Public Health Impact Award—June 21-22
A presentation by Vijayalakshmi Varma, Ph.D., titled “Adipocyte Fructose Metabolism and Its Influence on Glucose Metabolism in Human Adipocytes” was selected for the Public Health Impact Award at the 1st Annual FDA Foods Program Science and Research Conference held at the White Oak Campus. The presentation highlighted recent in vitro data that suggests fructose can alter the metabolism of glucose inside fat cells in a way that promotes the development of obesity, insulin resistance, and type II diabetes.
Antimicrobial-Resistant Pseudomonas in Imported Retail Shrimp
Although prohibited in the U.S., the administration of antibiotics is a common practice in the shrimp-farming industry of developing countries. NCTR scientists have isolated quinolone-resistant strains of Pseudomonas putida and Pseudomonas aeruginosa from imported shrimp purchased in retail stores in the U.S. and have identified novel mutations in their quinolone-resistance genes. This study provides further evidence that suggests the use of antimicrobial agents in aquaculture might promote an increase in the frequency of antibiotic-resistance genes in the microbiota of finfish, crustaceans, shellfish, and the environment. This work has recently been published in the journals Applied and Environmental Microbiology (Vol. 77, p. 1885-1887) and Foodborne Pathogens and Disease (Vol. 8, p. 451-453).
For additional information, please contact Carl E. Cerniglia, Ph.D., Division of Microbiology, FDA/NCTR.
Pig-a Genotoxicity Assay Validation
An international validation trial involving NCTR and over 20 laboratories from Europe, Japan, and North America has shown the Pig-a assay to be reproducible, transferable, and more sensitive than existing genotoxicity assays to agents that primarily induce gene mutation. In vivo (within the body) genotoxicity tests are used to assess the potential of regulated products to induce cancer and other diseases that involve mutation, or as follow-up to sensitive in vitro in vitro (outside the body) tests to determine if the detected genotoxicity is likely to occur in vivo. The Pig-a gene mutation assay, co-invented by FDA scientists, is a fast and simple procedure using an endogenous reporter gene to measure mutation in rat peripheral blood. The assay also shows promise for integration into routinely conducted 28-day general toxicology tests, thus potentially deriving additional information from animals used to conduct routine safety evaluations. A collection of manuscripts describing the validation trial has been accepted for publication in the journal Environmental and Molecular Mutagenesis and will appear in a special issue to appear later this year.
Strategic Planning for NIEHS—July 12-14
William Slikker, Jr., Ph.D., Director, NCTR/FDA, and Paul Howard, Ph.D., Associate Director, Office of Scientific Coordination, NCTR/FDA, participated in the National Institute of Environmental Health Sciences (NIEHS) Strategic Planning Stakeholder and Community Workshop meeting held in Durham, North Carolina. The workshop promoted discussions among NIEHS management and stakeholder scientists from U.S. government agencies, academia, industry, and nongovernment organizations, to refine the NIEHS strategic vision and plan for 2012-2017.
Detection of Mitochondrial Toxicity
NCTR scientists have demonstrated the utility of stable isotope 13C-labeled glucose techniques in following the toxicity in usnic acid-treated, liver cell (hepatocyte) cultures through the uncoupling of mitochondrial oxidative phosphorylation. Usnea extracts have been marketed as weight-loss agents, and reports of liver toxicity prompted the FDA to issue warnings regarding its use in the U.S. Since some weight-loss agents operate through uncoupling of mitochondrial production of adenosine triphosphate, this study demonstrates the potential of this in vitro approach to rapidly screen compounds for this mechanism of action and subsequent toxicity. A manuscript describing this study has been accepted for publication in Food and Chemical Toxicology.
For additional information, please contact Richard Beger, Ph.D., Division of Systems Biology, NCTR/FDA.
Pediatric Inhalation Anesthetic-Induced Neuronal Damage
NCTR scientists have shown that a relatively prolonged administration (8 hours) of the inhalation anesthetics, nitrous oxide and isoflurane, administered in a clinically relevant and balanced regimen, resulted in neuronal damage in multiple brain regions in a neonatal nonhuman primate model. This combination of inhalation anesthetics is commonly used to produce unconsciousness and analgesia (the inability to feel pain) during surgical procedures on human infants and children. The observation of neuronal damage in this nonhuman primate study is an extension of similar findings in rodents but is likely more relevant to the human infant patient.
A manuscript describing this study has recently been accepted for publication in Neurotoxicology and Teratology. To learn more about NCTR's and FDA's efforts to address the critical public-health issues associated with the safe use of anesthesia and sedatives in young children, visit www.smarttots.org2. SmartTots is a collaborative effort between FDA and the International Anesthesia Research Society34, in partnership with multiple stakeholders (e.g. professional societies, academic research institutions, patient advocacy groups, industry, and other government and nonprofit organizations) to address scientific and clinical gaps regarding the safe use of anesthetics and sedatives in children.
Identification of Biomarkers of Idiosyncratic Liver Toxicity
Scientists from NCTR and BG Medicine, Inc., have utilized a molecular-systems approach to explore genomic biomarkers of susceptibility that could predict the potential for idiosyncratic drug-induced liver injury (DILI). The study selected two approved drugs of the same chemical class (entacopone and tolcapone) that showed no indication of hepatotoxicity in preclinical studies. Subsequently, tolcapone was identified with a number of DILI cases in a subset of patients and was given a “black box” warning label after post-market analysis. This study identified five biochemical pathways in rats specific to the tolcapone treatment and a single gene (Vars2) that correlated to conventional diagnostic criteria in a small subset of tolcapone-treated rats. Subpopulations of patients sensitive to idiosyncratic response are not presently identifiable using conventional diagnostic criteria. Thus, the ability to characterize sensitive subpopulations in advance could greatly reduce the risk of idiosyncratic DILI. This study was recently published in the International Journal of Molecular Sciences (2011, 12(7): 4609-4624).
Genomic Biomarkers of Kidney Toxicity From Melamine and Cyanuric Acid Co-Exposure
NCTR scientists have shown that co-exposure to melamine and cyanuric acid increased the expression of five selected genes that encode proteins that have been proposed as urinary biomarkers of nephrotoxicity (KIM-1, TIMP1, clusterin, osteopontin and NGAL). In this study, the gene expression changes in rat kidney tissues were observed at doses that also induced toxicity detectable by histopathology and clinical chemistry. A number of studies have demonstrated that co-exposure to low levels of melamine and cyanuric acid elicits toxicity due to the formation of melamine cyanurate crystals in the kidney. This study adds support to the use of the five biomarkers as indicators of kidney injury and their corresponding gene expression may serve as an additional endpoint in pre-clinical studies. A manuscript describing this study has been accepted for publication in Toxicology Letters.
For additional information, please contact Luisa Camacho, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
Global Summit on Regulatory Science—August 11
NCTR and the Office of International Programs (OIP) co-sponsored the FDA’s Global Summit on Regulatory Science Research and Innovation in Little Rock, Arkansas. The summit included panel discussions and speakers from around the world, including FDA Commissioner Dr. Margaret Hamburg, to explore the future of scientific research as a tool for advancing regulatory science, the role of global collaborations, training, future directions, and innovations to promote global health.
NCTR Celebrates 40 Years of Service—August 12
NCTR officially celebrated its 40th Anniversary. Arkansas Governor Mike Beebe gave the keynote address followed by remarks from Arkansas Senator Mark Pryor, Congressman Mike Ross, and FDA Commissioner Dr. Margaret Hamburg. As part of the celebration, Dr. Hamburg, NCTR Director Dr. William Slikker, and Governor Beebe took part in an official signing of a Memorandum of Understanding (MOU) between the FDA, NCTR, and the State of Arkansas to create a Virtual Center of Excellence for Regulatory Science. Other invited guests included FDA senior scientists and management officials, former NCTR directors, international scientists, and distinguished guests from Arkansas government, the University of Arkansas system, Arkansas State University, hospitals, and private industry. Tours of the NCTR facility and the ORA Arkansas Regional Laboratory, and a poster session highlighting the scientific research conducted at NCTR completed the celebration agenda.
Women’s Health Research at NCTR—August 10
NCTR hosted an Office of Women’s Health sponsored workshop, “Updates and Strategies for FDA Regulatory Impact for 2020: A Vision for the Future." The workshop focused on critical needs for women’s health research identified in the Institute of Medicine 2010 Report and the Health and Human Services-National Institutes of Health Office of Women’s Health 2020 Strategic Plan that also affect FDA regulatory evaluations. In the field of personalized medicine for example, large disparities exist in mortality rates among certain ethnic groups in breast cancer, cardiovascular disease, and cervical cancer despite major advances in overall survival outcomes for these diseases. Specific research strategies also were discussed including the use of sex parameters in the design of animal model experiments; the development of information systems to collect, share, and compare clinical data; and the development of computational models that address qualitative and quantitative outcomes in clinical research related to women. These workshops further provide opportunity to form strategic alliances and partnerships that maximize resource utilization, and increase the impact of OWH-sponsored research.
Science Advisory Board Site Visit—August 16-17
A subject-matter expert subcommittee was convened by the NCTR Science Advisory Board (SAB) to conduct an in-depth evaluation of the NCTR/ORA Nanotechnology Core Facility. Representatives from the FDA’s Office of the Commissioner, CDRH, CDER, CVM, CBER, and CFSAN, as well as the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) participated in the evaluation. The site-visit report will be presented at the full meeting of the NCTR SAB scheduled for November 9-10, 2011. The NCTR SAB advises the NCTR Director in establishing, implementing, and evaluating the Center’s research program. The Nanotechnology Core Facility is jointly sponsored by the FDA’s NCTR and Office of Regulatory Affairs, and NIEHS/NTP to support nanotechnology-related scientific studies through the characterization and detection of nanomaterials in toxicology studies and to develop analytical methods to accurately monitor nanotechnology-based FDA-regulated products.
Reducing Salmonella in Egg and Poultry Production
NCTR scientists and collaborators from the Universities of Arkansas, Tennessee, and Minnesota have published a review (Applied and Environmental Microbiology 2011. 77: 4273-4279) that analyzes historical population shifts of Salmonella serotypes in commercial egg and poultry production settings. Shifts in Salmonella serotypes during production appear to be driven by a combination of bacterial factors, host-related factors, and management practices. An understanding of factors involved with changes in population dynamics suggest improved intervention strategies to control new Salmonella outbreaks and help limit the emergence of Salmonella serotypes with increased virulence and/or antimicrobial resistance in poultry operations. Multiple species of Salmonella are frequently present in the intestines of chickens and controlling the spread of pathogenic serotypes is a constant challenge in production facilities.
For additional information, please contact Steven Foley, Ph.D., Division of Microbiology, NCTR/FDA.
Drugs of Abuse and Addiction—August 23-26
NCTR scientists presented their research in Istanbul, Turkey at the 3rd International Drug Abuse Research Society (IDARS) meeting held August 23-26, 2011. Topics of FDA research included the neurotoxicity of pediatrics anesthetic agents, amphetamines, and nicotine and other tobacco-related chemicals. Additionally, William Slikker, Jr., Ph.D., Director, NCTR, and Merle Paule, Ph.D., Director, Division of Neurotoxicology, moderated a session on general anesthetics. IDARS is an international scientific organization that promotes and fosters the research and collaboration of scientists around the world in the area of substances of abuse and addiction.
Surface Coating of Single-Walled Carbon Nanotubes Reduces Toxicity
NCTR scientists, in collaboration with the University of Arkansas at Little Rock, have shown that coating single-walled carbon nanotubes with polyethylene glycol (PEG) significantly reduced the toxicity and the resulting expression of genes involved in oxidative stress in an in vitro model system. Single- and multi-walled carbon nanotubes are being developed for applications in multiple fields including imaging, drug delivery, photo- and acoustic-therapeutics, and inclusion in devices and packaging materials. This study supports existing data that show surface properties of many nanomaterials play an important role in biological responses. Those data can influence the development of low-toxicity surface treatments for carbon nanomaterials to be used in a number of nanomedicine applications ranging from tissue engineering to cancer targeting and destruction. A manuscript describing the study was recently accepted for publication in ACS Nano (DOI: 10.1021/nn2016259).
For additional information, please contact Yongbin Zhang, Ph.D.
EUROTOX 2011—August 28-31, 2011
William Slikker, Jr., Ph.D., Director, NCTR, served as organizer and co-chair of the SOT/EUROTOX Debate at the 47th Congress of the European Societies of Toxicology (EUROTOX) in Paris, France held August 28-31, 2011. The topic of the debate was “Biomarkers from blood and urine will replace traditional histopathological evaluation to determine adverse responses.” EUROTOX is a federation of national societies of toxicology throughout Europe with the mission of supporting toxicological research and education.
The 13th Meeting of the MicroArray Quality Control (MAQC) Project—September 13-14
The MAQC Project Meeting, held on September 13-14, 2011 on the SAS campus in Cary, North Carolina, focused on the third phase of the MAQC project (MAQC-III), which is also known as the Sequencing Quality Control (SEQC) Project. The two-day workshop addressed the applications of next-generation sequencing technologies in translational and regulatory sciences and was attended by government, academic, and industry scientists from the United States, China, Germany, Italy, Austria, and Australia. The participants discussed preliminary data obtained from the SEQC Project and also outlined plans for further development and publication of the results from the project. The MAQC project is an FDA-led community-wide effort to develop standards for genomic research and bioinformatics to support translational and personalized medicine.
Medical Countermeasures Lecture
Donna Mendrick, Ph.D., Director, Division of Systems Biology, NCTR/FDA, gave a lecture sponsored by FDA’s Medical Countermeasures initiative (MCMi) at the White Oak campus on September 15, 2011. The seminar, titled “New Approaches in Toxicology,” focused on:
- issues with drug safety and efficacy
- challenges for identification and qualification of biomarkers
- emerging alternative approaches, including omics, in silico modeling, bioimaging, stem cells, and zebrafish, which are being explored in multiple research divisions within NCTR.
For additional information or a copy of the PowerPoint presentation, please contact Dr. Donna Mendrick.
NCTR welcomed four invited speakers for seminars and discussions with the research staff.
- Glenn Millner, Ph.D., from the Center for Toxicology and Environmental Health, L.L.C., gave an update on the Gulf Oil Spill and their industrial-hygiene support activities during the clean-up.
- L. Michael Carastro, Jr., Ph.D., from the University of Tampa, presented an overview of his studies with the tumor-suppressor gene p53 and its relation to gene transcription and translation.
- Michael Waalkes, Ph.D., from the National Institute of Environmental Health Sciences and the National Toxicology Program (NTP/NIEHS), presented his work on carcinogenesis induced by whole-life exposure to arsenic in animal models. In his presentation, Dr. Waalkes emphasized the role that stem cells play in the mechanism of arsenic carcinogenicity.
- Harvey Clewell, Ph.D., from The Hamner Institutes for Health Sciences, presented an overview of The Hamner Institutes' plan for implementing in vitro toxicity testing in safety assessments for chemicals and drugs. This move is in response to the 2007 U.S. National Research Council report “Toxicity Testing in the 21st Century: A Vision and a Strategy” that proposed a shift in toxicity testing to high-throughput, mechanistic in vitro assays using human cells. The Hamner Institutes is an independent organization that works with academia, industry, and government in support of innovative research and technology development.
Visiting Speakers-September 26-30
NCTR welcomed three speakers for seminars and discussions with the science staff concerning potential collaborations during the week of September 26-30, 2011:
- Yvonne Will, Ph.D., from Pfizer Research and Development, gave a seminar on the use of mitochondrial screens early in the drug-discovery process to reduce the late-stage attrition of many drug candidates.
- Donald R. Mattison, M.D., Capt., U.S. Public Health Service, from the National Institute of Child Health and Human Development, gave a presentation on the roles of regulatory science in public health.
- Denita Williams, Ph.D., from the Centers for Disease Control and Prevention, presented her work on characterizing susceptibilities and assessing risk to Listeria monocytogenes exposure using pregnant animal models.