Associations of gestational exposure to organophosphate esters with thyroid hormones in cord plasma and the safety threshold of exposure in pregnant women

Abstract

Background

As a class of synthetic chemicals, organophosphate esters (OPEs) were shown to have thyroid hormones (THs) disrupting potentials in animal studies, while epidemiological evidence on gestational exposure to OPEs and thyroid disruption is limited. Besides, assessment on the safety threshold of OPEs exposure during gestation is especially scarce.

Methods

Based on the Shanghai Minhang Birth Cohort Study, we measured maternal urine concentration of 8 OPE metabolites and THs levels in cord plasma and examined their associations using multiple linear regression and quantile g-computation (QGC) models. The benchmark dose (BMD) and its lower limit (BMDL) of urine OPE metabolites concentrations were further estimated via the Bayesian Benchmark Dose Analysis System (BBMD) to reflect the safety threshold of exposure in pregnant women. The corresponding daily intake (DI) of BMDL was then calculated and compared with the current oral reference dose (RfD).

Results

A total of 309 mother-newborn pairs were included in this study. Gestational bis (2-butoxyethyl) phosphate (BBOEP) exposure was associated with higher total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4), and free thyroxine (FT4) in cord plasma, while bis(1,3-dichloro-2-propyl) phosphate (BDCPP) was observed to be associated with lower TT3 and FT3/FT4 but higher thyroid stimulating hormone (TSH). In addition, sex-specific effects were observed for bis (2-chloroethyl) phosphate (BCEP), which was associated with lower TT3 in cord plasma of female newborns, and lower TT4 and FT4 in male newborns. Similar results were obtained through QGC model and BBOEP was identified as the main contributor to the higher levels of TT3 and FT3. With benchmark response (BMR) of 10% and background response (P₀) of 97.5% for both TT3 and FT3, the BMDL₁₀ of urine BBOEP concentration was 0.50 μg/L. Further, the corresponding DI of tris (2-butoxyethyl) phosphate (TBOEP), which is the precursor of BBOEP, was 2.53 μg/kg BW/d.

Conclusions

Our findings suggest associations between gestational exposure to OPEs and altered THs biomarkers. According to the estimated BMD₁₀ (BMDL₁₀) of BBOEP and the corresponding DI, the current RfD of 15 μg/kg BW/d for TBOEP may not protect pregnant women and their newborns from thyroid disruption.