To the Editor:
Concerns have been raised about adverse health effects from ubiquitous exposure during pregnancy to phthalates and phenols. Toxicologic data suggest that some of these compounds can disrupt the hormonal signaling that regulates male genital organogenesis. Evidence from the epidemiologic literature assessing association between in utero exposure to these compounds and male genital anomalies is limited and inconclusive.1 – 3
We evaluated whether prenatal exposure to select phthalates and phenols was associated with occurrence of hypospadias and undescended testes in a case-control study (eTable 1, http://links.lww.com/EDE/A558) nested in the EDEN and PELAGIE mother–child cohorts (5200 pregnant women).4 Cases of hypospadias (n = 21) and undescended testis (unilateral or bilateral, not in scrotum, n = 50) were identified during the first days after birth by pediatricians or midwives. Three controls per case were selected among male singleton live births, matched with cases for residence area, gestational age at urine sample collection, and date and day of collection (Sunday–Monday vs. other). Urinary concentrations of 11 phthalate metabolites and 9 phenols (samples collected in the morning, eTable 2, http://links.lww.com/EDE/A558), determined without knowledge of case-control status, were standardized by sampling conditions that varied among participants using a 2-step standardization method based on regression residuals as described previously.4 As an alternative exposure metric, we used a specific job-exposure matrix (JEM).2,3
In all, 13 women (9%) were classified as possibly exposed to phthalates in the workplace. No correlation between occupational exposure to phthalates and the urinary concentrations of phthalate metabolites was seen (eTable3, http://links.lww.com/EDE/A558). Due to the short-lived nature of these compounds, the morning urinary biomarkers do not necessarily capture occupational exposures, such that both exposure metrics might reflect complementary exposure sources. Using conditional logistic regression, we observed slightly reduced risks of hypospadias with increasing urinary concentrations of all phthalate metabolites (Table, eTable4, http://links.lww.com/EDE/A558). Increased risk of undescended testis was observed in association with the second or third tertiles of urinary concentrations of bisphenol A (BPA), 2,4-dichlorophenol, and ethylparaben compared with the first tertile (Table); increases were more pronounced among term boys (eTable5, http://links.lww.com/EDE/A558). The odds ratio (OR) for hypospadias associated with possible maternal occupational exposure to phthalates was 4.2 (95% confidence interval [CI] 0.4–41.3; 2 exposed cases and 2 exposed matched controls), whereas the OR for undescended testes was 0.3 (0.0–3.1; 1 exposed case and 6 exposed matched controls). A possible role of co-occurring compounds in the corresponding occupations (n = 9 hairdressers in our study) cannot be discarded.
The main limitation of our study was the modest sample size, especially for results concerning phenols (available only in the EDEN cohort). Despite consistency with their estrogenic molecular activity, findings reported for phenols are subject to special caution because they are not supported by animal data. The use of a single spot urine sample may not efficiently reflect the average level of weekly or monthly exposure for compounds such as di(2-ethylhexyl) phthalate (DEHP) and BPA with an important dietary pathway,5 – 7 but it provides reliable exposure measures for low-molecular-weight phthalates and parabens, likely due to regular use of personal-care products.5,7
Our prospective study did not show evidence of increased risks of male genital anomalies with prenatal exposure to phthalates. We did not confirm the inverse relation between prenatal DEHP exposure and testicular descent (assessed at approximately 1 year old) previously suggested by a study relying on 12 cases1; both the earlier study and our study found no increased risk for other phthalates.1 In contrast, we observed an unexpected decrease in the risk of hypospadias with increased concentrations of maternal urinary phthalate metabolites, for which we have no clear explanation. We speculate on a possible role of PPAR (peroxisome proliferator-activated receptors) ligands (known for some phthalates) and its critical role in placenta development, as previously proposed.8
University Rennes I
Team of Environmental Epidemiology applied to Reproduction and Respiratory Health
Institut Albert Bonniot
University Joseph Fourier Grenoble
“Bien naître en Ille-et-Vilaine” Perinatal Network
Antonia M. Calafat
Manori J. Silva
Centers for Disease Control and Prevention
Team Epidemiology of diabetes, obesity and renal disease: lifelong approach
University Rennes I
1. Swan SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res. 2008;108:177–184.
2. Ormond G, Nieuwenhuijsen MJ, Nelson P, et al.. Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case-control study. Environ Health Perspect. 2009;117:303–307.
3. Vrijheid M, Armstrong B, Dolk H, van Tongeren M, Botting B. Risk of hypospadias in relation to maternal occupational exposure to potential endocrine disrupting chemicals. Occup Environ Med. 2003;60:543–550.
4. Philippat C, Mortamais M, Chevrier C, et al.. Exposure to phthalates and phenols during pregnancy and offspring size at birth. Environ Health Perspect. In press.
5. Preau JL Jr, Wong LY, Silva MJ, Needham LL, Calafat AM. Variability over 1 week in the urinary concentrations of metabolites of diethyl phthalate and di(2-ethylhexyl) phthalate among eight adults: an observational study. Environ Health Perspect. 2010;118:1748–1754.
6. Ye X, Wong LY, Bishop AM, Calafat AM. Variability of urinary concentrations of bisphenol A in spot samples, first morning voids, and 24-hour collections. Environ Health Perspect. 2011;119:983–988.
7. Hauser R, Meeker JD, Park S, Silva MJ, Calafat AM. Temporal variability of urinary phthalate metabolite levels in men of reproductive age. Environ Health Perspect. 2004;112:1734–1740.
8. Adibi JJ, Hauser R, Williams PL, et al.. Maternal urinary metabolites of Di-(2-Ethylhexyl) phthalate in relation to the timing of labor in a US multicenter pregnancy cohort study. Am J Epidemiol. 2009;169:1015–1024.
We are indebted to the cohort members and to the medical staff that participated in these projects. We acknowledge the CDC staff for technical assistance in measuring the urinary concentrations of phthalate metabolites, phenols, and creatinine. We thank Bernard Jégou and Jacques Auger for their helpful comments and Jo Ann Cahn for editing the manuscript.