The Toxicologist - Society of Toxicology

that genetic toxicology data are generated and incorporated in the disciplines of
toxicology and safety testing. The intention of this course is to illustrate the broader
impact that new genetic toxicology approaches are having on drug/chemicals safety
assessment and human risk analysis. The structure of the course will provide examples
of (1) Early discovery/high-throughput genotoxicity screening of chemical entities;
(2) Integration of genetic toxicology assays with repeat-dose in vivo toxicology
studies; and (3) New approaches for genotoxicity risk assessment, and conclude
with an update on genotoxic impurity management strategies for pharmaceuticals.
Speaker presentations will illustrate how genotoxicity testing is evolving from a hazard
identification based-discipline to an integrated approach that may ultimately
yield quantitative information that can be used for human risk assessment.
This course should be of interest to experienced genetic toxicologists as well as
those involved in general toxicology who want to learn about how incorporation of
new genotoxicity methods can improve test predictivity, lower costs, reduce animal
use, and may ultimately be applied to human risk assessment
12 PRACTICAL HOW-TO AND PITFALLS ASSOCIATED
WITH CURRENT EPIGENETIC STUDIES.
R. Rasoulpour 1 and C. Qin 2 . 1 The Dow Chemical Company, Midland, MI and
2 Merck & Co., Inc., West Point, PA.
The study of toxicant-induced epigenetic modifications is greatly expanding in
complexity and scope as new tools of measuring these changes become available.
Fundamental questions (e.g., how best to quantify changes) become enigmatic with
DNA methylation, histone modifications, and microRNA epigenetic modifications
that can affect imprinted, coding, non-coding, and global regions of the genome.
Understanding these questions is important in interpreting species/strain-specific
responses. This advanced course is a practical guide to techniques used in epigenetic
research with respect to toxicology for in vivo/ex vivo screening of rodent models,
post-fertilization embryos, developmental biology, and human disease states. Topics
range from advancements in techniques to screening strategies and tools, and include
techniques to correlate epigenetic changes to gene expression and apical end
points, use of imprinted genes as biomarkers, and profiling DNA methylation in
human population-based research. For screening tools to determine species-specific
responses, a variety of novel technologies will be analyzed such as epigenomic profiling
of DNA methylation in mouse tumors, pyrosequencing to examine the activity
of endogenous retroviruses (e.g., IAP), and assays to explore miRNA and histone
modification changes. In addition, cutting edge techniques such as deep
sequencing technologies of bisulfite-converted DNA will be discussed as these have
enabled the characterization of methylation changes at the genome level; however,
the significant challenge in using this technology is dealing with the massive
amount of information obtained and making sense of the observed methylation
changes. Scientists in academia, industry, and government will leave this course
with an understanding of the strengths and weaknesses of available epigenetic tools,
how these tools can be best used in screening and mode-of-action experiments, as
well as insight into future potential of mechanistic epigenetic toxicology.
13 QUANTITATIVE IN VITRO TO IN VIVO
EXTRAPOLATION: THE ESSENTIAL ELEMENT OF IN
VITRO ASSAY BASED RISK ASSESSMENT.
H. J. Clewell 1 and B. J. Blaauboer 2 . 1 The Hamner Institutes for Health Sciences,
Research Triangle Park, NC and 2 Utrecht University, Utrecht, Netherlands.
There is increasing recognition of the need to use efficient approaches to assess the
risk assessment of high numbers of chemicals in a short time. The reliance on approaches
consisting of animal experimentation has its drawbacks in terms of ethical,
economical, and – not least – scientific limitations in assessing risks in a highthroughput
mode. The quantitative interpretation of toxic effects of compounds in
in vitro studies, using in silico approaches such as systems biological descriptions of
toxicity pathways and physiologically based pharmacokinetic modeling (PBPK),
are a necessary component of the National Academy of Sciences vision on toxicity
testing in the 21st Century. The limited studies performed with this approach to
date have shown that good predictions for the risk of the use of chemicals can be
made. However, a number of limitations have also become clear and more standardization
of methods is needed before implementation of quantitative in vitro-in
vivo extrapolations (QIVIVE) in risk assessments can be achieved.
In this course, the following elements of the approach for assessing risks on the basis
of in vitro toxicity data will be discussed:
How can we improve the applicability of in vitro methods by determining the real
concentrations that come into contact with the cells in vitro, both for chemical
compounds and for particles?
How can we effectively and efficiently integrate the metabolism of compounds,
for clearance as well as for bioactivation?
How can we provide a flexible and yet robust scheme for integrating the different
elements in a high-throughput environment?
14 STEM CELLS UTILITY IN TOXICOLOGY SCREENING.
M. M. Sebastian 1 and Z. A. Radi 2 . 1 Columbia University, New York, NY and
2 Pfizer Global Research and Development, Cambridge, MA.
The development of toxicological screening tools for evaluating toxicity of new
drug candidates has been a major focus in the pharmaceutical industry. Human
embryonic stem (hESC) cells and induced pluripotent stem (iPS) cells and their
lineage cells can be used as tools to predict developmental and other toxicities of
drug candidates since several of the human biochemical pathways are active in these
cells. In addition, stem cells can also be used to help in the mechanistic understanding
of how a specific class of compounds leads to toxicity. Participation in this
course will provide a basic overview of the utility of stem cells in drug discovery and
update toxicologists on a variety of stem cells applications as screening tool for evaluating
toxicity in multiple organ systems, thereby giving toxicologists a better understanding
of the potential practical application of these in vitro methods for safety
and risk assessment.
15 THE BIOLOGY AND TOXICOLOGY OF THE PERI- AND
POST-NATAL DEVELOPMENT.
G. D. Cappon 1 and G. J. Chellman 2 . 1 Pfizer Global Research and Development,
Groton, CT and 2 Charles River Laboratories, Reno, NV.
The susceptibility to toxicity of organ systems during in utero and post-natal development
is a concern for both drugs and environmental chemicals. While developmental
toxicity can be manifested by death, structural abnormalities, and altered
growth, alterations in the functional competence are of special concern during postnatal
development. The primary focus in the past has been on functional toxicity to
the CNS and reproduction, but the potential for developmental exposure to impact
function of other systems such as the cardiovascular, respiratory, immune, endocrine,
and digestive systems is now widely recognized. This basic course will
begin with a review of post-natal development of major organ systems in humans
and how those developmental processes might translate to sensitive periods for toxicity.
Focus will be placed on study designs for evaluation of pharmaceuticals during
the pre- and post-natal development period and designs for juvenile animal toxicity
studies to support pediatric drug development. Next, designs will be presented for
assessment of post-natal and juvenile toxicity studies in non-human primates, a
rapidly expanding area given the increase in biopharmaceutical research. The course
will wrap up with a discussion of multigenerational studies used to assess potential
toxicity of environmental chemicals. Attendees will leave with an appreciation of
the complex biology of peri- and post-natal development periods and an overview
of current approaches to evaluating safety during this period.
16 EMERGING ISSUES AT THE INTERSECTION OF
REPRODUCTIVE AND MIXTURES TOXICOLOGY.
V. S. Wilson 1 and C. V. Rider 2 . 1 Reproductive Toxicology Branch, TAD, NHEERL,
ORD, U.S. EPA, Research Triangle Park, NC and 2 Toxicology Branch, NIEHS-NTP,
Research Triangle Park, NC.
Environmental contaminants have been implicated as having a role in reproductive
toxicity observed in both humans and wildlife. For example, estrogenic and antiandrogenic
chemicals have been hypothesized to be involved in the observed rise in
the incidence of testicular dysgenesis syndrome noted as a suite of related pathologies
including decreased semen quality, increased incidence of male reproductive
tract malformations, and testicular cancer. Additionally, endocrine disruptors from
concentrated animal feedlot operations and sewage effluent have been associated
with observed reproductive anomalies in aquatic species. While toxicological studies
and regulatory action have traditionally focused on individual chemicals, it is
clear that realistic exposures are made up of multiple chemicals. Sources of exposure
to endocrine active compounds are varied and include personal care products, pharmaceuticals,
agricultural, and industrial compounds. Many of these sources may
lead to constant, low dose exposures. Although individual chemicals are typically
present at low levels within the exposure milieu, the impact of mixtures of these
chemicals has only recently begun to be examined. Our panel of experts will provide
an overview of potential exposures to endocrine active mixtures and describe
current work on mixtures of reproductive and developmental toxicants from both a
human health and ecotoxicological perspective. In conclusion, we will address
emerging contaminants of concern and discuss the reproductive effects of relevant
chemical mixtures in humans and wildlife.
SOT 2011 ANNUAL MEETING 3