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NCTR Research Highlights October-December 2009


NAS Workshop on Computational Toxicology

National Center for Toxicological Research (NCTR) scientists represented FDA at a workshop sponsored by the National Academy of Sciences (NAS). The workshop was titled, "Computational Toxicology: From emerging sciences and knowledge databases for improving risk estimates on effects of environmental stressors on human health." Major topics included:

  • Limitations to predictive nature of high-throughput data
  • Identifying susceptible subpopulations
  • Dose-response assessment
  • Identification of environmental stressors

This is the second of three conferences convened to review applications of state-of-the-art sciences for regulatory decision making. The next conference is scheduled for February 25-26, 2010.

For more information, contact Dr. William Slikker, Director, NCTR, or Dr. Rick Beger, Division of Systems Toxicology, NCTR.

National Center for Toxicological Research (NCTR)/FDA International Outreach

Dr. William Slikker, NCTR Director, and Dr. Carl E. Cerniglia, Director of NCTR's Division of Microbiology, were featured presenters at the 2009 Symposium on "The Metabolism of Foods and Drugs by Intestinal Microflora" held in Seoul, Korea on October 20, 2009 and the follow-on colloquium at the National Institute of Food and Drug Safety Evaluation on October 21. The topics they discussed are listed below.

  • Symposium Presentations
    Dr. Slikker — "Advances in Approaches to Food and Drug Safety Assessment"
    Dr. Cerniglia — "Involvement of Human Intestinal Microbiota in the Metabolism of Antimicrobial Agents, Food Contaminants, Dietary Supplements, and Xenobiotic Compounds"
  • Colloquium Presentations
    Dr. Slikker — "The Direction of Future Collaboration Between NCTR/FDA and the National Institute of Food and Drug Safety Evaluation/Korea Food and Drug Administration"
    Dr. Cerniglia — "Recent NCTR Research Efforts in Food Safety and Food Biosecurity"

National Center for Toxicological Research (NCTR) Opens Bio-Imaging Facility

NCTR hosted an open house on October 30, 2009 for the newly completed Bio-Imaging Facility.  The new facility houses small animal Magnetic Resonance Imaging (MRI), Spectroscopy (MRS),and MicroPET technologies and is located within the vivarium providing multiple species access.  MRI and PET technologies are and have been used in clinical practice for over 20 years to distinguish changes in anatomical features (MRI) and biochemical processes (PET) in health and disease.  By comparison, the instruments in the Bio-Imaging Facility operate at higher field strengths and with less variability than clinical instruments providing investigators opportunities for more complex experimental designs and resulting discoveries. As with clinical applications, the non-invasive nature of these technologies enable continued monitoring of animals, providing new possibilities for biomarker discovery for safety and efficacy and for cross-species comparisons.  The facility is open to studies from all disciplines at NCTR and other FDA Centers and is managed by a newly-hired MRI/MRS specialist with more than a decade of pre-clinical imaging experience.

For more information contact Dr. William Slikker, Director, NCTR, or Dr. Merle Paule, Director, Division of Neurotoxicology, NCTR.


NCTR Toxicology Studies Reviewed by Toxicology Study Selection and Review Committee (TSSRC)

The TSSRC met November 3-4, 2009 at FDA's White Oak campus to discuss ongoing studies and newly proposed studies that generate toxicology data to support regulatory decision-making.

Ongoing studies that were discussed included:

  • bisphenol A (BPA) monomer (food contaminant) 
  • furan (food and tobacco smoke contaminant) 
  • di(2-ethylhexyl)phthalate (DEHP)(plasticizer in medical devices and environmental contaminant) 
  • melamine with cyanuric acid (food contaminant) 
  • nanoscale silver (food contaminant, medical device component/contaminant) 
  • bitter orange (Citrus aurantium) with caffeine (dietary supplement) 
  • glucosamine and chondroitin sulfate (dietary supplement) 
  • usnic acid and Usnea lichen (dietary supplement) 
  • permanent makeup inks 
  • AIDS therapeutics

The newly proposed studies included:

  • triclosan (antibacterial component in many products) 
  • pediatric anesthetics: predictive rapid, in vitro assay for potential adverse effects of the pediatric anesthetics and preventive measures
  • goldenseal/berberine (dietary supplement) 
  • cellular telephone radiation

The TSSRC is comprised of subject experts from the FDA Product Centers and ORA, scientists from the National Institute of Environmental Health Sciences (NIEHS), and invited subject matter experts from other government agencies, industry, and academia.  The committee meets twice a year and is responsible for scientific oversight of study design and progress of ongoing work.

Safety of Key Inhaled and Intravenous Drugs in Pediatrics (SAFEKIDS) Workshop

NCTR Director, Dr. William Slikker, Jr., and Dr. Merle Paule, Director, NCTR Division of Neurotoxicology, gave presentations at the "1st Scientific Workshop of the SAFEKIDS Initiative" held November 4, 2009 at FDA's White Oak campus.  These presentations discussed the effects of anesthesia on the developing animal brain and the cognitive defects in rhesus monkeys following early postnatal ketamine anesthesia.

Visitors to National Center for Toxicological Research (NCTR)

Dr. Thomas Colatsky, Director, and Dr. Rodney Rouse, Research Veterinary Medical Officer, Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, visited NCTR on November 9-10, 2009 and held discussions with each NCTR research division discussing programs of mutual interest.  Dr. Rouse presented a seminar on his work titled, “Kim-1 Responses During Gentamicin-Induced Acute Kidney Injury and Recovery.”

NCTR International Outreach

NCTR staff attended the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medical Products (VICH) Expert Working Group organized by FDA's Center for Veterinary Medicine on November 9-11, 2009.  The committee evaluated the VICH GL36 guideline focused on the human safety evaluation of veterinary antimicrobial drugs.
Dr. Martha Moore, Director, Division of Genetic and Reproductive Toxicology, represented NCTR at a workshop, “Using Mode of Action Information to Improve Regulatory Decision Making,” in London, England, on November 1-2, 2009.  The meeting, hosted by the European Centre for Ecotoxicology and Toxicology of Chemicals, and the International Life Sciences Institute’s Health and Environmental Sciences Institute and its research foundation, was attended by approximately 50 experts from North America and Europe.

Personalized Medicine—Liver Disease

National Center for Toxicological Research (NCTR) investigators have demonstrated that alterations of microRNA (miRNA) levels in animal models of nonalcoholic fatty-liver disease is an early and prominent event in the disease process. The miRNA are small molecules that control gene expression and are often investigated as targets for therapeutic intervention. The mice were fed fat-storage-inducing dietary regimens that produce metabolic syndrome and the progressive form of the disease known as NASH (nonalcoholic steatohepatitis), two of the most common liver disorders in humans. NASH can progress to cirrhosis and hepatocellular carcinoma. The successful prevention and treatment of NASH relies on the ability to identify vulnerable subpopulations and early intervention therapy. 

For further information contact Dr. Frederick Beland, Director, Division of Biochemical Toxicology, NCTR.


Scientific Presentations by NCTR Researchers—Imaging, Nanotechnology, Drug Safety
  • Three FDA scientists presented views at the December 1-2, 2009, Health and Environmental Sciences Institute (HESI)-sponsored workshop,"Translational Imaging in Preclinical Safety Assessment and Environmental Hazard Identification."  Dr. William Slikker, National Center for Toxicological Research Center Director, presented an address titled, "In Vivo Detection of Neuroapoptosis During Development." Drs. Laniyonu and Goodsaid from FDA's Center for Drug Evaluation and Research addressed the issues of regulatory challenges and qualification of biomarkers, respectively.
  • Dr. William Slikker presented the plenary lecture, "Nanotechnology: Pharmacological Applications and Approaches to Safety Assessment," at the annual meeting of the Argentina Society of Pharmacology on November 24, 2009.
  • Dr. Weida Tong was the keynote speaker at the Drug Non-Clinical Safety Academic conference held December 2-4, 2009, in Beijing, China and was also the keynote speaker at the Systems Biology and Safety Assessment Conference held December 5-9, 2009, in Hangzhou, China. Dr. Tong will hold further discussions at the MicroArray Quality Control III (MAQC-III) meetings in Shanghai, China, December 10-11, 2009.

For further information, contact Dr. William Slikker, Jr., Director, NCTR.

NCTR Employees' Invention Subject of Patent Application—Pattern Recognition Technology

The National Institutes of Health Office of Technology Transfer has contracted a Chicago firm to represent the intellectual property of a patent application led by two National Center for Toxicological Research (NCTR) employees, Drs. Dan Buzatu and Jon Wilkes. The provisional patent (Serial No. 61/261.170) was filed with the U.S. Patent Office on November 13, 2009.  This patent application represents the unique application of mathematical processes in a model to discriminate up to nine categories of brain tissue in Magnetic Resonance Spectroscopy (MRS) images with 96% accuracy. The model was designed as a tool to aid physicians with medical decisions based upon MRS images. Under current practice, the only option for a physician to substantiate a diagnosis, determine a prognosis, or follow the course of a disease is to perform a surgical biopsy. The nine categories of brain tissue conditions modeled were: necrosis, metastasized carcinoma, metastasized melanoma, demyelination, astrocytoma, oligodendroma, menigioma, glioblastoma multiforme, and ganglioma.

This work is the result of the NCTR researcher investigators' efforts to apply pattern-recognition mathematics to interpret medical-imaging technologies traditionally interpreted visually by physicians. The pattern-recognition technology initially was used by the investigators to develop rapid-detection assays in FDA counter-bioterrorism and food-safety efforts. The challenge for the imaging project was to develop a tool that could be used with the relatively low-resolution instruments commonly encountered in hospitals and clinics that operate with variances of hardware and/or other uncontrolled environmental factors.

The model uses distinct processing steps to transform variable spectroscopy into a set of defined conditions (biomarkers) for consistent interpretation:

  • Linear recalibration of spectra using two recognizable reference peaks
  • Enhancement of the most significant (reliable) peaks in spectra using a variable weighting process producing significant improvements of signal-to-noise ratios
  • Application of pattern recognition technology to the resulting processed spectrum to define signal sets that are characteristic of the different tissue conditions

The improved MRS spectrum processing steps hold promise to aid physicians in the practice of medicine. The process could reduce the need for surgical procedures, in itself improving the quality-of-life of the patient in all outcomes. Drs. Buzatu and Wilkes also plan to study further application of pattern-recognition technology to different tissue tumors and disease types.

NTP Board of Scientific Counselors Meeting

Dr. Paul C. Howard represented the U.S. Food and Drug Administration at the December 9-10, 2009, meeting of the National Toxicology Program (NTP) Board of Scientific Counselors (BSC). The NTP mission is to provide U.S. regulatory agencies with toxicology data to enable science-based risk assessment and to develop new toxicology methods with modern scientific methodology. The BSC received updates on: 

  • the Center for the Evaluation of Risks to Human Reproduction expert-panel reviews on "infant soy formula" (December 16-18, 2009) and "environmental exposure and diabetes and obesity" (date to be announced)
  • the NTP Host Susceptibility Branch research program using the mouse-genetic-diversity approach to address human susceptibility to environmental toxins
  • review of compounds for toxicity testing; including butterbur, evening primrose oil, hydroquinone, silica flour, and valerian

For more information about these activities contact Dr. Paul C. Howard (NCTR/FDA Liaison to the NTP).

New Investigator Presentation Award

Dr. Joshua C. Kwekel, a postdoctorate under the FDA mentorship of Dr. James Fuscoe in the Division of Systems Toxicology/Center for Functional Genomics, NCTR, is the winner of the "Best Platform Presentation 2009 by a New Investigator" at the Environmental Mutagen Society (EMS) annual meeting. The award will be acknowledged in the EMS winter newsletter, and Dr. Kwekel will be invited to submit a paper to the EMS jounal, Environmental and Molecular Mutagenesis. The title of Dr. Kwekel's presentation was "Age and Sex Differences in Hepatic Gene Expression During the Rat Life Cycle". 

Age- and sex-related susceptibility to adverse-drug reactions is a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of genes expressed at various developmental and life-cycle stages will impact susceptibility to adverse-drug reactions. Thus, understanding the natural-expression patterns of genes throughout the life span of the rat-surrogate model species in both sexes will inform our assessments of adverse-drug reactions. This work described the changing patterns of gene expression in the liver where the expression of hundreds of genes was found to change, including genes involved in xenobiotic metabolism, DNA damage control, and oxidative stress. Future studies will include analysis of other organ systems such as kidney and heart. 

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