APRIL 2009 NCTR HIGHLIGHTS
NCTR/ORA Methods Validation Workshop
NCTR hosted a joint Methods Validation Workshop with the FDA's Office of Regulatory Affairs (ORA) at Jefferson Laboratories on March 26 and 27. FDA representatives from the Center for Veterinary Medicine and the Center for Food Safety and Applied Nutrition joined the participants from Jefferson Laboratories. The workshop provided the following:
- an overview of current ORA field operations and analysis related to food
- a review of the current validation requirements for both chemical and microbiological methods
- a discussion of the efficient transfer of methods from the research laboratory to ORA
The workshop served as a framework for improving the development of analytical technologies that can detect, assess, manage, and prevent food contamination, and provided an agreement was made to proceed with the validation of one rapid-method technology, RAPID-B, developed at NCTR.
For more information, contact Dr. Margaret A. Miller, Associate Director for Regulatory Activities, NCTR.
Jefferson Laboratories Radiation Safety Program
In accordance with Nuclear Regulatory Commission (NRC) regulations, the NCTR Radiation Safety Officer (RSO) and the Radiation Safety Committee (RSC) recently completed an annual review/audit of the Jefferson Laboratories radiation safety program. The RSO and RSC reviewed program records to include user approvals, protocol applications, radioactive-material orders, inventory levels, and dosimetry records. The findings of this review concluded that the program is functioning as designed, is operating within the bounds of the Radiation Safety Committee's "As Low as Reasonably Achievable" (ALARA) guidance, and all necessary management controls and oversight are in place. The program is in compliance with all applicable NRC regulations set forth in the 10 CFR 20.1101 and license conditions found in the latest issuance of the NRC By-Product Materials license (June 22, 2007). This report provides the NCTR Director with necessary Assurances that the program is in compliance with all regulatory requirements.
For more information, contact Jennings Partridge, Associate Director, Regulatory Compliance and Risk Management, NCTR.
Janus Working Group Meeting
On April 15-16, 2009, the Janus Executive Sponsor, Project Manager, several members of the Janus Senior Management Team (SMT), and the Executive Director of the FDA Bioinformatics Board (BIB) met in Jefferson, Arkansas, with the staff from the NCTR Center for work (SOWs) for Janus to clearly identify responsible parties and delineate required action items. The Janus initiative is to provide the capability for electronic review and structured scientific data for more informed decision making and to pave the way for new methods needed for personalized medicine and nutrition.
For more information, contact Jeanne Anson, Executive Officer, NCTR.
NCTR Neurosciences Community Service
The NCTR Division of Neurotoxicology conducted a live question-and-answer session at the Eighth Annual Central Arkansas Brain Bee for grades 9-12 at the Museum of Discovery in Little Rock, Arkansas. The winner, from the Arkansas School for Mathematics, Sciences and the Arts, represented Arkansas at the National Brain Bee. The neuroscientists from NCTR also manned daylong interactive exhibits at the museum for children and parents. Visitors engaged in a battery of operant conditioning tasks that are used by NCTR to study cognitive function in laboratory animals. Even the youngest visitors participated by using red-colored cake icing to paint arteries onto brains molded from Jell-O. These activities are held to increase awareness of the neurosciences and the relationship of brain health to well-being.
For more information, contact Dr. Merle Paule, Director, Division of Neurotoxicology, NCTR.
MAY 2009 NCTR HIGHLIGHTS
Environmental Remediation Using Mycobacterium
The Division of Microbiology has completed a series of studies using systems-biology approaches to characterize the complete metabolic pathways for the degradation of high-molecular weight polycyclic-aromatic hydrocarbons (PAH) using Mycobacterium vanbaalenii PYR-1. Many high-molecular weight PAHs are known carcinogens and high-priority pollutants that have been detected in FDA surveys of finfish and shellfish. Reducing the environmental levels of PAH contamination is one option to reduce these concentrations in fish. The research approaches developed from these studies can serve as examples for sponsors responsible for documenting the environmental fate and toxicity profiles required to obtain approval for human and veterinary medical products. Similarly, crucial human antimicrobials have been detected in agribusiness environments that in turn have produced antimicrobial resistance in soil bacteria. Environmental remediation may again be a key to sustaining high levels of agri-production and decreasing risk of unwanted results of modern agri-medicine.
For further information, please contact Dr. Seong-Jae Kim or Dr. Carl E. Cerniglia, Division of Microbiology, NCTR.
New Mechanistic Information for a Standard Genetic Toxicology Assay
Experiments confirm the full spectrum of adverse genetic mutations induced by chemical agents is detected by the Mouse Lymphoma Gene-Mutation Assay (MLA). NCTR scientists have recently completed research that capitalizes on newly developed molecular and cytogenetic techniques and provide definitive proof that the MLA is capable of detecting most, if not all, of the chromosomal mutations known to be involved in human-cancer development and other genetically based human disease. The Mouse Lymphoma Gene-Mutation Assay is recommended in most international regulatory guidance, including the International Conference on Harmonization (ICH) and the Center for Food Safety and Applied Nutrition (CFSAN) Redbook as the in vitro gene-mutation assay for preclinical safety evaluation and for other regulatory decisions based on identifying the potential for a chemical to cause the induction of mutation and/or cancer. The original recommendation for preferring this gene-mutation assay over a number of other in vitro gene-mutation assays was based on research elucidating the types of genetic damage detected by the assay. Unfortunately, at the time this research was conducted, the findings were somewhat limited by the available technologies that could be applied to the analysis. Recognizing the need for further clarification, NCTR scientists conducted the key research and published the results in the latest issue of Toxicological Sciences 109(1): 96-105, 2009.
For further information, please contact Dr. Martha Moore, Director, Division of Genetic & Reproductive Toxicology, NCTR.
Epigenetic Changes—New Biomarkers for Cancer
Rapid identification and appropriate regulation of human carcinogens before dissemination into society is critical for the prevention of neoplasia (tumor formation). Historically, to assess safety, toxicologists have focused on measurements of DNA damage, DNA adduct formation, and mutations as the most appropriate indicator of carcinogenic potential. The recognition that epigenetic mechanisms have a roll in carcinogenesis has challenged the current approach to carcinogenicity testing and indicates the need for a new generation of cancer biomarkers. The results of several recent studies, conducted by NCTR scientists in the Division of Biochemical Toxicology, demonstrated that chemical carcinogens, in addition to specific carcinogen-induced genotoxic changes, resulted in:
- profound epigenetic alterations characterized by dysregulation of DNA methylation
- histone modifications
- altered gene expression
- miRNA expression
These findings are particularly significant because they demonstrate that different carcinogenic agents induce similar early epigenetic alterations that occur in target organ. The remarkable feature of carcinogen-induced epigenetic changes is their early appearance and correspondence to those frequently found in tumor cells, suggesting that these alterations may be used as biomarkers for carcinogenic process and as a novel approach for carcinogenicity testing and cancer risk assessment. The potential reversibility of epigenetic alterations makes them promising targets for chemoprevention strategies.
For more information, please contact Dr. Fred Beland, Director, Division of Biochemical Toxicology, NCTR.
Regulatory Research Studies Review
The Toxicology Study Selection and Review Committee (TSSRC) met May 19-20 at the National Center for Toxicological Research in Jefferson, Arkansas, to discuss ongoing studies and newly proposed study designs that are part of the interagency agreement between FDA and the National Toxicology Program/National Institute of Environmental Health Sciences (NTP/NIEHS) that support the FDA risk-assessment process.
Newly proposed studies include:
- Triclosan (antibacterial component in many products)
- Goldenseal (dietary supplement)
- Nanoscale zinc oxide (food contaminant, present in numerous products)
- Cell phone radiation
Ongoing studies that were discussed include:
- Acrylamide (cooking contaminant)
- Bitter orange (Citrus aurantium) with caffeine (dietary supplement)
- Bisphenol A (food contaminant)
- di(2-ethylhexyl)phthalate (DEHP; plasticizer in medical devices)
- Furan (cooking contaminant, carcinogen)
- Ketamine (anesthetic agent)
- Melamine with cyanuric acid (food contaminant)
- Nanoscale silver (food contaminant, medical device component/contaminant)
- AIDS therapeutics
- Usnic acid and Usnea lichen (dietary supplement)
- Permanent makeup inks (obtained from adverse event)
- Glucosamine and chondroitin sulfate (dietary supplement)
The TSSRC is comprised of subject experts from FDA, scientists from NIEHS, and invited subject-matter experts from other government agencies, industry, and academia. The committee meets twice a 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 FDA's White Oak campus in Maryland, November 3-4, 2009.
Food, Famine, and Future Technologies: Ethical Dilemmas in a Hungry World
This conference, which was held on May 22-23 at the Appignani Bioethics Center, provided an international forum for the exchange of ideas, experiences, and views regarding the priority needs and possible strategies of enhancing the capacities of developing and transitional economies to assess risk and monitor genetically modified organisms (GMO). Jim Kaput, Director of the Division of Personalized Nutrition and Medicine, National Center for Toxicological Research, presented a talk on "Nutrigenomics: Implications for Addressing Malnutrition" in the Perils and Promises of the Science of Nutrition production and use of in vitro meats for sustainable food production, agricultural practices, the politics of food, and the impact of biofuels on food availability in developing nations.
The conference was co-organized by the University of Montreal Bioethics Center and the Appignani Bioethics Center. The Appignani Center sponsors scholarly meetings on prventive medicine and partners with health care professionals and Non Government Organizations to provide education and opportunities for confronting various medical issues facing developing world countries.
JUNE 2009 NCTR HIGHLIGHTS
Several NCTR staff attended the third Interagency Computational Toxicology Colloquium on June 11, 2009, at the Environmental Protection Agency (EPA) located in Research Triangle Park, North Carolina. The meeting was hosted by Dr. Richard Judson, EPA. This is an evolving interagency collaborative effort that involves computational toxicology staff from Food and Drug Administration, EPA, Agency for Toxic Substances and Disease Registry, Department of Defense, National Institutes of Health, and National Institute of Environmental Health Sciences. Agenda topics included:
- Liver toxicity-testing prioritization strategies
- Development of virtual tissue models
- Metabolism-pathway modeling in silico (performed on a computer)
- Data sharing
- Futre of genomics for Computational Toxicology (toxicology in silico)
For more information, contact Dr. William Slikker, Director, NCTR, or Dr. Donna Mendrick, Director, Division of Systems Toxicology, NCTR.
Validation of E.Coli 0157 Rapid Assay
Scientists from the Arkansas Department of Health and Centers for Disease Control and Prevention have released a Food Emergency Response Network (FERN) Level-2 validation study for rapid detection of E.Coli 0157 in spinach, jalapeno peppers, and 80/20 ground beef. The innovative rapid assayknown as RAPID-B was introduced by National Center for Toxicological Research (NCTR) scientists and commercialized by Food and Drug Administration Cooperative Research and Development Agreement (CRADA) partner LITMUS RAPID-B, LLC.
RAPID-B outperformed the FDA BAM-reference method in speed and accuracy at low levels of contamination. RAPID-B demonstrated both 100% inclusivity and exclusivity in the tests. This class of bacteria is recognized as the primary cause of bloody diarrhea that may result in death. RAPID-B also has been shown useful in environmental testing/disinfection conditions, responding only to live bacteria and providing results in several minutes, from sample acquisition at low levels of contamination (~5 organisms/ml); and its range is extended to one organism per 25 grams of food following 4-6 hours of enrichment in nonselective Trypticase Soy Broth. RAPID-B is serviceable with minimal training and is both rugged and mobile for field deployment. NCTR and CRADA scientist have also neared completion of test-panel results for the Salmonella cultivars most frequently responsible for food poisoning.
For more information, contact Dr. William Slikker, Director, NCTR.
National AALAS Award
Three National Center for Toxicological Research (NCTR) employees were elected as officers on June 19, 2009, at the annual meeting of the Arkansas Branch of the American Association for Laboratory Animal Science (AALAS) that was held at the William Jefferson Clinton Library in Little Rock, Arkansas. It was also announced the Arkansas Branch was the winner of the national "AALAS Challenge," topping all 48 AALAS branches for percent increase membership growth.
Over 90% of NCTR's animal care workforce is AALAS certified reflecting both individual and institutional commitments to excellence in animal care and use.
The American Association for Laboratory Animal Science is dedicated to the humane care and treatment of laboratory animals. AALAS is the premier national animal-care certification organization, and it is the top forum for the exchange of information and expertise in laboratory animal science and certifies individuals who care for animals used in the conduct of responsible biomedical research.
For more information, contact Dr. Jeff Carraway, Director, Division of Veterinary Services, NCTR.