Transcript The Cincinnati Lead Study - Ohio Healthy Homes Network

The Cincinnati Lead Studies:
A 36 Year Perspective
Ohio Healthy Homes Network Spring Forum
Thursday, June 9, 2016
Kim N. Dietrich, Ph.D., M.A.
Professor of Epidemiology
The University of Cincinnati College of Medicine
Lead (Pb) and Health: The Flint,
Michigan ‘Crisis’
(2014-2015)
The Cincinnati Lead Study
(1979 – 2016)
The Cincinnati Lead Study
(1979-2016)
The Cincinnati Lead Study
(1979-2016)
• 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.
• Longest, continuously active prospective study of lead
exposure and child health and development in the world.
• Data collected on exposure (blood lead concentrations),
neurobehavior, child health, nutrition, environmental nurture,
and sociodemographic variables on a quarterly to yearly basis
since its inception.
Why Lead and the Developing Brain?
Pyramidal Cells
The human brain has a protracted period of development and potential vulnerability to environmental toxicants such as
lead. The human cerebral cortex eventually consists of 30 billion neurons, interconnected by 64,000 miles of axons
and dendrites and more than a trillion supportive neuroglia. Lead is known to interfere with this developmental process
In the womb and over at least the first five years of life.
Cincinnati Lead Study:
Blood Lead Assessment
Blood Lead Concentrations in the Cincinnati Lead Study
CDC “Action Level” 1979
CDC “Action Level” 1985
CDC “Action Level” 1991
CDC “Reference Level”
2012
Dietrich, et al. Pediatrics, 1993.
Dietrich, et al., Pediatrics, 1993
Cincinnati Lead Study Findings
(1979-2016)
Early Exposure to Lead and Child IQ
N = 1,333
Low-Level Environmental Lead
Exposure and Children’s Intellectual
Function: An International Pooled
Analysis
Bruce P. Lanphear,1,2 Richard Hornung,1,2,3 Jane Khoury,1,2 Kimberly Yolton,1
Peter Baghurst,4 David C. Bellinger,5 Richard L. Canfield,6 Kim N. Dietrich,1,2
Robert Bornschein,2 Tom Greene,7 Stephen J. Rothenberg,8,9 Herbert L.
Needleman,10 Lourdes Schnaas,11 Gail Wasserman,12 Joseph Graziano,13 and
Russell Roberts14
Beyond IQ
Adolescent and Adult Anti-Social
Behavior as an Outcome of
Childhood Lead Poisoning
Association of Blood Lead Levels and Self-Reported
Delinquency in 16 Year-Old Adolescents in the
Cincinnati Lead Study
9
Dietrich, et al. Neurotoxicol Teratol. 2001
Prenatal PbB
8
Average Childhood PbB
Total Score
7
78 Month PbB
6
5
4
3
2
1
0
Lowest
Low
Medium
Blood Lead Level
High
Questions from a Lead Study
Cohort
• 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 (ug/dL)
Blood Lead Concentration Profile of a 26 Year-Old 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 26 Year-Old CLS
Male Subject with a History of Adult Criminal Behavior
and Repeated Incarcerations
Age in Months
Lead’s Effects across the
Lifespan
Does Early Exposure to Pb Leave a LongTerm Signature in the Brains and
Behaviors of Adults?
The Cincinnati Lead Study (1979-2016)
• Neuroimaging studies
• Criminality studies
Environmental Factors in Criminal
Disposition
•
•
•
•
•
•
•
•
Parental dysfunction
Community violence
Poverty
Media
Lead
Nutrition
Alcohol
Illicit Drugs
Cincinnati, 1956
Covariates in Analyses of Adult
Criminality Data
•
•
•
•
•
•
•
•
•
•
•
•
Home Environment (HOME score)
Birth Weight
Gender
Age
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 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
8
Wright, Dietrich, Ris et al. 2008
7
Females
6
N = 250
Males
5
4
3
2
1
0
Lowest
Low
Medium
Blood Lead Level ug/dL
High
Blood Lead Concentrations to Six Years and Arrest Rate Ratio for
Violent Offenses*
Arrest Rate Ratio for Violent Crimes
7
Wright, Dietrich, Ris et al. 2008
6
5
4
3
2
1
0
3
6
9
12
15
18
Six Year Blood Lead (ug/dL)
*Any 5 ug/dL elevation in blood lead increased the rate of arrests for
violent offenses by 48 percent.
Early Exposure to Lead and Career Criminality
Imaging Studies of the Cincinnati Lead Study
Cohort: Volumetric and Functional MRI, MRS,
and Diffusion Tensor Imaging
Covariates in Analyses of CLS
Adult MRI Data
•
•
•
•
•
•
•
•
•
•
•
•
Home Environment (HOME score)
Birth Weight
Gender
Maternal Smoking During Pregnancy
Maternal Drug/ETOH Use During Pregnancy
Maternal Education
Maternal IQ
Socioeconomic Status
Household Size
Public Assistance
Age at time of imaging
Positive drug screen
Cincinnati Neuroradiological Studies
of Childhood Lead Exposure and Adult Brain
Outcomes
• fMRI – dose-dependent reductions in brain activation in
the traditional language areas (Yuan et al. 2006).
• HR Anatomical MRI – dose-dependent reductions in
cortical gray matter in the frontal lobe (Cecil et al. 2008).
• DT MRI – dose dependent injury to both myelin and
axonal structures (Brubaker et al. 2008).
• Proton MRS – dose-dependent reduction in gray matter
NAA along with white matter choline declines (Cecil et al.
2011).
Adult Cortical Gray Matter Loss in Cincinnati Lead Study Subjects in
Relationship to Postnatal Lead Exposure to Six Years
Composite
rendering
Single
voxel
significance
more significant
less significant
Cecil K.M., Brubaker C.J., Adler C.M., Dietrich K.N., et al. (2008). Decreased brain volume in adults with
childhood lead exposure. PLoS Medicine, 5m 741-750.
The Cincinnati Lead Study
(1979-2016)
New Investigations into the 21st Century
‘Early Exposure to Lead and Bone Health in African-American
Women’
Bone Health in African-American Women
Exposed to Lead as Children
(Bhattacharya, Dietrich, Chettle, & Kalkwarf)
K-Shell XRF
Treatment of Lead-Exposed Children (TLC)
Clinical Trial
(First and Only Controlled Clinical Trial of a Drug to
Reduce Lead Body Burden and Neurodevelopmental
Impact in Children)
CDC Policy at TLC Start
Blood lead
level ( µg/dL)
Actions
Time frame for
beginning
intervention
10-14
Provide caregiver lead education.
Provide follow-up testing. Refer the child
for social services if necessary.
Within 30 days
15-19
Above actions, plus:
If BLLs persist (i.e., 2 venous BLLs in
this range at least 3 months apart) or
increase, proceed according to actions
for BLLs 20-44.
Within 2 weeks
20-44
Above actions, plus:
Provide coordination of care (case
management).
Provide clinical evaluation and care.
Provide environmental investigation
and control current
lead hazards.
Within 1 week
45-70
Above actions and chelation therapy.
Within 48 hours
70 or higher
Above actions, plus hospitalize child for
chelation therapy immediately.
Within 24 hours
Succimer
COOH
H - C - SH
H - C - SH
COOH
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.
TLC
Eligibility
•At referral
–12-33 months old at
randomization
–referral blood lead 2044 ug/dL
–no disqualifying
medical condition
Succimer and Placebo
• 26-day course of therapy to
provide 1050 mg/m2 of body
surface area per day for the
first seven days, 700 mg/m2
day thereafter.
• Up to three courses of
treatment to achieve PbB <
15 ug/dL.
• Placebo subjects were
assigned retreatment to
match the frequency of
retreatment in the Succimer
group.
TLC Mean Blood Lead Concentrations Over
Time at Baseline & By Weeks After Treatment
By Treatment Group 1994-1997
TLC Neuropsychological Domains
• Cognition, Learning, Memory, and Attention
• Academic Achievement
• Behavioral Conduct
• Neuromotor Performance
Unadjusted Effects of Treatment
at Age 7 Years
Variable
Succimer
(323)
Mean SD
Placebo
(319)
Mean SD p-value
Full-Scale IQ
86.9 13.2
86.6 13.5 0.77
Reading
94.8 18.4
93.8 18.4 0.47
Externalizing
Problems
58.9 16.5
57.3 14.2 0.18
Executive
Functions
86.6 16.5
88.5 17.7 0.20
Dietrich, Ware, Salganik, et al., Pediatrics, 2004
qu
Se
en
en
ts
n
Ti
m
e
e
im
e
Ti
m
Pr
Sl
op
e
y
or
em
0.0
0.2
-0.2
0.0
0.2
Normalized effect of succimer
-0.2
Normalized effect of succimer
(a)
ov
em
M
d
ng
M
ct
io
ni
ar
st
A
ea
R
Le
it
H
st
A
tia
l
Li
Li
n/
Ex Fu
llec
Sc
ut
al
iv
e
e
I
F
Ex
Ad
un Q
te
a
ct
pt
rn
io
iv
al
ns
e
iz
R
Sk
in
e
a
g
d
Pr ills
Sc
(T ing
o
ea
Ex hoo ble
m
ch
lP
te
s
rn
er
ro
(T
al
b
ea )
iz
l
e
in
m
ch
g
er
Pr s (T
ob
ea )
le
m che
s
(P r)
ar
en
t)
io
At
te
nt
Normalized Effect of Succimer
at 7 Years
(b)
Dietrich, Ware, Salganik, et al., Pediatrics, 2004
TLC Summary
• Chelation therapy is ineffective in reversing or
minimizing adverse neurobehavioral
consequences of childhood lead exposure in
the range of 20-44 ug/dL.
• The only way to avoid lead-associated
neurodevelopmental morbidity is to prevent
exposure in the first place.
Funding for This Research
Recent Collaborators
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Kim M. Cecil (CCHMC)
M. Douglas Ris (formerly CCHMC)
Richard Hornung (CCHMC, UC DEH)
Bruce P. Lanphear (CCHMC, UC DEH)
John P. Wright (UC Criminal Justice)
Sandra Roda (UC DEH)
Mona Ho (CCHMC)
Stephanie Wessel (UC DEH)
Lisa Tully (CCHMC)
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)
Aimin Chen (UC DEH)
Amit Bhattacharya (UC DEH)
Cyndy Cox (UC DEH)
Lorenna Altman (UC DEH)
Subjects and Families of the Cincinnati Lead Studies
Copies of Research Reports
([email protected])
All of the studies reviewed today on the fetus, infant and child exposed
to lead in Cincinnati and elsewhere have been published in major
peer-reviewed medical journals.
I would be happy to provide copies of these upon request.
Questions and Discussion