Part 2, National Center for Toxicological Research, FY 2003 Annual Performance Plan

U.S. Food and Drug Administration
Performance Plan
2002

2.7 NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH

2.7.1 Program Description, Context, and Summary of Performance

Total Program Resources:

	FY 2003 Current Estimate	FY 2002 Current Estimate	FY 2001 Actual	FY 2000 Actual	FY 1999 Actual
Total ($000)	40,688	42,882	36,248	36,248	32,109

The National Center for Toxicological Research (NCTR) conducts FDA mission-critical, peer-reviewed research that is targeted to develop a more 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 toxicity and anticipate new product technology in order to support FDA's commitment to bring this technology to the market rapidly.
To understand mechanisms of toxicity and design better risk assessment/detection techniques and methods for use in pre-market review and product health surveillance.

The NCTR provides the Agency with a 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 best meet Agency 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 the ORA. NCTR's strategic research goals support the FDA's mission to bring safe and efficacious products to the market rapidly and to reduce the risks of products on the market. NCTR's strategic goals are as follows:

Develop new strategies and methods to test/predict toxicity and assess/detect risk for FDA- regulated products (new and those already on the market).
Develop computer-based systems (knowledge bases) that predict human toxicity to enhance the efficiency and effectiveness of pre-market product reviews.
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 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 adverse effects of FDA-regulated human 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 adverse effects 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.

Toxicology research is moving away from its dependence on whole animal test systems that use large numbers of animals and seek relatively few endpoints. These animal test systems are costly, time-intensive, and do not adequately mimic the human response. Thus, scientists must develop and use alternate systems and tests to better understand chemical toxicity and strengthen the extrapolation from animal models to humans. Because of America's quest for good health, increasing evidence of adverse drug/chemical reactions in humans, point to a need to identify and protect susceptible subpopulations 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 the potency of suspected carcinogens and mutagens 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 subpopulations, particularly as they relate to individual susceptibility (Performance Goal 2).

B. Summary of Performance Goals

Performance Goals	Targets	Actual Performance
1. Introduce the know-ledge of new genetic systems and computer-assisted toxicology (bioinformatics) into the application review process. (16001)	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 pre-dictive 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 03: FY 02: 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. FY 98: Utilized model animal and cell culture transgenic systems to evaluate risk to the human Genome. FY 97: Conducted genetic screening and evaluated additional toxic results (e.g., cell death and mutagenesis) in relationship to DNA biomarkers of damage.
2. Develop, with other organizations, gene chip and gene array technology. (16002)	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 suscep-tible subpopulations. FY 99: Complete biochemical and epidemiological studies to define the basis of susceptibility of humans to the toxicity of regulated products	FY 03: FY 02: FY 01: Risk chip used to screen population resulted in initiation of negotiations to extend the use of biomarkers and other subpopulations 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. FY 98: Conducted case Control molecular epidemiology studies to assess breast and prostate cancer in African-American women/men. FY 97: Initiated studies to evaluate the use of molecular biomarkers in clinical studies and to identify subpopulations of Increased risk.
TOTAL FUNDING: ($000)	FY 03: 25,242 FY 02: 29,361 FY 01: 23,271 FY 00: 17,160 FY 99: 15,084

Performance Goals

Targets

Actual Performance

Reference

1. Introduce the know-ledge of new genetic systems and computer-assisted toxicology (bioinformatics) into the application review process. (16001)

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 pre-dictive 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 03:

FY 02:

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.
FY 98: Utilized model animal and cell culture transgenic systems to evaluate risk to the human
Genome.
FY 97: Conducted genetic screening and evaluated additional toxic results (e.g., cell death and mutagenesis) in relationship to DNA biomarkers of damage.

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

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 suscep-tible subpopulations.

FY 99: Complete biochemical and epidemiological studies to define the basis of susceptibility of humans to the toxicity of regulated products

FY 03:

FY 02:

FY 01: Risk chip used to screen population resulted in initiation of negotiations to extend the use of biomarkers and other subpopulations 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.
FY 98: Conducted case
Control molecular epidemiology studies to assess breast and prostate cancer in African-American women/men.
FY 97: Initiated studies to evaluate the use of molecular biomarkers in clinical studies and to identify subpopulations of
Increased risk.

TOTAL FUNDING:
($000)

FY 03: 25,242
FY 02: 29,361
FY 01: 23,271
FY 00: 17,160
FY 99: 15,084

C. Goal by Goal Presentation of Performance

1. Introduce the knowledge of new genetic systems and computer-assisted toxicology into the application review process. (16001)

Context of Goal: Currently, industry has been submitting drug applications with data from transgenic systems. It is critical that NCTR scientists in collaboration with Agency reviewers understand and accurately interpret data derived from these systems in safety 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 will be the measure of applicability to the review process.
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.
Performance: Collaboratively with the Center for Drug Evaluation and Research (CDER), NCTR researchers will determine if animal data required for pre-market approval of drugs can adequately predict possible developmental 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 was modeled after a similar rodent lymphoma test already used internationally for hazard identification. 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. 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. These findings were submitted for review and will be published in scientific journals.

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

Context of Goal: The importance of risk chip technology is that it allows researchers to screen large numbers of people simultaneously for different types of biomarkers. 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 toxicities, including 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 private industry.
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.
Performance: Research focus is on the foodborne heterocyclic amines, environmental aromatic amines, and poylcyclic aromatic hydrocarbons, on widely used drugs including selected benzodiazepines, antihistamines, drugs inducing peroxisomal proliferation or oxidative stress, on estrogens, antiestrogens and endocrine disruptors, as well as tobacco usage. Projects ongoing include the etiology of human cancers of the colon/rectum, pancreas, larynx, breast, ovary, prostate, lung, urinary bladder, and bone marrow. Implementation of conventional genetic compositions was completed and validation studies carried out. Increasing evidence of adverse drug and chemical reactions in sub-populations (specific classifications such as race, gender, geographic location, common disease (inflicted) of humans, point t a need to identify and protect groups of people at higher risk from exposure to specific drugs, contaminated food, or other FDA-regulated products. 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.

Strategic Goal 2:
Develop computer-based systems (knowledge base) that predict human toxicity to enhance the efficiency and effectiveness of pre-market product reviews.

A. Strategic Goal Explanation

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

Estrogen exposure of the human population via plant-derived food is virtually universal and infants consuming soy formula are exposed to the highest doses. Additionally, estrogenic activity is found in environmental products, such as plastics and pesticides, and in FDA-regulated products. Thus, it is important to understand the varying toxicological and pharmacological properties of these compounds as well as their common mechanism of action.

B. Summary of Performance Goals

Performance Goals	Targets	Actual Performance	Reference
3. Develop computer-based models and infrastructure to predict the health impact of increased exposure to estrogens and anti-estrogen compounds. (16003)	FY 03: Maintain existing computational databases of estrogenic and androgenic compounds for use by reviewers. FY 02: Maintain existing computational databases of estrogenic and androgenic compounds for use by reviewers. FY 01: Validate a predictive model for androgens. FY 00: Validate predictive model for estrogenic or estrogenic-like compounds. FY 99: Demonstrate a model toxicity knowledge base to support and expedite product review	FY 03: FY 02: FY 01: Predictive model for androgen receptors was developed and assessment of 204 chemicals completed. FY 00: The estrogenicity of 150 chemicals was asses-sed using an estradiol receptor-binding assay validating the predictive model. Two additional assays were evaluated for androgen binding. FY 99: Thirty (30) chemicals for CFSAN and six chemicals for CDER have been used to confirm the predictive value of the computer modeling system. Partnering continues with other agencies (EPA, etc.) and industry (CMA). FY 98: Computer-based predictive system used to develop model for rodent and human estrogen receptor binding. FY 97: Prototype presented at FDA Science Forum.
TOTAL FUNDING: ($000)	FY 03: 15,466 FY 02: 13,521 FY 01: 12,977 FY 00: 4,382 FY 99: 3,853

C. Goal by Goal Presentation of Performance

3. Develop computer-based models and infrastructure to predict the health impact of increased exposure to estrogens and anti-estrogen compounds. (16003)

Context of Goal: NCTR scientists will identify and predict, using the Endocrine Disrupter Knowledge Base (EDKB), whether the increased exposure to naturally occurring and synthetic estrogens and anti-estrogens can adversely impact public health. Recent recognition that FDA-regulated drugs, food additives, food packaging and EPA-regulated environmental chemicals may have on estrogenic activity has affected the way regulators review human exposures. This raised the level of concern regarding adverse effects on human development/reproduction and contributions to high incidences of cancer and/or toxicity.
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.
Performance: Knowledge base has been used by product centers and the EPA to model estrogen activity. The development of the knowledge base for the binding of chemicals to the estrogen and androgen receptor; and, studies on androgen receptor (AR) binding continue. Scientists validated a predictive computer model for estrogenic or estrogen-like compounds. Replicate tests are now complete for 204 chemicals that bind to the male hormone receptor, thus potentially influencing the development of the male reproductive system.

Strategic Goal 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.

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 of human health and safety. 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.

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. NCTR is developing research protocols to study the mutagenicity and carcinogenicity of genetically modified foods using in vivo and in vitro transgenic systems that have been evaluated and validated in-house.

B. Summary of Performance Goals

Performance Goals	Targets	Actual Performance
4. Study FDA-regulated compounds to relate the mechanism(s) by which a chemical causes toxicity. (16004)	FY 03: Continue toxicological evaluations of anti-HIV therapeutics and photoactive compounds. FY 02: Initiate analytical/ biological studies to assess the toxicity of at least one, FDA high priority dietary supplement. FY 01: Study two FDA-regulated compounds. FY 00: Conduct studies to relate how a compound causes damage to the damage itself, thus strengthening the scientific basis for regulation of compounds. FY99: Develop faster, more accurate tests based on mechanisms of toxic actions.	FY 03: FY 02: FY 01: Developed protocols to conduct comprehensive toxicological evaluations of Aloe vera and mixtures of anti-HIV therapeutics. Conducted literature review of retinyl palmitate. FY 00: Bioassay and mechanistic studies on malachite and leucomal-achite green are ongoing. Animals are being tested to study the effects of hydroxy acids and to determine dose-response for the induction of skin edema on SKH-1 mouse skin as a screen for light-induced phototoxicity. FY 99: The experimental portion of the 2-year chronic study on urethane in ethanol has been completed and malachite green animal studies continue. Preliminary studies to assess risk of alpha- and beta-hydroxy acids in skin formulations continue using hairless mice. Portions of the studies on genistein, an endocrine disrupter, are completed. The chronic 2-year component is ongoing. FY 98: Report presented to regulate fumonisin B₁ exposure in foods and long- term chloral hydrate usage. FY 97: Complete dosing regimen for 2-year chronic bioassay on chloral hydrate and fumonisin B1; range- finding studies on genistein, methoxychlor, and nonyl-phenol were completed and data is being analyzed for toxic effects; phototoxicity assessment of alpha hydroxy acids was nominated for study.
5. Develop methods and build biological dose-response models to replicate bacterial survival in the stomach. (16007)	FY 03: Identify and characterize the role antibiotic resistance plays in emerging and evolving foodborne diseases. FY 02: 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. FY 01: Provide model to replicate bacterial survival in the stomach. FY 00: Develop methods of predicting, more quicklyand accurately, the risk associated with such foodborne pathogens as Salmonella spp., Shigella spp., and Campylobacter spp. FY 99: Develop rapid and sensitive methods for identifying pathogens, foodborne bacteria, and microbial contaminants.	FY 03: FY 02: FY 01: Performed pre-validation studies that examines the efffect of low-level antibiotic residues on the human intestinal microflora by using a chemostat to model the human intestinal tract. FY 00: Studies are con-tinuing on the in vitro model and molecular analysis of competitive exclusion pro-ducts; molecular screening methods have been devel-oped for the determination of vancomycin and fluoroquin-olone resistance in Campylo-bacter sp. isolated from poultry. FY 99: A project to detect simultaneously 13 species of foodborne pathogens in a single food sample was completed and is undergoing validation. CVM has been alerted to the danger associated with using antibiotic-resistant bacteria for competitive exclusion product in the poultry industry.
6. Catalogue biomarkers and develop standards to establish safety and effectiveness of imaging devices for potential use in the diagnosis of toxicity. (16012)	FY 03: Develop one instru-mental 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 FY 02: 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. FY01: Begin developing solid-phase colorimetric bacterial detection system. FY 00: Begin developing solid-phase colorimetric . bacterial detection system. FY 99: Develop method to identify biomarker proteins; translate method to colorimetric field kit.	FY 03: FY 02: FY 01:Application/extension of Fresh Tag^® technologies for detection of nitrogen-based explosives began. FY 00:
7.Use new technologies (bioinformatics, imaging, proteomics, and metabonomics) for diagnosis of toxicity. (16013)	FY 03: Evaluate, for use Agency-wide, one new technology such as proteomics or genomics for determining liver damage by regulated products. FY 02: Publish at least one scientific paper describing one technology for use in reviewing regulated compounds. FY 01: Develop at least three concept papers exploring new technologies for the assessment of toxicity.	FY 03: FY 02: FY 01: Three concept papers were submitted and approved: 1) design and analysis of gene array expression data; 2) development of glass-slide based oligonucleotide microarrays for rat and human genes; 3) two-dimensional micro-LC-proteonomics using stable-isotope affinity tags for differential display of toxicity-induced biomarkers.
TOTAL FUNDING: ($000)	FY 03: 16,263 FY 02: 14,791 FY 01: 14,559 FY 00: 14,980 FY 99: 13,172

C. Goal by Goal Presentation of Performance

4. Study FDA-regulated compounds to relate the mechanism(s) by which a chemical causes toxicity. (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 on only 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.
Data Sources: Evidence that mechanistic data are used in the regulatory process; NCTR Project Management System; peer-review through FDA/NCTR Science Advisory Board.
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 pertinent to humans. Major efforts are continuing in the area of phototoxicity with emphasis on the potential interaction between ultraviolet (UV) light and substances found in over-the-counter cosmetics. Scientists have studied alpha and beta hydroxy acids, glycolic and salicylic acids. Studies demonstrated that acids found in many skin cosmetics, when applied to the skin of mice in conjunction with ultraviolet (UV) radiation, induced skin tumors. Results suggest that the compound in sun-skin-care preparations may enhance the damage caused by the sun.

5. Develop methods and build biological dose-response models to replicate bacterial survival in the stomach. (16007)

Context of Goal: The Agency is mandated by the Presidential Food Safety Initiative to assure 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.
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.
Performance: Researchers at the NCTR and the Center for Veterinary Medicine (CVM), are continuing to perform pre-validation studies on an in vitro system that examines the effect of low-level antibiotic residues on the human intestinal microflora by using a chemostat to model the human intestinal tract. Other essential research ongoing includes the elucidation of the mechanisms of resistance to antimicrobial agents among bacteria from the human gastrointestinal tract. Three different concentrations of the fluoroquinolone antibiotic ciprofloxacin were tested. Studies clearly indicate that the in vitro system can be a valuable tool to evaluate the effects on the human intestinal microflora of low levels of antimicrobial agents in food.

6. Catalogue biomarkers and develop standards to establish safety and effectiveness of imaging devices for potential use in the diagnosis of toxicity. (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. NCTR has the capabilities of rapidly developing a BL3/BL4 containment laboratory that would be capable of doing high containment biological research on a wide variety of animal species. The BL3/BL4 laboratory will enable FDA to perform critical research in a relatively risk-free environment with a highly trained staff. 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. The research conducted in collaboration with the Center for Disease Control (CDC), the Department of Defense (DoD), Naval Research Labs, the Joint Institute for Food Safety Applied Nutrition (JIFSAN) and the Center for Food Safety and Applied Nutrition (CFSAN).
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.
Performance: For FY 2000, NCTR's goal was not met due to lack of funding. 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). For FY 01, NCTR used its unique Fresh Tag accomplishments to detect nitrogen-based explosives. This meant that NCTR refined its Fresh Tag technology which was originally developed to detect and identify deteriorating food to prevent consumption in the early stages of spoilage. This is a good example of NCTR's nimble reaction to current events to aid in the nation's fight against terrorism.

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

Context of Goal: Staying abreast of new technologies in science is important for the Agency to protect public health. This new 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.
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.
Performance: Researchers are developing new molecular technologies to be used in evaluating structural and functional changes in the genome of both rodents and humans. NCTR scientists are developing a new research focus area in these technologies and applying them to fundamental risk assessment questions. The concept papers developed include: 1) developing statistical and computational procedures for the design, analysis and interpretation of gene expression data from microarray experiments; 2) developing, printing, and establishing the methodology for using a "rat chip" containing approximately 4000 genes and a "human chip" containing approximately 8300 genes; and 3) addressing the need to develop biomarkers of toxicity, disease progression/regression, and efficacy of drug treatment. The techniques developed will further utilize the emerging knowledge of the human genome and rapid biological analyses to improve human health and to insure the safety of marketed products.

2.7.3 Verification and Validation

As a research component of the FDA, the National Center for Toxicological Research 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. Scientific program services are provided by the Science Advisory Board (SAB) composed of non-government scientists from industry, academia, and consumer organizations. The SAB is guided by a charter that defines the scope of the review to include quality of the science and the overall applicability to FDA regulatory need. This board is further supplemented with subject matter experts and scientists representing all of the FDA product centers. Programs described are evaluated at least once every five years by the SAB.

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 and technology transfer with industry, and grants or informal agreements with academic institutions.

NCTR uses several strategies 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 by and verified by internal and external peer review. Statistical analyses are performed by the principal investigator and reviewed by members of the Biometry and Risk Assessment staff. The analytic approach is checked by different members of the scientific staff and the Deputy Director for Research to verify the scientific integrity of the data.

To ensure that the performance data are accurate and timely, the NCTR Planning Division staff monitors research progress at the project level on a recurring basis. The Project Management System utilized by the Planning Staff is capable of tracking planned and actual research projects and expenditures in all three strategic goals and in the outlined performance goals. Quality Assurance Staff monitor the experiments that fall within the Good Laboratory Practices (GLP) guidelines. Research accomplishments and goals are published annually in the NCTR Research Accomplishments and Plans document. Publications reporting research findings are tracked by project, and final reports are archived and distributed to interested parties. Over the past four or five years, NCTR has published yearly 175-250 research documents, manuscripts, book chapters, and abstracts in recognized scientific journals.

NCTR's research findings are also 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. The scientists make over 400 presentations and invited speeches a year at local science seminars and at national and international meetings. Many NCTR scientists also serve on international scientific advisory boards.

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

Previous Section | Table of Contents | Next Section

Office of Planning Home Page
FDA Home Page | Search | A-Z Index | Site Map | Contact FDA

FDA/Office of Planning
Web page created by clb 2002-FEB-20.

2.7 NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH

2.7.1 Program Description, Context, and Summary of Performance

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 on the market).

Strategic Goal 2: Develop computer-based systems (knowledge base) that predict human toxicity to enhance the efficiency and effectiveness of pre-market product reviews.

Strategic Goal 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.

2.7.3 Verification and Validation

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

Strategic Goal 2:
Develop computer-based systems (knowledge base) that predict human toxicity to enhance the efficiency and effectiveness of pre-market product reviews.

Strategic Goal 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.