Association between phthalates and externalizing behaviors and cortical thickness in children with attention deficit hyperactivity disorder S. Park 1 , J.-M. Lee 2 , J.-W. Kim 3,4 , J. H. Cheong 5 , H. J. Yun 2 , Y.-C. Hong 6 , Y. Kim 1 , D. H. Han 7 , H.J. Yoo 4,8 , M.-S. Shin 3,4 , S.-C. Cho 3,4 and B.-N. Kim 3,4 * 1 Department of Child and Adolescent Psychiatry, Seoul National Hospital, Seoul, Republic of Korea 2 Department of Biomedical Engineering, Hanyang University, Seoul, Republic of Korea 3 Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University Hospital, Seoul, Republic of Korea 4 College of Medicine and Behavioral Medicine Institute, Seoul National University, Seoul, Republic of Korea 5 Uimyung Research Institute for Neuroscience, Sahmyook University, Seoul, Republic of Korea 6 Department of Preventive Medicine, Seoul National University College of Medicine and Institute of Environmental Medicine, Seoul, Republic of Korea 7 Department of Psychiatry, Chung Ang University, College of Medicine, Seoul, Republic of Korea 8 Department of Psychiatry, Seoul National University Bung dang Hospital, Seongnam, Republic of Korea Background. Previous studies have implicated the relationship between environmental phthalate exposure and atten- tion deficit hyperactivity disorder (ADHD) symptoms of childhood, but no studies have been conducted in children who have a confirmed diagnosis of ADHD obtained through meticulous diagnostic testing. We aimed to determine whether phthalate metabolites in urine would be higher in children with ADHD than in those without ADHD and would correlate with symptom severity and cortical thickness in ADHD children. Method. A cross-sectional examination of urine phthalate metabolite concentrations was performed; scores for ADHD symptoms, externalizing problems, and continuous performance tests were obtained from 180 children with ADHD, and brain-imaging data were obtained from 115 participants. For the control group, children without ADHD (N = 438) were recruited. Correlations between phthalate metabolite concentrations and clinical measures and brain cortical thickness were investigated. Results. Concentrations of phthalate metabolites, particularly the di(2-ethylhexyl) phthalate (DEHP) metabolite, were significantly higher in boys with ADHD than in boys without ADHD. Concentrations of the di-n-butyl phthalate (DBP) metabolite were significantly higher in the combined or hyperactive-impulsive subtypes compared to the inatten- tive subtype, and the metabolite was positively correlated with the severity of externalizing symptoms. Concentrations of the DEHP metabolite were negatively correlated with cortical thickness in the right middle and superior temporal gyri. Conclusions. The results of this study suggest an association between phthalate concentrations and both the diagnosis and symptom severity of ADHD. Imaging findings suggest a negative impact of phthalates on regional cortical matu- ration in children with ADHD. Received 9 July 2014; Revised 18 October 2014; Accepted 20 October 2014 Key words: Attention-deficit hyperactivity disorder, cortical thickness, neuropsychology, phthalate. Introduction Phthalates are a group of colorless, odorless liquids which are used as plasticizers or softeners. Their princi- pal use is to soften polyvinyl chloride (PVC). Plasticized PVC is used in a wide range of commercial products, in- cluding food packaging, PVC tubing, medical tubing and blood bags, toys, and cosmetics (Wormuth et al. 2006). Phthalates can leach into foods heated in plastic containers. Mouthing of toys containing phthalates can also result in phthalate exposure. Individuals re- ceiving feedings or transfusions through medical tubing containing phthalates are likely to be exposed to phtha- lates (U.S. EPA, 2007). Di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP) and benzyl-butyl phthalate (BBP) are now classified as reprotoxic sub- stances [i.e. category 1B according to Regulation (EC), category 2 according to Directive 67/548/EEC], and the use of these phthalates is prohibited in the production of toys and childcare articles [Registration, Evaluation, * Address for correspondence: Dr B.-N. Kim, Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University, College of Medicine, College of Medicine, 101 Daehakro, Chongro-Gu, Seoul, South Korea. (Email: kbn1@snu.ac.kr) Psychological Medicine, Page 1 of 12. © Cambridge University Press 2014 doi:10.1017/S0033291714002694 ORIGINAL ARTICLE