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NCTR Research Highlight - February 20, 2009
Science Advisory Board Review –
A site-visit team from the
NCTR Science Advisory Board (SAB) met at NCTR on February 18-19, 2009,
for an in-depth analysis of research programs within the Division of
Systems Toxicology. The site-visit team—led by SAB member, Dr. Cynthia
Afshari—was
comprised of subject experts from academia, industry, National Institutes
of Health, and Environmental Protection Agency.
Representatives from each of the other FDA Centers, Office of Commissioner, and Office
of Regulatory Affairs actively
participated to provide scientific and regulatory advice and to enhance
FDA-wide communication.
Scientists from the Division
of Systems Toxicology presented results and future plans for studies on
biomarker identification, food safety (rapid identification of
contaminants), personalized therapies, bioinformatics, and electronic
submission. The Division is composed of the following six interactive
Centers of Excellence working together to integrate biologically based
systems, chemistry, engineering, and computational science:
Functional Genomics
Hepatotoxicity
Innovative Technologies
Metabolomics
Proteomics
Toxicoinformatics NCTR Research Highlight - February 6, 2009New
Records Storage Facility –
The NCTR Federal Records Schedule has
been revised, approved, and published. The kickoff phase will begin in
March with a series of training sessions for all employees. These
sessions, presented by representatives from the National Archives and
Records Administration (NARA) and the NCTR Regulatory Compliance and
Risk Management staff, will provide a general overview of Federal
Records Management guidelines and specific information about NCTR’s
revised record schedules.
In
concert with the implementation of NCTR’s revised record schedule, NCTR
records are being moved into the newly constructed Records Storage
Facility. This 7,000 sq. ft. facility was designed to accommodate
NCTR’s scientific, financial, and administrative records in compliance
with NARA guidelines. During the move, NCTR Records Management staff
will verify record inventories and review disposition dates in
accordance with the new schedule. For
more information, contact Jennings Partridge, Associate Director,
Regulatory Compliance and Risk Management, NCTR. NCTR Research Highlight - January 30, 2009Retirement and Change in FDA Liaison to NTP – William T. Allaben, Ph.D., retired from the National Center for Toxicological Research (NCTR) effective January 3, 2009. Dr. Allaben served the public and the U.S. Government for a total of 36 years, with 33 of those years at the FDA/NCTR and was awarded the DHHS Career Achievement Award from Secretary Levitt. In 1992, Dr. Allaben was instrumental in founding the FDA-NCTR/NIEHS National Toxicology Program (NTP) Interagency Agreement (IAG), and he served as FDA’s Liaison to that IAG for 17 years. Dr. Allaben organized the FDA Chemical Selection Working Group, which forwards nominations to the NTP. All studies reviewed at the biannual Toxicology Study Selection and Review Committee meetings, chaired by Dr. Allaben and the NTP IAG Project Officer, Dr. John Bucher, included key personnel from all FDA Centers, NIEHS, EPA, NIH, and invited subject-matter experts from industry and academia. Under Dr. Allaben’s leadership, NCTR has worked with the NTP to provide FDA regulatory scientists with valuable scientific data on 31 compounds. Dr. Paul C. Howard succeeded Dr. Allaben as FDA’s Liaison of the NTP IAG effective January 2009. NCTR Research Highlight - January 23, 2009Hepatotoxicity Working Group – The first meeting of the Hepatotoxicity Working Group was held at NCTR on Friday, January 16, 2009. The working group included representatives from government, academia, and industry. Future areas of potential research and collaboration were discussed including one possible study involving data from multiple types of omic platforms from a number of compounds. This study could lead to biomarkers that would improve the detection of idiosyncratic drugs and lead to clues as to a drug’s mechanism underlying its ability to induce toxicity of an idiosyncratic nature. For more information, contact Dr. Donna Mendrick, Director, Division of Systems Toxicology, NCTR. NCTR Research Highlight - January 16, 2009The Human Variome Project (HVP) – NCTR participated in the HVP (http://www.humanvariomeproject.org/) planning meeting convened by the Genomics Disorders Research Centre in Melbourne, Australia. The HVP will systematically collect mutations that cause human disease and create the cyber infrastructure to link locus-specific databases to international databases such as the NIH Center of Biotechnology Information and the European Bioinformatics Institute. These efforts will generate datasets necessary for linking individual genetic variation to responses to food, environmental influences, medical treatments, and drugs. The HVP is recognition that significant population differences to the existing genome consensus sequence drive the differences in personalized nutrition and medicine. (In press; Kaput et al. Human Mutation 2009). For more information, contact Dr. James Kaput, Director, Division of Personalized Nutrition and Medicine, NCTR. NCTR Research Highlight - January 9, 2009Modernizing Tools for Safety Assessment – Fifty scientists from the FDA, EPA, CDC, and NIH convened at the 2nd Inter-Agency Computational Toxicology Colloquium held at NCTR on December 10 and 11, 2008. Three major initiatives were selected for development into cross-agency research proposals: · Development of in silico compound screening and prioritization models for liver toxicity in both animals and humans · Development of high-throughput screening data-based approach for chemical mixture component grouping, toxicity endpoint prediction, and risk/safety assessment · Use of high-information content data, such as microarray data, to predict individual susceptibilities and population risk to chemicals and drugs Written proposals for the in silico modeling and draft documents for chemical mixtures analysis initiatives are circulating among participant agencies for comment. For more information, contact Dr. William Slikker, Director, NCTR, or Dr. James Fuscoe, Division of Systems Toxicology, NCTR. NCTR Research Highlight - December 19, 2008Food Defense – NCTR and USDA scientists have characterized the survivability of Bacillius anthracis Stern (a surrogate for pathogenic B. anthracis) spores in processed liquid media of whole eggs, egg white, sugared egg yolk, or salted egg yolk. The most critical finding was that the spores were inactivated completely within 1-6 hours in egg white at cold, moderate, and high storage temperatures. The findings for the other products varied. This data can be used by government agencies to develop “value-added” risk-assessment models in evaluating the consequences of deliberate inoculation of anthrax spores in a high-volume commercial-food matrix such as eggs. (Accepted for publication in Food Microbiology.) For more information, contact Dr. Saeed Khan or Dr. Carl E. Cerniglia, NCTR. NCTR Research Highlight - December 12, 2008Scientists Promote International Harmonization – NCTR scientists attended the 37th Annual Meeting of the Japanese Environmental Mutagen Society and the International Symposium on Genotoxicity Assessment - New Concept, Strategy and Regulation December 3-6, 2008, in Okinawa, Japan. NCTR's invited presentations included:
NCTR scientists also participated in a planning session for the next International Workshop for Genotoxicity Testing, which will serve as a forum for the international discussion and harmonization of issues related to safety evaluations using genetic toxicology tests. The workgroups include experts from Europe, Japan, and the United States. For more information, contact Dr. Martha Moore, Director, Division of Genetic and Reproductive Toxicology, NCTR. NCTR Research Highlight - December 5, 2008
Drug-Induced Liver Injury –
Drug-induced
liver injury is the primary adverse event that results in withdrawal of
drugs from the market and a frequent reason for the failure of drug
candidates in development. For more information, contact Fred A. Beland, Ph.D., Division of Biochemical Toxicology, NCTR. NCTR Research Highlight - November 21, 2008NCTR Proposals Reviewed by TSSRC – The Toxicology Study Selection and Review Committee (TSSRC) met November 18-19 at the White Oak Campus to discuss ongoing studies and newly proposed study designs that are part of the interagency agreement between the FDA and the National Toxicology Program (NTP/NIEHS) that support the FDA risk assessment process. Dr. Frank Torti, FDA’s Chief Scientist and Deputy Commissioner, gave the opening comments.
The newly proposed studies included:
Ongoing studies that were discussed included:
NCTR Research Highlight - November 14, 2008
NCTR's Center for Innovative Technologies –
The Division of
Systems Toxicology, NCTR, would like to announce the formation of a new
Center of Excellence, the Center for Innovative Technologies. The
Center will be co-directed by Drs. Jon Wilkes and Dan Buzatu, two
research chemists who invented and developed several technologies
important to the FDA’s mission and public safety. Two of these
technologies are Spectrometric Data Activity Relationship (SDAR) and
RAPID-B.
For more information, contact Dr. Donna Mendrick, Director, Division of Systems Toxicology, NCTR, or Dr. William Slikker, Director, NCTR. NCTR Research Highlight - October 31, 2008Novel Algorithm To Select Stable Biomarkers for Prediction from High-Dimensional Data – NCTR statisticians have developed a novel algorithm that optimizes the selection of biomarkers that reliably produce better diagnosis of disease, an earlier intervention to disease, and/or a more effective assignment of therapies. Standard procedures for selection of classification biomarkers for cancer prognosis are highly variable depending on the disease status and the fact that the number of informative markers is small compared to the large number (i.e., high-dimensional data) of variables (e.g., clinical chemistries, genes, proteins, etc.) examined. The novel algorithm selects the most stable (reproducible) predictor set of biomarkers based on the most frequently selected criterion developed from cross-validation techniques. The resultant set of biomarkers from this algorithm is shown to be more stable than the set selected from standard procedures. This algorithm can be applied to any procedure for development of biomarker classifiers. For further information, contact Dr. James Chen, Division of Personalized Nutrition and Medicine, NCTR. NCTR Research Highlight - October 19, 2008
Food Safety Research—Azo/Sudan Dyes –
NCTR’s Division of
Microbiology scientists have expertise and a long-standing interest in
assessing the risks of exposing the gastrointestinal-tract microbiota of
human consumers to contaminated-food products, probiotics, antimicrobial
agents, and dietary supplements. Sudan dyes belong to a family of
industrial dyes normally used for coloring plastics and other synthetic
materials. Sudan dyes are not allowed to be added to food. There has
been worldwide concern about the contamination of chili powder, other
spices, and baked foods with Sudan dyes since they may have genotoxic
and carcinogenic effects (according to the International Agency for
Research on Cancer). The recent detection of Sudan dyes in various food
commodities require toxicological evaluation since adulteration of food
products by these dyes constitutes a public health risk. Although azo
dyes can be reduced by the mammalian liver to form aromatic amines, it
has been suggested that intestinal microbiota could be primarily
responsible for the in vitro reduction of azo dyes. For further information, please contact Dr. Huizhong Chen or Dr. Carl E. Cerniglia, NCTR. NCTR Research Highlight - October 3, 2008Laser Microdissection Technique Opened to FDA Investigators – Toxicologic Pathology Associates (TPA), the onsite NCTR pathology support contract, has opened its laser microdissection service for investigators. The laser microdissection (LMD) technique provides an easy and rapid method to isolate target cells for further analyses and more accurate results. LMD is particularly useful in capturing single-cell types for analysis in heterogeneous-cell populations that commonly occur in tumors. Material has been provided for several projects that have a potential to reveal biomarkers for early detection of tumors. TPA continues its trend to develop state-of-the-art core technology and expertise in support of investigators, including the video-technology systems that enable meetings of pathology-consultant groups established for consensus analysis of results from GLP studies. For further information, contact Drs. Ritchie Feuers or Thomas Flammang, NCTR. NIEHS Leadership Visits NCTR – Dr. Sam Wilson, Acting Director of the National Institute for Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP), and Dr. John Bucher, Associate Director for NTP, visited NCTR on October 3rd. Drs. Wilson and Bucher were given an overview of NCTR’s developing imaging and nanotechnology facilities, and they discussed applications for preclinical studies with NCTR scientists. The NCTR, NIEHS, and the NTP initiated joint studies in 1978, and they have collaborated continuously, since 1993, through an Interagency Agreement (IAG) to conduct research and testing on FDA-nominated agents to the NTP using FDA scientists as study directors and principal investigators. The visit concluded with a tour of the NCTR facilities, including the FDA/NCTR - NIEHS/NTP Phototoxicology Research and Testing Laboratory, designated the NTP Center for Phototoxicology. The next FDA-wide study review, conducted under the IAG, is scheduled on November 18-19, 2008, at FDA's White Oak campus. For more information, contact Dr. William T. Allaben, Associate Director for Scientific Coordination and FDA Liaison to the NTP, or Dr. William Slikker, Director, NCTR. NCTR Research Highlight - September 19, 2008Critical Path Initiative – Seven NCTR scientists presented their research programs at the Drug Information Association Critical Path Symposium held September 15-16 in Bethesda, Maryland. The presentations were grouped under three NCTR strategic initiatives: 1) increased productivity for pre and postmarket activities; 2) translational biomarkers of toxicity/safety; and 3) noninvasive and minimally invasive technologies for safety evaluation. Specific interests included:
Jefferson Laboratories World Fest – International diversity was celebrated at Jefferson Laboratories on September 18 as employees shared the color, music, traditions, and food from 15 countries. This year five new displays were added representing the culture of different states. The annual event has become popular on campus with each booth presenting samples of traditional recipes. For further information, contact Dr. William Slikker, Jr., Director, NCTR. NCTR Research Highlight - September 12, 2008
Novel Methodology Supporting Rapid Detection of Bacterial Food
Contaminants – NCTR
mathematicians have developed a novel algorithm to predict the optimal
testing range and then identify
characteristic bacterial genes found in comparative genomic microarray
(“gene chip”) technologies that are proposed for rapid detection of food
contamination. The novel statistical technology, known as
change-point estimation, relies upon
finding an optimal graphical representation from multiple data points in
noisy systems (multivariate adaptive regression spines).
It has outperformed existing
algorithms for specificity and accuracy in the analysis of two
publically available data sets. Comparative genomic analysis for
bacterial contaminants in foods requires more advanced statistical
techniques because of a high probability that food samples may
simultaneously contain several different species.
For further information, contact Dr.
James Chen, Division of Personalized Nutrition and Medicine, NCTR. NCTR Research Highlight - September 5, 2008Records Control Schedule Approved – The revised NCTR Records Control Schedule received final approval July 30, 2008 when the SF-115 was signed by the U.S. Archivist. The revised schedule includes NCTR Program Records, GLP (Good Laboratory Practice) experiment records, GCP (Good Clinical Practice) experiment records, technical reports, environmental and health records, and a variety of database records. The NCTR Records Management Staff will develop and present a series of training sessions to inform all employees of these new requirements. The goal is to implement an active and continuing program that ensures compliance with federal regulations for the creation, use, maintenance, and disposition of the Center’s federal records. Federal records must be stored in such a way that they are both sufficiently accessible and are safeguarded against loss. To meet federal requirements for the safekeeping of records, a new NCTR Records Repository and Archives is scheduled to be complete by October 2008. For more information, contact Jennings “Cody” Partridge, Associate Director, Regulatory Compliance and Risk Management, NCTR. NCTR Research Highlight - August 29, 2008Critical Path—Noninvasive Imaging – NCTR scientists have completed trial experiments in the new NCTR MicroPET Imaging Center investigating whether, early in development, anesthetic exposures alter patterns of normal programmed cell death. PET, or Positron Emission Tomography, is most commonly known for its use in oncology clinics to detect tumor masses and follow the course of disease and treatment effects. However, PET also is highly versatile in monitoring changes in body metabolism in health and disease through use of a variety of positron-emitting radiochemicals. Utilization of the NCTR facility is enhanced through cooperation with the nearby University of Arkansas for Medical Sciences cyclotron facilities that provide the short half-life radiochemicals required for this work. Use of MicroPET, which is configured specifically for very high quality imagery in small animals and other imaging techniques, will provide the FDA with noninvasive procedures for repeatedly monitoring and detecting the time-course of rarer toxicological events that may have direct applications in clinical settings. For further information, contact Dr. Merle Paule, Director, Division of Neurotoxicology or Dr. William Slikker, Jr., Director, NCTR. NCTR Research Highlight - August 22, 2008Science Advisory Board Meeting at NCTR – The National Center for Toxicological Research (NCTR) held a Science Advisory Board Meeting in Jefferson, Arkansas, on August 12 and 13. In attendance were all members of NCTR’s Science Advisory Board, representatives from the Office of the Commissioner, each of the Product Centers, a member of FDA’s Science Board, the University of Arkansas Little Rock, and the University of Arkansas for Medical Sciences (UAMS). On August 12, the NCTR Divisions provided the following updates: current research activities focusing on major finds of the past year, their importance, and major issues associated with their current research. The Site Visit Subcommittee Chair presented the visit review of the Division of Biochemical Toxicology, which occurred in April 2008.
The Site Visit Subcommittee Chair for the Division of Microbiology then presented the visit review, which occurred in August 2007.
The group meeting continued August 13, 2008, at UAMS. Dr. Slikker provided a center-wide update on scientific activities and discussed the NCTR alignment and strategic focus. Each of the FDA representatives had an opportunity to address their research needs and collaborative opportunities, including the consideration of future NCTR research issues. The meeting concluded with recommendations for follow-up actions by NCTR. For further information, please contact Dr. Margaret Miller, Associate Director for Regulatory Activities, NCTR NCTR Research Highlight - August 15, 2008Antibiotic Resistant Staphylococcus aureus – NCTR scientists have developed technologies for the detection and quantification of proteins expressed by Staphylococcus aureus in an effort to identify candidates that could potentially be used as targets for the development of novel therapeutic approaches for the prevention and treatment of diseases caused by antibiotic resistant S. aureus.
To date, one-dimensional polyacrylamide gel
electrophoresis (1D-PAGE) followed by nanocapillary liquid
chromatography coupled with mass spectrometry (nanoLC-MS/MS) has been
used to analyze proteins of S. aureus. This approach has
identified 1,263 staphylococcal proteins. In addition, the
relative abundance of proteins was determined using a quantitative value
termed, normalized-peptide number; and overall, proteins known to be
cell wall-associated were more abundant early in growth, while proteins
known to be secreted into the surrounding milieu were more abundant late
in growth. The use of 1D-PAGE, followed by nanoLC-MS/MS, offers a means
to generate comprehensive protein profiles of antibiotic-resistant S.
aureus, and bacteria, in general, for the purpose of identifying
proteins critical for disease and/or essential for bacterial viability.
These profiles, in turn, can then be used to develop alternatives, such
as passive immunization, in lieu of or in conjunction with antibiotic
therapy for the prevention and treatment of diseases caused by S.
aureus. For further information, please contact Drs. Mark E. Hart or Carl E. Cerniglia at NCTR; or see R.C. Jones, et al., J. Bacteriol, 190: 5265-5278, 2008. NCTR Research Highlight - August 8, 2008
Developing the Path to Personalized
Nutrition and Medicine Using Community-Based Participatory Research (CBPR) –
Advances in experimental technologies
for analyzing genomes, proteins, metabolites, and RNA transcripts are
laying the foundation for developing recommendations for personalized
nutrition and optimizing medical treatments for each individual.
However, current experimental strategies for identifying the risk of
carrying a gene variant linked to a disease rely on studies that yield
the average risk for a population. Similarly, the risk associated with
eating a particular nutrient is also derived from the association of the amount
of that nutrient eaten and the incidence of disease in the population.
Developing research strategies that determine individual risk factors
for inheriting a gene variant (e.g., single nucleotide polymorphism) or
an individual's exposure to certain nutrients or foods is a challenge for
developing personalized medicine and nutrition. One approach to this
challenge is to monitor participants in a study that involves more than the usual
single event where blood is drawn and diet history is recorded. The program is a pilot project for introducing biomedical research to the Arkansas Phillips County community. Additional studies involving school-age children and the adult population are planned for 2009. The concepts of using CBPR in biomedical research have been described in the following publication currently in press: Beverly McCabe-Sellers et al., (2008) Personalizing Nutrigenomics Research Through Community Based Participatory Research and Omics Technologies, Omics, A Journal of Integrative Biology. For more information, contact Dr. Jim Kaput, Director, Division of Personalized Nutrition and Medicine, NCTR.NCTR Research Highlight - August 1, 2008Increased Recycling and Reduced Environmental Emissions – The NCTR Office of Regulatory Compliance and Risk Management (RCRM) is instituting a major program to transform waste-management practices at the Jefferson Laboratories. The new waste-management system will provide significant benefits in both financial costs and environmental impacts. NCTR will suspend the use of the on-site waste incinerator reducing air emissions and saving the cost of natural gas used to operate the unit. The program also increases waste minimization practices by increasing recycling efforts – primarily in cardboard, glass, and paper products. These activities are an element of the recently developed Jefferson Labs Environment, Safety and Health Management System (ESHMS) and will be managed in accordance with international/national standards that are incorporated in the ESHMS.
FDA Principal Deputy Commissioner and
Chief Scientist, Dr. Frank Torti, Stresses Importance of FDA's Food
Protection Plan –
For further information, please contact Dr. Margaret A. Miller or Dr. William Slikker, Director, NCTR. NCTR Research Highlight - July 17, 2008Scientists from Korean National Research Institute of Toxicological Research (NITR) at Korea FDA (kFDA) Visit NCTR – On July 15-16, 2008, NCTR was pleased to host scientists, Drs. Sue-Nie Park, Hong-Ki Min, Ki Sook Park, Ho-Sang Jeong, and Wan-Seob Cho, from the NITR/kFDA for a workshop to explore potential for collaborative research. Scientific focus areas discussed included:
The workshop included presentations, development of an outline for research projects, and a tour of NCTR. For more information, contact Dr. Weida Tong, Division of Systems Toxicology, NCTR. FDA Principal Deputy Commissioner and Chief Scientist, Dr. Frank Torti, Visits NCTR July 16-17 – On July 16, a meeting in Little Rock with Arkansas with Dr. Torti, NCTR leadership, and academic and federal collaborators provided a forum for Dr. Torti to get a broad overview of NCTR's educational and research collaborations within Arkansas. Collaborators included: On July 17, the NCTR senior scientists met with Dr. Torti to discuss current and future research. After a tour of the Center, NCTR working groups on Bisphenol A and nanotechnology (including Arkansas Regional Laboratory) also met with Dr. Torti, followed by an All-Hands meeting. Prior to his departure, Dr. Torti gave opening remarks at the Food Protection Plan research planning meeting at NCTR. For more information, contact Dr. William Slikker, Director, NCTR. NCTR Research Highlight - July 11, 2008The Toxicity of Nanomaterials – Dr. Paul Howard, from the Division of Biochemical Toxicology, and Dr. Syed Ali, from the Division of Neurotoxicity, gave invited presentations at the first United States Air Force Workshop on Biological Interactions of Engineered Nanomaterials. The workshop, held June 24-25, 2008, at Wright-Patterson Air Force Base, was convened to discuss the current and proposed uses of manufactured nanomaterials and the risk to personnel. Specific topics of interest were the distribution of nanomaterials following contamination, the ingestion and potential toxicity of materials through inhalation, the potential for dermal penetration, and the toxicity expressed using in vitro systems. The title of Dr. Howard’s presentation was “Sentinel Organ Approach to Determining Dermal Penetration of Nanomaterials.” Dr. Ali’s talk was titled “Nanoparticles and Nanomaterials: Friends or Foe." For more information, contact Drs. William Slikker, Paul Howard, or Syed Ali. NCTR Research Highlight - July 3, 2008Eli Lilly Selects ArrayTrack™ – ArrayTrack™ is a free, publicly available bioinformatics tool developed by the NCTR for FDA research and review of pharmacogenomics data submitted by the sponsors in the Voluntary Genomics Data Submission (VGDS) program. ArrayTrack™ has been expanded to other omics dataset types, and over 100 FDA scientists and reviewers have been trained to use the ArrayTrack™ tools. Recently, Eli Lilly formed an evaluation team of experts for a rigorous review of ArrayTrack™'s:
Eli Lilly selected the ArrayTrack™ platform for their clinical gene-expression data storage and baseline analysis and further stated, “The level of commitment demonstrated by the ArrayTrack™ group strengthened our confidence in our ability to work together on some of the current gaps in making ArrayTrack™ fully functional for Lilly scientists.” NCTR Research Highlight - June 27, 2008STEP Program Begins at NCTR – NCTR’s Science Training and Exchange Professional (STEP) Development Program hosted its first participant last week, a reviewer from the Center for Veterinary Medicine (CVM). The program is intended to facilitate the sharing of expertise across the FDA Centers through short-term training or research at the NCTR and/or by the exchange of technical information and the fostering of networking and collaborations. In this case, the CVM reviewer sought background on a new assay for measuring genotoxicity in dogs, a method that was being used in a product submission. The assay, which utilizes flow cytometry to measure chromosomal damage (micronuclei) in red blood cells, previously was validated through research conducted by NCTR’s Division of Genetic and Reproductive Toxicology (DGRT). The reviewer spent three days in the DGRT, during which the assay was performed and the interpretation of assay data was discussed in detail. For further information, contact Dr. Margaret Miller, Associate Director for Regulatory Activities, or Dr. William Slikker, Director, NCTR. NCTR Research Highlight - June 20, 2008NCTR Public Outreach – NCTR members of the Arkansas Chapter of the Society for Neuroscience played a major role in the recent Central Arkansas Brain Bee and other activities associated with Brain Awareness Week, an event sponsored by the Society for Neuroscience. Several staff from NCTR’s Division of Neurotoxicology had key roles in organizing and judging the competition for high school students held in Little Rock, Arkansas. The winner and her mentor received funds for travel to participate in the National Brain Bee in Baltimore, Maryland. The grand finale of the Arkansas Brain Awareness Week took place at the Museum of Discovery in Little Rock. Activities included interactive displays on neuroscience-related topics, including NCTR’s Operant Test Battery, a computerized system for assessing cognitive abilities in which children press buttons and levers in response to visual stimuli and earn candy reinforcers for correct responses. The system was originally designed for assessing brain function in monkeys but has also found great utility in human subjects who enjoy playing these ‘brain’ games. An additional display, “Your Brain on Jell-O,” was presented by NCTR scientists. Children were given the opportunity to place “arteries” (red cake icing) on Jell-O brains. This display helps children understand the fragility of the human brain and the importance of protecting it. Over 500 children and adults attended the event. NCTR scientists, collaborating with neuroscientists at the nearby University of Arkansas for Medical Sciences, obtained grant support from the Society for Neuroscience to help pay for these events. For additional information, contact Dr. John Bowyer, Division of Neurotoxicology, NCTR. NCTR Research Highlight - June 13, 2008
Food Safety Research
– NCTR scientists
have developed an in vitro human-cell line model colonized with
human gastrointestinal (GI)-tract bacteria to detect the adverse effects
of low concentrations of antimicrobial drugs that might be present in
animal-derived food products to the consumer. The in vitro model
system was used to determine the effect of a low-concentration of drug
residues on the functional role of intestinal bacteria as a barrier that
protects intestinal cells from invasion of the gastrointestinal tract by
microbial pathogens. The intended application of the model system will
be to accumulate data to calculate acceptable daily intake (ADI) levels
of antimicrobial drug residues present in food. Regulatory agencies use
microbiological studies to calculate ADI levels as part of the overall risk
assessment to evaluate human food safety of antimicrobial drug residues
in animal-derived foods. For further information, please contact Dr. R. Doug Wagner or Dr. Carl E. Cerniglia at NCTR. NCTR Research Highlight - June 6, 2008Translational Medicine for Risk Identification – Scientists from NCTR and Teijin Pharma, a Cooperative Research and Development Agreement (CRADA) partner in Tokyo, Japan, have developed a sensitive and practical in vivo gene-mutation assay using red blood cells that is applicable for preclinical safety testing. The assay requires only one hour to quantify mutations in the Pig-A gene; and using only a few micro-liters of peripheral blood for a determination, the assay is a practical procedure for repeated blood sampling and a candidate for use in follow-on clinical studies. In vivo and in vitro batteries are used for evaluating gene mutation; however, a number of notable carcinogens (e.g., acrylamide, urethane, and benzene) are much more readily detected with in vivo methods. The Pig-A assay represents the first rapid and sensitive in vivo gene mutation assay.Future work on the Pig-A assay will establish its sensitivity and specificity for detecting the genotoxicity of a wide variety of test agents and explore expansion of the technique in other cell types and species. These studies were presented to CDER scientists on May 29 and have been accepted for publication in the journal, Environmental and Molecular Mutagenesis. For more information, contact Dr. Robert H. Heflich, Division of Genetic and Reproductive Toxicology, NCTR. NCTR Research Highlight - May 30, 20082008 Summer Science Research Program (SSRP) – Orientation was held May 27 to introduce the National Center for Toxicological Research (NCTR) summer research interns to the mission of the FDA and to meet their mentors for the ten-week program. The 2008 students represent nine institutions of higher learning, including:
The nine students will participate in ongoing studies alongside their mentors in five different NCTR research divisions. The studies include:
The ten-week appointments end with the formal presentation of results to the NCTR staff on July 31. The SSRP at NCTR is administered by the Oak Ridge Institute for Science and Education (ORISE). For more information, contact Dr. Tucker Patterson, Division of Neurotoxicology, NCTR. NCTR Research Highlight - May 23, 2008
NCTR Proposals Reviewed by TSSRC
– The Toxicology
Study Selection and Review Committee (TSSRC) met on May 13 and 14 at
the National Center for Toxicological Research (NCTR) to discuss ongoing and newly proposed study designs that support
the FDA risk assessment process. The newly proposed studies included:
The TSSRC is comprised of subject experts from the FDA Product Centers and the ORA as well as from the NIEHS, 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 White Oak this fall. For more information, contact Dr. William Allaben or Dr. Paul Howard, NCTR. NCTR Research Highlight - May 16, 2008The MAQC Project Toward Personalized Medicine – On March 24-26, 2008, the FDA-led MicroArray Quality Control (MAQC) project held its 8th face-to-face meeting at the FDA facilities in Rockville, Maryland. Partially funded by the Critical Path Initiative with participants from six FDA Centers, NIH, EPA, NIST, academia, and industry, the MAQC project is aimed at reaching consensus on the “best practices” for developing and validating microarray-based predictive models for personalized medicine. Over 100 participants from 60 organizations representing eight countries attended the meeting. More than 30 organizations presented their data analysis protocols and analysis results using the same clinical and preclinical microarray gene expression and genotyping data sets distributed by the MAQC project. Manuscript proposals were discussed at the meeting, and the MAQC is on track to submit a set of manuscripts for peer-reviewed publication by the end of 2008. For further information, visit http://edkb.fda.gov/MAQC/ or contact Dr. James C. Fuscoe, Acting Director, Division of Systems Toxicology or Dr. William Slikker, Jr., Director, NCTR.
NCTR Research Highlight - May 9, 2008Electronic Imaging as a Tool for Pathology Review – There has been an ongoing need for a cost-effective method to archive images of pathology data with the concurrent ability to review. Methods for electronic imaging have been developed and now validated by scientists at the National Center for Toxicological Research (NCTR). This new state-of-the-art technology allows pathologists at remote sites to observe slide images for review and/or comment. A program has been created that allows multiple users to review the same image from off-site locations using identical PC/notebooks, monitors, and software specifically designed for this purpose. The identity of slides is protected by the addition of unique bar codes. Slides are converted to electronic images using the Aperio ScanScope XT at 40X magnification, and the images are then stored on a secure server at NCTR. A copy of each image can be transferred to a remote and secure server (vsrimages.fda.gov) using a unique file-transfer protocol. The images then become available for review through the Spectrum Web Viewer. Because an important requirement for the system was that users see the same image at the same resolution, this became an integral part of the validation process. Validation also included a side-by-side comparison of traditional techniques with the new system. This is a technological advance that will allow for multiple participants to review slides in real time while providing consultative expertise from remote sites. In addition, there will be significant savings of time and resources while security and integrity of the study material is maintained. For further information, contact Dr. Ritchie Feuers or Dr. William Slikker, Jr., Director, NCTR. NCTR Research Highlight - May 2, 2008Science Advisory Board Review – A site visit team from the NCTR Science Advisory Board met at NCTR on April 29-30 for an in-depth analysis of research programs within the Division of Biochemical Toxicology. The site visit team, led by Board Chair, Dr. James Popp, was comprised of subject experts from academia, industry, NIH, and each FDA product-line Center and ORA. The Division presented results and future plans from studies on risk evaluation of food, drugs, and cosmetics. Risk evaluations included: · tattoo inks · nano-scale titanium dioxide sunscreen
·
topically and
orally administered Aloe vera · topically applied retinoic acid · nephrotoxicity of melamine/cyanuric acid combinations · transgenic models for melanoma · pyrrolizidine alkaloid-containing dietary/herbal supplements · the food contaminant acrylamide · multigenerational reproductive studies of estrogenic compounds · mixtures of anti-HIV/AIDS drugs · epigenetic mechanisms of carcinogenesis · varied PAH exposure used as surrogates for evaluating mixtures · idiosyncratic liver injury The site visit report will be formally presented at the full NCTR Science Advisory Board meeting to be held at NCTR on August 12-13, 2008. For further information, contact Dr. William Slikker, Jr., Director, NCTR.NCTR Research Highlight - April 11, 2008Food Safety Research – NCTR and ORA scientists combined genetic (chromosomal and plasmid) and antibiotic-sensitivity analysis to reproducibly characterize hundreds of Salmonella enterica (S. enterica) strains isolated from seafood samples imported into the United States from 26 different countries during the years 2001-2005. The 37 S. enterica Weltevreden strains, the most common of the 64 different serotype isolates, were further characterized to the genotype level. Salmonella Weltevreden can cause acute enteritis (inflammation of the intestinal tract), and some of these isolates were found to be resistant to several veterinary and clinically important antibiotics. The combination of molecular methods (chromosomal analysis, plasmid profile, and antibiotic resistance) used in these studies can be used to trace outbreaks and epidemic spreads of S. enterica and implement surveillance programs in imported seafood. (Food Microbiology, 25: pp. 29-35, 2008) For further information, please contact Dr. Ashraf A. Khan or Dr. Carl E. Cerniglia, NCTR.
NCTR Research Highlight - April 4, 2008Mutagenicity Assay Use in Preclinical Studies – CDER and NCTR scientists have recently completed a book chapter discussing the use of in vitro mammalian mutagenicity assays in preclinical safety evaluation studies. The chapter serves as a guide describing the principles of each different assay, the critical parameters affecting assay performance, and the interpretation of data from each different assay. (C.A.H. Bigger, M.M. Moore and R.H. Heflich (2008) “In vitro mammalian cell mutation assay,” Preclinical Development Handbook: Toxicology, S.C. Gad (ed.), John Wiley & Sons, Inc, 129-153) For more information, contact Dr. Martha Moore, Director, Division of Genetic and Reproductive Toxicology or Dr. William Slikker, Director, NCTR.
NCTR Research Highlight - March 21, 2008The Virtual Pathology Environment – NCTR has established a secure digital-imaging and software system to be used by Pathology Working Groups (PAGs) in the formal peer review of GLP studies. Although digital imaging has been used informally by pathologists to share information for a long time, advances in technologies have allowed these applications to be incorporated into the formal pathology peer-review environment. This virtual-pathology environment significantly reduces procedural costs and facilitates the organization of global professionals producing the most expert and timely reviews possible.
NCTR Research Highlight - March 14, 2008Computational Toxicology – NCTR, CDC, ATSDR, EPA, NIOSH, and NIH scientists met February 14, 2008, in Atlanta, Georgia, for the inaugural meeting of the Inter-Agency Computational Toxicology Colloquium. The conferees discussed formation of inter-agency computational toxicology projects in areas of mutual interest, including: identification and qualification of biomarkers, development of prediction algorithms, chemical-testing prioritization using high throughput screening methodology, quantitative-structure activity relationships, integrative systems biology, utilization of “omic” data in risk assessments, and computer-based approaches to safety and risk assessment. Subgroups were identified to outline research proposals to be discussed at the second Colloquium that will be hosted by NCTR. For further information contact Drs. James C. Fuscoe, Acting Director, Division of Systems Toxicology or William Slikker, Director, NCTR. NCTR Research Highlight - March 5, 2008Safety Evaluation of Cosmetic Preparation – The National Toxicology Program (NTP) Board of Scientific Counselors Technical Reports Subcommittee met February 27, 2008, to review NCTR’s comprehensive assessment for the topical application of the cosmetic ingredient Aloe vera (plant leaf extract). The subcommittee concluded that, at dose levels above human exposure, the plant fractions had no, to marginal, effects on the carcinogenicity of simulated sunlight in mice. The cream doses contained aloe gel, whole leaf, decolorized whole leaf extracts, or aloe-emodin. CFSAN scientists will use this data to determine what risk, if any, Aloe preparations may pose for humans. Aloe vera preparations have found widespread use in skincare products; however, published reports suggest that these preparations may synergize with UV radiation and enhance skin cancer. The one-year studies were conducted in the NTP/FDA Phototoxicology Center at NCTR using the hairless (SKH-1) mouse model to evaluate the potential of the typical standardized aloe preparations to enhance the photocarcinogenicity of simulated sunlight. For further information, contact Drs. William T. Allaben or William Slikker, Jr., at NCTR. NCTR Research Highlight - February 29, 2008
Women's Health
–
A woman’s lifetime
exposure to estrogen is a factor for increased risk of breast cancer;
estrogen stimulates the growth of estrogen-dependent breast cancer.
NCTR Research Highlight - February 22, 2008Diet/Drug Interactions – A collaboration between NCTR and the University of Southern California has shown that circulating levels of tamoxifen and its therapeutically active metabolites in Asian women (n=380) undergoing therapy for breast cancer was not affected by dietary soy intake. By comparison, this study also showed that age/menopausal status, body weight, and use of hypertensive medications, particularly diuretics, significantly influenced the circulating levels of tamoxifen and its metabolites. However, approximately one-third of patients with estrogen-receptor positive tumors do not ever respond to tamoxifen therapy, and patients eventually can become resistant to the therapeutic benefits of tamoxifen treatment. Future studies that include breast cancer survival and relapse assessments will be needed to determine whether soy isoflavones can affect the overall efficacy of tamoxifen chemotherapy. These findings recently were published by Wu et al. in Journal of Clinical Oncology published 2007; Vol 25; 3024-3030. For further information, contact Dr. Tom Flammang or Dr. Dan Doerge at NCTR.
NCTR Research Highlight - February 15, 2008PET Imaging at NCTR – PET (or positron emission tomography) is an established clinical imaging tool used to detect and follow the biological course of several diseases at the molecular level before anatomical changes may be apparent; e.g., several cancers, heart disease including coronary artery disease, neurological disorders including Alzheimer’s, Parkinson’s, and epilepsy. NCTR’s high-resolution microPET installation has been completed and will be used in preclinical studies to evaluate the emergence and development of toxicity. The first NCTR protocol, “Methods Development for High Resolution micro-Positron Emission Tomography (microPET) to Assess Rodent Neuroplasticity and Toxicity during Development,” will be used to evaluate system performance.High-resolution microPET will dramatically increase the level and sophistication of data that can be obtained from animal models of toxicity and disease and provide direct links to clinical applications. For more information, contact Dr. Merle Paule, Director, Division of Neurotoxicology, NCTR or Dr. William Slikker, Director, NCTR. NCTR Research Highlight - February 1, 2008Arkansas State Representative David Rainey is Keynote Speaker at Dr. Martin Luther King, Jr. Commemorative Luncheon – On Thursday, January 24, 2008, the Jefferson Laboratories and the Central Arkansas Chapter of Blacks in Government (BIG) co-sponsored a commemorative luncheon and program celebrating the life and legacy of Dr. Martin Luther King, Jr. The program included a presentation by the Honorable David Rainey, the state representative for Arkansas District 11 that includes Jefferson County. Dr. Paul Norris, Director, Arkansas Regional Laboratory, and Dr. William Slikker, Director, National Center for Toxicological Research, each paid tribute to the theme of love, hope, and a commitment to continue to work in unity for the public good that was presented by Representative Rainey in recognizing Dr. King. Critical Path – Automated Assays – The in vivo rodent erythrocyte micronucleus test is used in regulatory safety assessment to evaluate the potential of agents to cause chromosomal damage. The use of nonhuman primates (NHPs) also may have value in the genotoxicity testing of regulated products, especially human pharmaceuticals. Conducting the micronucleus test in NHPs, however, is extraordinarily resource intensive, often requiring the sacrifice of the animal to obtain bone marrow and the manual scoring of thousands of cells with a microscope. NCTR led a collaborative study that found that flow cytometry evaluation of micronuclei in peripheral blood was both more efficient and precise than the traditional methods. The flow cytometry method uses only a small amount of blood allowing multiple samples to be taken from the same animal, which also provides its own baseline values. This improved procedure for evaluating genetic toxicology in NHPs is not only faster and more precise than the traditional microscopic analysis but also lends itself to analyzing micronuclei in conjunction with other toxicological endpoints, thus improving the preclinical safety assessment. These findings recently were published by C. E. Hotchkiss et al. in Toxicological Sciences (e-publication in advance of print). For further information, contact Dr. Martha Moore, NCTR. NCTR Research Highlight - January 25, 2008
Towards Toxicology In Silico –
NCTR
scientists have developed a predictive model for dioxin isomer toxicity
using Quantitative Spectral Data Activity Relationships (QSDAR), Pat. 6,898,533. Different Quantitative Structure
Activity Relationship (QSAR) models have been used for years to predict
properties of chemicals including toxicity and to design more effective
drugs. The QSDAR model predicted high toxicity for four dioxin isomers not thought to be important. Dr. Stephen Safe, Texas A&M, was able to provide authentic samples of two isomers, and ORA scientists at the Arkansas Regional Laboratory demonstrated: 1) the purity of each authentic isomer 2) each isomer had commensurately high values in the AH-receptor assay, a traditional model for evaluating potential dioxin isomer toxicity 3) mass spectrometry peaks for these same two isomers were indeed present in the historical dioxin assay program database. (Accepted for publication: Wilkes et al., Toxicological Sciences, Advance Access published December 7, 2007; DOI: 10.1093/toxsci/kfm294) QSDAR has been used previously to create accurate prediction models for estrogenicity, corticosteroid binding, and aromatase binding. Future projects will evaluate the effectiveness of QSDAR models measuring the biological action of a series of drugs within a structural class.
Arkansas Congressional Delegation Meet at NCTR –
NCTR Research Highlight - December 21, 2007Critical Path – New methods to evaluate clinical outcomes – The biostatisticians in the Division of Personalized Nutrition and Medicine, NCTR, have developed a novel classification tool (i.e., classification algorithm) to address the statistical challenge that arises in most clinical studies where huge sets of measurements are gathered on relatively few clinical trial participants. If not carefully considered, analysis of high-dimensional data of this type can easily generate models that do not predict the correct treatment strategies. The newly developed algorithm was used to analyze genomic data sets obtained from lymphoma patients and lung cancer patients to distinguish disease subtypes for optimal treatment and to analyze genomic data obtained from breast cancer patients to identify patients most likely to benefit from adjuvant chemotherapy after surgery. The performance of the proposed algorithm is consistently highly ranked compared to the other classification algorithms. A description of this algorithm has been published in the journal Artificial Intelligence in Medicine (Vol. 41, pp. 197–297, 2007). While much work remains to test and use these and other algorithms for clinical practice, the statistical classification method for individualized treatment of diseases developed is expected to play a critical role in developing safer and more effective therapies that replace one-size-fits-all treatments. For more information about this algorithm, contact Dr. Jim Chen of the Division of Personalized Nutrition and Medicine, NCTR. NCTR Research Highlight - December 14, 2007
Critical Path: NCTR Operant Test Battery (OTB) – Dr.
Merle Paule, Director, Division of Neurotoxicology, presented an invited
lecture titled “Interspecies
Comparisons of Cognitive Function: Biomarkers of Neurotoxicity and
Relevance for Juvenile Studies,” at the
Second Annual Juvenile Toxicity Symposium held in Belgium on November
29-30. The lecture focused primarily on the use of the nonhuman primate model in studies of
drug effects on brain function and engaged intense discussion as
attendees grappled with the conduct of preclinical studies most relevant
to human pediatrics. These discussions continue and will be revisited when Dr. Paule presents an invited lecture titled "Critical Contributions of Primate Models for Biopharmaceutical Drug Development" at the upcoming 17th Münster Primate Symposium held in Germany in April 2008. NCTR's Division of Neurotoxicology has long been known for its state-of-the art nonhuman primate studies, particularly in the area of drug effects on complex brain function and particularly during early development through adolescence. NCTR Research Highlight - December 07, 2007Intercenter Research Communication – The National Center for Toxicological Research Division of Microbiology Director, Dr. Carl E. Cerniglia, presented a seminar on December 6 to the Center for Veterinary Medicine (CVM) Staff College titled "The Effect of Veterinary Antimicrobial Agents in Food on the Human Intestinal Microbiota.” Dr. Cerniglia addressed the current issues that must be considered to evaluate the safety of veterinary drugs used in food animals for potential human health risks. Dr. Cerniglia also discussed the research collaboration with CVM scientists that led to the harmonized approach described in FDA Guidance 159 to determine the safety evaluation and risk assessment of antimicrobial agent residues in foods. NCTR Research Highlight - November 30, 2007Dr. Allan B. Okey, Professor Emeritus, Department of Pharmacology and Toxicology, University of Toronto and dioxin-toxicity expert, presented a seminar at NCTR on November 27 titled: “The Rat that Wouldn’t Die: Using Genetics and Gene Expression to Identify Pathways of Dioxin Toxicity.” The direct causal events leading to dioxin toxicity certainly involves the aryl hydrocarbon receptor (AHR) and AHR-mediated dysregulation of gene expression. The differences in sensitivity to toxicity and to type of toxic outcome that result from exposure to dioxin and dioxin-like chemical exposure is highly variable across animal species; humans by comparison are less sensitive. Furthermore, 30 years of study in multiple laboratories using traditional toxicology and pharmacodynamic methods have not resolved this mystery. Dr. Okey’s research group currently utilizes a systems biology approach to examine the different toxicological outcomes. The approach combines dioxin-sensitive and dioxin-resistant animal models in traditional breeding paradigms and the new genomics analysis to dissect the mystery. The results are mapping AHR-mediated gene expression in a variety of biological systems and are identifying which dysregulated genes underlie specific forms of dioxin toxicity. It was noted that similar approaches could be, or are, in use to predict adverse outcomes in the development of therapeutic agents that rely on preclinical animal data to predict adverse events in humans. NCTR Research Highlight - November 16, 2007Toxicology Study Selection and Review Committee met at FDA’s White Oak Campus on November 14 & 15, 2007 – The Toxicology Study Selection and Review Committee (TSSRC) met November 14 and 15, 2007, at FDA’s White Oak Campus Conference Center. The TSSRC is a committee comprised of the Food and Drug Administration (FDA), the National Institute for Environmental Health Sciences (NIEHS), and outside scientific experts charged with scientific oversight for all studies conducted under an interagency agreement between the NIEHS's National Toxicology Program and the FDA's National Center for Toxicological Research. FDA product centers/offices select and nominate FDA-regulated chemicals and agents for which safety and risk issues exist that require further research and testing to resolve. The TSSRC meets twice a year; a spring meeting at NCTR in Jefferson, Arkansas and a fall meeting in the Washington, DC area. Studies that were reviewed during the two-day meeting included: Ketamine – rodent and nonhuman primate perinatal studies investigating brain remodeling after exposure to anesthetic agents including ketamine Acrylamide – pharmacokinetic, mechanistic, cancer and neurotoxicology studies in rodents after exposure to the food contaminant acrylamide AIDs Therapeutic Agents – rodent studies investigating potential long-term risk to newborn and young adults after transplacental and transplacental/neonate exposure to various AIDs therapeutic agents administered alone or in combination Bitter Orange – developmental and physiological studies in rodents exposed to the dietary supplement ingredient, bitter orange, alone and in combination with caffeine at rest and with exercise Aloe Vera – rodent studies that are investigating the safety of aloe vera when administered orally or dermally Nanoscale Titanium Dioxide – a review of studies using manufactured nanoscale titanium dioxide in skin penetration studies There were updates on the progress of studies that investigate: Cell phone radiation in rodents, Q-T prolongation in canines, Potential toxic outcomes using DNA therapeutics. The TSSRC also reviewed protocols or preliminary data that investigate: Usnea barbata, glucosamine and chondroitin – the potential toxic outcomes as a consequence of exposure to these dietary supplements alone and in combination Di (2-ethylhexyl) phthalate (DEHP) – potential testicular toxicity as a consequence of exposure to this plasticizer in medical devices Nano-silver and nano-gold particles – the ADME and the potential toxicity of these manufactured particles Furana – PBPK study with furan, plus special furan toxicology studies Permanent makeup (tattoo pigments) – allergic reactions as a consequence of exposure to permanent makeup (tattoo pigments)
Full AAALAC Accreditation Continued for NCTR – To maintain a “state-of-the-art” research facility requires round-the-clock skilled animal-care personnel and animal-care facilities. NCTR has a long history of providing both. The NCTR animal facilities are a vital resource in the conduct of FDA research. A site visit team from the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC) evaluated the NCTR animal-care infrastructure and support capabilities in June 2007 as part of the ongoing AAALAC accreditation process. Their goal was to make an independent and objective evaluation of the Center’s animal care and diet preparation operations, including personnel and infrastructure. The site visit team report received in November 2007 grants NCTR "continued full accreditation." NCTR is home to 82 AAALAC-accredited breeding and conventional animal rooms and a nonhuman primate research center. NCTR Research Highlight - November 02, 2007Toxicogenomics Integrated with Environmental Sciences (TIES) – NCTR, NIEHS/NIH, and North Carolina State University jointly hosted the first international conference on TIES-2007 on October 25-26, in the McKimmon Center of North Carolina State University in Raleigh, North Carolina. The goal of the TIES conference is focused on the application of bioinformatics in the fields of toxicogenomics and environmental genomics. TIES provides a venue where multidisciplinary scientists can exchange the current advances in bioinformatics for elucidating biological mechanisms and pathways through "omics" technologies. The conference featured four keynote speakers, invited presentations, and a poster session, as well as a special session on the FDA-led MicroArray Quality Control project. The conference was well-received with about 140 participants. The NCTR Director, Dr. William Slikker, opened the conference with remarks on the current status of toxicogenomics applied in environmental sciences across agencies and countries. The international participants included the keynote speaker from Germany, the platform presenter from Korea, and the program committee members from China. Given the success of the TIES-2007, the next two TIES conferences will take place in China in 2009 and Germany in 2011. NCTR Research Highlight - October 24, 2007Environment, Safety and Health Management System – The Jefferson Laboratories of the Food and Drug Administration has become the first FDA facility to implement an Environment, Safety and Health Management System (ESHMS) in accordance with national (ANSI-Z10) and international (ISO-1400) guidelines and standards. The Jefferson Laboratories ESHMS was developed over the course of nine months by the Arkansas Regional Laboratory and the National Center for Toxicological Research Cross-Functional Team. On August 1-2, 2007, an internal audit of the ESHMS was conducted, and a Jefferson Labs management review was held on August 2. The audit report was issued September 7, 2007, completing implementation of the Jefferson Labs ESHMS. The Jefferson Labs ESHMS also incorporates a continuous quality-improvement plan that establishes procedures for performing corrective actions to audit findings, maintenance, systems refinement, audit schedules, and management reviews. The ESHMS fulfills the directives of Executive Order 13423. NCTR Research Highlight - October 19, 2007The American Association for Cancer Research (AACR) Meeting – AACR is announcing the first AACR Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved. This conference will be held November 27-30, 2007, at the Atlanta Marriott Marquis in Atlanta, Georgia. In October 2006, the NCI Center to Reduce Cancer Health Disparities sponsored a “Think Tank” on research issues related to cancer health disparities. Participants in this “Think Tank” included clinical researchers, epidemiologists, molecular biologists, social scientists, geneticists, pathologists, and patient advocates from a variety of work settings including academia, industry, government, and not-for-profit organizations. The goal of this historic conference is to bring together scientists and other professionals working in a variety of disciplines to discuss the latest findings in the field and to stimulate the development of new research in cancer health disparities. This conference will address various topics in basic science, clinical research, population science, behavioral research, and cancer survivorship. The conference will begin with four educational workshops: 1) Cancer Health Care Communications, 2) Research Methods in Cancer Disparities, 3) Systems Biology, and 4) Biomarkers/Genetics. Plenary and concurrent sessions will be held throughout the conference. Beverly D. Lyn-Cook, Ph.D., a senior scientist in NCTR’s Division of Personalized Nutrition and Medicine is a co-chairperson of the conference. More information may be obtained from the AACR Web site at www.aacr.org. NCTR Research Highlight - October 05, 2007
Food Safety – NCTR scientists in
the Division of Microbiology, in collaboration with the FDA PRW-SW
Laboratory in California, have investigated the extent of genetic
diversity among Salmonella enterica serovar Weltevreden isolated
from imported seafood samples using antibiotic resistance, genomic
restriction fragment analysis by pulsed-field gel electrophoresis (PFGE)
and plasmid profiles. The Salmonella enterica serovar Weltevreden
strains were isolated from imported seafood from 20 countries during FY
2000-2005.
Selection of NCTR Associate Director for Regulatory Activities – As Associate Director, Dr. Miller will serve in the Office of Center Director, NCTR with an office in NCTR’s Parklawn Building suite in Rockville, MD and at the NCTR in Jefferson, AR. The ADRA is responsible for: • identifying FDA research needs; • strengthening the communication interactions and collaborations between NCTR and other FDA product Centers; • facilitating the awareness of NCTR research activities by other Agency components; • proactively creating interactions and interdisciplinary collaborative research endeavors that expand and strengthen the Agency’s science foundation; and • fostering the use of research results in the FDA regulatory decision-making process. Dr. Miller will have an office in NCTR’s Parklawn Building suite and at the NCTR in Jefferson, AR. Dr. Miller is exquisitely prepared for this opportunity and has an excellent record of significant contributions to the Agency. She joined FDA in 1989 in the Division of Toxicology, Office of New Animal Drug Evaluation, in the Center for Veterinary Medicine (CVM). She held several positions within the CVM including Deputy Director for Human Food Safety in the Office of New Animal Drug Evaluation. In 1999, Dr. Miller joined FDA’s Office of Women’s Health as the Manager of Science Programs. In this position, she initiated several successful research initiatives that promote the health of women including studies to investigate the pharmacokinetics of drugs in pregnant women. She recently completed a two-year detail at the Department of Food Safety, Zoonoses and Foodborne Diseases at the World Health Organization, where she worked on improving the provision of scientific advice, building the INFOSAN network, and developing consumer informational materials. NCTR Research Highlight - September 28, 2007NCTR Scientist Provides Training to CBER and CDER PharmTox Reviewers – Dr. Martha Moore, Chair of the Mouse Lymphoma Assay Workgroup of the International Workshop on Genotoxicity Test Procedures (IWGT), conducted a training session for CBER and CDER PharmTox reviewers on September 25th. The training provided reviewers with the latest internationally harmonized consensus standards for the proper interpretation of mouse lymphoma gene mutation assay (MLA) data that are submitted as a part of preclinical safety evaluations. Reviewers submitted troublesome data sets, and the interpretation of positive and negative responses was discussed. The information in the training class was the result of a multiple-year effort by IWGT to standardize the MLA. The MLA panel is comprised of experts from Japan, Europe, and the United States. For further information, contact Dr. Martha Moore at NCTR. NCTR Research Highlight - September 20, 2007
Dietary
Supplements –
NCTR and CFSAN
scientists have demonstrated that usnic acid preparations derived from
Usnea lichens are significantly more toxic when fed to mice and
rats than pure preparations of the acid. For further information, contact Dr. William Slikker, Jr. or Dr. William Allaben at NCTR. NCTR Research Highlight - September 7, 2007Critical Path – NCTR research on genomics helps the development of new guidance document for industry on pharmacogenomic data submissions – On August 28, 2007, the FDA issued a new draft guidance for industry, “Pharmacogenomic Data Submissions - Companion Guidance” (http://www.fda.gov/cder/guidance/7735dft.pdf). This new guidance, to be used as a companion to the guidance “Pharmacogenomic Data Submissions” (March 2005), reflects experiences the Agency gained over the past three years. NCTR scientists have been instrumental in the management, analysis, and interpretation of Voluntary Genomic Data Submissions (VGDS) by providing a much-needed bioinformatics infrastructure (ArrayTrack™) and through close collaborations with scientists and reviewers from CDER, CBER, and CDRH. In addition, NCTR has been leading the MicroArray Quality Control (MAQC) project (http://edkb.fda.gov/MAQC/), a community-wide effort (with participation of all six FDA Centers) aimed at addressing performance, standards, quality, and data analysis issues on the application of microarray genomic data in clinical and preclinical settings. Experiences gained through the VGDS and MAQC efforts provided the regulatory and scientific foundations for the newly released pharmacogenomics guidance. For further information, contact Dr. Weida Tong, Division of Systems Toxicology, NCTR, 870-543-7142. NCTR Honor Awards Ceremony – The National Center for Toxicological Research (NCTR) held its annual honor awards ceremony on August 29, 2007, at the Harbor Oaks Championship Golf Course & Restaurant located in Pine Bluff, Arkansas. The honor awards ceremony recognized employees for outstanding accomplishments in support of the DHHS, FDA, and the NCTR. Awards presented included the: DHHS/PHS Outstanding Unit Citation, DHHS/PHS Crisis Response Service Award, FDA Commissioner’s Special Citation, Award of Merit, Group Recognition Award, Outstanding Service Award; Equal Opportunity Achievement Award, Quality-of-Work-Life Award, Leveraging/Collaboration Award, Diversity-in-Action Award, and Scientific Achievement Award. NCTR’s honor awards presented included the: NCTR Director’s Award, Outstanding Service Award, and Quality-of-Work-Life Awards. NCTR Director, Dr. William Slikker, Jr., presented the awards with assistance from the employee’s supervisors and/or government project officers to the recipients in front of their peers. Mrs. Vicky Ross-Barsh, Associate Director for Management Services, emceed the ceremony. In recognition of the occasion, the honorees participated in a luncheon preceding the ceremony. NCTR Research Highlight - September 5, 2007Legislative Visit – On August 21, Price Feland, Arkansas Senator Mark Pryor’s Legislative Assistant, visited NCTR. Mr. Feland met with NCTR Director, Dr. William Slikker, Jr., who presented an overview of NCTR's programs followed by a tour of the Center. Included in his tour were the Divisions of Neurotoxicology (Dr. Merle Paule) and Microbiology (Dr. John Sutherland) and two Centers of Excellence, Metabolomics in the Division of Systems Toxicology (Drs. Rick Beger and Laura Schnackenberg) and Phototoxicology in the Division of Biochemical Toxicology (Dr. Paul Howard). Mr. Feland was especially interested in the work assessing toxicity related to nano particles. New Pine Bluff Arsenal Commander – NCTR, located in Jefferson, Arkansas, sits adjacent to the Army's Pine Bluff Arsenal (PBA). On August 15, Dr. William Slikker hosted a visit and tour of NCTR for the recently appointed PBA Commander, Colonel William Barnett, and his Civilian Executive Assistant, Mr. Larry Wright; and the recently appointed commander of the Pine Bluff Chemical Activity, Lt. Colonel Clifton Johnston, and his Civilian Executive Assistant, Mr. Steve Lowry. Dr. Slikker presented an overview of NCTR capabilities followed by a walking tour of the Center. Discussions during the visit resulted in an agreement to initiate a series of seminars between the facilities to identify potential areas of collaboration in addition to continuing the ongoing Interagency agreement with the PBA for provision of essential support services to the NCTR/Jefferson Laboratories community. NCTR Research Highlight - August 27, 2007NCTR welcomes new Pine Bluff Arsenal Commander – NCTR, located in Jefferson, Arkansas, sits adjacent to the Army's Pine Bluff Arsenal (PBA). On August 15, 2007, Dr. William Slikker hosted a visit and tour of NCTR for the recently appointed PBA Commander, Colonel William Barnett; his Civilian Executive Assistant, Mr. Larry Wright; and the recently appointed commander of the Pine Bluff Chemical Activity, Lt. Colonel Clifton Johnston; and his Civilian Executive Assistant, Mr. Steve Lowry. Dr. Slikker presented an overview of NCTR capabilities followed by a walking tour of the Center. Discussions during the visit resulted in an agreement to initiate a series of seminars between the facilities to identify potential areas of collaboration in addition to continuing the ongoing IAG with the PBA for provision of essential support services to the NCTR/Jefferson Laboratories community. NCTR Research Highlight - August 10, 2007NCTR Scientists Participate in CFSAN Food Safety Grand Rounds – The first CFSAN Office of Food Additive Safety Grand Rounds of 2007 was held on July 31 and August 1, and addressed the topic Genetic Toxicology: Supporting Regulatory Decisions.
The discipline of genetic toxicology is concerned with assessing the ability of chemicals to alter genetic material. Because genetic damage is important in tumor development, data on the potential toxicity of a substance is used as a part of the evaluation of food substances, both for approval and for other regulatory decisions.In addition to the scientific presentations, the Grand Rounds provided an opportunity for CFSAN and NCTR scientists to share information and develop new ideas for continued collaboration and exchange of technical expertise. NCTR Hosts FDA Assistant Commissioner for Food Protection – On August 7-8, 2007, Dr. David Acheson visited the NCTR. His seminar presentation, titled Food Protection, provided the NCTR/Jefferson Laboratories staff with a better understanding of the linkage of food defense and food/feed safety that comprise the Food Protection initiative in the Agency. Each NCTR division provided a brief overview of their research focus and capabilities followed by a walking tour of the NCTR/Jefferson Laboratories campus. Dr. Acheson’s visit provided him with a better understanding of how NCTR expertise and capabilities can assist him in addressing food protection issues for the Agency. NCTR Research Highlight - August 3, 2007On July 24-25, 2007, the NCTR Division of Microbiology’s Research and Surveillance Programs were reviewed by a subcommittee of the NCTR Science Advisory Board that includes FDA liaison members. The review subcommittee included scientists from government, industry, and academia and was chaired by Dr. Anthony L. Pometto, Professor, Department of Food Science & Human Nutrition, Iowa State University. Representatives from CFSAN, CVM, CBER, and ORA participated in the review. Dr. Carl E. Cerniglia, Director of the Division of Microbiology, presented an overview of the research program, and the division research scientists described their current research interests.
NCTR Research Highlight - July 20, 2007Critical Path – Impact of Genomics Technologies on Regulatory Policies – Escalating amounts of information and a panoply of methodologies emanating from genomics research are clearly impacting the disciplines of toxicology and public health. As greater insight from these technologies is obtained, there is increasing focus and pressure on governmental regulatory agencies to evaluate the utility and validity of information generated using “omics" technologies. Several government agencies, including but not limited to the Food and Drug Administration, Department of Agriculture, and Environmental Protection Agency, have been addressing many of the issues raised by “omics” technologies.
In addition, a special workshop entitled “Progress in Omics Technologies" provided a forum in which to highlight specific technological advances. Peer-reviewed manuscripts describing FDA, EPA, and USDA current thinking on these issues, along with technical strengths and limitations of “omics” technologies, were recently published under the editorship of Dr. James Fuscoe (FDA) and Dr. Kerry Dearfield (USDA). The set of manuscripts (Environmental and Molecular Mutagenesis 48:5, 2007) collectively outlines the impact of “omics” technologies on regulatory programs and policies. These policies will play a major role in the implementation of genomics technologies as they relate to important public health issues and movement toward personalized medicine. For further information, contact Dr. James Fuscoe, Division of Systems Toxicology, NCTR, 870-543-7126. NCTR Research Highlight - July 13, 2007Measurement of Melamine and Cyanuric Acid in Complex Food Matricies – NCTR organic chemists have synthesized and supplied to a number of laboratories non-radioactive melamine and cyanuric acid standards for certification of analytical methods that will be used for evaluating the levels of these contaminants in foods. The laboratories include the Animal Drug Research Center, Denver District Office; the Kansas City District Office; USDA, FSIS, OPHS; CFSAN; CVM; ORA Forensic Chemistry Center; and the Arkansas Regional Laboratory.
These custom synthesized chemicals, incorporating heavy nitrogen (15N)
or carbon (13C), are not commercially available and can be conveniently
used to assay very low levels using mass spectrometry techniques. The
utilization of non-radioactive isotopes in the compounds also has the
advantage of reducing environmental problems that are encountered with the
use of radioactively labeled standards. NCTR Research Highlight - June 29, 2007FDA 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. NCTR Research Highlight - June 22, 2007AAALAC 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.
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. NCTR Research Highlight - June 15, 2007Food 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.
For further information, contact Dr. William Slikker, Director, NCTR, or Dr. Rajesh Nayak, Division of Microbiology, NCTR. NCTR Research Highlight - June 8, 2007Improvements 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.
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. NCTR Research Highlight - June 1, 2007Detecting 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).
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. NCTR Research Highlight - May 24, 2007Critical 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).
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. NCTR Research Highlight - May 18, 2007Multigenerational 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.
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. NCTR Research Highlight - May 11, 2007Semiannual 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:
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. NCTR Research Highlight - May 7, 2007Critical Path - Public Release of Windows®-Based Modeling Software -
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. NCTR Research Highlight - April 26, 2007Translational Research – Pediatric anesthetic ketamine --
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. NCTR Research Highlight - April 18, 2007Food 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 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. NCTR Research Highlight - April 13, 2007Continuous 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.
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. NCTR Research Highlight - March 30, 2007Searching for Molecular Biomarkers of Liver Toxicity – Liver toxicity is one of the most common causes for the recall of drugs that have been approved by the FDA for use in humans. Preclinical (animal) studies are used to determine if drugs may be toxic, and the liver is a major target organ of early screening efforts in the pharmaceutical industry. In spite of this, there have been a number of instances in which drugs that gave no indication of liver toxicity in preclinical studies turned out to be toxic to the liver after being approved for marketing.
This will be accomplished by treating rats orally for 28 days with a pair of similar drugs, one of which causes liver toxicity in humans. The first pair to be investigated includes tolcapone, which was discovered to cause liver toxicity only after being approved for use in humans, and entacapone, which has not shown any indications of causing liver toxicity. During the first days of administering the drugs, urine will be collected and analyzed to determine if there are certain metabolites that are unique to the drug (tolcapone) that causes liver toxicity. After 28 days of treatment, the rats will be humanely killed and various techniques will be used to analyze their urine, blood, and liver with the goal of determining if certain parameters are unique in the rats administered the drug (tolcapone) that causes liver toxicity. If successful, the molecular biomarkers developed during the course of this study can then be applied during drug development to prevent the inadvertent administration of drugs that cause liver toxicity to humans. For further information, contact Dr. Fred Beland, Director, Division of Biochemical Toxicology, NCTR. NCTR Research Highlight - November 17, 2006Critical 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.
Several examples for the use of this non-invasive technology are discussed: characterization of inborn errors in metabolism, organ transplant rejection, applications to disease, profiling of toxicity, applications to nutrition, and mechanism-dependent response. For further information, contact Dr. William Slikker, Jr., Director, NCTR/FDA. NCTR Research Highlight - November 3, 2006TSSRC 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, and preliminary results using manufactured nanoscale titanium dioxide in skin penetration studies.
New proposals to investigate exposures to the dietary supplements Usnea barbata and glucosamine/chondrotin, non-human 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. NCTR Research Highlight - October 27, 2006Critical Path - Non-Invasive 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.
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), micro-PET, 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 - 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 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. NCTR Research Highlight - October 12, 2006Critical 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.
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. Research Highlight - October 10, 2006Predicting 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.
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.
NCTR Research Highlight - September 22, 2006NCTR Hosts Acting Commissioner von Eschenbach – On Thursday, September 21, 2006, NCTR was privileged to have the Acting Commissioner, Food and Drugs, spend the day at the FDA Jefferson Laboratories. The Acting Commissioner enjoyed a walking tour and discussions with the NCTR senior scientific staff that focused on the value and evolution of science that will bridge discovery with intervention to make a difference in patients’ lives.
NCTR science provides a base infrastructure that is a critical component of the FDA. Dr. von Eschenbach stated “FDA must not only be science based, but a science led organization.” He is committed to the success of the NCTR. For further information, contact Dr. William Slikker, Jr., Acting Director, NCTR/FDA. william.slikker@fda.hhs.gov NCTR Research Highlight - September 18, 2006Critical Path Initiative: Microarray QC - The MicroArray Quality Control (MAQC) project was initiated by the FDA’s National Center for Toxicological Research (NCTR), Jefferson, Arkansas, on February 11, 2005, in order to address reliability concerns as well as other performance, quality, and data analysis issues. One hundred and thirty-seven scientists from 51 organizations including government agencies, manufacturers of microarray platforms and RNA samples, microarray service providers, academic laboratories, and other stakeholders designed a study plan. Two distinct, commercially available reference RNA samples were generated and analyzed at multiple test sites using a variety of microarray-based and alternative technology platforms, resulting in a rich dataset with over 1,300 microarray hybridizations. The MAQC project observed intraplatform consistency across test sites as well as high interplatform concordance in terms of genes identified as differentially expressed.
Data are available through GEO (series accession number: GSE5350), ArrayExpress (accession number: E-TABM-132), ArrayTrack™ ( http://www.fda.gov/nctr/science/centers/toxicoinformatics/ArrayTrack/ ), and the MAQC website ( http://www.fda.gov/nctr/science/centers/toxicoinformatics/maqc/ ). For further information, contact Dr. William Slikker, Jr., Acting Director, NCTR/FDA. william.slikker@fda.hhs.gov NCTR Research Highlights - August 21, 2006Critical Path – Decisional Tools - NCTR met with officials of Systems Pathology Company, LLC, to discuss a joint initiative for continued development and testing of a computer-assisted pathology software system (CAPS™). The completed system will include a comprehensive library of “smart imaging” programs to assist pathologists in conducting microscopic evaluation of tissues. The programs are designed to differentiate normal versus non-normal tissues.
For further information, contact Dr. Thomas Flammang, NCTR. Critical Path – Decisional Tools -
Gene Ontology (GO) that characterizes and categorizes the functions of genes and their products according to biological processes, molecular functions, and cellular components, has been emerging as a common practice for interpreting differentially expressed gene data from genomics and proteomics technologies. GOFFA provides five interactive functions (Tree View, Terms View, Genes View, GO Path and GO TreePrune) to analyze the gene ontology data, including two unique functions, GO Path and GO TreePrune. The GO Path function displays the statistically most probable GOFFA Tree paths in order, and GO TreePrune provides a visual display of the GO based on user-specified statistical cut-offs of the data. The visual display represents the intuitive depiction of the most likely relevant biological functions. For further information, contact Dr. Weida Tong, Division of Systems Toxicology, NCTR. Critical Path – Clinical Tools - Epigenetic changes are stable and heritable alterations in gene expression that do not involve gene mutation and are increasingly recognized to be involved in the origins and progression of disease including cancers.
A team of scientists from NCTR and the University of Lethbridge in Canada have overcome common problems with known protocols for identifying changes in DNA methylation patterns. They have demonstrated a new laboratory procedure that was able to differentiate clearly, identify, and characterize a number of novel unique DNA sequences with differentially methylated (increased and decreased) sites in normal and human breast cancer cell lines and in normal and rat tumor liver tissues. For further information, contact Dr. Igor Pogribny, Division of Biochemical Toxicology, NCTR. NCTR Research Highlight - July 6, 2006Critical Path – Safety Evaluation: In vitro and in vivo assays are used in regulatory test batteries to predict the carcinogenic potential of chemical agents. Several compounds test as weak, or negative, using in vitro genotoxin assays, but they test positive in the in vivo assays. The reasons for these differences include metabolism; influence of gut microflora; effects on pharmacology, in particular, folate metabolism, etc.
For more information, contact Dr. Robert Heflich, Division of Genetic and Reproductive
Toxicology, NCTR. NCTR Research Highlight - June 5, 2006Critical Path – New Mouse Model:? Scientists from NCTR and the National Institute of Environmental Health Sciences have completed preliminary studies demonstrating their newly created transgenic mouse model (C3H/HeNTac x B6.129SvEv)F1+ -/Trp53tm1Brd) is robust. The model has good reproductive success and survivability for testing potential toxicity and carcinogenicity of compounds such as AZT and 3TC in short-term, 45-week studies. Transgenic animals have held tremendous promise for toxicity testing through incorporation of critical genes (in this model a “+/-“, haplodeficient p53 tumor suppressor gene). However, many strains are not robust or express other non-desirable traits.
For more information, contact Dr. Julian Leakey, Office of Research, NCTR. Email: julian.leakey@fda.hhs.gov NCTR Research Highlight - May 24, 2006Study Protocols: On May 16-17, the Toxicology Study Selection and Review Committee (TSSRC) met at NCTR.
The committee reviewed updates on current studies including: rodent and non-human primate studies of the anesthetic ketamine; neurotoxicology, PB/PK, mechanistic, and chronic studies of the food contaminant acrylamide; AIDS therapeutics; topical and oral studies of aloe vera; skin penetration of nanoscale-engineered material (quantum dots); and metabolic, physiologic, and developmental toxicology studies of the dietary supplement bitter orange (ephedra substitute). The TSSRC also reviewed the protocol design for the plasticizer, diethyl-hexylpthalate; for usnic acid; for the dietary supplement glucosamine/chondritin studies in diabetic rats; and for permanent make-up. The TSSRC membership is composed of representatives from each FDA Center and from other governmental organizations, academia, and industry as required to review the specialized topics under discussion. For further information, contact Dr. William T. Allaben, Associate Director for Scientific Coordination, NCTR. Email: william.allaben@fda.hhs.gov NCTR Research Highlight - April 7, 2006Critical Path – Automated Assays - The in vivo rodent erythrocyte micronucleus test is used in regulatory safety assessment to evaluate the potential of agents to cause chromosomal damage. The test is resource intensive requiring a separate bioassay protocol and expert microscopic evaluation of bone marrow.
The flow cytometry method uses only a small amount of blood allowing multiple samples to be taken from the same animal, which also provides its own baseline values. This improved procedure for conducting the in vivo phase of the genetic toxicology battery provides not only a faster more precise analysis but also the possibility that the micronucleus endpoint can be evaluated in conjunction with other toxicological endpoints, thus improving the preclinical safety assessment. For more information, contact Dr. Martha Moore, Director, Division of Genetic and Reproductive Toxicology, NCTR. Email: martha.moore@fda.hhs.gov NCTR Research Highlight - March 13, 2006Characterization of Tetracycline-Resistant Aeromonas spp. from Catfish - Aeromonas spp. are opportunistic pathogens that cause infectious diseases in fish and humans.
NCTR scientists isolated 81 tetracycline-resistant Aeromonas spp. from 190 catfish samples obtained from commercial ponds in 3 states. Conventional biochemical techniques grouped the 81 isolates into 5 different species. However, the molecular method (PCR-RFLP of the 16S rRNA) indicated that all 81 tetracycline-resistant aeromonads were strains of Aeromonas veronii. All isolates were resistant to multiple antibiotics. A multiplex PCR was designed to amplify the tetracycline-resistant determinants (tetA-E) from the genomic DNA of all 81 isolates. The assay indicated that tetE was the most dominant tet gene in aeromonads. These isolates were further characterized by pulsed field gel electrophoresis (PFGE). Based on the SpeI-PFGE profiles and dendogram analysis, 15 distinct patterns were observed among the 81 isolates. The results indicate the need for use of molecular techniques for typing the isolates and the prevalence of catfish as a reservoir of tet genes. For more information, contact Dr. M. Nawaz, Division of Microbiology, NCTR. Email: mohamed.nawaz@fda.hhs.gov. |
