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About FDA

April-June 2008


Mutagenicity Assay Use in Preclinical Studies 

CDER and NCTR scientists have recently completed a book chapter discussing the use of in vitro mammalian mutagenicity assays in preclinical safety evaluation studies. The chapter serves as a guide describing the principles of each different assay, the critical parameters affecting assay performance, and the interpretation of data from each different assay. (C.A.H. Bigger, M.M. Moore and R.H. Heflich (2008) “In vitro mammalian cell mutation assay,” Preclinical Development Handbook: Toxicology, S.C. Gad (ed.), John Wiley & Sons, Inc, 129-153)

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

Food Safety Research

NCTR and ORA scientists combined genetic (chromosomal and plasmid) and antibiotic-sensitivity analysis to reproducibly characterize hundreds of Salmonella enterica (S. enterica) strains isolated from seafood samples imported into the United States from 26 different countries during the years 2001-2005. The 37 S. enterica Weltevreden strains, the most common of the 64 different serotype isolates, were further characterized to the genotype level. Salmonella Weltevreden can cause acute enteritis (inflammation of the intestinal tract), and some of these isolates were found to be resistant to several veterinary and clinically important antibiotics. The combination of molecular methods (chromosomal analysis, plasmid profile, and antibiotic resistance) used in these studies can be used to trace outbreaks and epidemic spreads of S. enterica and implement surveillance programs in imported seafood. (Food Microbiology, 25: pp. 29-35, 2008) 

For further information, please contact Dr. Ashraf A. Khan or Dr. Carl E. Cerniglia, NCTR.


Science Advisory Board Review 

A site-visit team from the NCTR Science Advisory Board met at NCTR on April 29-30 for an in-depth analysis of research programs within the Division of Biochemical Toxicology. The site visit team, led by Board Chair, Dr. James Popp, was comprised of subject experts from academia, industry, NIH, and each FDA product-line Center and ORA.

The Division presented results and future plans from studies on risk evaluation of food, drugs, and cosmetics. Risk evaluations included:

  • tattoo inks
  • nano-scale titanium dioxide sunscreen
  • topically and orally administered Aloe vera
  • topically applied retinoic acid
  • nephrotoxicity of melamine/cyanuric acid combinations
  • transgenic models for melanoma
  • pyrrolizidine alkaloid-containing dietary/herbal supplements
  • the food contaminant acrylamide
  • multigenerational reproductive studies of estrogenic compounds
  • mixtures of anti-HIV/AIDS drugs
  • epigenetic mechanisms of carcinogenesis
  • varied PAH exposure used as surrogates for evaluating mixtures
  • idiosyncratic liver injury

The site visit report will be formally presented at the full NCTR Science Advisory Board meeting to be held at NCTR on August 12-13, 2008.

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

Electronic Imaging as a Tool for Pathology Review

There has been an ongoing need for a cost-effective method to archive images of pathology data with the concurrent ability to review. Methods for electronic imaging have been developed and now validated by scientists at the National Center for Toxicological Research (NCTR). This new state-of-the-art technology allows pathologists at remote sites to observe slide images for review and/or comment. A program has been created that allows multiple users to review the same image from off-site locations using identical PC/notebooks, monitors, and software specifically designed for this purpose. The identity of slides is protected by the addition of unique bar codes. Slides are converted to electronic images using the Aperio ScanScope XT at 40X magnification, and the images are then stored on a secure server at NCTR. A copy of each image can be transferred to a remote and secure server ( using a unique file-transfer protocol. The images then become available for review through the Spectrum Web Viewer.

Because an important requirement for the system was that users see the same image at the same resolution, this became an integral part of the validation process. Validation also included a side-by-side comparison of traditional techniques with the new system. This is a technological advance that will allow for multiple participants to review slides in real time while providing consultative expertise from remote sites. In addition, there will be significant savings of time and resources while security and integrity of the study material is maintained. 

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

The MAQC Project Toward Personalized Medicine

On March 24-26, 2008, the FDA-led MicroArray Quality Control (MAQC) project held its 8th face-to-face meeting at the FDA facilities in Rockville, Maryland. Partially funded by the Critical Path Initiative with participants from six FDA Centers, NIH, EPA, NIST, academia, and industry, the MAQC project is aimed at reaching consensus on the “best practices” for developing and validating microarray-based predictive models for personalized medicine. Over 100 participants from 60 organizations representing eight countries attended the meeting. More than 30 organizations presented their data analysis protocols and analysis results using the same clinical and preclinical microarray gene expression and genotyping data sets distributed by the MAQC project. Manuscript proposals were discussed at the meeting, and the MAQC is on track to submit a set of manuscripts for peer-reviewed publication by the end of 2008. 

For further information, visit MicroArray Quality Control (MAQC) or contact Dr. Donna Mendrick, Director, Division of Systems Toxicology or Dr. William Slikker, Jr., Director, NCTR.

NCTR Proposals Reviewed by TSSRC

The Toxicology Study Selection and Review Committee (TSSRC) met on May 13 and 14 at the National Center for Toxicological Research (NCTR) to discuss ongoing and newly proposed study designs that support the FDA risk assessment process. The newly proposed studies included:

  • bisphenol A monomer (universal food contaminant)
  • melamine/cyanuric acid (pet-food contaminant)
  • di(2-ethylhexyl)phthalate (DEHP) (plasticizer in medical devices)
  • nanoscale silver and nanoscale gold particles (food/medical device contaminant)
  • Usnea barbata/usnic acid (dietary supplement)
  • permanent makeup inks (tattoo inks)
  • ketamine and nitrous oxide/isoflurane (anesthetic agents)
  • bitter orange (Citrus aurantium component)/caffeine (dietary supplement)
  • nanoscale titanium dioxide (sunscreen component)
  • acrylamide (potential cooking carcinogen)
  • glucosamine and chondroitin sulfate (dietary supplement)
  • furan (cooking contaminant and carcinogen)

The TSSRC is comprised of subject experts from the FDA Product Centers and the ORA as well as from the NIEHS, 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 White Oak this fall.
For more information, contact Dr. William Allaben or Dr. Paul Howard, NCTR.

2008 Summer Science Research Program (SSRP)

Orientation was held May 27 to introduce the National Center for Toxicological Research (NCTR) summer research interns to the mission of the FDA and to meet their mentors for the ten-week program. The 2008 students represent nine institutions of higher learning, including:

  • Allegheny College
  • Hendrix College
  • Indiana University
  • Ouachita Baptist University
  • Philander Smith College
  • University of Arkansas at Fayetteville
  • University of Arkansas for Medical Sciences
  • University of Arkansas at Pine Bluff
  • University of Missouri

The nine students will participate in ongoing studies alongside their mentors in five different NCTR research divisions. The studies include:

  • sex-specific effects of adolescent-methylphenidate treatment on later risk for substance-abuse disorders
  • toxicity of resveratrol, an antibiotic produced by grapes and other plants
  • genetic characterization of enterohemorrhagic Escherichia coli strains recovered from humans
  • epigenetic mechanisms in the development of resistance of cancer cells to chemotherapeutic agents
  • epigenetic approaches to overcome cancer-cell drug resistance
  • identification of proteins expressed by Staphylococcus aureus

The ten-week appointments end with the formal presentation of results to the NCTR staff on July 31. The SSRP at NCTR is administered by the Oak Ridge Institute for Science and Education (ORISE).

For more information, contact Dr. Tucker Patterson, Division of Neurotoxicology, NCTR.


Translational Medicine for Risk Identification

Scientists from NCTR and Teijin Pharma, a Cooperative Research and Development Agreement (CRADA) partner in Tokyo, Japan, have developed a sensitive and practical in vivo gene-mutation assay using red blood cells that is applicable for preclinical safety testing. The assay requires only one hour to quantify mutations in the Pig-A gene; and using only a few micro-liters of peripheral blood for a determination, the assay is a practical procedure for repeated blood sampling and a candidate for use in follow-on clinical studies. 

In vivo and in vitro batteries are used for evaluating gene mutation; however, a number of notable carcinogens (e.g., acrylamide, urethane, and benzene) are much more readily detected with in vivo methods. The Pig-A assay represents the first rapid and sensitive in vivo gene mutation assay. Future work on the Pig-A assay will establish its sensitivity for detecting the genotoxicity of a wide variety of test agents and explore expansion of the technique in other cell types and species. These studies were presented to CDER scientists on May 29 and have been accepted for publication in the journal, Environmental and Molecular Mutagenesis.

For more information, contact Dr. Robert H. Heflich, Division of Genetic and Reproductive Toxicology, NCTR.

Food Safety Research

NCTR scientists have developed an in vitro human-cell line model colonized with human gastrointestinal (GI)-tract bacteria to detect the adverse effects of low concentrations of antimicrobial drugs that might be present in animal-derived food products to the consumer. The in vitromodel system was used to determine the effect of a low-concentration of drug residues on the functional role of intestinal bacteria as a barrier that protects intestinal cells from invasion of the gastrointestinal tract by microbial pathogens. The intended application of the model system will be to accumulate data to calculate acceptable daily intake (ADI) levels of antimicrobial drug residues present in food. Regulatory agencies use microbiological studies to calculate ADI levels as part of the overall risk assessment to evaluate human food safety of antimicrobial drug residues in animal-derived foods. 

Results of the recent study show that the minimal inhibitory concentration (MIC) technique, that is often used as the major indicator of drug effects on the GI tract for ADI determinations, does not detect the effects of multiple species of bacteria in the GI-tract population or the sensitivity of their barrier effect in the case of Salmonella tissue invasion. Use of the new assay to measure how antimicrobial drug concentration affects thresholds on the barrier property of the intestinal bacteria population may be an alternative approach to in vitro and in vivo models currently used to assess the safety of antimicrobial drug residues in food products of animal origin. (Antimicrobial Agents and Chemotherapy, 52: pp. 1230-1237, 2008.)

For further information, please contact Dr. R. Doug Wagner or Dr. Carl E. Cerniglia at NCTR.

NCTR Public Outreach

NCTR members of the Arkansas Chapter of the Society for Neuroscience played a major role in the recent Central Arkansas Brain Bee and other activities associated with Brain Awareness Week, an event sponsored by the Society for Neuroscience. Several staff from NCTR’s Division of Neurotoxicology had key roles in organizing and judging the competition for high school students held in Little Rock, Arkansas. The winner and her mentor received funds for travel to participate in the National Brain Bee in Baltimore, Maryland. The grand finale of the Arkansas Brain Awareness Week took place at the Museum of Discovery in Little Rock. Activities included interactive displays on neuroscience-related topics, including NCTR’s Operant Test Battery, a computerized system for assessing cognitive abilities in which children press buttons and levers in response to visual stimuli and earn candy reinforcers for correct responses. The system was originally designed for assessing brain function in monkeys but has also found great utility in human subjects who enjoy playing these ‘brain’ games. An additional display, “Your Brain on Jell-O,” was presented by NCTR scientists. Children were given the opportunity to place “arteries” (red cake icing) on Jell-O brains. This display helps children understand the fragility of the human brain and the importance of protecting it. Over 500 children and adults attended the event. NCTR scientists, collaborating with neuroscientists at the nearby University of Arkansas for Medical Sciences, obtained grant support from the Society for Neuroscience to help pay for these events.

For additional information, contact Dr. John Bowyer, Division of Neurotoxicology, NCTR.

STEP Program Begins at NCTR

NCTR’s Science Training and Exchange Professional (STEP) Development Program hosted its first participant last week, a reviewer from the Center for Veterinary Medicine (CVM). The program is intended to facilitate the sharing of expertise across the FDA Centers through short-term training or research at the NCTR and/or by the exchange of technical information and the fostering of networking and collaborations. In this case, the CVM reviewer sought background on a new assay for measuring genotoxicity in dogs, a method that was being used in a product submission. The assay, which utilizes flow cytometry to measure chromosomal damage (micronuclei) in red blood cells, previously was validated through research conducted by NCTR’s Division of Genetic and Reproductive Toxicology (DGRT). The reviewer spent three days in the DGRT, during which the assay was performed and the interpretation of assay data was discussed in detail.

For further information, contact Dr. Margaret Miller, Associate Director for Regulatory Activities, or Dr. William Slikker, Director, NCTR.

Contact FDA

National Center for Toxicological Research

Food and Drug Administration

3900 NCTR Road

Jefferson, AR 72079

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