Incidence of uterine leiomyoma in relation to urinary concentrations of phthalate and phthalate alternative biomarkers: A prospective ultrasound study

Abstract

Background: Numerous studies suggest that some phthalates have adverse reproductive effects. However, literature on the association between phthalates and incidence of uterine leiomyomata (UL) is limited and inconsistent, with no existing prospective studies.

Objectives: We examined the association of urinary concentrations of phthalate and phthalate alternative biomarkers with UL incidence.

Methods: We conducted a case-cohort analysis within a subgroup of 754 participants in the Study of the Environment, Lifestyle, and Fibroids (SELF), a prospective cohort of premenopausal Black women aged 23-35 years who were recruited during 2010-2012. We quantified fourteen phthalates and two phthalate alternative [1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH)] biomarkers in urine collected at baseline, 20 months, and 40 months. Transvaginal ultrasounds identified UL at baseline and every 20 months during 60 months of follow-up. We evaluated the individual biomarkers, molar sum of di(2-ethylhexyl) phthalate [ΣDEHP] and potency-weighted sum of anti-androgenic [WΣAA] biomarkers. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between biomarkers and UL incidence. We then used quantile g-computation to examine joint associations of multiple phthalate biomarkers with UL incidence.

Results: Most individual biomarkers showed weak-to-moderate inverse associations with UL incidence. HRs comparing highest vs. lowest quartiles of mono-isobutyl phthalate (MiBP) and mono-hydroxyisobutyl phthalate (MHiBP) concentrations were 0.63 (95% CI: 0.40, 1.01) and 0.61 (95% CI: 0.38, 0.96), respectively. Inverse associations for specific phthalates were stronger among women with BMI ≥ 30 kg/m². HRs comparing detectable vs. nondetectable concentrations of DINCH biomarkers were 0.92 (95% CI: 0.62, 1.35) for cyclohexane-1,2-dicarboxylic acid mono hydroxyisononyl ester (MHNCH) and 0.68 (95% CI: 0.38, 1.18) for cyclohexane-1,2-dicarboxylic acid mono carboxyisoocytl ester (MCOCH). For the DEHP metabolite of mono(2-ethylhexyl) phthalate (MEHP), we observed weak-to-moderate positive associations. HRs comparing highest vs. lowest quartiles for MEHP and ΣDEHP were 1.29 (95% CI: 0.82, 2.06) and 0.96 (95% CI: 0.61, 1.50), respectively. In the mixtures analysis, the HR for a joint quartile increase in phthalate biomarker concentrations was 0.90 (95% CI: 0.73, 1.08).

Discussion: In this prospective ultrasound study of reproductive-aged Black women, urinary concentrations of phthalate and DINCH biomarkers were not appreciably associated with higher risk of UL, either individually or jointly.

Keywords: Endocrine disrupting chemicals; Environmental epidemiology; Phthalates; Reproductive health; Uterine leiomyoma; Women's health.

Figure 1.. Hazard Ratio (HR) and 95% Confidence Intervals (CI) for association between cumulatively-averaged creatinine-standardized quartiles of phthalate biomarker concentrations (ng/mL) and risk of uterine leiomyomata.

Model adjusted for age at menarche, smoking, alcohol use, BMI, education, parity, age at first birth, years since last birth, history of infertility, fish intake, creatinine, and current hormonal contraceptive use. ΣDEHP is the total molar sum of di(2-ethylhexyl) phthalate metabolites (μmol/L) [ΣDEHP (MEHP + MEHHP + MEOHP + MECPP)]. WΣAA is the potency weighted sum of anti-androgenic metabolites [ WΣAA (Weighted (MBP+ MiBP + MBzP + MEHP + MEHHP + MEOHP + MECPP + MEP + MHBP + MCOP + MHiBP)]. Green points correspond to the multiple DBP metabolites (MBP, MHBP). Purple points correspond to the multiple DiBP metabolites (MIBP, MHiBP). Orange points correspond to the multiple DEHP metabolites (MEHHP, MEHP, MEOHP, MECPP). Blue points correspond to the multiple DNP metabolites (MCOP, MNP). Metabolite abbreviations: mono-n-butyl phthalate (MBP), mono-hydroxybutyl phthalate (MHBP), mono-isobutyl phthalate (MiBP), mono-hydroxyisobutyl phthalate (MHiBP), Monobenzyl phthalate (MBzP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), monoethyl phthalate (MEP), mono carboxyisooctyl phthalate (MCOP), mono-isononyl phthalate (MNP), mono-3-carboxypropyl phthalate (MCPP) and mono carboxyisononyl phthalate (MCNP). Parent compound abbreviations: Di-n-butyl phthalate (DBP), Di-isobutyl phthalate (DiBP), Benzylbutyl phthalate (BzBP), Di(2-ethylhexyl) phthalate (DEHP), Di-ethyl phthalate (DEP), Di-isonoyl phthalate (DNP), Di-n-octyl [(DOP)/DBP], Di-isodecyl phthalate (DDP).

Figure 2.. Hazard Ratio (HR) and 95% Confidence Intervals (CI) for association between cumulatively-averaged creatinine-standardized quartiles of phthalate biomarker concentrations (ng/mL) and risk of uterine leiomyomata, quartile 2, 3, and 4 (Q2-Q4) vs. reference, stratified by Body Mass Index (BMI) at baseline (<30 vs. >=30 kg/m²).

Model adjusted for age at menarche, smoking, alcohol use, BMI, education, parity, age at first birth, years since last birth, history of infertility, fish intake, creatinine, and current hormonal contraceptive use. ΣDEHP is the total molar sum of di(2-ethylhexyl) phthalate biomarkers (μmol/L) [ΣDEHP (MEHP + MEHHP + MEOHP + MECPP)]. WΣAA is the potency weighted sum of anti-androgenic biomarkers [ WΣAA (Weighted (MBP+ MiBP + MBzP + MEHP + MEHHP + MEOHP + MECPP + MEP + MHBP + MCOP + MHiBP)]. Metabolite abbreviations: mono-n-butyl phthalate (MBP), mono-hydroxybutyl phthalate (MHBP), mono-isobutyl phthalate (MiBP), mono-hydroxyisobutyl phthalate (MHiBP), Monobenzyl phthalate (MBzP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), monoethyl phthalate (MEP), mono carboxyisooctyl phthalate (MCOP), mono-isononyl phthalate (MNP), mono-3-carboxypropyl phthalate (MCPP) and mono carboxyisononyl phthalate (MCNP). Parent compound abbreviations: Di-n-butyl phthalate (DBP), Di-isobutyl phthalate (DiBP), Benzylbutyl phthalate (BzBP), Di(2-ethylhexyl) phthalate (DEHP), Di-ethyl phthalate (DEP), Di-isonoyl phthalate (DNP), Di-n-octyl [(DOP)/DBP], Di- isodecyl phthalate (DDP).

Figure 3.. Weights corresponding to the proportion of the positive or negative partial effect per phthalate biomarker in the quantile g-computation model.

The length of the bars corresponds to the effect size only relative to other effects in the same direction. The darker shading in the negative direction indicates overall mixtures effect in that direction. Results presented for first imputation data set; findings were similar for other imputation data sets.