Dr. Campbell reconvened the ACClPP meeting at 8:40 a.m. on October 20,2004 and
yielded the floor to the first presenter. Dr. Walter Rogan is ACClPP's ex officio member
for NIH/National Institute of Environmental Health Sciences (NIEHS). He provided an
overview of the TlC Trial. The study is a formal clinical trial to evaluate the use of
succimer as an oral chelating drug in preventing or reducing lead-associated cognitive,
behavioral and neuropsychological deficits in toddlers. Nationally representative
prevalence data of 16.4 million U.S. homes were reviewed to determine the number of
homes and percentage of children ~6 years of age with a lead hazard based on age of
home. The number of homes built in the time periods of pre-1940, 1940-1959, 1960
1977 and 1978-1998 ranged from <58,000--2 million. Of these homes, the percentage
of lead hazards was estimated to range from <1 %-81 %. Of homes in which children ~6years of age resided, 25% had lead hazards in 2000.
 μg/dL
In 1976, the mean Bll was 15 μg/dL among U.S. children 1-6 years of age, the
prevalence of Blls >10 μg/dL was 88%, and 13.5 million children had Blls >10 μg/dL.
Significant progress has been made since that time as evidenced by nationally
representative prevalence data. In 1999-2000, the mean Bll was 2.2 μg/dL, the
prevalence of Blls >10 μg/dL was 2%, and <500,000 million children had Blls >10
μg/dL. In 1991 , the broad scientific consensus was that cognitive impairment followed
lead exposure at low levels and blood lead at two years of age was associated with
deficits beginning at four years of age and continuing thereafter. Data showed that
Blls at birth were not associated with defects and 10 in children five years of age.
Blls at two years of age begin to be associated with full-scale 10 at five years of age.
The postnatal mean was strongly influenced by the peak Bll and associated with 10 at
five years of age. The overall size of the effect was -3 10 points per 10 jJg/dl of blood
lead, particularly in Blls 10-20 μg/dL.

CDC redefined "lead poisoning" in 1991 as Blls ~10 jJg/dl and also recommended
universal screening. Because the published guidance created thousands of new cases,
several agencies were concerned that children would be given succimer inappropriately.
The drug is orally administered and only licensed for children with Blls >45 jJg/dl, but
can be given in an outpatient setting in a controlled lead-safe environment. Succimer is
a white crystalline powder that is extremely difficult to administer to children due to the
large size and unpleasant odor and taste of the capsule.

NIEHS and a drug manufacturer sponsored TlC to demonstrate that oral administration
of succimer would lower Blls. TlC is a mufti-center, randomized, placebo-controlled
and double-blind clinical trial of succimer among 780 children for the prevention of lead
induced cognitive and neuropsychological impairment, growth retardation and behavior
disorders in toddlers. All children in TlC received vitamin and mineral supplementation
and home cleanup for lead dust suppression.

TlC sites included Baltimore, Cincinnati, Newark and Philadelphia because these cities
represented large volumes of pediatric lead poisoning cases. The cohort was 12-33months 
of age at randomization with referral Blls of 20-44 μg/dl and no disqualifying
medical conditions. During the pre-treatment phase, field investigators drew two Blls
that were confirmed by CDC to be between 20-44 μg/dl; obtained consent; distributed
vitamins and minerals; and conducted an evaluation to determine whether the house
could be cleaned according to the TlC protocol. Of the succimer group in 1994, 55%
were male, 5% had Spanish speaking parents, 76% were black, 72% had parents
without partners, 41 % had parents with less than a high school education, and 96%
were on public assistance.

The randomized subjects were 24 months of age with a mean Bll of 26 μg/dl, mean
birth weight of 3.1 kg, a Bayley Mental Developmental Index of 84 and parental 10 of81. 
The baseline characteristics were comparable to the placebo group. The succimer
group had a Bll that was 0.5 μg/dl higher than the placebo group at baseline, but this
difference was statistically indistinguishable. Blls of the succimer group decreased to
a mean of 13 μg/dl after one week of receiving the drug compared to the mean Bll of 23 μg/dl of the placebo group.
 However, Blls of the succimer group increased at week 20 as lead mobilized from bone. 
 Of children who received the first round of succimer, 80% did not have Blls <15 μg/dl on day 43 of TlC.

At 36 months of follow-up, the TlC cohort was five years of age and was tested for full
scale 10, behavioral index as well as attention/executive and sensorimotor functions.
These functions measure the child's hand-to-eye coordination and ability to pay attention to a task, 
suppress the urge to answer prior to knowledge of a question, and answer immediately after hearing a question.
No differences were seen between the succimer and placebo groups for any of the tests.
The psychometric tests were not administered until 36 months of age because instruments
to measure brain function are unreliable and unstable in children ~3 years of age. 
The children were followed until school entry and sophisticated tests were performed 
to identify deficits in cognitive, attention/executive and sensorimotor functions.

The data showed an extremely small statistical difference in attention/executive function
of children seven years of age in the succi mer group. The findings also suggested that
the attention of the succimer group was a little better than the placebo group. However,
TlC did not produce evidence to demonstrate that succi mer is beneficial to children.
Treatment was not found to lead to better scores on cognitive, neuropsychological or
behavioral tests at 36 months of follow-up when the children were five years of age or
additional follow-up at seven and 7.5 years of age.

TlC did not generate data on the use of succimer, but 41% of families reported
difficulties in administering the drug. The succimer group was associated with
unexplained, excess trauma based on hospitalization, history and physical examination
data. Events reported in the succimer group included a near drowning, asthma attacks
and head injury from an iron. Succimer is an expensive drug that is taken for six
months and resulted in symptoms in children who were previously asymptomatic. The
findings do not support conducting another trial to determine if succimer would be
effective in children with Blls <45 μg/dL. The investigators reasonably inferred that the
prevention of lead exposure at the outset is the most effective approach to preventing
lead-associated defects.

ACCLPP suggested that the TlC investigators use animal models to identify expression
or repression of genes in response to lead, determine pathways and locate small
molecules to enhance repair. TlC data should be used to emphasize the importance of
improving the environment, particularly housing-based problems that cause lead
poisoning. Dr. Brown has learned from one state that Medicaid will not reimburse for
succimer if the child's Bll is 44 μg/dL or lower.