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About FDA

October-December 2007


Food Safety
NCTR scientists in the Division of Microbiology, in collaboration with the FDA PRW-SW Laboratory in California, have investigated the extent of genetic diversity among Salmonella enterica serovar Weltevreden isolated from imported seafood samples using antibiotic resistance, genomic restriction fragment analysis by pulsed-field gel electrophoresis (PFGE) and plasmid profiles. The Salmonella enterica serovar Weltevreden strains were isolated from imported seafood from 20 countries during FY 2000-2005.

Isolates were screened for susceptibility to several clinically important antibiotics, and the results showed a low frequency of antibiotic resistance. The combination of molecular techniques with antibiotic resistance profiles indicated genetic diversity and temporal persistence of Salmonella enterica serovars Weltevreden in imported seafood. This investigation is helpful to trace possible seafood-borne outbreaks of Salmonella enterica, to predict and assess epidemic spreads of infectious diseases, and increase consumer safety confidence in FDA seafood monitoring programs. The results of this study have recently been accepted for publication in Food Microbiology. 

For further information, contact Dr. Ashraf Khan or Dr. Carl E. Cerniglia, Director, Division of Microbiology, NCTR.

Selection of NCTR Associate Director for Regulatory Activities

The National Center for Toxicological Research is pleased to announce the selection of Margaret “Peggy” Miller, Ph.D., as the Associate Director for Regulatory Activities. As Associate Director, Dr. Miller will serve in the Office of Center Director, NCTR with an office in NCTR’s Parklawn Building suite in Rockville, MD and at the NCTR in Jefferson, AR. The ADRA is responsible for:

  • identifying FDA research needs
  • strengthening the communication interactions and collaborations between NCTR and other FDA product Centers
  • facilitating the awareness of NCTR research activities by other Agency components
  • proactively creating interactions and interdisciplinary collaborative research endeavors that expand and strengthen the Agency’s science foundation
  • fostering the use of research results in the FDA regulatory decision-making process

Dr. Miller will have an office in NCTR’s Parklawn Building suite and at the NCTR in Jefferson, AR.

Dr. Miller is exquisitely prepared for this opportunity and has an excellent record of significant contributions to the Agency. She joined FDA in 1989 in the Division of Toxicology, Office of New Animal Drug Evaluation, in the Center for Veterinary Medicine (CVM). She held several positions within the CVM including Deputy Director for Human Food Safety in the Office of New Animal Drug Evaluation. In 1999, Dr. Miller joined FDA’s Office of Women’s Health as the Manager of Science Programs. In this position, she initiated several successful research initiatives that promote the health of women including studies to investigate the pharmacokinetics of drugs in pregnant women. She recently completed a two-year detail at the Department of Food Safety, Zoonoses and Foodborne Diseases at the World Health Organization, where she worked on improving the provision of scientific advice, building the INFOSAN network, and developing consumer informational materials.

The American Association for Cancer Research (AACR) Meeting
AACR is announcing the first AACR Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved. This conference will be held November 27-30, 2007, at the Atlanta Marriott Marquis in Atlanta, Georgia. In October 2006, the NCI Center to Reduce Cancer Health Disparities sponsored a “Think Tank” on research issues related to cancer health disparities. Participants in this “Think Tank” included clinical researchers, epidemiologists, molecular biologists, social scientists, geneticists, pathologists, and patient advocates from a variety of work settings including academia, industry, government, and not-for-profit organizations. The goal of this historic conference is to bring together scientists and other professionals working in a variety of disciplines to discuss the latest findings in the field and to stimulate the development of new research in cancer health disparities. This conference will address various topics in basic science, clinical research, population science, behavioral research, and cancer survivorship. The conference will begin with four educational workshops: 1) Cancer Health Care Communications, 2) Research Methods in Cancer Disparities, 3) Systems Biology, and 4) Biomarkers/Genetics. Plenary and concurrent sessions will be held throughout the conference. Beverly D. Lyn-Cook, Ph.D., a senior scientist in NCTR’s Division of Personalized Nutrition and Medicine is a co-chairperson of the conference. 

More information may be obtained from the AACR Web site.

Environment, Safety and Health Management System
The Jefferson Laboratories of the Food and Drug Administration has become the first FDA facility to implement an Environment, Safety and Health Management System (ESHMS) in accordance with national (ANSI-Z10) and international (ISO-1400) guidelines and standards. The Jefferson Laboratories ESHMS was developed over the course of nine months by the Arkansas Regional Laboratory and the National Center for Toxicological Research Cross-Functional Team. On August 1-2, 2007, an internal audit of the ESHMS was conducted, and a Jefferson Labs management review was held on August 2. The audit report was issued September 7, 2007, completing implementation of the Jefferson Labs ESHMS.

The Jefferson Labs ESHMS also incorporates a continuous quality-improvement plan that establishes procedures for performing corrective actions to audit findings, maintenance, systems refinement, audit schedules, and management reviews. The ESHMS fulfills the directives of Executive Order 13423.


Toxicogenomics Integrated with Environmental Sciences (TIES)
NCTR, NIEHS/NIH, and North Carolina State University jointly hosted the first international conference on TIES-2007 on October 25-26, in the McKimmon Center of North Carolina State University in Raleigh, North Carolina. The goal of the TIES conference is focused on the application of bioinformatics in the fields of toxicogenomics and environmental genomics. TIES provides a venue where multidisciplinary scientists can exchange the current advances in bioinformatics for elucidating biological mechanisms and pathways through "omics" technologies. The conference featured four keynote speakers, invited presentations, and a poster session, as well as a special session on the FDA-led MicroArray Quality Control project. The conference was well-received with about 140 participants. The NCTR Director, Dr. William Slikker, opened the conference with remarks on the current status of toxicogenomics applied in environmental sciences across agencies and countries. The international participants included the keynote speaker from Germany, the platform presenter from Korea, and the program committee members from China. Given the success of the TIES-2007, the next two TIES conferences will take place in China in 2009 and Germany in 2011.

Toxicology Study Selection and Review Committee met at FDA’s White Oak Campus on November 14 & 15, 2007

The Toxicology Study Selection and Review Committee (TSSRC) met November 14 and 15, 2007, at FDA’s White Oak Campus Conference Center. The TSSRC is a committee comprised of the Food and Drug Administration (FDA), the National Institute for Environmental Health Sciences (NIEHS), and outside scientific experts charged with scientific oversight for all studies conducted under an interagency agreement between the NIEHS's National Toxicology Program and the FDA's National Center for Toxicological Research. FDA product centers/offices select and nominate FDA-regulated chemicals and agents for which safety and risk issues exist that require further research and testing to resolve. The TSSRC meets twice a year; a spring meeting at NCTR in Jefferson, Arkansas and a fall meeting in the Washington, DC area. Studies that were reviewed during the two-day meeting included:

  • Ketamine — rodent and nonhuman primate perinatal studies investigating brain remodeling after exposure to anesthetic agents including ketamine
  • Acrylamide — pharmacokinetic, mechanistic, cancer and neurotoxicology studies in rodents after exposure to the food contaminant acrylamide
  • AIDs Therapeutic Agents — rodent studies investigating potential long-term risk to newborn and young adults after transplacental and transplacental/neonate exposure to various AIDs therapeutic agents administered alone or in combination
  • Bitter Orange — developmental and physiological studies in rodents exposed to the dietary supplement ingredient, bitter orange, alone and in combination with caffeine at rest and with exercise
  • Aloe Vera — rodent studies that are investigating the safety of aloe vera when administered orally or dermally
  • Nanoscale Titanium Dioxide — a review of studies using manufactured nanoscale titanium dioxide in skin penetration studies

There were updates on the progress of studies that investigate:

  • Cell phone radiation in rodents
  • Q-T prolongation in canines
  • Potential toxic outcomes using DNA therapeutics

The TSSRC also reviewed protocols or preliminary data that investigate:

  • Usnea barbata, glucosamine and chondroitin — the potential toxic outcomes as a consequence of exposure to these dietary supplements alone and in combination
  • Di (2-ethylhexyl) phthalate (DEHP) — potential testicular toxicity as a consequence of exposure to this plasticizer in medical devices
  • Nano-silver and nano-gold particles — the ADME and the potential toxicity of these manufactured particles
  • Furana — PBPK study with furan, plus special furan toxicology studies
  • Permanent makeup (tattoo pigments) — allergic reactions as a consequence of exposure to permanent makeup (tattoo pigments)

Full AAALAC Accreditation Continued for NCTR
To maintain a “state-of-the-art” research facility requires round-the-clock skilled animal-care personnel and animal-care facilities. NCTR has a long history of providing both. The NCTR animal facilities are a vital resource in the conduct of FDA research. A site visit team from the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC) evaluated the NCTR animal-care infrastructure and support capabilities in June 2007 as part of the ongoing AAALAC accreditation process. Their goal was to make an independent and objective evaluation of the Center’s animal care and diet preparation operations, including personnel and infrastructure. The site visit team report received in November 2007 grants NCTR "continued full accreditation." NCTR is home to 82 AAALAC-accredited breeding and conventional animal rooms and a nonhuman primate research center.

Combination of Breeding Paradigms and New Genomics Analysis to Dissect Mystery

Dr. Allan B. Okey, Professor Emeritus, Department of Pharmacology and Toxicology, University of Toronto and dioxin-toxicity expert, presented a seminar at NCTR on November 27 titled: “The Rat that Wouldn’t Die: Using Genetics and Gene Expression to Identify Pathways of Dioxin Toxicity.” The direct causal events leading to dioxin toxicity certainly involves the aryl hydrocarbon receptor (AHR) and AHR-mediated dysregulation of gene expression. The differences in sensitivity to toxicity and to type of toxic outcome that result from exposure to dioxin and dioxin-like chemical exposure is highly variable across animal species; humans by comparison are less sensitive. Furthermore, 30 years of study in multiple laboratories using traditional toxicology and pharmacodynamic methods have not resolved this mystery. Dr. Okey’s research group currently utilizes a systems biology approach to examine the different toxicological outcomes. The approach combines dioxin-sensitive and dioxin-resistant animal models in traditional breeding paradigms and the new genomics analysis to dissect the mystery. The results are mapping AHR-mediated gene expression in a variety of biological systems and are identifying which dysregulated genes underlie specific forms of dioxin toxicity. It was noted that similar approaches could be, or are, in use to predict adverse outcomes in the development of therapeutic agents that rely on preclinical animal data to predict adverse events in humans.


Intercenter Research Communication
The National Center for Toxicological Research Division of Microbiology Director, Dr. Carl E. Cerniglia, presented a seminar on December 6 to the Center for Veterinary Medicine (CVM) Staff College titled "The Effect of Veterinary Antimicrobial Agents in Food on the Human Intestinal Microbiota.” Dr. Cerniglia addressed the current issues that must be considered to evaluate the safety of veterinary drugs used in food animals for potential human health risks. Dr. Cerniglia also discussed the research collaboration with CVM scientists that led to the harmonized approach described in FDA Guidance 159 to determine the safety evaluation and risk assessment of antimicrobial agent residues in foods.

Critical Path — NCTR Operant Test Battery (OTB)
Dr. Merle Paule, Director, Division of Neurotoxicology, presented an invited lecture titled “Interspecies Comparisons of Cognitive Function: Biomarkers of Neurotoxicity and Relevance for Juvenile Studies,” at the Second Annual Juvenile Toxicity Symposium held in Belgium on November 29-30. The lecture focused primarily on the use of the nonhuman primate model in studies of drug effects on brain function and engaged intense discussion as attendees grappled with the conduct of preclinical studies most relevant to human pediatrics. The model exemplified how NCTR OTB can be used for identical behavioral assessments across species, including children, to allow for the objective, quantitative assessment of complex brain functions that include learning, short-term memory, time perception, motivation, and visual discrimination.

These discussions continue and will be revisited when Dr. Paule presents an invited lecture titled "Critical Contributions of Primate Models for Biopharmaceutical Drug Development" at the upcoming 17th Münster Primate Symposium held in Germany in April 2008. NCTR's Division of Neurotoxicology has long been known for its state-of-the art nonhuman primate studies, particularly in the area of drug effects on complex brain function and particularly during early development through adolescence.

Critical Path — New Methods to Evaluate Clinical Outcomes
The biostatisticians in the Division of Personalized Nutrition and Medicine, NCTR, have developed a novel classification tool (i.e., classification algorithm) to address the statistical challenge that arises in most clinical studies where huge sets of measurements are gathered on relatively few clinical trial participants. If not carefully considered, analysis of high-dimensional data of this type can easily generate models that do not predict the correct treatment strategies. The newly developed algorithm was used to analyze genomic data sets obtained from lymphoma patients and lung cancer patients to distinguish disease subtypes for optimal treatment and to analyze genomic data obtained from breast cancer patients to identify patients most likely to benefit from adjuvant chemotherapy after surgery. The performance of the proposed algorithm is consistently highly ranked compared to the other classification algorithms. A description of this algorithm has been published in Artificial Intelligence in Medicine (Vol. 41, pp. 197–297, 2007).

While much work remains to test and use these and other algorithms for clinical practice, the statistical classification method for individualized treatment of diseases developed is expected to play a critical role in developing safer and more effective therapies that replace one-size-fits-all treatments. 

For more information about this algorithm, contact Dr. Jim Chen of the Division of Personalized Nutrition and Medicine, NCTR.

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