Low Blood Lead Levels Associated with Clinically Diagnosed Attention-Deficit/Hyperactivity Disorder and Mediated by Weak Cognitive Control

Published:September 17, 2007DOI:


      Attention-deficit/hyperactivity disorder (ADHD) and low-level lead exposure are high-prevalence conditions among children, and studies of large populations have suggested that these conditions are related. We examine this relationship in children from a community sample exposed to average background levels of lead who have a diagnosis of ADHD that is established by clinical criteria.


      One hundred fifty children ages 8–17 years participated (mean age = 14 years; 53 control subjects, 47 ADHD Predominantly Inattentive type, 50 ADHD-Combined type). Diagnosis was formally established with a semi-structured clinical interview and parent and teacher ratings. Children completed intelligence quotient (IQ) measures and the stop task (a neuropsychological measure). Lead was assayed from whole blood with inductively coupled plasma mass spectrometry.


      Blood lead levels in this sample closely matched US population exposure averages, with a maximum level of 3.4 μg/dL. Blood lead levels were statistically significantly higher in ADHD-combined type than in non-ADHD control (p < .05) children. Blood lead was associated with symptoms of hyperactivity-impulsivity but not inattention-disorganization, after control of covariates. Blood lead levels were linked with a lower IQ (p < .05), but IQ did not account for effects on hyperactivity. Instead, hyperactivity mediated effects of lead on IQ. Effects of blood lead on hyperactivity-impulsivity were mediated by poor performance on the stop task. This mediation effect was independent of effects of lead on IQ.


      Low-level lead exposure might be an important contributor to ADHD. Its effects seem to be mediated by less effective cognitive control, consistent with a route of influence via striatal-frontal neural circuits.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        4th ed. American Psychiatric Association, Washington, DC2000 (Text Rev)
        • Rappley M.D.
        Clinical practice.
        New Engl J Med. 2005; 352: 165-173
        • Jensen P.S.
        • Hinshaw S.P.
        • Kraemer H.C.
        • Lenora N.
        • Newcorn J.H.
        • Abikoff H.B.
        • et al.
        ADHD comorbidity findings from the MTA study: Comparing comorbid subgroups.
        J Am Acad Child Adolesc Psychiatry. 2001; 40: 147-158
        • Milich R.
        • Balentine A.C.
        • Lynam D.R.
        ADHD combined type and ADHD predominantly inattentive type are distinct and unrelated disorders.
        Clin Psychol: Science Pract. 2001; 8: 463-468
        • Nigg J.T.
        What Causes ADHD?.
        The Guilford Press, New York2006
        • Sonuga-Barke E.J.
        Causal models of attention-deficit/hyperactivity disorder: From common simple deficits to multiple developmental pathways.
        Biol Psychiatry. 2005; 57: 1231-1238
        • Nigg J.T.
        • Casey B.J.
        An integrative theory of attention-deficit/ hyperactivity disorder based on the cognitive and affective neurosciences.
        Dev Psychopathol. 2005; 17: 785-806
        • Castellanos F.X.
        • Sonuga-Barke E.J.
        • Milham M.P.
        • Tannock R.
        Characterizing cognition in ADHD: Beyond executive dysfunction.
        Trends Cogn Sci. 2006; 10: 117-123
        • Kala S.V.
        • Jadhav A.L.
        Low level lead exposure decreases in vivo release of dopamine in the rat nucleus accumbens: A microdialysis study.
        J Neurochem. 1995; 65: 1631-1655
        • Jadhav A.L.
        • Ramesh G.T.
        Pb-induced alterations in tyrosine hydroxylase activity in rat brain.
        Mol Cell Biochem. 1997; 175: 137-141
        • Lewis M.W.
        • Pitts D.K.
        Inorganic lead exposure in the rat activates striatal cFOS expression at lower blood levels and inhibits amphetamine-induced cFOS expression at higher blood levels.
        J Pharmacol Exp Ther. 2004; 310: 815-820
        • Fewtrell L.J.
        • Pruss-Ustun A.
        • Landrigan P.
        • Ayuso-Mateos J.L.
        Estimating the global burden of disease of mild mental retardation and cardiovascular diseases from environmental lead exposure.
        Environ Res. 2004; 94: 120-133
        • Lanphear B.P.
        • Hornung R.
        • Khoury J.
        • Yolton K.
        • Baghurst P.
        • Bellinger D.C.
        • et al.
        Low-level environmental lead exposure and children’s intellectual function: An international pooled analysis.
        Environ Health Perspect. 2005; 113: 894-899
        • Canfield R.L.
        • Kreher D.A.
        • Cornwell C.
        • Henderson C.R.
        Low-level lead exposure, executive functioning, and learning in early childhood.
        Child Neuropsychol. 2003; 9: 35-53
        • Canfield R.L.
        • Gendle M.H.
        • Cory-Slechta D.A.
        Impaired neuropsychological functioning in lead-exposed children.
        Dev Neuropsychol. 2004; 26: 513-540
        • Tuthill R.W.
        Hair lead levels related to children’s classroom attention-deficit behavior.
        Arch Environ Health. 1996; 51: 214-220
        • Minder B.
        • Das-Smaal E.A.
        • Brand E.F.
        • Orlebeke J.F.
        Exposure to lead and specific attentional problems in schoolchildren.
        J Learn Disabil. 1994; 27: 393-399
        • Gittelman R.
        • Eskenazi B.
        Lead and hyperactivity revisited.
        Arch Gen Psychiatry. 1983; 40: 827-833
        • Silva P.A.
        • Hughes P.
        • Williams S.
        • Faed J.M.
        Blood lead, intelligence, reading attainment, and behaviour in eleven year old children in Dunedin, New Zealand.
        J Child Psychol Psychiatry. 1988; 29: 43-52
        • Thomson G.O.
        • Raab G.M.
        • Hepburn W.S.
        • Hunter R.
        • Fulton M.
        • Laxen D.P.
        Blood-lead levels and childrens behavior results from the Edinburg Lead Study.
        J Child Psychol Psychiatry. 1989; 30: 515-528
        • Centers for Disease Control
        Third National Report on Human Exposure to Environmental Chemicals.
        National Center for Environmental Health, Atlanta, Georgia2005 (Publication No. 05–0570)
        • Barkley R.A.
        Attention-deficit/hyperactivity disorder, self-regulation, and time: Toward a more comprehensive theory.
        J Dev Behav Pediatr. 1997; 18: 271-279
        • Achenbach T.M.
        Manual for the Child Behavior Checklist/4-18 and 1991 Profile.
        University of Vermont Department of Psychiatry, Burlington, Vermont1991
        • Conners C.K.
        Conners Rating Scales-Revised.
        Multi-Health Systems, Toronto1997
        • DuPaul G.J.
        • Power T.J.
        • Anastopolous A.D.
        • Reid R.
        ADHD Rating Scale—IV: Checklists, Norms, & Clinical Interpretation.
        Guilford Press, New York1998
        • Wechsler D.
        Wechsler Intelligence Scale for Children-4th ed.: Technical and Interpretive Manual.
        The Psychological Corporation, San Antonio2003
        • Wechsler D.
        Weschler Individual Achievement Test–2nd ed.
        Psychological Corporation, San Antonio2005
        • Lahey B.B.
        • Applegate B.
        • McBurnett K.
        • Biederman J.
        • Greenhill L.
        • Hynd G.W.
        • et al.
        DSM-IV field trials for attention deficit hyperactivity disorder in children and adolescents.
        Am J Psychiatry. 1994; 151: 1673-1685
        • Logan G.D.
        • Schachar R.J.
        • Tannock R.
        Impulsivity and inhibitory control.
        Psych Sci. 1997; 8: 60-64
        • Preacher K.J.
        • Hayes A.F.
        SPSS and SAS procedures for estimating indirect effects in simple mediation models.
        Behav Res Methods Instrum Comput. 2004; 36: 717-731
        • MacKinnon D.P.
        Analysis of mediating variables in prevention and intervention research.
        in: Cázares A. Beatty L. Scientific Methods for Prevention Intervention Research (NIDA Monograph No. 139). National Institute on Drug Abuse, Rockville, Maryland1994: 127-153
        • Baron R.M.
        • Kenny D.A.
        The moderator-mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations.
        J Person Social Psychol. 1986; 51: 1173-1182
        • Waldman I.D.
        • Gizer I.R.
        The genetics of attention deficit hyperactivity disorder.
        Clin Psychol Rev. 2006; 26: 396-432
        • Purcell S.
        Variance components models for gene-environment interactions in twin analysis.
        Twin Research. 2002; 5: 554-571
        • Cory-Slechta D.A.
        Relationships between lead-induced learning impairments and changes in dopaminergic, cholinergic and glutamatergic neurotransmitter system functions.
        Annu Rev Pharmacol Toxicol. 1995; 35: 391-415
        • Sagvolden T.
        • Johansen E.B.
        • Aase H.
        • Russell V.A.
        A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes.
        Behav Brain Sci. 2005; 28: 397-419
        • Braun J.
        • Kahn R.S.
        • Froehlich T.
        • Auinger P.
        • Lanphear B.P.
        Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children.
        Environ Health Perspect. 2006; 114: 1904-1909
        • Cory-Slechta D.A.
        Lead-induced impairments in complex cognitive function: Offerings from experimental studies.
        Child Neuropsychol. 2003; 9: 54-75
        • Johnston M.V.
        • Goldstein G.W.
        Selective vulnerability of the developing brain to lead.
        Curr Opin Neurol. 1998; 11: 689-693
        • Hu H.
        • Rabinowitz M.
        • Smith D.
        Bone lead as a biological marker in epidemiologic studies of chronic toxicity: Conceptual paradigms.
        Environ Health Perspect. 1998; 106: 1-8
        • Manton W.I.
        • Angle C.R.
        • Stanek K.L.
        • Reese Y.R.
        • Kuehnemann T.J.
        Acquisition and retention of lead by young children.
        Environ Res. 2000; 82: 60-80
        • David O.J.
        • Hoffman S.P.
        • Sverd J.
        • Clark J.
        Lead and hyperactivity: Lead levels among hyperactive children.
        J Abnorm Child Psychol. 1977; 5: 405-416