National Center for Toxicological Research

	FY 2000 Actual	FY 2001 Appropriation	FY 2001 Current Estimate ^1/	FY 2002 Estimate^{, 3/}	FY 2002 +/- FY 2001 Current Estimate
Total Program Level ^2/ Center ($000) FTE	$36,522,000 $36,522,000 217	$35,568,000 $35,568,000 230	$35,490,000 $35,490,000 230	$36,943,000 $36,943,000 232	+ $1,453,000 + $1,453,000 + 2
Budget Authority ^2/Pay Increases Food Safety	$36,522,000	$35,568,000	$35,490,000	$36,943,000	+ $1,453,000 +1,094,000 +400,000

			$2,354,000	$2,754,000

^1/ Reflects enacted levels adjusted for the 0.22 percent rescission, accounting for $78,000 in the NCTR program.
^2/ Reflects decrease in base funding from FY 2001 of $41,000, for Human Subject Protection & Bioterrorism.
^3/ Pay increases shown on separate line, and not reflected in individual program areas.

Historical Funding and FTE Levels

Fiscal Year	Program Level	Budget Authority	Program Level FTE
1998 Actuals	$32,189,000	$32,189,000	218
1999 Actuals	$32,109,000	$32,109,000	223
2000 Actuals	$36,522,000	$36,522,000	217
2001 Current Estimate	$35,490,000	$35,490,000	230
2002 Estimate	$36,943,000	$36,943,000	232

MISSION

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 premarket review and post-market surveillance;
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;
Develop methods to measure human exposure to products that have been adulterated or to assess effectiveness and/or safety of a product; and,
Provide the scientific findings used by the FDA product centers for pre-market application review and product safety assurance to the scientific community for the betterment of public health.

REQUESTED INCREASES

Pay Increase + $1,094,000

FDA’s request for funds to cover pay cost increases is vital to the Agency because personnel are so essential to accomplishing its mission. Pay increases have a major impact on FDA because the Agency is more people-intensive than many other government agencies. Payroll accounts for over 60 percent of the total FDA budget. This has a significant impact on all activities in FDA. The costs of the pay increases are necessary to ensure the integrity of the Agency's work at the NCTR for research functions.

In order to maintain the level of activities carried out in FY 2001, FDA is requesting $40,000,000 to cover the cost of the FY 2002 pay raise, annualization of the FY 2001 pay raise, anticipated within grade increases, and one extra day of pay. The NCTR program portion of this increase is $1,094,000.

Food Safety + $400,000 and 2 FTE

An effective food safety system must be based on sound science and be capable of dealing quickly and effectively with current and emerging public health concerns on the basis of the risk they present to the consumer. Risk analyses, including an assessment of food safety and public health risks and benefits, are helpful in defining the extent of scientific certainty and in helping decision-makers make the difficult decisions a science-based food safety system requires. In order to protect health and manage risk, effective production, marketplace and disease surveillance monitoring and other basic public health functions are essential. FDA must identify, contain and respond to food borne outbreaks, assess antimicrobial resistance, and manage the array of animal drugs used in feed domestically and in foreign countries, thus reducing the exposure to dangerous drug residues. Information and education play a critical role in ensuring that everyone involved fulfills their responsibilities for food safety. Creating effective food safety policies and programs and building public confidence in the food safety system requires open, transparent decision making and accurate, timely exchange of information and ideas among government and other stakeholders.

As part of the national food safety initiative to improve and protect our nation's food supply, NCTR has taken full advantage of its multi-disciplinary, intra-center research capabilities and continues to focus resources on developing new scientific techniques and risk assessment models in support of the Food Safety Initiative. NCTR will:

Develop new methodologies to identify adverse effects of genetically modified foods, drug residues in foods and antibiotic-resistant strains of bacteria, using new molecular biomarkers and methods resulting from identification of the human genome. These methods involve combining information on genes and proteins with computer technology to understand what causes specific biological events; and,
Develop new risk assessment methods. A new approach will be validated for incorporating model uncertainties into microbial risk assessment.

JUSTIFICATION OF BASE

Activities Related to Increases for FY 2002

Payroll

FDA’s National Center for Toxicological Research conducts 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. The center provides the scientific findings used by the FDA product centers for pre-market application review and product safety assurance to the scientific community for the betterment of public health. NCTR develops methods to measure human exposure to products that have been adulterated or to assess effectiveness and/or safety of a product.

Food Safety

Develop new methods to assess antibiotic resistance on the farm and in processed food, as part of the Food Safety Initiative.

Other Activities Related to High Priority Areas

Premarket Activities

Create databases used to predict adverse impact of estrogenic or hormonal compounds in humans. This work is being conducted in conjunction with the American Chemistry Council and scientists at the Environmental Protection Agency.
Assess individual susceptibility to toxicants using advanced technology tools such as DNA microchip arrays and bioinformatics to more rapidly interpret the data generated by microarray and proteomic technology. Scientists are studying the effects of toxicants on gene expression profiles and are developing techniques to predict individual susceptibility to disease/drugs. Several of these efforts are collaborative between the NCTR, industry and academia.
Geneticists are developing and validating sensitive and predictive transgenic systems, which cross species boundaries to identify, quantify and understand how chemicals damage human genes.

Postmarket Activities

Develop, patent and market products to detect food decomposition, such as Fresh Tag ^TM, a product selected by Popular Science as the “Best of What’s New” Award for 1999.
Provide data to set new standards of assessment and improve risk decisions for FDA-regulated compounds such as corn contaminants, pediatric sedatives, and aquaculture therapeutics.
Conduct carcinogenicity studies on the combined effect of exposure to sunlight and the use of cosmetic products containing alpha-and beta-hydroxy acids. This is a joint effort with the National Institute of Environmental Health Sciences.

Selected FY 2000 Accomplishments

Developed new strategies and methods to predict toxicity and assess/detect risk for FDA regulated products (new and on the market)

Used a multi disciplinary approach to predict human toxicity and to evaluate human risk using appropriate animal and non-animal models.
Predicted human toxicity using transgenic rodents carrying critical reporter genes and human cell lines. Researchers continued to develop laboratory methods that closely mimic human genetic response and predict human genetic damage due to drug and/or product interactions.
Developed a new biological assay to measure genetic changes and validated two existing models that predict human genetic damage. These systems are capable of simulating human exposure, increasing the ability to detect weak carcinogens, and decreasing the time required for determining mutation induction in the human genome.
Established a Collaborative Research and Development Agreement with private industry to develop gene chip and gene array technology. The importance of risk chip technology is that it allows researchers to screen large numbers of people simultaneously for different types of biological indicators of effect. Each person has a different genetic profile. By looking at an individual’s enzyme profile or the proteins in their blood, scientists can identify specific markers that allow the identification of individuals at risk for adverse drug reactions. This facilitates FDA review of individual susceptibility using profiles of agents with known toxicities and allows selection of a diverse group of individuals for clinical trials.
Research includes thirteen major studies to identify ten biomarkers of the most frequently occurring cancers (pancreatic, colorectal, breast, larynx, ovary, lung, urinary bladder, bone marrow, esophagus, and prostate) in highly susceptible subpopulations. Scientists have focused their research on the food borne carcinogens, drugs, and natural occurring chemicals that have hormonal activity.
The results to-date have proven that the DNA microarray chip has a 99 percent agreement rate with traditional genotyping but is much faster. This work provides assessment of the relative risks of dietary and environmental carcinogens in human cancer so critical to risk decision-making.

Developed computer-based systems (knowledge bases) that predict human toxicity to enhance the efficiency and effectiveness of pre-market product reviews

Estrogenic activity is found in FDA regulated products as well as environmental chemicals, such as plastics and pesticides. Thus, it is important to understand the varying toxicological and pharmacological properties and the mechanisms of action of these regulated compounds.

Partnered with private industry, NCTR scientists developed a knowledge base for the binding of chemicals to the estrogen and androgen receptor. This knowledge base addresses FDA’s needs for a better, more rapid and cheaper method for evaluating chemicals for potential estrogenic activity. Over 230 chemicals have estrogenic activity that may be used to predict whether these compounds are hazardous to females at risk for breast or uterine cancer. Studies on androgen receptor binding involving prostate cancer are continuing.
Made NCTR’s knowledge base available for use by the Center for Food Safety and Applied Nutrition (CFSAN) and the Center for Drug Evaluation and Research (CDER) to model estrogenic activity of products being reviewed.
Incorporated these models into the NCTR Endocrine Disruptor Knowledge Base (EDKB). The development of the computer-based estrogen models done in conjunction with industry via a cooperative research and development agreement (CRADA) has provided a prototype and framework for developing models for predicting other types of chemically induced toxic responses. These chemical classes include androgens (male hormones) and compounds toxic to nerve cells.
Developed computer models by working with other scientists in the agency that use measurable chemical properties (nuclear magnetic resonance and mass spectrometry spectra) of FDA regulated products to predict human risk. These techniques will help industry predict the safety of developed products and are a part of an FDA submitted patent. These models will continue to be applied to specific regulatory issues across a number of FDA product centers, and will aid in the making of regulatory decisions.

Conducted fundamental research to understand mechanisms of toxicity assess new product technology and provide methods for use in FDA standards development and product risk surveillance

Research supported through an interagency agreement with the National Institutes for Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) permits the NCTR to modify the rodent bioassay by including protocols to study mechanisms of toxic action that improve interpretation of data. As a result, time for product review is decreased resulting in a reduction in the cost of pre-clinical trials. Studies of malachite green (used in aquaculture) and endocrine-disrupting compounds (naturally-occurring and synthetic estrogens that effect reproduction) are in process.

Conducting long-term, multi-generation studies of compounds that disrupt normal endocrine function, such as genistein (found in soybeans) and nonylphenol (found in food packaging). These studies are providing data on how estrogens and anti-estrogens may affect human development and may contribute to increasing cancer rates.
Utilized the newly designed Photo toxicity Facility at NCTR to evaluate the harmful effects of skin exfoliants, such as alpha-hydroxy acids. Use of alpha-hydroxy acid containing cosmetics is increasing as the beauty-conscious public seeks drugs or cosmetic preparations that will give a more youthful appearance. The impact of continuous use of this type of treatment on the incidence of sunlight-induced skin cancer is not known. The Photo toxicity Facility allows the research subjects (i.e., mice) to be exposed to either simulated solar light or ultra-violet (UV) light. This research addresses the Agency’s need to evaluate compounds of regulatory concern, such as alpha-hydroxy acids, found in many over-the-counter cosmetics.
Developing methods to identify markers of food borne pathogens and to assess whether these microorganisms are undergoing change, thus becoming more virulent. This effort is in collaboration with the FDA’s CFSAN, Center for Veterinary Medicine (CVM), and as part of the Food Safety Initiative. This research capitalizes on partnerships with other agencies such as the United States Department of Agriculture (USDA). The Agency needs state-of-the-art measurement of toxicity to strengthen its risk assessment of products on the market.
Developed a project with the CVM for isolation and identification of the bacteria in competitive exclusion cultures, using the most reliable genetic microbial identification techniques available. Preliminary results have alerted CVM to the possibility that competitive exclusion products can introduce bacteria with undesirable antibiotic-resistance into the human food supply. Scientists have also been evaluating a cell culture module that can determine more quickly and accurately whether a competitive exclusion product can effectively exclude Salmonella sp., Shigella spp., and Campylobacter spp from intestinal cells. This assay will be available to producers and the FDA to evaluate the efficacy of competitive exclusion products.