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U.S. Department of Health and Human Services

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Director: Merle G. Paule, Ph.D.

Introduction        NCTR Imaging Center      Current Research Projects


Fifty-million Americans have a permanent, neurological disability that limits their daily activities. One in three will experience some form of mental disorder during their lifetime. Annual health care, lost productivity, and other economic costs associated with brain-related diseases are estimated to exceed $500 billion. Disability from depression alone exceeds that of diabetes, hypertension, gastrointestinal, and lung diseases and costs over $43 billion annually. The number of persons with Alzheimer’s and other age-related neurological disorders will increase dramatically as our population ages. Known and suspected causes of brain-related disorders include exposures to chemicals, such as therapeutic drugs, food additives, food products, cosmetic ingredients, pesticides, and naturally occurring substances. Recent advances in technology are currently providing our scientists with a variety of new tools with which to better study and understand the etiology of brain-related disorders and the mechanisms associated with chemically induced neurotoxicity and to further reduce the risks associated with neurotoxic events.

The number of neuroactive chemicals that require FDA regulation is estimated to be in the thousands. Thus, identifying methods and approaches for assessing neurotoxicity is critical for the development of guidelines applicable for the assessment of neurotoxic risk. It is clear that chemicals that are known or suspected causes of brain-related disorders are vital to the national economy and our quality of life. Therefore, the challenge is to determine at what doses, or exposure levels, and under what conditions these compounds can be used effectively while minimizing the likelihood that they will cause adverse effects on the nervous system.

The overall goals of the Division of Neurotoxicology are to develop and validate quantitative biomarkers and identify biological pathways associated with the expression of neurotoxicity. Towards this end, specific research efforts address several focal areas of fundamental research designed to broadly examine the involvement of: 

  1. monoamine-neurotransmitter systems as targets for neurotoxicity
  2. mitochondrial dysfunction and oxidative stress as mechanisms of neurotoxicity
  3. NMDA (N-methyl-D-aspartic acid) receptor complex as a mediator of adult and developmental neurotoxicity
  4. role of amyloid ß-peptide (Aß) aggregation in the expression of neurotoxicity.

An increased understanding of the processes associated with neurotoxic outcomes will provide opportunities for improved assessments of risk and identification of potential therapeutic approaches. The strategy employed for achieving these goals has been to use multidisciplinary approaches that capitalize on the neurochemistry, molecular neurobiology, neuropathology, neurophysiology, and behavioral expertise of Division personnel. The Division is expanding capabilities in the area of imaging by adding both microPET and magnetic resonance imaging (MRI) instruments and personnel. In addition, efforts to develop sensitive, high-throughput systems for screening potential neurotoxicants are underway. 

Other unique features of the Division’s research capabilities include the ability to: 

  1. determine chemical concentrations and cellular-level interactions in target tissue
  2. determine changes in gene and protein expression associated with chemical exposures
  3. effect high-throughput, comprehensive cognitive or behavioral assessments
  4. employ multiple species including nonhuman primates, rodents, and, in some cases, humans, in the risk-assessment process to reduce the uncertainty associated with extrapolating findings across species
  5. develop novel histochemical tracers to aid in the evaluation of chemical-induced pathologies

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Current Research Projects 
  • ASK CHILDREN Study - Assess Specific Kinds of Children Challenges for Neurologic Devices (E0734301)
  • Assessment of Gaseous Anesthetics in the Developing Nonhuman Primate (E0728501)
  • Assessment of iron oxide nanoparticle-induced Neurotoxicity in Cell Cultures and Whole Animal Models (E0739401)
  • Assessment of Ketamine in the Developing Nonhuman Primate (E0718901)
  • Assessment of the pharmacokinetics, pharmacodynamics, and neurotoxic effects of an anesthetic in juvenile non-human primates undergoing various surgical procedures (E0738101)
  • Characterizing the Amphetamine-Induced Changes in Vascular Tone, Vasotrauma and Alterations in Angiogenesis in Rodent Brain (E0729501)
  • Complex Brain Function in Children as Measured by Performance in the NCTR Operant Test Battery (E0703301)
  • Complex Brain-Function Study in Children With and Without Major Depression (E0717701)
  • Development and Validation of Interspecies Cognitive Assessments (E0735501)
  • Development of MRI Imaging and Informatics Techniques for Tissue Sampling to Guide and Confirm Classical Neuropathology (E0741801)
  • Development of Novel Histochemical Markers of Brain-Vascular Elements and Their Application for Localizing Neurotoxicant-Induced Pathologies (E0731201)
  • Developmental Neurotoxicity Assessment of Acrylamide in Rats: LONG-TERM STUDIES (E0215101)
  • Due diligence for the development of rodent and nonhuman primate nicotine self-administration laboratories at NCTR (E0745601)
  • Effect of Pediatric Anesthetics on Zebrafish embryos: Neurotoxicity vs. Gene Expression Changes and Neuronal Kinase (Cdk5) as a Mediator of Toxicity (E0736301)
  • Effects of Anxiety on Complex Brain Function in Children (E0721701)
  • Effects of Prenatal Cocaine on Behavioral Plasticity (E0663307)
  • Evaluation and characterization of blood-brain barrier (BBB) pathology in MPTP-probenecid-induced Parkinsons disease (PD)-like conditions in a mice model and it's potential amelioration by Endoplasmic Reticulum stress reducers (molecular chaperones) (E0745101)
  • Further Studies on the Effects of Afmid/TK Deficiencies and Brain, Liver, and Kidney Function (E0726101)
  • Histochemical Test Battery for Evaluating the Efficacy and Toxicity of Putative Alzheimer's Disease Therapeutics of FDA Relevance (E0727301)
  • In Vitro Assay to Predict Developmental Neurotoxicity of Pediatric Anesthetics (E0740501)
  • Investigation of Potential Functional Effects of Ventricular Enlargement in Sprague-Dawley rats (E0744801)
  • Long term consequences of neonatal ketamine anesthesia in rhesus monkeys:  extended cognitive assessments (E0736401)
  • Long-Term Effects of Morphine Treatment in Preterm Infants Exposed to Repetitive Neonatal Pain (E0724301)
  • Long-term Neurodevelopmental Follow-up of Children Administered Ketamine Prior to Cardiac Surgery in Infancy (SAFEKIDS study) (E0738801)
  • Methods Development for High-Resolution Dedicated Positron Emission Tomography (microPET) to Rodent Neuroplasticity and Toxicity During Development (E0726401)
  • Methods Development for Toxicity Assays using the Zebrafish Embryo as a Model System: Whole Animal High Throughput Assays for Chemical Testing (E0735901)
  • Methylphenidate (Ritalin) Exposure during Pregnancy: Assessment of Neurotoxicity in Offspring (E0731801)
  • Neural stem cells, developmental biomarkers, and biological tools to advance mechanistic understanding of pediatric anesthesia-related neurodegeneration (E0741701)
  • Neurotoxicity Assessment of Cell Phone Radio Frequency Radiation using Rat and Bovine Brain Microvascular Endothelial Cells as Model Blood Brain Barrier Systems, PC-12 Cultured Cells, and Whole Animal Models (Mice and Rats). (E0217301)
  • Neurotoxicity Assessment of Manganese (Mn) Nanoparticles in PC-12 Cells and in Mice (E0725701)
  • Neurotoxicity Assessment of Silver (Ag) Nanoparticles in PC-12 Cells and in Rats (E0728201)
  • Novel Studies on Sites-of-Action and Mechanisms in Chronic Balance Dysfunction (E0722301)
  • Studies comparing the neurotoxicology of amphetamine with methamphetamine and methylphenidate (E0740101)
  • The impact of a Glial Modulator - PPF - on Methamphetamine-induced Dopamine Dynamics:  A Microdialysis Study in Rats and Mice (E0743301)
  • Wireless Deep-Brain Stimulation in Nonhuman Primates with MPTP-Induced Parkinson's Disease (E0723801)
  • Zebrafish Breeding and Maintenance for Embryo Studies (E0738701) 

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The NCTR Annual Report provides information on the latest accomplishments and plans for the Division of Neurotoxicology as well as project and publication listings for NCTR.


Contact FDA

National Center for Toxicological Research

Food and Drug Administration

3900 NCTR Road

Jefferson, AR 72079