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Attention-Deficit/Hyperactivity Disorder: A Preventable Epidemic?

Attention-Deficit/Hyperactivity Disorder: A Preventable Epidemic? Attention-deficit/hyperactivity disorder (ADHD), one of the most common brain disorders of childhood, affects about 1 in 10 children in the United States.1,2 Attention-deficit/hyperactivity disorder is not a specific disorder but a medley of maladaptive behaviors, the most prominent of which are hyperactivity, impulsivity, and inattention.1 Children who have ADHD often have other coexisting problems, such as aggressive behavior or anxiety; about 1 in 2 children have a learning disorder. Attention-deficit/hyperactivity disorder has ostensibly increased over the past decade in the United States. The Centers for Disease Control and Prevention found that the percentage of children who had parent-reported ADHD increased by 22%, from 7.8% in 2003 to 9.5% in 2007.2 Garfield et al3 estimated that the number of outpatient visits for ADHD increased by 66%, from 6.2 million in 2000 to 10.4 million in 2010. It is difficult to draw any firm conclusions about trends in ADHD, however, because there are no serial surveys of ADHD using a validated instrument. Still, a brain disorder that affects 1 in 10 children is, by definition, epidemic. The study by Sagiv et al,4 which tested whether prenatal exposure to methyl mercury was associated with the development of ADHD-related behaviors, is an important and rigorously conducted prospective birth cohort study. Short of randomly assigning children to be dosed with mercury, there is little of consequence that the investigators could have done to enhance their study. The authors used maternal hair, a validated biomarker, to measure fetal mercury exposure. They adjusted for an extensive variety of potential confounders, including maternal depression and blood lead levels. The inclusion of so many key covariates and potential confounders enhances the rigor of their analysis, even if it might unintentionally diminish the true association of mercury with the development of ADHD symptoms. Some readers will be quick to list the limitations of this type of research. The list, which was dutifully assembled over decades by industry-funded commentators and well-intentioned critics, is, by now, familiar; confounding, subtle effects and poor measures of exposure. It is important to put these limitations in context because they affect how pediatricians and parents will interpret this evidence, and when policy makers will promulgate standards to control or reduce exposures to putative risk factors for ADHD. Confounding results from a failure to account for risk factors that are associated with both the exposure and the outcome. The effect of a confounder, if it is ignored, is to increase or decrease the estimated effect of an exposure. We usually fixate about confounders whose absence might erroneously inflate the effect of environmental contaminants, but failure to include both fish intake and mercury in previous studies has been shown to diminish or repress the estimated cognitive deficits attributed to mercury.5 Sagiv et al4 did not find that fish intake repressed the effect of mercury on ADHD, but higher fish intake seemed to protect against it. This novel finding, which has direct (albeit complex) policy implications, is not inconsistent with the results of earlier studies.5 The difficulty of untangling the toxic effects of mercury from the beneficial effects of fish intake—which is the predominant and proximal source of methyl mercury—serves to remind us that confounding can work both ways; it is as likely to obscure or diminish a true risk factor as it is to illuminate a false one. Video Until recently, it was difficult to accurately measure exposure to environmental contaminants, such as mercury. Earlier studies often relied on questionnaires about fish intake or proximity to an industry to estimate exposure. Increasingly, however, biomarkers of exposure, which enhance our ability to quantify an individual's internal dose of a contaminant, are revolutionizing the study of toxicants in the same way genetic tests are revolutionizing the study of heritability.7 Still, the timing of the exposure and how well a particular tissue reflects the target organ for a specific contaminant is not always understood. Mercury in maternal hair is particularly useful because it correlates with mercury concentrations in the fetal brain. Mercury in cord blood may be a better indicator of fetal exposure, but this is quibbling. The study by Sagiv et al4 is part of a growing body of evidence implicating environmental toxicants in the epigenesis of ADHD. Exposures to some environmental toxicants—particularly lead and tobacco—are recognized risk factors for ADHD.6,8,9 Data are sparser for other contaminants, such as mercury, organophosphate insecticides, polychlorinated biphenyls, and bisphenol A, but a flurry of human and toxicologic studies are implicating these chemicals as risk factors for ADHD or ADHD-related behaviors.8-13 Dopamine or dopaminergic neurons in the prefrontal cortex seem to be particularly sensitive to environmental toxicants.14 Some critics have argued that the concentrations of environmental contaminants routinely found in pregnant women and children are too low to be biologically active. Yet, therapeutic levels of methylphenidate, the most commonly prescribed drug used to modify ADHD symptoms in children,3 are comparable to the concentrations in which the toxic effects of some environmental contaminants have been observed.15 Ironically, our primary response to the ADHD epidemic has been to dose children with chemicals. During the past 2 decades, psychopharmacologic therapy in children has increased dramatically.16 Still, many parents and pediatricians are wary about starting a chronic pharmacologic regimen for children and, while there are some short-term benefits for some children, it does not alter the course of ADHD.17 In contrast, there has been too little focus on prevention, perhaps because ADHD is erroneously perceived to result predominantly from poor parenting or genetic influences. The key to prevent ADHD is to identify and eliminate prevalent and modifiable risk factors. There are likely to be many because ADHD represents an array of behaviors or deficits that exist on a continuum. This should be obvious, but it is surprising how frequently we pit one risk factor against another in an apparent search for the singular, but ever-elusive, cause of ADHD. How much evidence is necessary to ban, control, or restrict the use of a suspected or confirmed toxicant? We require evidence from randomized controlled trials before we prescribe a drug using the principle, “First, do no harm.” In contrast, most of the environmental contaminants and toxicants that are readily found in our tissues—such as organophosphate pesticides, lead, flame retardants, bisphenol A, and phthalates—did not undergo premarket testing. Instead, we haphazardly conduct studies after pregnant women and children are routinely, and often universally, exposed to environmental contaminants to try to tease apart the toxic effects of a particular contaminant from a multitude of other risk factors. The European Union has taken a different approach; it requires industries to provide evidence that the environmental chemicals in their products are not toxic. What are the implications of the Sagiv et al4 study and other research on environmental contaminants and ADHD? First, we can take some comfort in recent legislation to reduce mercury contamination, at least from domestic sources. Second, these studies should spur our efforts to enhance the collection of data needed to calculate national estimates and trends in ADHD. Third, it is time to convene a national scientific advisory panel to evaluate environmental influences of ADHD and make recommendations about what can be done to prevent it. Fourth, this study and a flurry of new evidence linking environmental contaminants with ADHD reinforce the urgency of revising the regulatory framework for environmental contaminants and toxicants.18 The results of a growing number of rigorously conducted studies make it absolutely clear that we can no longer dismiss the toxicity of low-level environmental contaminants as insubstantial. Video References 1. 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):857-86417768285PubMedGoogle ScholarCrossref 2. Centers for Disease Control and Prevention (CDC). Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children—United States, 2003 and 2007. MMWR Morb Mortal Wkly Rep. 2010;59(44):1439-144321063274PubMedGoogle Scholar 3. Garfield CF, Dorsey ER, Zhu S, et al. Trends in attention deficit hyperactivity disorder ambulatory diagnosis and medical treatment in the United States, 2000-2010. Acad Pediatr. 2012;12(2):110-11622326727PubMedGoogle ScholarCrossref 4. Sagiv SK, Thurston SW, Bellinger DC, Amarasiriwardena C, Korrick SA. Prenatal exposure to mercury and fish consumption during pregnancy and attention-deficit/hyperactivity disorder–related behavior in children (published online October 8, 2012). Arch Pediatr Adolesc Med. 2012;166(12):1123-1131Google Scholar 5. Choi AL, Cordier S, Weihe P, Grandjean P. Negative confounding in the evaluation of toxicity: the case of methylmercury in fish and seafood [published correction appeared in Crit Rev Toxicol. 2009;39(1):95]. Crit Rev Toxicol. 2008;38(10):877-89319012089PubMedGoogle ScholarCrossref 6. Froehlich TE, Lanphear BP, Auinger P, et al. Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder [published online November 23, 2009]. Pediatrics. 2009;124(6):e1054-e1063http://pediatrics.aappublications.org/content/124/6/e1054. Accessed November 26, 200819933729PubMedGoogle ScholarCrossref 7. Lanphear BP, Bearer CF. Biomarkers in paediatric research and practice. Arch Dis Child. 2005;90(6):594-60015908624PubMedGoogle ScholarCrossref 8. Nigg JT, Knottnerus GM, Martel MM, et al. Low blood lead levels associated with clinically diagnosed attention-deficit/hyperactivity disorder and mediated by weak cognitive control. Biol Psychiatry. 2008;63(3):325-33117868654PubMedGoogle ScholarCrossref 9. Langley K, Rice F, van den Bree MB, Thapar A. Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour: a review. Minerva Pediatr. 2005;57(6):359-37116402008PubMedGoogle Scholar 10. Eubig PA, Aguiar A, Schantz SL. Lead and PCBs as risk factors for attention deficit/hyperactivity disorder. Environ Health Perspect. 2010;118(12):1654-166720829149PubMedGoogle ScholarCrossref 11. Hoffman K, Webster TF, Weisskopf MG, Weinberg J, Vieira VM. Exposure to polyfluoroalkyl chemicals and attention deficit/hyperactivity disorder in U.S. children 12-15 years of age. Environ Health Perspect. 2010;118(12):1762-176720551004PubMedGoogle ScholarCrossref 12. Marks AR, Harley K, Bradman A, et al. Organophosphate pesticide exposure and attention in young Mexican-American children: the CHAMACOS study. Environ Health Perspect. 2010;118(12):1768-177421126939PubMedGoogle ScholarCrossref 13. Braun JM, Kalkbrenner AE, Calafat AM, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 2011;128(5):873-88222025598PubMedGoogle ScholarCrossref 14. Swanson JM, Kinsbourne M, Nigg J, et al. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev. 2007;17(1):39-5917318414PubMedGoogle ScholarCrossref 15. Teicher MH, Polcari A, Foley M, et al. Methylphenidate blood levels and therapeutic response in children with attention-deficit hyperactivity disorder, I: effects of different dosing regimens. J Child Adolesc Psychopharmacol. 2006;16(4):416-43116958567PubMedGoogle ScholarCrossref 16. Zito JM, Safer DJ, dosReis S, Magder LS, Gardner JF, Zarin DA. Psychotherapeutic medication patterns for youths with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 1999;153(12):1257-126310591302PubMedGoogle ScholarCrossref 17. Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry. 2007;46(8):989-100217667478PubMedGoogle ScholarCrossref 18. Council on Environmental Health. Chemical-management policy: prioritizing children's health [published online April 25, 2011]. Pediatrics. 2011;127(5):983-990http://www.pediatrics.aappublications.org/content/127/5/983. Accessed April 19, 201121518722PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Pediatrics & Adolescent Medicine American Medical Association

Attention-Deficit/Hyperactivity Disorder: A Preventable Epidemic?

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Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
1072-4710
eISSN
1538-3628
DOI
10.1001/archpediatrics.2012.1900
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Abstract

Attention-deficit/hyperactivity disorder (ADHD), one of the most common brain disorders of childhood, affects about 1 in 10 children in the United States.1,2 Attention-deficit/hyperactivity disorder is not a specific disorder but a medley of maladaptive behaviors, the most prominent of which are hyperactivity, impulsivity, and inattention.1 Children who have ADHD often have other coexisting problems, such as aggressive behavior or anxiety; about 1 in 2 children have a learning disorder. Attention-deficit/hyperactivity disorder has ostensibly increased over the past decade in the United States. The Centers for Disease Control and Prevention found that the percentage of children who had parent-reported ADHD increased by 22%, from 7.8% in 2003 to 9.5% in 2007.2 Garfield et al3 estimated that the number of outpatient visits for ADHD increased by 66%, from 6.2 million in 2000 to 10.4 million in 2010. It is difficult to draw any firm conclusions about trends in ADHD, however, because there are no serial surveys of ADHD using a validated instrument. Still, a brain disorder that affects 1 in 10 children is, by definition, epidemic. The study by Sagiv et al,4 which tested whether prenatal exposure to methyl mercury was associated with the development of ADHD-related behaviors, is an important and rigorously conducted prospective birth cohort study. Short of randomly assigning children to be dosed with mercury, there is little of consequence that the investigators could have done to enhance their study. The authors used maternal hair, a validated biomarker, to measure fetal mercury exposure. They adjusted for an extensive variety of potential confounders, including maternal depression and blood lead levels. The inclusion of so many key covariates and potential confounders enhances the rigor of their analysis, even if it might unintentionally diminish the true association of mercury with the development of ADHD symptoms. Some readers will be quick to list the limitations of this type of research. The list, which was dutifully assembled over decades by industry-funded commentators and well-intentioned critics, is, by now, familiar; confounding, subtle effects and poor measures of exposure. It is important to put these limitations in context because they affect how pediatricians and parents will interpret this evidence, and when policy makers will promulgate standards to control or reduce exposures to putative risk factors for ADHD. Confounding results from a failure to account for risk factors that are associated with both the exposure and the outcome. The effect of a confounder, if it is ignored, is to increase or decrease the estimated effect of an exposure. We usually fixate about confounders whose absence might erroneously inflate the effect of environmental contaminants, but failure to include both fish intake and mercury in previous studies has been shown to diminish or repress the estimated cognitive deficits attributed to mercury.5 Sagiv et al4 did not find that fish intake repressed the effect of mercury on ADHD, but higher fish intake seemed to protect against it. This novel finding, which has direct (albeit complex) policy implications, is not inconsistent with the results of earlier studies.5 The difficulty of untangling the toxic effects of mercury from the beneficial effects of fish intake—which is the predominant and proximal source of methyl mercury—serves to remind us that confounding can work both ways; it is as likely to obscure or diminish a true risk factor as it is to illuminate a false one. Video Until recently, it was difficult to accurately measure exposure to environmental contaminants, such as mercury. Earlier studies often relied on questionnaires about fish intake or proximity to an industry to estimate exposure. Increasingly, however, biomarkers of exposure, which enhance our ability to quantify an individual's internal dose of a contaminant, are revolutionizing the study of toxicants in the same way genetic tests are revolutionizing the study of heritability.7 Still, the timing of the exposure and how well a particular tissue reflects the target organ for a specific contaminant is not always understood. Mercury in maternal hair is particularly useful because it correlates with mercury concentrations in the fetal brain. Mercury in cord blood may be a better indicator of fetal exposure, but this is quibbling. The study by Sagiv et al4 is part of a growing body of evidence implicating environmental toxicants in the epigenesis of ADHD. Exposures to some environmental toxicants—particularly lead and tobacco—are recognized risk factors for ADHD.6,8,9 Data are sparser for other contaminants, such as mercury, organophosphate insecticides, polychlorinated biphenyls, and bisphenol A, but a flurry of human and toxicologic studies are implicating these chemicals as risk factors for ADHD or ADHD-related behaviors.8-13 Dopamine or dopaminergic neurons in the prefrontal cortex seem to be particularly sensitive to environmental toxicants.14 Some critics have argued that the concentrations of environmental contaminants routinely found in pregnant women and children are too low to be biologically active. Yet, therapeutic levels of methylphenidate, the most commonly prescribed drug used to modify ADHD symptoms in children,3 are comparable to the concentrations in which the toxic effects of some environmental contaminants have been observed.15 Ironically, our primary response to the ADHD epidemic has been to dose children with chemicals. During the past 2 decades, psychopharmacologic therapy in children has increased dramatically.16 Still, many parents and pediatricians are wary about starting a chronic pharmacologic regimen for children and, while there are some short-term benefits for some children, it does not alter the course of ADHD.17 In contrast, there has been too little focus on prevention, perhaps because ADHD is erroneously perceived to result predominantly from poor parenting or genetic influences. The key to prevent ADHD is to identify and eliminate prevalent and modifiable risk factors. There are likely to be many because ADHD represents an array of behaviors or deficits that exist on a continuum. This should be obvious, but it is surprising how frequently we pit one risk factor against another in an apparent search for the singular, but ever-elusive, cause of ADHD. How much evidence is necessary to ban, control, or restrict the use of a suspected or confirmed toxicant? We require evidence from randomized controlled trials before we prescribe a drug using the principle, “First, do no harm.” In contrast, most of the environmental contaminants and toxicants that are readily found in our tissues—such as organophosphate pesticides, lead, flame retardants, bisphenol A, and phthalates—did not undergo premarket testing. Instead, we haphazardly conduct studies after pregnant women and children are routinely, and often universally, exposed to environmental contaminants to try to tease apart the toxic effects of a particular contaminant from a multitude of other risk factors. The European Union has taken a different approach; it requires industries to provide evidence that the environmental chemicals in their products are not toxic. What are the implications of the Sagiv et al4 study and other research on environmental contaminants and ADHD? First, we can take some comfort in recent legislation to reduce mercury contamination, at least from domestic sources. Second, these studies should spur our efforts to enhance the collection of data needed to calculate national estimates and trends in ADHD. Third, it is time to convene a national scientific advisory panel to evaluate environmental influences of ADHD and make recommendations about what can be done to prevent it. Fourth, this study and a flurry of new evidence linking environmental contaminants with ADHD reinforce the urgency of revising the regulatory framework for environmental contaminants and toxicants.18 The results of a growing number of rigorously conducted studies make it absolutely clear that we can no longer dismiss the toxicity of low-level environmental contaminants as insubstantial. Video References 1. 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):857-86417768285PubMedGoogle ScholarCrossref 2. Centers for Disease Control and Prevention (CDC). Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children—United States, 2003 and 2007. MMWR Morb Mortal Wkly Rep. 2010;59(44):1439-144321063274PubMedGoogle Scholar 3. Garfield CF, Dorsey ER, Zhu S, et al. Trends in attention deficit hyperactivity disorder ambulatory diagnosis and medical treatment in the United States, 2000-2010. Acad Pediatr. 2012;12(2):110-11622326727PubMedGoogle ScholarCrossref 4. Sagiv SK, Thurston SW, Bellinger DC, Amarasiriwardena C, Korrick SA. Prenatal exposure to mercury and fish consumption during pregnancy and attention-deficit/hyperactivity disorder–related behavior in children (published online October 8, 2012). Arch Pediatr Adolesc Med. 2012;166(12):1123-1131Google Scholar 5. Choi AL, Cordier S, Weihe P, Grandjean P. Negative confounding in the evaluation of toxicity: the case of methylmercury in fish and seafood [published correction appeared in Crit Rev Toxicol. 2009;39(1):95]. Crit Rev Toxicol. 2008;38(10):877-89319012089PubMedGoogle ScholarCrossref 6. Froehlich TE, Lanphear BP, Auinger P, et al. Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder [published online November 23, 2009]. Pediatrics. 2009;124(6):e1054-e1063http://pediatrics.aappublications.org/content/124/6/e1054. Accessed November 26, 200819933729PubMedGoogle ScholarCrossref 7. Lanphear BP, Bearer CF. Biomarkers in paediatric research and practice. Arch Dis Child. 2005;90(6):594-60015908624PubMedGoogle ScholarCrossref 8. Nigg JT, Knottnerus GM, Martel MM, et al. Low blood lead levels associated with clinically diagnosed attention-deficit/hyperactivity disorder and mediated by weak cognitive control. Biol Psychiatry. 2008;63(3):325-33117868654PubMedGoogle ScholarCrossref 9. Langley K, Rice F, van den Bree MB, Thapar A. Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour: a review. Minerva Pediatr. 2005;57(6):359-37116402008PubMedGoogle Scholar 10. Eubig PA, Aguiar A, Schantz SL. Lead and PCBs as risk factors for attention deficit/hyperactivity disorder. Environ Health Perspect. 2010;118(12):1654-166720829149PubMedGoogle ScholarCrossref 11. Hoffman K, Webster TF, Weisskopf MG, Weinberg J, Vieira VM. Exposure to polyfluoroalkyl chemicals and attention deficit/hyperactivity disorder in U.S. children 12-15 years of age. Environ Health Perspect. 2010;118(12):1762-176720551004PubMedGoogle ScholarCrossref 12. Marks AR, Harley K, Bradman A, et al. Organophosphate pesticide exposure and attention in young Mexican-American children: the CHAMACOS study. Environ Health Perspect. 2010;118(12):1768-177421126939PubMedGoogle ScholarCrossref 13. Braun JM, Kalkbrenner AE, Calafat AM, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 2011;128(5):873-88222025598PubMedGoogle ScholarCrossref 14. Swanson JM, Kinsbourne M, Nigg J, et al. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev. 2007;17(1):39-5917318414PubMedGoogle ScholarCrossref 15. Teicher MH, Polcari A, Foley M, et al. Methylphenidate blood levels and therapeutic response in children with attention-deficit hyperactivity disorder, I: effects of different dosing regimens. J Child Adolesc Psychopharmacol. 2006;16(4):416-43116958567PubMedGoogle ScholarCrossref 16. Zito JM, Safer DJ, dosReis S, Magder LS, Gardner JF, Zarin DA. Psychotherapeutic medication patterns for youths with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med. 1999;153(12):1257-126310591302PubMedGoogle ScholarCrossref 17. Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry. 2007;46(8):989-100217667478PubMedGoogle ScholarCrossref 18. Council on Environmental Health. Chemical-management policy: prioritizing children's health [published online April 25, 2011]. Pediatrics. 2011;127(5):983-990http://www.pediatrics.aappublications.org/content/127/5/983. Accessed April 19, 201121518722PubMedGoogle ScholarCrossref

Journal

Archives of Pediatrics & Adolescent MedicineAmerican Medical Association

Published: Dec 1, 2012

Keywords: attention-deficit/hyperactivity disorder,epidemics,adult attention deficit hyperactivity disorder

References