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About FDA

October-December 2008


Laser Microdissection Technique Opened to FDA Investigators
Toxicologic Pathology Associates (TPA), the onsite NCTR pathology support contract, has opened its laser microdissection service for investigators. The laser microdissection (LMD) technique provides an easy and rapid method to isolate target cells for further analyses and more accurate results. LMD is particularly useful in capturing single-cell types for analysis in heterogeneous-cell populations that commonly occur in tumors. Material has been provided for several projects that have a potential to reveal biomarkers for early detection of tumors. TPA continues its trend to develop state-of-the-art core technology and expertise in support of investigators, including the video-technology systems that enable meetings of pathology-consultant groups established for consensus analysis of results from GLP studies.

For further information, contact Drs. Ritchie Feuers or Thomas Flammang, NCTR.

NIEHS Leadership Visits NCTR
Dr. Sam Wilson, Acting Director of the National Institute for Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP), and Dr. John Bucher, Associate Director for NTP, visited NCTR on October 3rd. Drs. Wilson and Bucher were given an overview of NCTR’s developing imaging and nanotechnology facilities, and they discussed applications for preclinical studies with NCTR scientists. The NCTR, NIEHS, and the NTP initiated joint studies in 1978, and they have collaborated continuously, since 1993, through an Interagency Agreement (IAG) to conduct research and testing on FDA-nominated agents to the NTP using FDA scientists as study directors and principal investigators. The visit concluded with a tour of the NCTR facilities, including the FDA/NCTR - NIEHS/NTP Phototoxicology Research and Testing Laboratory, designated the NTP Center for Phototoxicology. The next FDA-wide study review, conducted under the IAG, is scheduled on November 18-19, 2008, at FDA's White Oak campus.

For more information, contact Dr. William T. Allaben, Associate Director for Scientific Coordination and FDA Liaison to the NTP, or Dr. William Slikker, Director, NCTR.

Food Safety Research — Azo/Sudan Dyes
NCTR’s Division of Microbiology scientists have expertise and a long-standing interest in assessing the risks of exposing the gastrointestinal-tract microbiota of human consumers to contaminated-food products, probiotics, antimicrobial agents, and dietary supplements. Sudan dyes belong to a family of industrial dyes normally used for coloring plastics and other synthetic materials. Sudan dyes are not allowed to be added to food. There has been worldwide concern about the contamination of chili powder, other spices, and baked foods with Sudan dyes since they may have genotoxic and carcinogenic effects (according to the International Agency for Research on Cancer). The recent detection of Sudan dyes in various food commodities require toxicological evaluation since adulteration of food products by these dyes constitutes a public health risk. Although azo dyes can be reduced by the mammalian liver to form aromatic amines, it has been suggested that intestinal microbiota could be primarily responsible for the in vitro reduction of azo dyes. Scientists in the Division of Microbiology demonstrated that some of these Sudan dyes can be metabolized by intestinal microbiota azoreductases to produce genotoxic compounds. Biochemical, molecular characterization, and crystal structure studies of azoreductases have been completed. Site-directed mutagenesis analysis of the active site of the azoreductase was performed to determine the amino acid residues involved in cofactor binding and azo dye reductase activity. These approaches will allow the FDA to gain a clearer understanding of the potential health risk of consuming foods contaminated with Sudan dyes. These findings were published in Microbiology, 2008 154:2659-2667; Applied and Environmental Microbiology 2007 Vol. 73:7759-7762; Arch. Biochem Biophys 2007 Vol. 463:68-77.
For further information, please contact Dr. Huizhong Chen or Dr. Carl E. Cerniglia, NCTR.

Novel Algorithm To Select Stable Biomarkers for Prediction from High-Dimensional Data
NCTR statisticians have developed a novel algorithm that optimizes the selection of biomarkers that reliably produce better diagnosis of disease, an earlier intervention to disease, and/or a more effective assignment of therapies. Standard procedures for selection of classification biomarkers for cancer prognosis are highly variable depending on the disease status and the fact that the number of informative markers is small compared to the large number (i.e., high-dimensional data) of variables (e.g., clinical chemistries, genes, proteins, etc.) examined. The novel algorithm selects the most stable (reproducible) predictor set of biomarkers based on the most frequently selected criterion developed from cross-validation techniques. The resultant set of biomarkers from this algorithm is shown to be more stable than the set selected from standard procedures. This algorithm can be applied to any procedure for development of biomarker classifiers.

For further information, contact Dr. James Chen, Division of Personalized Nutrition and Medicine, NCTR.


NCTR's Center for Innovative Technologies

The Division of Systems Toxicology, NCTR, would like to announce the formation of a new Center of Excellence, the Center for Innovative Technologies. The Center will be co-directed by Drs. Jon Wilkes and Dan Buzatu, two research chemists who invented and developed several technologies important to the FDA’s mission and public safety. Two of these technologies are Spectrometric Data Activity Relationship (SDAR) and RAPID-B.

  • SDAR is a novel method for developing computer-pattern recognition models based on chemical spectra. SDAR models predict biological activities and toxicological properties for drugs and other chemicals very accurately (80 to 100%). For example, models predicting dioxin toxicity and chemical estrogenicity were successfully developed and validated. The dioxin model results were presented by Dr. Wilkes at the Computational Toxicology Forum sponsored by EPA at Research Triangle Park, North Carolina, during the spring of 2007. Various model results, including estrogenic potential and novel antipsychotic drug development, were presented by Drs. Wilkes and Buzatu in San Francisco in March 2008 at the Cambridge Healthtech Institute’s (CHI) Molecular Medicine Tri Conference. SDAR was also presented via conference bridge by Dr. Buzatu at the CDER’s Ground Rounds last month.
  • RAPID-B is a revolutionary technology that uses flow cytometry to identify bacteria in minutes. Assays have been developed for Salmonella, Listeria, E. coli 0157, and total plate count (TPC). The technology was presented both in 2007 and 2008 at the International Association of Food Protection (IAFP) meetings in Orlando, Florida, and Columbus, Ohio, respectively. It was also presented in September 2008 at CFSAN during the FDA’s Food Protection Plan Meeting. Both technologies are patented, licensed, and currently being commercialized by LITMUS, LLC, of Little Rock, Arkansas.

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

NCTR Proposals Reviewed by TSSRC
The Toxicology Study Selection and Review Committee (TSSRC) met November 18-19 at the White Oak Campus to discuss ongoing studies and newly proposed study designs that are part of the interagency agreement between the FDA and the National Toxicology Program (NTP/NIEHS) that support the FDA risk assessment process. Dr. Frank Torti, FDA’s Chief Scientist and Deputy Commissioner, gave the opening comments.

The newly proposed studies included:

  • bisphenol A monomer (BPA) (food contaminant)
  • melamine with cyanuric acid (food contaminant)
  • di(2-ethylhexyl)phthalate (DEHP) (plasticizer in medical devices)
  • nanoscale silver (food contaminant, medical device component/contaminant)
  • furan (cooking contaminant and carcinogen)

Ongoing studies that were discussed included:

  • acrylamide (food cooking contaminant)
  • bitter orange (Citrus aurantium) with caffeine (dietary supplement)
  • triclosan (antibacterial component in many products)
  • ketamine (anesthetic agent)
  • usnic acid and Usnea lichen (dietary supplement)
  • permanent makeup inks
  • glucosamine and chondroitin sulfate (dietary supplement)

The TSSRC is comprised of subject experts from the FDA Centers and ORA, scientists from the 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. The next meeting of the TSSRC will be held at the NCTR in May 2009.


Drug-Induced Liver Injury
Drug-induced liver injury is the primary adverse event that results in withdrawal of drugs from the market and a frequent reason for the failure of drug candidates in development. Initial studies of NCTR scientists and Cooperative Research and Development Agreement (CRADA) partner, BG Medicine, show that it is feasible to use a molecular systems approach to detect reliably hepatotoxic effects of drugs at doses that are not associated with conventional signals of preclinical toxicity. The structurally similar drugs, tolcapone (clinically hepatotoxic) and entacapone (not clinically hepatotoxic), were administered at three dose levels and two dosing durations to male and female rats. Although there were not any conventional indicators of hepatotoxicity in either case, subsequent bioanalytical measurements and data analysis on liver, plasma, and urine tissue yielded differences between tolcapone and entacapone. These results indicate that putative biomarkers of liver toxicity in preclinical studies may be useful for predicting clinical liver toxicity in susceptible humans.
For more information, contact Fred A. Beland, Ph.D., Division of Biochemical Toxicology, NCTR.

Scientists Promote International Harmonization
NCTR scientists attended the 37th Annual Meeting of the Japanese Environmental Mutagen Society and the International Symposium on Genotoxicity Assessment - New Concept, Strategy and Regulation December 3-6, 2008, in Okinawa, Japan. NCTR's invited presentations included:

  • research to elucidate the mode-of-action for acrylamide-induced tumors
  • research developing a new mutation biomarker that can be readily detected using flow cytometry and a small sample of blood from rodents, nonhuman primates, and humans exposed to potentially mutagenic drugs and other chemicals
  • the latest recommendations for interpreting data from the in vitro mammalian gene mutation regulatory preclinical safety evaluation assay

NCTR scientists also participated in a planning session for the next International Workshop for Genotoxicity Testing, which will serve as a forum for the international discussion and harmonization of issues related to safety evaluations using genetic toxicology tests. The workgroups include experts from Europe, Japan, and the United States.

For more information, contact Dr. Martha Moore, Director, Division of Genetic and Reproductive Toxicology, NCTR.

Food Defense
NCTR and USDA scientists have characterized the survivability of Bacillius anthracis Stern (a surrogate for pathogenic B. anthracis) spores in processed liquid media of whole eggs, egg white, sugared egg yolk, or salted egg yolk. The most critical finding was that the spores were inactivated completely within 1-6 hours in egg white at cold, moderate, and high storage temperatures. The findings for the other products varied. This data can be used by government agencies to develop “value-added” risk-assessment models in evaluating the consequences of deliberate inoculation of anthrax spores in a high-volume commercial-food matrix such as eggs. (Accepted for publication in Food Microbiology.)

For more information, contact Dr. Saeed Khan or Dr. Carl E. Cerniglia, NCTR.

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