Grantee Research Project Results
Final Report: Adolescent Exposure to BPA/Phthalates Cognitive and Behavioral Development
EPA Grant Number: R834593C002Subproject: this is subproject number 002 , established and managed by the Center Director under grant R834593
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Water Innovation Network for Sustainable Small Systems
Center Director: Reckhow, David A.
Title: Adolescent Exposure to BPA/Phthalates Cognitive and Behavioral Development
Investigators: Korrick, Susan A.
Institution: Harvard University
EPA Project Officer: Hahn, Intaek
Project Period: February 15, 2010 through February 14, 2014
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The aim of this pilot project was to assess the relation of adolescent phthalate and bisphenol A (BPA) exposure with adolescent neurobehavior. The proposal was built on an ongoing prospective birth cohort study designed to assess the relation of early life organochlorine and metal exposures with subsequent development among 788 children followed since birth. Children participating in the parent study were born to mothers residing in towns adjacent to a Superfund site, the New Bedford Harbor, in New Bedford, MA. This pilot study took advantage of the parent study's established infrastructure and rich data to address the following hypotheses:
Primary hypothesis: Adolescent exposure to phthalates and BPA (assessed as urine metabolite concentrations) are each independently associated with adolescent visual spatial abilities, verbal abilities, working memory, and attention deficit hyperactivity disorder (ADHD)-related behaviors and psychiatric symptoms.
Secondary hypothesis: Associations of adolescent exposure to phthalates or BPA with adolescent behavior and cognitive function will differ between boys and girls or by pubertal status.
Summary/Accomplishments (Outputs/Outcomes):
Study Recruitment: A key component of this pilot was collection of urine samples from the New Bedford Birth Cohort (NBC) participants at the time of an extensive neurodevelopmental assessment conducted via an ongoing NIEHS funded R01 grant (ES014864; PI: Korrick). We originally anticipated collection of urine samples on ~263 NBC participants but, because of funding and start-up delays, completed urine sample collection on 205 NBC participants. Still, participation rates were excellent, with 81% of adolescents examined during this pilot providing at least one urine sample and 144 (70%) providing two urine samples, approximately 1 week apart (see exposure assessment). The mean age of participants was 16 years. The NBC is a sociodemographically diverse population with approximately 25% of mothers and almost 35% of children of non-white or Latino ethnicity, most parents with a high school education or less, and a substantial proportion of unmarried mothers (45%) and low income households (38%).
Exposure Assessment: In response to increasing concerns regarding the reproducibility of urine BPA and phthalate levels that became apparent over the course of this grant, we modified our original design to analyze two urine samples on 50 adolescents rather than one urine sample on 100 adolescents. Thus, the CDC laboratory measured urine total BPA and 11 phthalate metabolites in the first 50 adolescents assessed using a random urine sample collected in our study clinic (at the time of neurobehavioral testing) and a second sample collected about 1 week later at a study home visit. BPA was detectable in 98% of clinic and 94% of home urine samples; and, except for MEHP, phthalate metabolites were detected in 100% of urine samples. For a more stable measure (given variability in these biomarkers over time), we used the average of the two urine levels (corrected for specific gravity) to estimate exposure.
Our study hypotheses were focused on potentially sexually dimorphic cognitive and behavioral characteristics given the potential for BPA or phthalates to interfere with sex hormone-mediated processes. Thus, for these modest-sized pilot analyses, we focused on two exposure indices with a priori mechanistic interest—total urine BPA (given its estrogenic activity) and the sum of metabolites from phthalates with demonstrable anti-androgenic activity, as evidenced in the toxicology literature. The median (range) of urine total BPA and anti-androgenic phthalate metabolite levels were 4.2 (1.0-32.2) µg/L and 0.7 (0.1-2.0) µmol/L, respectively.
Associations of BPA and Phthalates with Cognitive Function: The cognitive outcomes targeted by our study hypotheses were measured with standardized, validated psychometric instruments including the Wide Range Assessment of Visual Motor Abilities (WRAVMA) as a comprehensive measure of visual-motor and visual-spatial skills; the Wide Range Assessment of Memory and Learning (WRAML2) as a measure of short-term memory, working memory, and learning; and the Wide Range Achievement Test (WRAT-4) to assess school achievement in reading and math. In multivariable linear regression models, there were suggestive (but not statistically significant) associations of higher urine BPA with poorer visual spatial and verbal memory skills as well as poorer reading and math achievement with girls showing generally greater BPA-associated decrements on cognitive measures than boys (Table 1). For example, in multivariable models, each log unit increase in adolescent urine total BPA concentration was associated with an overall 5.0 point decline (95% CI -10.1, 0.1) in visual-spatial scores on the WRAVMA at age 16 years with greater declines in girls than boys (-5.8 vs. -3.3 points). Urine levels of anti-androgenic phthalates were not associated with cognitive measures in these modest-sized pilot analyses (e.g., model n = 45 after adjustment for covariates). Given small numbers and relative homogeneity in pubertal status, we did not do analyses by pubertal status.
Associations of BPA and Phthalates with Behavior: The behavioral measures targeted by our study hypotheses were measured with behavioral rating scales completed by each adolescent's teacher including: (1) the Conners' Attention Deficit Scale (CADS_t), a questionnaire rating problem behaviors in school using DSM-IV diagnostic criteria for diagnosis of Attention Deficit Hyperactivity Disorder (ADHD); and (2) the Behavioral Assessment System for Children (BASC-2) reporting observed behaviors related to a range of problems such as depression, anxiety, and social and school dysfunction. Behavioral rating scores are standardized to a mean of 50, SD of 10 with higher scores reflecting more adverse behavior. In multivariable analyses using a priori cut points for high risk behavior patterns, both higher urine anti-androgen phthalates and BPA were associated with greater teacher-reported ADHD-like behavior (Table 2). In addition, anti-androgenic phthalates were associated with increased risk of other adverse behaviors such as social difficulties. Differences in effect by sex were not seen for these behavioral measures. Given small numbers and relative homogeneity in pubertal status, we did not do analyses by pubertal status.
Conclusions:
Our findings provide strong preliminary support for the hypothesized association of adolescent BPA, but not anti-androgenic phthalate exposure, with poorer cognitive function in specific domains with likely sexual dimorphism in performance (Table 1). Furthermore, our findings provide preliminary support for the our secondary hypothesis of potential differential effects of exposure on boys vs. girls for cognitive measures (Table 1). Both exposures (BPA, anti-androgenic phthalates) were associated with adverse behavior, especially ADHD-like behavior (Table 2). However, because of small numbers in this pilot study (by design), analyses were adjusted for a limited number of potential confounders and, for many results, confidence limits were wide so it is not yet possible to make definitive conclusions. Most importantly, these formative center findings contributed to a research project proposal for a successful full Children's Environmental Health and Disease Prevention Research Center (P01 grant). With analysis of the full study (n = 205 children) made possible via the full Center P01, we will be able to assess the reproducibility of these stronge preliminary models, use more comprehensive models to account for confounding, and assess associations with functional measures (e.g., reaction time and errors on a continuous performance test, CPT) for which short-term exposure effects are possible.
Supplemental Keywords:
RFA, Health, Scientific Discipline, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Children's Health, biological markersProgress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R834593 Water Innovation Network for Sustainable Small Systems Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834593C001 Prenatal Exposure to BPA/Phthalates: Infant Physical and Behavioral Development
R834593C002 Adolescent Exposure to BPA/Phthalates Cognitive and Behavioral Development
R834593C003 Mechanisms of In Utero BPA Exposure on Fetal Gonad Development
R834593C004 Effects of Bisphenol A on the Developing Cortex
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.