Linking Low-Level Lead Exposure with ADHD-Related Behaviors

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1 Linking Exposures to Environmental Toxicants with Psychopathology in Children and Adolescents Developmental Pediatrics Grand Rounds Alberta Children s Hospital Bruce Lanphear, M.D., M.P.H. Cincinnati Children s Environmental Health Center Cincinnati Children s Hospital Medical Center Canfield R, et al. NEJM ;8:57-5. New Morbidities of Childhood Trends in Neuropsychiatric Disorders among Children in Denmark (per,), 99 to 999 Birth Cohorts Prevalence 8 8 Autism Conduct Disorder Learning Disability ADHD Asthma Preterm Birth Boyle C, et al. Pediatrics 99:9:99-; Branum AM, et al. Paediatr Perinat Epidemiol ;:8-5; Hedley AA, et al. JAMA ;9:87-5. Lanphear BP, et al.pediatrics Froehlich T, et al. Arch Ped Adolesc Med 7;:857-8; Braun J, et al. (in press). Atladottir HO, et al. Arch Pediatr Adolesc Med 7;:9-98. Lead-Associated Behavioral and Emotional Problems in School-age Children Linking Low-Level Lead Exposure with ADHD-Related Behaviors Needleman HL, et al. N Engl J Med 979;:89-95.

2 Mean Number of Symptoms of Inattention and Restlessness by Tooth Lead (μg/g) Methods Mean No. Symptoms p <.5 to to 5 to 8 9 to > Tooth Lead (μg/g) National Health and Examination Survey The NHANES is a cross-sectional household survey of the non-institutionalized civilian population,7 children, age to 5 years, were used in these analyses The case definition of ADHD was based on parent report of doctor-diagnosis of ADHD by a physician or psychologist and ADHD medication use. Symptoms scores, based on parent and teacher report, are derived from the Rutter and Conners questionnaires. Fergusson DM, et al. J Child Psychol Psychiatry 99::5-7. Risk of ADHD by Blood Lead Levels in US Children, to 5 years, NHANES 999- Risk of ADHD by Blood Lead Levels in US Children, to 5 years, NHANES < > Blood Lead (μg/dl) <.79.8 to.9. to.9.5 to.9 >. Quintiles of Blood Lead Concentration (µg/dl) Adjusted for child s age, sex, race and ethnicity, preschool attendance, serum ferritin, prenatal tobacco exposure and health insurance status. Braun J, et al. EHP ;7:5-55. Adjusted for child s age, sex, race and ethnicity, preschool attendance, serum ferritin, prenatal tobacco exposure, poverty-income ratio, and health insurance status. Methods Risk of ADHD by Blood Lead Levels in US Children, 8 to 5 years, NHANES - National Health and Examination Survey -. The NHANES is a cross-sectional household survey of the non-institutionalized civilian population,7 children, age 8 to 5 years, were used in these analyses The Diagnostic Interview Schedule for Children (DISC) was used to assess the presence of ADHD in the last year based on DSM-IV criteria. Parents were asked to report symptoms via telephone interview. <.9.9 to. >. Terciles of Blood Lead Concentration (µg/dl) Adjusted for child s age, sex, race and ethnicity, preschool attendance, maternal age at birth, birth weight, serum ferritin, poverty-income ratio, prenatal tobacco exposure (Froehlich T, et al in preparation.)

3 Schematic Diagram of a Dopaminergic Terminal Gene-Environment Interactions for Endophenotypes of ADHD Thapar, A. et al. Hum. Mol. Genet. 5 :R75-8R; doi:.9/hmg/ddi Clarifying Disease Phenotypes by Linking Biomarkers with Endophenotypes Methods Prospective birth cohort recruited from urban Rochester between 99 to 99 7 children, age months, were examined in these analyses Children s month blood lead levels were selected a priori as a concurrent measure of lead exposure Children with DRD-7 allele (DRD-7 +/+ or +/-) were compared with all other children Measures of executive function obtained using CANTAB Castellanos FX, et al. Nat Rev Neuro ;:7 Attentional Flexibility in Boys by DRD Genotype and Blood Lead Concentration Attentional Flexibility in Girls by DRD Genotype and Blood Lead Concentration Total Trials (Adjusted) DRD-7 Repeat Non-DRD, 7-Repeat BPb x DRD, p =. 8 8 Blood Lead Concentration (μg/dl) Adjusted for child s sex, race, prenatal tobacco exposure, prenatal alcohol exposure, household income, maternal IQ, iron status. Froehlich TE, et al. Biol Psychiatry 7;:-9. 5 DRD-7 Repeat Non-DRD, 7-Repeat 5 5 BPb x DRD, p = Blood Lead Concentration (μg/dl) Froehlich TE, et al. Biol Psychiatry 7;:-9. Total Trials (Adjusted)

4 Control. µm Pb. µm Pb. µm Pb Planning Performance by Blood Lead Concentration and Sex No Lead A. Lead Reduces Neurite Length in Dopaminergic Neurons after 8 Hr Exposure to Lead Acetate Mean No. Moves to Solve Problem 8 Boys Girls BPb x Sex interaction, p = µm. µg/dl. µm. µg/dl B. C. Neurite Length (microns) Control. µm Pb. µm Pb. µm Pb The lowest concentration of lead acetate used (. µm) caused a significant decrease in neurite length that was exacerbated by incubation in higher concentrations of lead (. and. µm). Blood Lead Concentration (μg/dl) Froehlich TE, et al. Biol Psychiatry 7;:-9. Schneider J, et al., Neurotoxicology and Teratology, 5 () Dopamine Concentration in Rat Brains following Lead Exposure Linking Biomarkers of Lead Exposure and Putative Effects with ADHD.9 Blood Lead Brain Volume Loss ADHD Dopamine (μg/g) <.79.8 to.9. to.9.5 to.9 >. Quintiles of Blood Lead (µg/dl).5 Control 5 8 Lead Exposure (μg/g) Neurite Length (microns) Neurite Length Dopamine Deficit Chandra SV, et al. Arch Toxicology 98;9:9-5. Association of Blood Lead Levels and Self- Reported Delinquent Behaviors in Adolescents Linking Environmental Lead Exposure With Antisocial Behaviors Total Score Prenatal PbB Average Childhood PbB Month PbB 78 Lowest Low Medium High Blood Lead Level Dietrich KN, et al. Neurotox & Teratol ;:5-58.

5 Methods Number of Arrest among Young Adults by Quartiles of Childhood Lead Exposure and Sex Prospective birth cohort recruited from impoverished Cincinnati community from 979 to 98 were excluded if addicted to drugs of abuse, diabetic or had recognized psychiatric disorder 5 children, age 8 to years, were examined in these analyses Criminal arrests were obtained from criminal justice records and coded by two independent reviewers Minor offences, such as speeding or driving without a license, were excluded from these analyses. No. of Arrests Female Male < 5 5 to 7 7 to > Six-Year Blood Lead (μg/dl) Wright JP, et al. PLoS Medicine 8 (in press). Number of Arrests by Childhood Lead Exposure: 8 The Cincinnati Lead Study Relationship of Lead Exposure and Murder Rate (/,) in the United States Number of Arrests Males Females 5 5 Six-Year Blood Lead Levels (µg/dl) Accounting for birthweight, age, prenatal tobacco exposure, maternal age at delivery, maternal IQ, HOME Inventory. Source: Wright J, et al. PLoS Medicine (in press). 5 Nevin R. Environmental Research :8;- Methods Risk of Conduct Disorder by Blood Lead Concentration in US Children, 8 to 5 years, NHANES - National Health and Examination Survey, - The NHANES is a cross-sectional household survey of the non-institutionalized civilian population 9 8,8 children, age 8 to 5 years, were used in these 7 analyses 5 The Diagnostic Interview Schedule for Children (DISC) was used to assess for the presence of CD in the last year based on DSM-IV criteria. Parents were asked to report symptoms via telephone interview. <.7.9 to.. to. >. Tertiles of Blood Lead Concentration (µg/dl) Adjusted for child s age, sex, race and ethnicity, preschool attendance, serum ferritin, prenatal tobacco exposure and health insurance status.

6 Gray Matter Loss by Childhood Lead Exposure (n=57) Reduction in Gray Matter by Childhood Blood Lead Levels and Subject s Sex (n=8) (n=7) Adjusted for child s age, birth weight. Sex, gestational age, IQ, prenatal tobacco, prenatal alcohol, prenatal marijuana, total intracranial volume, SES and HOME Inventory did not alter results (Cecil K, PLoS Medicine, et al. in press). Adjusted for child s age, birth weight. Sex, gestational age, IQ, prenatal tobacco, prenatal alcohol, prenatal marijuana, total intracranial volume, SES and HOME Inventory did not alter results (Cecil K, Brubaker C, Dietrich KN, et al. PLoS Medicine in press). Development of the Brain and Timing of Exposure to Environmental Toxicants Developmental Trajectory of Lead Exposure by Gray Matter Deficits Year Year From: UCLA Lab of Neuroimaging Developmental Trajectory of Lead Exposure by Gray Matter Deficits Year Year Developmental Trajectory of Lead Exposure by Gray Matter Deficits Year 5 Year

7 Prenatal Exposure to Tobacco Smoke and Teacher- Rated Behavioral Problems in Children Linking Tobacco Smoke Exposure With Psychopathology Mean Problem Score Conduct Attention Deficit Disruptive Behaviors Fergusson DM, et al. Pediatrics 99;9:85-8. Case Control Studies of ADHD by Prenatal Tobacco Smoke Exposure Risk of ADHD by Prenatal Tobacco Exposure in US Children, to 5 years, NHANES 999- Author (year) McIntosh (995) Milberger (998) Mick () No. Cases 8 No. Controls 5 9 Age of Children s AOR (95%CI).7 (.-7.). (.-5.5). (.-.) Langley (5) -7. (.-.5) Schmitz () -8. (.-) Unexposed Exposed Prenatal Tobacco Exposure Pooled analysis Adjusted for race/ethnicity, sex, age, blood lead level, ferritin level, presence of a smoker in the home, preschool attendance, and insurance. Source: Braun J, et al. EHP ;:9-99. Risk of ADHD by Prenatal Tobacco Exposure in US Children, 8 to 5 years, NHANES - Unexposed Prenatal Tobacco Exposure Exposed Adjusted for race/ethnicity, sex, age, blood lead level, ferritin level, presence of a smoker in the home, preschool attendance, and insurance. (Source: Froehlich T, et al. in preparation). Joint Effect of DAT (8) and Prenatal Tobacco Exposure with ADHD-Related Behaviors in Children Conners score (SD ) p<. No prenatal smoke-dat +/- or -/- No prenatal smoke-dat +/+ Prenatal smoke-dat +/- or -/- Prenatal smoke-dat +/+ NS p<. Hyperactive-Impulsive Inattentive Oppositional Kahn RS, et al. J Pediatrics ::-.

8 Prenatal Chlorpyrifos Exposure and Pervasive Developmental Disorder in -year old Children 8 Linking Prenatal Organophosphorus Pesticide Exposure With Pervasive Developmental Disorder Low High Chlorpyrifos Exposure Rauh V, et al. Pediatrics ; Effect of Prenatal OP Pesticide (Total DAPs) Exposure on Behavioral Problems Limitations NS p <.5 Studies did not account for all relevant risk factors (e.g., parental psychopathology) Diagnosis of ADHD, PDD and conduct disorder used validated surveys based on parent report Other exposures, such as tobacco and alcohol, often relied on maternal report ADHD PDD Eskenazi B, et al. EHP 7;5: Adjusted for sex, age at assessment, breastfeeding duration, HOME Inventory, household income, parity, maternal PPVT and maternal depression. Failure of Toxicity Testing Of the nearly, high production volume chemicals, 75% lack even the most basic toxicity tests. Of the registered pesticides EPA considers to be neurotoxic, the majority have not been tested for developmental neurotoxicity. Animal testing may not be sensitive enough to protect humans. Lack animal models for important human skills, such as reading. It's all of a piece. Thalidomide and pesticides - they represent our willingness to rush ahead and use something new without knowing what the results are going to be. Rachel Carson. Claudio L. Toxicol Appl Pharm ;:-.. Rice D. Env Health Persp 99;:5-5.

9 Lessons from the FDA Flow Chart of the EU s Framework for Regulating Chemicals Summary Increasing evidence linking toxicant exposures with child and adolescent psychopathology Large prospective birth cohort studies are needed to confirm results and explore GEi Contemporary studies are needed to explore relationships at lower levels of exposure Examine specific environmental risk factors for endophenotypes and variants of ADHD, autism spectrum disorders and antisocial behaviors Implications for Protecting Children from Prevalent Environmental Toxicants Require developmental neurotoxicity testing for all high-production volume chemicals Ban, replace or control recognized or suspected environmental toxicants Observational studies of low-level exposure to prevalent, persistent toxicants using biomarkers Predicted Size of Cortical Gray Matter Matter by Age Few tragedies can be more extensive than the stunting of life, few injustices deeper than the denial of an opportunity to strive or even to hope, by a limit imposed from without, but falsely identified as lying within. Stephen Jay Gould Giedd et al., Nat. Neurosci. 999;:8-8.

10 Developmental Trajectory of Lead Exposure by Gray Matter Deficits by Sex One Year Blood Lead Developmental Trajectory Year of Lead Exposure by Gray Matter Deficits by Sex - Two Year Blood Lead Developmental Trajectory Year of Lead Exposure by Gray Matter Deficits by Sex - Three Year Blood Lead Developmental Trajectory Year of Lead Exposure by Gray Matter Deficits by Sex Four Year Blood Lead Developmental Trajectory Year of 5Lead Exposure by Gray Matter Deficits by Sex Five Year Blood Lead Developmental Trajectory Year of Lead Exposure by Gray Matter Deficits by Sex Six Year Blood Lead