Toxicity Assessment of Tobacco Products
Investigators from NCTR and the Center for Disease Control (CDC) have shown that cytotoxic and mutagenic potencies differ among various cigarette smoke condensates (CSC) generated from commercial cigarettes containing from 5 mg to 34.6 mg of tar per cigarette, and that the mutagenic potency does not correlate with either tar or nicotine levels. These results indicate a complex relationship between the components of CSCs and mutagenicity and that low tar or low nicotine cigarettes are not necessarily less hazardous. CSCs, which are the particulate fraction of cigarette smoke and are a complex mixture of thousands of chemical components, were evaluated using one of the regulatory genetic toxicology assays, the mouse lymphoma mutation assay. The relative mutagenic potency provides a useful measure to assess the relative toxicity of tobacco products and provides a basis to address the overall health risks associated with tobacco use. A manuscript describing this study has been recently accepted for publication (Mutagenesis, 2010).
For additional information, please contact Martha Moore, Ph.D., Director, Division of Genetic and Molecular Toxicology, FDA/NCTR.
MicroPET Imaging of Apoptosis
NCTR investigators have shown that high-resolution positron emission tomography (microPET) imaging is capable of distinguishing differences in retention of [18F]-DFNSH (dansylhydrazone of p-fluorobenzaldehyde) in the brain, a tracer compound that may serve as a marker of neuronal apoptosis. Previous studies have suggested that dansyl compounds can accumulate within apoptotic cells. This study showed that [18F]-DFNSH distributes quickly into the brain after administration and concentrates within the frontal cortical region of brains from rats treated with the pediatric anesthetic ketamine. With the development of appropriate tracers, microPET imaging has been proposed as a minimally-invasive method to repeatedly monitor neuronal apoptosis. A manuscript describing this work has recently been accepted for publication (Journal of Neural Transmission, 2010).
For additional information, please contact Merle Paule, Ph.D., Division of Neurotoxicology, Director, FDA/NCTR.
Rapid Identification of Bacteria by Spectral Profiles
NCTR investigators presented the following research results at the American Society for Mass Spectrometry (ASMS) Asilomar Conference on Mass Spectrometry in Pacific Grove, California, on October 8-12, 2010. The investigators developed a new method (Direct Impact Corona Ionization, DICI) to ionize bacteria that creates a spectral profile that can be used to distinguish bacterial strains with subspecies accuracy. DICI utilizes a high-voltage corona to vaporize/ionize the sample, generating a signal that is approximately 40-fold higher than obtained from ordinary pyrolysis (controlled heating). The resulting spectral profiles seem to be sufficiently reproducible to create a library of patterns for rapid identification of unknown bacterial strains. The DICI process with pattern recognition has many other applications besides rapid bacterial identification, including detection of trace organic contaminants in drug or food ingredients. This discovery is being reported as an HHS Employee Invention Report for patenting.
For additional information, please contact Jon Wilkes, Ph.D., Division of Systems Biology, FDA/NCTR.
Alliance for Risk Assessment Workshop
NCTR presented a case study at the workshop “Beyond Science and Decisions: From Issue Identification to Dose-Response” organized by the Alliance for Risk Assessment in Crystal City, Virginia, October 11-13, 2010. This is the second in a series of three workshops to develop consensus concerning key considerations in applying dose-response assessment techniques for common risk assessment applications.
For additional information, please contact Martha Moore, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.
NCTR Science Advisory Board Meeting
The annual NCTR Science Advisory Board (SAB) meeting was held October 19-20, 2010. The FDA Science Board was represented by Drs. James Broach and Stephen Spielberg, and the Office of the Commissioner was represented by Drs. Leonard Sacks and Jeff Farrar. The Board heard presentations on the current NCTR Strategic plan and brief overviews from the six Division Directors. Each of the Center and Office of the Commissioner representatives presented the priorities and research views of their respective FDA office or product center. A representative from the Center for Tobacco Products outlined the new legislation and the scientific challenges it represents. Following the presentations, the Board members discussed the future strategic direction for research at the NCTR. In addition to the annual meeting, the NCTR Science Advisory Board convenes subject expert Site Visit Teams that review and make recommendations to the current and future programs of each research division. The next meeting of the NCTR SAB will be held during the fall of 2011.
For additional information, please contact Margaret Miller, Ph.D., Associate Director, Regulatory Affairs, FDA/NCTR.
Congressional Budget Visits
On October 19, 2010, NCTR and the Arkansas Regional Laboratory (ARL) hosted a visit by Patrick McGarey, Director, FDA Office of Budget, six Senate appropriations staff members, and staff from the offices of Senators Mark Pryor and Blanche Lincoln. The visit focused on the accomplishments and future plans of several funded initiatives including the Nanotechnology Infrastructure and Core Facility and regulatory sciences, including rapid pathogen detection and advances in bioinformatics facilitating product review and analysis. ARL, co-partners in the NCTR ARL Nanotechnology Core Facility also demonstrated the capabilities of their six mobile field laboratories and initiatives related to the Deepwater Horizon oil spill in the Gulf of Mexico.
For additional information, please contact William Slikker, Ph.D., Director, FDA/NCTR.
Kraft Foods Visits
On October 18, 2010, NCTR hosted four members of Kraft Foods to discuss possible nutritional and food research programs of common interest, including micronutrient utilization, metabolic and energy balance, and amelioration of obesity, Type 2 diabetes and clinical diarrhea in developing countries. It was agreed that additional discussions will be held to create a government - industry - academic partnership to address these issues.
For additional information, please contact Jim Kaput, Ph.D., Director, Division of Personalized Nutrition and Medicine, FDA/NCTR.
Dose-Response Toxicity for Co-Administered Melamine and Cyanuric Acid
Collaborative studies by investigators at NCTR, CFSAN, and CVM suggest that the Tolerable Daily Intake values for melamine (and its analogues) may need to be reviewed to ensure an adequate safety margin for dietary exposure to melamine and its analogues. Evaluation of dose response studies for co-exposure of melamine and cyanuric acid in rodents showed a significant increase in kidney toxicity over studies evaluating exposure of each chemical individually. Cyanuric acid is a common contaminating product of scrap melamine and together these chemicals form an unusually stable crystal structure that can destroy the kidney structure and eventually lead to death. This was particularly striking in the United States, when a large number of cats and dogs died of kidney failure after ingesting pet food intentionally adulterated with melamine and derivatives. A manuscript presenting the results of the study has recently been accepted for publication in Toxicological Sciences.
For additional information, please contact Fredrick Beland, Ph.D., Division Director, or Goncalo Gamboa da Costa, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
International Science Exchange Program
Representatives from NCTR and FDA’s Beijing office participated in a workshop held November 2, 2010, at the Chinese National Institute for the Control of Pharmaceutical and Biological Products in Beijing. Three scientists from the Chinese State Food and Drug Administration (SFDA) shared their experiences at NCTR as part of the International Science Exchange Program (ISEP). During the 4.5 months at NCTR, the scientists developed hands-on experience in applying bioinformatics technologies to regulatory data. NCTR established the ISEP in cooperation with FDA’s Office of International Programs (OIP) to provide training to students, regulators, and academicians from developing countries and to build the scientific infrastructure needed to be successful in the global environment.
For additional information, please contact Weida Tong, Ph.D., Center for Bioinformatics, Division of Systems Biology, NCTR/FDA.
Environmental Mutagen Society
Investigators from multiple NCTR Divisions presented their research at the Environmental Mutagen Society annual meeting held in Fort Worth, Texas, on October 23-27, 2010. Topics included work on mutation assay development, validation, and application; mitochondrial toxicity; and epigenetic changes in toxicity related to the assessment of product safety. Detection and interpretation of changes to our genes and their regulation by drugs and environmental and lifestyle factors are crucial components of the regulatory process. An NCTR scientist also organized and chaired a symposium session titled: “Next Generation Sequencing Technology and Applications.” As sequencing technologies become more scientifically robust, and economically accessible, an individual’s genome sequence promises to become an important component of medical decision making.
For additional information, please contact Donna Mendrick, Ph.D., or Jim Fuscoe, Ph.D., Division of Systems Biology, NCTR/FDA.
November 12, 2010
Regulatory Sciences—BioNanoTox Conference
Dr. Merle Paule presented a plenary lecture titled “The Biology of Neurotoxicity: Using Technology to Advance Discovery” on November 4-5, 2010 at the 5th Annual BioNanoTox and Applications Research Conference held in Little Rock, Arkansas. Additional NCTR investigators presented their research on:
- engineered nanomaterials
- evaluation of genotoxicity of titanium dioxide nanoparticles
- tissue distribution of silver nanoparticles
- transcriptome and microRNA analyses of kidneys from aristolochic acid-treated rats
- bacteria identification by direct impact corona ionization mass spectrometry (DICI MS)
- optimization of analytical methods for measuring low levels of bisphenol A (BPA) and ethinyl estradiol
The BioNanoTox Conference is designed to generate interactions among a variety of disciplines, including biology, chemistry, toxicology, nanotechnology, computational sciences, and engineering.
For additional information, please contact William Slikker, Jr., Ph.D., Director, NCTR/FDA.
Regulatory Science Research Studies Reviewed
The 36th meeting of the Toxicology Study Selection and Review Committee (TSSRC) was held on November 16-17, 2010 at the FDA White Oak Facility, to discuss ongoing studies and newly proposed study designs that are part of the interagency agreement between the FDA and the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) that support the FDA risk assessment process.
The newly proposed studies included:
- Oxybenzone (sunscreen)
- Goldenseal (dietary supplement)
Ongoing studies in the following areas were discussed:
- Food contaminants (Acrylamide, Bisphenol A, Furan, Nanoscale silver, and Melamine)
- Dietary supplements (Bitter orange with caffeine, Usnic acid and Usnea lichen, and Glucosamine and chondroitin sulfate)
- Medical device components/contaminants (DEHP and Nanoscale silver)
- AIDS therapeutics
- Antibacterial chemicals (Triclosan)
The TSSRC is comprised of regulatory scientists and 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 each 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 NCTR, May 17-18, 2011.
FDA Chief Scientist Visits NCTR
FDA Chief Scientist, Jesse Goodman, Ph.D., visited NCTR and Arkansas Children’s Hospital (ACH) on November 30, 2010. Dr. Goodman was briefed by senior NCTR science staff on research priorities and ongoing initiatives, followed by a tour of the facilities at NCTR, ORA's Arkansas Regional Laboratory, and the NCTR satellite laboratory at ACH.
For additional information, please contact William Slikker, Jr., Ph.D., Director, FDA/NCTR.
The Association for Assessment and Accreditation of Laboratory Animal Care, International (AAALAC) granted continued full accreditation to NCTR’s animal facilities and programs. The accreditation team noted excellence in NCTR animal health, training, sanitation/maintenance, occupational safety and health programs, and the extensive certifications of staff veterinarians and animal care staff. NCTR has been fully accredited by AAALAC since 1977, demonstrating a continued commitment to excellence in the conduct of experiments using animals.
For additional information, please contact Jeff Caraway, Division of Veterinary Medicine, Veterinary Services, FDA/NCTR.
Several NCTR scientists presented their research at the Annual Meeting of the Society for Neuroscience held November 13-17, 2010, in San Diego, California. Presentations included studies using a variety of in vitro and in vivo models (neuronal cell cultures, blood-brain barrier models, zebrafish, rodents, and nonhuman primates) to evaluate the expression of neurotoxicity associated with FDA-regulated products; e.g., central nervous system stimulants and anesthetics, nanoparticles, and food contaminants. The Society for Neuroscience is an international multidisciplinary group united by a common interest in the nervous system, and the annual meeting provides the premiere forum for research in this area.
For additional information, please contact Merle Paule, Ph.D., Director, Division of Neurotoxicology, FDA/NCTR.
NTP Board of Scientific Counselors
The National Toxicology Program (NTP) Board of Scientific Counselors (BSC) met November 30 - December 1, 2010, at the National Institute of Environmental Health Sciences. The meeting included:
- A briefing on the Tox21 initiative including an overview of the program
- Reports from Tox21 partners (Environmental Protection Agency, National Institutes of Health Genomics Center, and Food and Drug Administration)
- Updates from Tox21 working groups
- Updates on the science components of the program
Additional, the BSC reviewed toxicology study proposals concerning a mouse methylome project, complex mixture toxicity using cholesterol and lipid modulating agents, N-butylbenzenesulfonamide, and selected flame retardants
The BSC is a federally chartered advisory committee that provides scientific advice to the NTP Director and evaluates the scientific merit of the NTP’s intramural and collaborative projects. Find out more information about FSA's role in the Tox21 Inititative.
For additional information, please contact Paul Howard, Ph.D., Liaison to the NTP, FDA/NCTR.
MicroArray Quality Control (MAQC) Project Meeting
The 12th MAQC (SEQC) Project Meeting was held on December 6-7, 2010, on the campuses of the National Institutes of Health and the U.S. Food and Drug Administration, respectively, and was attended by over 100 participants, including representatives from Germany, France, Russia, and China. The first day focused on discussion of MAQC-III (also known as Sequencing Quality Control, SEQC), including analysis of the results from pilot study data sets, new SEQC study designs, and standards on next generation sequencing data format and analysis. Discussions during the second day dealt with the MAQC-II findings on developing and validating genomic classifiers and the follow-up actions to be taken to ensure the reproducibility of genomic research. The MAQC project is a FDA-led community-wide effort to develop standards for genomic research and bioinformatics to support translational and personalized medicine.
Genomics and Blood-Borne Biomarkers
The identification of new biomarkers of disease and drug toxicity is a growing field of research with many potential biomarkers having been identified; however, many of these studies fail to adequately validate and assess the specificity of the biomarker panel. For clinical utility, emphasis must be on noninvasive biomarkers and recent publications suggest genomic evaluation (mRNA and miRNA) of blood may have great promise. For example, potential blood-borne genomic biomarkers have been identified for various neurological diseases, inflammatory diseases, and adverse drug events. As this science matures, proper qualification and validation of these biomarkers must be addressed (as in the MAQC-II consortia) in order for genomics to fulfill its potential in personalized medicine and improving public health. An invited review on this topic will be published in an upcoming issue of Pharmacogenomics (2011).