Systematic Review of Low Blood Lead Levels and Associations with Cognitive and Neuro-behavioral Outcomes in Children (Abridged Version)

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1 Systematic Review of Low Blood Lead Levels and Associations with Cognitive and Neuro-behavioral Outcomes in Children (Abridged Version) It has been well established that high blood lead levels can result in adverse neuro-cognitive and behavioral consequences in children (Juberg 1997, Schwartz 1994, Wakefield 2002). The current definition of an elevated blood lead level is 10 ug/dl, established in 1991 by the CDC. In the past 15 years, studies have found cognitive deficits associated with blood lead levels below 10 ug/dl. A threshold value below which lead has no apparent adverse developmental effect has not been identified (Bellinger 2004). It is widely accepted that no safe level of lead has yet been established (WHO 1995, Wigle and Lanphear 2005). This is a summary from a review of scientific literature on the association between low blood lead levels (<10 ug/dl) and: 1) overall cognitive function 2) ADHD 3) anti-social behavior and 4) other neuro-behavioral effects in children. The researcher selected relevant studies from a PubMed search of articles from 1994 to The studies included were evaluated on criteria based on methodological design, control of co-variates and relevance to the study question. Of the 157 studies reviewed only 26 were included in the review. The majority of studies were prospective cohort studies, though well-designed cross-sectional case-control and one retrospective cohort were included. Most of these studies focused on children up to 72 months of age and used a variety of cognitive and behavioral assessment tools. Data Synthesis The results from the cohort studies provide sufficient evidence that the associations between BLL in children <72 months and cognitive outcomes are significant, consistent and robust, particularly among those with BLL between 5 and 10 ug/dl. Of the 9 cohort studies all the relationships with cognitive deficits were inversely associated and 8 were statistically significant after adjustment for confounder. In summary adverse outcomes, including reduced IQ and academic deficits are associated with BLL below 10 ug/dl; the association is not linear, the strongest effects noted at lower levels. Some studies suggest that the rate of decline in performance is greater at levels below 10 than above 10. (Lanphear 2000, 2005, Kordas 2006, Tellez-Rojo 2006, Hu 2006, Schnaas 2006). A large study of children from the National Health and Nutrition Examination Survey found that those in the highest quintile of BLL had more than 4 times the odds of having ADHD compared to the lowest quintile of BLL, even among those <5 ug/dl (Braun 2006). Cohort studies found associations with verbal intelligence (Walkowiak 1998), inability to sustain attention (Walkowiak 1998), deficits in reading (Lanphear

The current definition of an elevated blood lead level is 10 ug/dl, established in 1991 by the CDC.

2 2000) arithmetic (Lanphear 2000, Kordas), short-term memory (Lanphear 2000, Kordas), Peabody Picture Vocabulary Test (PPVT) (Kordas 2006), cognitive function (Solon 2008) and perceptual scores (Tubbs-Hait 2009). Conclusion Summary and Discussion The studies presented this systematic review indicate there is no threshold that can be considered a safe BLL The 1991 CDC 10 ug/dl BLL guideline was intended to serve as a risk guidance and management tool at the community level. It has been commonly and incorrectly been considered acceptable for the individual child (Bellinger 2004). Clinicians should aim to reduce BLL even when they are below 10 ug/dl. The clinically acceptable level should be any detectable amount. At this time, most laboratories are able to detect BLL as low as 2 ug/dl. Noted points of summary: Because lead is ubiquitous in our environment it is difficult to find compare unexposed controls for those exposed to low levels of lead. Although the exposure is lower than it was in the past, virtually no one is unexposed. The mechanism that would generate a log-linear/supralinear relationship is unknown, but presumably involves a lead-sensitive pathway that is rapidly saturated at BLL <10 and other, less rapidly saturated pathways at BLL>10. Non-linear relationships are, however, common in toxicology. (Bellinger 2008) Adverse outcomes, such as reduced IQ and academic deficits occur <10. Some studies suggest that the rate of decline in performance is greater at levels below 10 than above 10. (Lanphear 2000, 2005, Kordas 2006, Tellez-Rojo 20006, Hu 2006, Schnaas 200) Increased exposure is also associated with neuropsychiatric disorders such as ADHD and antisocial behavior. A political debate has formed over the question of whether or not to lower the blood lead level considered as elevated by the CDC (Ferber 2002, Gilbert and Weiss 2006, Juberg 1997). The 1991 CDC 10 ug/dl BLL guideline was intended to serve as a risk guidance and management tool at the community level. It has been commonly and incorrectly been considered acceptable for the individual child (Bellinger 2004). However, some clinicians have continued to aim to reduce BLL even when they are already below 10 ug/dl.

Conclusion Summary and Discussion The studies presented this systematic review indicate there is no threshold that can be considered a safe BLL The 1991 CDC 10 ug/dl BLL guideline was intended to

3 References: Bellinger DC. Lead. Pediatrics Apr;113(4 Suppl): Bellinger DC. Very low lead exposures and children's neurodevelopment. Curr Opin Pediatr Apr;20(2): Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP. Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect Dec;114(12): Canfield RL, Henderson CR Jr, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. Intellectual impairment in children with blood lead concentrations below 10 mcg per deciliter. N Engl J Med Apr 17;348(16): Chandramouli K, Steer CD, Ellis M, Emond AM. Effects of early childhood lead exposure on academic performance and behaviour of school age children. Arch Dis Child Nov;94(11): Ferber D. Toxicology. Overhaul of CDC panel revives lead safety debate. Science Oct 25;298(5594):732. Gilbert SG, Weiss B. A rationale for lowering the blood lead action level from 10 to 2 microg/dl. Neurotoxicology Sep;27(5): Hu H, Téllez-Rojo MM, Bellinger D, Smith D, Ettinger AS, Lamadrid-Figueroa H, Schwartz J, Schnaas L, Mercado-García A, Hernández-Avila M. Fetal lead exposure at each stage of pregnancy as a predictor of infant mental development. Environ Health Perspect Nov;114(11): Hubbs-Tait L, Mulugeta A, Bogale A, Kennedy TS, Baker ER, Stoecker BJ. Main and interaction effects of iron, zinc, lead, and parenting on children's cognitive outcomes. Dev Neuropsychol. 2009;34(2): Juberg DR, Kleiman CF, Kwon SC. Position paper of the American Council on Science and Health: lead and human health. Ecotoxicol Environ Saf Dec;38(3): Jusko TA, Henderson CR, Lanphear BP, Cory-Slechta DA, Parsons PJ, Canfield RL. Blood lead concentrations < 10 microg/dl and child intelligence at 6 years of age. Environ Health Perspect Feb;116(2): Kordas K, Canfield RL, López P, Rosado JL, Vargas GG, Cebrián ME, Rico JA, Ronquillo D, Stoltzfus RJ. Deficits in cognitive function and achievement in Mexican firstgraders with low blood lead concentrations. Environ Res Mar;100(3): Lanphear BP, Dietrich K, Auinger P, Cox C. Cognitive deficits associated with blood lead concentrations <10 microg/dl in US children and adolescents. Public Health Rep Nov-Dec;115(6):521-9.

2006 Dec;114(12):1904-9. Canfield RL, Henderson CR Jr, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. Intellectual impairment in children with blood lead concentrations below 10 mcg per deciliter.

4 Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, Canfield RL, Dietrich KN, Bornschein R, Greene T, Rothenberg SJ, Needleman HL, Schnaas L, Wasserman G, Graziano J, Roberts R. Low-level environmental lead exposure and children's intellectual function: an international pooled analysis. Environ Health Perspect Jul;113(7): Schnaas L, Rothenberg SJ, Flores MF, Martinez S, Hernandez C, Osorio E, Velasco SR, Perroni E. Reduced intellectual development in children with prenatal lead exposure. Environ Health Perspect May;114(5): Surkan PJ, Zhang A, Trachtenberg F, Daniel DB, McKinlay S, Bellinger DC. Neuropsychological function in children with blood lead levels <10 microg/dl. Neurotoxicology Nov;28(6):

Schnaas L, Rothenberg SJ, Flores MF, Martinez S, Hernandez C, Osorio E, Velasco SR, Perroni E. Reduced intellectual development in children with prenatal lead exposure.

5 Figure 1. Flow diagram of article inclusion and exclusion for review. PubMed Search: 157 Included for full text review: 51 Excluded based on abstract review: 106 * Review/Comment/News (39) * Age >72 months (14) * Study of other subject (12) * High BLL (12) * Methodological issues (8) * Prenatal BLL only (5) * No cognitive outcome (5) * No BLL (3) * Not able to separate low BLL effects (2) * Non-English Language (2) Added from reference lists: 2 Included in systematic review: 26 Excluded based on full text review: 27 * High BLL (11) * Methodological issues (6) * Review/Comment/News (4) * Not able to separate low BLL effects (3) * No cognitive outcome (1) * Study of other subject (1) * Age >72 months (1)

BLL (12) * Methodological issues (8) * Prenatal BLL only (5) * No cognitive outcome (5) * No BLL (3) * Not able to separate low BLL effects (2) * Non-English Language (2) Added

Prevention Paradox. Why a Little Lead is Too Much

Prevention Paradox. Why a Little Lead is Too Much Prevention Paradox Why a Little Lead is Too Much Bruce Lanphear, MD, MPH Child & Family Research Institute, BC Children s Hospital Faculty of Health Sciences Simon Fraser University Binder S, Falk H. Strategic