The Toxicologist - Society of Toxicology

1 BIODEGRADABLE MATERIALS FOR TISSUE
ENGINEERING: APPLICATIONS AND SAFETY
ASSESSMENT.
R. P. Brown 1 and R. W. Hutchinson 2 . 1 U.S. FDA, Silver Spring, MD and 2 Johnson
& Johnson, The Woodlands, TX.
The incorporation of biodegradable materials as a fundamental component in tissue
regeneration strategies began in the early 1980’s and continues today. The function
of a biodegradable material is to act as a temporary support matrix for transplanted
or host cells so as to restore, maintain, or improve tissue. In order for this
function to be achieved, biodegradable materials must undergo a number of critical
examinations to define their properties. For example, degradation rate, degradation
products, and the tissue response to these products must all be characterized. In this
presentation we will introduce a number of natural and synthetic biodegradable
materials that are commonly considered in regenerative medicine, as well as some
recently developed novel materials. The techniques utilized to describe their physical
properties and the relationship between physical properties and tissue response
will be examined, and advanced techniques for material characterization and toxicological
effects will be considered. Finally, the application of these biodegradable
materials in tissue engineering strategies will be described.
2 BEST PRACTICES FOR DEVELOPING,
CHARACTERIZING, AND APPLYING
PHYSIOLOGICALLY BASED PHARMACOKINETIC
MODELS IN RISK ASSESSMENT.
B. Meek 1 and J. C. Lipscomb 2 . 1 University of Ottowa, Ottowa, ON, Canada and
2 U.S. EPA, Cincinnatti, OH.
This course is aimed at increasing confidence in the evaluation and application of
PBPK models in quantitative health risk assessments, through systematic consideration
of relevant criteria for their development and documentation, based on guidance.
These principles (Best Practices for PBPK Modeling Applied to Health Risk
Assessment) have been recently collected and expanded upon in guidance published
by the WHO International Programme on Chemical Safety (2010), and
have been the subject of several other peer-reviewed publications. The course comprises
lectures describing the link between mode of action, dose-response characterization
and risk assessment, and the role of PBPK models in reducing and characterizing
uncertainty and variability. The course will present principles for the
development, characterization, and communication and criteria for evaluation of
PBPK models for risk assessment applications. A novel inclusion will be a projected
demonstration of real-time changes in model outcome that depend on choice of
model parameter values (e.g., breathing rate, metabolic activity). The demonstration
of user-friendly model development software will be demonstrated in the final
lecture. This will show the impact of choices for parameter values, and models will
be exercised and the results interpreted to produce quantitative values to be used in
place of uncertainty factors in health risk assessments.
3 CURRENT NON-CLINICAL STRATEGIES AND
METHODS FOR EVALUATING DRUG-INDUCED
CARDIOVASCULAR TOXICITY.
H. Wang 1 and D. J. Murphy 2 . 1 Genentech Inc., South San Francisco, CA and
2 GlaxoSmithKline Pharmaceuticals, King of Prussia, PA.
Cardiovascular (CV) toxicity is among the major causes of withdrawal of drugs or
restriction in their labeling and has had an impact on public health and the rising
cost of developing new drugs. Early identification and characterization of CV liabilities,
better understanding of the predictive values of nonclinical models, and an
integrated and iterative approach during drug development could greatly facilitate
the development of safe and effective medicines for patients. This course will describe
the current in vitro and in vivo methods for evaluation of functional and
structural CV liabilities, and discuss the strategies that can be applied at early stages
of drug development to help reduce attrition and to avoid unanticipated liabilities
at later development stages in either animal studies or in the clinic. Study design
and data interpretation will be discussed, as well as the advantages, limitations, and
future directions of current methods involving both functional and structural assessments.
Specific topics such as integration of functional CV endpoints into repeat-dose
toxicity studies, methods for identification and characterization of cardiac
arrhythmia, and special considerations for testing oncology and diabetes drugs
and biologics will be covered. In addition, case study examples will be provided to
highlight how these data can be used to inform decisions at different stages of development.
A regulatory perspective on the challenges and gaps of CV safety evaluations
and opportunities available to improve the overall CV safety assessment par-
adigm will also be presented. Overall, this course will provide participants with a
broad overview of the types of drug-induced CV liabilities, the current nonclinical
strategies and methodologies for early detection of CV liabilities, and a regulatory
perspective on the impact of CV toxicity on the drug-development process.
4 DEALING WITH THE DATA DELUGE: A LIVE DATA
DISCOVERY AND ANALYSIS COURSE.
M. E. Gillespie 1 and S. M. Bello 2 . 1 Saint Johns University, Jamaica, NY and
2 Jackson Laboratory, Bar Harbor, ME.
Using web-based resources and tools to gain novel scientific insights and advance
your research is a significant step for all researchers. As the pace of science accelerates,
experimental technologies continue to evolve and the quantity of data increases.
With the evolution in biological research comes an increasing reliance on
database resources and computational analysis tools to parse and integrate this
growing mass of biological data. The field of toxicology is not exempt from these
challenges. In this course, a diverse group of data resources have joined their efforts
to present a unique series of hands-on tutorials. The tutorials follow a hypothetical
researcher through the various stages of experimental design and data analysis,
demonstrating how the different workshop resources can be used to facilitate all
steps of the research process. Participants will identify orthologous biological information
across different species; identify biological trends (pathway, function, phenotype,
xenobiotic interactions) within a submitted data set; investigate an individual
data set with on-line resources, identifying supplementary information available
across multiple data sets; and gain hands on experience with formatting and submitting
data to a diverse set of on-line data resources.
Today toxicologists must select appropriate model organisms, manage abundant
high-throughput data, understand legacy data, and develop pathway-based understanding
of environmental factors influencing biological systems. Mastery of these
concepts improves toxicity prediction while providing insights into environmentally
influenced diseases and phenotypes. A clear understanding of the diverse online
data resource aims and limitations equips the researcher with the best combination
of resources to effectively address their questions.
5 EPIGENETICS IN TOXICOLOGY: INTRODUCTION,
MECHANISTIC UNDERSTANDING, AND
APPLICATIONS IN SAFETY ASSESSMENT.
M. S. Mitra 1 and T. Sussan 2 . 1 Washington University School of Medicine, Saint
Louis, MO and 2 Johns Hopkins University Bloomberg School of Public Health,
Baltimore, MD.
Epigenetics refers to molecular mechanisms that cause heritable changes in gene expression
without altering the DNA sequence. The most widely studied epigenetic
mechanisms encompass DNA methylation, histone modifications, and gene regulation
by non-coding RNAs, such as microRNAs. Typically these mechanisms are required
for normal cellular development and differentiation; however, perturbations
in them can lead to diseases, notably cancer. Increasing evidence suggests that environmental
factors such as diet, stress, and exposure to radiation and xenobiotics can
induce heritable changes in the epigenetic status, potentially affecting the health of
the present and future generations. Importantly, the long-term and life-threatening
consequences of environment/chemical-induced changes in epigenetics makes this
field a critical area for future exploration by toxicologists. The course will begin by
introducing the fundamental concepts of epigenetics and reviewing the various underlying
mechanisms. Methods to assess epigenetic changes will be discussed, followed
by a discussion of the role of DNA cytosine methylation in the regulation of
carcinogen-inducible CYP450 genes. Mechanistic understanding of the role of
microRNAs in the regulation of cellular toxicity and the influence of environment
on epigenetics that cause developmental defects will also be presented. Finally, the
future of epigenetics in toxicology and its potential applications for safety assessment
will be discussed. Students as well as toxicologists working in academia, federal
and pharmaceutical industries, and researchers interested in mechanistic toxicology
will benefit from taking this course.
6 PROTECTING HUMAN HEALTH: USE OF
TOXICOLOGICAL AND EPIDEMIOLOGICAL DATA IN
DETERMINING SAFE LEVELS FOR HUMAN
EXPOSURE.
E. P. Hayes 1 and T. Gordon 2 . 1 EP Hayes Toxicology Services LLC, Longmont, CO
and 2 New York University School of Medicine, Tuxedo, NY.
Toxicological and epidemiological data are essential to risk assessment processes
used to determine acceptable levels of exposure, both for the general public who
may be exposed to pollutants via ambient air and/or drinking water, for workers
SOT 2011 ANNUAL MEETING 1