The Voices of Yesterday’s Children: Lead Poisoning’s Lifetime Legacy Kim N. Dietrich Division of Epidemiology and Biostatistics Department of Environmental Health

Brain and the Environment Enormous increase in the number of children diagnosed with Autism Spectrum Disorder Enormous increase in the diagnosis of attention deficit hyperactivity disorder and its treatment with stimulants in the last two decades Speculation abounds regarding the role of environmental chemical exposures in these and other clinical trends.

The Cincinnati Lead Study (1979 – 2008)

Clark, et al. 1985, Environ Res

Age of Maximum Ingestion of Environmental Lead

The Age of Maximum Lead Ingestion and Early Cerebral Development Conel, J.L., 1959

The Cincinnati Lead Study Prospective, longitudinal study examined the early and late effects of childhood lead exposure on growth and development with a particular emphasis on central nervous system outcomes. Data collected on exposure (blood lead concentrations), neurobehavior, child health, environment, and sociodemographic variables on a quarterly to yearly basis since its inception.

Dietrich, et al. Neurotoxicol Teratol, 1991 Blood Lead Concentrations Birth to Four Years in the Cincinnati Lead Study CDC “Action Level” 1991 CDC “Action Level” 1985 CDC “Action Level” 1979

Blood Lead Assessment

Blood Lead Concentrations in the Cincinnati Lead Study Dietrich, et al., Pediatrics, 1993 Dietrich, et al. Pediatrics, CDC “Action Level” 1991 CDC “Action Level” 1985

In the Meantime…. ?

Concurrent Blood Lead (μg/dL) IQ Log-linear Restricted Cubic Spline N = 1,333 Pooled Analysis of International Prospective Studies Lanphear, et al., 2005

Lead-Associated Reading Deficits in U.S. Children: NHANES-III Blood Lead Levels ug/dL Reading Score N = 4,853 Lanphear, Dietrich, Auinger, & Cox., 2000

Adjusted Odds Ratio Quintiles of Blood Lead Concentration (ug/dL) Risk of ADHD by Blood Lead Levels in US Children, NHANES N = 4,704 Braun, et al. 2006

A Lead-Exposed Cohort’s Search for Answers Why can’t I hold onto a job? Why can’t I get along with my girl friend/wife? Why am I angry all of the time? Why can’t I concentrate? Why can’t my son/daughter stay out of trouble?

Blood Lead Concentration Profile of a CLS Male Subject with a History of Domestic Violence and Delinquent/Criminal Behavior Age in Months Blood Lead Concentration (ug/dL)

Blood Lead Concentration Profile of a CLS Male Subject with a History of Adult Criminal Behavior and Repeated Incarcerations Age in Months Blood Lead Concentration (ug/dL)

Adult Anti-Social Behavior as an Outcome of Childhood Lead Poisoning

Environmental Factors in Criminal Disposition Parental dysfunction Community violence Poverty Media Lead Nutrition Alcohol Illicit Drugs

Association of Blood Lead Levels and Self-Reported Delinquency in 16 Year-Old Adolescents in the Cincinnati Lead Study Dietrich, et al. Neurotoxicol Teratol. 2001

Average Number of Criminal Arrests in the Cincinnati Lead Study Cohort (M Age = 22 years) by Average Blood Lead Concentration and Gender (Unadjusted) Average Number of Arrests Blood Lead Level ug/dL N = 250 Wright, Dietrich, Ris et al. 2008

Covariates in Analyses of Adult Criminality Data Home Environment (HOME score) Birth Weight Gender Maternal Smoking During Pregnancy Maternal Drug/ETOH Use During Pregnancy Maternal Education Maternal IQ Total Prior Maternal Arrests Socioeconomic Status Household Size Public Assistance

Average Childhood Blood Lead Concentration and Arrest Rate Ratio for Violent Offenses* *Any 5 ug/dL elevation in blood lead increased the rate of arrests for violent offenses by 30 percent. Wright, Dietrich, Ris et al. 2008

Six-year Blood Lead Concentration and Arrest Rate Ratio for Violent Offenses* *Any 5 ug/dL elevation in blood lead increased the rate of arrests for violent offenses by 48 percent. Wright, Dietrich, Ris et al. 2008

Imaging Studies of the Cincinnati Lead Study Cohort: Volumetric and Functional Magnetic Resonance Imaging (MRI)

Cincinnati Volumetric MRI Lead Study (Cecil, et al. 2008) MRI scans were conducted on a subset of 157 young adult subjects from the Cincinnati Lead study during using whole brain, three dimensional, high resolution 1.5 Tesla magnetic resonance imaging (MRI) Associations between childhood blood lead levels and brain volume were investigated by multiple regression analysis on a voxel by voxel basis Maps of the strength of the adjusted lead-volume association were converted to color renderings and overlaid on a standard brain model

Composite rendering Renderings are maps of statistical association Composite rendering Voxel based morphometric approach involves normalizing individual structural scans to a standard template to allow voxel-by-voxel comparisons between subjects and regression analyses of associations with blood lead measures. Relationship of individual brain volume with mean four year childhood blood lead concentration within a medial frontal cluster. Cluster threshold is of 700 contiguous voxels and P <

Age 2 Blood Pb Map of strength of association between yearly blood lead level and population-wide loss of gray matter volume. Single-voxel minimum significance threshold is p < (uncorrected), found within a cluster of at least 700 voxels less significant more significant Single voxel significance Composite rendering

Age 3 Blood Pb Map of strength of association between yearly blood lead level and population-wide loss of gray matter volume. Single-voxel minimum significance threshold is p < (uncorrected), found within a cluster of at least 700 voxels less significant more significant Single voxel significance Composite rendering

Age 4 Blood Pb less significant more significant Map of strength of association between yearly blood lead level and population-wide loss of gray matter volume. Single-voxel minimum significance threshold is p < (uncorrected), found within a cluster of at least 700 voxels Single voxel significance Composite rendering

Age 5 Blood Pb Map of strength of association between yearly blood lead level and population-wide loss of gray matter volume. Single-voxel minimum significance threshold is p < (uncorrected), found within a cluster of at least 700 voxels less significant more significant Single voxel significance Composite rendering

Age 6 Blood Pb Map of strength of association between yearly blood lead level and population-wide loss of gray matter volume. Single-voxel minimum significance threshold is p < (uncorrected), found within a cluster of at least 700 voxels less significant more significant Single voxel significance Composite rendering

Voices of Yesterday’s Children Clip 1 Clip 2 Clip 3 Clip 4

The Cincinnati Lead Study (1979 – 2008)

Collaborators Kim M. Cecil (CCHMC) M. Douglas Ris (CCHMC) Richard Hornung (CCHMC, UC DEH) Bruce P. Lanphear (CCHMC, UC DEH) John P. Wright (UC Criminal Justice) Mona Ho (CCHMC) Stephanie Wessel (UC DEH) Caleb Adler (UC Psychiatry) Kelly Jarvis (UC Psychiatry) Mekibib Altaye (CCHMC) John C. Egelhoff (UC Radiology) Ilayaraja Elangovan (UC Radiology) Christopher Brubaker (UCCM MD/PhD Program) Mary N. Rae (UC DEH) Subjects and Families of the Cincinnati Lead Study

Acknowledgement

Can neurodevelopmental deficits in cognition and behavior be minimized or reversed?

TLC Goal TLC was designed to test the hypothesis that children with moderate blood lead levels who were given succimer would have better scores than children given placebo on measures of central nervous system function.

Succimer COOH H - C - SH COOH

Normalized Effect of Succimer at 7 Years Dietrich, Ware, Salganik, et al., Pediatrics, 2004

Other Remedies Although there is not specific literature supporting the use of enrichment programs in lead-poisoned children, programs aimed at children with delay from another cause should be effective in lead-poisoned children.