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2.7.1 Program Description, Context, and Summary of Performance

The National Center for Toxicological Research (NCTR) conducts FDA mission-critical, peer-reviewed research that is targeted to develop a scientifically sound basis for regulatory decisions and reduce risks associated with FDA-regulated products to protect, promote, and enhance America's public health. Specific aims of NCTR's research are to:

• Develop new strategies, methods, and systems to predict risk and anticipate new product technology in support of FDA's commitment to bring this technology to the market rapidly.
• Understand mechanisms of toxicity and design better risk assessment/management techniques and methods for use in premarket review and product health surveillance.

The NCTR provides the Agency with a risk focused high-quality, cost-effective, health science research program, which provides new scientific knowledge through the application and leveraging of research findings from the National Institutes of Health (NIH) and academia to enhance the FDA's regulatory practices. NCTR also leverages Agency scientific research resources through partnerships with other federal agencies, national and international organizations, and industry to meet the Agency's risk management and communication needs.

As a critical resource for enhancing the science base of the FDA, the center director and scientists foster scientific forums with NCTR's stakeholders, namely the product centers and the Office of Regulatory Affairs (ORA). These recurring discussions allow NCTR the opportunity to present and validate its planned/ongoing research, as it relates to the Agency's priorities, as well as to solicit the anticipated research needs of the product centers and ORA. NCTR's strategic research goals support FDA's mission to bring safe and efficacious products to the market rapidly and to reduce the risks of regulated products. NCTR's strategic goals are to:

1. Develop new strategies and methods to test/ predict toxicity and assess/ detect risk for FDA- regulated products (new and those already on the market).
2. Develop computer-based systems (knowledge bases) that predict human risk to enhance the efficiency and effectiveness of pre-market product reviews or post market safety.
3. Conduct fundamental research to understand mechanisms of toxicity, assess new product technology, and provide methods for use in FDA standards development and product risk surveillance.

2.7.2 Strategic Goals

Strategic Goal 1:
Develop new strategies and methods to test/ predict toxicity and assess/ detect risk for FDA-regulated products (new and those already on the market).

A. Strategic Goal Explanation

One of the NCTR's highest priorities is to increase the ability of FDA reviewers to evaluate and predict rapidly and accurately the risk associated with FDA-regulated products. This capability is critical to the Agency's ability to carry out its mission to analyze the safety and efficacy of FDA-regulated products during the pre-market application review process. To adequately predict the risk of human exposure to a toxic agent, a group of tests must be developed, validated, and applied. NCTR uses a multi-disciplinary approach to predict human toxicity and to evaluate human risk using appropriate animal and non-animal models.

Scientists are developing and using new technologies and tests to better understand chemical toxicity and strengthen the extrapolation from animal models to humans. America's quest for good health, in addition to increasing evidence of adverse drug/chemical reactions in humans, point to a need to identify and protect susceptible sub-populations of people at higher risk from exposure to drugs, contaminated foods, or other regulated products.

The NCTR methods used in the identification of and quantitative measurement of carcinogenic and mutagenic risk are essential to the FDA regulatory process. The systems developed and characterized (Performance Goal 1) are capable of simulating human exposure, and increasing the ability to detect weak carcinogens. Other NCTR programs, through partnerships and collaborative projects with other federal agencies, use human data they have collected to better understand the mechanisms of carcinogenesis and to provide new knowledge on the identification of sub-populations, particularly as they relate to individual susceptibility (Performance Goal 2).

B.   Summary of Performance Goals

Performance Goals	Targets	Actual Performance	Reference
1. Introduce the knowledge of new genetic systems and computer-assisted toxicology (toxicoinformatics) into the risk management process. (16001)	FY 04: Use toxicoinformatics, combining information technology with toxicity data, to assess human risk for one regulated product (proof of concept) FY 03: Provide an evaluation of the new molecular technology for detecting alterations in multiple genes. FY 02: Conduct one biologically based mechanistic study combined with predictive modeling to improve extrapolation of animal data to the human condition. FY 01: Provide peer reviewed articles on new Genetic and transgenic systems and knowledge to product reviewers. FY 00: Evaluate a new biological assay to measure genetic changes and validate two existing models that predict human genetic damage. FY 99: Develop better Biological assays to measure genetic changes and predict human genetic damage	FY 04: FY 03: FY 02: A series of investigations in neonatal mice were conducted to examine genotoxic consequences of AIDS drugs. FY 01: Publications submitted to peer reviewed journals: (1) describing methodology damage to mitochondria and (2) providing a review of the possibility of using new genotypic selection for risk assessment. FY 00: Validated the Big Blue Rat and Tk+/- in vivo models by using mutations, micronuclei, apoptotic cells measurements; utilized AHH 1 human lympho-blastoid system to evaluate risk to human genome. FY 99: The Big Blue Rat and NCTR Tk+/- in vivo bioassays were developed and two cell lines were used to predict human genetic damage.	4
2. Develop, with other organizations, gene chip and gene array technology. (16002) (16002)	FY 04: Develop a method for using a rat and human gene chip to obtain an enzyme profile for each species. FY 03: Present one finding and publish one result of the microarray technology polymorphism study. FY 02: Support at least two multi-disciplined DNA and RNA-based microarray technologies. FY 01: Develop "risk chip" technology to screen large numbers of people for biomarkers simultaneously. FY 00: Conduct molecular epidemiology studies to Identify biomarkers of the most frequently occurring cancers in highly susceptible sub-populations. FY 99: Complete biochemical and epidemiological studies to define the basis of susceptibility of humans to the toxicity of regulated products	FY 04: FY 03: FY 02: Scientists used microarray gene expression analysis to identify a number of genes altered in rodents given dichloroacetic acid.Established a fully automated microarray printing process to screen known rodent and human genes. FY 01: Risk chip used to screen population resulted in initiation of negotiations to extend the use of biomarkers and other sub-populations for further investigation. FY 00: Established and validated conventional genotyping methods for 28 gene targets and polymor-phisms; 686 colonoscopy individuals were genotyped for all common NAT2 alleles; analysis ongoing on completed case-control colorectal cancer study. FY 99: Biochemical studies on pancreatic and colorectal cancer were completed and epidemiology studies on cancer are in the enrollment phase.	4
TOTAL FUNDING: ($ 000)	FY 04: 18,871 FY 03: 19,123 FY 02: 18,451 FY 01: 23,271 FY 00: 17,1601	Numbers in the Reference column corresponds to the relevant strategic goal in the HHS Strategic Plan

C.   Goal-By-Goal Presentation of Performance

1. Introduce the knowledge of new genetic systems and computer-assisted toxicology (toxicoinformatics) into the risk management process. (16001)

Context of Goal: Rapid identification of risk is important to the public health mission of the Agency. It is critical that NCTR scientists, in collaboration with Agency reviewers and inspectors, understand and accurately interpret scientific data dealing with risk assessments. NCTR is developing, evaluating and comparing in vivo and in vitro transgenic systems and computer-assisted toxicology knowledge bases for this purpose. Reviewer requests for data or information on transgenic systems and/or microbial biomarkers will be the measure of applicability to the regulatory process.
Performance: Collaboratively with other FDA centers, NCTR researchers will determine if animal data required for pre-market approval of drugs and other products can adequately predict possible toxicity risks in humans. Data collection began from both literature and the FDA files on various drugs. Scientists developed a new animal test for the evaluation of genetic change. The test, which studies the chemical basis of genetic damage, is shown to detect most, if not all, of the mutational events leading to human cancer. Initial experiments indicated that zidovudine, but not lamivudine, is mutagenic, and that lamivudine does not alter the responses induced by zidovudine. During FY 2002 these studies were expanded to include other AIDS drugs (stavudine, didanosine, zalcitabine, and nevirapine). The data generated from the animal and cell culture systems provide a more accurate and rapid assessment of the potential risk to the human population.
Data Sources: NCTR Project Management System, peer-review through FDA/NCTR Science Advisory Board; presentations at national and international scientific meetings; manuscripts prepared for publication in peer-reviewed journals.

2. Develop, with other organizations, gene chip and gene array technology. (16002)

Context of Goal: The importance of gene chip technology is that it allows researchers to screen large numbers of samples, either rodent or human, simultaneously for different types of genes. This will allow the identification of individuals at risk for adverse drug reactions and will facilitate FDA review of individual susceptibility using profiles of agents with known toxicities and allow selection of a diverse group for clinical trials. For instance, the technology will allow scientists to identify people at high risk for various adverse effects, such as liver toxicity. Additionally, DNA gene expression microarrays are being developed to better understand interspecies extrapolation. Development of some of these techniques is being done in collaboration with universities and industry.
Performance: Research focus is on developing and printing a complete rat and human gene chip that will be used to establish a genetic profile for each species. Increasing evidence of adverse drug and chemical reactions in sub-populations of humans (specific classifications such as race, gender, geographic location, common disease), point to a need to identify and protect groups of people at higher risk from exposure to specific drugs, contaminated food, or other FDA-regulated products. NCTR scientists in collaboration with scientists at the University of Arkansas for Medical Sciences (UAMS) have established a fully automated microarray printing process to screen known rodent and human genes. The human data produced with utilization of this technology will provide FDA with a better understanding of how some individuals react adversely to drugs and regulated products. NCTR scientists collaborated with Environmental Protection Agency (EPA) scientists and successfully used microarray gene expression analysis to identify a number of genes altered in rodents given dichloroacetic acid, a known rodent carcinogen, in their drinking water. They identified specific genes that are involved in cell growth, tissue modeling, normal cell death, cancer progression, and foreign chemical metabolism. This study demonstrates the potential utility of the new DNA microarray technology in evaluating the mechanisms by which chemicals exert their toxicity.
Data Sources: NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board; presentations at national and international scientific meetings; manuscripts prepared for publication in peer-reviewed journals.

Strategic Goal 2:
Develop computer-based systems (knowledge base) that predict human risk to enhance the efficiency and effectiveness of premarket product reviews or postmarket safety.

A. Strategic Goal Explanation

To meet the challenges of rapidly changing technology, the Agency needs unique computer-based predictive systems to aid in assessing human risk and to improve the safety of regulated products. FDA reviewers and investigators face an ever-increasing quantity and complexity of data in new drug, import and product applications. Clearly, tools that provide quick access to relevant scientific information and a capability for predicting risk can expedite important decisions.

An integrated information technology knowledge base that puts relevant scientific knowledge in the hands of an inspector or reviewer can have an immediate effect on assessing and managing human risk.

B.   Summary of Performance Goals

C.   Goal-By-Goal Presentation of Performance

3. 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, each storing experiment information. These databases are continually being updated and enhanced with new linkages and additional experimental data. These databases have been used to assess compounds for NCTR, CFSAN, CDER and EPA.
Data Sources: Use of the predictive and knowledge-based systems by the FDA reviewers and other government regulators; NCTR Project Management System; peer-review through the FDA/NCTR Science Advisory Board; presentations at national and international meetings.

Strategic Goal 2:
Conduct fundamental research to understand mechanisms of toxicity, assess new product technology, and provide methods for use in FDA standards development and product risk surveillance.

A. Strategic Goal Explanation

Most regulatory research begins as a precise exploration of a specific agent, a concept or the use of a particular method. Once techniques are developed, these novel approaches can be applied to answer compelling questions regarding human risk. This strategic goal includes three performance goals that address the Agency strategy for developing science-based product and process standards.

The identification of carcinogens has depended classically upon two approaches: epidemiological studies and lifetime animal exposure studies, each of which has its own strengths and weaknesses. The development of new techniques to assess carcinogenic risk provides the basis for alternative methods of assessing carcinogenic potential that can augment, or perhaps, even replace, the need for expensive animal testing and/or human clinical trails.

Committed to the Food Safety Initiative, the NCTR will continue studies that will identify markers of foodborne pathogens and assess whether these microorganisms undergo change, thus becoming more virulent. Excessive use of antibiotics in medicine and the food industry has led to widespread antibiotic resistance among pathogenic bacteria and is now considered a potentially dangerous health problem.

NCTR scientists will continue to build biologically based dose-response models of microbial infection to assess survival, growth, and infectious components of microbial risk. Research into how microorganisms may be used by bioterrorists continues to be of interest to scientists at the Center. Techniques are being developed to rapidly characterize both native and engineered biological organisms; to identify explosives in enclosed containers and to explore the risk associated with low dose exposure to neurotoxins in seafood.

B.   Summary of Performance Goals

C.   Goal-By-Goal Presentation of Performance

4. Study the risk associated with how a FDA regulated compound or product interacts with the human body. (16004)

Context of Goal: There is a need for expanding the infrastructure for and the conduct of improved comprehensive assessments of FDA-regulated compounds to identify and set new standards of assessment and improve risk decisions impacting public health. Resource limitations (e.g., staff, laboratory space and equipment) along with other NCTR/Agency/ Center projects and priorities permit NCTR to initiate studies only on high-priority, FDA-nominated compounds. These compounds are submitted by the centers and chosen by an FDA committee for study under the NIEHS/NTP Interagency Agreement which helps both Agencies leverage scarce federal dollars in order to meet both their scientific and regulatory needs.
Performance: In addition to providing basic information on toxicological endpoints, such as cancer, the studies being performed also form the basis for mechanistic studies to ascertain if the response detected in the experimental model is relevant to human risk. Major efforts are continuing in the area of phototoxicity with emphasis on the potential interaction between ultraviolet (UV) light and substances found in dietary supplements, such as aloe vera and ephedra. Besides using aloe vera as a topical ointment, oral products are now on the market for ingestion. Studies that were conducted on the herb-drug interactions of the supplement St. John's Wort, garlic oil, Panax ginseng, and Ginkgo biloba have shown measurable induction of the activity of cytochromes that may be used to predict herb-drug interactions in the public. The task of determining human risk of these products rests with the FDA.
Data Sources: Evidence that mechanistic data are used in the regulatory process; NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board.

5. Develop risk assessment methods and build biological dose-response models in support of the Food Safety Initiative. (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 safety 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. With the FY 2004 increase, NCTR will be bringing the BSL-3 laboratory online by initiating samples analysis to evaluate the effect of possible contamination agents.
Performance: Researchers at the NCTR 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.
Data Sources: NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board; presentations at national and international scientific meetings; and manuscripts prepared for publication in peer-reviewed journals.

6. 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). NCTR will upgrade the Center's BSL-3 animal quarantine facility to evaluate the effects of possible bioterrorism agents.
Performance: Chemical sensor technology for the assessment of food quality was further developed and the concept evolved into both a commercial version and a consumer version. The research extended to detect other endpoints that are measures of product quality and freshness. As an extension of this work, an interagency agreement was established with the Federal Aviation Administration (FAA) to detect explosives in airline cargo. Studies are being conducted to compare and contrast several new mass spectrometry techniques to more rapidly evaluate microbial risk.
Data Sources: NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board, the NTP Scientific Board of Counselors, and the Food Safety Initiative Coordinating Committee; presentations at national and international scientific meetings; and manuscripts prepared for publication in peer-reviewed journals.

7. Use new technologies (bioinformatics, imaging, proteomics, and metabonomics) for diagnosis of risk. (16013)

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. 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 scientists are developing a new research focus area in these technologies and applying them to fundamental risk assessment questions. The quantitative structure-activity relationship (QSAR) was developed and validated against experimental data. This QSAR approach was then applied to three environmental data sets identified by EPA, and to a list of chemicals of concern identified by CFSAN and CDER. The QSAR screen provided a list of priority chemicals for further experimental evaluation and/or regulatory decision-making.
Data Sources: NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board and the NTP Scientific Board of Counselors; presentations at national and international scientific meetings; and manuscripts prepared for publication in peer-reviewed journals.

Contact Information:
Planning Staff, Office of Planning, FDA
Phone: 301-827-5210

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