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Association of Exposure to Endocrine-Disrupting Chemicals During Adolescence With Attention-Deficit/Hyperactivity Disorder–Related Behaviors

Association of Exposure to Endocrine-Disrupting Chemicals During Adolescence With... Key Points Question Is exposure to endocrine- IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood disrupting chemicals during adolescence neurobehavioral disorder. Studies suggest that prenatal and early childhood exposure to endocrine- a risk factor for behaviors associated disrupting chemicals may be associated with ADHD, but the association during adolescence has not with attention-deficit/hyperactivity been studied to date. disorder (ADHD)? Findings In this cross-sectional analysis OBJECTIVE To evaluate the association between exposure to select endocrine-disrupting chemicals of data from 205 adolescents during adolescence and ADHD-related behaviors. participating in a prospective birth cohort study, exposure to select DESIGN, SETTING, AND PARTICIPANTS For this cross-sectional analysis, data were collected from phthalates was associated with an 205 adolescents in the New Bedford Cohort, an ongoing prospective birth cohort, between June 18, increased risk of ADHD-related 2011, and June 10, 2014. The adolescents provided spot urine samples and underwent behaviors. Associations were strongest neurodevelopmental testing. Statistical analyses performed from January 15 to December 31, 2019, for phthalates with antiandrogenic used a repeated-measures analysis with multivariate modified Poisson models to estimate the activity. adjusted relative risk of ADHD-related behaviors associated with exposure to endocrine-disrupting chemicals. Meaning These findings support the potential importance of exposures to EXPOSURES Urinary biomarker concentrations of endocrine-disrupting chemicals or their endocrine-disrupting chemicals, metabolites, including phthalates, parabens, phenols, and triclocarban, were quantified. Summary especially phthalates, during exposure measures were created, combining biomarker concentrations of chemicals with a shared adolescence as correlates of ADHD- mechanism of action, exposure pathway, or chemical class. related behaviors. MAIN OUTCOMES AND MEASURES Behaviors related to ADHD were assessed with up to 14 indices Supplemental content from self-, parent-, and teacher-completed behavioral checklists using validated and standardized instruments; specifically, the Conners Attention Deficit Scale and the Behavior Assessment System Author affiliations and article information are listed at the end of this article. for Children, Second Edition. Scores on each index were dichotomized to identify those with evidence of a significant behavioral problem, defined by each scale’s interpretive guidelines. RESULTS Among the 205 participants, the mean (SD) age at assessment was 15.3 (0.7) years, with 112 girls (55%) and 124 non-Hispanic White participants (61%). The median urine concentrations were 0.45 μmol/L of Σantiandrogenic phthalates, 0.13 μmol/L of ΣDEHP metabolites, 0.49 μmol/L of Σpersonal care product phthalates, 0.35 μmol/L of Σparabens, 0.02 μmol/L of Σbisphenols, and 0.02 μmol/L of Σdichlorophenols. A total of 82 (40%) had scores consistent with a significant behavioral problem, whereas 39 (19%) had an ADHD diagnosis. Each 2-fold increase in the sum of antiandrogenic phthalate concentrations was associated with a 1.34 (95% CI, 1.00-1.79) increase in the risk of significant ADHD-related behavior problems, whereas a 2-fold increase in the sum of dichlorophenols was associated with a 1.15 (95% CI, 1.01-1.32) increased risk. These associations tended to be stronger in male participants, but comparisons of sex-specific differences were imprecise. (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 1/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Abstract (continued) CONCLUSIONS AND RELEVANCE Endocrine-disrupting chemicals are used in a wide variety of consumer products resulting in ubiquitous exposure. The study findings suggest that exposure to some of these chemicals, particularly certain phthalates, during adolescence may be associated with behaviors characteristic of ADHD. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 Introduction Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood, affecting approximately 9.4% of children in the United States. Attention-deficit/ hyperactivity disorder is characterized by difficulty maintaining attention, controlling impulses, and regulating activity level and may be associated with academic and social problems as well as 2-5 difficulties throughout adulthood. There is growing evidence that exposure to endocrine-disrupting chemicals (EDCs), such as 6-9 phthalates and phenols, may be associated with ADHD. Phthalates and phenols are widely used in consumer products, including food processing and packaging equipment, personal care products 6,10,11 (eg, cosmetics and fragrances), and pharmaceuticals, resulting in ubiquitous exposure. Although epidemiologic studies have reported associations between prenatal and early childhood exposure 8,12,13 to EDCs and ADHD-like behaviors, few studies have examined the association of exposure to these chemicals during adolescence with ADHD-like behaviors. Similar to the prenatal period, adolescence is a critical time for brain development, characterized by structural and functional changes in the brain as well as the onset of behavioral problems, some of which may be due to hormonal changes. As such, exposure to EDCs during adolescence may be particularly detrimental. The objective of this study is to examine the association of adolescent exposure to EDCs, specifically phthalates, phenols, and triclocarban, with ADHD-related behaviors. We hypothesize that exposure to certain EDCs during adolescence is particularly detrimental to adolescent behavior given the rapid brain development that occurs during this time. Methods Study Population We analyzed data from the New Bedford Cohort, a prospective birth cohort of mother-infant pairs recruited after delivery at a New Bedford, Massachusetts, hospital between 1993 and 1998. The original aim of the study was to examine the association of prenatal organochlorine and metal exposures with subsequent neurodevelopment among children living near the New Bedford Harbor Superfund site. Eligibility requirements included newborns who were vaginally delivered to mothers who were at least 18 years of age and who were available for neonatal examination. In-person neurodevelopmental testing was performed when participants were approximately 15 years of age between 2008 and 2014. Of the 788 newborns enrolled in the New Bedford Cohort, 660 (84%) met eligibility criteria (residence in the study region, absence of catastrophic central nervous system injury or disease, available biomarkers of early chemical exposure, and contact information) for these assessments and, of those newborns, 528 (80%) completed assessments. Midway through the 15-year follow-up, the study added assessment of exposure to EDCs. We invited the 252 participants who were evaluated in this last half of the study to provide spot urine samples at 2 points: during neurodevelopmental assessments and approximately 1 week later (mean duration of time after assessment, 7 days [range, 1-35 days]) (eFigure in the Supplement). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The study research protocol was reviewed and approved by the human participants committee of the JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 2/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Brigham and Women’s Hospital (Boston, Massachusetts). Written informed parental consent and child assent were obtained from participants. The analysis of deidentified specimens at the Centers for Disease Control and Prevention (CDC) laboratory (Atlanta, Georgia) was determined not to constitute engagement in human participants research. Urine Sample Collection and EDC Measurement Urine sample collection and analysis have been described elsewhere. In brief, of the 252 adolescents invited to provide urine samples, 205 (81%) provided at least 1 sample. Urine samples were collected in sterile polypropylene cups and frozen until processing and analysis. It was not possible to analyze all urine specimens, owing to resource limitations; of the 144 adolescents (57%) who provided 2 samples, 60 had each sample analyzed separately, and the mean concentration was used in analyses. For the remaining 84, equal volumes of the 2 samples were pooled for analysis. Specific gravity was measured using a digital refractometer (Pocket PAL-10S; ATACO USA Inc). Urine concentrations of 28 biomarkers were quantified at the CDC in 2 batches (2012 and 16-20 2016), based on the timing of collection. Batch 1 included 11 phthalate metabolites and 8 phenols. Five additional biomarkers of phthalates or the phthalate substitute cyclohexane-1,2- dicarboxylic acid, monohydroxy isononyl ester (MHINCH), 3 additional phenols, and triclocarban were measured in batch 2 (Table 1). Because batch 1 analyses did not include all biomarkers, urinary concentrations of all analytes were available for 178 participants (87%), with the remaining 27 participants missing concentrations of MHINCH, monohydroxyisobutyl phthalate (MHiBP), monoisononyl phthalate (MNP), monohydroxybutyl phthalate (MHBP), bisphenol F (BPF), bisphenol S (BPS), ethylparaben, and triclocarban. The limits of detection for the target analytes ranged from 0.2 to 2.3 μg/L; for concentrations less than the limit of detection, instrument readings were used in data analyses. The study-specific urine quality assurance and quality control samples for both between-batch and within-batch analyses demonstrated the excellent reproducibility of the analytic chemistry methods used. Exposure Assessment Because people are routinely exposed to multiple EDCs, we created summary exposure measures by combining biomarker concentrations for chemicals with a shared mechanism of action, exposure pathway, or chemical class. As described elsewhere, the molar sum (Σ) of 11 phthalate metabolites derived from antiandrogenic parent compounds was created to estimate Σantiandrogenic phthalates (in units of micromoles per liter): mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2- ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5- carboxypentyl phthalate (MECPP), mono-n-butyl phthalate (MBP), monoisobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), MHiBP, monocarboxyoctyl phthalate (MCOP), MNP, and 16,21-23 MHBP. Summary measures for phthalates found in personal care products (Σpersonal care products; in units of micromoles per liter) was the molar sum of monoethyl phthalate (MEP), MBP, MHBP, MiBP, and MHiBP; the sum of di(2-ethylhexyl) phthalate (DEHP) metabolites (ΣDEHP; in units of micromoles per liter) was the molar sum of MECPP, MEHHP, MEOHP, and MEHP; total parabens (Σparabens; in units of micromoles per liter) was the molar sum of butyl, ethyl, methyl, and propyl paraben; total bisphenols (Σbisphenols; in units of micromoles per liter) was the molar sum of bisphenol A (BPA) and its replacements BPF and BPS; and total dichlorophenols (Σdichlorophenols; in units of micromoles per liter) was the molar sum of 2,4-dichlorophenol and 2,5-dichlorophenol. Behavior Assessment Attention-deficit/hyperactivity disorder–related behaviors were assessed using validated behavioral checklists from the Behavior Assessment System for Children, Second Edition (BASC-2; parent-, teacher-, and self-reported) and Conners Attention Deficit Scale (CADS; parent- and 24,25 teacher-reported). Both instruments have excellent internal reliability, with coefficient α values JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 3/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD of 0.85 to 0.96 for the CADS and 0.74 to 0.95 for the BASC-2 (hyperactivity and attention problem scales), depending on the reporter. The BASC-2 scales are moderately correlated (r  0.5-0.6) with 24,25 the Conners ADHD index, which, in turn, has excellent discriminant validity for ADHD diagnosis. Parents and adolescents completed these checklists at the study visit and first urine sample collection, while teachers completed them a median (SD) of 2.5 (6.6) months after the first urine sample collection. The BASC-2 consists of 139 to 176 questions, and the CADS consists of 14 to 15 Table 1. Distribution of Urinary Biomarker Concentrations of Phthalates, Phenols, Their Substitutes, and Triclocarban Among 205 Adolescent Participants in the New Bedford Cohort Who Provided Urine Samples From 2011 to 2014 Biomarker Full chemical name 5th Percentile 25th Percentile 50th Percentile 75th Percentile 95th Percentile b,c ΣAntiandrogen phthalates NA 0.11 0.26 0.45 0.71 1.41 ΣDEHP metabolites NA 0.03 0.08 0.13 0.19 0.50 ΣPersonal care product NA 0.09 0.24 0.49 0.97 3.22 phthalates b,c ΣParabens NA 0.03 0.05 0.35 1.15 5.83 ΣBisphenols NA 0.01 0.01 0.02 0.03 0.07 ΣDichlorophenols NA 0.00 0.01 0.02 0.03 0.15 Individual chemicals MEP Monoethyl phthalate 7.90 23.9 45.0 122 423 MBP Mono-n-butyl phthalate 2.40 8.50 16.0 24.3 53.6 MiBP Monoisobutyl phthalate 2.10 6.60 11.5 19.3 38.0 MHBP Monohydroxybutyl phthalate 0.20 0.70 1.50 2.85 6.60 MHiBP Monohydroxyisobutyl phthalate 1.10 2.30 4.00 7.30 17.5 MBzP Monobenzyl phthalate 1.3 4.5 9.3 17.8 64.3 MEHP Mono-2-ethylhexyl phthalate 0.10 (<LOD) 0.70 1.50 3.20 9.70 MEHHP Mono-2-ethyl-5-hydroxyhexyl 2.20 6.20 10.5 17.4 45.4 phthalate MEOHP Mono-2-ethyl-5-oxohexyl phthalate 1.60 4.80 7.70 11.7 33.7 MECPP Mono-2-ethyl-5-carboxypentyl 5.20 11.60 18.5 28.1 70.8 phthalate MCOP Monocarboxyoctyl phthalate 7.40 26.0 49.4 103.0 214.0 MNP Mono-isononyl phthalate 0.20 0.70 1.60 4.30 15.1 MCNP Monocarboxynonyl phthalate 1.30 2.90 4.65 7.10 13.60 MCPP Mono-3-carboxypropyl phthalate 0.9 2.5 5.0 10.2 43.6 c,d MHINCH Cyclohexane-1,2-dicarboxylic acid, 0.00 (<LOD) 0.10 0.30 0.50 1.10 monohydroxy isononyl ester M-paraben Methyl paraben 3.60 7.50 42.4 140 598 P-paraben Propyl paraben 0.30 1.00 3.70 18.6 117 E-paraben Ethyl paraben 0.20 0.40 0.70 2.10 29.0 B-paraben Butyl paraben 0.00 (<LOD) 0.00 (<LOD) 0.20 0.50 4.1 BPA Bisphenol A 0.50 1.00 1.70 2.80 6.70 BPS Bisphenol S 0.10 0.20 0.40 0.80 2.30 BPF Bisphenol F 0.00 (<LOD) 0.10 0.20 0.60 5.50 BP-3 Benzophenone-3 4.15 13.0 38.3 172 1148 2,4-DCP 2,4-Dichlorophenol 0.15 0.40 0.60 1.10 2.30 2,5-DCP 2,5-Dichlorophenol 0.40 0.80 1.65 4.20 22.7 TCS Triclosan 1.50 3.20 8.50 49.9 381 TCC Triclocarban 0.00 (<LOD) 0.00 (<LOD) 0.10 0.20 4.70 Abbreviations: DEHP, di(2-ethylhexyl) phthalate; LOD, limit of detection; NA, not sum of MECPP, MEHHP, MEOHP, MEHP; Σparabens (μmol/L): molar sum of B-paraben, applicable; Σ, molar sum. E-paraben, M-paraben, and P-paraben; Σbisphenols (μmol/L): molar sum of BPA, BPF, a and BPS; and Σdichlorophenols (μmol/L): molar sum of 2,4-dichlorophenol and Units for sums are μmol/L and units for individual biomarkers are μg/L. 2,5-dichlorophenol. Concentrations were calculated as follows: Σantiandrogen phthalates (μmol/L): molar Because some chemicals were not measured in the first batch of Centers for Disease sum of MEHHP, MEHP, MEOHP, MECPP, MBP, MiBP, MBzP, MHiBP, MCOP, MNP, and Control and Prevention analyses, Σantiandrogen phthalates, Σpersonal care product MHBP (MCOP and MNP were downweighted by multiplying their molar concentrations phthalates, Σparabens, Σbisphenols, MHINCH, MCOCH, BPS, BPF, MNP, MHBP, MHiBP, by 0.43 prior to summing to reflect the potency of their parent compound relative to TCC, and E-paraben concentrations were available for only 178 of the 205 participants. the other antiandrogenic phthalates); Σpersonal care product phthalates (μmol/L): molar sum of MBP, MHBP, MEP, MiBP, and MHiBP; ΣDEHP metabolites (μmol/L): molar Phthalate replacement. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 4/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD questions, depending on the reporter. For each question, the frequency of adverse behavior is ranked using a 4-point Likert scale. Responses generate composite behavioral indices expressed as age- and sex-adjusted T-scores standardized to a mean (SD) of 50 (10), where a higher score indicates more adverse behavior. These measures generate 14 ADHD-related behavior indices. From the BASC-2, we included indices of inattention (teacher-, parent-, and self-reported), hyperactivity (teacher-, parent-, and self-reported), and executive function (teacher- and parent-reported). From the CADS parent and teacher reports, we included indices for inattention and hyperactivity based on Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnostic criteria and a CADS index of overall ADHD behaviors. All 205 adolescents with exposure data had at least 1 outcome measure, 204 (99.5%) had parent- and self-completed checklists, and 173 (84%) had teacher- completed checklists. Covariates Data on parental demographic charateristics (race/ethnicity, educational level, and income), health history, and tobacco use during pregnancy were collected in a questionnaire administered to mothers approximately 2 weeks after delivery. When the child was 15 years of age, the data on demographic characteristics, smoking habits, and child medical history (including behavioral disorder diagnoses and medication use) were updated via medical record reviews and questionnaires. Self- reported adolescent tobacco, alcohol, and marijuana use was ascertained with the CDC Youth Risk Behavior Survey. Umbilical cord serum levels of polychlorinated biphenyls and dichlorodiphenyldichloroethylene were used as biomarkers of prenatal organochlorine exposures. Childhood blood lead levels were abstracted from medical records of lead exposure screening; the maximum concentration between 12 and 36 months of age was calculated. Using a structured diary, adolescents recorded food consumption and personal care product use for the 24 hours prior to urine sample collection. Diary data were used to estimate exposure risk factors during that 24-hour period, including the number of personal care products used and caffeinated beverages consumed, as well as the amount of fast food or canned food consumed. Height and weight were measured at the time of urine sample collection, and body mass index z scores were calculated using CDC US reference data. Statistical Analysis Statistical analyses were performed from January 15 to December 31, 2019. Regression diagnostics supported log transformation of urinary biomarker concentrations. We dichotomized outcomes at the 98th percentile, which BASC-2 and CADS guidelines define as indicative of significant behavioral problems. To leverage the multiple indices of ADHD-related behavior, maximize power, and avoid multiple comparisons, we used a repeated-measures analysis design, considering each of the 14 27,28 binary indices as a repeated measure reflecting a single underlying outcome. We used multivariate modified Poisson models with robust error variance and an independent working correlation that can accommodate missing behavioral scores, so participants with at least 1 behavioral measure were included. Analyses were performed using SAS, version 9.4 (SAS Institute Inc). We examined whether a child’s sex modified the association between urinary biomarker concentrations and ADHD-related behavior. In secondary analyses, we dichotomized outcomes at the 85th percentile, indicating a possible significant behavior problem. We also considered individual chemicals not included in summary exposure measures (benzophenone-3, triclosan, triclocarban, mono-3-carboxypropyl phthalate [MCPP], monocarboxynonyl phthalate [MCNP], and MHINCH), as well as the individual chemicals that comprised the summary measures. All models included the child’s sex and mean age at completion of BASC-2 and CADS to adjust for fundamental determinants of behavior, urine-specific gravity to account for urine dilution, and an indicator for ADHD measure. We then used prior literature to inform a directed acyclic graph to select other covariates, including the child’s race/ethnicity (non-Hispanic White vs other) and the following JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 5/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD maternal characteristics at the time of delivery: age (as a continuous variable), marital status (married vs unmarried), educational level (<high school vshigh school), annual household income (<$20 000 vs$20 000), and smoking during pregnancy (yes or no). Because not all biomarkers were measured in the first batch of urine samples, some biomarker measures were missing for 27 participants, and some covariate information was missing for 14 participants; thus, our complete case analyses had a sample size of 164 to 190 depending on the urine biomarker measure. In a sensitivity analysis, we imputed missing values (PROC MI/MIANALYZE, Unix SAS, version 9.1.4; SAS Institute Inc) based on 20 imputations using models with all covariates, behavioral outcomes, and biomarker concentrations in this analysis. We performed additional sensitivity analyses, including adjusting for umbilical cord serum polychlorinated biphenyls and dichlorodiphenyldichloroethylene, and adjusting for 12-month to 36-month maximum blood lead levels, because exposure to these chemicals hase been associated with ADHD-related behaviors in the New Bedford Cohort. We adjusted for whether adolescents had smoked cigarettes in the past 30 days or ever tried alcohol or marijuana (n = 60). We also conducted an unadjusted analysis and analyses separately examining measures reflecting attention vs hyperactivity and impulsivity problems, adjusting for factors associated with increased EDC exposure risk, adjusting for body mass index, adjusting for a family history (parent or sibling) of mental illness (n = 86), adjusting for diagnosis of behavioral problems other than ADHD (n = 74), removing those with a diagnosis of ADHD (n = 39), removing those taking prescription medication for behavioral problems (n = 22), and removing siblings (n = 14). We removed individual BASC-2 behavior measures (12 indices) with instrument validity indicators that suggested a negative or positive bias or lack of internal consistency. Results The mean (SD) age of the 205 participants at assessment was 15.3 (0.7) years, with 112 girls (55%) and 124 non-Hispanic White participants (61%). A substantial proportion of study adolescents were born to mothers who, at the time of delivery, were unmarried (87 [42%]), had less than a high school education (30 [15%]), or had annual household incomes less than $20 000 (66 [32%]) (Table 2 and eTable 1 in the Supplement). Compared with the 528 adolescents participating in the full 15-year follow-up, those in this analysis were younger, and a higher percentage were non-White, but, otherwise, the 2 groups did not differ (eTable 1 in the Supplement). The median urine concentrations were 0.45 μmol/L of Σantiandrogenic phthalates, 0.13 μmol/L of ΣDEHP metabolites, 0.49 μmol/L of Σpersonal care product phthalates, 0.35 μmol/L of Σparabens, 0.02 μmol/L of Σbisphenols, and 0.02 μmol/L of Σdichlorophenols (Table 1). Individual biomarker concentrations among study participants were similar to those observed in US adolescents in the 2011-2012 National Health and Nutrition Examination Survey. Of the 205 adolescents in this analysis, 82 (40%) had scores consistent with a significant behavioral problem as defined by at least 1 BASC-2 or CADS ADHD-related measure (Table 3), whereas 39 (19%) had an ADHD diagnosis (Table 2), which is higher than US population estimates (approximately 10%). In covariate-adjusted models, summary measures of phthalates were consistently associated with an increased risk of significant ADHD-related behavior problems (Figure; Table 4). A 2-fold increase in Σantiandrogenic phthalates was associated with a 1.34 (95% CI, 1.00-1.79) increased risk of significant ADHD-related behavior problems, whereas a 2-fold increase in ΣDEHP metabolites was associated with a 1.29 (95% CI, 1.07-1.55) increased risk. A smaller 1.16 (95% CI, 0.98-1.37) increased risk was observed with a 2-fold increase in Σpersonal care products. Adverse associations were observed with each individual phthalate metabolite; the strongest association was for MBP (relative risk [RR], 1.45; 95% CI, 1.15-1.84) (eTable 3 in the Supplement). We observed stronger associations for hyperactive behaviors compared with inattentive behaviors for Σantiandrogenic phthalates JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 6/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Table 2. Distribution of Characteristics of New Bedford Cohort Adolescents (With EDC Measures) by Parent-Reported ADHD Index on the CADS Adolescents, No. (%) Without significant or possible Possible significant Significant behavior behavior problem on CADS behavior problem on CADS problem on CADS a a a Characteristic ADHD index (n = 148) ADHD index (n = 56) ADHD index (n = 29) Maternal characteristics at time of child’s birth Age, y <20 14 (10) 7 (13) 1 (4) 20-29 89 (60) 37 (66) 21 (72) ≥30 45 (30) 12 (21) 7 (24) Household income, $/y <20 000 42 (28) 24 (43) 9 (31) 20 000 to <40 000 47 (32) 23 (41) 17 (59) 40 000 to <75 000 44 (30) 9 (16) 3 (10) ≥75 000 10 (7) NA NA Missing 5 (3) NA NA Educational level <High school 12 (8) 18 (32) 10 (34) ≥High school 131 (89) 38 (68) 19 (66) Missing 5 (3) NA NA Marital status Unmarried 53 (36) 34 (61) 14 (48) Married 88 (59) 18 (32) 12 (41) Missing 7 (5) 4 (7) 3 (10) Smoking during pregnancy No 109 (74) 25 (45) 12 (41) Yes 31 (21) 25 (45) 14 (48) Missing 8 (5) 6 (10) 3 (10) Child characteristics Sex Male 67 (45) 25 (45) 12 (41) Female 81 (55) 31 (55) 17 (59) Mean age at assessment, y 14-15 118 (80) 45 (80) 23 (79) 16-17 30 (20) 11 (20) 6 (21) Race Non-Hispanic White 99 (67) 25 (45) 16 (55) Non-White 49 (33) 31 (55) 13 (45) b,c ADHD diagnosis No 137 (93) 28 (50) 12 (41) Yes 11 (7) 28 (50) 17 (59) Behavioral problem other b,c than ADHD No 107 (72) 23 (41) 11 (38) Yes 41 (28) 33 (59) 18 (62) Use of prescription medication for behavioral b,d problem No 138 (93) 44 (79) 21 (72) Yes 10 (7) 12 (21) 8 (28) Mean number of caffeinated beverages in past 24 h 0 46 (31) 21 (37) 10 (34) 1 72 (49) 29 (52) 19 (66) ≥2 30 (20) 6 (11) NA (continued) JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 7/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Table 2. Distribution of Characteristics of New Bedford Cohort Adolescents (With EDC Measures) by Parent-Reported ADHD Index on the CADS (continued) Adolescents, No. (%) Without significant or possible Possible significant Significant behavior behavior problem on CADS behavior problem on CADS problem on CADS a a a Characteristic ADHD index (n = 148) ADHD index (n = 56) ADHD index (n = 29) Personal care product use ≤6 Products/d 73 (49) 32 (57) 15 (52) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CADS, Conners Attention Deficit Scale; EDC, ≥7 Products/d 75 (51) 23 (41) 13 (45) endocrine-disrupting chemical; NA, not applicable. Missing NA 1 (2) 1 (3) Significant behavior problem: scale T-score Fast food consumption dichotomized at the 98th percentile; possible 0 Servings/d 75 (51) 23 (41) 16 (55) significant problem: scale T-score dichotomized at 1 Servings/d 65 (44) 27 (48) 11 (38) the 85th percentile. >1 Servings/d 8 (5) 5 (9) 1 (3) b P < .05 for comparisons between those with possible Missing NA 1 (2) 1 (3) significant behavior problem on CADS ADHD index and those without using the χ test. Canned food consumption Medical record or parent-reported diagnosis of a 0 Servings/d 114 (77) 49 (87) 23 (79) behavioral disorder. ≥1 Serving/d 34 (23) 7 (13) 6 (21) f Parent-reported child use of medication for a Adolescent substance use behavioral disorder. No 105 (71) 39 (70) 19 (66) Mean from two 24-hour diary reports (or one Yes 43 (29) 17 (30) 10 (34) 24-hour diary report if only 1 urine sample provided) Peak childhood blood lead regarding personal care product use, fast food or level, μg/dL canned food consumption, and consumption of <5 57 (38) 19 (34) 10 (34) caffeinated beverages. ≥5 71 (48) 31 (55) 17 (59) Adolescent report of having smoked a cigarette in Missing 20 (14) 6 (11) 2 (7) the past 30 days or ever having tried marijuana Body mass index z score or alcohol. percentile Peak childhood blood lead levels between 12 and 36 <5th 3 (2) 1 (2) 1 (3) months of age. 5th-84th 86 (58) 35 (62) 16 (55) Age and sex standardized using Centers for Disease ≥85th 59 (40) 20 (36) 12 (41) Control and Prevention US reference population. Table 3. Frequency of ADHD-Related Behavioral Problems in New Bedford Cohort Adolescents as Reported on Teacher-, Parent-, or Self-reported BASC-2 and CADS Behavioral Assessments No. (%) Significant behavior Possible significant behavior c d Behavioral scale problem problem BASC-2 teacher-reported inattention 24/173 (14) 55/173 (32) BASC-2 teacher-reported hyperactivity 16/173 (9) 36/173 (21) BASC-2 teacher-reported executive function 11/173 (6) 24/173 (14) BASC-2 parent-reported inattention 13/204 (6) 50/204 (25) Abbreviations: ADHD, attention-deficit/hyperactivity BASC-2 parent-reported hyperactivity 12/204 (6) 31/204 (15) disorder; BASC-2, Behavior Assessment System for BASC-2 parent-reported executive function 12/204 (6) 36/204 (18) Children, Second Edition; CADS, Conners Attention Deficit Scale. BASC-2 self-reported inattention 21/204 (10) 57/204 (28) A total of 204 had parent-reported and self-reported BASC-2 self-reported hyperactivity 12/204 (6) 45/204 (22) scales and 173 had teacher-reported scales. CADS teacher-reported ADHD 42/173 (24) 60/173 (35) A total of 82 had a significant ADHD-associated CADS teacher-reported inattention 30/173 (17) 43/173 (25) behavior problem on at least 1 scale and 134 had a CADS teacher-reported hyperactivity 35/173 (20) 45/173 (26) possible significant ADHD-associated behavior CADS parent-reported ADHD 29/204 (14) 56/204 (27) problem on at least 1 scale. CADS parent-reported inattention 20/204 (10) 45/204 (22) Scale T-score dichotomized at the 98th percentile. CADS parent-reported hyperactivity 27/204 (13) 45/204 (22) Scale T-score dichotomized at the 85th percentile. (RR, 1.40 [95% CI, 1.07-1.84] vs 1.26 [95% CI, 0.87-1.83]), Σpersonal care products (RR, 1.25 [95% CI, 1.07-1.47] vs 1.06 [95% CI, 0.95-1.18]), and Σdichlorophenols (RR, 1.22 [95% CI, 1.04-1.42] vs 1.05 [95% CI, 0.90-1.23]) (Table 4). JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 8/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Associations tended to be stronger among male adolescents than among female adolescents, most notably with respect to the ΣDEHP metabolites (P = .002 for interaction), in which a 2-fold increase corresponded to a 1.62 (95% CI, 1.38-1.91) increased risk of significant ADHD-related behavior problems in male adolescents compared with a 1.06 (95% CI, −1.15 to 1.33) increased risk in female adolescents (Figure; eTable 2 in the Supplement). The remaining sex-specific differences were estimated with less precision. A 2-fold increase in Σdichlorophenols was also associated with an increased risk of ADHD- related behaviors (RR, 1.15; 95% CI, 1.01-1.32) (Table 4). However, we did not observe associations with urinary biomarker concentrations of Σparabens or Σbisphenols or with the individual components of Σparabens or Σbisphenols summary measures, triclocarban, triclosan, benzophenone-3, or MHINCH (Figure; eTables 2 and 3 in the Supplement). When considering the more inclusive threshold for those with possible significant behavioral problems (>85th percentile), we observed similar, albeit slightly attenuated, findings. For example, each 2-fold increase in Σantiandrogenic phthalates was associated with a 1.21 (95% CI, 1.00-1.47) increased risk of possible significant (vs 1.34 for clearly significant) ADHD-related behavior problems (Table 4), and this difference appeared to be more pronounced among male adolescents (eTable 2 in the Supplement). Associations were similar, but more precise, in models imputing missing data (eTable 4 in the Supplement). Associations were stronger for summary phthalate measures when we excluded adolescents with an ADHD diagnosis. We did not observe substantive changes in results with the other sensitivity analyses, including exclusion of those taking medications (eTables 4 and 5 in the Supplement). Figure. Adjusted Relative Risk of Multiple Measures of Clinically Significant Attention-Deficit/Hyperactivity Disorder (ADHD)–Associated Behaviors Corresponding to a 2-Fold Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents (Sample Size From 164 to 190) Combined Male 2 Female 0.5 b d e f ΣAntiandrogenic ΣDEHP ΣPersonal care ΣParabens ΣBisphenols ΣDichlorophenols a c phthalates product phthalates Adjusted for child characteristics: sex, race/ethnicity, mean test age (across teacher- phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5- reported, parent-reported, and self-reported Behavior Assessment System for Children, carboxypentyl phthalate (MECPP), monocarboxyoctyl phthalate, 2nd Edition [BASC-2] and Conners Attention Deficit Scale [CADS] measures), and urine monohydroxyisobutyl phthalate (MHiBP), monohydroxybutyl phthalate (MHBP), and specific gravity; maternal characteristics at delivery: age, income, marital status, mono-isononyl phthalate. smoking, and educational level; and test indicator. The ADHD-associated behavior Sum of MECPP, MEHHP, MEOHP, and MEHP. measures include CADS parent-reported and teacher-reported inattention, Sum of MBP, MHBP, monoethyl phthalate, MiBP, and MHiBP. hyperactivity, and ADHD; BASC-2 parent-reported, teacher-reported, and self-reported Sum of butyl, ethyl, methyl, and propyl parabens. hyperactivity and inattention; and BASC-2 parent-reported and teacher-reported executive function. Significant behavior problem: scale T-score dichotomized at the 98th Sum of bisphenol A, bisphenol F, and bisphenol S. percentile. f Sum of 2,4-dichlorophenol and 2,5-dichlorophenol. Sum of mono-n-butyl phthalate (MBP), monoisobutyl phthalate (MiBP), monobenzyl phthalate, mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 9/14 Relative risk of ADHD behaviors JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Discussion In a population with a high prevalence of ADHD-related behaviors, our findings support an association of adolescent exposure to EDCs, particularly select phthalates, with an increased risk of significant ADHD-related behavior problems at exposure biomarker concentrations typical of adolescents in the general US population. These results are consistent with previously reported findings in the New Bedford Cohort associating adolescent EDC exposure, particularly to antiandrogenic phthalates, with increased externalizing behaviors (a BASC-2 composite of hyperactivity, aggression, and conduct problems). Previous studies have reported associations of prenatal and early postnatal exposure to phthalates and BPA with an increase in ADHD-related behaviors. However, to our knowledge, no other published studies have analyzed associations between adolescent EDC biomarker concentrations and ADHD-related behaviors. Adolescence is a critical period for brain development and may be another time of heightened vulnerability to EDC exposure. Several cross-sectional studies (with children of wide age ranges, including some adolescents) have reported associations 5,7,9,32 between increased urinary phthalate and BPA concentrations and ADHD-related behaviors. Experimental animal studies also support the potential for EDC exposures to be associated with 33-36 adverse behavior in adolescence, including behaviors consistent with ADHD. Furthermore, there is well-established evidence demonstrating the unique association that neurotoxicant exposures (eg, 37,38 alcohol and organophosphates) during adolescence have with adverse behavior. This analysis focused on ADHD-related behaviors as opposed to clinical ADHD diagnosis. By relying on multiple indices of ADHD-related behavior (from the BASC-2 and CADS) from multiple Table 4. Adjusted Relative Risk of Multiple Measures of Clinically Significant Behavioral Subgroups of ADHD Behaviors Associated With a 2-Fold Increase in Urinary Biomarker Concentrations in New Bedford Cohort a,b Adolescents (Sample Size From 164 to 190) Adjusted relative risk c d Chemical biomarker Combined ADHD measures Attention problems Hyperactivity problems ΣAntiandrogenic phthalates 1.34 (1.00-1.79) 1.26 (0.87-1.83) 1.40 (1.07-1.84) ΣDEHP 1.29 (1.07-1.55) 1.29 (1.03-1.60) 1.27 (1.06-1.52) ΣPersonal care products 1.16 (0.98-1.37) 1.06 (0.85-1.32) 1.25 (1.07-1.47) ΣParabens 1.06 (0.96-1.18) 1.06 (0.93-1.21) 1.06 (0.95-1.18) ΣBisphenols 1.09 (0.91-1.31) 1.08 (0.87-1.33) 1.04 (0.84-1.29) ΣDichlorophenols 1.15 (1.01-1.32) 1.05 (0.90-1.23) 1.22 (1.04-1.42) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BASC-2, Behavior Assessment System for Children, 2nd edition; CADS, Conners Attention Deficit Scale; DEHP, di(2-ethylhexyl) phthalate. Adjusted for child: sex, mean test age (across teacher-reported, parent-reported, and self-reported BASC and CADS measures), and urine specific gravity; maternal characteristics at delivery: age, income, marital status, smoking, and educational level; and test indicator. Attention-deficit/hyperactivity disorder–related behavior measures include CADS parent-reported and teacher-reported inattention, hyperactivity, and ADHD; BASC-2 parent-reported, teacher-reported, and self-reported hyperactivity and inattention; and BASC-2 parent-reported and teacher-reported executive function. Significant behavior problem: scale T-score dichotomized at the 98th percentile. Attention problems subset includes CADS teacher-reported and parent-reported inattention and BASC-2 teacher- reported, parent-reported, and self-reported inattention. Hyperactivity subset includes CADS teacher-reported and parent-reported hyperactive behavior and BASC-2 teacher- reported, parent-reported, and self-reported hyperactive behavior. Sum of MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCOP, MHiBP, MHBP, and MNP (full chemical names in Table 1). Sum of MECPP, MEHHP, MEOHP, and MEHP (full chemical names in Table 1). Sum of MBP, MHBP, MEP, MiBP, and MHiBP (full chemical names in Table 1). Sum of butyl, ethyl, methyl, and propyl parabens. Sum of BPA, BPF, and BPS (full chemical names in Table 1). Sum of 2,4-dichlorophenol and 2,5-dichlorophenol. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 10/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD observers (teachers, parents, and self), we were able to leverage a uniquely comprehensive characterization of adolescent behavior, including behaviors that can vary over time (eg, inattention) and thus may be susceptible to variations in exposure risk factors. In particular, combining information from these multiple measures increased the power of our analysis, resulting in more stable estimates of association than would have been possible by examining each behavioral measure individually. In addition, by expressing multiple measures as a single outcome, we did not induce the statistical issues associated with multiple comparisons. Limitations This study has some limitations. The assessed EDCs have short elimination half-lives, as well as short- term variability in exposure, resulting in the potential for nondifferential exposure misclassification, which could bias results toward the null. However, our study collected urine samples at 2 different times from most participants, allowing us to better characterize each participant’s mean or usual exposure. Given the cross-sectional design of this analysis, another challenge is the potential for reverse causation, such that existing behavioral problems may alter habits that enhance EDC 39-42 exposure via changes in, for instance, diet, substance use, and/or personal care product use. However, adjustments for these factors did not affect associations, suggesting that reverse causation from these habits was unlikely. Furthermore, excluding adolescents with a diagnosis of ADHD enhanced the existing associations (eTable 4 in the Supplement). Although data on participants’ prenatal EDC exposure are lacking, we do not expect this lack of data would confound associations with adolescent exposure; weak within-person correlations have been reported between prenatal and childhood exposures to phthalates and BPA, and we would expect similar or weaker correlations 43,44 between prenatal and adolescent time periods. In addition, participants were from a small geographical region, which may potentially affect the generalizability of our findings. Conclusions Our results support the importance of adolescent exposure to EDCs, particularly phthalates, as a potential risk factor for significant ADHD-related behavior problems. Attention-deficit/hyperactivity disorder is a common and costly neurobehavioral disorder; US health care and education expenditures associated with ADHD in children and adolescents are estimated to be $38 billion to $72 billion annually, while costs associated with ADHD in adults, including lost wages, are much 2,45 higher, ranging from $143 billion to $266 billion annually. The identification of modifiable risk factors for ADHD is of great public health importance. These findings contribute new insights into the potential detrimental neurobehavioral outcomes of EDC exposure during adolescence. ARTICLE INFORMATION Accepted for Publication: June 15, 2020. Published: August 28, 2020. doi:10.1001/jamanetworkopen.2020.15041 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Shoaff JR et al. JAMA Network Open. Corresponding Author: Jessica R. Shoaff, PhD, Channing Division of Network Medicine, Harvard Medical School, Brigham and Women’s Hospital, 401 Park Dr, 3rd Floor West, Boston, MA 02215 (jessica.shoaff@channing. harvard.edu). Author Affiliations: Channing Division of Network Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts (Shoaff, Korrick); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Shoaff); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Coull); Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Coull, Bellinger, Korrick); Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts (Weuve); Department of Neurology and Psychiatry, Boston Children’s JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 11/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Hospital and Harvard Medical School, Boston, Massachusetts (Bellinger); Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia (Calafat); Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana (Schantz); Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana (Schantz). Author Contributions: Drs Shoaff and Korrick had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Shoaff, Schantz, Korrick. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Shoaff, Weuve, Korrick. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Shoaff, Coull, Weuve, Korrick. Obtained funding: Schantz, Korrick. Administrative, technical, or material support: Korrick. Supervision: Korrick. Conflict of Interest Disclosures: Dr Coull reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study, receiving grants from the US Environmental Protection Agency and the NIH, and working on the Apple Women’s Health Study outside the submitted work. Dr Korrick reported receiving grants from the NIH/National Institute of Environmental Health Sciences during the conduct of the study. No other disclosures were reported. Funding/Support: Support for this research was provided by the following grants: RD-83459301 and RD-835434010 from the US Environmental Protection Agency; and P20 ES018163, P01 ES022848, and R01 ES014864 from the NIH/National Institute of Environmental Health Sciences. Dr Shoaff was supported by National Institute of Environmental Health Sciences training grant T32 ES007069. Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention, the Public Health Service, the US Department of Health and Human Services, or the US Environmental Protection Agency. REFERENCES 1. Danielson ML, Bitsko RH, Ghandour RM, Holbrook JR, Kogan MD, Blumberg SJ. Prevalence of parent-reported ADHD diagnosis and associated treatment among U.S. children and adolescents, 2016. J Clin Child Adolesc Psychol. 2018;47(2):199-212. doi:10.1080/15374416.2017.1417860 2. Abright AR. Estimating the costs of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51(10):987-989. doi:10.1016/j.jaac.2012.07.012 3. Froehlich TE, Lanphear BP, Auinger P, et al. Association of tobacco and lead exposures with attention-deficit/ hyperactivity disorder. Pediatrics. 2009;124(6):e1054-e1063. doi:10.1542/peds.2009-0738 4. Froehlich TE, Lanphear BP, Epstein JN, Barbaresi WJ, Katusic SK, Kahn RS. Prevalence, recognition, and treatment of attention-deficit/hyperactivity disorder in a national sample of US children. Arch Pediatr Adolesc Med. 2007;161(9):857-864. doi:10.1001/archpedi.161.9.857 5. Tewar S, Auinger P, Braun JM, et al. Association of bisphenol A exposure and attention-deficit/hyperactivity disorder in a national sample of U.S. children. Environ Res. 2016;150:112-118. doi:10.1016/j.envres.2016.05.040 6. Braun JM, Yolton K, Dietrich KN, et al. Prenatal bisphenol A exposure and early childhood behavior. Environ Health Perspect. 2009;117(12):1945-1952. doi:10.1289/ehp.0900979 7. Chopra V, Harley K, Lahiff M, Eskenazi B. Association between phthalates and attention deficit disorder and learning disability in U.S. children, 6-15 years. Environ Res. 2014;128:64-69. doi:10.1016/j.envres.2013.10.004 8. Rochester JR, Bolden AL, Kwiatkowski CF. Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis. Environ Int. 2018;114:343-356. doi:10.1016/j.envint.2017.12.028 9. Kim BN, Cho SC, Kim Y, et al. Phthalates exposure and attention-deficit/hyperactivity disorder in school-age children. Biol Psychiatry. 2009;66(10):958-963. doi:10.1016/j.biopsych.2009.07.034 10. Braun JM, Sathyanarayana S, Hauser R. Phthalate exposure and children’s health. Curr Opin Pediatr. 2013;25 (2):247-254. doi:10.1097/MOP.0b013e32835e1eb6 JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 12/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD 11. Harley KG, Kogut K, Madrigal DS, et al. Reducing phthalate, paraben, and phenol exposure from personal care products in adolescent girls: findings from the HERMOSA Intervention Study. Environ Health Perspect. 2016;124 (10):1600-1607. doi:10.1289/ehp.1510514 12. Engel SM, Miodovnik A, Canfield RL, et al. Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environ Health Perspect. 2010;118(4):565-571. doi:10.1289/ehp.0901470 13. Engel SM, Villanger GD, Nethery RC, et al. Prenatal phthalates, maternal thyroid function, and risk of attention- deficit hyperactivity disorder in the Norwegian mother and child cohort. Environ Health Perspect. 2018;126(5): 057004. doi:10.1289/EHP2358 14. Casey BJ, Jones RM, Hare TA. The adolescent brain. Ann N Y Acad Sci. 2008;1124:111-126. doi:10.1196/annals. 1440.010 15. Korrick SA, Altshul LM, Tolbert PE, Burse VW, Needham LL, Monson RR. Measurement of PCBs, DDE, and hexachlorobenzene in cord blood from infants born in towns adjacent to a PCB-contaminated waste site. J Expo Anal Environ Epidemiol. 2000;10(6, pt 2):743-754. doi:10.1038/sj.jea.7500120 16. Shoaff JR, Calafat AM, Schantz SL, Korrick SA. Endocrine disrupting chemical exposure and maladaptive behavior during adolescence. Environ Res. 2019;172:231-241. doi:10.1016/j.envres.2018.12.053 17. Silva MJ, Jia T, Samandar E, Preau JL Jr, Calafat AM. Environmental exposure to the plasticizer 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) in U.S. adults (2000-2012). Environ Res. 2013;126:159-163. doi:10. 1016/j.envres.2013.05.007 18. Silva MJ, Samandar E, Preau JL Jr, Reidy JA, Needham LL, Calafat AM. Quantification of 22 phthalate metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;860(1):106-112. doi:10.1016/j. jchromb.2007.10.023 19. 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 Analyt Technol Biomed Life Sci. 2006;844(1):53-59. doi:10.1016/j. jchromb.2006.06.037 20. 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(16):5407-5413. doi:10.1021/ac050390d 21. Hannas BR, Lambright CS, Furr J, Howdeshell KL, Wilson VS, Gray LE Jr. Dose-response assessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate, and diisononyl phthalate. Toxicol Sci. 2011;123(1):206-216. doi:10.1093/toxsci/kfr146 22. Howdeshell KL, Rider CV, Wilson VS, Furr JR, Lambright CR, Gray LE Jr. Dose addition models based on biologically relevant reductions in fetal testosterone accurately predict postnatal reproductive tract alterations by a phthalate mixture in rats. Toxicol Sci. 2015;148(2):488-502. doi:10.1093/toxsci/kfv196 23. Larsson K, Ljung Björklund K, Palm B, et al. Exposure determinants of phthalates, parabens, bisphenol A and triclosan in Swedish mothers and their children. Environ Int. 2014;73:323-333. doi:10.1016/j.envint.2014.08.014 24. Conners C. Conners’ Rating Scales—Revised Technical Manual. North Tonawanda, NY: Multi-Health Systems; 25. Reynolds CR, Kamphaus RW. Behavior Assessment System for Children Manual. 2nd ed. AGS; 2004. 26. Centers for Disease Control and Prevention. CDC growth charts. Accessed May 12, 2019. https://www.cdc.gov/ growthcharts/cdc_charts.htm 27. Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344 (15):1132-1138. doi:10.1056/NEJM200104123441504 28. Weuve J, Korrick SA, Weisskopf MG, et al. Cumulative exposure to lead in relation to cognitive function in older women. Environ Health Perspect. 2009;117(4):574-580. doi:10.1289/ehp.11846 29. Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research. Epidemiology. 1999;10(1):37-48. doi:10.1097/00001648-199901000-00008 30. SAS/STATA: 13.1 User's Guide. Cary, NC: SAS Institute Inc; 2013. 31. Centers for Disease Control and Prevention. Fourth National Report on Human Exposure to Environmental Chemicals: updated tables, March 2018, volume one. Published 2018. Accessed February 2, 2019. https://www.cdc. gov/exposurereport/pdf/FourthReport_UpdatedTables_Volume1_Jan2019-508.pdf 32. Findlay LC, Kohen DE. Bisphenol A and child and youth behaviour: Canadian Health Measures Survey 2007 to 2011. Health Rep. 2015;26(8):3-9. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 13/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD 33. Ishido M, Masuo Y, Kunimoto M, Oka S, Morita M. Bisphenol A causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immunoreactivity. J Neurosci Res. 2004;76(3):423-433. doi:10.1002/ jnr.20050 34. Ishido M, Masuo Y, Sayato-Suzuki J, Oka S, Niki E, Morita M. Dicyclohexylphthalate causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immunoreactivity. J Neurochem. 2004;91(1):69-76. doi:10.1111/j.1471-4159.2004.02696.x 35. Ishido M, Masuo Y, Terasaki M, Morita M. Rat hyperactivity by bisphenol A, but not by its derivatives, 3-hydroxybisphenol A or bisphenol A 3,4-quinone. Toxicol Lett. 2011;206(3):300-305. doi:10.1016/j.toxlet.2011. 08.011 36. Zhou R, Bai Y, Yang R, et al. Abnormal synaptic plasticity in basolateral amygdala may account for hyperactivity and attention-deficit in male rat exposed perinatally to low-dose bisphenol-A. Neuropharmacology. 2011;60(5): 789-798. doi:10.1016/j.neuropharm.2011.01.031 37. Spear LP. Effects of adolescent alcohol consumption on the brain and behaviour. Nat Rev Neurosci. 2018;19 (4):197-214. doi:10.1038/nrn.2018.10 38. Rohlman DS, Ismail A, Bonner MR, et al. Occupational pesticide exposure and symptoms of attention deficit hyperactivity disorder in adolescent pesticide applicators in Egypt. Neurotoxicology. 2019;74:1-6. doi:10.1016/j. neuro.2019.05.002 39. Oddy WH, Robinson M, Ambrosini GL, et al. The association between dietary patterns and mental health in early adolescence. Prev Med. 2009;49(1):39-44. doi:10.1016/j.ypmed.2009.05.009 40. Trapp GS, Allen KL, Black LJ, et al. A prospective investigation of dietary patterns and internalizing and externalizing mental health problems in adolescents. Food Sci Nutr. 2016;4(6):888-896. doi:10.1002/fsn3.355 41. Walker LR, Abraham AA, Tercyak KP. Adolescent caffeine use, ADHD, and cigarette smoking. Children's Health Care 2010. 39(1):17. doi:10.1080/02739610903455186 42. Cortese S, Angriman M, Maffeis C, et al. Attention-deficit/hyperactivity disorder (ADHD) and obesity: a systematic review of the literature. Crit Rev Food Sci Nutr. 2008;48(6):524-537. doi:10.1080/ 43. Stacy SL, Eliot M, Calafat AM, et al. Patterns, variability, and predictors of urinary bisphenol A concentrations during childhood. Environ Sci Technol. 2016;50(11):5981-5990. doi:10.1021/acs.est.6b00794 44. Shoaff J, Papandonatos GD, Calafat AM, et al. Early-life phthalate exposure and adiposity at 8 years of age. Environ Health Perspect. 2017;125(9):097008. doi:10.1289/EHP1022 45. Doshi JA, Hodgkins P, Kahle J, et al. Economic impact of childhood and adult attention-deficit/hyperactivity disorder in the United States. J Am Acad Child Adolesc Psychiatry. 2012;51(10):990-1002.e2. doi:10.1016/j.jaac. 2012.07.008 SUPPLEMENT. eTable 1. Characteristics of 528 New Bedford Cohort Participants Assessed as Adolescents Compared With the Subset of 205 Who Provided Urine Samples for EDC Exposure Assessment eTable 2. Adjusted Relative Risk (95% Confidence Intervals) of ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents (N = 164-190) eTable 3. Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems in New Bedford Cohort Adolescents Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations (N = 164-190) for Individual, Rather Than Summed, Chemical Measures eTable 4. Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD- Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents eTable 5. Additional Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents eFigure. Determination of Final Analytic Sample for Assessment of New Bedford Cohort Adolescents JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 14/14 Supplementary Online Content Shoaff JR, Coull B, Weuve J, et al. Association of exposure to endocrine-disrupting chemicals during adolescence with attention-deficit/hyperactivity disorder–related behaviors. JAMA Netw Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 eTable 1. Characteristics of 528 New Bedford Cohort Participants Assessed as Adolescents Compared With the Subset of 205 Who Provided Urine Samples for EDC Exposure Assessment eTable 2. Adjusted Relative Risk (95% Confidence Intervals) of ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents (N=164-190) eTable 3. Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD- Related Behavior Problems in New Bedford Cohort Adolescents Associated With a 2- Fold (log2) Increase in Urinary Biomarker Concentrations (N=164-190) for Individual, Rather Than Summed, Chemical Measures eTable 4. Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents eTable 5. Additional Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents eFigure. Determination of Final Analytic Sample for Assessment of New Bedford Cohort Adolescents This supplementary material has been provided by the authors to give readers additional information about their work. © 2020 Shoaff JR et al. JAMA Network Open. eTable 1. Characteristics of 528 New Bedford Cohort Participants Assessed as Adolescents Compared With the Subset of 205 Who Provided Urine Samples for EDC Exposure Assessment Urine study Full sample sample (n=205) (n=528) Frequency of ADHD-related behavioral problems (n, (%)) Significant ADHD-associated behavior 218 (41) problem on at least one scale 82 (40) Possible significant ADHD-associated 346 (65) behavior problem on at least one scale 134 (65) Child Characteristics (n (%)) Gender Male 93 (45) 255 (48) Female 112 (55) 273 (52) Missing 0 (0) 0 (0) Race Non-Hispanic White 124 (60) 364 (69) Non White 81 (40) 164 (31) Missing 0 (0) 0 (0) Age at in-person testing 14-15 164 (80) 328 (62) 16-17 41 (20) 200 (38) Missing Diagnosis of a behavioral disorder other than ADHD No 131 (64) 346 (66) Yes 74 (36) 182 (34) Missing 0 (0) 0 (0) Use of medication for a behavioral disorder No 183 (89) 480 (91) Yes 22 (11) 48 (9) Missing 0 (0) 0 (0) Maternal Characteristics at time of Child’s Birth (n (%)) Age (years) <20 21 (10) 67 (13) 20-29 127 (62) 307 (58) 57 (28) 154 (29) Missing 0 (0) 0 (0) Household income ($/year) <20,000 66 (32) 166 (31) 20-<40,000 70 (34) 179 (34) 40-<75,000 53 (26) 152 (29) 10 (5) 18 (3) Missing 6 (3) 13 (2) Marital status © 2020 Shoaff JR et al. JAMA Network Open. Married 106 (52) 296 (56) Unmarried 87 (42) 206 (39) Missing 12 (6) 26 (5) Education <High School 30 (15) 76 (14) High School or more 169 (82) 440 (83) Missing 6 (3) 12 (2) Smoking during pregnancy Yes 56 (27) 125 (24) No 134 (65) 362 (69) Missing 15 (7) 41 (8) Alcohol consumption during pregnancy Yes 38 (19) 92 (17) No 141 (69) 358 (68) Missing 26 (13) 78 (15) ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of hyperactivity and inattention; and BASC parent/teacher-report of executive function. b th Significant behavior problem: scale t-score dichotomized at the 98 percentile; Possible significant problem: scale t-score th dichotomized at the 85 percentile Pediatric medical record or parental reported diagnosis of a behavioral disorder Parental reported child use of medication for a behavioral disorder © 2020 Shoaff JR et al. JAMA Network Open. a b eTable 2. Adjusted Relative Risk (95% Confidence Intervals) of ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents (N=164-190) b b Chemical Biomarker Significant behavior problem Possible significant behavior problem Combined Males Females Combined Males Females Antiandrogenic phthalates 1.34 (1.00, 1.79) 1.63 (1.14, 2.34) 1.16 (0.84, 1.60) 1.21 (1.00, 1.47) 1.19 (0.87, 1.63) 1.23 (0.99, 1.52) DEHP 1.29 (1.07, 1.55) 1.62 (1.38, 1.91)* 1.06 (0.85, 1.33)* 1.20 (1.05, 1.37) 1.28 (1.06, 1.55) 1.14 (0.98, 1.32) Personal care products 1.16 (0.98, 1.37) 1.20 (0.97, 1.50) 1.12 (0.90, 1.40) 1.11 (0.99, 1.25) 1.08 (0.90, 1.30) 1.14 (0.98, 1.32) Parabens 1.06 (0.96, 1.18) 1.05 (0.94, 1.16) 1.09 (0.91, 1.30) 1.04 (0.97, 1.11) 1.01 (0.93, 1.09) 1.08 (0.96, 1.21) Bisphenols 1.09 (0.91, 1.31) 1.11 (0.76, 1.64) 1.08 (0.88, 1.32) 1.01 (0.88, 1.17) 0.92 (0.70, 1.22) 1.06 (0.89, 1.26) Dichlorophenols 1.15 (1.01, 1.32) 1.18 (0.99, 1.40) 1.12 (0.90, 1.39) 1.09 (0.99, 1.20) 1.07 (0.94, 1.21) 1.13 (0.97, 1.33) Adjusted for: Child: sex, race, mean test age (across teacher/parent/self-report BASC and CADS measures), urine specific gravity, race; Maternal characteristics at delivery: age, income, marital status, smoking, education; test indicator ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of hyperactivity and inattention; and BASC th th parent/teacher-report of executive function. Significant behavior problem: scale t-score dichotomized at the 98 percentile; Possible significant problem: scale t-score dichotomized at the 85 percentile. sum of: MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCOP, MHIBP, MHBP, MNP sum of: MECPP, MEHHP, MEOHP, MEHP sum of: MBP, MHBP, MEP, MiBP, MHIBP sum of: butyl, ethyl, methyl, and propyl parabens sum of: BPA, BPF, BPS sum of: 2,4-dichlorophenol, 2,5-dichlorophenol *Interaction p-value <0.05 © 2020 Shoaff JR et al. JAMA Network Open. a b eTable 3. Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems in New Bedford Cohort Adolescents Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations (N=164-190) for Individual, Rather Than Summed, Chemical Measures s Individual measures phthalates not included in a sum MECPP 1.27 (1.05, 1.54) MECPP 1.27 (1.05, 1.54) MBP 1.45 (1.15, 1.84) Butyl 0.98 (0.95, 1.02) BPA 1.02 (0.93, 1.12) 2,4-DCP 1.11 (1.00, 1.24) TCC 1.03 (1.00, 1.07) MEHHP 1.26 (1.06, 1.49) MEHHP 1.26 (1.06, 1.49) MIBP 1.32 (1.07, 1.64) Ethyl 1.07 (0.98, 1.17) BPF 1.01 (0.97, 1.05) 2,5-DCP 1.08 (0.94, 1.25) TCS 0.99 (0.89, 1.09) MEHP 1.05 (0.98, 1.12) MEHP 1.05 (0.98, 1.12) MHIBP 1.16 (0.96, 1.41) Methyl 1.05 (0.94, 1.16) BPS 1.02 (0.94, 1.10) BP-3 0.97 (0.9, 1.04) MEOHP 1.28 (1.07, 1.53) MEOHP 1.28 (1.07, 1.53) MHBP 1.25 (1.03, 1.51) Propyl 1.00 (0.92, 1.09) MHINCH 0.99 (0.94, 1.05) MBP 1.45 (1.15, 1.84) MEP 1.07 (0.93, 1.23) MCNP 1.19 (0.95, 1.49) MIBP 1.32 (1.07, 1.64) MCPP 1.12 (1.02, 1.23) MHIBP 1.16 (0.96, 1.41) MHBP 1.25 (1.03, 1.51) MBZP 1.22 (1.05, 1.42) MNP 1.03 (0.97, 1.10) MCOP 1.05 (0.91, 1.23) Adjusted for: Child: sex, race, mean test age (across teacher/parent/self-report BASC and CADS measures), urine specific gravity; Maternal characteristics at delivery: age, income, marital status, smoking, education; test indicator ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of hyperactivity and inattention; and BASC th parent/teacher-report of executive function. Significant behavior problem: scale t-score dichotomized at the 98 percentile © 2020 Shoaff JR et al. JAMA Network Open. eTable 4. Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents Chemical Main Unadjusted Multiple Exclude Exclude Exclude Adjusted for Adjusted for Exclude c d Biomarker adjusted model imputation BASC participants participants behavioral family siblings measures taking with ADHD diagnosis history of model with indices medications diagnosis other than mental g h indicating a for ADHD illness potential behavioral threat to disorder validity N=205 N=164-190 N=149-171 N=135-156 N=164-190 N=164-190 N=153-177 N=164-190 N=178-205 1.34 (1.00, 1.79) 1.27 (1.03, 1.56) 1.37 (1.21, 1.55) 1.34 (1.01, 1.78) 1.26 (0.90, 1.78) 1.76 (1.33, 2.32) 1.34 (1.01, 1.78) 1.40 (1.03, 1.89) 1.33 (0.99, 1.79) Antiandrogenic phthalates DEHP 1.29 (1.07, 1.55) 1.19 (1.02, 1.39) 1.25 (1.14, 1.38) 1.28 (1.06, 1.54) 1.32 (1.07, 1.62) 1.46 (1.19, 1.80) 1.30 (1.09, 1.56) 1.30 (1.08, 1.58) 1.29 (1.07, 1.55) Personal care 1.16 (0.98, 1.37) 1.20 (1.03, 1.39) 1.15 (1.05, 1.25) 1.16 (0.98, 1.37) 1.11 (0.90, 1.37) 1.31 (1.09, 1.57) 1.15 (0.97, 1.36) 1.18 (1.00, 1.40) 1.18 (0.99, 1.41) products 1.06 (0.96, 1.18) 1.06 (0.96, 1.17) 1.03 (0.98, 1.08) 1.05 (0.95, 1.17) 1.07 (0.95, 1.20) 1.09 (0.99, 1.20) 1.06 (0.96, 1.17) 1.09 (0.98, 1.21) 1.07 (0.96, 1.18) 1.09 (0.91, 1.31) 1.09 (0.91, 1.31) 1.10 (0.99, 1.23) 1.06 (0.87, 1.27) 1.12 (0.92, 1.36) 1.13 (0.88, 1.45) 1.10 (0.91, 1.33) 1.12 (0.94, 1.33) 1.08 (0.91, 1.29) Bisphenols 1.15 (1.01, 1.32) 1.09 (0.94, 1.26) 1.11 (1.03, 1.20) 1.15 (1.01, 1.31) 1.12 (0.96, 1.32) 1.15 (1.00, 1.33) 1.17 (1.02, 1.34) 1.15 (1.00, 1.33) 1.18 (1.02, 1.35) Dichlorophenols Adjusted for: Child: sex, race, mean test age (across teacher/parent/self-report BASC and CADS measures), urine specific gravity; Maternal characteristics at delivery: age, income, marital status, smoking, education; test indicator ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of hyperactivity th and inattention; and BASC parent/teacher-report of executive function. Significant behavior problem: scale t-score dichotomized at the 98 percentile. Adjusted for specific gravity to account for urine dilution and test indicator imputation for covariates and chemicals, but not ADHD-related measures Internal BASC indices indicating potential threats to validity from several factors (overly negative, lack of internal consistency, etc). Based on medical record review Based on medical record review and parent report Based on parent report sum of: MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCOP, MHIBP, MHBP, MNP sum of: MECPP, MEHHP, MEOHP, MEHP sum of: MBP, MHBP, MEP, MiBP, MHIBP sum of: butyl, ethyl, methyl, and propyl parabens sum of: BPA, BPF, BPS sum of: 2,4-dichlorophenol, 2,5-dichlorophenol © 2020 Shoaff JR et al. JAMA Network Open. eTable 5. Additional Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents Chemical Main adjusted Adjusted for Adjusted for Adjusted for Adjusted for Adjusted for Adjusted for Adjusted for Biomarker model adolescent max cord serum adolescent caffeine personal care canned food d d BMI z-score childhood PCBs and substance consumption product use and fast food c d blood lead DDE use consumption N=164-190 N=164-190 N=147-189 N=163-189 N=164-190 N=164-190 N=163-189 N=163-189 1.34 (1.00, 1.79) 1.33 (0.99, 1.78) 1.30 (0.97, 1.76) 1.36 (1.01, 1.83) 1.27 (0.96, 1.68) 1.34 (1.01, 1.78) 1.37 (1.02, 1.85) 1.36 (1.00, 1.85) phthalates 1.29 (1.07, 1.55) 1.29 (1.07, 1.55) 1.26 (1.05, 1.52) 1.29 (1.06, 1.57) 1.25 (1.03, 1.51) 1.30 (1.09, 1.56) 1.29 (1.08, 1.55) 1.31 (1.08, 1.59) 1.16 (0.98, 1.37) 1.16 (0.97, 1.38) 1.14 (0.94, 1.38) 1.16 (0.98, 1.38) 1.15 (0.95, 1.38) 1.15 (0.97, 1.36) 1.16 (0.98, 1.38) 1.17 (0.98, 1.39) products 1.06 (0.96, 1.18) 1.07 (0.96, 1.18) 1.07 (0.96, 1.19) 1.04 (0.94, 1.15) 1.04 (0.94, 1.14) 1.06 (0.96, 1.17) 1.07 (0.97, 1.18) 1.07 (0.96, 1.18) Bisphenols 1.09 (0.91, 1.31) 1.09 (0.90, 1.30) 1.05 (0.87, 1.27) 1.08 (0.90, 1.29) 1.09 (0.90, 1.33) 1.10 (0.91, 1.33) 1.08 (0.90, 1.31) 1.07 (0.88, 1.31) Dichlorophenols 1.15 (1.01,1.32) 1.15 (1.01, 1.32) 1.19 (1.01, 1.40) 1.17 (1.02, 1.34) 1.13 (0.98, 1.31) 1.17 (1.02, 1.34) 1.16 (1.01, 1.33) 1.16 (1.01, 1.33) Adjusted for: Child: sex, mean test age (across teacher/parent/self-report BASC and CADS measures), urine specific gravity; Maternal characteristics at delivery: age, income, marital status, smoking, education; test indicator ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of th hyperactivity and inattention; and BASC parent/teacher-report of executive function. Significant behavior problem: scale t-score dichotomized at the 98 percentile Adolescent report of having smoked a cigarette in the past 30 days or ever having tried marijuana or alcohol Average from two 24-hour diary reports (or one 24-hour diary report if only one urine sample provided) regarding personal care product use, canned/fast food consumption, and consumption of caffeinated beverage sum of: MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCOP, MHIBP, MHBP, MNP sum of: MECPP, MEHHP, MEOHP, MEHP sum of: MBP, MHBP, MEP, MiBP, MHIBP sum of: butyl, ethyl, methyl, and propyl parabens sum of: BPA, BPF, BPS sum of: 2,4-dichlorophenol, 2,5-dichlorophenol © 2020 Shoaff JR et al. JAMA Network Open. © 2020 Shoaff JR et al. JAMA Network Open. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Association of Exposure to Endocrine-Disrupting Chemicals During Adolescence With Attention-Deficit/Hyperactivity Disorder–Related Behaviors

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American Medical Association
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Copyright 2020 Shoaff JR et al. JAMA Network Open.
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2574-3805
DOI
10.1001/jamanetworkopen.2020.15041
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Abstract

Key Points Question Is exposure to endocrine- IMPORTANCE Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood disrupting chemicals during adolescence neurobehavioral disorder. Studies suggest that prenatal and early childhood exposure to endocrine- a risk factor for behaviors associated disrupting chemicals may be associated with ADHD, but the association during adolescence has not with attention-deficit/hyperactivity been studied to date. disorder (ADHD)? Findings In this cross-sectional analysis OBJECTIVE To evaluate the association between exposure to select endocrine-disrupting chemicals of data from 205 adolescents during adolescence and ADHD-related behaviors. participating in a prospective birth cohort study, exposure to select DESIGN, SETTING, AND PARTICIPANTS For this cross-sectional analysis, data were collected from phthalates was associated with an 205 adolescents in the New Bedford Cohort, an ongoing prospective birth cohort, between June 18, increased risk of ADHD-related 2011, and June 10, 2014. The adolescents provided spot urine samples and underwent behaviors. Associations were strongest neurodevelopmental testing. Statistical analyses performed from January 15 to December 31, 2019, for phthalates with antiandrogenic used a repeated-measures analysis with multivariate modified Poisson models to estimate the activity. adjusted relative risk of ADHD-related behaviors associated with exposure to endocrine-disrupting chemicals. Meaning These findings support the potential importance of exposures to EXPOSURES Urinary biomarker concentrations of endocrine-disrupting chemicals or their endocrine-disrupting chemicals, metabolites, including phthalates, parabens, phenols, and triclocarban, were quantified. Summary especially phthalates, during exposure measures were created, combining biomarker concentrations of chemicals with a shared adolescence as correlates of ADHD- mechanism of action, exposure pathway, or chemical class. related behaviors. MAIN OUTCOMES AND MEASURES Behaviors related to ADHD were assessed with up to 14 indices Supplemental content from self-, parent-, and teacher-completed behavioral checklists using validated and standardized instruments; specifically, the Conners Attention Deficit Scale and the Behavior Assessment System Author affiliations and article information are listed at the end of this article. for Children, Second Edition. Scores on each index were dichotomized to identify those with evidence of a significant behavioral problem, defined by each scale’s interpretive guidelines. RESULTS Among the 205 participants, the mean (SD) age at assessment was 15.3 (0.7) years, with 112 girls (55%) and 124 non-Hispanic White participants (61%). The median urine concentrations were 0.45 μmol/L of Σantiandrogenic phthalates, 0.13 μmol/L of ΣDEHP metabolites, 0.49 μmol/L of Σpersonal care product phthalates, 0.35 μmol/L of Σparabens, 0.02 μmol/L of Σbisphenols, and 0.02 μmol/L of Σdichlorophenols. A total of 82 (40%) had scores consistent with a significant behavioral problem, whereas 39 (19%) had an ADHD diagnosis. Each 2-fold increase in the sum of antiandrogenic phthalate concentrations was associated with a 1.34 (95% CI, 1.00-1.79) increase in the risk of significant ADHD-related behavior problems, whereas a 2-fold increase in the sum of dichlorophenols was associated with a 1.15 (95% CI, 1.01-1.32) increased risk. These associations tended to be stronger in male participants, but comparisons of sex-specific differences were imprecise. (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 1/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Abstract (continued) CONCLUSIONS AND RELEVANCE Endocrine-disrupting chemicals are used in a wide variety of consumer products resulting in ubiquitous exposure. The study findings suggest that exposure to some of these chemicals, particularly certain phthalates, during adolescence may be associated with behaviors characteristic of ADHD. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 Introduction Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood, affecting approximately 9.4% of children in the United States. Attention-deficit/ hyperactivity disorder is characterized by difficulty maintaining attention, controlling impulses, and regulating activity level and may be associated with academic and social problems as well as 2-5 difficulties throughout adulthood. There is growing evidence that exposure to endocrine-disrupting chemicals (EDCs), such as 6-9 phthalates and phenols, may be associated with ADHD. Phthalates and phenols are widely used in consumer products, including food processing and packaging equipment, personal care products 6,10,11 (eg, cosmetics and fragrances), and pharmaceuticals, resulting in ubiquitous exposure. Although epidemiologic studies have reported associations between prenatal and early childhood exposure 8,12,13 to EDCs and ADHD-like behaviors, few studies have examined the association of exposure to these chemicals during adolescence with ADHD-like behaviors. Similar to the prenatal period, adolescence is a critical time for brain development, characterized by structural and functional changes in the brain as well as the onset of behavioral problems, some of which may be due to hormonal changes. As such, exposure to EDCs during adolescence may be particularly detrimental. The objective of this study is to examine the association of adolescent exposure to EDCs, specifically phthalates, phenols, and triclocarban, with ADHD-related behaviors. We hypothesize that exposure to certain EDCs during adolescence is particularly detrimental to adolescent behavior given the rapid brain development that occurs during this time. Methods Study Population We analyzed data from the New Bedford Cohort, a prospective birth cohort of mother-infant pairs recruited after delivery at a New Bedford, Massachusetts, hospital between 1993 and 1998. The original aim of the study was to examine the association of prenatal organochlorine and metal exposures with subsequent neurodevelopment among children living near the New Bedford Harbor Superfund site. Eligibility requirements included newborns who were vaginally delivered to mothers who were at least 18 years of age and who were available for neonatal examination. In-person neurodevelopmental testing was performed when participants were approximately 15 years of age between 2008 and 2014. Of the 788 newborns enrolled in the New Bedford Cohort, 660 (84%) met eligibility criteria (residence in the study region, absence of catastrophic central nervous system injury or disease, available biomarkers of early chemical exposure, and contact information) for these assessments and, of those newborns, 528 (80%) completed assessments. Midway through the 15-year follow-up, the study added assessment of exposure to EDCs. We invited the 252 participants who were evaluated in this last half of the study to provide spot urine samples at 2 points: during neurodevelopmental assessments and approximately 1 week later (mean duration of time after assessment, 7 days [range, 1-35 days]) (eFigure in the Supplement). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The study research protocol was reviewed and approved by the human participants committee of the JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 2/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Brigham and Women’s Hospital (Boston, Massachusetts). Written informed parental consent and child assent were obtained from participants. The analysis of deidentified specimens at the Centers for Disease Control and Prevention (CDC) laboratory (Atlanta, Georgia) was determined not to constitute engagement in human participants research. Urine Sample Collection and EDC Measurement Urine sample collection and analysis have been described elsewhere. In brief, of the 252 adolescents invited to provide urine samples, 205 (81%) provided at least 1 sample. Urine samples were collected in sterile polypropylene cups and frozen until processing and analysis. It was not possible to analyze all urine specimens, owing to resource limitations; of the 144 adolescents (57%) who provided 2 samples, 60 had each sample analyzed separately, and the mean concentration was used in analyses. For the remaining 84, equal volumes of the 2 samples were pooled for analysis. Specific gravity was measured using a digital refractometer (Pocket PAL-10S; ATACO USA Inc). Urine concentrations of 28 biomarkers were quantified at the CDC in 2 batches (2012 and 16-20 2016), based on the timing of collection. Batch 1 included 11 phthalate metabolites and 8 phenols. Five additional biomarkers of phthalates or the phthalate substitute cyclohexane-1,2- dicarboxylic acid, monohydroxy isononyl ester (MHINCH), 3 additional phenols, and triclocarban were measured in batch 2 (Table 1). Because batch 1 analyses did not include all biomarkers, urinary concentrations of all analytes were available for 178 participants (87%), with the remaining 27 participants missing concentrations of MHINCH, monohydroxyisobutyl phthalate (MHiBP), monoisononyl phthalate (MNP), monohydroxybutyl phthalate (MHBP), bisphenol F (BPF), bisphenol S (BPS), ethylparaben, and triclocarban. The limits of detection for the target analytes ranged from 0.2 to 2.3 μg/L; for concentrations less than the limit of detection, instrument readings were used in data analyses. The study-specific urine quality assurance and quality control samples for both between-batch and within-batch analyses demonstrated the excellent reproducibility of the analytic chemistry methods used. Exposure Assessment Because people are routinely exposed to multiple EDCs, we created summary exposure measures by combining biomarker concentrations for chemicals with a shared mechanism of action, exposure pathway, or chemical class. As described elsewhere, the molar sum (Σ) of 11 phthalate metabolites derived from antiandrogenic parent compounds was created to estimate Σantiandrogenic phthalates (in units of micromoles per liter): mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono-2- ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5- carboxypentyl phthalate (MECPP), mono-n-butyl phthalate (MBP), monoisobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), MHiBP, monocarboxyoctyl phthalate (MCOP), MNP, and 16,21-23 MHBP. Summary measures for phthalates found in personal care products (Σpersonal care products; in units of micromoles per liter) was the molar sum of monoethyl phthalate (MEP), MBP, MHBP, MiBP, and MHiBP; the sum of di(2-ethylhexyl) phthalate (DEHP) metabolites (ΣDEHP; in units of micromoles per liter) was the molar sum of MECPP, MEHHP, MEOHP, and MEHP; total parabens (Σparabens; in units of micromoles per liter) was the molar sum of butyl, ethyl, methyl, and propyl paraben; total bisphenols (Σbisphenols; in units of micromoles per liter) was the molar sum of bisphenol A (BPA) and its replacements BPF and BPS; and total dichlorophenols (Σdichlorophenols; in units of micromoles per liter) was the molar sum of 2,4-dichlorophenol and 2,5-dichlorophenol. Behavior Assessment Attention-deficit/hyperactivity disorder–related behaviors were assessed using validated behavioral checklists from the Behavior Assessment System for Children, Second Edition (BASC-2; parent-, teacher-, and self-reported) and Conners Attention Deficit Scale (CADS; parent- and 24,25 teacher-reported). Both instruments have excellent internal reliability, with coefficient α values JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 3/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD of 0.85 to 0.96 for the CADS and 0.74 to 0.95 for the BASC-2 (hyperactivity and attention problem scales), depending on the reporter. The BASC-2 scales are moderately correlated (r  0.5-0.6) with 24,25 the Conners ADHD index, which, in turn, has excellent discriminant validity for ADHD diagnosis. Parents and adolescents completed these checklists at the study visit and first urine sample collection, while teachers completed them a median (SD) of 2.5 (6.6) months after the first urine sample collection. The BASC-2 consists of 139 to 176 questions, and the CADS consists of 14 to 15 Table 1. Distribution of Urinary Biomarker Concentrations of Phthalates, Phenols, Their Substitutes, and Triclocarban Among 205 Adolescent Participants in the New Bedford Cohort Who Provided Urine Samples From 2011 to 2014 Biomarker Full chemical name 5th Percentile 25th Percentile 50th Percentile 75th Percentile 95th Percentile b,c ΣAntiandrogen phthalates NA 0.11 0.26 0.45 0.71 1.41 ΣDEHP metabolites NA 0.03 0.08 0.13 0.19 0.50 ΣPersonal care product NA 0.09 0.24 0.49 0.97 3.22 phthalates b,c ΣParabens NA 0.03 0.05 0.35 1.15 5.83 ΣBisphenols NA 0.01 0.01 0.02 0.03 0.07 ΣDichlorophenols NA 0.00 0.01 0.02 0.03 0.15 Individual chemicals MEP Monoethyl phthalate 7.90 23.9 45.0 122 423 MBP Mono-n-butyl phthalate 2.40 8.50 16.0 24.3 53.6 MiBP Monoisobutyl phthalate 2.10 6.60 11.5 19.3 38.0 MHBP Monohydroxybutyl phthalate 0.20 0.70 1.50 2.85 6.60 MHiBP Monohydroxyisobutyl phthalate 1.10 2.30 4.00 7.30 17.5 MBzP Monobenzyl phthalate 1.3 4.5 9.3 17.8 64.3 MEHP Mono-2-ethylhexyl phthalate 0.10 (<LOD) 0.70 1.50 3.20 9.70 MEHHP Mono-2-ethyl-5-hydroxyhexyl 2.20 6.20 10.5 17.4 45.4 phthalate MEOHP Mono-2-ethyl-5-oxohexyl phthalate 1.60 4.80 7.70 11.7 33.7 MECPP Mono-2-ethyl-5-carboxypentyl 5.20 11.60 18.5 28.1 70.8 phthalate MCOP Monocarboxyoctyl phthalate 7.40 26.0 49.4 103.0 214.0 MNP Mono-isononyl phthalate 0.20 0.70 1.60 4.30 15.1 MCNP Monocarboxynonyl phthalate 1.30 2.90 4.65 7.10 13.60 MCPP Mono-3-carboxypropyl phthalate 0.9 2.5 5.0 10.2 43.6 c,d MHINCH Cyclohexane-1,2-dicarboxylic acid, 0.00 (<LOD) 0.10 0.30 0.50 1.10 monohydroxy isononyl ester M-paraben Methyl paraben 3.60 7.50 42.4 140 598 P-paraben Propyl paraben 0.30 1.00 3.70 18.6 117 E-paraben Ethyl paraben 0.20 0.40 0.70 2.10 29.0 B-paraben Butyl paraben 0.00 (<LOD) 0.00 (<LOD) 0.20 0.50 4.1 BPA Bisphenol A 0.50 1.00 1.70 2.80 6.70 BPS Bisphenol S 0.10 0.20 0.40 0.80 2.30 BPF Bisphenol F 0.00 (<LOD) 0.10 0.20 0.60 5.50 BP-3 Benzophenone-3 4.15 13.0 38.3 172 1148 2,4-DCP 2,4-Dichlorophenol 0.15 0.40 0.60 1.10 2.30 2,5-DCP 2,5-Dichlorophenol 0.40 0.80 1.65 4.20 22.7 TCS Triclosan 1.50 3.20 8.50 49.9 381 TCC Triclocarban 0.00 (<LOD) 0.00 (<LOD) 0.10 0.20 4.70 Abbreviations: DEHP, di(2-ethylhexyl) phthalate; LOD, limit of detection; NA, not sum of MECPP, MEHHP, MEOHP, MEHP; Σparabens (μmol/L): molar sum of B-paraben, applicable; Σ, molar sum. E-paraben, M-paraben, and P-paraben; Σbisphenols (μmol/L): molar sum of BPA, BPF, a and BPS; and Σdichlorophenols (μmol/L): molar sum of 2,4-dichlorophenol and Units for sums are μmol/L and units for individual biomarkers are μg/L. 2,5-dichlorophenol. Concentrations were calculated as follows: Σantiandrogen phthalates (μmol/L): molar Because some chemicals were not measured in the first batch of Centers for Disease sum of MEHHP, MEHP, MEOHP, MECPP, MBP, MiBP, MBzP, MHiBP, MCOP, MNP, and Control and Prevention analyses, Σantiandrogen phthalates, Σpersonal care product MHBP (MCOP and MNP were downweighted by multiplying their molar concentrations phthalates, Σparabens, Σbisphenols, MHINCH, MCOCH, BPS, BPF, MNP, MHBP, MHiBP, by 0.43 prior to summing to reflect the potency of their parent compound relative to TCC, and E-paraben concentrations were available for only 178 of the 205 participants. the other antiandrogenic phthalates); Σpersonal care product phthalates (μmol/L): molar sum of MBP, MHBP, MEP, MiBP, and MHiBP; ΣDEHP metabolites (μmol/L): molar Phthalate replacement. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 4/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD questions, depending on the reporter. For each question, the frequency of adverse behavior is ranked using a 4-point Likert scale. Responses generate composite behavioral indices expressed as age- and sex-adjusted T-scores standardized to a mean (SD) of 50 (10), where a higher score indicates more adverse behavior. These measures generate 14 ADHD-related behavior indices. From the BASC-2, we included indices of inattention (teacher-, parent-, and self-reported), hyperactivity (teacher-, parent-, and self-reported), and executive function (teacher- and parent-reported). From the CADS parent and teacher reports, we included indices for inattention and hyperactivity based on Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnostic criteria and a CADS index of overall ADHD behaviors. All 205 adolescents with exposure data had at least 1 outcome measure, 204 (99.5%) had parent- and self-completed checklists, and 173 (84%) had teacher- completed checklists. Covariates Data on parental demographic charateristics (race/ethnicity, educational level, and income), health history, and tobacco use during pregnancy were collected in a questionnaire administered to mothers approximately 2 weeks after delivery. When the child was 15 years of age, the data on demographic characteristics, smoking habits, and child medical history (including behavioral disorder diagnoses and medication use) were updated via medical record reviews and questionnaires. Self- reported adolescent tobacco, alcohol, and marijuana use was ascertained with the CDC Youth Risk Behavior Survey. Umbilical cord serum levels of polychlorinated biphenyls and dichlorodiphenyldichloroethylene were used as biomarkers of prenatal organochlorine exposures. Childhood blood lead levels were abstracted from medical records of lead exposure screening; the maximum concentration between 12 and 36 months of age was calculated. Using a structured diary, adolescents recorded food consumption and personal care product use for the 24 hours prior to urine sample collection. Diary data were used to estimate exposure risk factors during that 24-hour period, including the number of personal care products used and caffeinated beverages consumed, as well as the amount of fast food or canned food consumed. Height and weight were measured at the time of urine sample collection, and body mass index z scores were calculated using CDC US reference data. Statistical Analysis Statistical analyses were performed from January 15 to December 31, 2019. Regression diagnostics supported log transformation of urinary biomarker concentrations. We dichotomized outcomes at the 98th percentile, which BASC-2 and CADS guidelines define as indicative of significant behavioral problems. To leverage the multiple indices of ADHD-related behavior, maximize power, and avoid multiple comparisons, we used a repeated-measures analysis design, considering each of the 14 27,28 binary indices as a repeated measure reflecting a single underlying outcome. We used multivariate modified Poisson models with robust error variance and an independent working correlation that can accommodate missing behavioral scores, so participants with at least 1 behavioral measure were included. Analyses were performed using SAS, version 9.4 (SAS Institute Inc). We examined whether a child’s sex modified the association between urinary biomarker concentrations and ADHD-related behavior. In secondary analyses, we dichotomized outcomes at the 85th percentile, indicating a possible significant behavior problem. We also considered individual chemicals not included in summary exposure measures (benzophenone-3, triclosan, triclocarban, mono-3-carboxypropyl phthalate [MCPP], monocarboxynonyl phthalate [MCNP], and MHINCH), as well as the individual chemicals that comprised the summary measures. All models included the child’s sex and mean age at completion of BASC-2 and CADS to adjust for fundamental determinants of behavior, urine-specific gravity to account for urine dilution, and an indicator for ADHD measure. We then used prior literature to inform a directed acyclic graph to select other covariates, including the child’s race/ethnicity (non-Hispanic White vs other) and the following JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 5/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD maternal characteristics at the time of delivery: age (as a continuous variable), marital status (married vs unmarried), educational level (<high school vshigh school), annual household income (<$20 000 vs$20 000), and smoking during pregnancy (yes or no). Because not all biomarkers were measured in the first batch of urine samples, some biomarker measures were missing for 27 participants, and some covariate information was missing for 14 participants; thus, our complete case analyses had a sample size of 164 to 190 depending on the urine biomarker measure. In a sensitivity analysis, we imputed missing values (PROC MI/MIANALYZE, Unix SAS, version 9.1.4; SAS Institute Inc) based on 20 imputations using models with all covariates, behavioral outcomes, and biomarker concentrations in this analysis. We performed additional sensitivity analyses, including adjusting for umbilical cord serum polychlorinated biphenyls and dichlorodiphenyldichloroethylene, and adjusting for 12-month to 36-month maximum blood lead levels, because exposure to these chemicals hase been associated with ADHD-related behaviors in the New Bedford Cohort. We adjusted for whether adolescents had smoked cigarettes in the past 30 days or ever tried alcohol or marijuana (n = 60). We also conducted an unadjusted analysis and analyses separately examining measures reflecting attention vs hyperactivity and impulsivity problems, adjusting for factors associated with increased EDC exposure risk, adjusting for body mass index, adjusting for a family history (parent or sibling) of mental illness (n = 86), adjusting for diagnosis of behavioral problems other than ADHD (n = 74), removing those with a diagnosis of ADHD (n = 39), removing those taking prescription medication for behavioral problems (n = 22), and removing siblings (n = 14). We removed individual BASC-2 behavior measures (12 indices) with instrument validity indicators that suggested a negative or positive bias or lack of internal consistency. Results The mean (SD) age of the 205 participants at assessment was 15.3 (0.7) years, with 112 girls (55%) and 124 non-Hispanic White participants (61%). A substantial proportion of study adolescents were born to mothers who, at the time of delivery, were unmarried (87 [42%]), had less than a high school education (30 [15%]), or had annual household incomes less than $20 000 (66 [32%]) (Table 2 and eTable 1 in the Supplement). Compared with the 528 adolescents participating in the full 15-year follow-up, those in this analysis were younger, and a higher percentage were non-White, but, otherwise, the 2 groups did not differ (eTable 1 in the Supplement). The median urine concentrations were 0.45 μmol/L of Σantiandrogenic phthalates, 0.13 μmol/L of ΣDEHP metabolites, 0.49 μmol/L of Σpersonal care product phthalates, 0.35 μmol/L of Σparabens, 0.02 μmol/L of Σbisphenols, and 0.02 μmol/L of Σdichlorophenols (Table 1). Individual biomarker concentrations among study participants were similar to those observed in US adolescents in the 2011-2012 National Health and Nutrition Examination Survey. Of the 205 adolescents in this analysis, 82 (40%) had scores consistent with a significant behavioral problem as defined by at least 1 BASC-2 or CADS ADHD-related measure (Table 3), whereas 39 (19%) had an ADHD diagnosis (Table 2), which is higher than US population estimates (approximately 10%). In covariate-adjusted models, summary measures of phthalates were consistently associated with an increased risk of significant ADHD-related behavior problems (Figure; Table 4). A 2-fold increase in Σantiandrogenic phthalates was associated with a 1.34 (95% CI, 1.00-1.79) increased risk of significant ADHD-related behavior problems, whereas a 2-fold increase in ΣDEHP metabolites was associated with a 1.29 (95% CI, 1.07-1.55) increased risk. A smaller 1.16 (95% CI, 0.98-1.37) increased risk was observed with a 2-fold increase in Σpersonal care products. Adverse associations were observed with each individual phthalate metabolite; the strongest association was for MBP (relative risk [RR], 1.45; 95% CI, 1.15-1.84) (eTable 3 in the Supplement). We observed stronger associations for hyperactive behaviors compared with inattentive behaviors for Σantiandrogenic phthalates JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 6/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Table 2. Distribution of Characteristics of New Bedford Cohort Adolescents (With EDC Measures) by Parent-Reported ADHD Index on the CADS Adolescents, No. (%) Without significant or possible Possible significant Significant behavior behavior problem on CADS behavior problem on CADS problem on CADS a a a Characteristic ADHD index (n = 148) ADHD index (n = 56) ADHD index (n = 29) Maternal characteristics at time of child’s birth Age, y <20 14 (10) 7 (13) 1 (4) 20-29 89 (60) 37 (66) 21 (72) ≥30 45 (30) 12 (21) 7 (24) Household income, $/y <20 000 42 (28) 24 (43) 9 (31) 20 000 to <40 000 47 (32) 23 (41) 17 (59) 40 000 to <75 000 44 (30) 9 (16) 3 (10) ≥75 000 10 (7) NA NA Missing 5 (3) NA NA Educational level <High school 12 (8) 18 (32) 10 (34) ≥High school 131 (89) 38 (68) 19 (66) Missing 5 (3) NA NA Marital status Unmarried 53 (36) 34 (61) 14 (48) Married 88 (59) 18 (32) 12 (41) Missing 7 (5) 4 (7) 3 (10) Smoking during pregnancy No 109 (74) 25 (45) 12 (41) Yes 31 (21) 25 (45) 14 (48) Missing 8 (5) 6 (10) 3 (10) Child characteristics Sex Male 67 (45) 25 (45) 12 (41) Female 81 (55) 31 (55) 17 (59) Mean age at assessment, y 14-15 118 (80) 45 (80) 23 (79) 16-17 30 (20) 11 (20) 6 (21) Race Non-Hispanic White 99 (67) 25 (45) 16 (55) Non-White 49 (33) 31 (55) 13 (45) b,c ADHD diagnosis No 137 (93) 28 (50) 12 (41) Yes 11 (7) 28 (50) 17 (59) Behavioral problem other b,c than ADHD No 107 (72) 23 (41) 11 (38) Yes 41 (28) 33 (59) 18 (62) Use of prescription medication for behavioral b,d problem No 138 (93) 44 (79) 21 (72) Yes 10 (7) 12 (21) 8 (28) Mean number of caffeinated beverages in past 24 h 0 46 (31) 21 (37) 10 (34) 1 72 (49) 29 (52) 19 (66) ≥2 30 (20) 6 (11) NA (continued) JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 7/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Table 2. Distribution of Characteristics of New Bedford Cohort Adolescents (With EDC Measures) by Parent-Reported ADHD Index on the CADS (continued) Adolescents, No. (%) Without significant or possible Possible significant Significant behavior behavior problem on CADS behavior problem on CADS problem on CADS a a a Characteristic ADHD index (n = 148) ADHD index (n = 56) ADHD index (n = 29) Personal care product use ≤6 Products/d 73 (49) 32 (57) 15 (52) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CADS, Conners Attention Deficit Scale; EDC, ≥7 Products/d 75 (51) 23 (41) 13 (45) endocrine-disrupting chemical; NA, not applicable. Missing NA 1 (2) 1 (3) Significant behavior problem: scale T-score Fast food consumption dichotomized at the 98th percentile; possible 0 Servings/d 75 (51) 23 (41) 16 (55) significant problem: scale T-score dichotomized at 1 Servings/d 65 (44) 27 (48) 11 (38) the 85th percentile. >1 Servings/d 8 (5) 5 (9) 1 (3) b P < .05 for comparisons between those with possible Missing NA 1 (2) 1 (3) significant behavior problem on CADS ADHD index and those without using the χ test. Canned food consumption Medical record or parent-reported diagnosis of a 0 Servings/d 114 (77) 49 (87) 23 (79) behavioral disorder. ≥1 Serving/d 34 (23) 7 (13) 6 (21) f Parent-reported child use of medication for a Adolescent substance use behavioral disorder. No 105 (71) 39 (70) 19 (66) Mean from two 24-hour diary reports (or one Yes 43 (29) 17 (30) 10 (34) 24-hour diary report if only 1 urine sample provided) Peak childhood blood lead regarding personal care product use, fast food or level, μg/dL canned food consumption, and consumption of <5 57 (38) 19 (34) 10 (34) caffeinated beverages. ≥5 71 (48) 31 (55) 17 (59) Adolescent report of having smoked a cigarette in Missing 20 (14) 6 (11) 2 (7) the past 30 days or ever having tried marijuana Body mass index z score or alcohol. percentile Peak childhood blood lead levels between 12 and 36 <5th 3 (2) 1 (2) 1 (3) months of age. 5th-84th 86 (58) 35 (62) 16 (55) Age and sex standardized using Centers for Disease ≥85th 59 (40) 20 (36) 12 (41) Control and Prevention US reference population. Table 3. Frequency of ADHD-Related Behavioral Problems in New Bedford Cohort Adolescents as Reported on Teacher-, Parent-, or Self-reported BASC-2 and CADS Behavioral Assessments No. (%) Significant behavior Possible significant behavior c d Behavioral scale problem problem BASC-2 teacher-reported inattention 24/173 (14) 55/173 (32) BASC-2 teacher-reported hyperactivity 16/173 (9) 36/173 (21) BASC-2 teacher-reported executive function 11/173 (6) 24/173 (14) BASC-2 parent-reported inattention 13/204 (6) 50/204 (25) Abbreviations: ADHD, attention-deficit/hyperactivity BASC-2 parent-reported hyperactivity 12/204 (6) 31/204 (15) disorder; BASC-2, Behavior Assessment System for BASC-2 parent-reported executive function 12/204 (6) 36/204 (18) Children, Second Edition; CADS, Conners Attention Deficit Scale. BASC-2 self-reported inattention 21/204 (10) 57/204 (28) A total of 204 had parent-reported and self-reported BASC-2 self-reported hyperactivity 12/204 (6) 45/204 (22) scales and 173 had teacher-reported scales. CADS teacher-reported ADHD 42/173 (24) 60/173 (35) A total of 82 had a significant ADHD-associated CADS teacher-reported inattention 30/173 (17) 43/173 (25) behavior problem on at least 1 scale and 134 had a CADS teacher-reported hyperactivity 35/173 (20) 45/173 (26) possible significant ADHD-associated behavior CADS parent-reported ADHD 29/204 (14) 56/204 (27) problem on at least 1 scale. CADS parent-reported inattention 20/204 (10) 45/204 (22) Scale T-score dichotomized at the 98th percentile. CADS parent-reported hyperactivity 27/204 (13) 45/204 (22) Scale T-score dichotomized at the 85th percentile. (RR, 1.40 [95% CI, 1.07-1.84] vs 1.26 [95% CI, 0.87-1.83]), Σpersonal care products (RR, 1.25 [95% CI, 1.07-1.47] vs 1.06 [95% CI, 0.95-1.18]), and Σdichlorophenols (RR, 1.22 [95% CI, 1.04-1.42] vs 1.05 [95% CI, 0.90-1.23]) (Table 4). JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 8/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Associations tended to be stronger among male adolescents than among female adolescents, most notably with respect to the ΣDEHP metabolites (P = .002 for interaction), in which a 2-fold increase corresponded to a 1.62 (95% CI, 1.38-1.91) increased risk of significant ADHD-related behavior problems in male adolescents compared with a 1.06 (95% CI, −1.15 to 1.33) increased risk in female adolescents (Figure; eTable 2 in the Supplement). The remaining sex-specific differences were estimated with less precision. A 2-fold increase in Σdichlorophenols was also associated with an increased risk of ADHD- related behaviors (RR, 1.15; 95% CI, 1.01-1.32) (Table 4). However, we did not observe associations with urinary biomarker concentrations of Σparabens or Σbisphenols or with the individual components of Σparabens or Σbisphenols summary measures, triclocarban, triclosan, benzophenone-3, or MHINCH (Figure; eTables 2 and 3 in the Supplement). When considering the more inclusive threshold for those with possible significant behavioral problems (>85th percentile), we observed similar, albeit slightly attenuated, findings. For example, each 2-fold increase in Σantiandrogenic phthalates was associated with a 1.21 (95% CI, 1.00-1.47) increased risk of possible significant (vs 1.34 for clearly significant) ADHD-related behavior problems (Table 4), and this difference appeared to be more pronounced among male adolescents (eTable 2 in the Supplement). Associations were similar, but more precise, in models imputing missing data (eTable 4 in the Supplement). Associations were stronger for summary phthalate measures when we excluded adolescents with an ADHD diagnosis. We did not observe substantive changes in results with the other sensitivity analyses, including exclusion of those taking medications (eTables 4 and 5 in the Supplement). Figure. Adjusted Relative Risk of Multiple Measures of Clinically Significant Attention-Deficit/Hyperactivity Disorder (ADHD)–Associated Behaviors Corresponding to a 2-Fold Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents (Sample Size From 164 to 190) Combined Male 2 Female 0.5 b d e f ΣAntiandrogenic ΣDEHP ΣPersonal care ΣParabens ΣBisphenols ΣDichlorophenols a c phthalates product phthalates Adjusted for child characteristics: sex, race/ethnicity, mean test age (across teacher- phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono-2-ethyl-5- reported, parent-reported, and self-reported Behavior Assessment System for Children, carboxypentyl phthalate (MECPP), monocarboxyoctyl phthalate, 2nd Edition [BASC-2] and Conners Attention Deficit Scale [CADS] measures), and urine monohydroxyisobutyl phthalate (MHiBP), monohydroxybutyl phthalate (MHBP), and specific gravity; maternal characteristics at delivery: age, income, marital status, mono-isononyl phthalate. smoking, and educational level; and test indicator. The ADHD-associated behavior Sum of MECPP, MEHHP, MEOHP, and MEHP. measures include CADS parent-reported and teacher-reported inattention, Sum of MBP, MHBP, monoethyl phthalate, MiBP, and MHiBP. hyperactivity, and ADHD; BASC-2 parent-reported, teacher-reported, and self-reported Sum of butyl, ethyl, methyl, and propyl parabens. hyperactivity and inattention; and BASC-2 parent-reported and teacher-reported executive function. Significant behavior problem: scale T-score dichotomized at the 98th Sum of bisphenol A, bisphenol F, and bisphenol S. percentile. f Sum of 2,4-dichlorophenol and 2,5-dichlorophenol. Sum of mono-n-butyl phthalate (MBP), monoisobutyl phthalate (MiBP), monobenzyl phthalate, mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-hydroxyhexyl JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 9/14 Relative risk of ADHD behaviors JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Discussion In a population with a high prevalence of ADHD-related behaviors, our findings support an association of adolescent exposure to EDCs, particularly select phthalates, with an increased risk of significant ADHD-related behavior problems at exposure biomarker concentrations typical of adolescents in the general US population. These results are consistent with previously reported findings in the New Bedford Cohort associating adolescent EDC exposure, particularly to antiandrogenic phthalates, with increased externalizing behaviors (a BASC-2 composite of hyperactivity, aggression, and conduct problems). Previous studies have reported associations of prenatal and early postnatal exposure to phthalates and BPA with an increase in ADHD-related behaviors. However, to our knowledge, no other published studies have analyzed associations between adolescent EDC biomarker concentrations and ADHD-related behaviors. Adolescence is a critical period for brain development and may be another time of heightened vulnerability to EDC exposure. Several cross-sectional studies (with children of wide age ranges, including some adolescents) have reported associations 5,7,9,32 between increased urinary phthalate and BPA concentrations and ADHD-related behaviors. Experimental animal studies also support the potential for EDC exposures to be associated with 33-36 adverse behavior in adolescence, including behaviors consistent with ADHD. Furthermore, there is well-established evidence demonstrating the unique association that neurotoxicant exposures (eg, 37,38 alcohol and organophosphates) during adolescence have with adverse behavior. This analysis focused on ADHD-related behaviors as opposed to clinical ADHD diagnosis. By relying on multiple indices of ADHD-related behavior (from the BASC-2 and CADS) from multiple Table 4. Adjusted Relative Risk of Multiple Measures of Clinically Significant Behavioral Subgroups of ADHD Behaviors Associated With a 2-Fold Increase in Urinary Biomarker Concentrations in New Bedford Cohort a,b Adolescents (Sample Size From 164 to 190) Adjusted relative risk c d Chemical biomarker Combined ADHD measures Attention problems Hyperactivity problems ΣAntiandrogenic phthalates 1.34 (1.00-1.79) 1.26 (0.87-1.83) 1.40 (1.07-1.84) ΣDEHP 1.29 (1.07-1.55) 1.29 (1.03-1.60) 1.27 (1.06-1.52) ΣPersonal care products 1.16 (0.98-1.37) 1.06 (0.85-1.32) 1.25 (1.07-1.47) ΣParabens 1.06 (0.96-1.18) 1.06 (0.93-1.21) 1.06 (0.95-1.18) ΣBisphenols 1.09 (0.91-1.31) 1.08 (0.87-1.33) 1.04 (0.84-1.29) ΣDichlorophenols 1.15 (1.01-1.32) 1.05 (0.90-1.23) 1.22 (1.04-1.42) Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BASC-2, Behavior Assessment System for Children, 2nd edition; CADS, Conners Attention Deficit Scale; DEHP, di(2-ethylhexyl) phthalate. Adjusted for child: sex, mean test age (across teacher-reported, parent-reported, and self-reported BASC and CADS measures), and urine specific gravity; maternal characteristics at delivery: age, income, marital status, smoking, and educational level; and test indicator. Attention-deficit/hyperactivity disorder–related behavior measures include CADS parent-reported and teacher-reported inattention, hyperactivity, and ADHD; BASC-2 parent-reported, teacher-reported, and self-reported hyperactivity and inattention; and BASC-2 parent-reported and teacher-reported executive function. Significant behavior problem: scale T-score dichotomized at the 98th percentile. Attention problems subset includes CADS teacher-reported and parent-reported inattention and BASC-2 teacher- reported, parent-reported, and self-reported inattention. Hyperactivity subset includes CADS teacher-reported and parent-reported hyperactive behavior and BASC-2 teacher- reported, parent-reported, and self-reported hyperactive behavior. Sum of MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCOP, MHiBP, MHBP, and MNP (full chemical names in Table 1). Sum of MECPP, MEHHP, MEOHP, and MEHP (full chemical names in Table 1). Sum of MBP, MHBP, MEP, MiBP, and MHiBP (full chemical names in Table 1). Sum of butyl, ethyl, methyl, and propyl parabens. Sum of BPA, BPF, and BPS (full chemical names in Table 1). Sum of 2,4-dichlorophenol and 2,5-dichlorophenol. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 10/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD observers (teachers, parents, and self), we were able to leverage a uniquely comprehensive characterization of adolescent behavior, including behaviors that can vary over time (eg, inattention) and thus may be susceptible to variations in exposure risk factors. In particular, combining information from these multiple measures increased the power of our analysis, resulting in more stable estimates of association than would have been possible by examining each behavioral measure individually. In addition, by expressing multiple measures as a single outcome, we did not induce the statistical issues associated with multiple comparisons. Limitations This study has some limitations. The assessed EDCs have short elimination half-lives, as well as short- term variability in exposure, resulting in the potential for nondifferential exposure misclassification, which could bias results toward the null. However, our study collected urine samples at 2 different times from most participants, allowing us to better characterize each participant’s mean or usual exposure. Given the cross-sectional design of this analysis, another challenge is the potential for reverse causation, such that existing behavioral problems may alter habits that enhance EDC 39-42 exposure via changes in, for instance, diet, substance use, and/or personal care product use. However, adjustments for these factors did not affect associations, suggesting that reverse causation from these habits was unlikely. Furthermore, excluding adolescents with a diagnosis of ADHD enhanced the existing associations (eTable 4 in the Supplement). Although data on participants’ prenatal EDC exposure are lacking, we do not expect this lack of data would confound associations with adolescent exposure; weak within-person correlations have been reported between prenatal and childhood exposures to phthalates and BPA, and we would expect similar or weaker correlations 43,44 between prenatal and adolescent time periods. In addition, participants were from a small geographical region, which may potentially affect the generalizability of our findings. Conclusions Our results support the importance of adolescent exposure to EDCs, particularly phthalates, as a potential risk factor for significant ADHD-related behavior problems. Attention-deficit/hyperactivity disorder is a common and costly neurobehavioral disorder; US health care and education expenditures associated with ADHD in children and adolescents are estimated to be $38 billion to $72 billion annually, while costs associated with ADHD in adults, including lost wages, are much 2,45 higher, ranging from $143 billion to $266 billion annually. The identification of modifiable risk factors for ADHD is of great public health importance. These findings contribute new insights into the potential detrimental neurobehavioral outcomes of EDC exposure during adolescence. ARTICLE INFORMATION Accepted for Publication: June 15, 2020. Published: August 28, 2020. doi:10.1001/jamanetworkopen.2020.15041 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Shoaff JR et al. JAMA Network Open. Corresponding Author: Jessica R. Shoaff, PhD, Channing Division of Network Medicine, Harvard Medical School, Brigham and Women’s Hospital, 401 Park Dr, 3rd Floor West, Boston, MA 02215 (jessica.shoaff@channing. harvard.edu). Author Affiliations: Channing Division of Network Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts (Shoaff, Korrick); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Shoaff); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Coull); Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (Coull, Bellinger, Korrick); Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts (Weuve); Department of Neurology and Psychiatry, Boston Children’s JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 11/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD Hospital and Harvard Medical School, Boston, Massachusetts (Bellinger); Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia (Calafat); Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana (Schantz); Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana (Schantz). Author Contributions: Drs Shoaff and Korrick had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Shoaff, Schantz, Korrick. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Shoaff, Weuve, Korrick. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Shoaff, Coull, Weuve, Korrick. Obtained funding: Schantz, Korrick. Administrative, technical, or material support: Korrick. Supervision: Korrick. Conflict of Interest Disclosures: Dr Coull reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study, receiving grants from the US Environmental Protection Agency and the NIH, and working on the Apple Women’s Health Study outside the submitted work. Dr Korrick reported receiving grants from the NIH/National Institute of Environmental Health Sciences during the conduct of the study. No other disclosures were reported. Funding/Support: Support for this research was provided by the following grants: RD-83459301 and RD-835434010 from the US Environmental Protection Agency; and P20 ES018163, P01 ES022848, and R01 ES014864 from the NIH/National Institute of Environmental Health Sciences. Dr Shoaff was supported by National Institute of Environmental Health Sciences training grant T32 ES007069. Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention, the Public Health Service, the US Department of Health and Human Services, or the US Environmental Protection Agency. REFERENCES 1. Danielson ML, Bitsko RH, Ghandour RM, Holbrook JR, Kogan MD, Blumberg SJ. Prevalence of parent-reported ADHD diagnosis and associated treatment among U.S. children and adolescents, 2016. J Clin Child Adolesc Psychol. 2018;47(2):199-212. doi:10.1080/15374416.2017.1417860 2. Abright AR. Estimating the costs of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51(10):987-989. doi:10.1016/j.jaac.2012.07.012 3. Froehlich TE, Lanphear BP, Auinger P, et al. Association of tobacco and lead exposures with attention-deficit/ hyperactivity disorder. Pediatrics. 2009;124(6):e1054-e1063. doi:10.1542/peds.2009-0738 4. Froehlich TE, Lanphear BP, Epstein JN, Barbaresi WJ, Katusic SK, Kahn RS. Prevalence, recognition, and treatment of attention-deficit/hyperactivity disorder in a national sample of US children. Arch Pediatr Adolesc Med. 2007;161(9):857-864. doi:10.1001/archpedi.161.9.857 5. Tewar S, Auinger P, Braun JM, et al. Association of bisphenol A exposure and attention-deficit/hyperactivity disorder in a national sample of U.S. children. Environ Res. 2016;150:112-118. doi:10.1016/j.envres.2016.05.040 6. Braun JM, Yolton K, Dietrich KN, et al. Prenatal bisphenol A exposure and early childhood behavior. Environ Health Perspect. 2009;117(12):1945-1952. doi:10.1289/ehp.0900979 7. Chopra V, Harley K, Lahiff M, Eskenazi B. Association between phthalates and attention deficit disorder and learning disability in U.S. children, 6-15 years. Environ Res. 2014;128:64-69. doi:10.1016/j.envres.2013.10.004 8. Rochester JR, Bolden AL, Kwiatkowski CF. Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis. Environ Int. 2018;114:343-356. doi:10.1016/j.envint.2017.12.028 9. Kim BN, Cho SC, Kim Y, et al. Phthalates exposure and attention-deficit/hyperactivity disorder in school-age children. Biol Psychiatry. 2009;66(10):958-963. doi:10.1016/j.biopsych.2009.07.034 10. Braun JM, Sathyanarayana S, Hauser R. Phthalate exposure and children’s health. Curr Opin Pediatr. 2013;25 (2):247-254. doi:10.1097/MOP.0b013e32835e1eb6 JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 12/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD 11. Harley KG, Kogut K, Madrigal DS, et al. Reducing phthalate, paraben, and phenol exposure from personal care products in adolescent girls: findings from the HERMOSA Intervention Study. Environ Health Perspect. 2016;124 (10):1600-1607. doi:10.1289/ehp.1510514 12. Engel SM, Miodovnik A, Canfield RL, et al. Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environ Health Perspect. 2010;118(4):565-571. doi:10.1289/ehp.0901470 13. Engel SM, Villanger GD, Nethery RC, et al. Prenatal phthalates, maternal thyroid function, and risk of attention- deficit hyperactivity disorder in the Norwegian mother and child cohort. Environ Health Perspect. 2018;126(5): 057004. doi:10.1289/EHP2358 14. Casey BJ, Jones RM, Hare TA. The adolescent brain. Ann N Y Acad Sci. 2008;1124:111-126. doi:10.1196/annals. 1440.010 15. Korrick SA, Altshul LM, Tolbert PE, Burse VW, Needham LL, Monson RR. Measurement of PCBs, DDE, and hexachlorobenzene in cord blood from infants born in towns adjacent to a PCB-contaminated waste site. J Expo Anal Environ Epidemiol. 2000;10(6, pt 2):743-754. doi:10.1038/sj.jea.7500120 16. Shoaff JR, Calafat AM, Schantz SL, Korrick SA. Endocrine disrupting chemical exposure and maladaptive behavior during adolescence. Environ Res. 2019;172:231-241. doi:10.1016/j.envres.2018.12.053 17. Silva MJ, Jia T, Samandar E, Preau JL Jr, Calafat AM. Environmental exposure to the plasticizer 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) in U.S. adults (2000-2012). Environ Res. 2013;126:159-163. doi:10. 1016/j.envres.2013.05.007 18. Silva MJ, Samandar E, Preau JL Jr, Reidy JA, Needham LL, Calafat AM. Quantification of 22 phthalate metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;860(1):106-112. doi:10.1016/j. jchromb.2007.10.023 19. 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 Analyt Technol Biomed Life Sci. 2006;844(1):53-59. doi:10.1016/j. jchromb.2006.06.037 20. 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(16):5407-5413. doi:10.1021/ac050390d 21. Hannas BR, Lambright CS, Furr J, Howdeshell KL, Wilson VS, Gray LE Jr. Dose-response assessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate, and diisononyl phthalate. Toxicol Sci. 2011;123(1):206-216. doi:10.1093/toxsci/kfr146 22. Howdeshell KL, Rider CV, Wilson VS, Furr JR, Lambright CR, Gray LE Jr. Dose addition models based on biologically relevant reductions in fetal testosterone accurately predict postnatal reproductive tract alterations by a phthalate mixture in rats. Toxicol Sci. 2015;148(2):488-502. doi:10.1093/toxsci/kfv196 23. Larsson K, Ljung Björklund K, Palm B, et al. Exposure determinants of phthalates, parabens, bisphenol A and triclosan in Swedish mothers and their children. Environ Int. 2014;73:323-333. doi:10.1016/j.envint.2014.08.014 24. Conners C. Conners’ Rating Scales—Revised Technical Manual. North Tonawanda, NY: Multi-Health Systems; 25. Reynolds CR, Kamphaus RW. Behavior Assessment System for Children Manual. 2nd ed. AGS; 2004. 26. Centers for Disease Control and Prevention. CDC growth charts. Accessed May 12, 2019. https://www.cdc.gov/ growthcharts/cdc_charts.htm 27. Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344 (15):1132-1138. doi:10.1056/NEJM200104123441504 28. Weuve J, Korrick SA, Weisskopf MG, et al. Cumulative exposure to lead in relation to cognitive function in older women. Environ Health Perspect. 2009;117(4):574-580. doi:10.1289/ehp.11846 29. Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research. Epidemiology. 1999;10(1):37-48. doi:10.1097/00001648-199901000-00008 30. SAS/STATA: 13.1 User's Guide. Cary, NC: SAS Institute Inc; 2013. 31. Centers for Disease Control and Prevention. Fourth National Report on Human Exposure to Environmental Chemicals: updated tables, March 2018, volume one. Published 2018. Accessed February 2, 2019. https://www.cdc. gov/exposurereport/pdf/FourthReport_UpdatedTables_Volume1_Jan2019-508.pdf 32. Findlay LC, Kohen DE. Bisphenol A and child and youth behaviour: Canadian Health Measures Survey 2007 to 2011. Health Rep. 2015;26(8):3-9. JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 13/14 JAMA Network Open | Environmental Health Endocrine-Disrupting Chemical Exposure in Adolescence and ADHD 33. Ishido M, Masuo Y, Kunimoto M, Oka S, Morita M. Bisphenol A causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immunoreactivity. J Neurosci Res. 2004;76(3):423-433. doi:10.1002/ jnr.20050 34. Ishido M, Masuo Y, Sayato-Suzuki J, Oka S, Niki E, Morita M. Dicyclohexylphthalate causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immunoreactivity. J Neurochem. 2004;91(1):69-76. doi:10.1111/j.1471-4159.2004.02696.x 35. Ishido M, Masuo Y, Terasaki M, Morita M. Rat hyperactivity by bisphenol A, but not by its derivatives, 3-hydroxybisphenol A or bisphenol A 3,4-quinone. Toxicol Lett. 2011;206(3):300-305. doi:10.1016/j.toxlet.2011. 08.011 36. Zhou R, Bai Y, Yang R, et al. Abnormal synaptic plasticity in basolateral amygdala may account for hyperactivity and attention-deficit in male rat exposed perinatally to low-dose bisphenol-A. Neuropharmacology. 2011;60(5): 789-798. doi:10.1016/j.neuropharm.2011.01.031 37. Spear LP. Effects of adolescent alcohol consumption on the brain and behaviour. Nat Rev Neurosci. 2018;19 (4):197-214. doi:10.1038/nrn.2018.10 38. Rohlman DS, Ismail A, Bonner MR, et al. Occupational pesticide exposure and symptoms of attention deficit hyperactivity disorder in adolescent pesticide applicators in Egypt. Neurotoxicology. 2019;74:1-6. doi:10.1016/j. neuro.2019.05.002 39. Oddy WH, Robinson M, Ambrosini GL, et al. The association between dietary patterns and mental health in early adolescence. Prev Med. 2009;49(1):39-44. doi:10.1016/j.ypmed.2009.05.009 40. Trapp GS, Allen KL, Black LJ, et al. A prospective investigation of dietary patterns and internalizing and externalizing mental health problems in adolescents. Food Sci Nutr. 2016;4(6):888-896. doi:10.1002/fsn3.355 41. Walker LR, Abraham AA, Tercyak KP. Adolescent caffeine use, ADHD, and cigarette smoking. Children's Health Care 2010. 39(1):17. doi:10.1080/02739610903455186 42. Cortese S, Angriman M, Maffeis C, et al. Attention-deficit/hyperactivity disorder (ADHD) and obesity: a systematic review of the literature. Crit Rev Food Sci Nutr. 2008;48(6):524-537. doi:10.1080/ 43. Stacy SL, Eliot M, Calafat AM, et al. Patterns, variability, and predictors of urinary bisphenol A concentrations during childhood. Environ Sci Technol. 2016;50(11):5981-5990. doi:10.1021/acs.est.6b00794 44. Shoaff J, Papandonatos GD, Calafat AM, et al. Early-life phthalate exposure and adiposity at 8 years of age. Environ Health Perspect. 2017;125(9):097008. doi:10.1289/EHP1022 45. Doshi JA, Hodgkins P, Kahle J, et al. Economic impact of childhood and adult attention-deficit/hyperactivity disorder in the United States. J Am Acad Child Adolesc Psychiatry. 2012;51(10):990-1002.e2. doi:10.1016/j.jaac. 2012.07.008 SUPPLEMENT. eTable 1. Characteristics of 528 New Bedford Cohort Participants Assessed as Adolescents Compared With the Subset of 205 Who Provided Urine Samples for EDC Exposure Assessment eTable 2. Adjusted Relative Risk (95% Confidence Intervals) of ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents (N = 164-190) eTable 3. Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems in New Bedford Cohort Adolescents Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations (N = 164-190) for Individual, Rather Than Summed, Chemical Measures eTable 4. Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD- Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents eTable 5. Additional Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents eFigure. Determination of Final Analytic Sample for Assessment of New Bedford Cohort Adolescents JAMA Network Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 (Reprinted) August 28, 2020 14/14 Supplementary Online Content Shoaff JR, Coull B, Weuve J, et al. Association of exposure to endocrine-disrupting chemicals during adolescence with attention-deficit/hyperactivity disorder–related behaviors. JAMA Netw Open. 2020;3(8):e2015041. doi:10.1001/jamanetworkopen.2020.15041 eTable 1. Characteristics of 528 New Bedford Cohort Participants Assessed as Adolescents Compared With the Subset of 205 Who Provided Urine Samples for EDC Exposure Assessment eTable 2. Adjusted Relative Risk (95% Confidence Intervals) of ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents (N=164-190) eTable 3. Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD- Related Behavior Problems in New Bedford Cohort Adolescents Associated With a 2- Fold (log2) Increase in Urinary Biomarker Concentrations (N=164-190) for Individual, Rather Than Summed, Chemical Measures eTable 4. Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents eTable 5. Additional Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents eFigure. Determination of Final Analytic Sample for Assessment of New Bedford Cohort Adolescents This supplementary material has been provided by the authors to give readers additional information about their work. © 2020 Shoaff JR et al. JAMA Network Open. eTable 1. Characteristics of 528 New Bedford Cohort Participants Assessed as Adolescents Compared With the Subset of 205 Who Provided Urine Samples for EDC Exposure Assessment Urine study Full sample sample (n=205) (n=528) Frequency of ADHD-related behavioral problems (n, (%)) Significant ADHD-associated behavior 218 (41) problem on at least one scale 82 (40) Possible significant ADHD-associated 346 (65) behavior problem on at least one scale 134 (65) Child Characteristics (n (%)) Gender Male 93 (45) 255 (48) Female 112 (55) 273 (52) Missing 0 (0) 0 (0) Race Non-Hispanic White 124 (60) 364 (69) Non White 81 (40) 164 (31) Missing 0 (0) 0 (0) Age at in-person testing 14-15 164 (80) 328 (62) 16-17 41 (20) 200 (38) Missing Diagnosis of a behavioral disorder other than ADHD No 131 (64) 346 (66) Yes 74 (36) 182 (34) Missing 0 (0) 0 (0) Use of medication for a behavioral disorder No 183 (89) 480 (91) Yes 22 (11) 48 (9) Missing 0 (0) 0 (0) Maternal Characteristics at time of Child’s Birth (n (%)) Age (years) <20 21 (10) 67 (13) 20-29 127 (62) 307 (58) 57 (28) 154 (29) Missing 0 (0) 0 (0) Household income ($/year) <20,000 66 (32) 166 (31) 20-<40,000 70 (34) 179 (34) 40-<75,000 53 (26) 152 (29) 10 (5) 18 (3) Missing 6 (3) 13 (2) Marital status © 2020 Shoaff JR et al. JAMA Network Open. Married 106 (52) 296 (56) Unmarried 87 (42) 206 (39) Missing 12 (6) 26 (5) Education <High School 30 (15) 76 (14) High School or more 169 (82) 440 (83) Missing 6 (3) 12 (2) Smoking during pregnancy Yes 56 (27) 125 (24) No 134 (65) 362 (69) Missing 15 (7) 41 (8) Alcohol consumption during pregnancy Yes 38 (19) 92 (17) No 141 (69) 358 (68) Missing 26 (13) 78 (15) ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of hyperactivity and inattention; and BASC parent/teacher-report of executive function. b th Significant behavior problem: scale t-score dichotomized at the 98 percentile; Possible significant problem: scale t-score th dichotomized at the 85 percentile Pediatric medical record or parental reported diagnosis of a behavioral disorder Parental reported child use of medication for a behavioral disorder © 2020 Shoaff JR et al. JAMA Network Open. a b eTable 2. Adjusted Relative Risk (95% Confidence Intervals) of ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents (N=164-190) b b Chemical Biomarker Significant behavior problem Possible significant behavior problem Combined Males Females Combined Males Females Antiandrogenic phthalates 1.34 (1.00, 1.79) 1.63 (1.14, 2.34) 1.16 (0.84, 1.60) 1.21 (1.00, 1.47) 1.19 (0.87, 1.63) 1.23 (0.99, 1.52) DEHP 1.29 (1.07, 1.55) 1.62 (1.38, 1.91)* 1.06 (0.85, 1.33)* 1.20 (1.05, 1.37) 1.28 (1.06, 1.55) 1.14 (0.98, 1.32) Personal care products 1.16 (0.98, 1.37) 1.20 (0.97, 1.50) 1.12 (0.90, 1.40) 1.11 (0.99, 1.25) 1.08 (0.90, 1.30) 1.14 (0.98, 1.32) Parabens 1.06 (0.96, 1.18) 1.05 (0.94, 1.16) 1.09 (0.91, 1.30) 1.04 (0.97, 1.11) 1.01 (0.93, 1.09) 1.08 (0.96, 1.21) Bisphenols 1.09 (0.91, 1.31) 1.11 (0.76, 1.64) 1.08 (0.88, 1.32) 1.01 (0.88, 1.17) 0.92 (0.70, 1.22) 1.06 (0.89, 1.26) Dichlorophenols 1.15 (1.01, 1.32) 1.18 (0.99, 1.40) 1.12 (0.90, 1.39) 1.09 (0.99, 1.20) 1.07 (0.94, 1.21) 1.13 (0.97, 1.33) Adjusted for: Child: sex, race, mean test age (across teacher/parent/self-report BASC and CADS measures), urine specific gravity, race; Maternal characteristics at delivery: age, income, marital status, smoking, education; test indicator ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of hyperactivity and inattention; and BASC th th parent/teacher-report of executive function. Significant behavior problem: scale t-score dichotomized at the 98 percentile; Possible significant problem: scale t-score dichotomized at the 85 percentile. sum of: MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCOP, MHIBP, MHBP, MNP sum of: MECPP, MEHHP, MEOHP, MEHP sum of: MBP, MHBP, MEP, MiBP, MHIBP sum of: butyl, ethyl, methyl, and propyl parabens sum of: BPA, BPF, BPS sum of: 2,4-dichlorophenol, 2,5-dichlorophenol *Interaction p-value <0.05 © 2020 Shoaff JR et al. JAMA Network Open. a b eTable 3. Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems in New Bedford Cohort Adolescents Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations (N=164-190) for Individual, Rather Than Summed, Chemical Measures s Individual measures phthalates not included in a sum MECPP 1.27 (1.05, 1.54) MECPP 1.27 (1.05, 1.54) MBP 1.45 (1.15, 1.84) Butyl 0.98 (0.95, 1.02) BPA 1.02 (0.93, 1.12) 2,4-DCP 1.11 (1.00, 1.24) TCC 1.03 (1.00, 1.07) MEHHP 1.26 (1.06, 1.49) MEHHP 1.26 (1.06, 1.49) MIBP 1.32 (1.07, 1.64) Ethyl 1.07 (0.98, 1.17) BPF 1.01 (0.97, 1.05) 2,5-DCP 1.08 (0.94, 1.25) TCS 0.99 (0.89, 1.09) MEHP 1.05 (0.98, 1.12) MEHP 1.05 (0.98, 1.12) MHIBP 1.16 (0.96, 1.41) Methyl 1.05 (0.94, 1.16) BPS 1.02 (0.94, 1.10) BP-3 0.97 (0.9, 1.04) MEOHP 1.28 (1.07, 1.53) MEOHP 1.28 (1.07, 1.53) MHBP 1.25 (1.03, 1.51) Propyl 1.00 (0.92, 1.09) MHINCH 0.99 (0.94, 1.05) MBP 1.45 (1.15, 1.84) MEP 1.07 (0.93, 1.23) MCNP 1.19 (0.95, 1.49) MIBP 1.32 (1.07, 1.64) MCPP 1.12 (1.02, 1.23) MHIBP 1.16 (0.96, 1.41) MHBP 1.25 (1.03, 1.51) MBZP 1.22 (1.05, 1.42) MNP 1.03 (0.97, 1.10) MCOP 1.05 (0.91, 1.23) Adjusted for: Child: sex, race, mean test age (across teacher/parent/self-report BASC and CADS measures), urine specific gravity; Maternal characteristics at delivery: age, income, marital status, smoking, education; test indicator ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of hyperactivity and inattention; and BASC th parent/teacher-report of executive function. Significant behavior problem: scale t-score dichotomized at the 98 percentile © 2020 Shoaff JR et al. JAMA Network Open. eTable 4. Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents Chemical Main Unadjusted Multiple Exclude Exclude Exclude Adjusted for Adjusted for Exclude c d Biomarker adjusted model imputation BASC participants participants behavioral family siblings measures taking with ADHD diagnosis history of model with indices medications diagnosis other than mental g h indicating a for ADHD illness potential behavioral threat to disorder validity N=205 N=164-190 N=149-171 N=135-156 N=164-190 N=164-190 N=153-177 N=164-190 N=178-205 1.34 (1.00, 1.79) 1.27 (1.03, 1.56) 1.37 (1.21, 1.55) 1.34 (1.01, 1.78) 1.26 (0.90, 1.78) 1.76 (1.33, 2.32) 1.34 (1.01, 1.78) 1.40 (1.03, 1.89) 1.33 (0.99, 1.79) Antiandrogenic phthalates DEHP 1.29 (1.07, 1.55) 1.19 (1.02, 1.39) 1.25 (1.14, 1.38) 1.28 (1.06, 1.54) 1.32 (1.07, 1.62) 1.46 (1.19, 1.80) 1.30 (1.09, 1.56) 1.30 (1.08, 1.58) 1.29 (1.07, 1.55) Personal care 1.16 (0.98, 1.37) 1.20 (1.03, 1.39) 1.15 (1.05, 1.25) 1.16 (0.98, 1.37) 1.11 (0.90, 1.37) 1.31 (1.09, 1.57) 1.15 (0.97, 1.36) 1.18 (1.00, 1.40) 1.18 (0.99, 1.41) products 1.06 (0.96, 1.18) 1.06 (0.96, 1.17) 1.03 (0.98, 1.08) 1.05 (0.95, 1.17) 1.07 (0.95, 1.20) 1.09 (0.99, 1.20) 1.06 (0.96, 1.17) 1.09 (0.98, 1.21) 1.07 (0.96, 1.18) 1.09 (0.91, 1.31) 1.09 (0.91, 1.31) 1.10 (0.99, 1.23) 1.06 (0.87, 1.27) 1.12 (0.92, 1.36) 1.13 (0.88, 1.45) 1.10 (0.91, 1.33) 1.12 (0.94, 1.33) 1.08 (0.91, 1.29) Bisphenols 1.15 (1.01, 1.32) 1.09 (0.94, 1.26) 1.11 (1.03, 1.20) 1.15 (1.01, 1.31) 1.12 (0.96, 1.32) 1.15 (1.00, 1.33) 1.17 (1.02, 1.34) 1.15 (1.00, 1.33) 1.18 (1.02, 1.35) Dichlorophenols Adjusted for: Child: sex, race, mean test age (across teacher/parent/self-report BASC and CADS measures), urine specific gravity; Maternal characteristics at delivery: age, income, marital status, smoking, education; test indicator ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of hyperactivity th and inattention; and BASC parent/teacher-report of executive function. Significant behavior problem: scale t-score dichotomized at the 98 percentile. Adjusted for specific gravity to account for urine dilution and test indicator imputation for covariates and chemicals, but not ADHD-related measures Internal BASC indices indicating potential threats to validity from several factors (overly negative, lack of internal consistency, etc). Based on medical record review Based on medical record review and parent report Based on parent report sum of: MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCOP, MHIBP, MHBP, MNP sum of: MECPP, MEHHP, MEOHP, MEHP sum of: MBP, MHBP, MEP, MiBP, MHIBP sum of: butyl, ethyl, methyl, and propyl parabens sum of: BPA, BPF, BPS sum of: 2,4-dichlorophenol, 2,5-dichlorophenol © 2020 Shoaff JR et al. JAMA Network Open. eTable 5. Additional Sensitivity Analyses for the Adjusted Relative Risk (95% Confidence Interval) of Significant ADHD-Related Behavior Problems Associated With a 2-Fold (log2) Increase in Urinary Biomarker Concentrations in New Bedford Cohort Adolescents Chemical Main adjusted Adjusted for Adjusted for Adjusted for Adjusted for Adjusted for Adjusted for Adjusted for Biomarker model adolescent max cord serum adolescent caffeine personal care canned food d d BMI z-score childhood PCBs and substance consumption product use and fast food c d blood lead DDE use consumption N=164-190 N=164-190 N=147-189 N=163-189 N=164-190 N=164-190 N=163-189 N=163-189 1.34 (1.00, 1.79) 1.33 (0.99, 1.78) 1.30 (0.97, 1.76) 1.36 (1.01, 1.83) 1.27 (0.96, 1.68) 1.34 (1.01, 1.78) 1.37 (1.02, 1.85) 1.36 (1.00, 1.85) phthalates 1.29 (1.07, 1.55) 1.29 (1.07, 1.55) 1.26 (1.05, 1.52) 1.29 (1.06, 1.57) 1.25 (1.03, 1.51) 1.30 (1.09, 1.56) 1.29 (1.08, 1.55) 1.31 (1.08, 1.59) 1.16 (0.98, 1.37) 1.16 (0.97, 1.38) 1.14 (0.94, 1.38) 1.16 (0.98, 1.38) 1.15 (0.95, 1.38) 1.15 (0.97, 1.36) 1.16 (0.98, 1.38) 1.17 (0.98, 1.39) products 1.06 (0.96, 1.18) 1.07 (0.96, 1.18) 1.07 (0.96, 1.19) 1.04 (0.94, 1.15) 1.04 (0.94, 1.14) 1.06 (0.96, 1.17) 1.07 (0.97, 1.18) 1.07 (0.96, 1.18) Bisphenols 1.09 (0.91, 1.31) 1.09 (0.90, 1.30) 1.05 (0.87, 1.27) 1.08 (0.90, 1.29) 1.09 (0.90, 1.33) 1.10 (0.91, 1.33) 1.08 (0.90, 1.31) 1.07 (0.88, 1.31) Dichlorophenols 1.15 (1.01,1.32) 1.15 (1.01, 1.32) 1.19 (1.01, 1.40) 1.17 (1.02, 1.34) 1.13 (0.98, 1.31) 1.17 (1.02, 1.34) 1.16 (1.01, 1.33) 1.16 (1.01, 1.33) Adjusted for: Child: sex, mean test age (across teacher/parent/self-report BASC and CADS measures), urine specific gravity; Maternal characteristics at delivery: age, income, marital status, smoking, education; test indicator ADHD-related behavior measures include: CADS parent/teacher-report of inattention, hyperactivity, and ADHD; BASC parent/teacher/self-report of th hyperactivity and inattention; and BASC parent/teacher-report of executive function. Significant behavior problem: scale t-score dichotomized at the 98 percentile Adolescent report of having smoked a cigarette in the past 30 days or ever having tried marijuana or alcohol Average from two 24-hour diary reports (or one 24-hour diary report if only one urine sample provided) regarding personal care product use, canned/fast food consumption, and consumption of caffeinated beverage sum of: MBP, MiBP, MBzP, MEHP, MEHHP, MEOHP, MECPP, MCOP, MHIBP, MHBP, MNP sum of: MECPP, MEHHP, MEOHP, MEHP sum of: MBP, MHBP, MEP, MiBP, MHIBP sum of: butyl, ethyl, methyl, and propyl parabens sum of: BPA, BPF, BPS sum of: 2,4-dichlorophenol, 2,5-dichlorophenol © 2020 Shoaff JR et al. JAMA Network Open. © 2020 Shoaff JR et al. JAMA Network Open.

Journal

JAMA Network Open – American Medical Association

Published: Aug 28, 2020

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