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October-December 2006


OCTOBER: NCTR RESEARCH HIGHLIGHTS


Predicting Acrylamide Toxicity in Humans
National Toxicology Program-sponsored rodent carcinogenicity bioassay studies of the food contaminant, acrylamide, at NCTR are yielding valuable knowledge at this point in the studies. NCTR investigators also have developed a physiologically based pharmacokinetic (PBPK) model for toxicity of acrylamide in rodents and humans. The model is based on extensive experimental determinations of rodent serum and tissue toxicokinetics and biomarker formation (DNA and hemoglobin adducts; urinary metabolites) in acrylamide-treated animals. The model also includes a pharmacodynamic (PD) module to link internal exposures to acrylamide with accumulation of the biomarkers.

Using available human biomarker data, the model is used to predict the steady state level of DNA damage in people consuming acrylamide through the diet.

Because steady state levels of DNA damage often predict tumor incidences in rodent carcinogenicity bioassays, this PBPK/PD model can decrease the uncertainty inherent in extrapolating human cancer risks from dietary acrylamide using rodent carcinogenicity studies conducted at much higher doses.

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

 

Critical Path ─ Modeling Pediatric Toxicity
Changes in anatomy, physiology and biochemistry during development makes it difficult to predict drug effects for developing fetus, infant or child.

CDER and NCTR scientists used doses of valproic acid, a frequently prescribed anticonvulsant drug, in a multi-age rat model to demonstrate the potential of the system to characterize toxicities across different pediatric stages of life.

For example, the highest drug-induced mortality was observed in 10-day-old animals (infant equivalents), lowest in 40-day-old animals (teenager equivalents), with 80-day-old animals (adult equivalents) less vulnerable than 25-day-old animals (toddler equivalents). These results are consistent with previously-published reports that the highest numbers of valproic acid hepatotoxic deaths occurred in children younger than two. This, as well as other parallel comparisons, demonstrates the utility of a multi-stage animal model, in addition to conventional non-clinical studies, can more accurately characterize toxicity across different pediatric ages.

For further information, contact Dr. William Slikker, Jr., Acting Director, NCTR/FDA, or Dr. Rick Beger, NCTR/FDA.

 

Critical Path — Joint Research Projects Utilizing Clinical Technologies
Noninvasive technology faculty from the Departments of Radiology and Otolaryngology at the University of Arkansas for Medical Sciences visited NCTR on October 25th to discuss joint research projects utilizing clinical technologies.

The objective is to improve detection, prognosis, and monitoring of treatment therapies for disease.

In addition to an array of clinical instruments, the departments contain non-invasive technologies ideal for use in preclinical model studies; e.g., multinuclear, wide-bore Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), microPET, micro-Computed Tomography (CT), and high resolution optical and ultrasound imaging and the supporting cyclotron laboratory.

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

 

Critical Path — Development of Environment, Safety and Health Management System (ESHMS)
NCTR, in conjunction with the Arkansas Regional Laboratory, has initiated the process of developing an Environment, Safety and Health Management System (ESHMS) for the Jefferson Laboratories campus.

The purpose of the ESHMS is to enhance the current program for protecting the environment while ensuring the safety and health of the workforce.

The kick-off meeting and training at NCTR on October 24th was directed by representatives from the FDA Safety Staff.

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


NOVEMBER: NCTR RESEARCH HIGHLIGHTS


TSSRC Meetings held in Washington DC
FDA, NIEHS, and outside scientific experts met 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 cancer endpoints in rodents exposed to the dietary contaminant acrylamide
  • long-term risk associated with exposure to combination AIDS therapeutic mixtures in neonatal and young adult rodent models
  • developmental and physiologic studies in rodents exposed to the dietary supplement bitter orange
  • oral and dermal rodent studies of Aloe vera exposure
  • preliminary results using manufactured nanoscale titanium dioxide in skin penetration studies

The Toxicology Study Selection and Review Committee (TSSRC) meets twice annually under the IAG agreement to provide oversight to the design and execution of studies that provide data essential for regulatory decision making in the FDA.

New proposals to investigate exposures to the dietary supplements Usnea barbata and glucosamine/chondrotin, nonhuman primate studies of the plasticizer DEHP to investigate testicular toxicity, and allergic reactions to tattoo pigments in permanent makeup were also discussed.

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

 

Critical Path — Metabolomics Primer
The current issue (October 2006) of the journal Pharmacogenomics of the Future Medicine series features a series of articles describing results and potentials of metabolomics for personalized medicine in health, disease, and therapeutics.

NCTR scientist, Laura Schnackenberg, provides an introductory editorial describing the general phenomenon and its expected role of metabolomics in personalized health care.

Drs. Schnackenberg’s and Beger’s review article provides a more in-depth discussion of the use of nuclear magnetic resonance and mass spectrophotometry techniques for the global metabolic profiling of biofluids and tissues.

Several examples for the use of this noninvasive technology are discussed: 

  • characterization of inborn errors in metabolism
  • organ transplant rejection
  • applications to disease
  • profiling of toxicity
  • applications to nutrition
  • mechanism-dependent response

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