Early childhood exposures to phthalates in association with attention-deficit/hyperactivity disorder behaviors in middle childhood and adolescence in the ReCHARGE study.

BACKGROUND: Early-life exposure to phthalates alters behaviors in animals. However, epidemiological evidence on childhood phthalate exposure and attention-deficit/hyperactivity disorder (ADHD) behaviors is limited. METHODS: This study included 243 children from the ReCHARGE (Revisiting Childhood Autism Risks from Genetics and Environment) study, who were previously classified as having autism spectrum disorder (ASD), developmental delay, other early concerns, and typical development in the CHARGE case-control study. Twenty phthalate metabolites were measured in spot urine samples collected from children aged 2-5 years. Parents reported on children's ADHD symptoms at ages 8-18 years using Conners-3 Parent Rating Scale. Covariate-adjusted negative binomial generalized linear models were used to investigate associations between individual phthalate metabolite concentrations and raw scores. Weighted quantile sum (WQS) regression with repeated holdout validation was used to examine mixture effects of phthalate metabolites on behavioral scores. Effect modification by child sex was evaluated. RESULTS: Among 12 phthalate metabolites detected in >75% of the samples, higher mono-2-heptyl phthalate (MHPP) was associated with higher scores on Inattentive (ß per doubling = 0.05, 95% confidence interval [CI]: 0.02, 0.08) and Hyperactive/Impulsive scales (ß = 0.04, 95% CI: 0.00, 0.07), especially among children with ASD. Higher mono-carboxy isooctyl phthalate (MCiOP) was associated with higher Hyperactivity/Impulsivity scores (ß = 0.07, 95% CI: -0.01, 0.15), especially among typically developing children. The associations of the molar sum of high molecular weight (HMW) phthalate metabolites and a phthalate metabolite mixture with Hyperactivity/Impulsivity scores were modified by sex, showing more pronounced adverse associations among females. CONCLUSION: Exposure to phthalates during early childhood may impact ADHD behaviors in middle childhood and adolescence, particularly among females. Although our findings may not be broadly generalizable due to the diverse diagnostic profiles within our study population, our robust findings on sex-specific associations warrant further investigations.

Urine metabolic phenotyping in children with nocturnal enuresis and comorbid neurobehavioral disorders.

Nocturnal enuresis (NE) is a common problem among 10% school-aged children. The etiologies underlying childhood NE is complex and not fully understood nowadays. Nevertheless, increasing evidence suggests a potential link between neurobehavioral disorders and enuresis in children. In this study, we aimed to explore novel metabolomic insights into the pathophysiology of NE and also, its association with pediatric psychiatric problems. Urine collected from 41 bedwetting children and 27 healthy control children was analyzed by using 1H-nuclear magnetic resonance spectroscopy from August 2017 to December 2018. At regular follow-up, there were 14 children with refractory NE having a diagnosis of attention deficient hyperactivity disorder (ADHD) or anxiety. Eventually, we identified eight significantly differential urinary metabolites and particularly increased urinary excretion of betaine, creatine and guanidinoacetate linked to glycine, serine and threonine metabolism were associated with a comorbidity of neurobehavioral disorders in refractory bedwetting children. Notably, based on physiological functions of betaine acting as a renal osmolyte and methyl group donor, we speculated its potential role in modulation of renal and/or central circadian clock systems, becoming a useful urinary metabolic marker in diagnosis of treatment-resistant NE in children affected by these two disorders.

Evaluating the reliability of hair analysis in monitoring the compliance of ADHD patients under treatment with Lisdexamphetamine.

Considering the high clinical and forensic relevance of pharmaco-adherence during lisdexamphetamine (LDX) treatment for attention-deficit/hyperactivity disorder (ADHD), the aim here was to evaluate hair analysis as a tool for monitoring compliance in patients currently undergoing long term treatment with LDX, by detecting possible interruptions of medication intake or changes in dosage. For this purpose, a total of 24 patients from an outpatient clinic for ADHD were recruited. Hair and urine samples were taken after three consecutive therapy sessions over a 7-month period and analyzed for amphetamine (AMP) enantiomers and other drugs, using chiral and achiral liquid chromatography-tandem mass spectrometry (LC-MS/MS). Participants also provided information on the condition of their hair, the consumption of illegal psychotropic substances and the regularity of taking LDX. Two participants withdrew from the study early. Urine analyses were positive for D-AMP in all urine samples and therapy sessions, except in two patients who did not take LDX on a daily basis. D-AMP was detected in all hair samples; however, no correlation was found between prescribed dose/day and D-AMP concentrations in proximal hair segments. Qualitative interpretation of hair analysis showed that 18 of the 22 study completers were compliant concerning the intake of LDX without additional consumption of illegal D,L-AMP. Analysis of urine taken during the therapy sessions showed no correlation between D-AMP concentrations and prescribed dosage, with or without normalization for creatinine. In conclusion, chiral LC-MS/MS hair analysis might represent a non-invasive way to confirm LDX use within the approximate period covered by the hair segment tested, but it does not allow for quantitative therapeutic drug monitoring because of interindividual variability of concentrations in hair. Drug concentrations in hair at different stages of long-term treatment should thus be interpreted with caution by clinicians and forensic experts alike when making assessments of treatment adherence.

High Levels of Glycosaminoglycans in the Urines of Children with Attention-Deficit/Hyperactivity Disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral/neurodevelopmental disorder. Some early studies indicated that increased intake of added sugars might have a role in ADHD. In the present study, we tested this possibility by evaluating the urinary excretion of oligosaccharides and glycosaminoglycans (GAGs) in ADHD and control subjects. Forty ADHD subjects matched with 34 controls were enrolled in the study. The subjects underwent a standardized dietary regimen. The urine levels of oligosaccharides and GAGs were quantified biochemically, and their covariance and association were evaluated statistically. Fructose (21/40, 52.5%), maltose (26/40, 65%), galactose (30/40, 75%), and lactose (38/40, 95%) excretions were frequently found in the urine of ADHD subjects (p < 0.05), an excretion which does not occur normally. Furthermore, these subjects showed a pathologic tGAG (glycosaminoglycan) excretion (40/40, 100%). The present study supports the thesis that carbohydrate metabolism differs in ADHD subjects compared with control subjects.

Attention deficit hyperactivity disorder and its association with heavy metals in children from northern Chile.

INTRODUCTION: Exposure to lead and arsenic has been associated with child behavior problems. In Arica, a northern city of Chile, the natural presence of arsenic in water has been registered. Also, the city has a history of heavy metals contamination of anthropogenic origin. The purpose of this study was to explore the association between the concentration of blood lead and urinary inorganic arsenic with attention deficit hyperactivity disorder (ADHD) as reported by parents. METHODS: Cross-sectional design with data analysis of 2656 children between the ages of 3 and 17 enrolled at the Environmental Health Center of Arica between 2009 and 2015. The diagnosis of ADHD was made based on the parents' response to questions about health history. Multiple logistic regression models were used to adjust for confounding variables. RESULTS: The prevalence of ADHD was 6.4%. The means urinary inorganic arsenic and blood lead were 21 µg/L and 1.5 µg/dl, respectively. In the lead model adjusted for sex, age, housing material quality and exposure to secondhand tobacco smoke report; children with blood lead concentrations ≥5 µg/dl were more likely to develop ADHD [Odds Ratio (OR): 2.33 95% confidence intervals (CI) 1.32-4.12)]. Regarding arsenic, the adjusted model revealed a higher chance of developing ADHD in the fifth quintile of exposure (OR = 2.02 IC 95% 1.12-3.61). CONCLUSION: The findings of this study suggest that exposure of children to lead and inorganic arsenic was associated with ADHD. This study provides additional evidence to existing literature regarding the potential role of toxic metals such as lead and arsenic in children's behavior. However, our findings should be interpreted with caution due to the limitations of the study.

Associations between urinary cotinine and symptoms of attention deficit/hyperactivity disorder and autism spectrum disorder.

BACKGROUND: The present study investigated associations between urinary cotinine levels as a biomarker of secondhand smoke exposure and symptoms of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). METHODS: A total of 520 child participants (200 with ADHD, 67 with ASD, and 253 normal control subjects) were assessed using the Korean version of the ADHD rating scale (K-ARS), Autism spectrum screening questionnaire (ASSQ), and Behavioral Assessment System for Children, second edition (BASC-2). The Korean version of the computer-based continuous performance test was used to assess cognitive function. Urinary cotinine was evaluated as a biomarker of secondhand smoke exposure. RESULTS: Urinary cotinine levels were significantly and positively associated with K-ARS score (B = 4.00, p < 0.001), ASSQ score (B = 1.71, p = 0.030), the behavioral problem subscales of the BASC-2 (B = 1.68-3.52, p < 0.001-0.045), and omission and commission errors in the continuous performance test (B = 6.21-8.42, p < 0.001-0.019). Urinary cotinine levels were also associated with the increased odds ratio of ADHD (OR = 1.55, 95% CI 1.05-2.30, p = 0.028) and ASD (OR = 1.89, 95% CI 1.12-3.21, p = 0.018). CONCLUSION: Urinary cotinine levels were associated with lower behavioral adaptation and cognitive function and increased odds ratios of ADHD and ASD, indicating a negative effect of secondhand smoke exposure on the symptomatic manifestation of ADHD and ASD.

Prenatal Phthalates, Maternal Thyroid Function, and Risk of Attention-Deficit Hyperactivity Disorder in the Norwegian Mother and Child Cohort.

BACKGROUND: There is growing concern that phthalate exposures may have an impact on child neurodevelopment. Prenatal exposure to phthalates has been linked with externalizing behaviors and executive functioning defects suggestive of an attention-deficit hyperactivity disorder (ADHD) phenotype. OBJECTIVES: We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case-control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008. METHODS: Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD (n=297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (n=553) from the MoBa population was obtained. RESULTS: In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of ∑DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest [OR=2.99 (95% CI: 1.47, 5.49)]. When ∑DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% [OR=1.47 (95% CI: 1.09, 1.94)]. We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery. CONCLUSIONS: In this population-based case-control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD. https://doi.org/10.1289/EHP2358.

No Tryptophan, Tyrosine and Phenylalanine Abnormalities in Children with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: The aim of the current study was to explore the role of aromatic amino acids (AAAs) in blood in relation to attention-deficit/hyperactivity disorder (ADHD). Given their impact on the synthesis of serotonin and dopamine, decreased concentrations of the AAAs tryptophan, tyrosine and phenylalanine in blood may contribute to the expression of ADHD symptoms. Decreased AAA blood concentrations, in turn, may be related to lowered dietary protein intake or to abnormal AAA catabolism, as evidenced by increased urinary AAA concentrations. METHODS: Eighty-three children with ADHD (75% males) and 72 typically developing (TD) children (51% males), aged 6 to 13 years, participated in the study. AAA concentrations were assessed in blood spots and an 18-hour urinary sample. A nutritional diary was filled out by parents to calculate dietary protein intake. Parent and teacher questionnaires assessed symptoms of ADHD, oppositional defiant disorder, conduct disorder, and autism spectrum disorder. RESULTS: Children with ADHD showed normal AAA concentrations in blood spots and urine, as well as normal protein intake compared to controls. No associations between AAA concentrations and symptoms of ADHD or comorbid psychiatric disorders were found. CONCLUSIONS: This study is the first to explore AAA metabolism in children with ADHD using a well-defined and relatively large sample. We found that AAA deficiencies are not related to ADHD. The results do not support treatment with AAA supplements in children with ADHD. Future studies regarding the cause of serotonin and dopamine alterations in ADHD should focus on other explanations, such as effects of altered transport of AAAs.

Association of current phthalate exposure with neurobehavioral development in a national sample.

BACKGROUND: Previous studies have indicated that phthalate exposure may influence the development of children, but the current data are limited, and controversy remains regarding the sex-specific and age-specific effects of phthalate exposure. METHODS: We investigated the sex- and age-specific associations of current phthalate exposure with neurobehavioral development scores in a nationally representative sample of 6-18-year-olds participating in the Korean Environmental Health Survey in Children and Adolescents (KorEHS-C). Neurobehavioral development was assessed using the Korean Child Behavior Checklist (CBCL, N=1723) and the Korean Attention Deficit Hyperactivity Disorder Rating Scale (ARS, N=867). We measured the concentrations of phthalate metabolites in urine samples using high-performance liquid chromatography tandem mass spectrometry. The associations between urine phthalate metabolite concentrations and neurobehavioral development were examined by survey regression analysis for complex sampling and penalized regression splines using a generalized additive model. RESULTS: Survey regression analysis revealed that a higher mono-n-butyl phthalate (MnBP) level was associated with social (ß=0.60; 95% confidence interval=0.15-1.05), thought (0.55; 0.08-1.03), and attention (0.68; 0.21-1.14) problems on the CBCL. A significant association was found between the MnBP level and the ARS hyperactivity subscale score (0.42; 0.05-0.58). Higher levels of MnBP (0.87; 0.20-1.54), mono-2-ethyl-5-oxohexyl phthalate (MEOHP, 0.61; 0.11-1.11) and mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP, 0.51; 0.04-0.97) were associated with an increase in thought problems among the girls. Among the younger children aged 6-11 years, significant positive associations between the MnBP (0.71; 0.09-1.33), MECPP (0.74, 0.14-1.34), MEOHP (0.65; 0.10-1.20), and MEHHP (0.71; 0.21-1.21) levels and social problems and between the MnBP (1.11; 0.37-1.84), MEOHP (0.64; 0.13-1.15), and MEHHP (0.66; 0.18-1.14) levels and attention problems were observed. The penalized regression splines for the age-specific relationships between the urinary MnBP, MEOHP, and MEHHP levels and social and attention problems exhibited positive supralinear relationships with downward curvature in the 6-11 year age group. In contrast, the score for social problems exhibited nearly linear relationships with these levels in the 12-18 year age group. CONCLUSIONS: In this national sample, increased phthalate exposure exhibited supralinear associations with social, thought and attention problems in children aged 6-11 years, who showed greater vulnerability to phthalate exposure. The results highlight the need for the environmental regulation of phthalate exposure in younger children, even at low dosages.

Attention Deficit/Hyperactivity Disorder and Urinary Nonylphenol Levels: A Case-Control Study in Taiwanese Children.

OBJECTIVE: Nonylphenol (NP) belongs to the family of endocrine disruptors, and it is widely used in industrial applications and is ubiquitous in daily foods. Animal studies have suggested that NP exposure might promote motor hyperactivity, likely by causing deficits in dopaminergic neurons. However, research assessing NP exposure and epidemiology studies on human populations are limited. The aim of this study was to explore the association between child NP exposure and ADHD while considering particular covariants, such as lead levels and dopamine-related gene variations. METHODS: A case-control study was conducted on patients with clinically diagnosed ADHD; the Swanson, Nolan and Pelham, Fourth Revision (SNAP-IV) questionnaire was used to identify normal controls aged 4-15 years. Participants were examined for urinary NP concentrations, blood lead levels, and select single-nucleotide polymorphisms of two dopamine-related genes (D4 dopamine receptor, DRD4, and dopamine transporter, DAT1). Socio-demographic variables, maternal lifestyle factors during pregnancy and family medical history were obtained using a questionnaire. RESULTS: A total of 97 children with doctor-diagnosed ADHD and 110 normal controls were enrolled. The blood lead levels in both groups were similar (1.57±0.73 vs. 1.73±0.77 µg/dL, p = 0.15). No significant difference in urinary NP concentration was found between the children with ADHD and the control subjects (4.52±3.22 µg/g cr. vs. 4.64±2.95 µg/g cr., p = 0.43). ADHD was significantly more prevalent among males in this study (male to female ratio: 5:1 for the ADHD group and 1.3:1 for the control group, p<0.01). The analysis was repeated after excluding the females, but this had no effect on the association between NP and ADHD. The regression model, including or excluding females, indicated no increased odds of having ADHD in the context of NP exposure after adjusting for covariants. CONCLUSION: This study indicated that NP exposure might not promote ADHD in children, even though children in Taiwan had relatively high levels of NP compared to those reported previously and those in developed nations.

Increased urinary 6-hydroxymelatoninsulfate levels in attention deficit hyperactivity disorder diagnosed children and adolescent.

There are some studies in attention deficit hyperactivity disorder (ADHD) which note altered circadian rhythms, suggesting abnormalities in melatonin physiology. In order to better characterize the possible melatonin alteration in ADHD, in this study we aimed to detect daytime, nighttime and 24 h levels of 6-hydroxymelatoninsulfate (6-OH MS) in the patients diagnosed with ADHD. Twenty-seven patients between 6 and 16 years-old, who had been diagnosed initially with ADHD, but without other physical and psychiatric disease history and who had not taken psychotropic pharmacotherapy for six months, plus 28 healthy volunteer controls, were included in the study. Urine samples were collected during the whole 24 h cycle, daytime and nighttime separately to assess the time-dependent excretion of the 6-OH MS, which is the main urine metabolite of melatonin. The Enzyme-Linked Immunosorbent Assay (ELISA) method was used for measuring the urine 6-OH MS level. Daytime (15.4 (8.9-24.8) ng/ml vs 6.9 (2.5-15.9) ng/ml, p=0.002), nighttime (102.9 (65.3-197.7) ng/ml vs 61.5 (37.2-114.4) ng/ml, p=0.012) and 24 h (54.1 (34.6-83.9) ng/ml vs 27.3 (14.3-48.9) ng/ml, p=0.000) 6-OH MS levels median (25p-75p) were found to be significantly higher in the ADHD group. After adjustment for age and sex, there was a statistically significant difference between the ADHD group (59.8 ± 4.9) and control group (33.8 ± 4.8) in 24-h 6-OH MS levels (F(1, 51)=13.673, p=.001, partial η2=.211). There was no relationship between 6-OH MS levels and Conners Parent Rating Scale short form subscale scores for the ADHD group. These findings indicate that melatonin production is increased in ADHD cases. Further research is needed to determine and thereby understand the mechanisms underlying the higher melatonin production, to assess the impact of altered melatonin on the pathophysiology of ADHD.

Reduced Symptoms of Inattention after Dietary Omega-3 Fatty Acid Supplementation in Boys with and without Attention Deficit/Hyperactivity Disorder.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common child psychiatric disorders, and is often treated with stimulant medication. Nonpharmacological treatments include dietary supplementation with omega-3 fatty acids, although their effectiveness remains to be shown conclusively. In this study, we investigated the effects of dietary omega-3 fatty acid supplementation on ADHD symptoms and cognitive control in young boys with and without ADHD. A total of 40 boys with ADHD, aged 8-14 years, and 39 matched, typically developing controls participated in a 16-week double-blind randomized placebo-controlled trial. Participants consumed 10 g of margarine daily, enriched with either 650 mg of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) each or placebo. Baseline and follow-up assessments addressed ADHD symptoms, fMRI of cognitive control, urine homovanillic acid, and cheek cell phospholipid sampling. EPA/DHA supplementation improved parent-rated attention in both children with ADHD and typically developing children. Phospholipid DHA level at follow-up was higher for children receiving EPA/DHA supplements than placebo. There was no effect of EPA/DHA supplementation on cognitive control or on fMRI measures of brain activity. This study shows that dietary supplementation with omega-3 fatty acids reduces symptoms of ADHD, both for individuals with ADHD and typically developing children. This effect does not appear to be mediated by cognitive control systems in the brain, as no effect of supplementation was found here. Nonetheless, this study offers support that omega-3 supplementation may be an effective augmentation for pharmacological treatments of ADHD (NCT01554462: The Effects of EPA/DHA Supplementation on Cognitive Control in Children with ADHD; http://clinicaltrials.gov/show/NCT01554462).

Association between phthalates and externalizing behaviors and cortical thickness in children with attention deficit hyperactivity disorder.

BACKGROUND: Previous studies have implicated the relationship between environmental phthalate exposure and attention 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 inattentive 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 maturation in children with ADHD.

Association between urine phthalate levels and poor attentional performance in children with attention-deficit hyperactivity disorder with evidence of dopamine gene-phthalate interaction.

Although there is some evidence supporting the existence of an association between prenatal maternal or postnatal child's urine phthalate metabolite concentrations and poor attentional performances, the interaction between urine phthalate metabolite levels and genetic variation for neuropsychological deficit of attention-deficit hyperactivity disorder (ADHD) has not been examined. The aim of this study was to determine whether phthalate metabolites in urine are associated with poor neuropsychological performance in children with ADHD, and whether such association is affected by genotype-phthalate interaction. A cross-sectional examination of urine phthalate metabolite concentrations and the continuous performance test (CPT) were performed in 179 Korean children with ADHD recruited from department of psychiatry of university hospital. Correlations between urine phthalate metabolite concentrations and the CPT scores were investigated, and the interaction of phthalate metabolite levels with the selected polymorphisms at major candidate genes for ADHD, namely dopamine receptor D4 (DRD4), dopamine transporter, α-2A-adrenergic receptor, and norepinephrine transporter genes. For the subjects with the DRD4 4/4 genotype, there were significant associations of the urine phthalate metabolite concentrations with the number of omission errors, the number of commission errors, and the response time variability scores on the CPT. However, for the subjects without the DRD4 4/4 genotype, no significant associations were found. The results of this study suggest a possible association between phthalate metabolite concentrations and poor attentional performances of ADHD as well as a genetic influence on this association. Further prospective and epigenetic studies are needed to investigate causality and pathophysiological mechanisms.

Urinary polycyclic aromatic hydrocarbon metabolites and attention/deficit hyperactivity disorder, learning disability, and special education in U.S. children aged 6 to 15.

Exposure to polycyclic aromatic hydrocarbons (PAHs) adversely affects child neurodevelopment, but little is known about the relationship between PAHs and clinically significant developmental disorders. We examined the relationship between childhood measures of PAH exposure and prevalence of attention deficit/hyperactivity disorder (ADHD), learning disability (LD), and special education (SE) in a nationally representative sample of 1,257 U.S. children 6-15 years of age. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2001-2004. PAH exposure was measured by urinary metabolite concentrations. Outcomes were defined by parental report of (1) ever doctor-diagnosed ADHD, (2) ever doctor- or school representative-identified LD, and (3) receipt of SE or early intervention services. Multivariate logistic regression accounting for survey sampling was used to determine the associations between PAH metabolites and ADHD, LD, and SE. Children exposed to higher levels of fluorine metabolites had a 2-fold increased odds (95% C.I. 1.1, 3.8) of SE, and this association was more apparent in males (OR 2.3; 95% C.I. 1.2, 4.1) than in females (OR 1.8; 95% C.I. 0.6, 5.4). No other consistent pattern of developmental disorders was associated with urinary PAH metabolites. However, concurrent exposure to PAH fluorine metabolites may increase use of special education services among U.S. children.

[Blood and urine lead levels in children with attention deficit hyperactivity disorder]. / Niveles de plomo en niños con diagnóstico de trastorno por déficit de atención e hiperactividad.

BACKGROUND: Attention deficit hyperactivity disorder is the most common neuropsychiatric disorder in children; symptoms can persist into adult life by 60 %. Our objective was to quantify the levels of lead in blood and urine in pediatric patients with attention deficit hyperactivity disorder. METHODS: We did an observational study which included a captive population of children diagnosed with attention deficit hyperactivity disorder in the mental health service of Hospital General, from Centro Médico Nacional La Raza. Lead levels were determined in blood and urine by atomic absorption technique. RESULTS: We included 39 patients, 932 % male, with a mean age of 9.2 ± 2.16 years. The deficit and hyperactivity disorder combined type was the most frequent (69.2 %); 49 % of patients were found with toxic lead levels in blood (above 10 mg/dL); 17.9 % with stage III and 5.12 % with stage IV, according to the Mexican Official Standard (NOM-199-SSA-2000). Significant association was found between blood lead levels and the clinical expression of attention deficit hyperactivity disorder. CONCLUSIONS: Levels of lead exposure during early childhood have been shown to be inversely proportional to neurological development in the first seven years of life. Data results are insufficient to relate them with causality.

INTRODUCCIÓN: los síntomas del trastorno por déficit de atención e hiperactividad pueden persistir hasta la vida adulta en 60 % de quienes la padecieron en la niñez. Nuestro objetivo fue cuantificar los niveles de plomo en la sangre y la orina en niños con diagnóstico de trastorno por déficit de atención e hiperactividad para identificar si existe alguna relación. MÉTODOS: estudio observacional que incluyó a una muestra cautiva del Servicio de Higiene Mental del Hospital General del Centro Médico Nacional La Raza, con diagnóstico de trastorno por déficit de atención e hiperactividad. Se cuantificaron los niveles séricos y urinarios del plomo mediante la técnica de absorción atómica. RESULTADOS: se incluyeron 39 pacientes, 92.3 % del sexo masculino, con una edad promedio de 9.2 ± 2.16 años. El trastorno por déficit de atención e hiperactividad combinado fue el más frecuente (69.2 %). En 49 % de los pacientes se encontraron niveles de plomo en sangre superiores a 10 ?g/dL. Conforme los parámetros establecidos en la NOM-199-SSA1-2000, 17.9 % clasificaba en estadio III y 5.12 % en estadio IV. Se encontró relación significativa entre los niveles de plomo y la expresión clínica del trastorno por déficit de atención e hiperactividad. CONCLUSIONES: los niveles de exposición al plomo durante la infancia temprana han demostrado ser inversamente proporcionales al desarrollo neurológico en los primeros siete años de vida. Los datos son insuficientes para inferir la causalidad.

Association between phthalates and attention deficit disorder and learning disability in U.S. children, 6-15 years.

OBJECTIVE: This study investigates the association between urinary phthalate metabolite levels and attention deficit disorder (ADD), learning disability (LD), and co-occurrence of ADD and LD in 6-15-year-old children. METHODS: We used cross-sectional data from the National Health and Nutrition Examination Survey (NHANES, 2001-2004). Phthalate metabolites with ≥75% detection in urine samples were examined. The study population comprised 1493 children with parent-reported information on ADD or LD diagnosis and phthalate concentrations in urine. Phthalate concentrations were creatinine-adjusted and log10-transformed for analysis. All models controlled for child sex, age, race, household income, blood lead, and maternal smoking during pregnancy. RESULTS: There were 112 ADD cases, 173 LD cases, and 56 ADD and LD cases in the sample. After adjusting for potential confounders, we found increased odds of ADD with increasing urinary concentration of di-2-ethylhexyl phthalates (OR: 2.1; 95% CI: 1.1, 3.9) and high molecular weight phthalates (OR: 2.7; 95% CI: 1.2, 6.1). In addition, dibutyl phthalates (OR: 3.3; 95% CI: 0.9, 12.7) and high molecular weight phthalates (OR: 3.7; 95% CI: 0.9, 14.8) were marginally associated with increased odds of co-occurring ADD and LD. We did not find associations for any phthalate and LD alone. We observed stronger associations between phthalates and ADD and both ADD and LD in girls than boys in some models. CONCLUSIONS: We found cross-sectional evidence that certain phthalates are associated with increased odds of ADD and both ADD and LD. Further investigations with longitudinal data are needed to confirm these results.

Attention-deficit hyperactivity disorder (ADHD) as a pyridoxine-dependent condition: urinary diagnostic biomarkers.

The data obtained in children with different forms of epilepsy allowed us to consider epilepsy as an inborn error of pyridoxine (vitamin B6) metabolism (Dolina et al., 2012). Mutual interconnections between ADHD and epilepsy indicate that such an approach is reasonable for ADHD. To check such an assumption we analyzed in ADHD patients the same parameters of pyridoxal phosphate (PLP)-dependent tryptophan (TRP) degradation, which were analyzed in epileptic children. The level of TRP and concentrations of compounds formed or metabolized by TRP degradation, the ratios between some of them, and the level of 4-pyridoxic acid were HPLC detected in ADHD children and healthy controls. The data obtained, including low values of 4PA/TRP, IND/TRP and IND/KYN ratios, have evidenced dramatically impaired activity of pyridoxine-dependent enzymes in ADHD patients. Ritalin treatment did not change the general pattern of TRP degradation, but still created a kind of balance between some of detected metabolites. However, the 4PA/TRP, IND/TRP and IND/KYN ratios remained as low as in untreated patients, keeping the importance of diagnostic markers. Almost identical parameters of TRP degradation in untreated ADHD and epileptic patients allow to assume that inborn disorders of vitamin B6 metabolism are the common biochemical background of both diseases. The disturbed activity of PLP dependent enzymes apparently forms those profound disturbances of neurotransmitter systems, which are inherent in ADHD: low concentrations of monoamines and disordered amino acid metabolism. If vitamin B6 disorders are the core biochemical disturbances inherent in ADHD, then the long-term pyridoxine treatment is pathogenetically based replacement therapy of the disease. According to our data, multi-year pyridoxine treatment normalizes completely the pattern of ADHD behavior, without causing any serious side effects.

Association between urine cotinine levels, continuous performance test variables, and attention deficit hyperactivity disorder and learning disability symptoms in school-aged children.

BACKGROUND: We examined the cross-sectional relationship between environmental tobacco smoke exposure, continuous performance test (CPT) measures, and attention deficit hyperactivity disorder (ADHD) or learning disability symptoms in school-aged children. METHOD: In total, 989 children (526 boys, mean age 9.1 ± 0.7 years), recruited from five South Korean cities participated in this study. We used urine cotinine as a biomarker for environmental tobacco smoke exposure, and obtained the children's scores on a CPT. Parents completed the Korean versions of the ADHD rating scale-IV (ADHD-RS) and learning disability evaluation scale (LDES). Using generalized linear mixed model (GLMM), we assessed the associations between urine cotinine concentrations, neuropsychological variables, and symptoms of ADHD and learning disabilities. Additionally, we conducted structural equation models to explore the effects' pathways. RESULTS: After adjusting for a range of relevant covariates, GLMM showed urinary cotinine levels were significantly and positively associated with CPT scores on omission errors, commission errors, response time, and response time variability, and with parent- and teacher-rated ADHD-RS scores. In addition, urine cotinine levels were negatively associated with LDES scores on spelling and mathematical calculations. The structural equation model revealed that CPT variables mediated the association between urine cotinine levels and parental reports of symptoms of ADHD and learning disabilities. CONCLUSIONS: Our data indicate that environmental exposure to tobacco smoke is associated with ADHD and learning disabilities in children, and that impairments in attention and inhibitory control probably mediate the effect.

A HPLC-MS method to detect and quantify guanfacine in urine.

BACKGROUND: Guanfacine, an α2-adrenergic α2A)agonist long indicated to treat hypertension, is now being used to treat attention deficit-hyperactivity disorder (ADHD) in adolescents. This new therapeutic use may require urine testing to document compliance or abuse. A simple rapid high pressure liquid chromatography-mass spectrometry (HPLC-MS) method to detect and quantify guanfacine in urine following therapeutic administration is presented. METHODS: Guanfacine and protriptyline internal standard were extracted from alkalinized urine with ethyl acetate. The organic layer was evaporated, reconstituted with mobile phase and analyzed on a YMC Basic S-5 micron, 2.0 × 150 mm HPLC column connected to an MS detector operated in positive electrospray ionization mode with selected ion resonance. Elution times were <5 min. RESULTS: The analytical measurement range for guanfacine was 20-2000 ng/mL. The limit of detection and quantitation were 5 ng/mL and 20 ng/mL, respectively. Precision as %CV was <15% at 40, 100 and 500 ng/mL (n=6). Percentage recovery using the same concentrations was >89%. Interference with drugs and biological constituents was assessed; no interferences were noted. Analysis of 100 random post-diagnostic urine specimens yielded 11 guanfacine positive results with concentrations ranging from 11 to 6390 ng/mL. CONCLUSIONS: This HPLC-MS method provides a simple and rapid method for the routine detection and quantitation of guanfacine in urine specimens.