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2002 Continuing
Education Courses
The Continuing
Education Program offers a wide-range of courses that cover state-of-the-art
knowledge in toxicology, as well as new developments in toxicology
and related disciplines. Courses can be applied toward certifying
and licensing board requirements and may also be used for recertification
with the American Board of Toxicology (ABT). Both basic and advanced
course topics are offered. The basic course is intended to provide
a broad overview of an area or to assist individuals in learning
new techniques or approaches. The advanced course is intended
to be of interest to individuals with previous knowledge of the
subject or already working in the field.
Use
of Laser Capture Microdissection (LCM) in Molecular Toxicology
Research
Sunrise Mini-Course
1 Basic
Governor's
A
Speaker: Jeffrey I. Everitt, CIIT Centers for
Health Research, Research Triangle Park, NC.
Endorsed
by:
The Molecular Biology Specialty Section
The Toxicologic and Exploratory Pathology Specialty Section
Laser capture
microdissection (LCM) is a recently developed technique that allows
one to rapidly procure morphologically defined cell populations
from sections of heterogenous tissues using direct visualization.
This technique has greatly expanded the ability of the toxicologist
to conduct molecular analyses on a wide array of specific target
cells and tissues of interest. Cells obtained by microdissection
have been used as a source of genomic DNA, the isolation of mRNA
amenable to reverse transcription polymerase chain reaction (RT-PCR),
and the generation of expression libraries. LCM has been combined
with cDNA microarray hybridization techniques and proteomic methods
to provide new and exciting approaches for combining gene expression
with traditional morphological methods. This seminar will review
microdissection methods and equipment and discuss the utility
of LCM in toxicology studies.
A
Practical Approach to Blood and Lymphoid Tissue (BLT) in Toxicology
Assessments
AM 2 Basic
Presidential
B
Chairpersons:
JoAnn C. L. Schuh, Applied Veterinary Pathobiology, Bainbridge
Island, WA and Lynda Lanning, BioReliance, Rockville, MD.
Endorsed
by:
The Toxicologic and Exploratory Pathology Specialty Section
Blood, bone
marrow, thymus, spleen, lymph nodes and mucosa-associated lymphoid
tissue are a complicated, but important interactive system of
tissues and cells modulated directly and indirectly by xenobiotics.
Evaluation of blood and lymphoid tissues (BLT) has always been
part of a standard histopathology and toxicology screen, but advanced
evaluations of BLT are becoming increasingly important to the
rapidly changing fields of immunotoxicology and immunotherapeutic
development. The objective of this basic course is to provide
contemporary information on the pathophysiology of BLT useful
to individuals in regulatory and research areas of toxicology.
This course will review important features of i) basic anatomy,
function, and evaluation of blood and blood forming organs, ii)
anatomy and function of lymphoid tissues and their component parts,
iii) terminology, iv) general and toxic immunomodulation, and
v) pathophysiology (neoplastic and non-neoplastic responses).
Species, sex and age specific differences that may affect the
design and outcome of studies, and techniques used to evaluate
BLT will be discussed. A practical understanding of the anatomy,
terminology, and toxicologic pathology associated with BLT, will
aid toxicologists in making proper interpretation of treatment-related
changes in safety and efficacy studies, and in communicating this
information between disciplines, within teams and to regulatory
agencies.
- Practical
Approaches to BLT: Finding Them, Collecting Them, and Analyzing
Them, Lynda Lanning, BioReliance, Rockville, MD.
- Bare
Bones Blood and Bone Marrow, Gregg Travlos, NIEHS, Research
Triangle Park, NC.
Essential Lymph Nodes, Peter Mann, Experimental Pathology Labs.,
Inc., Research Triangle Park, NC.
- Thymic
and Splenic Splendor, Michael Leach, BASF, Worcester, MA.
- Lymphoid
Aggregates of Mucosal and Nonlymphoid Tissues, JoAnn C.
L. Schuh, Applied Veterinary Pathobiology, Bainbridge Island,
WA.
Alterations
in Gene Expression as a Mechanism of Toxicant Action
AM 3 Advanced
Governor's
A
Chairperson:
Ronald N. Hines, Medical College of Wisconsin, Milwaukee, WI.
Endorsed
by:
The Molecular Biology Specialty Section
The Regulatory and Safety Evaluation Specialty Section
The Reproductive and Developmental Specialty Section
Over the last
several years, it has become apparent that many environmental
toxicants exert their effects by the activation or disruption
of specific signaling pathways, ultimately resulting in alterations
in gene expression. With the completion of the human genome project
and the advent of many powerful new technologies, there has been
a revolution in our understanding of these mechanisms on the molecular
level. This continuing education course will review our current
state of knowledge regarding toxicant-induced alterations in gene
expression and also identify future directions and research opportunities.
The first speaker will focus on our current understanding of the
mechanism(s) whereby four receptors, i.e., the Ah receptor (AhR),
the Constitutive Androstane Receptor (CAR), the Pregnane X Receptor
(PXR), and the Peroxisome Proliferator Activated Receptor (PPAR),
mediate the toxicity of four broad classes of chemicals. In contrast
to these specific receptor mechanisms, metals exert their toxicity
through both stress-response pathways, as well as specific metal-responsive
transcription factors. The second speaker will focus on our current
understanding of these pathways of toxicant action. The third
speaker will review the many exciting discoveries in our understanding
of how toxicants alter gene expression during specific windows
of development and thereby exert their teratogenic effects. Finally,
the fourth speaker will discuss the role of tissue-selective transcription
factors on the expression of xenobiotic metabolizing enzymes and
how this process impacts toxicant susceptibility. As an advanced
course, this curriculum should appeal to toxicologists whose research
is in or immediately peripheral to this focus area, but who are
interested in gaining a better understanding of the overall subject
and its future direction.
- Receptor-Mediated
Toxicant Action, Qiang Ma, CDC/NIOSH, Morgantown, WV.
- Metal-Induced
Alterations in Gene Expression, Glen K. Andrews, University
of Kansas Medical Center, Kansas City, KS.
- Alterations
in Gene Expression as a Mechanism of Teratogenesis, Philip
E. Mirkes, University of Washington, Seattle, WA.
- Role
of Tissue-Selective Transcription Factors in Regulating Xenobiotic
Metabolizing Enzymes, Ronald N. Hines, Medical College of
Wisconsin, Milwaukee, WI.
Integrating
Toxicologic Pathology into Compound Evaluation and Risk Assessment
AM 4 Basic
Governor's
B
Chairpersons: Douglas C. Wolf, USEPA, Durham, NC and
Jerry F. Hardisty, Experimental Pathology Laboratory, Research
Triangle Park, NC.
Endorsed
by:
The Comparative and Veterinary Specialty Section
The Regulatory and Safety Evaluation Specialty Section
The Toxicologic and Exploratory Pathology Specialty Section
Pathology
endpoints are the central response around which human health risk
assessment is determined. This course is designed for the general
toxicology community to gain an understanding of the basics of
toxicologic pathology. Toxicologic pathology encompasses the study
of changes in tissue morphology that help define the risk of exposure
to xenobiotics. The first presentation will review the basics
of pathology studies including tissue processing, pathology review,
standard techniques, and efforts being made to standardize the
conduct, review, and reporting of pathology studies which are
important for appropriate interpretation of data. Other speakers
will discuss the structural and functional aspects of the liver
and kidney and the general concepts of mechanisms of injury, species
and sex differences, background and induced lesions, which are
necessary for appropriate risk characterization. The liver is
the most common target for xenobiotic-induced adverse effects
and the kidney has a central role in filtration, metabolism, and
excretion and is frequently a site of toxic injury. Correlating
clinicopathology with morphologic and functional alterations is
necessary for full understanding of adverse effects. Finally,
diagnostic terminology, study data relative to cancer bioassay
findings, the steps in tumor development, and their relevance
to human health risk will be presented.
- The
Pathologist and Pathology Data—the Art and the Craft,
Jerry F. Hardisty, Experimental Pathology Laboratory, Research
Triangle Park, NC.
- Integrating
Liver Pathology into Toxicity Evaluation, Richard T. Miller,
GlaxoSmithKline, Research Triangle Park, NC.
- Integrating
Kidney Pathology into Toxicity Evaluation, Jeffrey I. Everitt,
CIIT Centers for Health Research, Research Triangle Park, NC.
- Interpreting
the Pathology from Chemical Carcinogens for Risk Assessment,
Douglas C. Wolf, USEPA, Durham, NC.
Basic
Principles and Protocols in Molecular Toxicology
AM 5 (repeats
as PM 13) Basic
Presidential
E
Chairpersons:
William B. Mattes, Pharmacia, Kalamazoo, MI and John W. Davis,
II, Schering Plough Research Institute, Lafayette, NJ.
Endorsed
by:
The Molecular Biology Specialty Section
Many of the
mechanisms through which xenobiotics affect tissues or cells occur
at the molecular level. Over the past ten or fifteen years the
use of molecular techniques to dissect mechanisms of toxicity
has grown greatly. These techniques are used to identify growth
regulatory pathways, alterations in gene and/or protein expression,
as well as protein-DNA and protein-protein interactions. Accordingly,
there has been an explosion in the number of reagents and kits
that are commercially available. While these kits and reagents
have facilitated the detection of mechanisms of toxicity, a basic
understanding of the methods used is just as important. This course
will detail a number of basic techniques currently in use in an
attempt to give a researcher new to this area information as to
which tools may be most relevant with regards to their specific
research area. Presentations will include the practical considerations
when setting up a given technique as well as references that will
help the investigator trouble shoot these systems. Finally, actual
data will be shown in an effort to demonstrate the kinds of information
that can be obtained by these experiments and the ways in which
this information can be interpreted and used to develop hypothesis-driven
research. This is a basic level course intended to introduce to
the researcher the tools and references that are available to
him or her.
- Basic
Protocols and Principles in Nucleic Acid Manipulation, Mary
K. Walker, University of New Mexico, Albuquerque, NM.
- Using
Polymerase Chain Reaction in Molecular Toxicology, Jack
P. Vanden Heuvel, Penn State University Center for Molecular
Toxicology, University Park, PA.
- Design,
Construction and Use of Reporter and Expression Vectors,
Michael S. Denison, University of California-Davis, Davis, CA.
- Basic
Techniques in Detecting Proteins and Protein: Protein Interactions,
John W. Davis, II, Schering Plough Research Institute, Lafayette,
NJ.
Two-Stepping
through Toxicogenomics: A Basic Primer
AM 6 Basic
Presidential
A
Chairpersons:
Mary Jane Cunningham, Molecular Mining Corporation, Kingston,
Ontario, Canada and Timothy Zacharewski, Michigan State University,
East Lansing, MI.
Endorsed
by:
The In Vitro Specialty Section
The Mechanisms Specialty Section
The Risk Assessment Specialty Section
Toxicogenomics
as used here is broadly defined as gene and protein expression
technologies and their application to addressing pertinent issues
of toxicology. This basic course will start with an overview of
how genomics and proteomics came into existence. Different microarray
formats will be covered including cDNA, oligonucleotide, fiber
optic, and high-throughput versions of gene expression microarrays
as well as a broad overview on proteomics and data analysis. Several
landmark papers will be discussed showing how genomics and proteomics
can be applied. An in-depth presentation will follow detailing
how to set up and run your own microarrays and will cover array
manufacture, sample preparation, array hybridization and scanning,
and image analysis. In addition, setting up and running 2D protein
gels will be discussed as well as their interpretation using mass
spectroscopy. With all of these technologies, complex data sets
are generated and the final presentation will discuss alternative
statistical and bioinformatic methods which can be used to analyze
the data.
- Genomics
and Proteomics: History and Application to Toxicology, Mary
Jane Cunningham, Molecular Mining Corporation, Kingston, Ontario,
Canada.
- Gene
Expression Microarrays: The Do-It-Yourself Guide, Timothy
Zacharewski, Michigan State University, East Lansing, MI.
- Elements
and Functions of a Toxicoproteomics Lab.,
B. Alex Merrick, NIEHS, Research Triangle Park, NC.
- Various
Data Analysis Formats for Gene and Protein Expression Methods,
Roland Somogyi, Molecular Mining Corporation, Kingston, Ontario,
Canada.
Challenges
in Development of Anticancer Drugs
AM 7 Basic
Presidential
C
Chairpersons: Vijayapal Reddy, Eli Lilly and Company,
Greenfield, IN and Adaline Smith, National Cancer Institute, Rockville,
MD.
Endorsed
by:
The Comparative and Veterinary Specialty Section
The Regulatory and Safety Evaluation Specialty Section
Preclinical
and clinical drug development for anticancer drugs differ from
other pharmaceuticals, because of the life-threatening nature
of the disease. Treatment with anticancer drugs at clinically
efficacious doses usually induces serious side effects, but often
less threatening to patients than their disease. The design of
preclinical toxicology studies for anticancer drugs is intended
to identify a safe clinical starting dose, characterize toxicities
that may be encountered in human clinical trial, and determine
whether these toxicities are reversible, manageable, and predictable.
This basic course will focus on different aspects of preclinical
and clinical anticancer drug development. The first speaker will
present differences in the preclinical drug development philosophy
between different classes of anticancer drugs (e.g., cytotoxic,
immunomodulators, and modulatory drugs). The second speaker will
discuss the prediction of human tolerated dose using in vitro
hematotoxicity tests and the integration of this knowledge into
preclinical modeling and toxicology. The third speaker will focus
on regulatory considerations for preclinical development of anticancer
drugs. The fourth speaker will discuss the clinical development
of anticancer drugs. The final speaker will review the special
preclinical and clinical regulatory issues associated with the
development of biologics for the treatment of cancer. This basic
drug development course is targeted to government, biotechnology
and pharmaceutical toxicologists, as well as physicians and general
toxicologists with an interest in cancer chemotherapy.
- Preclinical
Development Philosophy between Different Classes of Anticancer
Drugs, Joseph E. Tomaszeski, National Cancer Institute,
Bethesda, MD.
- Myelotoxic
Effects of Anticancer Drugs on Human, Canine, and Murine Myeloid
Progenitor Cells Using In Vitro Hematotoxicology Assays,
Ralph E. Parchment, Karmanos Cancer Institute, Detroit, MI.
- Regulatory
Considerations for Preclinical/Clinical Development of Anticancer
Drugs, John K. Leighton USFDA, Rockville, MD.
- Clinical
Development of Anticancer Drugs, John Wright, National Cancer
Institute, Bethesda, MD.
- Preclinical
and Clinical Regulatory Issues Associated with the Development
of Biologics, Alexandra Worobec, USFDA, Rockville, MD.
Incorporation
of Pharmacokinetic and Pharmacodynamic Data into Risk Assessments
AM 8 Advanced
Governor's
C
Chairpersons: John C. Lipscomb, USEPA/ORD/NCEA, Cincinnati,
OH and Lynne Haber, Toxicology Excellence for Risk Assessment,
Cincinnati, OH.
Endorsed
by:
The Biological Modeling Specialty Section
The In Vitro Specialty Section
The Risk Assessment Specialty Section
The increasing
attention to chemical-specific mechanistic data in human health
risk assessments should encourage researchers and programmers
to identify and develop risk-relevant information. Recently, guidance
for replacing default uncertainty factors with adjustment factors
based on chemical-specific data has been made available. This
course will investigate recent and emerging approaches to metabolism,
pharmacokinetics, and pharmacodynamics with respect to producing
data adequate for inclusion in human health risk assessments,
and methods to use such data in risk assessment. Physiologically-based
pharmacokinetic (PBPK) modeling has developed risk-relevant information,
but the "validation" of these models for some chemicals
in humans may be problematic. In some instances, the best available
data may be generated in vitro and in silico and
require extrapolation to the in vivo setting. PBPK models
then become attractive and can be used to estimate risk-relevant,
mechanistically-related PK outcomes, and variance thereof, when
adequate biochemical and physiologic/anatomic information are
incorporated. Human interindividual variance is presently addressed
in the uncertainty factors (UFH) used to derive safe levels of
exposure. The quantification of human variance through in vivo,
in vitro, and in silico approaches will be presented.
This will include the evaluation of genetic and environmental
modulation of biochemical individuality (e.g., polymorphisms and
co-exposures) and their impact on tissue dosimetry and age-related
differences in humans.
- Overview/Introduction:
Pharmacokinetics, Uncertainty Factors and the Risk Assessment
Process, John C. Lipscomb, USEPA /ORD/NCEA, Cincinnati,
OH.
- Guidance
for Adequacy of Data as a Basis for Development of Compound-Specific
Adjustment Factors, Bette Meek, Health Canada, Ottawa, Ontario,
Canada.
- In
Silico Approaches for PBPK Modeling and Estimation
of Interindividual Variance, Kannan Krishnan, University
of Montreal, Montreal, Quebec, Canada.
- In
Vitro to In Vivo Extrapolations of Metabolic
Rate Constants and their Use in PBPK Modeling, Gregory L.
Kedderis, CIIT Centers for Health Research, Research Triangle
Park, NC.
- Use
of PBPK Modeling to Evaluate Implications of Human Variability,
Harvey Clewell, ENVIRON Corporation, Ruston, LA.
Toxicology
of Naturally Occurring Toxins — Don't Mess with Mother Nature!
PM 9 Basic
Governor's
B
Chairperson: Frederick W. Oehme, Comparative Toxicology
Laboratories-Kansas State University, Manhattan, KS and Robert
W. Coppock, Alberta Research Council, Vegreville, AB, Canada.
Endorsed
by:
The Comparative and Veterinary Specialty Section
The Food Safety Specialty Section
The Toxicologic and Exploratory Pathology Specialty Section
Natural toxins
are generally not recognized for their true importance. The benign
perception that nature is all healing is contradicted by the numerous
but often little appreciated public risks from contact with venomous
animals and use of plants as herbal remedies. Lack of understanding
these hazards produces a false sense of societal security. To
update the SOT membership about the range, potency, and mechanisms
of action of poisons found in nature, this basic course will illustrate
the chemical risks, compositions, mechanisms of action, effects
and effective therapies for animal venoms, growing plants, and
herbal products. Each speaker is a nationally recognized expert
in their presentation's themes. Drs. Wallace and Peterson recognize
and manage snake, reptile, and arthropod envenomations in their
daily toxicology practices. Poison Center director, Dr. Furbee,
overviews repeated exposures to poisonous plants with a working
knowledge of each plant's poisonous principle(s). Dr. Kois west
coast laboratory deals with the variety of toxicology events from
herbal products. Each speaker will provide personal experiences
and the characteristics, toxicologic mechanisms and effects of
specific intoxications, alerting toxicologists more familiar with
sterile and urban environments with the circumstances and dangers
afforded by Mother Nature. This unique continuing education course
gives insight into the living dangers around us by providing current
toxicological knowledge about these everyday lifestyle hazards.
"Naturally Occurring Toxins" will be timely, of wide
professional and public interest, and certainly stimulating to
our broad audience.
- Rattlesnake
and Gila Monster Envenomations, Kevin L. Wallace, Good Samaritan
Regional Medical Care-Phoenix, Phoenix, AZ.
- Venomous
Arthropods, Michael E. Peterson, Reid Veterinary Hospital,
Albany, OR.
- Plant
Poisons,
Brent Furbee, Indiana Poison Center, Indianapolis, IN.
- Herbal
Toxicity, Richard Ko, California Department of Health Services,
Sacramento, CA.
Regulation
of Drug and Chemically-Induced Apoptotic Cell Death: New In
Vivo Perspectives
PM 10 Advanced
Presidential
B
Chairpersons: Sid D. Ray, Long Island University, Brooklyn,
NY and Stephen B. Pruett, Louisiana State University Medical Center,
Shreveport, LA.
Endorsed
by:
The Molecular Biology Specialty Section
Apoptosis
is a natural consequence in vivo, and there is now substantial
evidence that apoptosis plays an important role in the toxic effects
of a number of drugs and chemicals. Although it is a naturally-orchestrated
self-limiting program, a vast majority of the investigators employ
in vitro models to interpret in vivo mechanisms.
While in vitro assays are relatively sensitive, specific,
and reliable, an ongoing question is the reproducibility of such
mechanisms in complex in vivo systems. Therefore, one of
the primary goals of this course is to discuss coherently numerous
proposed pathways that regulate this cell suicidal process and
test their feasibility in in vivo models. The overall objectives
of this CE course are: (i) an overview of role of apoptosis during
target organ toxicities (cardiotoxicity, hepatotoxicity, nephrotoxicity,
and immunotoxicity), (ii) a broad review of mechanisms of action
of target-organ specific apoptogenic drugs and chemicals; and
(iii) a discussion of mechanisms that regulate apoptosis at the
organ, cellular, sub cellular, and molecular levels. Since oxidative
stress, caspases, caspase-activated DNAse, reactive oxygen species,
mitochondrial, and cell cycle-related events are known to modulate
this process, their contributory roles will be a brief part of
the curriculum. The concepts gained from this course will be useful
to teachers and researchers involved in target organ toxicology,
biochemical toxicology, general toxicology, carcinogenesis, molecular
toxicology, and mechanistic toxicology.
- Drug
and Chemically-induced Apoptotic and Anti-Apoptotic Mechanisms
in the Liver and Kidneys In Vivo, Sid D. Ray, Long
Island University, Brooklyn, NY.
- Apoptosis
and Cardiotoxicity: Signaling Mechanisms, James Kang, University
of Louisville, Louisville, KY.
- Apoptosis
in Immunotoxicology: Roles of Caspases, Stephen B. Pruett,
Louisiana State University Medical Center, Shreveport, LA.
- Apoptosis
and Cell Cycle Control: Recent Advances, Nelu Jena, WhiteHead
Institute, MIT, Cambridge, MA.
Internal
Dosimetry: Measurement of DNA Damage as an Indicator of Internal
Exposure to Genotoxicants
PM 11 Advanced
Presidential
A
Chairperson: Barbara S. Shane, Integrated Laboratory Systems,
Research Triangle Park, NC.
Endorsed
by:
The Carcinogenesis Specialty Section
The Environmental Mutagen Society
The Epidemiology Specialty Section
Large molecular
weight chemical carcinogens, including polycyclic aromatic hydrocarbons,
aromatic and heterocyclic amines, and aflatoxins, are encountered
in the ambient environment, the work place and in our food supply.
These carcinogens usually require metabolic activation before
becoming adducted to DNA. The covalent DNA adducts which are formed,
often termed "bulky" adducts, distort the conformation
of the DNA helix and are typically removed from the DNA by nucleotide
excision repair. However, some proportion of these adducts are
not repaired and following cell division can result in a mutation.
Other pro-mutagenic events (malondialdehyde-DNA adducts) occur
as the result of oxidative damage resulting from endogenous metabolic
processes and exposure to xenobiotics that initiate a lipid peroxidation
cascade. A third type of DNA damage results from agents that induce
strand breaks or crosslinking. The first two talks will discuss
the spectrometric-, immunochemical-, and postlabeling-based approaches
that can be used to measure both bulky adducts and those caused
by lipid peroxidation products. The third talk will describe the
single cell gel (Comet) assay that is used to measure strand breaks,
alkali-labile sites, and crosslinking. The final talk will focus
on the consequence of DNA damage, namely mutations, particularly
those found in infants and young children. The measurement of
these mutations using the T-lymphocyte cloning assay that quantifies
the mutant frequency (MF) of the HPRT gene will be described.
This course will be suitable for those toxicologists that are
interested in the latest techniques used to measure DNA damage
and how these endpoints can be used as an internal dosimeter for
epidemiological monitoring of human populations.
- Human
Biomonitoring for DNA Adducts Induced by Xenobiotic Carcinogens
of Large Molecular Weight, Miriam Poirier, National Institutes
of Health, Bethesda, MD.
- Measurement
of DNA Damage by Lipid Oxidation Products in People, Lawrence
Marnett, Vanderbilt University Medical Center, Nashville, TN.
- Single
Cell Gel (Comet) Assay to Measure DNA Damage in Humans,
Raymond Tice, Integrated Laboratory Systems, Durham, NC.
- The
Analysis of HPRT Mutations During the Late Stages of Fetal Development
and Childhood as a Biomarker for Leukemogenesis in Infants and
Children, Barry Finette, University of Vermont, Burlington,
VT.
Toxicity
Profiling of Genes and Proteins by Toxicologists: Advanced Topics
in Toxicogenomics
PM 12 Advanced
Governor's
A
Chairpersons: B. Alex Merrick and Darlene Dixon, NIEHS,
Research Triangle Park, NC.
Endorsed
by:
The Mechanisms Specialty Section
The Toxicologic and Exploratory Pathology Specialty Section
Chemical toxicity
profiling using gene expression technologies will soon become
more accessible to practicing toxicologists through contract,
industrial, and academic core facilities. It is anticipated that
gene expression data for many compounds will begin to appear in
preclinical drug evaluations, new drug applications, and environmental
risk assessment documents as well as basic toxicology research.
Although many toxicologists have an understanding of genomics
and proteomics, the best use of their applications, attendant
bioinformatics, and associated databases still present a challenge.
This advanced course is aimed at research and industrial toxicologists
to better familiarize them with gene expression technologies at
the transcript and protein level. The course is structured around
four areas, genomics, genoinformatics, proteomics, and proteoinformatics.
Experts in each area will cover the latest technological advances,
specific applications and how to relate and interpret the high
toxicogenomic information density with bioinformatic tools and
relevant databases.
- Toward
Construction of a Transcript Profile Database Predictive of
Chemical Toxicity, Chris Corton, CIIT Centers for Health
Research, Research Triangle Park, NC.
- The
ToxicoInformatics Challenge in Genomics Database Development
and Functional Interpretation of Data, Pierre Bushel, NIEHS,
Research Triangle Park, NC.
- Proteomics:
Applications and Opportunities in Toxicology, Frank A. Witzmann,
Indiana University School of Medicine, Indianapolis, IN.
- Proteome
BioKnowledge Library: Curated Protein Information for Functional
Proteomics, Susan Rabatin, Applied Biosystems, Santa Fe,
NM.
Basic
Principles and Protocols in Molecular Toxicology
PM 13 (repeat
of AM 5) Basic
Presidential
E
Chairpersons: William B. Mattes, Pharmacia, Kalamazoo,
MI and John W. Davis, II, Schering Plough Research Institute,
Lafayette, NJ.
Endorsed
by:
The Molecular Biology Specialty Section
Many of the
mechanisms through which xenobiotics affect tissues or cells occur
at the molecular level. Over the past ten or fifteen years the
use of molecular techniques to dissect mechanisms of toxicity
has grown greatly. These techniques are used to identify growth
regulatory pathways, alterations in gene and/or protein expression,
as well as protein-DNA and protein-protein interactions. Accordingly,
there has been an explosion in the number of reagents and kits
that are commercially available. While these kits and reagents
have facilitated the detection of mechanisms of toxicity, a basic
understanding of the methods used is just as important. This course
will detail a number of basic techniques currently in use in an
attempt to give a researcher new to this area information as to
which tools may be most relevant with regards to their specific
research area. Presentations will include the practical considerations
when setting up a given technique as well as references that will
help the investigator trouble shoot these systems. Finally, actual
data will be shown in an effort to demonstrate the kinds of information
that can be obtained by these experiments and the ways in which
this information can be interpreted and used to develop hypothesis-driven
research. This is a basic level course intended to introduce to
the researcher the tools and references that are available to
him or her.
- Basic
Protocols and Principles in Nucleic Acid Manipulation, Craig
B. Marcus, University of New Mexico College of Pharmacy, Albuquerque,
NM.
- Using
Polymerase Chain Reaction in Molecular Toxicology, Jack
P. Vanden Heuvel, Penn State University Center for Molecular
Toxicology, University Park, PA.
- Design,
Construction and Use of Reporter and Expression Vectors,
Michael S. Denison, University of California-Davis, Davis, CA.
- Basic
Techniques in Detecting Proteins and Protein: Protein Interactions,
John W. Davis, II, Schering Plough Research Institute, Lafayette,
NJ.
Strategies
and Issues in Non-Clinical Development of Intravenous Infusion
Drug Products
PM 14 Basic
Presidential
C
Chairpersons: William Halliwell, Schering-Plough Research
Institute, Lafayette, NJ and George Lulham, JTI-Macdonald Corp.,
Toronto, Ontario, Canada.
Endorsed
by:
The Regulatory and Safety Evaluation Specialty Section
The Reproductive and Developmental Specialty Section
A large number
of pharmaceutical and biotechnology products intended for administration
by intravenous infusion in the clinic have entered into non-clinical
development during the past decade. Many of these have shown early
success in the clinic and subsequently required additional safety
evaluation. Non-clinical testing has also utilized the intravenous
route to avoid issues associated with short drug half-life or
poor absorption that preclude using more traditional clinical
dosing routes. Additionally, continuous infusion studies are conducted
with non-infusion drugs to control blood levels, such as fetal/neonatal
exposure, for mechanistic studies. As a result, the use of intravenous
infusion for non-clinical studies has increased steadily over
the past number of years. There are unique design, conduct, and
interpretation issues associated with this route of drug administration
as a tool in evaluating product safety. Toxicologists and regulators
in pharmaceutical/biotech product development are increasingly
likely to be involved in designing, conducting, interpreting,
and assessing mechanisms of toxicity for non-clinical safety programs
using the intravenous infusion route. The goal of this course
is to explore the scientific and technical challenges associated
with the use of continuous and intermittent intravenous infusion
in drug development. The utility and special considerations of
this treatment route for reproductive studies of intravenously
infused drug products and non-infusion products where there may
be a need to achieve specific systemic exposures will also be
addressed.
- Scientific,
Technical and Design Considerations in the Conduct and Interpretation
of Infusion Toxicology Studies, Glenn Washer, ClinTrials
BioResearch, Ltd., Senneville (Montreal), Quebec, Canada.
- The
Design and Conduct of a Safety Evaluation Program for Eptifibatide,
a Clinically Approved Inhibitor of Platelet Aggregation,
William Halliwell, Schering-Plough Research Institute, Lafayette,
NJ.
- Conduct
of Reproduction Toxicity Studies by Continuous Intravenous Infusion,
Kok-Wah Hew, Purdue Pharma L.P., Ardsley, NY.
- Scientific
Challenges in Drug Development Using Continuous Intravenous
Infusion, Joy A. Cavagnaro, Access BIO, Leesburg, VA.
Current
Approaches for Validation and Regulatory Acceptance of Novel Test
Methods
PM 15 Basic
Governor's
C
Chairpersons: Sidney Green, Howard University College
of Medicine, Washington, DC., Leonard M. Schechtman, USFDA, NCTR,
Rockville, MD and William S. Stokes, NIEHS, Research Triangle
Park, NC.
Endorsed
by:
The In Vitro Specialty Section
New technologies
such as toxicogenomics are providing a mechanistic basis for the
improvement of existing toxicity testing methods and for the development
of new improved methods. The new and revised methods may be faster,
more economical, and reduce animal use. In order for regulatory
authorities and industries to embrace methods that incorporate
new technologies, there must be an effective process for determining
their scientific validity and acceptability for regulatory use.
Enactment of the Interagency Coordinating Committee on the Validation
of Alternative Methods (ICCVAM) Authorization Act of 2000 established
ICCVAM as a permanent committee, and requires federal agencies
to determine that methods are valid for their proposed use prior
to their adoption. Federal regulatory agencies have implemented
processes to consider the applicability and acceptability of ICCVAM-recommended
methods, and to inform the regulated community of their decisions.
A parallel organization has been established in the European Union
(European Center for the Validation of Alternative Methods, ECVAM).
Five methods have successfully completed the ICCVAM and ECVAM
evaluation/validation processes and have been adopted by regulatory
authorities. International acceptance of new methods is an essential
prerequisite for widespread use. This course will review new initiatives
by national and international authorities to achieve acceptance
of new and revised toxicological testing methodologies. Also,
current issues relevant to validation and regulatory acceptance
will be addressed. This course is targeted for toxicologists and
scientists involved in developing, validating, or using toxicological
test methods to meet national and international regulatory testing
requirements. The course is particularly relevant as differential
gene expression is rapidly being applied to new and existing test
methods to identify more sensitive and specific decision criteria.
- The
Role of the Interagency Coordinating Committee on the Validation
of Alternative Methods (ICCVAM) and the NTP in the Regulatory
Acceptance of New and Revised Test Methods, William S. Stokes,
NIEHS, Research Triangle Park, NC.
- The
FDA Process for Consideration of ICCVAM Recommended Test Methods,
Leonard M. Schechtman, USFDA, NCTR, Rockville, MD.
- The
EPA Process of Considering ICCVAM Recommended Test Methods,
Karen Hamernik, USEPA, Washington, DC.
- The
Validation and Acceptance of Alternative Methods in the European
Union, Andrew Worth, European Centre for the Evaluation
of Alternative Methods, Varese, Italy.
- The
Role of OECD in Achieving International Acceptance of Harmonized
Test Guidelines, Herman Koeter, Organisation for Economic
Co-operation and Development, Paris, France.
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