In epidemiologic studies, classifying episodic exposures to chemicals with short half-lives, such as phthalates and phenols, is challenging. We assessed whether accounting for sources of variability unrelated to exposure pathways would improve the reproducibility of urine concentrations of select phthalate metabolites and phenols. In 2011, a subset of pregnant women (n = 19) enrolled in a prospective study provided first morning urine samples every 3–4 weeks between 16 and 36 weeks gestation. At the time of collection, we identified potential contributors to variations in urinary concentrations: weight gain, gestational age, time slept, time since awoke, time since last food/drink, and time since last void. We estimated intraclass correlation coefficients (ICCs) among repeat urine concentrations with and without adjustment for sources of variability using a random intercept linear mixed model. Concentrations of monoethyl phthalate, butyl, and propyl parabens were the most reproducible (ICCs: 0.68, 0.56, and 0.56, respectively). However, adjustment for potential sources of variability unrelated to exposure pathways did not materially improve reproducibility nor the ability of a single sample to predict exposure based on average biomarker concentrations across pregnancy. Future studies should carefully consider the exposure timeframe and the reliability of using biomarker concentrations from a single time point to represent exposures over pregnancy.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Centers for Disease Control and Prevention. Fourth report on human exposure to environmental chemicals, updated tables. US Department of Health and Human Services, Centers for Disease Control and Prevention: Atlanta, GA, USA. Retrieved from: https://www.cdc.gov/biomonitoring/pdf/FourthReport_UpdatedTables_Feb2015.pdf (accessed on May 20, 2015).
Diamanti-Kandarakis E, Bourguignon J-P, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: an Endocrine Society Scientific Statement. Endocr Rev. 2009;30:293–342.
Meeker JD. Exposure to environmental endocrine disruptors and child development. Arch Pediatr Adolesc Med. 2012;166:952–8.
Braun JM, Kalkbrenner AE, Calafat AM, Bernert JT, Ye X, Silva MJ, et al. Variability and predictors of urinary bisphenol A concentrations during pregnancy. Environ Health Perspect. 2011;119:131.
Centers for Disease Control and Prevention. Biomonitoring Summary: Parabens. US Department of Health and Human Services, Centers for Disease Control and Prevention: Atlanta, GA, USA. Retrieved from: http://www.cdc.gov/biomonitoring/Parabens_BiomonitoringSummary.html (accessed on October 5, 2015).
Centers for Disease Control and Prevention. Biomonitoring Summary: 2,4-Dichlorophenol. US Department of Health and Human Services, Centers for Disease Control and Prevention: Atlanta, GA, USA. Retrieved from: http://www.cdc.gov/biomonitoring/24D_BiomonitoringSummary.html (accessed on October 5, 2015).
Centers for Disease Control and Prevention. Biomonitoring Summary: 2,5-Dichlorophenol. US Department of Health and Human Services, Centers for Disease Control and Prevention: Atlanta, GA, USA. Retrieved from: http://www.cdc.gov/biomonitoring/25D_BiomonitoringSummary.html (accessed on October 5, 2015).
Wang L, Asimakopoulos AG, Kannan K. Accumulation of 19 environmental phenolic and xenobiotic heterocyclic aromatic compounds in human adipose tissue. Environ Int. 2015;78:45–50.
Kim S, Choi K. Occurrences, toxicities, and ecological risks of benzophenone-3, a common component of organic sunscreen products: a mini-review. Environ Int. 2014;70:143–57.
Philippat C, Wolff MS, Calafat AM, Ye X, Bausell R, Meadows M, et al. Prenatal exposure to environmental phenols: concentrations in amniotic fluid and variability in urinary concentrations during pregnancy. Environ Health Perspect. 2013;121:1225.
Meeker JD, Cantonwine DE, Rivera-González LO, Ferguson KK, Mukherjee B, Calafat AM, et al. Distribution, variability, and predictors of urinary concentrations of phenols and parabens among pregnant women in Puerto Rico. Environ Sci Technol. 2013;47:3439–47.
Braun JM, Smith KW, Williams PL, Calafat AM, Berry K, Ehrlich S, et al. Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy. Environ Health Perspect. 2012;120:739.
Guidry VT, Longnecker MP, Aase H, Eggesbø M, Zeiner P, Reichborn-Kjennerud T, et al. Measurement of total and free urinary phenol and paraben concentrations over the course of pregnancy: assessing reliability and contamination of specimens in the Norwegian mother and child cohort study. Environ Health Perspect. 2015;123:705–11.
Calafat AM, Ye X, Wong L-Y, Reidy JA, Needham LL. Exposure of the US population to bisphenol A and 4-tertiary-octylphenol: 2003-4. Environ Health Perspect. 2008;116:39–44.
Kato K, Silva MJ, Needham LL, Calafat AM. Determination of 16 phthalate metabolites in urine using automated sample preparation and on-line preconcentration/high-performance liquid chromatography/tandem mass spectrometry. Anal Chem. 2005;77:2985–91.
Silva MJ, Samandar E, Preau JL, Reidy JA, Needham LL, Calafat AM. Quantification of 22 phthalate metabolites in human urine. J Chromatogr B. 2007;860:106–12.
Ye X, Kuklenyik Z, Needham LL, Calafat AM. Automated on-line column-switching HPLC-MS/MS method with peak focusing for the determination of nine environmental phenols in urine. Anal Chem. 2005;77:5407–13.
Ye X, Kuklenyik Z, Bishop AM, Needham LL, Calafat AM. Quantification of the urinary concentrations of parabens in humans by on-line solid phase extraction-high performance liquid chromatography–isotope dilution tandem mass spectrometry. J Chromatogr B. 2006;844:53–9.
Duty SM, Ackerman RM, Calafat AM, Hauser R. Personal care product use predicts urinary concentrations of some phthalate monoesters. Environ Health Perspect. 2005;113:1530–5.
SAS Institute Inc. Release version 9.1.3. SAS Institute Inc, Cary, NC. 2000–2004.
Shoukri MM, Donner A, El-Dali A. Covariate-adjusted confidence interval for the intraclass correlation coefficient. Contemp Clin Trials. 2013;36:244–53.
Cox KJ, Porucznik CA, Anderson DJ, Brozek EM, Szczotka KM, Bailey NM, et al. Exposure classification and temporal variability in urinary bisphenol A concentrations among couples in Utah—the HOPE study. Environ Health Perspect. 2016;124:498.
Mortamais M, Chevrier C, Philippat C, Petit C, Calafat AM, Ye X, et al. Correcting for the influence of sampling conditions on biomarkers of exposure to phenols and phthalates: a 2-step standardization method based on regression residuals. Environ Health. 2012;11:29.
Adibi JJ, Whyatt RM, Calafat AM, Camann D, Nelson H, Bhat HK, et al. Characterization of phthalate exposure among pregnant women assessed by repeat air and urine samples. Environ Health Perspect. 2008;116:467–73.
Irvin EA, Calafat AM, Silva MJ, Aguilar-Villalobos M, Needham LL, Hall DB, et al. An estimate of phthalate exposure among pregnant women living in Trujillo, Peru. Chemosphere. 2010;80:1301–7.
Casas M, Valvi D, Ballesteros-Gomez A, Gascon M, Fernández MF, Garcia-Esteban R, et al. Exposure to bisphenol A and phthalates during pregnancy and ultrasound measures of fetal growth in the INMA-Sabadell cohort. Environ Health Perspect. 2016;124:521–8.
Ferguson KK, McElrath TF, Ko Y-A, Mukherjee B, Meeker JD. Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth. Environ Int. 2014;70:118–24.
Abduljalil K, Furness P, Johnson TN, Rostami-Hodjegan A, Soltani H. Anatomical, physiological and metabolic changes with gestational age during normal pregnancy. Clin Pharmacokinet. 2012;51:365–96.
Casas L, Fernández MF, Llop S, Guxens M, Ballester F, Olea N, et al. Urinary concentrations of phthalates and phenols in a population of Spanish pregnant women and children. Environ Int. 2011;37:858–66.
Castorina R, Bradman A, Fenster L, Barr DB, Bravo R, Vedar MG, et al. Comparison of current-use pesticide and other toxicant urinary metabolite levels among pregnant women in the CHAMACOS cohort and NHANES. Environ Health Perspect. 2010;118:856.
Mortensen ME, Calafat AM, Ye X, Wong L-Y, Wright DJ, Pirkle JL, et al. Urinary concentrations of environmental phenols in pregnant women in a pilot study of the National Children’s Study. Environ Res. 2014;129:32–38.
Philippat C, Mortamais M, Chevrier C, Petit C, Calafat AM, Ye X, et al. Exposure to phthalates and phenols during pregnancy and offspring size at birth. Environ Health Perspect. 2012;120:464–70.
Wolff MS, Engel SM, Berkowitz GS, Ye X, Silva MJ, Zhu C, et al. Prenatal phenol and phthalate exposures and birth outcomes. Environ Health Perspect. 2008;116:1092.
Bertelsen RJ, Engel SM, Jusko TA, Calafat AM, Hoppin JA, London SJ, et al. Reliability of triclosan measures in repeated urine samples from Norwegian pregnant women. J Expo Sci Environ Epidemiol. 2014;24:517–21.
Fisher M, Arbuckle TE, Mallick R, LeBlanc A, Hauser R, Feeley M, et al. Bisphenol A and phthalate metabolite urinary concentrations: daily and across pregnancy variability. J Expo Sci Environ Epidemiol. 2015;25:231–9.
Woodruff TJ, Zota AR, Schwartz JM. Environmental chemicals in pregnant women in the United States: NHANES 2003-4. Environ Health Perspect. 2011;119:878.
Berman T, Hochner-Celnikier D, Calafat AM, Needham LL, Amitai Y, Wormser U, et al. Phthalate exposure among pregnant women in Jerusalem, Israel: results of a pilot study. Environ Int. 2009;35:353–7.
Bornehag C-G, Carlstedt F, Jönsson BA, Lindh C, Jensen TK, Bodin A, et al. Prenatal phthalate exposures and anogenital distance in Swedish boys. Environ Health Perspect. 2015;123:101–7.
de Renzy-Martin KT, Frederiksen H, Christensen JS, Kyhl HB, Andersson A-M, Husby S, et al. Current exposure of 200 pregnant Danish women to phthalates, parabens and phenols. Reproduction. 2014;147:443–53.
Swan SH, Sathyanarayana S, Barrett ES, Janssen S, Liu F, Nguyen RHN, et al. First trimester phthalate exposure and anogenital distance in newborns. Human Reprod. 2015;30:963–72.
Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005;113:1056–61.
Ye X, Pierik FH, Hauser R, Duty S, Angerer J, Park MM, et al. Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: the Generation R study. Environ Res. 2008;108:260–7.
Yolton K, Xu Y, Strauss D, Altaye M, Calafat AM, Khoury J. Prenatal exposure to bisphenol A and phthalates and infant neurobehavior. Neurotoxicology Teratol. 2011;33:558–66.
Arbuckle TE, Marro L, Davis K, Fisher M, Ayotte P, Bélanger P, et al. Exposure to free and conjugated forms of bisphenol A and triclosan among pregnant women in the MIREC cohort. Environ Health Perspect. 2015;123:277.
Ye X, Lee-Yang W, Zhou X, Calafat AM. Urinary concentrations of 2, 4-dichlorophenol and 2, 5-dichlorophenol in the US population (National Health and Nutrition Examination Survey, 2003-10): trends and predictors. Environ Health Perspect. 2014;122:351.
Calafat AM, Wong L-Y, Ye X, Reidy JA, Needham LL. Concentrations of the sunscreen agent benzophenone-3 in residents of the United States: National Health and Nutrition Examination Survey 2003-4. Environ Health Perspect. 2008;116:893.
Jusko TA, Shaw PA, Snijder CA, Pierik FH, Koch HM, Hauser R, et al. Reproducibility of urinary bisphenol A concentrations measured during pregnancy in the Generation R Study. J Expo Sci Environ Epidemiol. 2014;24:532–6.
Cantonwine DE, Ferguson KK, Mukherjee B, McElrath TF, Meeker JD. Urinary bisphenol A levels during pregnancy and risk of preterm birth. Environ Health Perspect. 2015;123:895–901.
Smith KW, Braun JM, Williams PL, Ehrlich S, Correia KF, Calafat AM, et al. Predictors and variability of urinary paraben concentrations in men and women, including before and during pregnancy. Environ Health Perspect. 2012;120:1538–43.
We thank the study participants for their time and participation which made this work possible. We also thank Manori Silva, Prabha Dwivedi, Ella Samandar, Jim Preau, Xiaoliu Zhou, and Tao Jia for technical assistance in measuring the urinary concentrations of phenols and phthalate metabolites.
Support for this research was provided by the following grants: RD-83459301 and RD-835434010 from the U.S. Environmental Protection Agency; P20 ES018163, P20 ES018163-S1, P01 ES022848, and R01 ES014864 from the National Institute of Environmental Health Sciences (NIEHS/NIH). MMY was supported by NIEHS training grant T32 ES007069.
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Yazdy, M.M., Coull, B.A., Gardiner, J.C. et al. A possible approach to improving the reproducibility of urinary concentrations of phthalate metabolites and phenols during pregnancy. J Expo Sci Environ Epidemiol 28, 448–460 (2018). https://doi.org/10.1038/s41370-018-0050-0
- Child exposure/health
- Endocrine disruptors
- Prenatal exposure