Lead and Neuroprotection by Iron in ADHD
Environ Health Perspect 115:395-399 (2007). doi:10.1289/ehp.10304 available via http://dx.doi.org [Online 24 June 2007]
Referencing: Exposures to Environmental Toxicants and Attention Deficit Hyperactivity Disorder in U.S. Children
We read with special interest the article by Braun et al. (2006). In this large survey, the authors concluded that prenatal exposure to tobacco and environmental lead are risk factors for attention deficit hyperactivity disorder (ADHD).
We would like to focus on the potential neuroprotective role of iron against the deleterious effect of lead on the development of ADHD symptoms.
Although the mechanisms underlying ADHD remain unclear, both genetic and environmental factors have been implicated. In a recent review on the implication of the dopaminergic system in the etiology of ADHD, Swanson et al. (2007) highlighted the importance of environmental risk factors as possible etiologies of dopamine deficit. Among these environmental factors, Swanson et al. (2007) cited the effects of lead exposure (at levels < 10 µg/dL) on ADHD-related behaviors and ADHD diagnosis.
Lead in the central nervous system may contribute to dopaminergic dysfunction inducing alteration of dopamine release and dopamine receptor density (Gedeon et al. 2001; Lidsky et al. 2003). Moreover, lead may disrupt the structure of the blood–brain barrier function essential for brain integrity (Dyatlov et al. 1998). Interestingly, Wang et al. (2007) recently reported that iron supplementation protects the integrity of the blood–brain barrier against lead insults. On the other hand, iron deficiency could increase the toxic effect of lead, suggesting a potent neuroprotective effect of iron supplementation on dopaminergic dysfunction due to lead exposure (Wright 1999; Wright et al. 2003)
In a controlled comparison group study, we (Konofal et al. 2004) showed that iron deficiency was correlated to ADHD symptoms severity, hypothesizing that iron supplementation may improve symptoms of ADHD in those subjects with low ferritin levels.
Given that lead exposure may contribute to ADHD and iron deficiency may exacerbate deleterious effects caused by lead, we recommend systematically seeking for iron deficiency in children with ADHD. We also think that controlled studies assessing the potential effectiveness of iron supplementation on ADHD symptoms should be encouraged. Such studies could aid the understanding of the complex pathophysiology underlying ADHD and provide effective therapeutic strategies for this disorder.
The authors declare they have no competing financial interests.
Eric Konofal
Samuele Cortese
Child Psychopathology Unit
University Hospital Robert Debré
Paris, France
References
Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP. 2006. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect 114:1904–1909.
Dyatlov VA, Platoshin AV, Lawrence DA, Carpenter DO. 1998. Lead potentiates cytokine- and glutamate-mediated increases in permeability of the blood-brain barrier. Neurotoxicology 19:283–291.
Gedeon Y, Ramesh GT, Wellman PJ, Jadhav AL. 2001. Changes in mesocorticolimbic dopamine and D1/D2 receptor levels after low level lead exposure: a time course study. Toxicol Lett 123(2-3):217–226.
Konofal E, Lecendreux M, Arnulf I, Mouren MC. 2004. Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 158(12):1113–1115.
Lidsky TI, Schneider JS. 2003. Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 126:5–19.
Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos GA, Volkow N, et al. 2007. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev 17(1):39–59.
Wang Q, Luo W, Zheng W, Liu Y, Xu H, Zheng G, et al. 2007. Iron supplement prevents lead-induced disruption of the blood-brain barrier during rat development. Toxicol Appl Pharmacol 219(1):33–41.
Wright RO. 1999. The role of iron therapy in childhood plumbism. Curr Opin Pediatr 11(3):255–258.
Wright RO, Tsaih SW, Schwartz J, Wright RJ, Hu H. 2003. Association between iron deficiency and blood lead level in a longitudinal analysis of children followed in an urban primary care clinic. J Pediatrics 142(1):9–14.
ADHD: Braun et al. Respond
Environ Health Perspect 115:395-399 (2007). doi:10.1289/ehp.10274R available via http://dx.doi.org [Online 24 June 2007]
We appreciate the comments of Brondum, and Konofal and Cortese, and the opportunity to clarify our results (Braun et al. 2006). It is common practice to select variables with a p-value of 0.2 for inclusion in multivariable models (Katz 1999). Although the association of blood lead levels and ADHD appeared "tenuous" in bivariate analysis (i.e., p = 0.19), this was largely an artifact of our decision to categorize blood lead levels. When we entered lead into our multivariable analysis as a continuous variable, we found a 1.2-fold increased odds [95% confidence interval (CI), 1.0–1.4; p = 0.02] of ADHD for each 1.0-µg/dL increase in blood lead levels. The blood lead quintiles were not divided into exactly equal sample sizes because we used weighted percentages to categorize the data. We decided a priori to present the analysis in quintiles to make the results easier to interpret and also to illustrate any dose–response relationships for blood lead levels and ADHD.
As we noted in the "Discussion" of our article (Braun et al. 2006), a limitation of our study was the inability to adjust for parental psychopathology. This is an unfortunate trade-off when using a large nationally representative survey. In other studies, prenatal tobacco exposure has been shown to be a risk factor for the development of ADHD after controlling for parental psychopathology (Mick et al. 2002; Weissman et al. 1999). Although there is considerable experimental and epidemiologic evidence linking lead exposure with behaviors consistent with ADHD, future studies of childhood lead exposure will need to confirm our results by accounting for parental psychopathology and other potential confounders.
The hypothesis proposed by Konofal and Cortese—that iron deficiency may play a role in symptom severity among children with ADHD—is intriguing. Indeed, it was their original research that prompted us to incorporate ferritin as a measure of iron status (Konofal et al. 2004). It is certainly plausible that iron deficiency may confound or modify the effects of environmental lead exposure on ADHD in children. Alternatively, lead exposure may act as a confounder or modifier for the observed effects of iron deficiency with ADHD. Unfortunately, we were not able to examine whether ferritin (or other indicators of iron status) was associated with ADHD symptom severity using the National Health and Nutrition Examination Survey. Nor did we specifically test for an association between iron deficiency and ADHD. Although iron or other micronutrient supplementation may protect children from lead toxicity, recent evidence from a double-blind randomized trial (Kordas et al. 2005) suggests that iron and zinc supplementation did not appreciably lower blood lead levels or improve child behavior, as measured by the Conners Rating Scales. However, Kordas et al. included only children without anemia in their trial.
The authors declare they have no competing financial interests.
Joe M. Braun
Department of Epidemiology
University of North Carolina-Chapel Hill
Chapel Hill, North Carolina
Bruce P. Lanphear
Robert S. Kahn
Tanya Froehlich
Department of Pediatrics
Peggy Auinger
Department of Pediatrics
University of Rochester School of Medicine
Rochester, New York
References
Braun JM, Froehlich TF, Kahn RS, Auinger P, Lanphear BP. 2006. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect 114:1904–1909.
Katz M. 1999. Multivariable Analysis: A Practical Guide for Clinicians. New York:Cambridge University Press.
Konofal E, Lecendreux M, Arnulf I, Mouren M. 2004. Iron deficiency in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 158:1113–1115.
Kordas K, Stoltzfus RJ, Lopez P, Rico JA, Rosado JL. 2005. Iron and zinc supplementation does not improve parent or teacher ratings of behavior in first grade Mexican children exposed to lead. J Pediatr 147:632–639.
Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S. 2002. Case-control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy. J Am Acad Child Adolesc Psychiatry 41:378–385.
Weissman MM, Warner V, Wickramaratne PJ, Kandel DB. 1999. Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood. J Am Acad Child Adolesc Psychiatry 38:892–899.