The Voices of Yesterday’s Children: Lead Poisoning’s

Lifetime Legacy

Kim N. DietrichDivision 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, 1993Dietrich, et al. Pediatrics, 1993.

CDC “Action Level” 1991

CDC “Action Level” 1985

In the Meantime….

?

Concurrent Blood Lead (μg/dL)

IQ

85

90

95

100

105

0 5 10 15 20 25 30 35 40 45 50

Log-linear

Restricted Cubic Spline

N = 1,333

Pooled Analysis of International Prospective StudiesLanphear, et al., 2005

Lead-Associated Reading Deficits

in U.S. Children: NHANES-III

75

80

85

90

95

100

105

<2.5 2.5 5 7.5 10

Blood Lead Levels ug/dL

Rea

din

g S

core

N = 4,853

Lanphear, Dietrich, Auinger, & Cox., 2000

0

1

2

3

4

5

<0.79 0.8 to 1.09 1.1 to 1.49 1.5 to 1.9 >2.0

Ad

just

ed

Odd

s R

atio

Quintiles of Blood Lead Concentration (ug/dL)

Risk of ADHD by Blood Lead Levels in US Children, NHANES 1999-2002

N = 4,704Braun, 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

Blo

od

Lea

d C

on

cen

trat

ion

(u

g/d

L)

Blood Lead Concentration Profile of a CLS Male Subject with a History of Adult Criminal Behavior and Repeated

Incarcerations

Age in Months

Blo

od

Lea

d C

on

cen

trat

ion

(u

g/d

L)

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

0

1

2

3

4

5

6

7

8

9

Lowest Low Medium High

Blood Lead Level

To

tal S

core

Prenatal PbB

Average Childhood PbB

78 Month PbB

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)

0

1

2

3

4

5

6

7

8

Lowest Low Medium High

Females

Males

Ave

rag

e N

um

ber

of

Arr

ests

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*

0

1

2

3

4

5

6

7

6 10 14 18 22 26 30

Average Childhood Blood Lead (ug/dL)

Arr

es

t R

ate

Ra

tio

fo

r V

iole

nt

Cri

me

s

*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 violentoffenses by 48 percent.

0

1

2

3

4

5

6

7

3 6 9 12 15 18

Six Year Blood Lead (ug/dL)

Arr

est

Rat

e R

atio

fo

r V

iole

nt

Cri

mes 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 2002-04 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 standardtemplate 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 andP < 0.001.

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 < 0.001 (uncorrected), found within a cluster of at least 700 voxels

less significant

more significant

Single voxelsignificance

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 < 0.001 (uncorrected), found within a cluster of at least 700 voxels

less significant

more significant

Single voxelsignificance

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 < 0.001 (uncorrected), found within a cluster of at least 700 voxels

Single voxelsignificance

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 < 0.001 (uncorrected), found within a cluster of at least 700 voxels

less significant

more significant

Single voxelsignificance

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 < 0.001 (uncorrected), found within a cluster of at least 700 voxels

less significant

more significant

Single voxelsignificance

Composite rendering

Voices of Yesterday’s Children

Clip 1

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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

H - C - SH

COOH

-0.2

0.0

0.2

(a)

Nor

mal

ized

effe

ct o

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Full-S

cale

IQ

Attent

ion/

Execu

tive

Functi

ons

Readi

ng

Adapt

ive S

kills

(Tea

cher

)

Extern

alizi

ng P

robl

ems (

Teac

her)

Schoo

l Pro

blem

s (Te

ache

r)

Extern

alizi

ng P

robl

ems (

Paren

t)

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ory

List

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Tim

e

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Normalized Effect of Succimer at 7 Years

Dietrich, Ware, Salganik, et al., Pediatrics, 2004

Other RemediesAlthough there is not specific literature supporting theuse of enrichment programs in lead-poisoned children,programs aimed at children with delay from anothercause should be effective in lead-poisoned children.