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FY 2007 Table of Contents

NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH

Statement of the Budget Request

The National Center for Toxicological Research (NCTR) is requesting $34,240,000 to conduct peer-reviewed translational research that supports and anticipates the FDA's current and future regulatory needs. The mission of NCTR is to:

• Conduct fundamental and applied research aimed at understanding critical biological events, such as adverse drug reactions and/or antibiotic resistance, to determine how people are adversely affected by exposure to products regulated by FDA.
• Conduct peer-reviewed scientific research that provides the basis for FDA to make sound, science-based regulatory decisions, and to promote the health of the American people through the Agency's core activities of pre-market review and post-market surveillance.
• Develop methods to measure human exposure to products that have been adulterated or to assess effectiveness and/or the safety of a product.
• Provide the scientific findings used by the FDA product centers for pre-market application review and product safety assurance for the betterment of public health.

Program Description

The NCTR conducts translational applied research specifically designed to define biological mechanisms of action underlying the toxicity of FDA-regulated products. This research aims at understanding critical biological events triggered by exposure to toxins and at developing methods to improve assessment of human exposure, susceptibility, and risk. This is particularly pertinent in supporting FDA's role in developing medical counter-measures and other preparatory efforts for the Department's bioterrorism activities.

Research performed at NCTR targets fulfillment of three program strategic research goals in support of FDA's public health mission:

• Risk Assessment for Regulated Products includes the development of new strategies and methods to test/predict toxicity and assess/detect risk for FDA regulated products, both new and on the market - this includes new genetic systems and computer-assisted toxicology for use in application review and development of gene chip and gene array technology.
• Knowledge Bases that Predict Human Toxicity takes in the development of computer-based systems as knowledge bases that predict human toxicity to enhance efficiency and effectiveness of premarket reviews.
• Methods for Use in FDA Standard Development and Product Risk Surveillance covers the conduct of fundamental research to understand mechanisms of toxicity assess new product technology and provide methods for use in FDA standards development and product risk surveillance.

NCTR conducts research that supports FDA's core mission areas through the dedicated efforts of staff in NCTR's Office of Research whose primary focus is on the study of systems biology, biochemical and molecular markers of cancer, neurotoxicity, applied and environmental microbiology. The divisions work closely in a seamless effort supporting FDA's mission to bring safe and efficacious products to the market rapidly and to reduce the risk of adverse health effects from products on the market.

NCTR is co-located with the Office of Regulatory Affairs' Arkansas Regional Laboratory on a large campus to form the Jefferson Laboratories (an FDA owned facility) located in Jefferson, Arkansas, situated near the city of Little Rock, Arkansas. The research work performed by NCTR occurs in 34 buildings and 4 trailers.

Performance Analysis

During the latest performance period, (FY 2005), the National Center for Toxicological Research successfully met all of the targets for the Center's four performance goals. For more information about these performance goals and results, please see the Performance Detail section.

NCTR continues to support the Agency's counterterrorism efforts by conducting research in the effort to protect the Nation's food supply from a terrorist's attack. The center has set ambitious targets in support of these efforts.

Performance Highlight:

Cost of Living-Pay: + $ 533,000

FDA's request for pay inflationary costs is essential to accomplishing its public health mission. Payroll costs account for over sixty-percent of our total budget, and the Agency is no longer able to absorb this level of inflation on such a significant portion of its resources. The increase will allow FDA to maintain staffing levels, including a national cadre of specially trained scientific staff. The total estimate for pay increases is $20,267,000. The NCTR's portion of this increase is $533,000. These resources are vitally important for FDA to fulfill its mission to protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use.

NCTR Redeployment: - $7,033,000 and - 7 FTE

To fund FY 2007 priority initiatives such as Food Defense, Pandemic Preparedness, and Human Tissues Initiatives, FDA re-deployed resources from base programs. To accomplish this strategic redeployment and fund new high priority initiatives, NCTR reductions include: infrastructure and contract support, and research support services including animal care/diet preparation, pathology and scientific information technology. NCTR is also reducing studies in the areas of systems biology, genetic and reproductive toxicology, and rapid identification methods for biohazards.

Justification of Base [1]

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

NCTR supports the strategic goal by developing new scientific tools and biomarkers to expedite FDA's critical path research in medical product discovery, development and assessment. NCTR will continue to:

• Develop 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. A systems biology approach to toxicity testing will provide data that are more easily extrapolated to humans, making data interpretation easier and relevant. Scientists believe these developments may prove that new disease markers and drug targets can be identified that will help design products to prevent, diagnose and treat disease.

• Provide software systems and analysis capability to manage and integrate data from new technologies (such as microarrays, proteomics, and functional genomics) with traditional toxicological data. NCTR computational scientists have developed ArrayTrack, a data management and analysis software used to store and analyze the thousands of data points generated by a single microarray experiment to provide a scientific basis for FDA regulatory standards.

• Analyze, using advanced proteomic technology, changes in a given sample after exposure to a toxicant allowing the identification of function and quantification of all proteins in the sample. A mass spectrometer analyzes the changes in proteins due to toxicant exposure in order to identify possible disease states in the brain, liver, prostate, and blood.
• Develop methods to measure human exposure to adulterated products and enhance the understanding of acute and chronic liver disease. This research is used by FDA's product centers for premarket application review and product safety assurance to improve product quality and better predict the toxicity of new drugs; thereby, managing public health risk.
• Determine, using chemical probes, if bacteria in food and food producing animals or their environment have developed resistance to commonly used antibiotics.

FDA Strategic Goal: Improving Product Quality, Safety, and Availability through Better Manufacturing and Product Oversight

• Address the potentially hazardous effects of sunlight with products used by the public. NCTR has one of only two phototoxicology laboratories in the world with the capacity to expose large numbers of animals to simulated solar light - almost any light to which humans are exposed. Studies of particular concern being conducted at NCTR include:
  • Interaction of sunlight and cosmetics;
  • Safety of products (such as dietary supplements, sports drinks, or skin creams) containing aloe vera; and,
  • Stability and toxicity of tattoo ink ingredients.
• Conduct studies to assess the toxicity of nanoscale materials (miniscule particles that measure less than 100 nanometers) and to assist the FDA in evaluation of nanotubes (extremely small tubes made from pure carbon) as safe delivery platforms for drugs.
• Conduct fundamental applied research, including animal and microbial bioterrorism research and analytical studies aimed at understanding critical biological events. This will assist determining adverse effects on people exposed to FDA-regulated products. It will also help develop a means for rapidly detecting potential biowarfare agents
• Conduct research studies of bacterial strains. This will enable the FDA to support the rapid detection and identification of biological warfare agents or foodborne contaminants through methods developed in a state-of-the-art Biosafety Level-3 laboratory facility located in Jefferson, Arkansas.
• Conduct studies, developing methods and recommending industry guidelines to evaluate the safety of antimicrobial agents for human health risks. Studies of emerging interest to FDA under the food security/counter terrorism initiative continuing at NCTR include:
  • Human flora-associated mouse model and in vitro cell-culture model evaluations of antimicrobial drug residue effects on colonization resistance and host immunity.
  • Development of a DNA microarray method for the detection of intestinal bacterial species and foodborne pathogens in human fecal samples to monitor drug-mediated perturbations in these indigenous populations.

FDA Strategic Goal: Transforming FDA Business Operations, Systems, and Infrastructure to Support FDA's Mission in the 21^st Century

NCTR supports this strategic goal by developing policies and strategies to enhance its resource utilization, while building its human capital capability to meet the critical needs of the Agency. NCTR will continue to:

• Reward and retain state-of-the-art scientists and health professionals.
• Increase the use of existing formal and informal training programs such as postdoctoral programs, student intern programs and mentorship experiences.
• Maintain state-of-the-art expertise by training scientists in emerging technologies.
• Redirect resources to programs more critical to FDA's research mission.
• Leverage NCTR's resources and scientific expertise with other agencies [through interagency agreements] and non-government groups [through cooperative research and development agreements] to support FDA critical research needs.

Selected FY 2005 Accomplishments

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

A key NCTR strength is our cadre of interdisciplinary research teams working with colleagues across the FDA and leveraging other agency resources to conduct research to develop new scientific tools. These tools include database and bioinformatics tools, genetic tools to assess populations susceptible to disease biomarkers, and systems tools (integration of genomics, proteomics, metabonomics, and bioinformatics). These tools will provide FDA with improved means of monitoring drug safety, the ability to advance personalized medicine through a better understanding of individualized responses based on genetics, and validated technologies for ultimate use by the reviewer in FDA.

Translational Research [2]

• Implemented ArrayTrack for interpretation of data received from DNA chromosome test studies. ArrayTrack is an integrated software package that plays a critical role in managing, analyzing and interpreting microarray data to study toxicology in human drug and food programs.
• Collaborated with NIH's components and commercial vendors to integrate ArrayTrack with a variety of tools and expanded the user base for the software to over 50 companies/institutions.
• Initiated the MicroArray Quality Control Project (MAQC), collected data from over 600 arrays, served as a test site for the MAQC project and held a conference with over 100 participants from government and industry.
• Collaborated with NIH to develop a draft document on standards in metabolomics and aid in dissemination of best practices for metabolomics.
• Identified with other Agency collaborators metabolic patterns of toxicity that correlated with cisplatin and gentamicin toxicity.
• Developed Protein Track software for the analysis of proteomic data.
• Examined utility of gene expression microarray data for providing toxicological insights for drug safety evaluations through the FDA's Interdisciplinary Pharmacogenomics Review Group and the Voluntary Genomics Data Submission group.
• Demonstrated the importance of optimal microarray scanner calibration on the quality of microarray data.

Toxicology Research

• Participated in international efforts that resulted in harmonization of guidance for the conduct of and interpretation of data from genetic toxicology assays. FDA used the information from genetic toxicology assays for drug, food additive and other product safety assessments.
• Conducted studies (under the FDA-NCTR/National Toxicology Program Interagency Agreement) to evaluate the possible genotoxic mode of action for the carcinogen acrylamide. The mode of action will impact the choice of low dose extrapolation model used for the quantitative risk assessment of acrylamide, produced as a by-product of the high heat cooking of starchy foods such as potatoes.
• Established a rodent model for studying the consequences of lifetime exposure to low doses of acrylamide (a common contaminant of carbohydrate-based foodstuffs cooked at high temperatures).
• Developed a new approach to using a quantitative evaluation of in vivo mutation data to better inform the decision as to whether a particular chemical is a mutagenic or non-mutagenic carcinogen, thus impacting the choice of low dose extrapolation model or providing evidence that there may be limited risk at low dose exposures.
• Discovered that individuals with a mutation in the CYP3A43 gene were at three-fold increased risk of prostate cancer than individuals without the mutation. This mutation was more common in African-Americans than in Caucasians suggesting that the CYP3A43 gene mutation may contribute to the disparity in prostate cancer risk. Additional common mutations continue to be studied to further understand the genetic causes of the disparity in prostate cancer risk.
• Obtained data from both in vivo and in vitro rodent and nonhuman primate models for assessing the consequences of developmental exposure to commonly used anesthetic agents (ketamine, benzodiazepines) on brain development. These data are critical for establishing Agency guidelines and labeling.
• Completed research on the toxicity of cosmetic ingredients due to their interaction with light. Research included studies on the combined effects of light with a- and ß-hydroxy acids, Aloe vera, retinyl palmitate, nanoscale titanium dioxide, and several coloring agents including iron oxide, Pigment Orange 13, Pigment Yellow 83, Pigment Orange 36, and Pigment Red 22. Experiments are continuing on tattoo dyes to determine the effect of light on the chemicals in those dyes, their metabolism in the body, and how they react with DNA following their metabolism.
• Assessed the effects of transplacental exposure of the anti-retroviral drugs (zidovudine and lamivudine) in combination with nevirapine and nelfinavir. In addition, range-finding studies were conducted in which the drugs were administered transplacentally and neonatally. Investigators have been measuring other endpoints (DNA incorporation, mutagenicity, and micronuclei induction) to determine the mechanisms for the adverse effects of these drugs.
• Developed Windows-based software for simultaneously implementing and linking as many as four physiologically based pharmacokinetic (PBPK) models, each of which incorporates postnatal growth and includes linkage for simulation of pharmacodynamic (PD) effects, such as DNA-adduct formation or cholinesterase inhibition. The user-friendly software will soon be made available to FDA researchers and reviewers, as well as to the scientific community.

FDA Strategic Goal: Improving Product Quality, Safety, and Availability through Better Manufacturing and Product Oversight

Working with colleagues within the agency, NCTR researchers conduct studies to assess the toxic effects of compounds in foods including antibiotics, pathogens, adulterants, etc. to develop risk identification standards for use in FDA guidance documents.

Nutrition Research

• Initiated under the FDA-NCTR/NTP IAG, a study investigating the hazardous effects of exposure to bitter orange, a dietary supplement chemically similar to ephedra.

Food Defense

• Developed, in collaboration with the Center for Veterinary Medicine (CVM), oligo-based microarray and recombinant DNA technology methodologies for the detection of antibiotic resistance genes in bacteria isolated from chicken and turkey farms.
• Assessed the safety of drugs and other compounds and their effects on the gastrointestinal tract microbiota. NCTR scientists played a critical role in the development of a decision tree for determining the limits on Acceptable Daily intake of antimicrobials in foods, which was adopted by the World Health Organization and recently used in the FDA/CVM Guidance for Industry #52.
• Investigated the ecology, epidemiology, virulence and molecular characteristics of foodborne pathogen populations of Salmonella, Vibrio, Campylobacter and E. coli for source tracking, delineating transmission pathways and better identifying targeted control measures in poultry, cattle, aquaculture and clinical environments. NCTR scientists used various molecular typing methods (such as pulsed-field gel electrophoresis, antibiogram patterns, multi-locus sequence typing, PCR-restriction fragment length polymorphism, ribosomal rRNA operon typing and ribotyping,) to create databases of bacterial DNA fingerprints.
• Published in the Risk Analysis Journal developed model-averaging techniques for benchmark-dose estimation in risk/safety assessment and other novel hierarchical models for probabilistic dose-response assessment and for proper propagation and management of uncertainty in inter- and intra-species extrapolations.

NCTR
Program Activity Data (PAD)

PROGRAM WORKLOAD AND OUTPUTS	FY 2005 Actuals	FY 2006 Estimate	FY 2007 Estimate
Research Publications	200	200	215
Scientific Presentations	286	285	250
Patents (Industry)	6	6	5
Interagency Agreements (IAG)	11	8	5
Cooperative Research & Development Agreements (CRADA)	11	11	11
Total Active Research Projects	196	210	192

[1] Congressional Appropriation Report 109-255 directed FDA to include additional justification on its research, development, and evaluation (RD&E) activities. In response to this report language, FDA is providing explanatory paragraphs detailing each program's RD&E activities. Because NCTR performs RD&E as its main activity, the justification of base also serves as the RD&E paragraphs for this program narrative. Other FDA programs include RD&E paragraphs within their justification of base activities, and these paragraphs are aligned by FDA strategic goal.

[2] In the past five years, NCTR has been developing and standardizing new technologies that will be used in developing biomarkers, micro-array data, and other models for FDA-regulatory applications. This precursory work supports the new Critical Path Initiative.

FY 2007 Table of Contents

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