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Cincinnati Children’s Environmental Health Center (2001-2006) Research Projects

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December 2006
Project 1 | Project 2 | Project 3 | Project 4 | Project 5

Project 1: Neurobehavioral Effects of Prevalent Toxicants in Children        
The Center is conducting a longitudinal cohort study of about 400 children, followed from before birth to 3 years of age, to examine the effect of low-level exposures (pre and postnatal) to prevalent neurotoxicants.  Included in the assessment are neurobehavioral outcomes and specific development conditions, including behavioral problems such as conduct disorder, and features consistent with ADHD, cognitive deficits and hearing loss.  Also included in this project is a nested, randomized, controlled trial to test the efficacy of lead hazard controls on blood lead concentrations.

Epidemiologic and experimental data have established the adverse effects of numerous environmental toxicants, including lead, alcohol, mercury, PCBs and environmental tobacco smoke (ETS) on children’s brain function. In utero exposure to these toxicants has been linked with cognitive deficits and behavioral problems. Lead exposure has been linked to specific behavioral problems, including conduct disorder and delinquency, mental retardation and ADHD-like behavior. However, many studies linking environmental toxicants with neurobehavioral effects have only examined children with high exposures. There is emerging evidence that adverse effect of exposure to lead, mercury, and PCBs occur at levels previously thought to be low. There is also data linking exposures to pesticides with adverse neurobehavioral effects, but the data are too sparse to draw any conclusions.

The ideal biomarkers for measuring in utero exposure to specific toxicants have not been established. Fetal exposure is typically measured with surveys, maternal blood, urine, or hair. Meconium, a longer-term measure of in utero exposure, has only been validated as a measure of cocaine and ETS exposure, but it offers numerous advantages. It is a non-invasive method that may be useful to simultaneously test for exposure to numerous toxicants. Still, it is unclear whether conventional biomarkers or meconium is more predictive of the adverse effects associated with specific toxicants.

The hypotheses for this project include:  (1)  In utero exposures measured by survey (alcohol and ETS), maternal and cord blood (lead and mercury), maternal and cord serum (ETS), and urine (pesticides) are less predictive of in utero effects of prevalent toxicants, including cognition, behavior problems, and growth and hearing compared with the same toxicants in meconium.  (2)  Prenatal and postnatal exposures to prevalent pesticides and ETS are associated with adverse neurobehavioral effects, growth delay, and hearing loss in children.  (3)  Children in the Lead Hazard Reduction Group will have blood lead concentrations that are 2.7 mg / dL (30%) or lower at 36 months of age, significantly higher cognitive scores, less hearing loss, greater growth velocity, and fewer behavioral problems and developmental disorders compared with those in the Control group. 

The hypotheses of this study are: (1) Children in the Lead Reduction Group are expected to have blood lead levels that are 2.7 μg/dL or lower, significantly higher cognitive scores, less hearing loss and fewer behavioral problems than those in the Control group at 36 months of age. (2) Fetal and postnatal exposures to pesticides, ETS (environmental tobacco smoke) and lead (at blood levels below 10μg/dL) are associated with adverse neurobehavioral effects, growth delay and hearing loss in early childhood.  (3) Fetal exposures to ETS (measured by survey), exposures to lead, methyl mercury, pesticides and ETS (measured by maternal and cord blood) and pesticide exposures (measured by urine samples) are less predictive of the adverse effects of toxicants on cognition, behavioral problems and hearing, compared with the same toxicants in meconium.

This project, in combination with other research, is testing the efficacy of an intervention for the primary prevention of lead toxicity, as measured by blood lead concentration and neurobehavioral functioning at 36 months of age. This project was also planned to serve as a model to evaluate the adverse effects of exposures to multiple prevalent environmental toxicants among fetuses and children, to test meconium levels as a biomarker of fetal exposure to such toxicants, and provide exposure and risk assessment data for residential pesticide exposure.
This study is also the first to attempt to validate meconium as a measure of exposure to numerous neurotoxicants and to test the efficacy of a lead hazard control on blood lead concentration and neurobehavioral functioning. This cohort study has simultaneously evaluated the adverse effects of exposures to multiple prevalent toxicants in the human population during early childhood and validate the use of meconium as a measure of in utero exposures to multiple environmental neurotoxins.

Project 2:  Validation of Meconium Markers of Fetal Neurotoxicant Exposures

Investigator: Cynthia F. Bearer, MD, PhD

Environmental toxicants have been implicated in a number of
developmental disorders. Unfortunately, the health effects subscribed to these exposures occur long after the actual exposure. For fetuses, exposure estimates are particularly difficult to quantify due to the problem of obtaining tissue for analysis. 
Validated biological markers for low to moderate exposure to environmental toxicants, as well as biological markers for adverse neurodevelopmental effects of these exposures, would allow earlier identification and intervention for affected infants, allow recognition of women at risk for exposure, and facilitate research on dose-response relationships between environmental exposures to mixtures of toxicants and to other known developmental neurotoxicants (ethanol and nicotine) and neurodevelopmental outcome. 

Meconium, the first stool passed by a newborn, has been used to establish exposure to drugs of abuse. The presence of environmental toxicants in meconium has been reported. Research in the Cincinnati Children’s Center laboratory has shown a significant association between maternal self-reported low to moderate levels of drinking during pregnancy and the presence of metabolites of ethanol in their infants’ meconium. 

Infants whose meconium contained more metabolites than that found in meconium of infants from abstaining women performed more poorly on the Bayley Scales of Infant Development.  Cincinnati researchers have proposed that environmental toxicants as well as nicotine and ethanol metabolites in meconium are useful biological markers for exposure to developmental neurotoxicants and may indicate infants at risk for poor neurodevelopment. 

Characterization of the quantity of each toxicant in meconium and the neurodevelopmental outcome of the infant is clearly relevant to validating meconium as a biological marker.   Objectives include testing the hypothesis that meconium samples can be used for simultaneous analysis of several different environmental toxicants, and that an association exists between the presence of environmental toxicants in meconium and maternal / infant / environmental measures of toxicant exposure.

A technique was developed to quantitatively analyze cotinine, lead, methyl mercury, organophosphate metabolites, pyrethrins, and ethanol metabolites in a single sample of meconium. Concentrations of toxicants and their metabolites in meconium will be compared to maternal and infant measures to determine the relationship between these markers and meconium markers.

These studies have provided preliminary data on the feasibility and utility of meconium analysis to gauge the influence of environmental neurotoxicants on human fetuses (Bearer et al 1999).

Reference:  Bearer CF, Lee S, Salvator AE, Minnes S, Swick A, Yamashita T, Singer LT 1999. Ethyl linoleate in meconium: a biomarker for prenatal ethanol exposure. Alcohol Clin Exp Res 23:487-493.  

Project 3:  Community-Based Participatory Research Project: Identifying Residential Hazards Using Home Test Kits
Investigator: Sandy Roda, BA


Numerous environmental agents have been linked to adverse neurobehavioral effects in children. Unfortunately, it is costly and difficult for families to determine if their home environment is safe for young children. This is a major concern for agencies such as the Better Housing League, whose mission is to make safe housing available to low-income families. 

The purpose of this project is to help families and communities identify and reduce health risks from lead, pesticides, and ultimately, other environmental hazards. Researchers at the Cincinnati Children’s Center have partnered with the Better Housing League in Cincinnati and nationally with the Alliance to End Childhood Lead Poisoning and the National Center for Healthy Housing. An aim of this project is to test tools for families to assess levels of contaminants in their home environment, This aim will strengthen right-to-know laws by providing families with tools to assess environmental contamination in their own homes. The second aim is to increase community awareness of the role of environmental agents in developmental disorders, hearing loss and school problems. Hypotheses include:

(1)  The predictive validity of home sampling kits to identify children who have blood lead concentration > 10 mg/dL collected by families is not significantly different than repeat samples taken by trained, community workers.   (2)  The group receiving video instruction about use of the home sampling kit will have environmental lead levels more consistent with trained workers than those in the group receiving written instructions only.

The project provided tools for families and communities to identify environmental neurotoxins and disseminate information by establishing the Healthy Home Resource Center at the Better Housing League. The results of this project are expected to stimulate community - wide prevention efforts and exposure assessment by participants in population-based studies.

Project 4:  Early Exposure to Lead and Adult Antisocial Outcome

Investigator: M. Douglas Ris, PhD

Lead exposure and antisocial behavior are both major public health concerns. Recent research indicates that early exposure to environmental lead is associated with increased risk for delinquency. However, there is, as yet, no scientific evidence to indicate whether or not this increased risk extends into adulthood. There is no clear understanding of what neurobehavioral factors mediate the relationship between lead and antisocial behavior. Cincinnati Children’s Center researchers are assessing the adult outcome of 280 participants in the Cincinnati Lead Study; a birth cohort whose development and exposure history have been exquisitely tracked for over 20 years. 

Hypotheses include:  (1)  There will be a significant relationship between pre-and post-natal lead levels and criminal activities measured by official criminal record and self-report.  (2)  There will be a significant relationship between pre- and post-natal lead levels and diagnosis of Substance Use Disorder.  (3) There will be a significant relationship between pre- and post-natal lead levels and diagnosis of Antisocial Personality Disorder.

Outcome is being measured in three ways to ensure accuracy and comprehensiveness. First, to assess criminal activities, official records were accessed through county agencies and the National Crime Information Center. Second, to diagnose antisocial personality disorder and substance use disorder, a structured psychiatric interview will be performed. Third, self report measures will be used, including the self-report of delinquent behavior to measure various law and norm violating behaviors. Neuropsychological measurements undertaken on the sample in late adolescence will be used to explore neurobehavioral mediating factors. Self-regulatory / executive abilities and academic skills are at risk in both the delinquent and lead exposed youth, leading us to propose these as critical mediational pathways. 

A better understanding of the remote behavioral effects of early lead exposure has allowed the Center to develop primary prevention methods
(environmental, cognitive and educational) to alter the developmental trajectories of large numbers of lead-exposed youths.

Project 5: Magnetic Resonance Assessment of Brain Function Altered by Lead Exposure

Investigator: Kim M. Cecil, PhD

Magnetic Resonance (MR) assessment of brain function altered by lead exposure seeks to relate environmental lead exposure with alterations in brain structure, neurochemistry and function assessed with magnetic resonance imaging (MRI) and spectroscopy (MRS). The population selected for study is the Cincinnati Lead Study (CLS); a unique cohort of about 240 subjects with detailed histories of exposure and behavioral outcomes in lead exposed children monitored for approximately 20 years. Historical and ongoing measures of behavior (Early Exposure to Lead and Adult Antisoclai Outcome) is integrated with this project to determine the significance of the imaging assessments. Childhood exposure to lead and specific outcomes of behavior in young adulthood are being compared, employing advanced brain imaging methodologies to test the following hypotheses:

  1. Childhood exposure to lead disrupts neuronal circuitry, resulting in changes in brain structure and metabolism as measured by MR.
  2. Delinquent behavior and anti-social outcomes (crime, violence, drug abuse, etc.) associated with childhood lead exposure correlate with differences in quantitative MR measures of brain structure and metabolism.

Structural and chemical findings should provide a neurobiological basis for improving our understanding of the in-vivo effects of lead exposure. Although the exposure level of this cohort is higher than contemporary exposures in the general community, the subjects are likely to demonstrate impaired brain function that will be relevant to inner-city, urban and lower levels of exposure. Ultimately, the development of these imaging tools in assessing environmental toxicant exposures and long-term effects could be applied to new cohorts to directly assess the impact of exposure on the developing brain.

The Cincinnati Children’s Center has utilized advanced in-vivo MR methods in approximately 150 subjects from the CLS to test these hypotheses according to the following specific aims:

  1. We are using localized proton MRS to measure brain metabolite concentrations of N-acetyl aspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) to determine if metabolite concentrations are related to levels of lead exposure and evaluate if metabolite concentrations are related to measures of anti-social outcome.
  2. We are using volumetric MRI to measure total brain volume, volumes of cortical gray matter, white matter and sub-structures within the basal ganglia to determine if structural volumes are related to levels of lead exposure and evaluate if structural volumes are related to measures of anti-social outcome.
  3. We are comparing the results of the MR measures with the cognitive, behavioral, and social assessments defined in Project 4 to determine the significance of individual and collective measures for assessing the brain-behavior relationships.

MR Spectroscopy performed in a population of lead-exposed individuals was used to attempt to identify regions of abnormal neuronal functioning (NAA declines), demyelination (elevated choline and lipids) and disturbances of astrocytic and other glial cells (increased myo-inositol). Researchers anticipated that young adults with a history of lead exposure would demonstrate lowered neuronal marker levels (NAA), particularly in the frontal lobe. The NAA concentration was expected to correlate with a composite measure of lead exposure level and duration. Anti-social outcomes were expected to also correlate with metabolite concentrations reflecting neuronal (NAA) and glial (mI, Cho) functioning. Reduction of volumes of the frontal lobe cortex and within the basal ganglia structures were expected to be related to lead exposure and anti-social outcomes.

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