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About FDA

April-June 2011

April Highlights
May Highlights
June Highlights

APRIL 2011

April 1
Medical Countermeasures Workshop—March 29-30, 2011

NCTR participated in panels at “Advancing Regulatory Science for Medical Countermeasure Development: An Institute of Medicine Workshop” in Washington, D.C.  The focus of the workshop was to identify opportunities and tools to improve and speed medical countermeasure development and to inform FDA’s Medical Countermeasure Initiative.  The workshop was conducted by the Institute of Medicine of the National Academies.

MCBIOS 2011—April 1-2, 2011

Scientists from NCTR presented their work at the Eighth Annual Conference of the MidSouth Computational Biology and Bioinformatics Society (MCBIOS) in College Station, Texas. The regional meeting provides a forum for networking and collaboration between academic, industry, and government scientists in the mid-south region to promote the development and advancement of bioinformatics and computational biology. The topics of the NCTR presentations included:

  • Methods for computational processing of mass-spectrometry data for rapid identification of bacteria
  • Computational methods to predict hepatic and renal toxicity
  • New data mining/modeling methods for repositioning of drugs
  • Determining relationships between drugs and adverse drug reactions
  • Identifying biomarkers 

Congratulations to NCTR scientist and MCBIOS Post Doc Award Winner Dr. Yan Li—April 2, 2011

Dr. Li was recently recognized for her work in, "Sex Differences in the Expression of Drug-Metabolizing Genes in Human Liver." Dr. Li, and fellow scientists Lun Yang, Leming Shi, and Baitang Ning focused their work on human sex differences in gene expression of drug-metabolizing enzymes and transporters (DMETs). Results from the research suggest that global regulatory pathways control the dimorphic enzymes of DMETs. Moreover, the implications of such differentially expressed DMETs were interpreted through drug-gene interactions.

April 8
Novel Algorithm to Identify Biomarkers of Susceptibility

NCTR scientists have developed a statistical model to identify and separate pharmacogenomic biomarkers of susceptibility from biomarkers of exposure for drug-induced toxicity.  The model delivers a significant improvement over current methods of biomarker identification. 

A well-defined set of susceptibility biomarkers could be instrumental in guiding treatment decisions by matching specific drugs with individual patients, thus avoiding adverse drug events. 

A simulation study conducted on a microarray gene expression dataset from a preclinical liver toxicity biomarker study at NCTR showed this approach may require larger sample sizes for adequate power and low false-positive rates.  The results of this study will be published in an upcoming issue of Pharmacogenomics (Vol. 12: Issue 4, 2011).

National Toxicology Program (NTP) Technical Report Review—April 5, 2011

NCTR scientists presented results of cancer bioassay studies on compounds of FDA regulatory interest at the NTP Technical Report Review Committee meeting on the National Institute of Environmental Health Sciences (NIEHS) campus in Research Triangle Park, North Carolina.  General conclusions of the committee included:

  • Aloe vera (non-decolorized whole leaf extracts of Aloe barbadensis Miller) was carcinogenic in male and female F344N rats, inducing intestinal tumors
  • Acrylamide in the drinking water was carcinogenic in multiple organ sites in male and female F344N rats and B6C3F1 mice
  • AZT (anti-viral therapeutic), alone or in combination with other anti-virals, showed no or equivocal evidence for carcinogenicity in male and female B6C3F1 mice

The full technical reports and details of the committee’s conclusions are posted at the NTP website.

April 15
Glucosamine Efficacy and Toxicity

NCTR scientists, under an Interagency Agreement with the NIEHS/NTP, have shown a potential mechanism for the reported beneficial effects of glucosamine therapy, but also have suggested a potential sclerotic side-effect following consumption of potent glucosamine preparations.  In the study, glucosamine was administered orally to rats at doses that lead to serum levels equivalent to levels achieved in humans taking oral glucosamine and was shown to induce growth factors that are associated with cartilage proliferation and repair.  The results of this study will be published this week in Archives of Biochemistry and Biophysics and will be the subject of a press release from the journal.

Nanotechnology and Health Care—April 6-9, 2011

NCTR scientists presented their research results at the Third Annual Nanotechnology and Health Care Conference held at the Winthrop Rockefeller Institute.  The international program included presentations from scientists studying human disease, medical product development, and nanotechnology, including William Slikker, Jr., Ph.D., Director, NCTR, and Paul Howard, Ph.D., Associate Director, Office of Scientific Coordination, NCTR. The annual meeting focuses on building collaborations between physicians and scientists on the development of nanotechnology-based products that could have an impact on health care.  For additional information, please contact Dr. Paul C. Howard, FDA/NCTR.

NTP Board of Scientific Counselors—April 13, 2011

The National Toxicology Program (NTP) held a meeting of the NTP Board of Scientific Counselors on the National Institute of Environmental Health Sciences campus in Research Triangle Park, NC. The agenda included presentations on the following NTP projects:

  • Potential for Environmental and Therapeutic Agents to Induce Immunotoxicity
  • NTP's Modified One-Generation Reproduction Toxicity Studies
  • Statistical Methods to Analyze Tumor Incidence in NTP Cancer Bioassay Program
  • Surveillance Program at Nanomaterial Manufacturing Sites
  • Development of Biospecimen Repository and Analysis Capabilities for NTP Exposure Assessment Projects
  • Workshop on Potential Health Effects of Excess Folic Acid

Some of the projects have overlap with the mission and goals of the FDA, and regulatory scientists at many of the FDA Centers have been involved in the discussion of the project concepts.

For additional information, please contact Paul Howard, Ph.D., Associate Director, Office of Scientific Coordination and FDA Liasion to NTP, FDA/NCTR.

April 22
Epigenetics in Cancer Risk Assessment

NCTR scientists have completed an invited journal article discussing accumulated knowledge and current theories for the role of epigenetic mechanisms in the etiology of cancer.  The journal article is titled, “Epigenetics is defined as heritable changes in gene expression that are not due to any alteration in the primary DNA sequence.”  The review discusses the advantages of markers of epigenetic processes in cancer-risk assessment compared to more traditional measures of cancer etiology, including DNA adduct formation and mutational changes to the genome.  The review will be published in Toxicology Mechanisms and Methods (2011). 21(4): 289-297.

American Society for Pharmacology and Experimental Therapeutics Scientific Program on Pharmacogenomics—April 13, 2011

Donna Mendrick, Ph.D., Director, Division of Systems Biology, NCTR organized a symposium titled "Pharmacogenomics to Address Adverse Drug Reactions" as part of the Experimental Biology meeting in Washington, D.C.  The symposium brought together representatives from government, academia, and industry to discuss how pharmacogenomics can enable regulatory science and improve patient care.  Presentations were given by representatives from NCTR, the FDA's Center for Drug Evaluation and Research, the Hamner Institutes for Health Sciences, and Pfizer, on pharmacogenomics and its application to regulatory safety assessments.

National Institutes of Health (NIH)-Industry Roundtable—April 21-22, 2011

NCTR scientists presented and participated in panel discussions at the NIH-Industry Roundtable titled “Exploring New Uses for Abandoned and Approved Therapeutics.”  Of particular importance was the discussion of “Relevant Government Research and Development Resources.”  The purpose of the meeting was to explore ways in which FDA and NIH can contribute existing nonconfidential resources to enable NIH- or academic-industry collaborations to research drug-rescue and -repurposing that may address important public health needs.

April 29
Urinary microRNAs as Biomarkers of Drug-Induced Liver Injury

NCTR scientists have shown that a single, high dose (1250 mg/kg) of acetaminophen consistently results in the elevation of 44 microRNAs in the urine of treated rats, with a smaller subset being elevated after administration of a lower, subtoxic dose (100 mg/kg).  This is in contrast to the high inter-animal variability seen with the current traditional endpoints of clinical pathology and histopathological indices of liver injury.  This suggests that specific urinary microRNAs could indicate the severity of APAP-induced liver injury and have potential as noninvasive preclinical and clinical biomarkers that are more sensitive and consistent than current traditional endpoints.  A manuscript describing this study has been accepted for publication in the Journal of Postgenomics: Drug & Biomarker Development

For additional information, please contact Willie Salminen, Ph.D., or Donna Mendrick, Ph.D., Division of Systems Biology, NCTR/FDA.

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MAY 2011

May 6
Human Microbiome Conference—April 27-28, 2011

Carl Cerniglia, Ph.D., Director, Division of Microbiology, served as a panel member at the National Academy of Sciences Environmental Health Decisions workshop, “Interplay of the Microbiome, Environmental Stressors and Human Health,” to discuss the impact of widespread antimicrobial use on susceptibility, global health, and drug toxicity.  The goal of the workshop was to facilitate discussions among government, industry, academia, and environmental groups concerning scientific advances and emerging knowledge on the microbiome and its relationship to human health.

Antimicrobial Resistance in Salmonella enterica serovar Dublin

NCTR scientists and collaborators from Sam Houston State University and the Marshfield Clinic Research Foundation have identified plasmids containing both antimicrobial-resistance genes and virulence genes from isolates of multidrug-resistant strains of Salmonella enterica serovar Dublin (S. Dublin).  Human infections by S. Dublin often result in severe invasive infections typically requiring hospitalization and antimicrobial therapy.  Furthermore, bacterial plasmids provide a mechanism for transfer of these genes to other bacteria.  (Food Research International, In Press).  Preprints are available from Steve Foley, Ph.D., Division of Microbiology, NCTR.

May 12
Technology Invented at NCTR for Rapid Bacterial Detection Being Further Validated at Local University

RAPID-B™ was invented by NCTR researchers in 2006 as part of a cooperative research and development agreement (CRADA) with LITMUS, LLC. Over the next several years the technology was advanced past the proof-of-concept stage and commercialized by LITMUS RAPID-B™. A Food Emergency Response Network Level-2 validation of the RAPID-B™ E.coli 0157 assay was performed by the Arkansas Department of Health in 2009 on difficult food matrices (spinach, jalapeño peppers, ground beef, bagged salad, cookie dough, salami, beef muscle, nut meat and frankfurters). This validation demonstrated that RAPID-B™ was more accurate than FDA's standard Bacteriological Analytical Manual (BAM) methods, the agency's preferred laboratory procedures for microbiological analyses of foods and cosmetics. An additional advantage of the former is the shorter time to results (9-15 hours) than the BAM method (5-7 days). Continued refinement of the RAPID-B™ assay at NCTR has dramatically reduced the time to results even further (30 minutes-5 hours).

Based on this and other successes, LITMUS RAPID-B™ entered into a collaboration with the Center for Food Safety at the University of Arkansas in Fayetteville in 2010 to further test and validate the platform.  Read the lead articledisclaimer icon in the University's newsletter for more information on this collaborative effort.

May 13
Leflunomide-Induced Hepatotoxicity

NCTR scientists have shown that inhibition of liver metabolism (enzymes CYP1A, CYP2B/2C and CYP3A) of the anti-arthritic drug, leflunomide, increased toxicity in primary rat-liver cells. The Black Box Warning for leflunomide was recently updated with stronger warnings about potential hepatotoxicity. These studies indicate that toxicity is caused by the parent form of leflunomide and its major metabolite (the product that remains after the drug is broken down, or metabolized, by the body) and not other downstream metabolites. Furthermore, these results indicate that drugs, dietary components (e.g., dietary supplements, herbal remedies such as St. John’s wort), and certain fruits such as grapefruit that result in alterations of CYP activity, may affect the safety of leflunomide. A manuscript describing this study has recently been accepted for publication in Toxicological Sciences.

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

Detection of Rare Cancer Gene Mutations

NCTR scientists have detected a rare mutation (1 mutant in 106 normal cells) in the cancer gene K-Ras, within one week after treatment of rats with the known carcinogen, azoxymethane. The mutation was detected using ACB-PCR, a sensitive molecular genetic approach developed at NCTR. This study illustrates how quantitative measurements of cancer-gene mutations may be a useful biomarker of genetic damage by carcinogens and their potential for estimating the carcinogenic potential and potency of test chemicals in 28- or 90-day toxicity studies. A manuscript describing the results of this study will be published in an upcoming issue of Environmental and Molecular Mutagenesis (2010, Vol. 52, Issue 2).

For additional information, please contact Page McKinzie, Ph.D., Division of Genetic and Molecular Toxicology.

Biomarkers of Nephrotoxicity—May 13

The NCTR Center for Metabolomics Research was invited by the Korean Society of Toxicology to present a lecture at the International Symposium in Seoul, South Korea.  The presentation was part of the “Systems Toxicology for Biomarker Discovery” symposium and focused on the utilization of metabolomics to identify noninvasive predictive biomarkers of nephrotoxicity for preclinical risk assessment, as well as clinical diagnostic applications.

For additional information or to request a copy of the presentation, “Biomarkers Development for Nephrotoxicity Using Metabolomics/Systems Toxicology,” contact Laura Schnackenberg, Ph.D., Division of Systems Biology, FDA/NCTR

May 20
Regulatory Science Research Studies Reviewed—May 17-18

The 37th meeting of the Toxicology Study Selection and Review Committee (TSSRC) was held at NCTR, to discuss ongoing studies and newly proposed study designs that are part of the interagency agreement between FDA and the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) that support the FDA risk-assessment process.
Ongoing studies in the following areas were discussed:

  • Food contaminants (bisphenol A, furan, melamine, and nanoscale silver)
  • Dietary supplements (aloe vera, senna, and glucosamine)
  • Topically applied compounds (oxybenzone and retinyl palmitate)
  • Medical device components/contaminants (DEHP and nanoscale silver)
  • Antibacterial chemicals (triclosan)
  • Cell phone radiation

The TSSRC is comprised of regulatory scientists and subject-matter experts from the FDA Centers (CBER, CDER, CDRH, CFSAN, and CVM), NIEHS/NTP, and the NIH Office of Dietary Supplements.  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 the FDA White Oak campus in Silver Spring, Maryland, November 15-16, 2011. 

In addition to the project reviews, the Dietary Herbal Supplements Working Group, composed of representatives from FDA (CFSAN, NCTR), NIEHS/NTP, and the NIH Office of Dietary Supplements, met on the second day of the TSSRC meeting.

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

May 27
SmartTots and Pediatric Anesthesia Research—May 23, 2011

The director of NCTR's Division of Neurotoxicology gave a presentation at the Annual Meeting of the International Anesthesia Research Society (IARS) in Vancouver, British Columbia.  The presentation titled “Ketamine Anesthesia During the First Week of Life Can Cause Long-Lasting Cognitive Deficits in Nonhuman Primates” was part of a panel organized to highlight the public launch of the SmartTots2disclaimer icon3 (Strategies for Mitigating Anesthesia-Related neuroToxicity in Tots) public-private partnership, an initiative jointly undertaken by FDA and IARS.  The mission of SmartTots is to support research that addresses the public-health issues related to the safe use of anesthetics and sedatives in pediatric patients.

For additional information or for a copy of the presentation please contact Merle Paule, Ph.D., Director, Division of Neurotoxicology, FDA/NCTR.

American Society for Microbiology Meeting—May21-24, 2011

NCTR scientists from the Division of Microbiology presented their research results at the 111th American Society for Microbiology Meeting in New Orleans, Louisiana. 
Presentation topics included:

  • diagnostic virology
  • comparative genomics of foodborne pathogens 
  • rapid detection of antimicrobial resistance genes and virulence factors in human clinical and foodborne isolates
  • mechanisms of antimicrobial resistance
  • microbial interactions with host cells
  • genomics, proteomics, and metabolomics of environmental microorganisms

For additional information on the presentations, please contact Carl E. Cerniglia, Ph.D., Director, Division of Microbiology, FDA/NCTR.

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JUNE 2011

June 3
Bitter Orange Extracts and Developmental Toxicity

NCTR scientists, in collaboration with scientists from the Center for Food Safety and Applied Nutrition (CFSAN), have shown that bitter orange extracts (Citrus aurantium), commonly used in dietary supplements and herbal weight-loss products, produced no adverse effects on fetal growth or development in rats at doses containing 50 mg/kg synephrine with or without caffeine (a common constituent of weight loss supplements).  By comparison, the suggested dose of synephrine (a sympathomimetic and the active ingredient of bitter orange) for a 60-70 kg individual is 3 mg/kg/day, which is far below the level tested in this study.  This study addresses a lack of information on the safety of these supplements when used during pregnancy and suggests that bitter orange is not a developmental toxicant.  A manuscript describing this study was recently accepted for publication in Birth Defects Research (Part B).  Bitter orange was nominated by CFSAN and the study was conducted at NCTR under an Interagency Agreement with the National Institute of Environmental Health Sciences/National Toxicology Program.

For additional information, please contact Deborah Hansen, Ph.D., Division of Personalized Nutrition and Medicine, FDA/NCTR.

June 10
European Food Safety Assessments—May 30 to June 1, 2011

An NCTR scientist served as an advisor in the “46th Plenary Meeting of the Scientific Panel on Contaminants in the Food Chain (CONTAM)” of the European Food Safety Authority (EFSA) in Parma, Italy.  The panel discussed the risk assessments of hepatocarcinogenic pyrrolizidine alkaloids, toxic ergot alkaloids, analgesic opium alkaloids, and the estrogenic mycotoxin, zearalenone.  The EFSA is an independent agency funded by the European Union (EU) to carry out scientific risk assessments and to inform the risk management and policy-making process associated with maintaining food safety throughout the EU.  EFSA’s Scientific Committee and Panels are composed of scientific experts from academia, research institutions, and food safety authorities and focus on different aspects of food safety.

For additional information, please contact Dan Doerge, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.

June 17
Toxicogenomic Models in Predictive Toxicology

NCTR studies showed that a short-term toxicogenomic (TGx) study outperformed Quantitative Structure-Activity Relationships (QSAR), an in silico approach, in predicting the power or tendency of 62 chemicals to produce cancer of the liver without causing genetic mutations.  These chemicals were selected from the NCTR Liver Cancer Database.  In an independent validation set, 1-, 3-, and 5-day TGx models had predictive accuracies of 0.77, 0.77, and 0.82, respectively, whereas the QSAR model had an accuracy of 0.55.  Thus, TGx modeling may provide a more accurate method to prioritize chemicals for the more time-consuming and labor-intensive 2-year rodent bioassay.  A manuscript describing this study has recently been accepted for publication in the journal, Chemical Research in Toxicology

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

Drug-Induced Hepatotoxicity in Pediatric Patients—June 8

William Salminen, Ph.D., presented an invited talk at the 10th Annual World Pharma Congress, Drug Safety Summit: New Assays and Tools for Predicting Hepatotoxicity in Philadelphia, Pennsylvania.  The presentation reviewed the major developmental phases of the maturing liver with an emphasis on phases that may pose unique sensitivities to drug-induced liver injury in children, which is an underserved area of research.

For additional information or a copy of the PowerPoint presentation, “Pediatric Drug-Induced Liver Injury – Children Are Not Just Small Adults,” please contact William Salminen, Ph.D., Division of Systems Biology, FDA/NCTR.

Identification of Nephrotoxicity Biomarkers Using Toxicoproteomics—June 9

An NCTR scientist presented work at a symposium, “Biomarkers of Drug/Metabolite Toxicity: LC-MS Methods” in Denver, Colorado.  The presentation focused on the utilization of toxicoproteomics to identify potential pathways and networks associated with nephrotoxicity and the identification of potential biomarkers of drug-induced nephrotoxicity that have been qualified by FDA for nonclinical use.

For additional information or a copy of the PowerPoint presentation, “Toxicoproteomics for the Identification of Nephrotoxicity Biomarkers and Pathways,” please contact LiRong Yu, Ph.D., Division of Systems Biology, FDA/NCTR.

June 24
Meta-Analysis for Biomarker Identification

Scientists from NCTR and the Center for Drug Evaluation and Research (CDER) have identified a 37-gene metasignature for systemic lupus erythematosus (SLE) using a pathway-based meta-analysis (statistical technique that combines results from two or more studies to improve reliability) of microarray gene-expression data from human peripheral blood mononuclear cells.  This novel approach allows for analysis of gene-expression data across unrelated microarray data sets and provides a simple, intuitive solution for combining microarray data sets to identify a strong metasignature.  SLE is a disease that has a significant impact on quality of life, yet is a difficult disease to diagnose and treat.  The metasignature identified in this study could potentially be used for diagnostic and monitoring purposes, as well as a source for identifying potential therapeutic targets for SLE.  A manuscript describing this study has recently been published in BMC Medicinedisclaimer icon (Volume 9: 65) and is also highlighted in a review in Genome Medicinedisclaimer icon (Verweij and Vosslamber, 2011).

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

NCTR Article Selected as Editor’s Choice

An NCTR research article titled “Accumulation of K-Ras Codon 12 Mutations in the F344 Rat Distal Colon Following Azoxymethane Exposure” was selected as the Editor’s Choice and is highlighted in the current issue of Environmental and Molecular Mutagenesis and will be highlighted on the Environmental Mutagen Society’s website.  The article reported the use of allele-specific competitive blocker-PCR (ACB-PCR) to detect a rare K-Ras mutation just one week after treatment of rats with a known cancer-causing agent.  This rapid detection indicates the sensitivity of ACB-PCR in measuring chemical induction of specific tumor-associated hotspot point mutations and its potential in evaluating the cancer-causing potency of chemicals.

For additional information, please contact Page McKinzie, Division of Genetic and Molecular Toxicology, FDA/NCTR.

NIEHS Director Visits NCTR—June 21, 2011

Linda S. Birnbaum, Ph.D., Director, National Institute of Environmental Health Sciences (NIEHS) and John R. Bucher, Ph.D., Associate Director, National Toxicology Program (NTP), met with the senior NCTR research staff on June 21 to foster collaborative interactions focused on regulatory science and innovation, and to exchange concepts for newer initiatives that would enhance the missions of FDA and of NIEHS.  Of particular note were the potentials of the new Clinical Research Unit at NIEHS and the Bio-Imaging Facility at NCTR.  NIEHS/NTP and FDA/NCTR have characterized the toxicity of nearly two dozen chemicals addressing the data gaps of concern to both agencies since inception of the Interagency Agreement in 1992.

For additional information, please contact William Slikker, Jr., Ph.D., Director, NCTR.

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