Foodborne illness in the United States is an extensive and expensive problem. The
Centers for Disease Control and Prevention (CDC) estimates those unsafe foods cause as
many as 76 million illnesses annually. The U.S. Department of Agriculture (USDA) estimates
that the costs associated with food borne illness due to seven pathogens, including:
Salmonella, Campylobacter and E. coli 0157:H7, range up to $37 billion annually. Federal
and state expenditures for activities to help ensure the safety of the nation's food
supply are also significant, with federal efforts alone exceeding $1 billion annually.
While there are 12 federal agencies with food safety responsibilities, FDA is responsible
for ensuring that (1) all foods moving in interstate and foreign commerce, except those
under USDA's Food Safety and Inspection Service jurisdiction, are safe, wholesome and
labeled properly; and (2) all animal drugs and feeds are safe, properly labeled and
produce no human health hazards when used in food-producing animals.
NCTR, in collaboration with CFSAN, CVM and other federal agencies, is supporting the
research outlined by National Food Safety Strategic Plan. Areas in which research is
currently being conducted include:
- Development of new risk assessment methods. A new approach has been presented for
incorporating model uncertainties into microbial risk assessment.
- Development of enhanced identification and surveillance systems, specifically in the
areas of mass spectrometry and polymerase chain reaction technology.
- Facilitation of the development of rapid, accurate tests for pathogenic microorganisms
including gene-based tests for pathogens, in food, food producing animals and human
intestinal microflora. NCTR scientists tested the effect of low levels of ciprofloxacin on
the ability of the normal human intestinal microflora to resist colonization by a
- Identification and characterization of emerging and evolving food borne diseases
resulting from the development of antibiotic resistance of foodborne pathogens such as
Salmonella DT 104.
- Isolation of ten vancomycin resistant bacteria from the competitive exclusion product
Government agencies have recently responded to the Presidential Decision Directive
(PDD62) by combining forces to develop plans and procedures to combat bioterrorism. In
collaboration with The Department of Justice, the Department of Health and Human Services,
and the Department of Defense, NCTR researchers are working on three areas of research:
identification of virulent biomarkers using mass spectrometry, rapid detection of
microorganisms using polymerase chain reaction (PCR) technology, and exploring safe and
efficacious neuroprotective strategies to protect exposed populations. NCTR is well-suited
and well-situated to contribute to the efforts to combat terrorism. The Center is
geographically located in the center of the country, physically adjacent to the U.S.
Army's Pine Bluff Arsenal, and has enjoyed a long history of formal agreements with the
Army. In addition, NCTR has an unusual breadth of toxicological expertise, thus providing
a strong base of knowledge and experience that can be applied to this area. Though NCTR
received no FY99 resources to support this work, initial efforts continued; including a
collaboration with the Department of Defense concerning mass spectrometry assessment and
identification of bacterial proteins (biomarkers), and in conjunction with the Food Safety
Initiative on PCR characterization of bacteria.
- NCTR researchers have developed a novel approach to rapidly identify biomarkers of
toxicity using a mass spectrometry-based method for detection of microorganisms. This
spectrometry-based procedure is designed to identify and detect biomarkers for the
presence of specific genes that identify biological agents or those that could be
introduced into otherwise harmless organisms. The value of this technique is that
important traits of microorganisms manifest themselves across species and offer
species-independent markers. Identification of these biomarkers can be associated with the
identity or properties of the types of biological warfare agents that would be used in a
terrorist threat. After identification of the biomarker-proteins using mass spectrometry,
it should be feasible to develop field diagnostic kits to identify these biomarkers. In a
terrorist situation, the timely identification of the problem agent will be critical.
- Molecular biology studies associated with the government-wide Food Safety Initiative are
also applicable to the bioterrorism initiative. Scientists at NCTR have used PCR
technology to identify and classify twelve foodborne pathogens and have developed
molecular procedures to individually detect known determinants of antibiotic resistance.
- Through safety assessment drug trials and outreach activities via the Interagency
Committee of Neurotoxicology and NCTR/FDA-organized International Neuroprotective
Conferences, NCTR researchers will continue to build a strong research base on which to
contract/develop predictive systems for neuroprotective drugs. Many of the agents
used to conduct terroristic activities are nerve agents for which few techniques are
available to protect humans. The application of new non-invasive imaging techniques can be
used to determine if exposure has occurred and can be used to assess the utility of
neuroprotective strategies. The development of prophylactic approaches to protect against
bio/chem terrorism depends on determining the potential toxicity of neuroprotective
approaches. NCTR plans to acquire the non-invasive imaging capabilities to explore
neuroprotective concepts likely to be effective in humans by first testing in laboratory
rodents and primates.
The NCTR conducts fundamental and applied research in toxicology that is
multidisciplinary in nature to support the FDAs needs. The sequencing of the human
genome has provided the scientific community with a wealth of new molecular, chemical,
computational and engineering tools that will allow us to better understand the genome and
its relationship to disease susceptibility. Additionally, these new DNA-, RNA- and
protein-based tools will allow us to better understand the models we use to predict
toxicity in humans. NCTR scientists are developing integrated programs that apply our
expertise in transgenics, genomics, proteomics, bioinformatics, computational biology and
- Transgenics: The NCTR has developed a transgenic mouse heterozygous at
the thymidine kinase locus. This model was developed to provide an in vivo somatic
mutagenesis system for use in detecting mutagenic carcinogens flagged by the International
Committee on Harmonization (ICH) battery of genotoxicity assays and to understand the
process by which DNA damage is processed to a mutation in an autosomal gene. This system
has broad utility because it detects all of the genetic events known to be associated with
the carcinogenesis process.
- DNA and Protein Based Technology: NCTR scientists are developing DNA
chips that are meant to identify polymorphisms in humans that serve as indicators of
biological effects. This technology may help in identifying humans susceptible to the
toxicity of specific chemicals regulated by the FDA and has the potential for use in
clinical testing of drugs. High throughput gene expression systems are also being
developed to compare species associated toxicity to chemicals regulated by the FDA
allowing development of greater confidence in data extrapolation from model systems to the
human. Initial efforts are occurring toward the development of an infrastructure to study
structure and function of proteins.
- Bioinfomatics and Computational Biology: The NCTR is developing an
integrated team made up of statisticians, computational chemists, biologists and software
engineers to address the application of high-speed computing technology to answer complex
biological questions associated with the NCTRs and FDAs mission to protect
Information Technology at NCTR encompasses support of a state-of-the-art infrastructure
and computational science. NCTR maintains an interoperable environment of servers, a high
speed LAN, and multiple T1 lines to FDA in Maryland. The LAN has more than 1000 devices
attached, ranging from desktop PCs to powerful scientific workstations. A team of software
engineers develops and maintains software for both administrative and scientific uses.
Computational scientists at NCTR work closely with biologists, chemists, systems engineers
and software developers to develop QSAR and chemometric models to predict toxicity based
solely on chemical structure.
- Web-based databases have been developed that enable mining of microarray and proteomic
data. Some approaches to data mining tools employs advanced scientific
- A prototype knowledge base has been developed in partnership with industry and other
government agencies capable of predicting hormonal activity of untested chemicals.
This prototype has been used to assess hormonal activity of chemicals of regulatory
concern for CDER and CFSAN.
The NCTR conducts fundamental and applied research specifically directed toward
developing and/or modifying standards for submission of products regulated by or of
interest to the Food and Drug Administration (FDA). This research centers on assessing the
toxicities and carcinogenic risk associated with specific products such as drugs,
cosmetics, biologics, food or veterinary products, and the introduction of new techniques
to assess risk. It is firmly rooted in mechanistic studies focused on the
understanding of toxicological endpoints, an approach that allows greater confidence in
the subsequent carcinogenic risk assessments particularly in humans. Research within the
Center capitalizes on scientific knowledge in the areas of biochemistry, organic
chemistry, cellular and molecular biology, immunology, biochemistry, and pharmacology. It
is supported by sound technical skills, the availability of state-of-the-art equipment,
and internal and external collaborations and funding. Over 60% of the research conducted
at the Center is categorized as applied. Some examples of current research being conducted
at the Center are given below:
- A large collaborative research program between the FDA and the National Institute of
Environmental Health Sciences is being conducted to assess the carcinogenecity of
compounds of interest to FDA. Currently studies are under way to investigate the risk
associated with, fumonisin, a corn contaminant; chloral hydrate, a pediatric sedative;
endocrine disrupters, compounds that may effect the male and female hormone levels;
malachite and leucomalachite green, an aquaculture therapeutic; and alpha- and
beta-hydroxyacids found in cosmetics. These studies will provide the scientific knowledge
to set safe, effective levels of exposure.
- Behavioral studies, in partnership with the Arkansas Children's Hospital, are designed
to measure risk associated with certain neuroactive-drugs across species, and in a
juvenile population. These studies hope to answer the questions: 1) are animal models
appropriate to predict human toxicity, and 2) what is the neurochemical risk of certain
drugs in children.
One key to FDA's success is its scientific strength, a prerequisite for all of its
regulatory responsibilities. As new technologies emerge and new product applications are
brought to FDA for review, state-of-the-art scientific expertise will continue to be
essential for FDA to determine the safety and efficacy of the products. It is essential
that the staff of the Agency keep pace with rapidly changing technology that occurs as a
result of scientific advances, even in the face of budgetary constraints. One of FDA's
primary goals is to insure that there is a solid science foundation underpinning all of
our product standards that are used in making review decisions. NCTR is conducting
fundamental research to develop strategies, methods and systems to predict toxicity and
anticipate new product technology.
- Studies are underway using molecular biological techniques to assess the effects
neurotoxic compounds have on neurogrowth and neurotropic factors. These new techniques
will provide valuable information on how brain and nervous tissue responds to external
chemicals such as drugs (amphetamines) and/or food contaminants (domoic acid, dietary
- Statisticians at NCTR are evaluating methods to measure risk associated with exposure to
a mixture of potentially dangerous compounds. Regulations are generally made based on the
risk to a single product, yet daily therapeutic doses of drugs quite often are made up of
multiple drugs or in the case of cancer therapy a chemotherapeutic cocktail. The risk
associated with multiple exposures is not well understood and can be critical to the
health of the consumer.
The NCTR in conjunction with the Center for Veterinary Medicine (CVM) have directed
their efforts within the Food Safety Initiative to combat antimicrobial resistance. The
Agency, through its regulatory and research centers, strives to ensure the use of
approved, safe and beneficial veterinary drugs intended for the treatment and/or
prevention of diseases in animals, and the improved production of food producing animal.
The availability of safe and effective animal drugs allows food animal producers to
maintain healthy animals with assurance that products will be safe, wholesome and free of
unsafe drug residues when they reach the consumer. In addition, FDA maintains continuing
surveillance over all animal drugs, devices and feeds marketed in interstate commerce in
order to minimize threats to human and/or animal health which might arise as a result of
the use of these products. NCTR has research underway to aid in understanding mechanism
and identifying methods to detect antimicrobial resistance.
- Development an understanding of the potential for non-resistant bacteria to transfer
their resistant mechanisms to potential pathogens in other animal species, including
humans. This will allow investigators to explore the potential for dissemination of
resistant genes following the introduction of an antimicrobial agent for use in food or
- Development of quality control standards for antimicrobial susceptibility testing of
bacterial pathogens isolated from foods derived from the aquaculture industry.
- Performance of studies using food producing animals to investigate optimal antimicrobial
dosing regimens in order to maximize clinical efficacy while minimizing the selection of
antimicrobial resistant zoonotic and target bacterial pathogens.
With the advent of protease inhibitors and new research on multi-drug therapies for
treatment of HIV infections more people are taking therapeutic drugs for longer periods of
time, including women of childbearing age. Many of the drugs that are currently being
prescribed for HIV infections were not intended for long term use, therefore the risk
associated with using these drugs under the current treatment regimes are unknown. NCTR
conducts neuotoxicological research on many of these drugs in collaboration other
government agencies, industry and academia. A new initiative is underway in
collaboration with NIEHS scientists, to evaluate the toxicity of multiple
- Scientists in the NCTR Division of Neurotoxicology are studying the behavioral
abnormalities caused by chronic exposure to HIV therapeutics, ddC and thalidomide, in
- Other studies at the Center use rodents to determine the long- term effect
anti-retroviral drugs have on the mother, the unborn child and the newborn. Each year
approximately 600,000 babies are infected worldwide with HIV due to mother-to-child
transmission, and in the United States each year six to seven thousand HIV-infected women
deliver children. In the absence of medical intervention, up to 45% of children born to
these HIV-positive women will become infected with the virus.