The Toxicologist - Society of Toxicology

who handle chemicals, and for patients exposed to both active pharmaceutical ingredients
(API) and impurities in the product. The goal of this course is to provide
an understanding of the regulatory background and the practical application of
both toxicological and epidemiological information in setting exposure levels considered
to be protective of public health. The objectives of this course are 1) to describe
the regulatory requirements that underlie development of acceptable levels of
exposure for either the general population or select populations (workers, patients)
via the media described above; and 2) to describe the evaluation of toxicological and
epidemiological data in determining acceptable levels of exposure. Case studies of
representative compounds will illustrate the processes. National and international
agencies (e.g., U.S. Environmental Protection Agency, U.S. Occupational Health
and Safety Administration, U.S. Food and Drug Administration, and European
Medicines Agency), as well as non-profit organizations (e.g., American Conference
of Government Industrial Hygienists, International Committee on Harmonization)
and employers, have well-defined processes for establishing ambient air quality
standards, drinking water maximum contaminant, permissible exposure limits for
the workplace and acceptable identification, reporting, and safety thresholds for impurities
in drug products. The course will highlight legal and customary definitions
of “acceptable risk,” as well as risk assessment methods for evaluating data to estimate
risk levels under these programs. The regulations and/or guidances will be detailed
and approaches used to comply with them will be described.
7 DRUG HYPERSENSITIVITY REACTIONS: RISK
ASSESSMENT AND MANAGEMENT.
M. Popovic 1 and J. Whritenour 2 . 1 Eli Lilly & Company, Indianapolis, IN and
2 Pfizer Global Research and Development, Groton, CT.
Drug hypersensitivity reactions are not a common problem in drug development;
however, when they do occur they can have a significant impact on the drug candidate’s
developmental success. Drug hypersensitivity reactions are usually discovered
in Phase II or III clinical trials, or in the post-marketing phase. Once allergic reactions
are observed in patients, one needs to determine if the reaction is mediated by
an immune response to the drug, or another mechanism. There are a few ex vivo diagnostic
methods that can be used to identify immune-mediated reactions, but one
needs to be aware of the limitations and advantages of each approach. In vitro
methods, or animal models presently being developed to predict drug’s potential to
trigger hypersensitivity reaction in the patient population are being developed, but
at present, they have significant limitations. Risk management strategies may include
selection of patient populations based on the HLA haplotype. This course is
intended as an introduction for those with limited background in the area of hypersensitivity,
or allergic reaction to drugs. The focus of the course will be on systemic
hypersensitivity reactions (drug administered orally or parenterally) and will
include discussions both on drugs that are small molecules and biologics.
8 TOXICOLOGY AND RISK ASSESSMENT OF CHEMICAL
MIXTURES.
J. Simmons 1 and C. J. Borgert 2 . 1 U.S. EPA, Research Triangle Park, NC and
2 Applied Pharmacology Toxicology, Inc., Gainesville, FL.
Assessment of the safety and risk of environmental chemicals, pharmaceuticals,
consumer and personal care products, pesticides, and food additives increasingly requires
consideration of the potential pharmacological and toxicological interactions
that might occur as these agents are encountered as mixtures by patients, consumers,
and through environmental exposures (e.g., mixtures present in air, water,
soil). Both toxicological evaluations and risk assessments of mixtures of chemicals
are complex due to the potential pharmacokinetic and pharmacodynamic mechanisms
that might result in nonadditive interactions. While greater than expected
toxicity is of most concern for environmental exposures, both less than and greater
than additive toxicity are of pharmacological concern. Toxicological evaluation of
chemical mixtures necessitates study designs, methods of analysis, and limits on interpretation
not required for single chemicals. This course will cover the fundamentals
of study design and data analysis for mixtures that apply to all classes and categories
of chemicals encountered by humans and animals, regardless of market
application. The objectives of this course are to 1) describe the basic principles that
underlie modern concepts of the toxicology and risk assessment of chemical mixtures;
2) survey the basic tools and techniques needed to design, conduct, analyze
and interpret experimental data with defined or complex mixtures of chemicals;
and 3) review the guidance, underlying assumptions, and techniques used in risk
assessment of chemical mixtures. This course will be of interest to experimentalists
who wish to conduct studies on mixtures that are meaningful for evaluation of risk
as well as safety and risk assessors who must evaluate and apply data on mixtures
and interactions in assessments.
2 SOT 2011 ANNUAL MEETING
9 APPLICATIONS OF COMPUTATIONAL SYSTEMS
BIOLOGY FOR TOXICOLOGY.
M. E. Andersen 1 and R. B. Conolly 2 . 1 The Hamner Institutes for Health Sciences,
Research Triangle Park, NC and 2 U.S. EPA, Research Triangle Park, NC.
The field of toxicity testing and risk assessment is undergoing a shift from reliance
on high-dose animal studies towards increased use of human in vitro systems that
promise to provide mechanistic understanding of toxicity for environmentally relevant
low-dose exposure. For this fundamental change, toxicologists will need to
adopt more integrated experimental and computational approaches to resolve the
structures of key signaling pathways, which are composed of functional network
motifs, and to understand the consequences of chemical perturbation on the dynamic
and steady-state behaviors of these pathways. This course introduces stateof-the-art
computational systems biology tools that are being used for organizing
and understanding molecular circuits under both physiological and perturbed conditions.
A broad overview will first provide a historical context of dose-response
studies based on understanding mode of action through cellular pathway perturbation.
The course will describe signaling properties of a suite of recurring network
motifs, including ultrasensitivity, feedback, and feedforward loops, to appreciate
the basic building blocks of complex biochemical pathways and networks.
Secondly, focusing on the DNA damage response and cell cycle progression pathways,
we will illustrate how these network motifs are organized into molecular circuits
to give rise to higher-level cellular functions and if perturbed, how functional
aberrations result. Signal transduction networks activated by growth factors are
then examined to show how pathway cross-talk and feedback loops define the activation
logic of the downstream MAPK, which is a key determinant of cell growth
and survival. Finally, we will shows how stochastic gene expression and the resulting
non-genetic cell-to-cell variability plays a role in influencing dose response curves
using examples such as B cell differentiation and its disruption by dioxin. The
course concludes with a short summary and suggestions for applying these computational
systems biology tools to future toxicity testing.
10 EVALUATING TOXICITY OF ENGINEERED
NANOMATERIALS: ISSUES WITH CONVENTIONAL
TOXICOLOGY APPROACHES.
S. S. Nadadur 1 and F. A. Witzmann 2 . 1 NIEHS-DERT, Research Triangle Park, NC
and 2 Indiana University School of Medicine, Indianapolis, IN.
Engineered nanomaterials (ENMs) have become an integral part of numerous consumer
products, cosmetics, building materials, medical devices, therapeutic agents,
and environmental remediation. Global demand for nanomaterials and nano-enabled
devices has been projected to surpass $3.1 trillion by 2015. The widespread
use of nanotechnology-derived products presents opportunities for intentional and
unintentional exposure to ENMs. The size and size-dependent novel physical and
chemical properties that make ENMs unique compared to micro-scale products of
similar chemical composition makes it difficult to determine their interaction with
biological matrices. The recent flood of toxicology literature without proper physical
and chemical characterization of ENMs proposes adverse to no health effects for
certain common ENMs such as carbon nanotubes and metal oxide nanoparticles.
The course will provide an overview of the issues facing nanotechnology that the
scientific community must grapple with in regard to predicting toxicity and biological
outcomes associated with nanoscale properties and the need to identify and integrate
novel approaches for safety of ENMs. To begin, focus will be placed on the
importance of incorporating physical and chemical characteristics of ENMs in interpreting
biological data. Then, in vitro approaches using multiple parameters to
classify ENMs toxicity profile will be covered. Altered proteomic profiles in a
model in vitro system to understand molecular alterations will be explored. Finally,
the interpretation of data from in vivo studies using inhalational routes of exposure
will be discussed. The goal of this course is to encourage both the novice and the
toxicologist trained in conventional toxicity assessment to think outside the box to
design rational toxicology studies in evaluating the safety of ENMs that are currently
in use, and to develop models to predict potential toxicity of second and
third generation ENMs.
11 NEW TECHNOLOGIES AND APPROACHES IN
GENETIC TOXICOLOGY AND THEIR EXPANDING
ROLE IN GENERAL TOXICOLOGY AND SAFETY
ASSESSMENT.
J. C. Bemis 1 and J. C. Sasaki 2 . 1 Litron Laboratories, Rochester, NY and 2 Johnson &
Johnson, Raritan, NJ.
For decades, genetic toxicology and the “genetox battery” have been a well-established
part of safety testing for pharmaceuticals and other chemical agents. Recent
advances in experimental methodologies are contributing to a change in the way