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Variability and Predictors of Urinary Concentrations of Phthalate Metabolites during Early Childhood

Variability and Predictors of Urinary Concentrations of Phthalate Metabolites during Early Childhood Article pubs.acs.org/est Terms of Use Variability and Predictors of Urinary Concentrations of Phthalate Metabolites during Early Childhood † † ‡,§ ∥ ⊥ Deborah J. Watkins, Melissa Eliot, Sheela Sathyanarayana, Antonia M. Calafat, Kimberly Yolton, ⊥,# ,† Bruce P. Lanphear, and Joseph M. Braun* Department of Epidemiology, Brown University, Providence, Rhode Island 02912, United States Department of Pediatrics, University of Washington, Seattle Children’s Research Institute, Seattle, Washington 98105, United States Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195, United States Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, United States Department of Pediatrics, Division of General and Community Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, United States Child and Family Research Institute, BC Children’s Hospital and the Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia V5A 1S6, Canada * Supporting Information ABSTRACT: The variability and predictors of urinary concentrations of phthalate metabolites in preschool-aged children have not been thoroughly examined. Additionally, the impact of temporal changes in the use and restriction of phthalates in children’s products has not been assessed. Our objective was to identify demographic, behavioral, and temporal predictors of urinary phthalate metabolite concentrations in young children. Between 2004 and 2011, we collected up to five urine samples from each of 296 children participating in a prospective birth cohort during annual study visits at ages 1− 5 years. We used linear mixed models to calculate intraclass correlation coefficients (ICCs), a measure of within-individual reproducibility, and identify demographic predictors of urinary phthalate metabolites. We used multi- variable linear regression to examine cross-sectional relationships between food packaging or personal care product use and phthalate metabolites measured at age 5 years. Across annual measurements, monoethyl phthalate exhibited the least variation (ICC = 0.38), while di-2-ethylhexyl phthalate (ΣDEHP) metabolites exhibited the most variation (ICC = 0.09). Concentrations changed with age, suggesting age-related changes in phthalate exposure and perhaps metabolism. Our findings suggest that fast food consumption may be a source of butylbenzyl phthalate and di-isononyl phthalate (DiNP) exposure, and some personal care products may be sources of diethyl phthalate exposure. Concentrations of ΣDEHP metabolites decreased over the study period; however, concentrations of DiNP metabolites increased. This finding suggests that manufacturer practices and regulations, like the Consumer Product Safety Improvement Act of 2008, may decrease DEHP exposure, but additional work characterizing the nature and toxicity of replacements is critically needed. INTRODUCTION routinely exposed to both LMW and HMW phthalates from 8−12 personal care products, food packaging, and vinyl flooring. Phthalates are used in a range of commercial products, resulting Early life exposure to phthalates may be associated with 1,2 in ubiquitous human exposure. Low molecular weight adverse health outcomes in childhood, including obesity, (LMW) phthalates, such as diethyl phthalate (DEP), di-n- 14−16 altered neurodevelopment, and asthma or allergic butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP), are symptoms. However, previous epidemiological studies have commonly used as solvents in personal care products, including typically measured phthalate metabolites in one spot urine 3,4 perfumes, lotions, and cosmetics, and as excipients in sample. Because phthalate exposure is likely episodic and medications. High molecular weight (HMW) phthalates, such as di-2-ethylhexyl phthalate (DEHP), butyl benzyl Received: April 8, 2014 phthalate (BBzP), di-n-octyl phthalate (DnOP), di-isononyl Revised: June 23, 2014 phthalate (DiNP), and di-isodecyl phthalate (DiDP), are used Accepted: June 30, 2014 6,7 to add flexibility to plastics. Adults, infants, and children are Published: June 30, 2014 © 2014 American Chemical Society 8881 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article phthalate metabolites have short biological half-lives, urine the study visit. If urine was present and the diaper was free of 2,18−20 concentrations can vary considerably within individuals. stool, the insert was placed into a polyethylene urine collection Sustained exposure could result from contact with phthalates cup, and urine was later expressed from the insert with a syringe present in household dust, although concentrations in indoor in the laboratory. For children who were in the process of being environments can also vary. Thus, phthalate exposure toilet trained, a training potty was lined with inserts to misclassification is an important consideration in epidemio- maximize urine collection. For children who were toilet trained, logical studies. urine samples were collected directly into a urine collection cup In response to growing concern about potential health with the aid of the child’s caregiver. All samples were impacts of phthalate exposure, the Consumer Product Safety refrigerated for <24 h prior to processing and then stored at Improvement Act (CPSIA) of 2008 banned the use of several −20 °C until shipment to the CDC, where they were stored at phthalates in children’s toys and other child care articles in the ≤−20 °C until analysis. United States. Specifically, DEHP and DnBP were banned from We measured 11 phthalate metabolites, including mono-2- all children’s toys, while DINP, DIDP, and DnOP were banned ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl from children’s toys that are more likely to be placed in a child’s phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate mouth. In addition, the patterns of phthalate use in consumer (MEOHP), mono-2-ethyl-5-carboxypentyl phthalate products have changed, likely in response to concerns over the (MECPP), monobenzyl phthalate (MBzP), mono-3-carbox- potential toxicity of these chemicals. ypropyl phthalate (MCPP), monocarboxyoctyl phthalate One previous study assessed temporal variability in urinary (MCOP), monocarboxynonyl phthalate (MCNP), monoethyl phthalate metabolite concentrations over a six month period phthalate (MEP), mono-n-butyl phthalate (MnBP), and among 6−10 year old minority children in New York City, monoisobutyl phthalate (MiBP), in urine (μg/L) using while another assessed spot urinary metabolite concentrations previously described methods described in detail in the among 5 and 6 year olds in Germany. However, we are not Supporting Information (SI) (Text S1). We created a summary aware of any studies evaluating the variability or predictors of DEHP metabolite measure (∑DEHP) by calculating the molar urinary phthalate metabolite biomarkers among toddlers or sum of MEHP, MEHHP, MEOHP, and MECPP. The molar preschool aged children. In addition, information is needed to sum was calculated by dividing each metabolite concentration identify potential sources of phthalate exposure and evaluate by its molar mass and then summing the individual metabolite whether regulations, like the 2008 CPSIA, have reduced concentrations (μmol/L). We were not able to measure children’s phthalate exposures. Our objective was to character- MEHP, MnBP, or MiBP in urine samples collected at 1, 2, ize variability in phthalate metabolite urinary concentrations and 3 year visits due to phthalate contamination from the and determine if demographic, behavioral, and temporal factors diaper inserts. Because MEHP contributed relatively little to predicted urinary phthalate metabolite concentrations in young ∑DEHP metabolite concentrations at 4 and 5 years of age, children using a robust, longitudinal study design. (Table S1, SI) the missing MEHP values are not likely to substantively affect the ΣDEHP metabolite summary measure MATERIALS AND METHODS from 1, 2, and 3 years of age. Predictors of Phthalate Concentrations. A computer- Study Participants. Our study sample comprised mothers assisted questionnaire was administered by trained research and their children participating in the Health Outcomes and staff to collect demographic information from participating Measures of the Environment (HOME) Study, an ongoing mothers. During pregnancy, we collected information on prospective birth cohort in Cincinnati, Ohio. Participant maternal race, maternal education, and other sociodemographic recruitment and eligibility criteria have been previously variables. We collected data on the sex of the child from described. Of 1263 eligible pregnant women, 468 enrolled hospital medical charts, and on the race of the child and in our study (37%) between March 2003 and January 2006. household income using questionnaires administered at annual The current analysis was restricted to 327 children for whom visits in early childhood. We measured serum cotinine in we had at least one urinary phthalate metabolite measurement samples collected at the 1, 2, and 3 year visits, which were from one of five annual visits conducted between 1 and 5 years averaged together for each participant as a summary measure of of age. Institutional review boards at Cincinnati Children’s second-hand smoke exposure over the entire study period. Hospital Medical Center and the Centers for Disease Control At the 5 year follow-up visit, we asked mothers questions and Prevention (CDC) approved this study, and all mothers about their child’s use of plastic food-packaging and personal provided written informed consent for themselves and their care products. These included how often their child ate or children prior to participation. drank food stored or heated in plastic, fast food, or prepackaged Urinary Phthalate Metabolite Concentrations. Chil- beverages, and if they had done so in the 48 h prior to the study dren provided urine samples during annual study visits between visit. We also asked if their child had used various personal care 2004 and 2011, which included an annual clinic visit at ages 1− products, including shampoo, conditioner, soap, hand sanitizer, 5 years and an annual home visit at ages 1−3 years. A subset of hairspray or gel, sunscreen, makeup, or nail polish in the 48 h 61 participants provided urine samples at both the home and prior to the study visit. clinic visit at the 1, 2, or 3 year study visit (n = 16, 25, and 26 Statistical Analysis. We did not normalize phthalate respectively). In our primary analyses, we gave priority to samples collected at the clinic visit if a child provided a urine metabolite measurements by creatinine values (i.e., standard- sample at both clinic and home visits. izing each individual phthalate value for the creatinine Prior to sample collection, each child’s genital area was wiped concentration of that specific sample) because changes in with a phthalate-free Wet Nap by their caregiver. For children kidney function, muscle mass, and other physiological factors who were not toilet trained, we collected urine samples by that occur during childhood influence urinary creatinine placing a surgical insert into a clean diaper at the beginning of excretion. Thus, comparing urinary creatinine or creatinine- the study visit. We checked the diapers for urine at the end of normalized biomarker concentrations between a one and a five 8882 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article Figure 1. Unadjusted urinary phthalate metabolite concentrations in HOME Study children (μg/L). Diamond indicates arithmetic mean, whiskers indicate minimum and maximum, edges of box indicate 25th and 75th percentile, and middle line indicates median. One year n = 277, 2 year n = 232, 3 year n = 234, 4 year n = 170, 5 year n = 201 (All subjects with at least 1 phthalate measurement). year old may be inappropriate. As an alternative, we trations in μmol/L for the ∑DEHP summary measure and μg/ compared methods of adjustment for urine dilution (i.e., L for individual phthalate metabolites. Beta estimates were including creatinine as a separate covariate in regression exponentiated to obtain the multiplicative difference between models) by calculating intraclass correlation coefficients groups for categorical predictors or per unit change for (ICC) for phthalate metabolites using three models: unadjusted continuous predictors, and are presented as percent difference for urine creatinine; adjusted for urine creatinine; and adjusted with a 95% confidence interval. for age-specific urine creatinine z-score. We calculated urine We evaluated temporal changes in phthalate exposure by creatinine z-scores separately for each annual study visit to examining children’s urinary phthalate metabolite concentra- tions as a function of age and time. We examined DiNP, DiDP, avoid comparing urine creatinine levels in children of different ages. and DiBP metabolites since use of these phthalates may have We calculated ICCs using random intercept linear mixed increased due to changes in manufacturer practices. We models with an unstructured covariance matrix to estimate evaluated BBzP, DnBP, DEP, and DEHP metabolites due to between- and within-subject variability of log -transformed more extensive restrictions on certain phthalate use in urinary phthalate metabolite concentrations. ICCs are a children’s products and concern over their potential toxicity. measure of the reproducibility of a measurement within an Specifically, the CPSIA regulations went into effect in early individual, where a value of zero indicates no reproducibility 2009 and could have reduced phthalate exposure in children and a value of one indicates perfect reproducibility. born in 2005−2006 since urine samples provided at 3, 4, and 5 We calculated ICCs for annual phthalate metabolite years of age would have been collected after the ban was in measurements over the entire study period (i.e., annual ICC), effect. Since participants born in 2003 would be 5 years old in using all participants who had phthalate measurements from at 2008 and all their samples would have been collected before the least two annual visits. We also calculated ICCs using the subset ban, we created a dichotomous “year of birth” variable to of participants who provided urine samples at both the home distinguish between children born in 2003−2004 from those and clinic portion of the 1, 2, and 3 year visits to quantify born in 2005−2006. We modeled phthalate metabolite variability over a shorter time frame (i.e., short-term ICC). On concentrations as a function of age, year of birth, and their average, these samples were collected 13 days apart (range 1− product interaction (age X year of birth). This model allowed 42 days). us to compare age and calendar time-related changes in We used linear mixed models to examine associations phthalate metabolite concentrations among children born in between urinary phthalate metabolite concentrations and 2005−2006, who would have been affected by the changes in demographic and temporal variables. Demographic variables phthalate use to those born in 2003−2004, who would have such as sex and race of the child, maternal education, and been less affected by these changes. We controlled these household income, as well as mean serum cotinine were analyses for sex and race of the child, household income, entered as fixed effects, while child age, and creatinine or maternal education, mean serum cotinine, and creatinine z- creatinine z-scores were entered as time-varying effects. We score. selected covariates based on prior knowledge and biological We used multivariable linear regression to examine food plausibility that they might be associated with both phthalate packaging and personal care product use as predictors of exposure and the predictors under investigation. The outcome urinary phthalate metabolites measured at the 5-year visit. We variables were log -transformed phthalate metabolite concen- assessed food packaging as a predictor of the metabolites of 8883 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article Table 1. Intraclass Correlation Coefficient of HOME Study Children’s Urinary Phthalate Metabolite Concentrations Collected (A) Annually from 1−5 Years of Age and (B) Twice ∼2 Weeks Apart at 1−3 Years of Age A: annual ICCs B: short-term ICCs b b metabolite all 1 year 2 years 3 yrs all c d unadjusted N = 283 subjects; 1,070 samples N = 16 subjects N = 25 subjects N = 27 subjects N = 61 subjects; 136 samples ∑DEHP 0.18 (0.10, 0.27) 0.35 (0.00, 0.61) 0.27 (0.00, 0.67) 0.44 (0.00, 0.73) 0.29 (0.05, 0.49) MBzP 0.26 (0.17, 0.35) 0.51 (0.30, 0.63) 0.14 (0.00, 0.42) 0.56 (0.29, 0.74) 0.34 (0.09, 0.54) MCPP 0.20 (0.12, 0.29) 0.57 (0.18, 0.85) 0.29 (0.00, 0.67) 0.45 (0.00, 0.75) 0.31 (0.09, 0.49) MCOP 0.17 (0.09, 0.26) 0.54 (0.13, 0.85) 0.00 (0.00, 0.37) 0.16 (0.00, 0.50) 0.15 (0.00, 0.33) MCNP 0.21 (0.13, 0.29) 0.71 (0.37, 0.86) 0.20 (0.00, 0.59) 0.25 (0.00, 0.70) 0.25 (0.09, 0.41) MEP 0.36 (0.26, 0.45) 0.30 (0.08, 0.52) 0.39 (0.15, 0.61) 0.53 (0.13, 0.79) 0.32 (0.08, 0.53) f f f f f MnBP 0.22 (0.02, 0.43) N/A N/A N/A N/A f f f f f MiBP 0.30 (0.10, 0.49) N/A N/A N/A N/A Creatinine Adjusted ∑DEHP 0.11 (0.03, 0.19) 0.41 (0.00, 0.85) 0.24 (0.00, 0.56) 0.52 (0.16, 0.81) 0.20 (0.00, 0.41) MBzP 0.25 (0.18, 0.35) 0.26 (0.08, 0.42) 0.25 (0.03, 0.56) 0.61 (0.35, 0.75) 0.39 (0.19, 0.57) MCPP 0.19 (0.11, 0.27) 0.60 (0.19, 0.91) 0.60 (0.21, 0.83) 0.34 (0.00, 0.63) 0.25 (0.07, 0.43) MCOP 0.15 (0.06, 0.24) 0.50 (0.00, 0.86) 0.00 (0.00, 0.26) 0.22 (0.00, 0.59) 0.03 (0.00, 0.20) MCNP 0.19 (0.09, 0.27) 0.72 (0.45, 0.91) 0.28 (0.00, 0.69) 0.17 (0.00, 0.79 0.19 (0.00, 0.38) MEP 0.35 (0.22, 0.44) 0.46 (0.29, 0.61) 0.28 (0.00, 0.72) 0.66 (0.38, 0.85) 0.29 (0.00, 0.52) f f f f f MnBP 0.20 (0.01, 0.39) N/A N/A N/A N/A f f f f f MiBP 0.31 (0.06, 0.50) N/A N/A N/A N/A Creatinine z-Score Adjusted ∑DEHP 0.09 (0.02, 0.16) 0.46 (0.07, 0.75) 0.28 (0.00, 0.53) 0.48 (0.26, 0.67) 0.20 (0.00, 0.40) MBzP 0.25 (0.16, 0.34) 0.39 (0.22, 0.53) 0.42 (0.20, 0.68) 0.59 (0.35, 0.79) 0.36 (0.16, 0.55) MCPP 0.19 (0.11, 0.26) 0.64 (0.43, 0.86) 0.59 (0.32, 0.78) 0.33 (0.07, 0.53) 0.25 (0.08, 0.43) MCOP 0.13 (0.03, 0.22) 0.47 (0.22, 0.63) 0.00 (0.00, 0.11) 0.22 (0.00, 0.40) 0.03 (0.00, 0.20) MCNP 0.20 (0.09, 0.28) 0.61 (0.51, 0.68) 0.24 (0.00, 0.53) 0.18 (0.00, 0.66) 0.19 (0.00, 0.38) MEP 0.39 (0.26, 0.48) 0.50 (0.36, 0.67) 0.33 (0.02, 0.69) 0.76 (0.30, 0.88) 0.33 (0.04, 0.56) f f f f f MnBP 0.16 (0.00, 0.38) N/A N/A N/A N/A f f f f f MiBP 0.31 (0.07, 0.50) N/A N/A N/A N/A creatinine 0.18 (0.08, 0.28) 0.45 (0.21, 0.65) 0.03 (0.00, 0.40) 0.30 (0.00, 0.54) 0.17 (0.00, 0.34) a b c ICC = intraclass correlation coefficient; N/A = not available. Models adjusted for visit number. All participants with at least 2 phthalate measurements, but not necessarily complete covariate information. Some participants provided 2 urine samples in multiple years but are counted e f only once in the final column. ∑DEHP= Sum of MEHP, MEHHP, MEOHP, and MECPP. MnBP and MiBP measured only at 4 and 5 years of age. DEHP, DiNP (i.e., MCOP), DiDP (i.e., MCNP), and BBzP did, however, observe age-related trends with some individual (i.e., MBzP) in urine, as these phthalates are potential food phthalate metabolites (Figure 1, Table S3, SI). Specifically, as 28,29 contaminants. Similarly, we assessed personal care product child age increased, MEP concentrations decreased slightly, use as predictors of MEP in urine, as DEP is the parent while MCOP concentrations increased. phthalate found in such products. We included the covariates Variability. The reproducibility of urinary phthalate sex, race, household income, maternal education, mean serum concentrations within individuals was low for most metabolites, cotinine, creatinine z-score, and year of birth in all models with annual ICCs ranging from 0.09 for ∑DEHP metabolites examining food packaging or personal care use as predictors of to 0.39 for MEP over the entire study period (adjusted for urinary phthalate metabolites. When modeling the use of creatinine z-score) (Table 1). In general, phthalate metabolite specificpersonalcareproductsas predictors of urinary concentrations in samples collected approximately 2 weeks phthalate metabolites, we additionally controlled for the total apart varied less than in annually collected samples (e.g., number of other personal care products used. ∑DEHP metabolites: short-term ICC = 0.20, annual ICC = 0.09). Among the subset of participants with urine samples RESULTS collected at both the clinic and home portion, short-term A total of 327 children provided at least one urine sample variability was generally lower when we looked at duplicate during their first 5 years of life. Of these children, 296 (n = sample pairs separately at 1, 2, and 3 years, rather than 1050 samples) had complete covariate information on race, sex, duplicate sample pairs from all visit years together. However, household income, maternal education, serum cotinine, and short-term ICCs fluctuated across visits for many phthalate urine creatinine (Table S2, SI). At age five, 190 children metabolites (e.g., MEP: visit 1 ICC = 0.50, n = 16; visit 2 ICC = provided a urine sample and had complete covariate 0.33, n = 25; visit 3 ICC = 0.76, n = 27), possibly because of the information. All measured phthalate metabolites were detected relatively small number of participants who contributed two in greater than 99% of urine samples with the exception of urine samples at more than one study visit, or they were not MEHP, which was detected in 79% of urine samples. consistently the same individuals from year to year. Methods Unadjusted measures of urinary ∑DEHP metabolite concen- trations did not change with age (Table S3, Figure S1, SI). We for urine dilution adjustment (unadjusted, creatinine adjusted, 8884 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article 8885 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Table 2. Adjusted Difference in HOME Study Children’s Urinary Phthalate Concentrations at 1-5 Years of Age According to Sociodemographic Factors or Serum Cotinine Levels (N = 296 With a Total of 1050 Repeated Measures) b c c ∑DEHP MBzP MCPP MCOP MCNP MEP MnBP MiBP d d d d d d d d N (%) or mean %difference %difference %difference %difference %difference %difference %difference %difference variable (SD) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Child Race non-hispanic white 194 (66) ref. ref. ref. ref. ref. ref. ref. ref. non-hispanic black 83 (28) −6(−17, 7) −6(−19, 10) −26 (−34, −17) −19 (−29, 8) −9(−19, 1) 91 (64, 123) −18 (−33, 1) 2 (−17, 25) other 19 (6) 6 (−13, 30) −1(−23, 26) −2(−18, 16) 1 (−18, 24) 12 (−6, 34) 97 (55, 152) 41 (1, 96) 53 (10, 113) Sex female 161 (54) ref. ref. ref. ref. ref. ref. ref. ref. male 135 (46) −2(−12, 10) 12 (−3, 28) 5 (−4, 16) −2(−13, 10) −4(−13, 6) −12 (−23, 0.3) −18 (−32, −1) −15 (−30, 3) Age (% change/year) 2.94 (1.47) −2(−5, 1) −2(−6, 1) −0.2 (−3, 3) 21 (18, 26) −6(−9, −4) −11 (−14, −7) −24 (−34, −13) −13 (−23, −1) Year of Birth born 2003−2004 142 (48) ref. ref. ref. ref. ref. ref. ref. ref. born 2005−2006 154 (52) −15 (−24, −6) −18 (−27, −6) −3(−11, 6) 1 (−9, 13) −4(−12, 5) −18 (−28, −7) −19 (−32, 4) −3(−18, 15) Household Income 62,276 (40,570) 0.5 (−1, 2) −4(−6, −1) 0 (−2, 2) −0.4 (−2, 2) −1(−2, 1) −2(−4, 1) 0.3 (−3, 3) −1(−3, 2) (% difference/$10,000) Maternal Education less than grade 12 25 (8) ref. ref. ref. ref. ref. ref. ref. ref. high school graduate 32 (11) 4 (−12, 23) −21 (−35, −3) −11 (−24, 3) 2 (−14, 22) −17 (−28, −4) 13 (−8, 38) −15 (−35, 12) −26 (−44, −3) some college 77 (26) 7 (−5, 21) −12 (−24, 2) −1(−11, 10) −0.1 (−12, 13) −11 (−20, −1) −14 (−26, −1) 17 (−3, 42) −2(−19, 19) college graduate 162 (55) −10 (−19, 0.1) −33 (−41, −24) −17 (−25, −10) −12 (−21, −2) −20 (−27, −12) −36 (−44, −28) −9(−23, 8) −8(−23, 9) Mean Cotinine 0.66 (1.97) 1 (−2, 5) 5 (−0.1, 10) 1 (−3, 4) −2(−5, 2) −1(−5, 2) 0 (−5, 5) 3 (−2, 9) 0.5 (−5, 6) (% difference/ng/mL) a b c Results adjusted for all other variables listed in Table 2 and urinary creatinine z-score. CI= confidence interval. ∑DEHP= MEHP, MEHHP, MEOHP, and MECPP. MnBP and MiBP measured only at d e visits 4 and 5. %Difference = percent difference in geometric means compared to the reference group for categorical variables or for a one unit increase for continuous variables. Other race = Asian, Pacific Islander, or American Indian. Environmental Science & Technology Article Table 3. Adjusted Difference in HOME Study Children’s Urinary Phthalate Metabolite Concentrations at 5 Years of Age According to Parent-Reported Child Food Packaging Use and Diet (N = 190) ∑DEHP (μmol/L) MBzP (μg/L) MCPP (μg/L) MCOP (μg/L) MCNP (μg/L) c c c c c variable N (%) % difference (95% CI) % difference (95% CI) % difference (95% CI) % difference (95% CI) % difference (95% CI) Food Stored in Plastic <1/week 15 (7.9) ref. ref. ref. ref. ref. 1−6/week 80 (42.1) 25 (1, 56) 32 (−7, 86) 11 (−12, 40) −4(−28, 30) 9 (−12, 35) ≥1/day 62 (32.6) −3(−25, 25) 28 (−14, 91) 5 (−19, 38) 38 (−2, 96) 20 (−6, 53) Food Stored in Plastic in Past 48 h no 39 (20.5) ref. ref. ref. ref. ref. yes 113 (59.5) −9(−27, 13) 15 (−19, 63) 0 (−21, 26) −7(−32, 26) 16 (−6, 44) Food Heated in Plastic <1/week 93 (48.9) ref. ref. ref. ref. ref. ≥1/week 64 (33.7) 3 (−19, 30) −3(−32, 40) −4(−24, 23) −3(−30, 33) 11 (−11, 39) Food Heated in Plastic in Past 48 h No 127 (66.8) ref. ref. ref. ref. ref. Yes 25 (13.2) −14 (−36, 14) −25 (−53, 19) −28 (−47, −3) −34 (−56, −0.4) −20 (−40, 5) Fast Food <1/week 85 (44.7) ref. ref. ref. ref. ref. ≥1/week 72 (37.9) −1(−22, 25) 55 (9, 123) 19 (−7, 51) 35 (−2, 85) 11 (−11, 39) Prepackaged Beverages <1/week 53 (27.9) ref. ref. ref. ref. ref. 1−6/week 65 (34.2) 1 (−20, 28) 15 (−20, 67) 22 (−5, 57) 15 (−17, 60) 17 (−6, 47) ≥1/day 37 (19.5) −17 (−36, 7) −29 (−53, 5) 14 (−12, 48) 16 (−19, 64) 1 (−21, 29) Prepackaged Beverages in Past 48 h no 68 (35.8) ref. ref. ref. ref. ref. yes 83 (43.7) 16 (−7, 44) −8(−35, 29) 29 (4, 62) 18 (−12, 57) 1 (−17, 24) Adjusting for sex, race of child, household income, maternal education, mean serum cotinine, urinary creatinine z-score and year of birth. CI = b c confidence interval. ∑DEHP= MEHP, MEHHP, MEOHP, and MECPP. %Difference = percent difference in geometric means compared to the reference category. creatinine z-score adjusted) did not meaningfully change our less than once per week, while children who ate foods that had reported measures of variability (Table 1). been heated in plastic within the past 48 h had MCOP Demographic Predictors. Race predicted select urinary concentrations 34% lower than those who did not (95% CI: phthalate concentrations, with black children having 91% (95% −56, −0.4). Urinary concentrations of the ∑DEHP metabo- CI: 64, 123) higher MEP concentrations, but 26% (95% CI: 34, lites, MCNP, MCPP (a nonspecific metabolite of HMW 17) lower MCPP concentrations, compared to white children phthalates and a minor metabolite of DnBP), and MBzP were after adjustment for confounders (Table 2). Children in the not associated with eating food stored or heated in plastic. “Other” race category (Asian, Pacific Islander, or American Drinking prepackaged beverages within the past 48 h was Indian) had higher concentrations of MEP, MnBP, and MiBP associated with 29% higher (95% CI: 4, 62) urinary MCPP compared to white children (Table 2), although this analysis concentrations, but was not associated with ΣDEHP metabo- was limited by the relatively small number of children in the lite, MCOP, MCNP, or MBzP concentrations. “Other” category (n = 19). Higher maternal education Most participants used shampoo and various types of soap predicted lower concentrations of all measured phthalates, within 48 h of urine collection, but less than 15% used hairspray with children of mothers who were college graduates having or hair gel, makeup, or nail polish. Recent use of hairspray or 10%, 33%, and 36% lower concentrations of ∑DEHP hair gel was associated with 63% higher urinary MEP metabolites, MBzP, and MEP, respectively, compared to concentrations (95% CI: 7, 148) among 5 year-old participants children of mothers who did not graduate from high school. after adjustment for covariates, while the use of other personal Boys had 12% (95% CI: −23, 0.3) lower urinary concentrations care products was not (Table S4, SI). of MEP compared to girls. Children’s average serum cotinine Temporal Trends vs Age. Increasing age and later year of birth (2005−2006 compared to 2003−2004) were both levels did not predict urinary phthalate metabolite concen- trations after adjustment for other covariates. associated with lower concentrations of several phthalate Food Packaging and Personal Care Products. Eating metabolites after adjusting for race, sex, household income, fast food at least once per week was associated with 35% higher maternal education, serum cotinine, and creatinine z-score MCOP (95% CI: −2, 85) and 55% higher MBzP (95% CI: 9, (Table 2). The association between birth year and ∑DEHP 123) urine concentrations compared to eating fast food less metabolites changed with age, where those born in 2005−2006 than once per week after adjustment for covariates (Table 3). had increasingly lower relative concentrations compared to Five year-old children who ate foods that had been stored in those born in 2003−2004 as they got older, although this plastic at least once per day had urinary MCOP concentrations interaction was not statistically significant after adjustment for 38% higher (95% CI: −2, 96) than those who ate such foods creatinine z-score (p = 0.24) (Figure 2, Table S5, SI). In 8886 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article Figure 2. Geometric mean concentrations and smoothed regression of urinary ∑DEHP metabolites and MCOP between 1 and 5 years of age among those born between 2003 and 2004 or 2005−2006. ∑DEHP = sum of MEHP, MEHHP, MEOHP, and MECPP. Children born in 2003− 2004 provided urine samples before the CPSIA went into effect, while children born in 2005−2006 provided their 3, 4, and 5 year urine samples after the CPSIA went into effect. contrast, age was positively associated with urinary MCOP short-term exposure to these phthalates. This may be especially concentrations and the association between birth year and true during infancy, when dietary variation tends to be limited MCOP or MCNP concentrations changed with age, such that and personal care product use is a routine part of child care. For MCOP and MCNP concentrations were higher among children example, in a study examining phthalate exposure among born in 2005−2006 compared to those born in 2003−2004 (p- infants, the significant association between recent use of baby value for interaction <0.0001 for both metabolites) (Figure 2). lotion and urinary MEP concentrations was strongest among For instance, compared to children born in 2003−2004, those infants less than 8 months old. Our results, which indicate that born in 2005−2006 had 22% lower MCOP concentrations at urinary MCOP, MCNP, and MCPP concentrations measured 2 one year of age, but 33% higher concentrations at five years of weeks apart varied less among one year-olds than older children age (Table S5, SI). (Table 1), are consistent with the hypothesis that exposures become more varied as children mature. While a single spot DISCUSSION sample may be sufficient to characterize exposure over a relatively narrow time window (e.g., weeks), one spot urine Our longitudinal study design allowed us to evaluate variability sample may not adequately capture exposure over months or of urinary phthalate metabolite concentrations during early years, particularly for toddlers and preschool aged children, childhood over both short and long-term exposure periods, as since diet and personal care product use, as well as physiology, well as the effect of policy and manufacturer related changes in change considerably over the first five years of life. Consistent phthalate use during the study period. In addition, our cross- with this hypothesis, the annual ICCs reported in the present sectional analysis allowed us to examine specific consumer study are generally lower, suggesting more variability, compared products as sources of phthalate exposure in preschool aged to ICCs reported in a number of studies in adult children. Our findings suggest that exposure to certain 18−20,33 populations. phthalates varies during early childhood by race, maternal We observed less variability (e.g., higher reproducibility) in education, use of personal care products such as hairspray or urinary MEP concentrations compared to other phthalate gel, consumption of fast food, and possibly consumption of 18−20,33 metabolites, consistent with previous studies. This may food stored in specific types of packaging. Our findings also be a result of the pathways by which most young children are suggest that changes in manufacturer practices due to market- exposed to the parent compound DEP. DEP is found mainly in forces and the CPSIA of 2008, which restricted DEHP use in personal care products, which are often used regularly, but their children’s products, may have resulted in decreased exposure to use varies substantially between people. In contrast, ∑DEHP DEHP among study participants. However, urinary concen- metabolites show substantial within-person variation, likely due trations of MCOP, a metabolite of DiNP, increased during this to diet being the primary source of exposure. same time period. It was difficult to separate the effects of physiological and We found that phthalate metabolite concentrations in spot behavioral patterns during child development from temporal urine samples collected approximately 2 weeks apart were changes in phthalates used in consumer products over the study weakly to moderately correlated, while concentrations meas- period on measured urinary phthalate metabolite concen- ured a year or more apart were less correlated. Since phthalates 31,32 trations. Because age-related physiological changes in kidney have biological half-lives of less than 24 h, urinary metabolite concentrations reflectonlyrecentexposure. function and muscle mass during early childhood affect However, because some phthalate exposures are linked to creatinine excretion, the use of creatinine to adjust for urine routine behaviors that may vary little over short periods of time, dilution is complicated. We observed increasing urinary a single spot urine sample may be a reasonable measure of creatinine concentrations from 1 to 5 years of age (SI Figure 8887 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article S2) and substantially lower ICCs when using creatinine misclassification. For comparison, a study of phthalate exposure normalization (data not shown). As children grow older and among infants found that use of baby lotion was positively more independent, age related changes in behavior may also associated with urinary MEP concentrations, while a recent affect phthalate exposures during this time. In addition, changes study of 8−13 year olds reported sex-specificpositive in manufacturer practices and the implementation of the associations between urinary MEP concentrations and deodor- CPSIA in February of 2009 further complicated this issue. ant, cologne or perfume, and hair conditioner use, but not use Indeed, after controlling for urine dilution using age-specific of hair spray or gel. creatinine z-scores, we detected differences in urinary ∑DEHP We found that consumption of fast food more than once a metabolite concentrations between children born in 2003− week was associated with higher urinary MBzP and MCOP 2004 and those born in 2005−2006. For example, at five years concentrations, although it is uncertain if fast food packaging, of age, children born later had lower ∑DEHP metabolite fast food itself, or both are sources of phthalate exposure. We concentrations, a phthalate targeted by CPSIA, but higher also observed a positive association between urinary MCOP MCOP concentrations compared to those born earlier. concentrations and eating food stored in plastic containers, but Our data are consistent with possible increasing use of DiNP a negative association between MCOP and eating food that had in consumer products in recent years, although the CPSIA also been heated in plastic within the past 48 h. Although these placed some restrictions on the use of this phthalate in specific associations did not reach statistical significance, these children’s products. It is estimated that DiNP and DiDP make contrasting findings make it difficult to reach a conclusion up about 33% of the U.S. plasticizer market. Our results about exposure via plastic food packaging among this suggest that changes in manufacturer practices and the CPSIA population. Our 48 h window may have been too long to may have played a role in reducing exposure to some key detect meaningful differences in phthalate metabolite concen- phthalates among the target population (children), as the later trations, and we did not collect potentially important born children had lower concentrations of ∑DEHP metabo- information such as food type and food storage time and lites and MCPP (a DnOP and DnBP metabolite) at all ages. temperature. In addition, we were not able to identify the Similar decreases in urinary phthalate metabolite concen- type or brand of plastic food containers used and different trations, specifically DEHP metabolites, can be seen in Europe plastic formulations may contain different amounts of phthalate as well. However, HOME study children who provided urine residues. A study evaluating predictors of phthalates among samples after the CPSIA went into effect had higher MCOP older children also did not observe an association between and MCNP concentrations than children providing urine maternal report of exposure to food packaging in the previous samples before the CPSIA. These are metabolites of DiNP and 48 h and urinary phthalate metabolites. However, researchers DiDP, respectively, which may have increased in use as DEHP evaluating food packaging as a source of phthalate exposure was phased out. Similar trends were recently reported among using dietary intervention observed a significant decrease in children, adolescents, and adults in data from the National urinary phthalate metabolite concentrations when participants Health and Nutrition Examination Survey (NHANES) were provided catered meals with minimal plastic packaging. collected from 2001 to 2010, where urinary DEHP metabolite, A major limitation of this analysis was that we used creatinine MnBP, and MBzP concentrations decreased over time, while to adjust for urine dilution. Because kidney function and muscle urinary MCOP, MCNP, and MiBP concentrations increased. mass are changing rapidly across the age range studied here, The CPSIA, which limited phthalate usage in children’s creatinine normalization is not an ideal method for adjustment products, would not be expected to lead to the observed because it could over- or underestimate exposure at different decreases in phthalate exposure among older children and ages. As an alternative, we included age-specific creatinine z- adults, suggesting that other factors, such as additional scores in regression models to adjust for urine dilution. In regulatory pressures and consumer-driven market forces, may addition, we did not ask participants how often their children have also played a role in decreasing exposure to specific played with toys made of plastic, the age of these toys, phthalates among children, as well as adults. mouthing behaviors, or collect other information that would We observed higher urinary MEP concentrations among have helped us more directly examine whether the temporal blacks and other nonwhite children compared to whites, but trends in certain urinary phthalate metabolites were a result of similar concentrations of most other phthalate metabolites. the CPSIA. We were also not able to report concentrations of This finding is consistent with observations among older the hydrolytic monoester metabolites MEHP, MnBP, and 1,36 children in biomonitoring studies such as NHANES. Higher MiBP in urine samples collected during visits 1, 2, or 3 due to urinary phthalate concentrations among black and other potential contamination from diaper inserts. Another nonwhite children could be due to differences in the frequency limitation is our modest sample size, which limits our ability or type of personal care products used. to detect associations, especially for behavioral factors that are Similar to previous studies, we observed lower urinary MEP less accurately reported. We also do not have measures of 1,6 concentrations in males compared to females. Among five phthalates in participant’s indoor environments, a potential 11,34 year-olds we also observed a positive association between the source of exposure particularly in this age group. Phthalate use of hairspray or gel within the past 48 h and urinary MEP concentrations in household dust can be quite high, and concentrations and 18 of the 22 participants who reported exposure through this pathway may substantially contribute to using these products were female. We did not see associations participant’s urinary phthalate metabolite levels. We also did between the use of other personal care products and MEP not investigate maternal use of personal care products as a concentrations, possibly due to the small number of potential pathway of child phthalate exposure, although this participants reporting use of most products or our reliance could be pursued in a future analysis. on maternal report of children’s exposure history. Self-reported In conclusion, urinary phthalate metabolite concentrations in information is often subject to misclassification, and a mother’s young children vary over time, likely due to a combination of recall of their child’s experience may result in additional age related changes in exposure and perhaps metabolism, as 8888 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article (7) Braun, J. M.; Sathyanarayana, S.; Hauser, R. Phthalate exposure well as changes in the use of phthalates in commercial products. and children’s health. Curr. Opin. Pediatr. 2013, 25 (2), 247−54. Consistent with previous reports in adults, our findings (8) Buckley, J. P.; Palmieri, R. T.; Matuszewski, J. M.; Herring, A. H.; suggest that personal care products are a source of exposure to Baird, D. D.; Hartmann, K. E.; Hoppin, J. A. 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Food packaging and bisphenol A and bis(2-Ethyhexyl) phthalate exposure: Findings from a dietary intervention. Environ. Health ASSOCIATED CONTENT Perspect. 2011, 119 (7), 914−920. (11) Carlstedt, F.; Jonsson, B. A. G.; Bornehag, C. G. PVC flooring is * S Supporting Information related to human uptake of phthalates in infants. Indoor Air 2013, 23 Additional tables and figures are available as Supporting (1), 32−39. Information as mentioned in the text. This material is available (12) Lewis, R. C.; Meeker, J. D.; Peterson, K. E.; Lee, J. M.; Pace, G. free of charge via the Internet at http://pubs.acs.org. G.; Cantoral, A.; Tellez-Rojo, M. M. Predictors of urinary bisphenol A and phthalate metabolite concentrations in Mexican children. AUTHOR INFORMATION ■ Chemosphere 2013, 93, 2390−2398. Corresponding Author (13) Teitelbaum, S. L.; Mervish, N.; Moshier, E. L.; Vangeepuram, N.; Galvez, M. P.; Calafat, A. M.; Silva, M. J.; Brenner, B. L.; Wolff, M. *E-mail: joseph_braun_1@brown.edu. S. 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Variability and Predictors of Urinary Concentrations of Phthalate Metabolites during Early Childhood

Environmental Science & Technology , Volume 48 (15) – Jun 30, 2014

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Article pubs.acs.org/est Terms of Use Variability and Predictors of Urinary Concentrations of Phthalate Metabolites during Early Childhood † † ‡,§ ∥ ⊥ Deborah J. Watkins, Melissa Eliot, Sheela Sathyanarayana, Antonia M. Calafat, Kimberly Yolton, ⊥,# ,† Bruce P. Lanphear, and Joseph M. Braun* Department of Epidemiology, Brown University, Providence, Rhode Island 02912, United States Department of Pediatrics, University of Washington, Seattle Children’s Research Institute, Seattle, Washington 98105, United States Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195, United States Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, United States Department of Pediatrics, Division of General and Community Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, United States Child and Family Research Institute, BC Children’s Hospital and the Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia V5A 1S6, Canada * Supporting Information ABSTRACT: The variability and predictors of urinary concentrations of phthalate metabolites in preschool-aged children have not been thoroughly examined. Additionally, the impact of temporal changes in the use and restriction of phthalates in children’s products has not been assessed. Our objective was to identify demographic, behavioral, and temporal predictors of urinary phthalate metabolite concentrations in young children. Between 2004 and 2011, we collected up to five urine samples from each of 296 children participating in a prospective birth cohort during annual study visits at ages 1− 5 years. We used linear mixed models to calculate intraclass correlation coefficients (ICCs), a measure of within-individual reproducibility, and identify demographic predictors of urinary phthalate metabolites. We used multi- variable linear regression to examine cross-sectional relationships between food packaging or personal care product use and phthalate metabolites measured at age 5 years. Across annual measurements, monoethyl phthalate exhibited the least variation (ICC = 0.38), while di-2-ethylhexyl phthalate (ΣDEHP) metabolites exhibited the most variation (ICC = 0.09). Concentrations changed with age, suggesting age-related changes in phthalate exposure and perhaps metabolism. Our findings suggest that fast food consumption may be a source of butylbenzyl phthalate and di-isononyl phthalate (DiNP) exposure, and some personal care products may be sources of diethyl phthalate exposure. Concentrations of ΣDEHP metabolites decreased over the study period; however, concentrations of DiNP metabolites increased. This finding suggests that manufacturer practices and regulations, like the Consumer Product Safety Improvement Act of 2008, may decrease DEHP exposure, but additional work characterizing the nature and toxicity of replacements is critically needed. INTRODUCTION routinely exposed to both LMW and HMW phthalates from 8−12 personal care products, food packaging, and vinyl flooring. Phthalates are used in a range of commercial products, resulting Early life exposure to phthalates may be associated with 1,2 in ubiquitous human exposure. Low molecular weight adverse health outcomes in childhood, including obesity, (LMW) phthalates, such as diethyl phthalate (DEP), di-n- 14−16 altered neurodevelopment, and asthma or allergic butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP), are symptoms. However, previous epidemiological studies have commonly used as solvents in personal care products, including typically measured phthalate metabolites in one spot urine 3,4 perfumes, lotions, and cosmetics, and as excipients in sample. Because phthalate exposure is likely episodic and medications. High molecular weight (HMW) phthalates, such as di-2-ethylhexyl phthalate (DEHP), butyl benzyl Received: April 8, 2014 phthalate (BBzP), di-n-octyl phthalate (DnOP), di-isononyl Revised: June 23, 2014 phthalate (DiNP), and di-isodecyl phthalate (DiDP), are used Accepted: June 30, 2014 6,7 to add flexibility to plastics. Adults, infants, and children are Published: June 30, 2014 © 2014 American Chemical Society 8881 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article phthalate metabolites have short biological half-lives, urine the study visit. If urine was present and the diaper was free of 2,18−20 concentrations can vary considerably within individuals. stool, the insert was placed into a polyethylene urine collection Sustained exposure could result from contact with phthalates cup, and urine was later expressed from the insert with a syringe present in household dust, although concentrations in indoor in the laboratory. For children who were in the process of being environments can also vary. Thus, phthalate exposure toilet trained, a training potty was lined with inserts to misclassification is an important consideration in epidemio- maximize urine collection. For children who were toilet trained, logical studies. urine samples were collected directly into a urine collection cup In response to growing concern about potential health with the aid of the child’s caregiver. All samples were impacts of phthalate exposure, the Consumer Product Safety refrigerated for <24 h prior to processing and then stored at Improvement Act (CPSIA) of 2008 banned the use of several −20 °C until shipment to the CDC, where they were stored at phthalates in children’s toys and other child care articles in the ≤−20 °C until analysis. United States. Specifically, DEHP and DnBP were banned from We measured 11 phthalate metabolites, including mono-2- all children’s toys, while DINP, DIDP, and DnOP were banned ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl from children’s toys that are more likely to be placed in a child’s phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate mouth. In addition, the patterns of phthalate use in consumer (MEOHP), mono-2-ethyl-5-carboxypentyl phthalate products have changed, likely in response to concerns over the (MECPP), monobenzyl phthalate (MBzP), mono-3-carbox- potential toxicity of these chemicals. ypropyl phthalate (MCPP), monocarboxyoctyl phthalate One previous study assessed temporal variability in urinary (MCOP), monocarboxynonyl phthalate (MCNP), monoethyl phthalate metabolite concentrations over a six month period phthalate (MEP), mono-n-butyl phthalate (MnBP), and among 6−10 year old minority children in New York City, monoisobutyl phthalate (MiBP), in urine (μg/L) using while another assessed spot urinary metabolite concentrations previously described methods described in detail in the among 5 and 6 year olds in Germany. However, we are not Supporting Information (SI) (Text S1). We created a summary aware of any studies evaluating the variability or predictors of DEHP metabolite measure (∑DEHP) by calculating the molar urinary phthalate metabolite biomarkers among toddlers or sum of MEHP, MEHHP, MEOHP, and MECPP. The molar preschool aged children. In addition, information is needed to sum was calculated by dividing each metabolite concentration identify potential sources of phthalate exposure and evaluate by its molar mass and then summing the individual metabolite whether regulations, like the 2008 CPSIA, have reduced concentrations (μmol/L). We were not able to measure children’s phthalate exposures. Our objective was to character- MEHP, MnBP, or MiBP in urine samples collected at 1, 2, ize variability in phthalate metabolite urinary concentrations and 3 year visits due to phthalate contamination from the and determine if demographic, behavioral, and temporal factors diaper inserts. Because MEHP contributed relatively little to predicted urinary phthalate metabolite concentrations in young ∑DEHP metabolite concentrations at 4 and 5 years of age, children using a robust, longitudinal study design. (Table S1, SI) the missing MEHP values are not likely to substantively affect the ΣDEHP metabolite summary measure MATERIALS AND METHODS from 1, 2, and 3 years of age. Predictors of Phthalate Concentrations. A computer- Study Participants. Our study sample comprised mothers assisted questionnaire was administered by trained research and their children participating in the Health Outcomes and staff to collect demographic information from participating Measures of the Environment (HOME) Study, an ongoing mothers. During pregnancy, we collected information on prospective birth cohort in Cincinnati, Ohio. Participant maternal race, maternal education, and other sociodemographic recruitment and eligibility criteria have been previously variables. We collected data on the sex of the child from described. Of 1263 eligible pregnant women, 468 enrolled hospital medical charts, and on the race of the child and in our study (37%) between March 2003 and January 2006. household income using questionnaires administered at annual The current analysis was restricted to 327 children for whom visits in early childhood. We measured serum cotinine in we had at least one urinary phthalate metabolite measurement samples collected at the 1, 2, and 3 year visits, which were from one of five annual visits conducted between 1 and 5 years averaged together for each participant as a summary measure of of age. Institutional review boards at Cincinnati Children’s second-hand smoke exposure over the entire study period. Hospital Medical Center and the Centers for Disease Control At the 5 year follow-up visit, we asked mothers questions and Prevention (CDC) approved this study, and all mothers about their child’s use of plastic food-packaging and personal provided written informed consent for themselves and their care products. These included how often their child ate or children prior to participation. drank food stored or heated in plastic, fast food, or prepackaged Urinary Phthalate Metabolite Concentrations. Chil- beverages, and if they had done so in the 48 h prior to the study dren provided urine samples during annual study visits between visit. We also asked if their child had used various personal care 2004 and 2011, which included an annual clinic visit at ages 1− products, including shampoo, conditioner, soap, hand sanitizer, 5 years and an annual home visit at ages 1−3 years. A subset of hairspray or gel, sunscreen, makeup, or nail polish in the 48 h 61 participants provided urine samples at both the home and prior to the study visit. clinic visit at the 1, 2, or 3 year study visit (n = 16, 25, and 26 Statistical Analysis. We did not normalize phthalate respectively). In our primary analyses, we gave priority to samples collected at the clinic visit if a child provided a urine metabolite measurements by creatinine values (i.e., standard- sample at both clinic and home visits. izing each individual phthalate value for the creatinine Prior to sample collection, each child’s genital area was wiped concentration of that specific sample) because changes in with a phthalate-free Wet Nap by their caregiver. For children kidney function, muscle mass, and other physiological factors who were not toilet trained, we collected urine samples by that occur during childhood influence urinary creatinine placing a surgical insert into a clean diaper at the beginning of excretion. Thus, comparing urinary creatinine or creatinine- the study visit. We checked the diapers for urine at the end of normalized biomarker concentrations between a one and a five 8882 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article Figure 1. Unadjusted urinary phthalate metabolite concentrations in HOME Study children (μg/L). Diamond indicates arithmetic mean, whiskers indicate minimum and maximum, edges of box indicate 25th and 75th percentile, and middle line indicates median. One year n = 277, 2 year n = 232, 3 year n = 234, 4 year n = 170, 5 year n = 201 (All subjects with at least 1 phthalate measurement). year old may be inappropriate. As an alternative, we trations in μmol/L for the ∑DEHP summary measure and μg/ compared methods of adjustment for urine dilution (i.e., L for individual phthalate metabolites. Beta estimates were including creatinine as a separate covariate in regression exponentiated to obtain the multiplicative difference between models) by calculating intraclass correlation coefficients groups for categorical predictors or per unit change for (ICC) for phthalate metabolites using three models: unadjusted continuous predictors, and are presented as percent difference for urine creatinine; adjusted for urine creatinine; and adjusted with a 95% confidence interval. for age-specific urine creatinine z-score. We calculated urine We evaluated temporal changes in phthalate exposure by creatinine z-scores separately for each annual study visit to examining children’s urinary phthalate metabolite concentra- tions as a function of age and time. We examined DiNP, DiDP, avoid comparing urine creatinine levels in children of different ages. and DiBP metabolites since use of these phthalates may have We calculated ICCs using random intercept linear mixed increased due to changes in manufacturer practices. We models with an unstructured covariance matrix to estimate evaluated BBzP, DnBP, DEP, and DEHP metabolites due to between- and within-subject variability of log -transformed more extensive restrictions on certain phthalate use in urinary phthalate metabolite concentrations. ICCs are a children’s products and concern over their potential toxicity. measure of the reproducibility of a measurement within an Specifically, the CPSIA regulations went into effect in early individual, where a value of zero indicates no reproducibility 2009 and could have reduced phthalate exposure in children and a value of one indicates perfect reproducibility. born in 2005−2006 since urine samples provided at 3, 4, and 5 We calculated ICCs for annual phthalate metabolite years of age would have been collected after the ban was in measurements over the entire study period (i.e., annual ICC), effect. Since participants born in 2003 would be 5 years old in using all participants who had phthalate measurements from at 2008 and all their samples would have been collected before the least two annual visits. We also calculated ICCs using the subset ban, we created a dichotomous “year of birth” variable to of participants who provided urine samples at both the home distinguish between children born in 2003−2004 from those and clinic portion of the 1, 2, and 3 year visits to quantify born in 2005−2006. We modeled phthalate metabolite variability over a shorter time frame (i.e., short-term ICC). On concentrations as a function of age, year of birth, and their average, these samples were collected 13 days apart (range 1− product interaction (age X year of birth). This model allowed 42 days). us to compare age and calendar time-related changes in We used linear mixed models to examine associations phthalate metabolite concentrations among children born in between urinary phthalate metabolite concentrations and 2005−2006, who would have been affected by the changes in demographic and temporal variables. Demographic variables phthalate use to those born in 2003−2004, who would have such as sex and race of the child, maternal education, and been less affected by these changes. We controlled these household income, as well as mean serum cotinine were analyses for sex and race of the child, household income, entered as fixed effects, while child age, and creatinine or maternal education, mean serum cotinine, and creatinine z- creatinine z-scores were entered as time-varying effects. We score. selected covariates based on prior knowledge and biological We used multivariable linear regression to examine food plausibility that they might be associated with both phthalate packaging and personal care product use as predictors of exposure and the predictors under investigation. The outcome urinary phthalate metabolites measured at the 5-year visit. We variables were log -transformed phthalate metabolite concen- assessed food packaging as a predictor of the metabolites of 8883 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article Table 1. Intraclass Correlation Coefficient of HOME Study Children’s Urinary Phthalate Metabolite Concentrations Collected (A) Annually from 1−5 Years of Age and (B) Twice ∼2 Weeks Apart at 1−3 Years of Age A: annual ICCs B: short-term ICCs b b metabolite all 1 year 2 years 3 yrs all c d unadjusted N = 283 subjects; 1,070 samples N = 16 subjects N = 25 subjects N = 27 subjects N = 61 subjects; 136 samples ∑DEHP 0.18 (0.10, 0.27) 0.35 (0.00, 0.61) 0.27 (0.00, 0.67) 0.44 (0.00, 0.73) 0.29 (0.05, 0.49) MBzP 0.26 (0.17, 0.35) 0.51 (0.30, 0.63) 0.14 (0.00, 0.42) 0.56 (0.29, 0.74) 0.34 (0.09, 0.54) MCPP 0.20 (0.12, 0.29) 0.57 (0.18, 0.85) 0.29 (0.00, 0.67) 0.45 (0.00, 0.75) 0.31 (0.09, 0.49) MCOP 0.17 (0.09, 0.26) 0.54 (0.13, 0.85) 0.00 (0.00, 0.37) 0.16 (0.00, 0.50) 0.15 (0.00, 0.33) MCNP 0.21 (0.13, 0.29) 0.71 (0.37, 0.86) 0.20 (0.00, 0.59) 0.25 (0.00, 0.70) 0.25 (0.09, 0.41) MEP 0.36 (0.26, 0.45) 0.30 (0.08, 0.52) 0.39 (0.15, 0.61) 0.53 (0.13, 0.79) 0.32 (0.08, 0.53) f f f f f MnBP 0.22 (0.02, 0.43) N/A N/A N/A N/A f f f f f MiBP 0.30 (0.10, 0.49) N/A N/A N/A N/A Creatinine Adjusted ∑DEHP 0.11 (0.03, 0.19) 0.41 (0.00, 0.85) 0.24 (0.00, 0.56) 0.52 (0.16, 0.81) 0.20 (0.00, 0.41) MBzP 0.25 (0.18, 0.35) 0.26 (0.08, 0.42) 0.25 (0.03, 0.56) 0.61 (0.35, 0.75) 0.39 (0.19, 0.57) MCPP 0.19 (0.11, 0.27) 0.60 (0.19, 0.91) 0.60 (0.21, 0.83) 0.34 (0.00, 0.63) 0.25 (0.07, 0.43) MCOP 0.15 (0.06, 0.24) 0.50 (0.00, 0.86) 0.00 (0.00, 0.26) 0.22 (0.00, 0.59) 0.03 (0.00, 0.20) MCNP 0.19 (0.09, 0.27) 0.72 (0.45, 0.91) 0.28 (0.00, 0.69) 0.17 (0.00, 0.79 0.19 (0.00, 0.38) MEP 0.35 (0.22, 0.44) 0.46 (0.29, 0.61) 0.28 (0.00, 0.72) 0.66 (0.38, 0.85) 0.29 (0.00, 0.52) f f f f f MnBP 0.20 (0.01, 0.39) N/A N/A N/A N/A f f f f f MiBP 0.31 (0.06, 0.50) N/A N/A N/A N/A Creatinine z-Score Adjusted ∑DEHP 0.09 (0.02, 0.16) 0.46 (0.07, 0.75) 0.28 (0.00, 0.53) 0.48 (0.26, 0.67) 0.20 (0.00, 0.40) MBzP 0.25 (0.16, 0.34) 0.39 (0.22, 0.53) 0.42 (0.20, 0.68) 0.59 (0.35, 0.79) 0.36 (0.16, 0.55) MCPP 0.19 (0.11, 0.26) 0.64 (0.43, 0.86) 0.59 (0.32, 0.78) 0.33 (0.07, 0.53) 0.25 (0.08, 0.43) MCOP 0.13 (0.03, 0.22) 0.47 (0.22, 0.63) 0.00 (0.00, 0.11) 0.22 (0.00, 0.40) 0.03 (0.00, 0.20) MCNP 0.20 (0.09, 0.28) 0.61 (0.51, 0.68) 0.24 (0.00, 0.53) 0.18 (0.00, 0.66) 0.19 (0.00, 0.38) MEP 0.39 (0.26, 0.48) 0.50 (0.36, 0.67) 0.33 (0.02, 0.69) 0.76 (0.30, 0.88) 0.33 (0.04, 0.56) f f f f f MnBP 0.16 (0.00, 0.38) N/A N/A N/A N/A f f f f f MiBP 0.31 (0.07, 0.50) N/A N/A N/A N/A creatinine 0.18 (0.08, 0.28) 0.45 (0.21, 0.65) 0.03 (0.00, 0.40) 0.30 (0.00, 0.54) 0.17 (0.00, 0.34) a b c ICC = intraclass correlation coefficient; N/A = not available. Models adjusted for visit number. All participants with at least 2 phthalate measurements, but not necessarily complete covariate information. Some participants provided 2 urine samples in multiple years but are counted e f only once in the final column. ∑DEHP= Sum of MEHP, MEHHP, MEOHP, and MECPP. MnBP and MiBP measured only at 4 and 5 years of age. DEHP, DiNP (i.e., MCOP), DiDP (i.e., MCNP), and BBzP did, however, observe age-related trends with some individual (i.e., MBzP) in urine, as these phthalates are potential food phthalate metabolites (Figure 1, Table S3, SI). Specifically, as 28,29 contaminants. Similarly, we assessed personal care product child age increased, MEP concentrations decreased slightly, use as predictors of MEP in urine, as DEP is the parent while MCOP concentrations increased. phthalate found in such products. We included the covariates Variability. The reproducibility of urinary phthalate sex, race, household income, maternal education, mean serum concentrations within individuals was low for most metabolites, cotinine, creatinine z-score, and year of birth in all models with annual ICCs ranging from 0.09 for ∑DEHP metabolites examining food packaging or personal care use as predictors of to 0.39 for MEP over the entire study period (adjusted for urinary phthalate metabolites. When modeling the use of creatinine z-score) (Table 1). In general, phthalate metabolite specificpersonalcareproductsas predictors of urinary concentrations in samples collected approximately 2 weeks phthalate metabolites, we additionally controlled for the total apart varied less than in annually collected samples (e.g., number of other personal care products used. ∑DEHP metabolites: short-term ICC = 0.20, annual ICC = 0.09). Among the subset of participants with urine samples RESULTS collected at both the clinic and home portion, short-term A total of 327 children provided at least one urine sample variability was generally lower when we looked at duplicate during their first 5 years of life. Of these children, 296 (n = sample pairs separately at 1, 2, and 3 years, rather than 1050 samples) had complete covariate information on race, sex, duplicate sample pairs from all visit years together. However, household income, maternal education, serum cotinine, and short-term ICCs fluctuated across visits for many phthalate urine creatinine (Table S2, SI). At age five, 190 children metabolites (e.g., MEP: visit 1 ICC = 0.50, n = 16; visit 2 ICC = provided a urine sample and had complete covariate 0.33, n = 25; visit 3 ICC = 0.76, n = 27), possibly because of the information. All measured phthalate metabolites were detected relatively small number of participants who contributed two in greater than 99% of urine samples with the exception of urine samples at more than one study visit, or they were not MEHP, which was detected in 79% of urine samples. consistently the same individuals from year to year. Methods Unadjusted measures of urinary ∑DEHP metabolite concen- trations did not change with age (Table S3, Figure S1, SI). We for urine dilution adjustment (unadjusted, creatinine adjusted, 8884 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article 8885 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Table 2. Adjusted Difference in HOME Study Children’s Urinary Phthalate Concentrations at 1-5 Years of Age According to Sociodemographic Factors or Serum Cotinine Levels (N = 296 With a Total of 1050 Repeated Measures) b c c ∑DEHP MBzP MCPP MCOP MCNP MEP MnBP MiBP d d d d d d d d N (%) or mean %difference %difference %difference %difference %difference %difference %difference %difference variable (SD) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Child Race non-hispanic white 194 (66) ref. ref. ref. ref. ref. ref. ref. ref. non-hispanic black 83 (28) −6(−17, 7) −6(−19, 10) −26 (−34, −17) −19 (−29, 8) −9(−19, 1) 91 (64, 123) −18 (−33, 1) 2 (−17, 25) other 19 (6) 6 (−13, 30) −1(−23, 26) −2(−18, 16) 1 (−18, 24) 12 (−6, 34) 97 (55, 152) 41 (1, 96) 53 (10, 113) Sex female 161 (54) ref. ref. ref. ref. ref. ref. ref. ref. male 135 (46) −2(−12, 10) 12 (−3, 28) 5 (−4, 16) −2(−13, 10) −4(−13, 6) −12 (−23, 0.3) −18 (−32, −1) −15 (−30, 3) Age (% change/year) 2.94 (1.47) −2(−5, 1) −2(−6, 1) −0.2 (−3, 3) 21 (18, 26) −6(−9, −4) −11 (−14, −7) −24 (−34, −13) −13 (−23, −1) Year of Birth born 2003−2004 142 (48) ref. ref. ref. ref. ref. ref. ref. ref. born 2005−2006 154 (52) −15 (−24, −6) −18 (−27, −6) −3(−11, 6) 1 (−9, 13) −4(−12, 5) −18 (−28, −7) −19 (−32, 4) −3(−18, 15) Household Income 62,276 (40,570) 0.5 (−1, 2) −4(−6, −1) 0 (−2, 2) −0.4 (−2, 2) −1(−2, 1) −2(−4, 1) 0.3 (−3, 3) −1(−3, 2) (% difference/$10,000) Maternal Education less than grade 12 25 (8) ref. ref. ref. ref. ref. ref. ref. ref. high school graduate 32 (11) 4 (−12, 23) −21 (−35, −3) −11 (−24, 3) 2 (−14, 22) −17 (−28, −4) 13 (−8, 38) −15 (−35, 12) −26 (−44, −3) some college 77 (26) 7 (−5, 21) −12 (−24, 2) −1(−11, 10) −0.1 (−12, 13) −11 (−20, −1) −14 (−26, −1) 17 (−3, 42) −2(−19, 19) college graduate 162 (55) −10 (−19, 0.1) −33 (−41, −24) −17 (−25, −10) −12 (−21, −2) −20 (−27, −12) −36 (−44, −28) −9(−23, 8) −8(−23, 9) Mean Cotinine 0.66 (1.97) 1 (−2, 5) 5 (−0.1, 10) 1 (−3, 4) −2(−5, 2) −1(−5, 2) 0 (−5, 5) 3 (−2, 9) 0.5 (−5, 6) (% difference/ng/mL) a b c Results adjusted for all other variables listed in Table 2 and urinary creatinine z-score. CI= confidence interval. ∑DEHP= MEHP, MEHHP, MEOHP, and MECPP. MnBP and MiBP measured only at d e visits 4 and 5. %Difference = percent difference in geometric means compared to the reference group for categorical variables or for a one unit increase for continuous variables. Other race = Asian, Pacific Islander, or American Indian. Environmental Science & Technology Article Table 3. Adjusted Difference in HOME Study Children’s Urinary Phthalate Metabolite Concentrations at 5 Years of Age According to Parent-Reported Child Food Packaging Use and Diet (N = 190) ∑DEHP (μmol/L) MBzP (μg/L) MCPP (μg/L) MCOP (μg/L) MCNP (μg/L) c c c c c variable N (%) % difference (95% CI) % difference (95% CI) % difference (95% CI) % difference (95% CI) % difference (95% CI) Food Stored in Plastic <1/week 15 (7.9) ref. ref. ref. ref. ref. 1−6/week 80 (42.1) 25 (1, 56) 32 (−7, 86) 11 (−12, 40) −4(−28, 30) 9 (−12, 35) ≥1/day 62 (32.6) −3(−25, 25) 28 (−14, 91) 5 (−19, 38) 38 (−2, 96) 20 (−6, 53) Food Stored in Plastic in Past 48 h no 39 (20.5) ref. ref. ref. ref. ref. yes 113 (59.5) −9(−27, 13) 15 (−19, 63) 0 (−21, 26) −7(−32, 26) 16 (−6, 44) Food Heated in Plastic <1/week 93 (48.9) ref. ref. ref. ref. ref. ≥1/week 64 (33.7) 3 (−19, 30) −3(−32, 40) −4(−24, 23) −3(−30, 33) 11 (−11, 39) Food Heated in Plastic in Past 48 h No 127 (66.8) ref. ref. ref. ref. ref. Yes 25 (13.2) −14 (−36, 14) −25 (−53, 19) −28 (−47, −3) −34 (−56, −0.4) −20 (−40, 5) Fast Food <1/week 85 (44.7) ref. ref. ref. ref. ref. ≥1/week 72 (37.9) −1(−22, 25) 55 (9, 123) 19 (−7, 51) 35 (−2, 85) 11 (−11, 39) Prepackaged Beverages <1/week 53 (27.9) ref. ref. ref. ref. ref. 1−6/week 65 (34.2) 1 (−20, 28) 15 (−20, 67) 22 (−5, 57) 15 (−17, 60) 17 (−6, 47) ≥1/day 37 (19.5) −17 (−36, 7) −29 (−53, 5) 14 (−12, 48) 16 (−19, 64) 1 (−21, 29) Prepackaged Beverages in Past 48 h no 68 (35.8) ref. ref. ref. ref. ref. yes 83 (43.7) 16 (−7, 44) −8(−35, 29) 29 (4, 62) 18 (−12, 57) 1 (−17, 24) Adjusting for sex, race of child, household income, maternal education, mean serum cotinine, urinary creatinine z-score and year of birth. CI = b c confidence interval. ∑DEHP= MEHP, MEHHP, MEOHP, and MECPP. %Difference = percent difference in geometric means compared to the reference category. creatinine z-score adjusted) did not meaningfully change our less than once per week, while children who ate foods that had reported measures of variability (Table 1). been heated in plastic within the past 48 h had MCOP Demographic Predictors. Race predicted select urinary concentrations 34% lower than those who did not (95% CI: phthalate concentrations, with black children having 91% (95% −56, −0.4). Urinary concentrations of the ∑DEHP metabo- CI: 64, 123) higher MEP concentrations, but 26% (95% CI: 34, lites, MCNP, MCPP (a nonspecific metabolite of HMW 17) lower MCPP concentrations, compared to white children phthalates and a minor metabolite of DnBP), and MBzP were after adjustment for confounders (Table 2). Children in the not associated with eating food stored or heated in plastic. “Other” race category (Asian, Pacific Islander, or American Drinking prepackaged beverages within the past 48 h was Indian) had higher concentrations of MEP, MnBP, and MiBP associated with 29% higher (95% CI: 4, 62) urinary MCPP compared to white children (Table 2), although this analysis concentrations, but was not associated with ΣDEHP metabo- was limited by the relatively small number of children in the lite, MCOP, MCNP, or MBzP concentrations. “Other” category (n = 19). Higher maternal education Most participants used shampoo and various types of soap predicted lower concentrations of all measured phthalates, within 48 h of urine collection, but less than 15% used hairspray with children of mothers who were college graduates having or hair gel, makeup, or nail polish. Recent use of hairspray or 10%, 33%, and 36% lower concentrations of ∑DEHP hair gel was associated with 63% higher urinary MEP metabolites, MBzP, and MEP, respectively, compared to concentrations (95% CI: 7, 148) among 5 year-old participants children of mothers who did not graduate from high school. after adjustment for covariates, while the use of other personal Boys had 12% (95% CI: −23, 0.3) lower urinary concentrations care products was not (Table S4, SI). of MEP compared to girls. Children’s average serum cotinine Temporal Trends vs Age. Increasing age and later year of birth (2005−2006 compared to 2003−2004) were both levels did not predict urinary phthalate metabolite concen- trations after adjustment for other covariates. associated with lower concentrations of several phthalate Food Packaging and Personal Care Products. Eating metabolites after adjusting for race, sex, household income, fast food at least once per week was associated with 35% higher maternal education, serum cotinine, and creatinine z-score MCOP (95% CI: −2, 85) and 55% higher MBzP (95% CI: 9, (Table 2). The association between birth year and ∑DEHP 123) urine concentrations compared to eating fast food less metabolites changed with age, where those born in 2005−2006 than once per week after adjustment for covariates (Table 3). had increasingly lower relative concentrations compared to Five year-old children who ate foods that had been stored in those born in 2003−2004 as they got older, although this plastic at least once per day had urinary MCOP concentrations interaction was not statistically significant after adjustment for 38% higher (95% CI: −2, 96) than those who ate such foods creatinine z-score (p = 0.24) (Figure 2, Table S5, SI). In 8886 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article Figure 2. Geometric mean concentrations and smoothed regression of urinary ∑DEHP metabolites and MCOP between 1 and 5 years of age among those born between 2003 and 2004 or 2005−2006. ∑DEHP = sum of MEHP, MEHHP, MEOHP, and MECPP. Children born in 2003− 2004 provided urine samples before the CPSIA went into effect, while children born in 2005−2006 provided their 3, 4, and 5 year urine samples after the CPSIA went into effect. contrast, age was positively associated with urinary MCOP short-term exposure to these phthalates. This may be especially concentrations and the association between birth year and true during infancy, when dietary variation tends to be limited MCOP or MCNP concentrations changed with age, such that and personal care product use is a routine part of child care. For MCOP and MCNP concentrations were higher among children example, in a study examining phthalate exposure among born in 2005−2006 compared to those born in 2003−2004 (p- infants, the significant association between recent use of baby value for interaction <0.0001 for both metabolites) (Figure 2). lotion and urinary MEP concentrations was strongest among For instance, compared to children born in 2003−2004, those infants less than 8 months old. Our results, which indicate that born in 2005−2006 had 22% lower MCOP concentrations at urinary MCOP, MCNP, and MCPP concentrations measured 2 one year of age, but 33% higher concentrations at five years of weeks apart varied less among one year-olds than older children age (Table S5, SI). (Table 1), are consistent with the hypothesis that exposures become more varied as children mature. While a single spot DISCUSSION sample may be sufficient to characterize exposure over a relatively narrow time window (e.g., weeks), one spot urine Our longitudinal study design allowed us to evaluate variability sample may not adequately capture exposure over months or of urinary phthalate metabolite concentrations during early years, particularly for toddlers and preschool aged children, childhood over both short and long-term exposure periods, as since diet and personal care product use, as well as physiology, well as the effect of policy and manufacturer related changes in change considerably over the first five years of life. Consistent phthalate use during the study period. In addition, our cross- with this hypothesis, the annual ICCs reported in the present sectional analysis allowed us to examine specific consumer study are generally lower, suggesting more variability, compared products as sources of phthalate exposure in preschool aged to ICCs reported in a number of studies in adult children. Our findings suggest that exposure to certain 18−20,33 populations. phthalates varies during early childhood by race, maternal We observed less variability (e.g., higher reproducibility) in education, use of personal care products such as hairspray or urinary MEP concentrations compared to other phthalate gel, consumption of fast food, and possibly consumption of 18−20,33 metabolites, consistent with previous studies. This may food stored in specific types of packaging. Our findings also be a result of the pathways by which most young children are suggest that changes in manufacturer practices due to market- exposed to the parent compound DEP. DEP is found mainly in forces and the CPSIA of 2008, which restricted DEHP use in personal care products, which are often used regularly, but their children’s products, may have resulted in decreased exposure to use varies substantially between people. In contrast, ∑DEHP DEHP among study participants. However, urinary concen- metabolites show substantial within-person variation, likely due trations of MCOP, a metabolite of DiNP, increased during this to diet being the primary source of exposure. same time period. It was difficult to separate the effects of physiological and We found that phthalate metabolite concentrations in spot behavioral patterns during child development from temporal urine samples collected approximately 2 weeks apart were changes in phthalates used in consumer products over the study weakly to moderately correlated, while concentrations meas- period on measured urinary phthalate metabolite concen- ured a year or more apart were less correlated. Since phthalates 31,32 trations. Because age-related physiological changes in kidney have biological half-lives of less than 24 h, urinary metabolite concentrations reflectonlyrecentexposure. function and muscle mass during early childhood affect However, because some phthalate exposures are linked to creatinine excretion, the use of creatinine to adjust for urine routine behaviors that may vary little over short periods of time, dilution is complicated. We observed increasing urinary a single spot urine sample may be a reasonable measure of creatinine concentrations from 1 to 5 years of age (SI Figure 8887 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article S2) and substantially lower ICCs when using creatinine misclassification. For comparison, a study of phthalate exposure normalization (data not shown). As children grow older and among infants found that use of baby lotion was positively more independent, age related changes in behavior may also associated with urinary MEP concentrations, while a recent affect phthalate exposures during this time. In addition, changes study of 8−13 year olds reported sex-specificpositive in manufacturer practices and the implementation of the associations between urinary MEP concentrations and deodor- CPSIA in February of 2009 further complicated this issue. ant, cologne or perfume, and hair conditioner use, but not use Indeed, after controlling for urine dilution using age-specific of hair spray or gel. creatinine z-scores, we detected differences in urinary ∑DEHP We found that consumption of fast food more than once a metabolite concentrations between children born in 2003− week was associated with higher urinary MBzP and MCOP 2004 and those born in 2005−2006. For example, at five years concentrations, although it is uncertain if fast food packaging, of age, children born later had lower ∑DEHP metabolite fast food itself, or both are sources of phthalate exposure. We concentrations, a phthalate targeted by CPSIA, but higher also observed a positive association between urinary MCOP MCOP concentrations compared to those born earlier. concentrations and eating food stored in plastic containers, but Our data are consistent with possible increasing use of DiNP a negative association between MCOP and eating food that had in consumer products in recent years, although the CPSIA also been heated in plastic within the past 48 h. Although these placed some restrictions on the use of this phthalate in specific associations did not reach statistical significance, these children’s products. It is estimated that DiNP and DiDP make contrasting findings make it difficult to reach a conclusion up about 33% of the U.S. plasticizer market. Our results about exposure via plastic food packaging among this suggest that changes in manufacturer practices and the CPSIA population. Our 48 h window may have been too long to may have played a role in reducing exposure to some key detect meaningful differences in phthalate metabolite concen- phthalates among the target population (children), as the later trations, and we did not collect potentially important born children had lower concentrations of ∑DEHP metabo- information such as food type and food storage time and lites and MCPP (a DnOP and DnBP metabolite) at all ages. temperature. In addition, we were not able to identify the Similar decreases in urinary phthalate metabolite concen- type or brand of plastic food containers used and different trations, specifically DEHP metabolites, can be seen in Europe plastic formulations may contain different amounts of phthalate as well. However, HOME study children who provided urine residues. A study evaluating predictors of phthalates among samples after the CPSIA went into effect had higher MCOP older children also did not observe an association between and MCNP concentrations than children providing urine maternal report of exposure to food packaging in the previous samples before the CPSIA. These are metabolites of DiNP and 48 h and urinary phthalate metabolites. However, researchers DiDP, respectively, which may have increased in use as DEHP evaluating food packaging as a source of phthalate exposure was phased out. Similar trends were recently reported among using dietary intervention observed a significant decrease in children, adolescents, and adults in data from the National urinary phthalate metabolite concentrations when participants Health and Nutrition Examination Survey (NHANES) were provided catered meals with minimal plastic packaging. collected from 2001 to 2010, where urinary DEHP metabolite, A major limitation of this analysis was that we used creatinine MnBP, and MBzP concentrations decreased over time, while to adjust for urine dilution. Because kidney function and muscle urinary MCOP, MCNP, and MiBP concentrations increased. mass are changing rapidly across the age range studied here, The CPSIA, which limited phthalate usage in children’s creatinine normalization is not an ideal method for adjustment products, would not be expected to lead to the observed because it could over- or underestimate exposure at different decreases in phthalate exposure among older children and ages. As an alternative, we included age-specific creatinine z- adults, suggesting that other factors, such as additional scores in regression models to adjust for urine dilution. In regulatory pressures and consumer-driven market forces, may addition, we did not ask participants how often their children have also played a role in decreasing exposure to specific played with toys made of plastic, the age of these toys, phthalates among children, as well as adults. mouthing behaviors, or collect other information that would We observed higher urinary MEP concentrations among have helped us more directly examine whether the temporal blacks and other nonwhite children compared to whites, but trends in certain urinary phthalate metabolites were a result of similar concentrations of most other phthalate metabolites. the CPSIA. We were also not able to report concentrations of This finding is consistent with observations among older the hydrolytic monoester metabolites MEHP, MnBP, and 1,36 children in biomonitoring studies such as NHANES. Higher MiBP in urine samples collected during visits 1, 2, or 3 due to urinary phthalate concentrations among black and other potential contamination from diaper inserts. Another nonwhite children could be due to differences in the frequency limitation is our modest sample size, which limits our ability or type of personal care products used. to detect associations, especially for behavioral factors that are Similar to previous studies, we observed lower urinary MEP less accurately reported. We also do not have measures of 1,6 concentrations in males compared to females. Among five phthalates in participant’s indoor environments, a potential 11,34 year-olds we also observed a positive association between the source of exposure particularly in this age group. Phthalate use of hairspray or gel within the past 48 h and urinary MEP concentrations in household dust can be quite high, and concentrations and 18 of the 22 participants who reported exposure through this pathway may substantially contribute to using these products were female. We did not see associations participant’s urinary phthalate metabolite levels. We also did between the use of other personal care products and MEP not investigate maternal use of personal care products as a concentrations, possibly due to the small number of potential pathway of child phthalate exposure, although this participants reporting use of most products or our reliance could be pursued in a future analysis. on maternal report of children’s exposure history. Self-reported In conclusion, urinary phthalate metabolite concentrations in information is often subject to misclassification, and a mother’s young children vary over time, likely due to a combination of recall of their child’s experience may result in additional age related changes in exposure and perhaps metabolism, as 8888 dx.doi.org/10.1021/es501744v | Environ. Sci. Technol. 2014, 48, 8881−8890 Environmental Science & Technology Article (7) Braun, J. M.; Sathyanarayana, S.; Hauser, R. Phthalate exposure well as changes in the use of phthalates in commercial products. and children’s health. Curr. Opin. Pediatr. 2013, 25 (2), 247−54. Consistent with previous reports in adults, our findings (8) Buckley, J. P.; Palmieri, R. T.; Matuszewski, J. M.; Herring, A. H.; suggest that personal care products are a source of exposure to Baird, D. D.; Hartmann, K. E.; Hoppin, J. A. Consumer product DEP, and that fast food consumption may be a source of exposures associated with urinary phthalate levels in pregnant women. exposure to DiNP and BBzP among young children. Finally, we J. Exposure Sci. Environ. Epidemiol. 2012, 22 (5), 468−475. found that DEHP exposure may have decreased over the course (9) Sathyanarayana, S.; Karr, C. J.; Lozano, P.; Brown, E.; Calafat, A. of our study, possibly in part as a result of market forces and the M.; Liu, F.; Swan, S. H. Baby care products: Possible sources of infant CPSIA, suggesting that the regulation of chemicals used in phthalate exposure. Pediatrics 2008, 121 (2), E260−E268. consumer products may be an effective method for decreasing (10) Rudel, R. A.; Gray, J. M.; Engel, C. L.; Rawsthorne, T. W.; exposure among sensitive populations, particularly with Dodson, R. E.; Ackerman, J. M.; Rizzo, J.; Nudelman, J. L.; Brody, J. G. compounds that have a short biological half-life. Food packaging and bisphenol A and bis(2-Ethyhexyl) phthalate exposure: Findings from a dietary intervention. Environ. Health ASSOCIATED CONTENT Perspect. 2011, 119 (7), 914−920. (11) Carlstedt, F.; Jonsson, B. A. G.; Bornehag, C. G. PVC flooring is * S Supporting Information related to human uptake of phthalates in infants. Indoor Air 2013, 23 Additional tables and figures are available as Supporting (1), 32−39. Information as mentioned in the text. This material is available (12) Lewis, R. C.; Meeker, J. D.; Peterson, K. E.; Lee, J. M.; Pace, G. free of charge via the Internet at http://pubs.acs.org. G.; Cantoral, A.; Tellez-Rojo, M. M. Predictors of urinary bisphenol A and phthalate metabolite concentrations in Mexican children. AUTHOR INFORMATION ■ Chemosphere 2013, 93, 2390−2398. Corresponding Author (13) Teitelbaum, S. L.; Mervish, N.; Moshier, E. L.; Vangeepuram, N.; Galvez, M. P.; Calafat, A. M.; Silva, M. J.; Brenner, B. L.; Wolff, M. *E-mail: joseph_braun_1@brown.edu. S. Associations between phthalate metabolite urinary concentrations Notes and body size measures in New York City children. Environ. Res. 2012, The authors declare the following competing financial 112, 186−193. interest(s): Two coauthors have potential conflicts of interest. (14) Whyatt, R. M.; Liu, X. H.; Rauh, V. A.; Calafat, A. M.; Just, A. Dr. Lanphear has served as an expert witness and as a C.; Hoepner, L.; Diaz, D.; Quinn, J.; Adibi, J.; Perera, F. P.; Factor- consultant to the California Attorney Generals Office (with no Litvak, P. Maternal prenatal urinary phthalate metabolite concen- compensation) and as a consultant on a US Environmental trations and child mental, psychomotor, and behavioral development Protection Agency research study (with compensation). Dr. at 3 years of age. Environ. Health Perspect. 2012, 120 (2), 290−295. Braun has provided statistical consulting to plaintiffs in a lead (15) Kim, Y.; Ha, E. H.; Kim, E. J.; Park, H.; Ha, M.; Kim, J. H.; Hong, Y. 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Published: Jun 30, 2014

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