About FDA

Neurotoxicology

Director: Merle G. Paule, Ph.D.

Introduction        NCTR Imaging Center      Current Research Projects

Introduction

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) GABA (gamma amino butyric acid) receptor complexes as mediators 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)
  • Aspects of nicotine self-administration in the nonhuman primate (E0753701)
  • Assessment of effects of tobacco product constituents on extracellular dopamine levels in the nucleus accumbens in rats (E0753801)
  • 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)
  • Bioinformatics Student Admissions Committee (S00676)
  • Brain Sexual Dimorphic Structures and Sex Hormone-like Compounds: Animal Request for Methods Development and Training (P00710)
  • Chronic Methylphenidate Administration in Rhesus Monkeys (E0742411)
  • Comorbidity of Alzheimer's disease (AD) and Type 2 diabetes (T2DM) in African Americans:  Comparison of biomarkers of inflammation in human tissues. (E0754101)
  • 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)
  • Developing more Complete Genomic and Histological Evaluations of Vascular Damage in the Brain Meninges and Choroid Plexus after Neurotoxic Insult (E0751901)
  • Development and maintenance of F344-AD Tg rat breeding colony (E0754601)
  • Development and Validation of Interspecies Cognitive Assessments (E0735501)
  • Development of a simple in-vitro approach for the rapid detection of neurotoxicity (E0752401)
  • Development of MRI Imaging and Informatics Techniques for Tissue Sampling to Guide and Confirm Classical Neurpathology (E0741811)
  • Development of Novel Histochemical Markers of Brain-Vascular Elements and Their Application for Localizing Neurotoxicant-Induced Pathologies (E0731211)
  • Developmental Neurotoxicity Assessment of Acrylamide in Rats: LONG-TERM STUDIES (E0215111)
  • Developmental Neurotoxicity Assessment of NMDA Receptor Antagonists in zebrafish (E0752801)
  • 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 BPA treatment on hippocampal NMDA receptors and ER receptors in rat brain (E0750801)
  • Establishing rodent and nonhuman primate behavioral pharmacology laboratories at NCTR: staffing and equipment (E0749201)
  • Evaluation and characterization of blood-brain barrier (BBB) pathology in MPTP-probenecid--induced Parkinson's disease (PD)-like conditions in a mice  model and its potential amelioration by Endoplasmic Reticulum stress reducers (molecular chaperones) and other putative anti-Parkinson therapeutics (E0751201)
  • Gender differences in neuronal reward circuit activation by nicotine and tobacco smoke using magnetic resonance spectroscopy (E0751001)
  • Histochemical Test Battery for Evaluating the Efficacy and Toxicity of Putative Alzheimer's Disease Therapeutics of FDA Relevance (E0727321)
  • Identification of protein biomarkers for neurotoxicity assessments using a high-throughput antibody microarray approach (E0747701)
  • Long term consequences of neonatal ketamine anesthesia in rhesus monkeys:  extended cognitive assessments (E0736401)
  • Long-term Neurodevelopmental Follow-up of Children Administered Ketamine Prior to Cardiac Surgery in Infancy (SAFEKIDS study) (E0738801)
  • Methods Development for Toxicity Assays using the Zebrafish Embryo as a Model System: Whole Animal High Throughput Assays for Chemical Testing (E0735911)
  • Methylphenidate (Ritalin) Exposure during Pregnancy: Assessment of Neurotoxicity in Offspring (E0731801)
  • Modulation of the effects of Parkinson's disease (PD) medications by nicotine (E0746601)
  • Neural stem cells, developmental biomarkers, and biological tools to advance mechanistic understanding of pediatric anesthesia-related neurodegeneration (E0741701)
  • Neurobehavioral effects of Bisphenol A across age and sex (E0219201)
  • 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 harmanes, norharmane and nicotine constituents of tobacco smoke in rats (E0745201)
  • Neurotoxicity Assessment of Silver (Ag) Nanoparticles in PC-12 Cells and in Rats (E0728201)
  • PET-CT imaging using translatable biomarkers for evaluating the CNS effects of chronic methylphenidate administration in rhesus monkeys (E0742401)
  • Preliminary quantification of the neurotoxicity/neuroprotection of Selective Estrogen Receptor Modulator (SERM) treatment in a female mouse model of Alzheimer's Disease utilizing Alzheimer brain-derived amyloid ß-protein (E0752301)
  • Proteomic assessment of the cytotoxic effects of nanoparticles on the blood-brain barrier (E0746001)
  • System Test of NCTR's Multispecies Behavioral Test System (MBS) Upgrade: Development of a Fixed Consecutive Number Task (E0751701)
  • Task Order's #746 - MBS: Develop and Deploy DROID on Linux; and #747 - MBS: Diagnostic Tools for DROID Implemented on Linux; and #823 - Implement new security rules for remote operant testing data collection; and #831 - Statistical Quality Control of Transition from MBS OS/2 to MBS DROID (E0703311)
  • The impact of a Glial Modulator - PPF - on Methamphetamine-induced Dopamine Dynamics:  A Microdialysis Study in Rats and Mice (E0743301)
  • The use of computed tomography (CT) combined with positron emission tomography (microPET) to evaluate the neurotoxicity associated with pediatric exposures to the anesthetics sevoflurane and propofol (E0749401)

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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

870-543-7000
National Center for Toxicological Research

Food and Drug Administration

3900 NCTR Road

Jefferson, AR 72079

Page Last Updated: 07/02/2014
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