1. Advances in Approaches to
Food and Drug Safety
Assessment
William Slikker, Jr., PhD, ATS
National Center for Toxicological Research
U.S. Food and Drug Administration
Jefferson, Arkansas
The views expressed in this presentation do not necessarily reflect those of the FDA.
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2. NCTR is Unique
Established in January 1971 by Executive
Order as a non-regulatory national
resource owned and managed within
DHHS by FDA to conduct integrated
toxicological research and foster
interagency, academic, and industrial
collaboration in support of risk assessment
needs related to public health.
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3. NCTR Vision
NCTR is an internationally recognized FDA research center that
provides innovative, vital scientific technology, training, and
technical expertise to improve public health.
NCTR—in partnership with researchers from government,
academia, and industry—develops, refines, and applies current
and emerging technologies to improve safety evaluations of
FDA-regulated Products.
NCTR fosters international and intragovernmental cooperation
to improve and protect public health and enhance the quality of
life for the American people.
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4. Department of Health and Human Services
Food and Drug Administration
National Center for Toxicological Research
HHS
… NIH FDA CDC …
CBER CDER CDRH CFSAN CTP CVM NCTR ORA
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5. FDA Strategic Goals
Strengthen FDA for today and tomorrow
– Science foundation
– Partnerships and communication
Improve Patient and Consumer Safety
– Strengthen science foundation
– Provide patients access to risk benefit information
Increase Access to New Medical and Food Products
– Critical Path to Personalized Nutrition and Medicine
Improve the Quality and Safety of Manufactured
Products and the Supply Chain
– Modernize science-based standards and tools to provide high quality
manufacturing processing and duplication
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6. NCTR Strategic Goals
Innovative toxicology for
regulatory decisions
Promote personalized
medicine and nutrition
Bioinformatics
Food safety
Mentorship/training
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7. NCTR/FDA Research Strategy
Focus research resources on:
– Regulatory issues to enhance decision making
– Technical innovations to speed FDA-regulated
product review and safety assessment
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8. Primate 9 BSL-3 ARL Bld. FDA Disaster NTP/FDA Photx.
Laboratories Suites Recovery Laboratories
FDA Nano
Core Facility
Bio-Imaging
Center
Dietary
General Animal Preparation
Housing
Visitor Housing 23 Pathology
Laboratories
82 Accredited animal and 123 experimental laboratories / 1M sq ft. in 30 buildings
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9. Department of Health and Human Services
Food and Drug Administration
National Center for Toxicological Research
Office of the Director
William Slikker, Jr. Ph.D.
Office of Research Coordinating Council
Jeanne F. Anson
Fred Beland, Ph.D. Jim Kaput, Ph.D. Paul Howard, Ph.D.
NCTR Executive Officer &
Dir., Division of Dir., Division of Personalized Assoc. Dir. for
Assoc. Dir. for Office of Planning
Biochemical Toxicology Nutrition & Medicine Scientific Coordination
& Resource Management
Martha Moore, Ph.D. Donna Mendrick, Ph.D. Thomas F. Flammang, Ph.D. Margaret Miller, Ph.D.
Dir., Division of Genetic & Dir., Division of Senior Advisor Assoc. Dir. for
Reproductive Toxicology Systems Toxicology for Science Regulatory Activities
Jeff Carraway, DVM Jennings Partridge Vicky Ross-Barsh,
Carl Cerniglia, Ph.D.
Dir., Division of Assoc. Dir. for Regulatory Assoc. Dir. for
Dir., Division of Microbiology
Veterinary Services Compliance & Risk Management Executive Programs & Services
Merle Paule, Ph.D.
Dir., Division of Neurotoxicology
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10. Advancing FDA Science
Nanotechnology
Food Safety
Critical Path
Bio-imaging
Nutrition and Obesity
Regulatory Science
Bioinformatics
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11. ArrayTrack™: An Integrated Solution for
Omics Research
Clinical and
nonclinical data
OH
HO H
Microarray data Chemical data
ArrayTrack™
Proteomics data Public data
Metabolomics data
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12. Results from the MicroArray Quality
Control (MAQC) Study
Six research papers
published in Nature Biotechnology on Sept and
Oct 2006
MAQC Main Paper
Validation of Microarray Results
RNA Sample Titrations
One-color vs. Two-color Microarrays
External RNA Controls
Rat Toxicogenomics Validation Nat. Biotechnol. 24(9) and 24(10s), 2006
137 Participants from 51 Organizations
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13. An Array of FDA Endeavors
Integrated Nature of VGDS, ArrayTrack™, MAQC, and Best Practice Document
E-Submission
VGDS MAQC
ArrayTrack™
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14. Bio-Imaging at FDA
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15. Bio-Imaging at NCTR/FDA
MicroPET Biospec MRI
23 cm bore 7 Telsa, 30 cm bore
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16. Pediatric Anesthetics
Ketamine, a non-competitive NMDA receptor
antagonist, has been used as a general pediatric
anesthetic for surgical procedures in infants.
Ketamine is one of the most commonly used agents
for mild sedation in pediatric emergency
departments, endoscopy suites, catheterization
laboratories, radiology suites, and intensive care
units.
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17. A Control (24-hr)
B Ketamine (24-hr)
C Control (24-hr)
D Ketamine (24-hr)
E Control (24-hr)
Control (24- hr)
E
F Ketamine (24-hr)
Slikker et al., 2007 17

18. 25
*
Caspase 3-Positive Neuronal Cells
Control
Effects of * Ketamine-infused
20
ketamine-
15
induced
10
anesthesia
5
on the
0
300
frontal *
Silver-staining (Grain Density)
250
cortex of the 200
developing
150
*
monkey
100
50
0
25
Fluoro-Jade C-Positive Neuronal Cells
20
* *
15
10
5
Slikker et al.,
2007
0
GD 122 PND 5 PND 35 PND 5
(24-hr) (24-hr) (24-hr) (3-hr) 18

19. (B)
(C)
Zou et al., 2009
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20. A
B
C
Slikker et al., 2007
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21. Dorsal
Left Right
Ventral
Drs. Xuan Zhang (NCTR), Marc Berridge (UAMS), Tucker Patterson,
Glenn Newport, Cheng Wang, and Merle Paule (NCTR)
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22. Dynamic Uptake of [18F]-AnnexinV
4
Control
Ketamine
3
SUV Ratio
2
1
0
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (s)
N=7 SUV=total radioactivity in ROI x body weight / injection dose 22

23. Nanotechnology at NCTR, ARL/ORA
Nanotechnology
“Will eventually impact all Centers of the FDA”
– Component of regulated products
– Contaminant in regulated products
– Challenge to our safety assessment paradigm
Nanotechnology Working Group
– Coordinate NCTR’s and ARL/ORA’s participation in FDA’s nanotechnology
effort
Nanotechnology Core Facility
– Support NCTR research efforts and serve as FDA core
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24. Nanotechnology at NCTR, ARL/ORA
Overall Strategy
Research projects requested by FDA Centers (protocol-based studies)
– FDA resources
– through NTP IAG
– through CRADA, MOU, etc
Support/Resources Engage/Dialogue
– NCTR/ORA Nanotechnology – FDA – NNI
Core Facility – NTP/NIEHS – OECD
– UALR – EPA – DOD
– UAMS – SOT
– UA
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25. Nanotechnology Core Facility
Resources (on site, purchased, or funds available)
– Transmission electron microscope (TEM)
– HPLC with light scatter detection
– Confocal microscopy (fluorescence detection)
– Confocal microscopy (Raman and FTIR detection)
– High resolution darkfield microscopy (hyperspectral detection)
– Atomic force microscope
– Particle size analyzers (1 nm -1 mm)
– Inductively coupled plasma mass spectrometer (ICP-MS)
– BET material surface analyzer
– Wavelength dispersive X-ray fluorescence spectrometer
– Sample preparation for electron microscopy
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26. Collaborations with Agencies/Universities/
Research Facilities
IAGs CRADAs
– Environmental Protection Agency (EPA) – Argus Research Laboratories
– Federal Aviation Administration (FAA) – Primedica Corp
– National Institute of Environmental Health – AstraZeneca
Science (NIEHS) – Litmus
– National Cancer Institute (NCI) – LLCPI
– National Institutes of Health (NIH)/National – Pfizer, Inc.
Institute of Environmental Health Science – RxGen, Inc.
(NIEHS)
– SAS Institutes, Inc.
– Environmental Protection Agency
(EPA)/National Health and Environmental – Sigma Tau Research, Inc.
Effects Research Laboratory (NHEERL) – University of Illinois
– National Institutes of Health (NIH)/National – University of Arkansas at Little
Institute of Child Health and Human Rock
Development (NICHD) – University of Arkansas for
– National Institutes of Health (NIH)/National Medical Sciences
Toxicology Program (NTP) 26

27. FDA/NIEHS IAG
..…to conduct comprehensive toxicological assessments on selected FDA and
NIEHS high priority chemicals nominated to the National Toxicology Program…
FDA Nominations NTP/NIEHS Nominations
Chloral Hydrate (CFSAN) Endocrine Active Chemicals
Fumonisin B1 (CFSAN) – Methoxychlor
Malachite Green (CVM) – Genistein (CFSAN)
Urethane/Ethanol (CFSAN) – Nonylphenol (CDER)
Riddelliine (CFSAN) – Vinclozolin
α & β Hydroxy Acids (CFSAN)* – Ethinyl Estradiol (CDER)
– Glycolic Acid Riddelliine (CFSAN/Adducts)
– Salicylic Acid Aloe vera (NCI-Oral & Dermal)
Ephedra (NCI/ODS - CFSAN) AIDS Therapeutics
Retinyl Palmitate (CFSAN) – Zidovudine (AZT)
Ketamine (CDER) – Nevirapine (NVP)
Bisphenol A (CFSAN) – Lamivudine (3TC)
Acrylamide (CFSAN) – Nelfinavir (NFV)
Bitter Orange (CFSAN) – Efavirenz
Usnic Acid (CFSAN) Glucosomine/Chrondroitin
Di-(2-ethylhexyl) Phthalate (CFSAN)
(CBER/CDRH) AZT P53 ko Mouse Study (CDER)
Permanent Makeup Pigments
(CFSAN)
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28. FDA and kFDA Collaboration
The letter of agreement was signed
NCTR/FDA and NITR/KFDA Joint Workshop on
Toxicogenomics - July 15-16, 2009
– kFDA Participants: Drs. Sue Nie Park, Hong-Ki Min, Ki-Suk
Park, Ho-Sang Jeong, and Wan-Seob Cho
Collaborative projects
– Liver Toxicity Knowledge Base (Dr. Weida Tong at NCTR
and Dr. Ho-Sang Jeong at kFDA)
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29. FDA Science
CFSAN
CBER CDER
NCTR
ORA CDRH
CVM
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