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October-December 2013


October 25
Antimicrobial-Resistant Salmonella in Swine Production Systems

Scientists from NCTR, Arkansas Public Health Laboratories, and from North Carolina State, Kansas State, and Ohio State Universities, highlighted the importance of farm and slaughter environments as separate reservoirs and as a crucial link in the spread of drug-resistant Salmonella in swine production systems.  The study showed a higher prevalence of Salmonella and a higher frequency of antimicrobial resistance in conventionally reared pigs than in pigs raised in antibiotic-free environments.  The Salmonella isolates exhibited the highest resistance to tetracycline, sulfisoxazole, and streptomycin; with nearly one-third of the isolates being resistant to more than three antimicrobial drugs.  The dynamics of Salmonella prevalence in pigs and carcasses were reciprocated in the farm and slaughter environment, indicating an exchange of this pathogen between the pigs and their environment.  This study was published in Applied and Environmental Microbiologydisclaimer icon(2013, 79: 5167-5178).

For additional information, please contact Rajesh Nayak, Ph.D., Division of Microbiology, FDA/NCTR.


November 15
In Silico Predictive Model for Drug-Induced Liver Injury (DILI)

Scientists from NCTR and Hannover Medical School (Germany) developed a quantitative structure-activity relationship (QSAR) model, based on FDA-approved drug labeling, to improve the prediction and prioritization of compounds based on their potential risk for causing DILI in humans.  The QSAR model, which was trained using 197 FDA-approved drug labels, demonstrated an overall accuracy of 68.9% in external validation tests against a total of 483 unique drugs; and this accuracy improves to 77% for high-confidence therapeutic subgroups.  Thus, this model may have utility early in the drug-development process by prioritizing compounds based on predicted DILI risk; especially for compounds such as analgesics, antibacterial agents, and antihistamines.  A manuscript detailing this model is accepted for publication in Toxicological Sciencesdisclaimer icon

For additional information, please contact Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics, FDA/NCTR.

Progress on FDA Studies Reviewed

The 42nd meeting of the Toxicology Study Selection and Review Committee (TSSRC) was held on November 13-14, 2013, at the FDA White Oak campus, to discuss ongoing studies that are part of the Interagency Agreement between FDA and the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) that supports toxicology studies providing data for the FDA risk-assessment process.

Ongoing studies at NCTR in the following areas were discussed:

  • Food contaminants [Bisphenol A (BPA), Furan, Nanoscale Silver, Melamine + Cyanuric Acid]
  • Topically applied compounds (Oxybenzone and Retinyl Palmitate) 
  • Medical device components (Nanoscale Silver)
  • Antibacterial chemicals (Triclosan)

NIEHS/NTP presented a summary of work being conducted at NTP in addition to the IAG-sponsored studies on eight sunscreen components and bisphenol-AF (bpa-AF).  The TSSRC is comprised of regulatory scientists and subject-matter experts from the FDA Product Centers (CBER, CDER, CDRH, CFSAN, CVM, and CTP), NIEHS/NTP, and the National Institutes of Health (NIH).  The committee meets twice each year and is responsible for scientific oversight of study design and progress of ongoing work under this Interagency Agreement.  The next meeting of the TSSRC will be held at NCTR, May 6-7, 2014. 

For additional information, please contact Paul C. Howard, Ph.D., Director, Office of Scientific Coordination, FDA/NCTR.

November 22
Society of Neuroscience 2013

NCTR scientists presented their preclinical research results at the annual meeting of the Society for Neuroscience held in San Diego, California, on November 9-13, 2013.  The topics of these presentations included:

  • The effects of developmental exposure to methylphenidate (ADHD medication) 
  • Application of PET/CT imaging to studies on pediatric anesthetic-induced neurotoxicity and neuroprotection 
  • Use of in vitro models of the blood-brain barrier in neurotoxicity studies 
  • In vitro and in vivo neurotoxicity assessments of nanomaterials 
  • Aging-associated changes in microvascular function in response to transient global ischemia 
  • Anti-inflammatory action and inhibition of beta-amyloid deposition by an amyloid plaque ligand

For more information, contact Merle Paule, Ph.D., Director, Division of Neurotoxicology, FDA/NCTR.


December 6
Organization of Economic Cooperation and Development (OECD) Test Guidelines

NCTR scientists participated in two OECD expert work groups on genotoxicity testing.

  • The “Expert Meeting on the Genotoxicity of Manufactured Nanomaterials” developed consensus statements on how to assess the genotoxicity of nanomaterials; and concluded that bacterial mutation assays (Ames test) are not recommended for testing some types of nanomaterials (insoluble particles >20 nm in size).
  • The “Expert Group on the Revision and Development of the OECD Test Guidelines on Genotoxicity” updated existing in vivo and in vitro Test Guidelines (TGs) for cytogenetics assays (the chromosome aberration and micronucleus tests), and worked on developing two new TGs covering in vitro gene mutation assays.

Updated draft TGs will be sent to FDA scientists and regulators for their comments within the coming weeks.

For additional information, please contact Tao Chen, Ph.D., or Robert H. Heflich, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.

December 13
Embryonic Stem Cell Test Revisited

FDA's NCTR and Center for Drug Evaluation and Research scientists reevaluated the embryonic stem cell test (EST) using eight compounds from the original European Center for the Validation of Alternative Methods (ECVAM) validation. All eight chemicals matched their previous classification as either non-toxic, weakly embryotoxic, or strongly embryotoxic demonstrating transferability of the experimental protocol.  However, the cell lines did show an increased sensitivity to some of the chemicals, indicating potential decreased stability and reliability of the cell lines in predicting developmental toxicity.  This study is published in the International Journal of Regulatory Sciencedisclaimer icon (2013, 1: 32-49).

For additional information, please contact Amy Inselman, Ph.D., Division of Systems Biology, FDA/NCTR.

Improved 3D-QSDAR Consensus Modeling of Aryl Hydrocarbon Receptor (AhR) Binding

NCTR scientists developed a consensus 3D-QSDAR (three dimensional spectral data-activity relationship) model. The model predicts binding strength of 94 aryl hydrocarbon receptor binders (including PCBs, PHDDs, and PCDFs) that demonstrated a 10.5% improvement in predictive performance over the individual partial least squares (PLS) and k-nearest neighbors (KNN) models.  The ability of 3D-QSDAR to provide structural interpretation was illustrated by a projection of the most important descriptors on the chemical structures, thus allowing identification of structural features related to receptor binding and toxicity.  The model was published in the Journal of Cheminformaticsdisclaimer icon (2013, 5:47). 

For additional information, please contact Richard Beger, Ph.D., Division of Systems Biology, FDA/NCTR.

December 20
Proteomics Quality Control and Standardization

NCTR scientists have authored a review article in the Journal of Proteomicsdisclaimer icon that discusses issues related to proteomics data and the need for regulatory standards to guide future proteomics data submissions. The authors discuss the following sources of variability that could complicate the evaluation of proteomics data in a regulatory setting.

  • Protein extraction methods
  • Protein concentration measurements
  • Liquid chromatography-mass spectrometry platform
  • Software analysis

Thus, the establishment of quality-control standards and guidelines for the generation and evaluation of proteomics data in biomarker qualifications and in regulatory decisions on FDA-regulated products is needed. 

For additional information, please contact Li-Rong Yu, Ph.D., Biomarkers and Alternative Models Branch, Division of Systems Biology, FDA/NCTR.

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