 (0.08) 0.53 (0.06) 0.39 (0.04) 0.03 (0.004) 0.06 (0.01)
 NH-Black 27.8 0.61 (0.10) 1.53 (0.27) 1.97 (0.25) 1.56 (0.23) 0.15 (0.03) 0.22 (0.03) 0.29 (0.07) 0.75 (0.19) 0.95 (0.21) 0.71 (0.15) 0.07 (0.02) 0.10 (0.02)
 Hispanic and Other 6.0 1.00 (0.35) 2.11 (0.48) 2.14 (0.60) 2.33 (0.60) 0.26 (0.12) 0.24 (0.08) 0.30 (0.16) 0.66 (0.32) 0.70 (0.27) 0.74 (0.23) 0.10 (0.05) 0.09 (0.005)
Term
 Preterm 9.4 0.67 (0.21) 1.68 (0.60) 2.12 (0.58) 2.13 (0.47) 0.13 (0.04) 0.20 (0.05) 0.19 (0.08) 0.47 (0.17) 0.59 (0.21) 0.58 (0.14) 0.04 (0.01) 0.06 (0.02)
 Normal term 90.6 1.12 (0.10) 2.41 (0.22) 2.24 (0.16) 1.78 (0.13) 0.16 (0.02) 0.28 (0.02) 0.32 (0.04) 0.69 (0.08) 0.64 (0.07) 0.47 (0.05) 0.04 (0.01) 0.08 (0.01)
Birth weight
 Low 5.1 0.87 (0.37) 2.09 (0.71) 3.27 (0.96) 2.26 (0.66) 0.12 (0.04) 0.21 (0.06) 0.30 (0.16) 0.72 (0.34) 1.12 (0.39) 0.74 (0.25) 0.04 (0.01) 0.07 (0.02)
 Normal 79.5 1.10 (0.11) 2.37 (0.24) 2.23 (0.18) 1.77 (0.14) 0.17 (0.02) 0.28 (0.02) 0.31 (0.04) 0.68 (0.09) 0.65 (0.08) 0.47 (0.05) 0.05 (0.01) 0.08 (0.01)
 High 15.4 0.97 (0.18) 2.22 (0.52) 1.97 (0.30) 1.91 (0.29) 0.14 (0.04) 0.26 (0.05) 0.24 (0.07) 0.55 (0.16) 0.49 (0.12) 0.46 (0.11) 0.03 (0.01) 0.06 (0.01)
Household income ($)
 <$50,000 44.4 0.88 (0.12) 1.80 (0.26) 2.32 (0.23) 1.75 (0.19) 0.15 (0.02) 0.26 (0.03) 0.31 (0.05) 0.66 (0.13) 0.85 (0.13) 0.61 (0.09) 0.05 (0.01) 0.09 (0.02)
 $50,000 to $74,999 15.0 1.22 (0.22) 3.31 (0.70) 2.02 (0.34) 1.70 (0.30) 0.16 (0.03) 0.30 (0.06) 0.31 (0.08) 0.83 (0.22) 0.52 (0.12) 0.40 (0.08) 0.04 (0.01) 0.08 (0.02)
 $75,000+ 40.6 1.26 (0.16) 2.73 (0.35) 2.22 (0.26) 1.92 (0.21) 0.17 (0.02) 0.28 (0.03) 0.29 (0.05) 0.61 (0.10) 0.50 (0.08) 0.40 (0.06) 0.04 (0.01) 0.06 (0.01)
Paternal asthma
 No 68.8 1.10 (0.12) 2.21 (0.24) 2.09 (0.19) 1.84 (0.16) 0.14 (0.02) 0.26 (0.02) 0.33 (0.05) 0.67 (0.10) 0.64 (0.08) 0.52 (0.06) 0.04 (0.01) 0.08 (0.01)
 Yes 31.2 0.99 (0.12) 2.64 (0.42) 2.59 (0.25) 1.75 (0.20) 0.21 (0.03) 0.31 (0.04) 0.24 (0.05) 0.64 (0.13) 0.64 (0.10) 0.41 (0.06) 0.05 (0.01) 0.08 (0.01)
Maternal asthma
 No 55.12 0.87 (0.09) 2.29 (0.27) 1.96 (0.18) 2.00 (0.20) 0.16 (0.02) 0.27 (0.03) 0.26 (0.04) 0.70 (0.11) 0.60 (0.08) 0.56 (0.07) 0.05 (0.01) 0.08 (0.01)
 Yes 44.87 1.38 (0.18) 2.38 (0.32) 2.62 (0.28) 1.61 (0.15) 0.15 (0.02) 0.28 (0.03) 0.36 (0.06) 0.61 (0.11) 0.69 (0.10) 0.40 (0.05) 0.04 (0.01) 0.07 (0.01)
Breastfed
 No 14.5 0.80 (0.23) 1.48 (0.43) 1.63 (0.35) 1.53 (0.36) 0.08 (0.02) 0.18 (0.04) 0.37 (0.13) 0.73 (0.29) 0.78 (0.24) 0.70 (0.18) 0.04 (0.01) 0.09 (0.02)
 Yes 85.5 1.12 (0.10) 2.53 (0.23) 2.36 (0.17) 1.86 (0.13) 0.18 (0.02) 0.29 (0.02) 0.29 (0.03) 0.65 (0.08) 0.61 (0.07) 0.46 (0.05) 0.04 (0.01) 0.07 (0.01)
Serum cotinine *
 < 0.10 71.8 1.26 (0.12) 2.68 (0.28) 2.27 (0.19) 1.84 (0.15) 0.18 (0.02) 0.30 (0.03) 0.31 (0.04) 0.67 (0.08) 0.57 (0.06) 0.44 (0.04) 0.04 (0.01) 0.07 (0.01)
 0.10 to 10 20.5 0.86 (0.17) 1.57 (0.32) 2.24 (0.33) 1.78 (0.32) 0.14 (0.03) 0.26 (0.04) 0.33 (0.10) 0.63 (0.21) 0.87 (0.24) 0.63 (0.17) 0.05 (0.02) 0.10 (0.03)
 > 10 7.7 0.45 (0.11) 1.91 (0.64) 1.87 (0.41) 1.65 (0.31) 0.08 (0.03) 0.14 (0.04) 0.15 (0.06) 0.71 (0.31) 0.71 (0.27) 0.60 (0.16) 0.03 (0.01) 0.05 (0.02)
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Abbreviation: NH: Non-Hispanic; TCEP: tris(2-chloroethyl) phosphate, TCIPP: tris(1-chloro-2-propyl) phosphate, TDCIPP: tris(1,3-dichloroisopropyl) phosphate, TPHP: triphenyl phosphate, EH-TBB: 2-ethylhexyl-2,3,4,5-tetrabromobenzoate, BEH-TEBP: bis(2-ethylhexyl) tetrabromophthalate.

Bold indicates significant difference in dust flame retardant concentrations or loadings across participants’ characteristics.

Intercorrelations between dust OPFRs and RBFRs concentrations and loadings

Separately, dust concentrations and loadings were highly correlated across multiple compounds as shown in Figures 1A and 1B. In addition, the correlations between dust concentrations and loadings were high for EH-TBB (r = 0.67), TCEP (r = 0.63), and TCIPP (r = 0.66) (Figure 1C).

Figure 1:

Figure 1:

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Heatmap for intercorrelation between dust OPFRs and RBFRs concentrations and loadings.

OPFRs and RBFRs Dust Concentrations and Loadings and Respiratory Outcomes

∑OPFRs dust concentrations at age 1 year were associated with higher risks of subsequent wheezing (RR: 1.68, 95% CI: 1.20–2.34), respiratory infections (RR: 4.01, 95% CI: 1.95–8.24), and hay fever or allergies (RR: 1.33, 95% CI: 1.10–1.60). The risk of wheeze was increased by 30% with log10-TCIPP dust concentrations (RR: 1.30, 95% CI: 1.03–1.64) and by 51% with log10-TDCIPP dust concentrations (RR: 1.51, 95% CI: 1.15–1.98). The risk of respiratory infections was 2.59 times as high with a 10-fold increase in TDCIPP dust concentrations (RR: 2.59, 95% CI: 1.42–4.71). The risk of hay fever or allergies was increased by 20% to 27% with log10-TCEP dust concentrations (RR: 1.27, 95% CI: 1.12–1.44), log10 TCIPP (RR: 1.20, 95% CI: 1.05–1.36), and log10 TDCIPP (RR: 1.21, 95% CI: 1.03–1.43) (Table 3). OPFRs and RBFRs dust concentrations were not associated with impaired lung function (Table 4).

Table 3:

Relative risks for association of dust OPFRs and RBFRs at child age of 1 year with the frequency of subsequently reported respiratory symptoms, HOME Study

Exposures Log10 Dust Flame-Retardant Concentrations Log10 Dust Flame-Retardant Loadings
Wheeze Respiratory infections Hay fever/allergies Wheeze Respiratory infections Hay fever/allergies
∑OPFR 1.68 (1.20, 2.34) ** 4.01 (1.95, 8.24) *** 1.33 (1.10, 1.60) ** 1.13 (0.92, 1.38) 1.87 (1.05, 3.34) * 1.34 (1.19, 1.51) ***
TCEP 1.16 (0.96. 1.41) Not computed 1.27 (1.12, 1.44) *** 1.02 (0.87, 1.19) 1.28 (0.85, 1.93) 1.30 (1.18, 1.43) ***
TCIPP 1.30 (1.03, 1.64) * 1.10 (0.54, 2.22) 1.20 (1.05, 1.36) ** 1.06 (0.91, 1.24) 1.05 (0.70, 1.57) 1.25 (1.14, 1.37) ***
TDCIPP 1.51 (1.15, 1.98) ** 2.59 (1.42, 4.71) ** 1.21 (1.03, 1.43) * 1.10 (0.92, 1.31) 1.54 (0.97, 2.46) 1.28 (1.15, 1.42) ***
TPHP 0.96 (0.73, 1.27) 1.20 (0.57, 2.53) 0.99 (0.84, 1.16) 0.93 (0.76, 1.14) 1.18 (0.65, 2.15) 1.13 (1.00, 1.28) *
∑BFR 1.17 (0.94, 1.46) Not computed 0.98 (0.85, 1.12) 1.00 (0.84, 1.19) 1.32 (0.94, 1.85) 1.10 (0.99, 1.22)
EH-TBB 1.01 (0.84, 1.22) Not computed 0.99 (0.88, 1.11) 0.93 (0.80, 1.09) 1.34 (1.01, 1.79) * 1.08 (0.98, 1.19)
BEH-TEBP 1.25 (0.97, 1.59) Not computed 0.98 (0.85, 1.12) 1.02 (0.85, 1.23) 1.29 (0.91, 1.82) 1.12 (1.00, 1.24) *
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*

P < 0.05

**

P < 0.01

***

P < 0.001

Not computed = relative risk not reported because the models did not converge.

Abbreviations: TCEP: tris(2-chloroethyl) phosphate, TCIPP: tris(1-chloro-2-propyl) phosphate, TDCIPP: tris(1,3-dichloroisopropyl) phosphate, TPHP: triphenyl phosphate, EH-TBB: 2-ethylhexyl-2,3,4,5-tetrabromobenzoate, BEH-TEBP: bis(2-ethylhexyl) tetrabromophthalate.

Models adjusted for child’s sex, child’s race/ethnicity, child’s birth weight, child’s gestational term, family income, breastfeeding, and child’s height.

Bold indicates significant association between exposures and reported respiratory outcomes.

Table 4:

Linear regression coefficients for association of dust OPFR and RBFR at child age of 1 year with FEV1 and PEF at 5 years of age, HOME Study

Exposure Log10 Dust Chemical Concentrations Log10 Dust Chemical Loadings
FEV1 (mL) PEF (mL/min) FEV1 (mL) PEF (mL/min)
∑OPFRs 71.23 (−56.98, 199.45) −10.46 (−25.32, 4.40) −1.45 (−79.87, 76.97) −12.10 (−21.10, −3.10) **
TCEP 14.79 (−71.84, 101.41) −2.06 (−12.45, 8.34) −11.00 (−74.00, 52.00) −6.43 (−14.01, 1.16)
TCIPP 39.50 (−59.08, 138.08) −1.97 (−13.83, 9.89) −5.99 (−66.56, 54.58) −6.65 (−13.92, 0.63)
TDCIPP 40.36 (−65.74, 146.46) −3.95 (−16.69, 8.80) −6.61 (−73.64, 60.43) −7.99 (−16.02, 0.04)
TPHP 38.46 (−64.44, 141.35) −7.26 (−19.14, 4.61) 2.19 (−77.68, 82.06) −10.21 (−19.40, −1.02) *
∑BFRs 27.34 (−67.20, 121.87) −1.35 (−12.06, 9.37) −6.40 (−78.55, 65.75) −8.48 (−17.07, 0.10)
EH-TBB 14.53 (−69.20, 98.26) −0.39 (−9.98, 9.19) −9.77 (−76.98, 57.44) −6.94 (−14.97, 1.09)
BEH-TEBP 24.08 (−72.48, 120.64) −2.18 (−13.13, 8.76) −9.29 (−81.87, 63.29) −9.05 (−17.67, −0.43) *
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*

P < 0.05

**

P < 0.01

Abbreviations: TCEP: tris(2-chloroethyl) phosphate, TCIPP: tris(1-chloro-2-propyl) phosphate, TDCIPP: tris(1,3-dichloroisopropyl) phosphate, TPHP: triphenyl phosphate, EH-TBB: 2-ethylhexyl-2,3,4,5-tetrabromobenzoate, BEH-TEBP: bis(2-ethylhexyl) tetrabromophthalate.

Models adjusted for child’s sex, child’s race/ethnicity, child’s birth weight, child’s gestational term, family income, breastfeeding, and child’s height. Bold indicates significant association between exposures and lung function.

∑OPFRs dust loadings were associated with higher risks of subsequent respiratory infections (RR: 1.87, 95% CI: 1.05–3.34) and hay fever or allergy (RR: 1.34, 95% CI: 1.19–1.51). The risk of hay fever or allergies were 13% to 34% higher with 10-fold increases of all the studied OPFRs: TCEP (RR: 1.30, 95% CI: 1.18–1.43), TCIPP (RR: 1.25, 95% CI: 1.14–1.37), TDCIPP (RR: 1.28, 95% CI: 1.15–1.42), and TPHP (RR: 1.13, 95% CI: 1.00–1.28). Among dust RBFRs loadings, log10-EH-TBB was also associated with higher risk of respiratory infections (RR: 1.34, 95% CI: 1.01–1.79) while log10 BEH-TEBP was associated with higher risk of hay fever or allergies (RR: 1.12, 95% CI: 1.00–1.24) (Table 3). Moreover, lower PEF (mL/min) was observed with higher ∑OPFRs (β: −12.10, 95% CI: −21.10, −3.10), TPHP (β: −10.21, 95% CI: −19.40, −1.02), and BEH-TEBP (β: −9.05, 95% CI: −17.67, −0.43) dust loadings (Table 4).

The dose-response relationships for the associations of ∑OPFRs dust concentrations and loadings with respiratory symptoms through age 5 years and lung function at age 5 years are reported in Figures 2 and 3. They demonstrated a positive exposure–response relationship between log10-transformed ∑OPFRs dust concentration and respiratory symptoms (Figure 2), and between log10-transformed ∑OPFRs dust loadings and lower PEF (Figure 3). Additional adjustment for cleanliness and clutter did not change our results (Supplemental Tables 1 & 2)

Figure 2:

Figure 2:

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Dose-response relationship for associations of ∑OPFRs dust concentrations and loading with the frequency of respiratory symptoms. Models adjusted for child’s sex, child’s race/ethnicity, child’s birth weight, child’s gestational term, family income, and breastfeeding. Bold indicates significant association between exposures and reported respiratory outcomes. *P < 0.05 **P < 0.01 ***P < 0.001

Figure 3:

Figure 3:

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Dose-response relationship for associations of ∑OPFRs dust concentrations and loadings with FEV1 and PEF. Models adjusted for child’s sex, child’s race/ethnicity, child’s birth weight, child’s gestational term, family income, breastfeeding, and child’s height. Bold indicates significant association between exposures and lung function. **P < 0.01

DISCUSSION

In this prospective cohort study, we found that exposure to dust OPFRs and RBFRs during infancy is associated with higher risk of adverse respiratory symptoms in childhood, while TPHP and BEH-TEBP dust loadings may be associated with lower PEF.

TCEP and Hay Fever or Allergy

There have been no previous reports of associations between house dust TCEP and adverse respiratory outcomes. A previous cross-sectional investigation by Araki et al. conducted among 182 children (24.4% of participants) and adults (75.6% of participants) in Japan analyzed TCEP concentrations in dust sampled from living room floor surfaces and from other multi-surfaces such as shelves, cupboards, door frames, windowsills, electronics, walls, and ceiling papers. The study reported much higher TCEP levels (medians: 8.69 μg/g dust in floor and 25.81 μg/g dust in multi-surface) compared to our report and found no association of TCEP with asthma, atopic dermatitis, allergic rhinitis and allergic conjunctivitis (Araki et al., 2014). Likewise, Canbaz et al. analyzed OPFRs concentrations in dust sampled from the mothers’ mattress at child age 2 months in association with asthma outcomes at child ages 4 to 8 years among 110 children participants in the BAMSE (Barn, Allergy, Milieu Stockholm Epidemiology) study. The authors found no significant differences in TCEP concentrations (Canbaz et al., 2016). The BAMSE study reported median TCEP concentrations in dust from mothers’ mattresses of 0.10 μg/g dust for both asthmatics and non-asthmatics (Canbaz et al., 2016). The Canadian CHILD Cohort Study also found no association between TCEP concentrations in house dust (median: 5.26 μg/g dust) at child age of 3 to 4 months and asthma at 5 years or recurrent wheezing between 2 and 5 years (Navaranjan et al., 2021). TCEP has been widely reported to be associated with oxidative stress in animal models and in human studies (Chen et al., 2015b; Lu et al., 2017). Such stress has been reported to promote T-helper (Th)-2 responses and to increase reactive oxygen species in antigen-presenting cells to cause allergic airway inflammation (Salo et al., 2022).

TCIPP, Wheeze, and Hay Fever or Allergy

Araki et al. reported a cross-sectional association between TCIPP dust concentrations (median 8.69 μg/g dust) from floor surfaces and atopic dermatitis, but not with asthma, allergic rhinitis, or allergic conjunctivitis in children and adults (Araki et al., 2014). The Canadian CHILD study (median TCIPP concentration of 6.06 μg/g dust) and the BAMSE cohort (median TCIPP in mothers’ mattresses: between 0.10 and 0.12 μg/g dust) found no association with asthma or wheeze (Canbaz et al., 2016; Navaranjan et al., 2021). Yet, there are several potential mechanisms through which TCIPP may be associated with wheeze or hay fever. TCIPP is an irritant to the skin and eyes of rats and could irritate the airways to cause wheezing (Marklund et al., 2005; Van der Veen & de Boer, 2012). TCIPP has also been shown to be toxic to different cell lines by suppressing cell viability, producing ROS, inducing DNA lesions, and increasing lactate dehydrogenase leakage in vitro (An et al., 2016). In a toxicogenomic analysis, TCIPP caused inflammation by altering the expression of gene encoding for inflammation effector as well as protein regulation and produced immune alterations (Krivoshiev et al., 2018). Moreover, urinary metabolites for TCIPP were reported to be associated with lower testosterone levels in 117 men aged 20 to 29 years recruited in Montreal, Canada (Siddique et al., 2022). Prior evidence suggests that testosterone may lower Th2 allergic inflammation and type 2 immune response (Fuseini & Newcomb, 2017).

TDCIPP, Wheeze, Respiratory Infections, and Hay Fever or Allergy

Araki et al. found that TDCIPP dust concentrations sampled from floors (median: 2.80 μg/g dust) were associated with atopic dermatitis, but not with asthma, allergic rhinitis, and allergic conjunctivitis in children and adults (Araki et al., 2014). However, multi-surface dust TDCIPP concentrations (median 10.81 μg/g dust) were not associated with any of the studied outcomes (Araki et al., 2014). In 128 school-aged children, TDCIPP dust concentrations (mean: 5.1 μg/g dust) were associated with eczema, but not with wheeze or rhino-conjunctivitis (Araki et al., 2018). Yet, in the BAMSE cohort, no differences in TDCIPP concentrations in mothers’ mattresses at child’s age 2 months were found between children with and without asthma at ages 4 and 8 years (median: 0.14 to 0.16 μg/g) (Canbaz et al., 2016). TDCIPP is reportedly an irritant to rabbit skin and the skin and eyes in rats, which could produce irritation of the airways if inhaled (Araki et al., 2014; Marklund et al., 2005; Van der Veen & de Boer, 2012). In vitro, it was reported that TDCIPP may be immunotoxic and induce oxidative stress in dendritic cells (Canbaz et al., 2017). In male C3H/HeJSlc mice orally receiving TDCIPP at low (0.02 μg/kg/day), medium (0.2 μg/kg/day), or high (2 μg/kg/day) doses, every two weeks from 5 to 11 weeks, TDCIPP triggered allergic pulmonary inflammation and promoted Th2 polarization (Yanagisawa et al., 2021). Moreover, TDCIPP may be agonistic to estrogen receptors which contribute to the regulation of allergic pulmonary inflammation and tissue remodeling in lungs (Watanabe et al., 2019).

Association of TPHP and BEH-TEBP with lower PEF

This report is the first on RBFRs and adverse respiratory outcome and the first to find an association between the OPFR TPHP and decreased lung function. Though most previous studies on TPHP and adverse respiratory as well as allergy outcomes found no association, the CHILD study observed that infants with the highest quartile of TPHP exposure (median 4.44 μg/g dust) had higher odds of asthma diagnosis at 5 years (Araki et al., 2014; Araki et al., 2018; Navaranjan et al., 2021). The reason TPHP and BEH-TEBP were associated with lower PEF but not lower FEV1 is unclear. FEV1 has been reported to be more reproducible than PEF and a low correlation has been found between the two measures (Aggarwal et al., 2006). Possible explanations for this are that PEF is highly dependent on lung volumes and may mostly assess airway function, while FEV1 may reflect both large and peripheral airway function (Aggarwal et al., 2006). Therefore, the discrepant association of TPHP and BEH-TEBP with PEF but not FEV1 may be due to the extent and site of airway constriction related to the exposure (Aggarwal et al., 2006).

Mechanistically, TPHP causes skin sensitization in humans and may be associated with lower testosterone levels (Blaner et al., 1990). TPHP exposure can also lead to oxidative stress and has been demonstrated to be immunotoxic in murine dendritic cells in vitro, to affect the immune function of the respiratory tract (Canbaz et al., 2017). Conversely, research on the toxicity of RBFRs is limited. RBFRs may be endocrine disrupting chemicals and have been reported to be anti-estrogenic and/or anti-androgenic by interacting with the estrogen and/or androgen receptors (Xiong et al., 2019). RBFRs can also interfere with GnRH activation of GnRH receptors and downregulate sex steroid hormone-producing enzymes to decrease sex hormones synthesis, which could affect lung function (Xiong et al., 2019).

Limitations and Strengths

One limitation of our study was that dust OPFRs and RBFRs were sampled only once at age 1 year. Chemicals’ concentrations measured in settled dust have been suggested to predict long time exposures; yet, the long-term stability of dust chemical loadings is unknown (Whitehead et al., 2012). Our study used OPFRs and RBFRs levels in house dust which reflects only indoor exposure to these chemicals and does not always capture outdoor exposure. However, children spend a significant amount of time indoors, and previous studies showed that exposure to outdoor flame retardants is negligible compared to indoor exposure (Wilford et al., 2004). For instance, in a Canadian study, the ranges of concentrations of flame retardants measured by passive sampling were approximately 50 times higher in indoor than outdoor air (Wilford et al., 2004). Our study did not capture indoor exposure at locations other than the children’s home, such as daycares and it did not use internal dose for exposure to these chemicals. We also did not adjust for exposure to tobacco smoke (ETS) and other environmental exposures that occurred during childhood; however, ETS has been found to not be associated with dust OPFRs and RBFRs (Percy et al. 2020). Nonetheless, our study had some strengths. It is the first study RBFRs and respiratory outcomes and the first on dust flame retardants to include exposure dust loadings as well as objective measure of lung function. It is one of only a few prospective cohorts on the topic. It included regular assessments of reported respiratory outcomes until age 5 years, which increased the rigor of outcome assessment and reduced the likelihood of measurement errors. Dust OPFRs and RBFRs were measured with rigorous quality control and assurance procedures. Our analysis was adjusted for several relevant covariates, which reduced residual confounding.

Conclusions

We found that exposure to OPFRs and RBFRs during infancy was associated with subsequent adverse respiratory outcomes and/or lower PEF. If the associations observed in the present study are confirmed in future studies, measures to reduce exposure to these novel chemicals may improve respiratory health and prevent adverse respiratory outcomes.

Supplementary Material

1

Highlights.

  • We studied the associations of house dust organophosphate (OPFRs) and replacement brominated flame retardants (RBFRs) during infancy with adverse respiratory outcomes

  • Dust OPFRs and RBFRs levels were associated with higher risks of subsequent wheeze, respiratory infections, and/or hay fever/allergies.

  • Peak expiratory flow (PEF) during childhood was lower with higher OPFRs dust loadings in infancy

  • PEF during childhood was also lower with bis(2-ethylhexyl) tetrabromophthalate dust loadings in infancy.

Funding:

This work was supported by the National Institute of Environmental Health Sciences (Grant Numbers R01ES034049, P01ES011261, R01ES014575, R01ES028277). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosures: Joseph M. Braun has been compensated as an expert witness for plaintiffs in litigation related to PFAS-contaminated drinking water. The authors have no disclosure related to the submitted manuscript.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT author statement

Angelico Mendy: Conceptualization, Formal analysis, Resources, Writing Original draft, Writing – Review & editing, visualization, funding acquisition. Zana Percy: Writing – Review & editing. Joseph M. Braun: Methodology, Investigation, Resources, Writing – Review & editing. Bruce Lanphear: Investigation, Resources, Writing – Review & editing. Mark J. La Guardia: Methodology, Writing – Review & editing. Robert Hale: Methodology, Writing – Review & editing. Kimberly Yolton: Methodology, Investigation, Resources, Writing – Review & editing. Aimin Chen: Methodology, Investigation, Resources, Writing – Review & editing.

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