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U.S. Department of Health and Human Services

About FDA

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April-June 2007


APRIL: NCTR RESEARCH HIGHLIGHTS


Continuous Quality Improvement

NCTR has established a Regulatory Compliance and Risk Management staff within the Office of the Director. The organizational change will increase focus on the development and management of systems and processes that maintain and support continuous quality improvement for NCTR staff and research activities.

The organization will consolidate activities previously held by the Environmental Health and Program Assurance Staff including: quality assurance, safety (chemical and industrial hygiene), security (facilities and personnel), biosafety, environmental protection, waste management, health physics (radiation safety), records management, internal controls, and the on-site occupational health clinic.

In addition, the reorganized staff will be responsible for oversight and administration of NCTR’s Human Subjects Research Quality Assurance/Control program, a campus-wide Environment, Safety and Health Management System, and will administer the quality assurance program for NCTR research designated for compliance with the FDA Good Laboratory Practice regulations.

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

 

Food Safety and Food Defense

Investigators at NCTR and CFSAN have co-developed a high-throughput, accurate DNA microarray chip for threat assessment of disease-causing potential during inadvertent or intentional Salmonella food contaminations. The technology evaluates 71 of the most common virulence genes that play a significant role in Salmonella pathogenicity.

The chip has been used successfully for threat assessment of Salmonella types isolated from pre-harvest poultry sources and Roma tomatoes; results will be reported in the May 2007 American Society for Microbiology meeting.

The technique continues to undergo intensive “ruggedness” testing by NCTR microbiologists for different field applications. Rapid and cost effective threat assessment of Salmonella pathogenicity will be critical to first responders in limiting the potential of accidental or bioterror-related contaminations.

For further information, contact Dr. Carl Cerniglia, Director, Division of Microbiology, NCTR.

 

Translational Research – Pediatric anesthetic ketamine

NCTR scientists have demonstrated that ketamine, a widely-used pediatric anesthetic, significantly increases (~20-150%) brain cell death in pre-term (75% of normal gestation) and 5-day old rhesus monkey infants when administered stable, 24-hour anesthetic doses.

No increase in ketamine-induced cell death was observed in the same experimental design with 35-day old infant rhesus, or in 5-day old animals maintained on an anesthetic dose of ketamine for only 3-hours. These results are consistent with previous experiments conducted in 7-day old rats. The monkey, specifically the rhesus monkey in this case, is generally accepted to be the most accurate model for stages of human neuronal development. Further studies are necessary for evaluating the safety of ketamine in pre-term infants and young children. Specific questions to be answered include: the assessment of safety during all stages of pregnancy and early childhood, the relationship of dose-level and anesthesia duration to cell death, an overall assessment if damage has lasting effects, or can the brain recover without loss of normal function.

For more information, contact Dr. William Slikker, Director, NCTR, or Dr. Merle Paule, Director, Division of Neurotoxicology, NCTR.


MAY: NCTR RESEARCH HIGHLIGHTS


Critical Path - Public Release of Windows®-Based Modeling Software

Scientists at the University of Missouri and NCTR have publicly released a user-friendly, Windows®-based physiologically based pharmacokinetic/pharmacodynamic effect (PBPK/PD) software (called Postnatal) to facilitate rapid testing of different models of metabolism and disposition of drugs against experimental data.

The PostNatal program originally was a general platform to investigate PBPK/PD parameters of any chemical during postnatal development. PostNatal has evolved to a package of four PBPK programs that can act independently, or can be totally integrated with each other and is capable in describing complex scenarios of drug metabolism and disposition in adult mice, rats, dogs, and humans. The integration also permits unusual flexibility in the kinds of studies that can be simulated: mixtures of administered compounds via various routes; enterohepatic recirculation; or direct comparisons of different routes of administration in common simulation.

For further information, contact Dr. William Slikker, Director, NCTR, or Dr. John Young, Director, Division of Personalized Nutrition and Medicine.

 

Semiannual TSSRC Meetings

Scientists representing the FDA product centers and the ORA, NIEHS, and outside scientific organizations met May 8th at the Jefferson Laboratories of the FDA in Jefferson, Ark., to review progress of NCTR research being conducted under the FDA/NIEHS National Toxicology Program IAG. Results from ongoing studies included:

  • rodent and nonhuman primate models with exposure to the anesthetic ketamine
  • neurotoxicology and carcinogenicity of the dietary contaminant acrylamide
  • long-term risk associated with exposure to combination AIDS therapeutic mixtures in rodent models
  • developmental and physiologic studies in rodents exposed to the dietary supplement bitter orange
  • oral and topical rodent studies of Aloe vera exposure
  • rodent studies with permanent makeup
  • nanoscale titanium dioxide and quantum dots studies conducted in the NIEHS/FDA Phototoxicology Laboratory

Preliminary results with the dietary supplement usnic acid (usnea sp.) and the impact on protocol design for the plasticizer DEHP were also discussed.

Technical reports on multigenerational reproductive and chronic toxicity studies of low-dose ethinyl estradiol (EE2), sponsored by the IAG and conducted at NCTR, will be presented and reviewed at the National Toxicology Program’s (NTP) Board of Scientific Counselors Toxicology Report Review Subcommittee meeting to be held in Research Triangle Park, N.C. on May 16 and 17.

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

 

Multigenerational Studies of Low-Dose Ethinyl Estradiol

Final reports on low-dose multigenerational reproductive and chronic toxicity studies of the potent pharmaceutical, ethinyl estradiol, conducted at NCTR were presented at the National Toxicology Program’s (NTP) Board of Scientific Counselors Toxicology Report Review Subcommittee held at Research Triangle Park, NC, on May 16 and 17.

Concerns based on low-level human exposures to ethinyl estradiol from environmental sources or continued use of oral contraceptives during early pregnancy led to the conduct of five-generation studies in rodents.

The complex protocol evaluated the carryover of adverse effects across generations, reversibility of adverse effects, and chronic toxicity using multiple exposure windows that encompassed the early developmental period.

Effects typical of estrogens were observed and provide some support for the hypothesis that low levels of estrogens can impact subsequent generations. Measures of fertility (mating, pregnancy, and fertility indices, time-to-mating, gestation length, litter size, pup birth weight) were not adversely affected by ethinyl estradiol under the conditions of this study. By comparison, there was a marginal increase of hyperplasia in the male mammary gland in the unexposed generation of the multigenerational reproductive study, and the third generation of males in the chronic study (the offspring of two prior generations of animals exposed to ethinyl estradiol who were themselves exposed from conception through weaning followed by control feed to 2 years) also showed a slight increase in tumors of glands in male sex organs. A complete report of these studies will be available from the National Toxicology Program.

For more information, contact Dr. Barry Delclos, Division of Biochemical Toxicology, NCTR.

 

Critical Path – Reviews on Metabolomics and its role in Systems Biology and Personalized Medicine

Metabolomics is a relatively new technology that measures the amounts and kinds of small molecules in cells, tissues and biofluids such as urine and blood. The levels of some small molecules are exquisitely sensitive indicators of health status and hold great promise in personalized medicine. NCTR scientists recently published three reviews of metabolomics and its role in the FDA Critical Path to Personalized Medicine initiatives (Schnackenberg and Beger, Pharmacogenomics, 7: 1077-1086, 2006; Schnackenberg and Beger, Am. Drug. Discovery Review. 1(2):22-29, 2006; Schnackenberg, Expert Rev. Mol. Diagnos. 7(3) 247-259, 2007).

These reviews highlight the use of metabolic profiling analyses in determining biomarkers of drug safety and effectiveness, disease diagnosis and prognosis, organ transplant rejection, nutritional status, and inborn errors of metabolism.

Combining information generated from metabolic profiling with information obtained from genetics and the measured activities of genes and proteins will pave the way for a better understanding of the mechanisms of diseases and drug toxicities. Metabolic profiling, currently incorporated into NCTR collaborative studies on liver and kidney toxicities, has a vital role in the application of personalized medicine and strengthening the new molecular paradigm in the FDA.

For further information, contact Dr. Richard Beger, Division of Systems Toxicology, NCTR.


JUNE: NCTR RESEARCH HIGHLIGHTS


Detecting UVB Light-Induced Mutations

NCTR scientists have recently developed a new transgenic assay that is particularly effective for detecting the types of mutational events induced by UVB light exposure. The assay uses a gene inserted into an embryonic mouse cell line (a transgenic cell line).

Transgenic cells have a very low spontaneous background mutation rate and a strong response to UVB. This new transgenic assay provides a sensitive approach that should be very useful in experiments assessing the effects of light exposure.

In collaboration with the NCTR/National Toxicology Program Center for Phototoxicity located at NCTR, future research to more fully assess the utility of this approach in whole mice and to address specific questions related to photomutagenicity is in development.


For more information, contact Dr. Carrie Valentine, Division of Genetic and Reproductive Toxicology, NCTR.

 

Improvements to the NCTR Occupational Health Clinic
In the accomplishment of their analytical and research mission, the Jefferson Laboratories’ (NCTR and the ARL) employees may be exposed to hazardous materials or conditions. This exposure potential has mandated that a strong and comprehensive environment, safety, and health program be developed and maintained.

In an effort to continually improve the service provided to employees, the NCTR Occupational Health Clinic (OHC) recently made two improvements in the areas of respiratory protection and employee potential exposure monitoring.

NCTR purchased and placed into service a respirator fit test instrument for all employees who must wear respirators in the conduct of their work to include staff who work in our animal holding facilities. The new instrument provides a quantitative measure of the performance of a respirator for each employee and enables a custom fit providing a significant improvement over the qualitative fit test method previously used.

In addition, the OHC recently rolled out a revised version of NCTR’s ChemHaz Potential Exposure Database. The interactive system allows all employees to keep tract of any potential exposure to hazardous chemicals or agents. The Occupational Safety and Health Administration (OSHA) requires employers to monitor the workplace for regulated materials only if the likelihood that an employee will be exposed to airborne concentrations of regulated materials is in excess of the Action Limit or the Permissible Exposure Limit. As a result, low-level or minor exposures can go undetected and/or unreported. Although these low-level exposures will likely have no significant impact on an employee’s health, employees are requested to use the ChemHaz system to report any and all potential exposures.

 

Food Protection – Salmonellosis
Even though there has been an overall decline in the number of cases of salmonellosis over the past decade in the United States, there has been a significant increase in infections from multidrug-resistant Salmonella enterica serovar Heidelberg in recent years. Scientists from NCTR, CVM, the National Farm Medicine Center, Marshfield, Wisconsin, the University of Central Arkansas, and North Dakota State University have characterized the antimicrobial resistance and potential for transfer of drug resistance between Salmonella Heidelberg strains isolated from a turkey production facility, veterinary diagnostics samples, processing plants, and retail meat samples.

The researchers documented that the most common resistance in S. Heidelberg strains was to antimicrobial agents in use for the longest time; greater diversity in resistance phenotypes was encountered in the processing facilities compared to single farm source, and approximately four percent of the Heidelberg strains were resistant to eight or more antimicrobial agents.

Experiments further indicated that transfer of drug resistance in S. enterica serovar Heidelberg strains can be largely explained by the presence and spread of mobile resistance elements.

Collectively, the results demonstrate that the prevalence and spread of multidrug-resistant Salmonella Heidelberg in pre- and post-harvest scenarios is an emerging health concern. The patterns of drug resistance profiles in this “emerging” pathogen should be closely monitored, and strategies should be developed to mitigate the spread of this pathogen in future outbreaks.

For further information, contact Dr. William Slikker, Director, NCTR, or Dr. Rajesh Nayak, Division of Microbiology, NCTR.

 

AAALAC Site Visit at the National Center for Toxicological Research (NCTR)
NCTR’s animal care and use program and animal facilities received its triennial assessment by three representatives from the Association for Assessment and Accreditation of Laboratory Animal Care, International (AAALAC) on June 14 and 15, 2007. NCTR has been fully accredited by AAALAC since 1977, demonstrating a continuing commitment to excellence in the conduct of experiments using animals. AAALAC accreditation symbolizes quality, promotes scientific validity, serves as a recruiting tool, demonstrates accountability, impresses funding sources, and shows a genuine commitment to humane animal care.

The site visit was conducted by three experienced professionals with expertise in veterinary medicine, laboratory animal management, regulatory compliance, and occupational health and safety. The animal care and use program and facilities were rigorously reviewed during the two-day visit, which concluded with a briefing of the site visitors’ findings.

Excellence was noted in the sanitation/maintenance program, the level of certification and training of animal care personnel, and in the Institutional Animal Care and Use Committee (IACUC) proceedings.

Recommendations for improvement were immediately implemented, and continued full accreditation is expected.

For more information, contact Dr. Jeff Carraway, Director, Division of Veterinary Services, NCTR.

 

FDA CIO and CTO Visit NCTR/Jefferson Laboratories
On June 25-26, 2007, NCTR hosted a visit by Mr. Timothy Stitely, FDA Chief Information Officer (CIO) and Mr. Joseph Klosky, FDA Chief Technology Officer (CTO). During the two days the CIO and CTO toured the NCTR/Jefferson Laboratories campus, they were given an overview of the integrated science IT capabilities, viewed progress on the development of the FDA COOP disaster recovery back-up location at NCTR, and participated in the pilot study discussion regarding electronic data submission noted below. On Tuesday afternoon, Dr. Slikker hosted an All Hands meeting for NCTR/Jefferson Laboratories staff with the CIO and CTO in which the CIO fielded questions concerning FDA IT.

 

Pilot Study for Electronic Data Submission
Collaborators from industry, NCI, CDER, and NCTR met at the Center on June 26, 2007, to discuss a proposed pilot study for electronic data submission, evaluation and storage of nonclinical, clinical, and pharmacogenomics data. The meeting resulted in consensus among the collaborators that NCTR will develop and submit a business case to the FDA pre-market bioinformatics review board to support NCTR’s coordination of nonclinical regulatory e-submission data via this pilot project. NCTR will continue to work on research-based, e-submission projects such as VGDS that includes both clinical and nonclinical data.