Tanya E. Froehlich

Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children

Objective The purpose of this study was to examine the association of exposures to tobacco smoke and environmental lead with attention deficit hyperactivity disorder (ADHD). Methods Data were obtained from the National Health and Nutrition Examination Survey 1999–2002. Prenatal and postnatal tobacco exposure was based on parent report; lead exposure was measured using blood lead concentration. ADHD was defined as having current stimulant medication use and parent report of ADHD diagnosed by a doctor or health professional. Results Of 4,704 children 4–15 years of age, 4.2% were reported to have ADHD and stimulant medication use, equivalent to 1.8 million children in the United States. In multivariable analysis, prenatal tobacco exposure [odds ratio (OR) = 2.5; 95% confidence interval (CI), 1.2–5.2] and higher blood lead concentration (first vs. fifth quintile, OR = 4.1; 95% CI, 1.2–14.0) were significantly associated with ADHD. Postnatal tobacco smoke exposure was not associated with ADHD (OR = 0.6; 95% CI, 0.3–1.3; p = 0.22). If causally linked, these data suggest that prenatal tobacco exposure accounts for 270,000 excess cases of ADHD, and lead exposure accounts for 290,000 excess cases of ADHD in U.S. children. Conclusions We conclude that exposure to prenatal tobacco and environmental lead are risk factors for ADHD in U.S. children.

Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder.

OBJECTIVE: The study objective was to determine the independent and joint associations of prenatal tobacco and childhood lead exposures with attention-deficit/hyperactivity disorder (ADHD), as defined by current diagnostic criteria, in a national sample of US children. METHODS: Data are from the 2001–2004 National Health and Nutrition Examination Survey, a cross-sectional, nationally representative sample of the US population. Participants were 8 to 15 years of age (N = 2588). Prenatal tobacco exposure was measured by report of maternal cigarette use during pregnancy. Lead exposure was assessed by using current blood lead levels. The Diagnostic Interview Schedule for Children was used to ascertain the presence of ADHD in the past year, on the basis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. RESULTS: A total of 8.7% (95% confidence interval [CI]: 7.3%–10.1%) of children met criteria for ADHD. Prenatal tobacco exposure (adjusted odds ratio [aOR]: 2.4 [95% CI: 1.5–3.7]) and higher current blood lead concentrations (aOR for third versus first tertile: 2.3 [95% CI: 1.5–3.8]) were independently associated with ADHD. Compared with children with neither exposure, children with both exposures (prenatal tobacco exposure and third-tertile lead levels) had an even greater risk of ADHD (aOR: 8.1 [95% CI: 3.5–18.7]) than would be expected if the independent risks were multiplied (tobacco-lead exposure interaction term, P < .001). CONCLUSIONS: Prenatal tobacco and childhood lead exposures are associated with ADHD in US children, especially among those with both exposures. Reduction of these common toxicant exposures may be an important avenue for ADHD prevention.

Evidence for Higher Reaction Time Variability for Children With ADHD on a Range of Cognitive Tasks Including Reward and Event Rate Manipulations

OBJECTIVE The purpose of the research study was to examine the manifestation of variability in reaction times (RT) in children with attention deficit hyperactivity disorder (ADHD) and to examine whether RT variability presented differently across a variety of neuropsychological tasks, was present across the two most common ADHD subtypes, and whether it was affected by reward and event rate (ER) manipulations. METHOD Children with ADHD-combined type (n = 51), ADHD-predominantly inattentive type (n = 53), and 47 controls completed five neuropsychological tasks (Choice Discrimination Task, Child Attentional Network Task, Go/No-Go task, Stop Signal Task, and N-back task), each allowing trial-by-trial assessment of RTs. Multiple indicators of RT variability including RT standard deviation, coefficient of variation and ex-Gaussian tau were used. RESULTS Children with ADHD demonstrated greater RT variability than controls across all five tasks as measured by the ex-Gaussian indicator tau. There were minimal differences in RT variability across the ADHD subtypes. Children with ADHD also had poorer task accuracy than controls across all tasks except the Choice Discrimination task. Although ER and reward manipulations did affect childrens RT variability and task accuracy, these manipulations largely did not differentially affect children with ADHD compared to controls. RT variability and task accuracy were highly correlated across tasks. Removing variance attributable to RT variability from task accuracy did not appreciably affect between-groups differences in task accuracy. CONCLUSIONS High RT variability is a ubiquitous and robust phenomenon in children with ADHD.

Association of environmental toxicants and conduct disorder in U.S. children: NHANES 2001-2004.

Objective The purpose of this study was to examine the association of tobacco smoke and environmental lead exposure with conduct disorder (CD). Methods The National Health and Nutrition Examination Survey (NHANES) 2001–2004 is a nationally representative cross-sectional sample of the noninstitutionalized U.S. population. We examined the association of prenatal tobacco, postnatal tobacco, and environmental lead exposure with CD in children 8–15 years of age (n = 3,081). We measured prenatal tobacco exposure by parent report of cigarette use during pregnancy, and postnatal tobacco using serum cotinine levels. We assessed lead exposure using current blood lead concentration. Parents completed the Diagnostic Interview Schedule for Children to determine whether their children met criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV ) for CD. Results Overall, 2.06% of children met DSM-IV criteria for CD in the past year, equivalent to 560,000 U.S. children 8–15 years of age. After adjustment, prenatal tobacco exposure was associated with increased odds for CD [odds ratio (OR) = 3.00; 95% confidence interval (CI), 1.36–6.63]. Increased blood lead levels (fourth vs. first quartile) and serum cotinine levels (fifth vs. first quintile) were associated with an 8.64-fold (95% CI, 1.87–40.04) and 9.15-fold (95% CI, 1.47–6.90) increased odds of meeting DSM-IV CD criteria. Increasing serum cotinine levels and blood lead levels were also associated with increased prevalence of CD symptoms (symptom count ratio, lead: 1.73; 95% CI, 1.23–2.43; symptom count ratio, cotinine: 1.97; 95% CI, 1.15–3.40). Conclusions These results suggest that prenatal tobacco exposure and environmental lead exposure contribute substantially to CD in U.S. children.

Update on Environmental Risk Factors for Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurobehavioral disorder affecting 5% to 10% of children. Although considered to be a highly familial disorder, ADHD heritability estimates of 60% to 80% highlight the considerable role that environmental factors may still play in disorder susceptibility. Proposed ADHD environmental risk factors include prenatal substance exposures, heavy metal and chemical exposures, nutritional factors, and lifestyle/psychosocial factors. This paper reviews the literature published in 2010 investigating the association between environmental risk factors and ADHD or related symptomatology. Sources of risk factor exposure and the proposed mechanism by which each exposure is linked to ADHD-related neurobehavioral changes are also reported. Methodologic limitations of the current literature are discussed, and guidelines for future study are proposed. An improved understanding of the role that environmental factors play in ADHD etiology is critical to future ADHD prevention efforts.

Progress and promise of attention-deficit hyperactivity disorder pharmacogenetics.

One strategy for understanding variability in attention-deficit hyperactivity disorder (ADHD) medication response, and therefore redressing the current trial-and-error approach to ADHD medication management, is to identify genetic moderators of treatment. This article summarizes ADHD pharmacogenetic investigative efforts to date, which have primarily focused on short-term response to methylphenidate and largely been limited by modest sample sizes. The most well studied genes include the dopamine transporter and dopamine D4 receptor, with additional genes that have been significantly associated with stimulant medication response including the adrenergic α2A-receptor, catechol-O-methyltransferase, D5 receptor, noradrenaline (norepinephrine) transporter protein 1 and synaptosomal-associated protein 25 kDa.Unfortunately, results of current ADHD pharmacogenetic studies have not been entirely consistent, possibly due to differences in study design, medication dosing regimens and outcome measures. Future directions for ADHD pharmacogenetics investigations may include examination of drug-metabolizing enzymes and a wider range of stimulant and non-stimulant medications. In addition, researchers are increasingly interested in going beyond the individual candidate gene approach to investigate gene-gene interactions or pathways, effect modification by additional environmental exposures and whole genome approaches. Advancements in ADHD pharmacogenetics will be facilitated by multi-site collaborations to obtain larger sample sizes using standardized protocols. Although ADHD pharmacogenetic efforts are still in a relatively early stage, their potential clinical applications may include the development of treatment efficacy and adverse effect prediction algorithms that incorporate the interplay of genetic and environmental factors, as well as the development of novel ADHD treatments.

Interactive Effects of a DRD4 Polymorphism, Lead, and Sex on Executive Functions in Children

BACKGROUND Prior studies have examined independent effects of a dopamine receptor D4 polymorphism (DRD4-7) and lead exposure on executive functions but not their interaction or the role of sex as a modifier of their effects. METHODS Multivariable analyses were used to examine effects of DRD4-7 genotype, 60-month blood lead level, and sex on spatial working memory, rule learning and reversal, spatial span, and planning for 174 children. RESULTS DRD4-7 was associated with poorer spatial working memory, and increasing blood lead levels were associated with impaired rule learning and reversal, spatial span, and planning. Adverse effects of lead on planning and rule learning and reversal were seen primarily for boys. In addition, the effect of lead on rule learning and reversal was evident predominately for those lacking DRD4-7. CONCLUSIONS We observed independent effects of DRD4-7 and lead on various executive functions and modifications of lead effects by DRD4 genotype and sex.

Effects of Stimulant Medication, Incentives, and Event Rate on Reaction Time Variability in Children With ADHD

This study examined the effects of methylphenidate (MPH) on reaction time (RT) variability in children with attention deficit hyperactivity disorder (ADHD). Using a broad battery of computerized tasks, and both conventional and ex-Gaussian indicators of RT variability, in addition to within-task manipulations of incentive and event rate (ER), this study comprehensively examined the breadth, specificity, and possible moderators of effects of MPH on RT variability. A total of 93 children with ADHD completed a 4-week within-subject, randomized, double-blind, placebo-controlled crossover trial of MPH to identify an optimal dosage. Children were then randomly assigned to receive either their optimal MPH dose or placebo after which they completed five neuropsychological tasks, each allowing trial-by-trial assessment of RTs. Stimulant effects on RT variability were observed on both measures of the total RT distribution (ie, coefficient of variation) as well as on an ex-Gaussian measure examining the exponential portion of the RT distribution (ie, τ). There was minimal, if any, effect of MPH on performance accuracy or RT speed. Within-task incentive and ER manipulations did not appreciably affect stimulant effects across the tasks. The pattern of significant and pervasive effects of MPH on RT variability, and few effects of MPH on accuracy and RT speed suggest that MPH primarily affects RT variability. Given the magnitude and breadth of effects of MPH on RT variability as well as the apparent specificity of these effects of MPH on RT variability indicators, future research should focus on neurophysiological correlates of effects of MPH on RT variability in an effort to better define MPH pharmacodynamics.

Clinical Utility of the Vanderbilt ADHD Rating Scale for Ruling Out Comorbid Learning Disorders

OBJECTIVE: The goal was to examine the clinical utility of using the Vanderbilt Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale (VARS) to determine when to refer children with ADHD for learningdisorder (LD) evaluations. METHODS: A total of 128 stimulant-naive children with ADHD, 7 to 11 years of age, were included in the study. The parents and teachers of 128 children with diagnosed ADHD completed the VARS. The reading, numerical operations, and spelling subtests from the Wechsler Individual Achievement Test, Second Edition, were used to identify children with a comorbid LD. We examined the predictive validity and clinical utility of the VARS performance items for ruling in/out the presence of a comorbid LD. RESULTS: Thirty-eight percent of the samples met the criteria for a comorbid LD. A cutoff score of 7.5 for the sum of the VARS parent and teacher reading items had excellent clinical utility for ruling out both reading and spelling LDs. Cutoff scores of 4 for the VARS teacher reading and writing items had excellent utility for ruling out comorbid reading and spelling LDs, respectively. None of the VARS performance items effectively identified or ruled out math LDs. CONCLUSION: The VARS performance items should be used with an interview about school functioning and a review of school records to rule out the presence of a comorbid reading or spelling LD for children with diagnosed ADHD.

National trends in psychotropic medication use in young children: 1994-2009.

OBJECTIVE: To examine recent national trends in psychotropic use for very young children at US outpatient medical visits. METHODS: Data for 2- to 5-year-old children (N = 43 598) from the 1994–2009 National Ambulatory and National Hospital Ambulatory Medical Care Surveys were used to estimate the weighted percentage of visits with psychotropic prescriptions. Multivariable logistic regression was used to identify factors associated with psychotropic use. Time effects were examined in 4-year blocks (1994–1997, 1998–2001, 2002–2005, and 2006–2009). RESULTS: Psychotropic prescription rates were 0.98% from 1994–1997, 0.83% from 1998–2001, 1.45% from 2002–2005, and 1.00% from 2006–2009. The likelihood of preschool psychotropic use was highest in 2002–2005 (1994–1997 adjusted odds ratio [AOR] versus 2002–2005: 0.67; 1998–2001 AOR versus 2002–2005: 0.63; 2006–2009 AOR versus 2002–2005: 0.64), then diminished such that the 2006–2009 probability of use did not differ from 1994–1997 or from 1998–2001. Boys (AOR versus girls: 1.64), white children (AOR versus other race: 1.42), older children (AOR for 4 to 5 vs 2 to 3 year olds: 3.87), and those lacking private insurance (AOR versus privately insured: 2.38) were more likely than children from other groups to receive psychotropic prescriptions. CONCLUSIONS: Psychotropic prescription was notable for peak usage in 2002–2005 and sociodemographic disparities in use. Further study is needed to discern why psychotropic use in very young children stabilized in 2006–2009, as well as reasons for increased use in boys, white children, and those lacking private health insurance.