National Center for Toxicological Research Performance Goals
|Long Term Goal: Increase the number of safe and effective new products by increasing the predictability, efficiency and effectiveness of product development, including products for unmet medical and public health needs, emerging infectious diseases and counterterrorism.|
|1. Use new technologies (toxicoinformatics, proteomics, metabolomics, and genomics) to study the risk associated with how an FDA-regulated compound or product interacts with the human body. (16014) (output)||2007||Test systems biology in the drug review process to assess value in drug review and approval.||1/08|
|2006||Present one finding utilizing novel technologies to assess changes in genes and pathology, and the relationship between chemical exposure, toxicity and disease.||1/07|
|2005||Develop at least one protocol (proof of concept) to aid in defining drug toxicity studies and studies into mechanistic age-associated degenerative disease.||Three protocols were developed in the Division of Systems Toxicology, including studies of biomarkers of liver toxicity and disease, PPARg agonist effects on rat liver gene expression and age-associated changes in gene expression in F344 rats.|
|2004||Use toxicoinformatics, combining information technology with toxicity data, to assess human risk for one regulated product (proof of concept)||Used biologically-based models of cancer-causing mutations to study skin tumor induction by regulated physical and chemical products.|
|2. Develop computer-based models and infrastructure to predict the health risk of biologically active products. (16003) (output)||2007||Demonstrate the utility of ArrayTrack in the regulatory environment.||1/08|
|2006||Interpret at least one toxicology study at the molecular level utilizing the DNA microarray database (ArrayTrack).||1/07|
|2005||Develop a computer-based system to integrate databases, libraries and analytical tools to support risk analysis and assessment.||ArrayTrack has been developed and implemented as a fully integrated system for microarray data management, analysis and interpretation.|
|2004||Expand current technologies to include risk assessment for two biologically active products of interest to the FDA.||Modeled in vivo gene mutation and genotoxicity data to gain insight into the mechanism of action and relative risk posed by liver and lung carcinogens.|
|2003||Maintain existing computational databases of estrogenic and androgenic compounds for use by reviewers.||The data is available for public access and allows for integration of information across health research fields.|
|2002||Maintain existing computational databases of estrogenic and androgenic compounds for use by reviewers.||Developed an integrated Toxicoinformatics System that includes a central data archive, mirrored public databases, and analysis functions.|
|Cross Reference: These performance measures support HHS Strategic Goal 2.|
|Long Term Goal: Prevent harm from products by increasing the likelihood of detection and interception of substandard manufacturing processes and products.|
|3. Develop risk assessment methods and build biological dose-response models in support of Food Security. (16007) (output)||2007||Through collaborative efforts, use flow cytometry to facilitate isolation of single bacteria from contaminated samples for rapid bacterial identification and for pyrolysis mass spectrometry.||1/08|
|2006||Demonstrate one utility of an oligonucleotide-microarray method as an integrated strategy to respond to antibiotic resistant agents in foodborne pathogens and bioterror agents.||1/07|
|2005||Develop molecular method (oligo-microarray) to detect and monitor foodborne pathogenic bacteria.||In collaboration with CFSAN, scientists in the Division of Microbiology developed and validated a Salmonella biochip using microarray technology for rapid and accurate identification of virulence and antimicrobial resistance genes in Salmonella.|
|2004||Under the Food Safety Initiative, establish a nutrition program in collaboration with other centers to address the risk associated with obesity in children, nutrition in pregnant women and poor nutrition in sub-populations; and initiate analysis on samples requiring high levels of containment in an accredited biosafety level 3 (BL-3) facility||Collaborative efforts that support this goal / target include participation on a committee involving CFSAN, CVM, and NCTR. This committee has prepared a white paper entitled, "Filling Critical FDA-Related Food and Nutrition Research Gaps." Analyzed surrogate microbes to test methodology as well as the public health risk for foodborne hazards.|
|2003||Identify and characterize the role antibiotic resistance plays in emerging and evolving foodborne diseases.||Studies are being conducted to determine whether antimicrobial resistance occurs in bacteria isolated from animal feeds containing antibiotics and to identify the pattern of resistance.|
|2002||Report at scientific meetings and/or publish preliminary results on the development of new methodologies to identify genetically modified foods, drug residues in foods and antibiotic-resistant strains of bacteria.||Researchers published approximately 50 publications and made approximately 20 presentations relating to food safety.|
|4. Catalogue biomarkers and develop standards to establish risk in a bioterrorism environment. (16012) (output)||
|Develop a novel and efficient carbon nanomaterial research method in collaboration with outside entities for the synthesis and chemical modification of unusual materials (i.e., nanofibers used in explosive detectors).||1/08|
|2006||Present one finding utilizing neuropathology and behavioral risk evaluation in the prediction of human outcome to food-borne toxicants.||1/07|
|2005||Present one finding using neural imaging to identify neurotoxicity in exposed populations.||Preliminary studies were conducted in the Division of Neurotoxicology to develop methods for multiple neuroimaging approaches in adult nonhuman primates. Functional data acquisition was accomplished utilizing positron emission tomography (PET).|
|2004||Apply neural imaging to identify and quantify neurotoxicity in exposed populations; and upgrade NCTR's animal quarantine facility to conduct animal research requiring BL3 containment in order to evaluate the effect of bioterrorism agents contaminating the food supply.||A proposal was generated that is designed to determine the reversibility of the development of the effects of the dissociative anesthetic, ketamine, with the use of MicroPET imaging techniques. A portion of the quarantine facility has been "up graded" to conduct animal BSL3) cryptosporidia studies.|
Develop one instrumental rapid sensor detection method.
Outfit upgraded laboratory, provide for supplies (agents, chemicals/pathogens) and construct library databases of proteins and test to find toxin related markers;
Recruit additional expertise in Computational Science, Chemistry and Microbiology.
|The Pyrolysis MAB MS computational system was installed and generating data that shows a very rapid characterization of potential bioterror bacterial strains is possible. Staff was recruited and the BSL-3 laboratory will be ready for use by mid 2004.|
Continue development of solid-phase colorimetric bacterial detection system. Acquire high-resolution mass spectrometer for use with protein from bacteria, food toxins and genomics studies.
Upgrade existing laboratory facilities to BSL-3 to support BSE/TSE and microbial bioterrorism work. Recruit additional expertise in Computational Science, Chemistry and Microbiology.
Scientists are working on streamlining this methodology for use on meat as well as seafood. Equipment was purchased and calibrated.
An outside firm assessed the NCTR facility for laboratory architecture and requirements; and, a floor plan was developed. One computational scientist, three chemists and two microbiologists were hired.
Data Validation: The National Center for Toxicological Research, under the auspices of the Food and Drug Administration (FDA), provides peer-reviewed research that supports the regulatory function of the Agency. To accomplish this mission, it is incumbent upon the Center to solicit feedback from its stakeholders and partners, which include other FDA centers, other government agencies, industry and academia.
The NCTR Science Advisory Board (SAB) is guided by a charter that requires an intensive review of each of the Center's scientific programs at least once every five years to ensure quality programs and overall applicability to FDA's regulatory needs. This board is composed of non-government scientists from industry, academia, and consumer organizations and further supplemented with subject matter experts and scientists representing all of the FDA product centers.
Research proposals are monitored through partnerships with other scientific organizations. Scientific and monetary collaborations include inter-agency agreements with other government agencies, Cooperative Research and Development Agreements, technology transfer with industry, and informal agreements with academic institutions.
NCTR also uses an in-house strategy to ensure the quality of its research and the accuracy of data collected in specific research studies. Study protocols are developed collaboratively by principal investigators and FDA product centers. Findings are recorded and verified by internal and external peer review. Statistical analyses and the analytic approach on each protocol are checked by members of the scientific staff and the Deputy Director for Research. The Project Management System utilized by the Planning and Resource Management staff at the Center tracks all planned and actual expenditures on each research project. The Quality Assurance Staff monitors the experiments that fall within the Good Laboratory Practices (GLP) guidelines.
NCTR's fiscal year research accomplishments, goals and publications are published in the NCTR Research Accomplishments and Plans document and on the web for interested parties. Research findings are presented at national and international scientific meetings and published in peer-reviewed scientific journals. Many of the scientific meetings are sponsored or co-sponsored by NCTR scientists. On a recurring basis the scientists also make presentations and invited speeches in the local university communities; and many serve on international scientific advisory boards.
|Cross Reference:These performance measures support HHS Strategic Goal 2.|
1. Use new technologies (toxicoinformatics, proteomics, metabolomics and genomics to study the risk associated with how an FDA-regulated compound or product interacts with the human body. (16014)
- Context of Goal: Staying abreast of new technologies in science is important for the Agency to protect public health. This goal is designed to establish core competencies within the FDA that can form a foundation for future high technology science thus harnessing technology to apply to the drug approval process. Techniques developed under this goal will utilize the emerging knowledge of the human genome and rapid biological analyses to improve human health, and to insure the safety of marketed products.
- Performance: NCTR developed a unique and sophisticated analytical infrastructure to assess the safety of FDA-regulated products using genomics, proteomics and metabolomics in conjunction with traditional biomarkers of safety. The development of this research approach is directed toward creation of a more relevant and quantitative risk assessment paradigm. A systems biology approach to toxicity testing will provide data that will be more easily extrapolated to the human, making data interpretation more facile and relevant. The result will be new disease markers and drug targets that aid in design of products to prevent, diagnose and treat disease. Systems toxicology provides a step on the critical path toward applying novel technologies used in the evaluation of safety assessment in emerging issues of potential risks. Scientists are actively pursuing collaborations in the systems biology realm of research with industry, academia, and within FDA.
2. Develop computer-based models and infrastructure to predict the health risk of biologically active products. (16003)
- Context of Goal: Using a scientifically based endocrine disruptor knowledge base (EDKB), FDA-regulated drugs, food additives, and food packaging have been shown to contain estrogenic activity. This raised the level of concern regarding adverse effects on human development/reproduction and contributions of these compounds to high incidences of cancer and/or risk of other diseases. Following the success achieved with the EDKB, NCTR scientists will identify and predict, using knowledge bases, whether the increased exposure to naturally occurring and other synthetic products can adversely impact public health.
- Performance: The development of the knowledge base for assessing risk associated with other regulated products continues. NCTR developed an integrated Toxicoinformatic System that includes a central data archive, mirrored public databases, and analysis functions. The central data archives contain a set of relations databases that store experimental information. These databases are continually being updated, enhanced with new linkages and additional experimental data and are being used to assess compounds for NCTR, CFSAN, CDER, EPA and the European Committee for Validating Alternative Methods. Scientists used biologically based models of skin tumor development that use oncogene and tumor suppressor gene mutation frequency to describe skin tumor development. Comparisons will be made between spontaneous tumor induction, after treatment with simulated solar light (as would be encountered in a tanning salon), and after simulated solar light in combination with various cosmetic products. Modeling also was performed with a number of model toxicants, including riddelline, a food contaminant that is a liver carcinogen and 1,6-dinitropyrene, a combustion product that is a lung carcinogen. FDA reviewers are being trained on the software, ArrayTrack, a fully integrated system for microarray data management, analysis, and interpretation; and, are using it as a pilot for assessing voluntary pharmacogenomic data submissions from industry to the Agency.
3. Develop risk assessment methods and build biological dose-response models in support of Food Security. (16007)
- Context of Goal: The Agency is mandated by law to assure that the American public is eating safe food. Therefore, the Agency must strengthen its scientific basis for food security policies and regulatory decisions through the development of novel, vigorous risk assessments (models and techniques) and through the use of artificial intelligence and computational science for risk assessments. Concurrently, the Agency must accelerate the identification and characterization of mechanisms and methods development/ implementation to support surveillance and risk assessment for imported foods and/or microbial contamination.
- Performance: Researchers at the NCTR, the Center for Food Safety and Applied Nutrition (CFSAN), and the Center for Veterinary Medicine (CVM) are continuing to perform studies on bacterial identification techniques both in the food supply and in microbial contamination. This research includes the elucidation of the mechanisms of resistance to antimicrobial agents among bacteria from poultry and vegetables. Microbiological experiments have been conducted that suggest a technique to reduce or eliminate contamination of the environment in agricultural uses of clinically important antibiotic drugs. The pattern of resistance development in bacteria found in animals fed antibiotic and differences in survival rates of drug-resistant pathogens compared to non-resistant pathogens will continue to be studied. Efforts included the evaluation of various molecular methods to detect and identify the foodborne pathogens Campylobacter and Salmonella species and Vibrio parahaemolyticus from various foods and environmental matrices. Development of the Salmonella biochip for rapid and accurate identification of virulence and antimicrobial resistance genes in Salmonella assists in meeting the future challenges of food biosecurity. The joint effort between NCTR and CFSAN microbiologists will be useful in transferring microarray technology to the FDA field laboratories and law enforcement mobile labs.
4. Catalogue biomarkers and develop standards to establish risk in a bioterrorism environment. (16012)
- Context of Goal: Identification of biomarkers is important because it will allow rapid identification of and response to potential contamination. These proteins identify specific genes that are potential targets for introduction of foodborne pathogenicity. The methodology as well as the biomarkers will be useful for rapid identification of hazards. Scientists will be able to expand a novel approach pioneered at the NCTR to rapidly identify biomarkers of toxicity associated with biological warfare agents. These types of agents used by bioterrorists would be difficult to detect using existing technology. This research is conducted in collaboration with the Centers for Disease Control (CDC), the Department of Defense (DOD), Naval Research Labs, the Joint Institute for Food Safety and Applied Nutrition (JIFSAN) and the Center for Food Safety and Applied Nutrition (CFSAN). The chemistry and microbiology programs compared novel mass spectrometric methods with cultural methods, serological tests and molecular genetic methods for rapid identification of foodborne pathogens. This method will reduce analysis time of contaminated food to a few hours which will protect public health in a suspected bioterrorist attack. NCTR has upgraded the Center's Biosafety Level-3 animal quarantine facility and will utilize the laboratory to evaluate the effect of possible contamination agents. NCTR has developed a multidisciplinary approach integrating neurochemical/neurobiological (including genomics and proteomics), neuropathological, neurophysiological, and behavioral assessments to determine adverse effects and explore modes of neurotoxic action. Unique features of NCTR's neurotoxicology research efforts are the capabilities to determine target-tissue chemical concentrations and cellular level interactions of neurotoxicants and to reduce the uncertainty associated with extrapolating findings across species by effectively using rodent and nonhuman primate animal models as well as humans, wherever possible.
- Performance: Studies are being conducted to compare and contrast several new mass spectrometry techniques to more rapidly evaluate microbial risk. Scientists have shared expertise and laboratory infrastructure to prevent or minimize threats from bioterrorism through the development of a Memorandum of Agreement with the Arkansas Department of Health. Scientists also developed in collaboration with the Arkansas Regional Laboratory a method for microbial isolation that dramatically reduces analysis time of contaminated food to only a few hours vs. 2-3 days. Preliminary neuroimaging studies conducted in the Division of Neurotoxicology at the NCTR include developing methods for multiple imaging approaches in adult nonhuman primates. These studies include risk assessment in primates exposed to cocaine during development while others served as non-dosed controls. Functional data acquisition was accomplished with 18F-fallypride for dopamine D2 receptors and FECNT for dopamine transporters using positron emission tomography (PET). Further studies using fMRI are planned.