The Toxicologist - Society of Toxicology

elated to oxidative stress by measuring ROS, oxidized proteins, and oxidative
DNA damage. Overt toxicity was measured by dye exclusion assay. Both sizes of
gold nanoparticles and 100 nm silver nanoparticles did not cause oxidative-stressrelated
premature cellular senescence in A549 cells. Induction of senescence as indicated
by SA-β-Gal activity was a more sensitive indicator of oxidative-stress-related
toxicity caused by 10 nm silver nanoparticles than the dye-exclusion assay.
1765 50 YEARS OF “THE PILL”: RISK REDUCTION AND
DISCOVERY OF BENEFITS BEYOND
CONTRACEPTION.
B. Mahadevan 1 , K. D. Chadwick 2 , R. T. Burkman 3 and B. Tornesi 1 . 1 Abbott
Laboratories, Abbott Park, IL, 2 Drug Safety Evaluation, Bristol-Myers Squibb, New
Brunswick, NJ, 3 Department of Obstetrics and Gynecology, Tufts University School of
Medicine, Springfield, MA and 4 Worldwide Licensing and Knowledge Management,
Merck Research Laboratories, Rahway, NJ.
Widely regarded as a revolutionary drug in its early years, “the pill” might retrospectively
be considered as the first designer or lifestyle drug. Since the introduction
of oral contraceptives (OCs) in the 1960s, both health benefits and safety concerns
have been attributed to their use. In most instances, the non-contraceptive benefits
of OCs outweigh the potential risks. OCs are highly effective, safe, and widely
used; approximately 85% of women in the United States will use an OC for an average
of five years. However, widespread use of OC formulations by women
throughout their reproductive life cycle has given rise to concerns about the effects
of OCs on risk factors for coronary heart disease. As with many drug firsts, many
lessons can be learned from its development and use. Indeed, “the pill” played a significant
role in reshaping pharmacology, social perceptions of medication, and the
regulatory process for new drugs during the second half of the 20th century. In addition
to the history and side effects/toxicity of OCs, the non-contraceptive health
benefits that women experience that expand far beyond pregnancy prevention will
be illuminated.
1766 PRECISION-CUT TISSUE SLICES REVISITED: A
CLASSICAL METHOD MEETS NEW CHALLENGES.
A. Wolf 1 , A. Vickers 2 , P. Olinga 3 , A. Braun 5 , C. Martin 6 , G. Groothuis 7 and N.
Shangari 4 . 1 Investigative Toxicology (iTOX), Novartis Institutes of Biomedical
Research (NIBR), Basel, Switzerland, 2 Investigative Sciences, Allergan Inc., Irvine,
CA, 3 GUIDE, University of Netherlands, Groningen Area, Netherlands, 4 iTOX,
NIBR, East Hanover, NJ, 5 Department of Immunology, Allergology and
Immunotoxicology, Fraunhofer Institute, Hanover, Germany, 6 Department of
Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany and 7 GUIDE,
University of Netherlands, Groningen Area, Netherlands.
The understanding of the underlying mechanisms of a potential drug safety liability
and the prediction of a potential risk to man is important from a safety and regulatory
perspective. Significant progress in molecular and cellular biology has lead
to in vitro models being applied for this purpose. Precision-cut organ slices is an
outstanding in vitro model, which maintains the in vivo tissue organization, contains
all in vivo relevant cell types, architecture and functional heterogeneity.
Historically, organ slice cultures have been applied to study drug metabolism, pharmacology,
and compound toxicity. Recently, it has been used to provide information
on immune and inflammatory responses, provide insight into pathways of
organ injury, assess the involvement of specific cell types in toxicity, and differentiate
between species specific responses, thus furthering our understanding in predicting
human toxicities and their underlying mechanisms. We will review this latest
state-of-the-art use of this technology by providing a forum for the users of
precision-cut slices to share their experiences. Our panel of experts will discuss the
strengths, opportunities, and limitations of the model to evaluate target organ toxicities.
A focal point of our discussions will be the use of slice technology used as a
predictive tool in drug development and bridging compound-related safety from
different animal species to man. We will provide an overview of the innovative use
of toxicity endpoints, functional markers, and demonstrate the use of the model for
tailor-made assessment of mechanisms of drug-induced target organ toxicity.
1767 THE APPLICATION OF THE THRESHOLD OF
TOXICOLOGICAL CONCERN CONCEPT TO THE
PRECLINICAL SAFETY ASSESSMENT OF NON-
PHARMACEUTICAL MEDICAL PRODUCTS,
INCLUDING MEDICAL DEVICES AND COMBINATION
DRUG-DEVICE PRODUCTS.
R. W. Hutchinson 1 ,R. Brown 2 ,M. A. Cheeseman 3 and J. Cammack 4 . 1 Preclinical,
Johnson&Johnson: Ethicon, Somerville, NJ, 2 CDRH, U.S. FDA, Silver Spring, MD,
3 CFSAN, U.S. FDA, Riverdale, MD and 4 ISIS Services, San Carlos, CA.
The Threshold of Toxicological Concern (TTC) is a concept used to estimate safe
exposure levels for chemicals for which toxicological data are not available. It is
based on chemical structure and known safety data for structurally related chemicals.
This value represents a low level of exposure with negligible risk to humans.
The process for demonstrating preclinical safety or biocompatibility of medical devices
often involves a staged approach starting with a thorough understanding of
the chemical composition of the device, then progressing through in vitro and in
vivo bioassays and ultimately continuing the risk management process through the
lifecycle of the product. The TTC concept is a tool that many risk assessors use to
make decisions early in this staged process, and international committees are actively
developing standardized methods for applying these techniques. In order to
adequately explore this topic, we begin by discussing the history of the TTC concept
along with an overview of the areas that this concept has been embraced up to
this point. We will provide a description of how tolerable intake levels are set for
medical device extractables when an adequate database of information about the extracted
chemical is known. In addition, information will be provided on how the
TTC concept can be used for extractable chemicals from medical devices for which
structural information is known but the toxicological database is insufficient.
Finally, the validation of a software package in the context of extractable chemicals
known to be relevant to medical devices will be described.
1768 FROM PILOT GRANTS TO HIGH-END JOURNALS: THE
SCIENCE OF WRITING.
M. C. Fortin 1 and A. E. Loccisano 2 . 1 Clinical Research and Occupational Medicine,
Environmental and Occupational Health Sciences Institute, Piscataway, NJ and 2 The
Hamner Institutes for Health Sciences, Research Triangle Park, NC.
Want to learn how to write effective grants and publications, or sharpen your scientific
writing skills to communicate better? As toxicologists, it is essential that we be
able to articulate new ideas in the form of grants and to disseminate the results of
research in the form of scientific publications. Thus effective communication
through writing is fundamental therefore it is crucial for early career scientists to
learn effective writing skills. Publishing is imperative in academic or non-profit sectors
and obtaining sufficient funding is a necessity when establishing a career and
reputation. However, most scientists do not receive any formal training in writing
and these skills are usually learned by following the style of a mentor or other authors.
This issue is particularly important for graduate students, postdoctoral fellows,
and other early career scientists who would like to enhance their critical writing
skills which are needed for good communication. Our panel of experts will
provide the audience with tactics to write promising NIH grant applications, general
approaches that enhance the publication success of scientific papers, as well as
concrete scientific writing strategies from an author’s and reader’s standpoint.
Attendees will be provided with tips to enhance their skills that will enable more effective
communication of both their ideas and their science, from grant proposals
to publication.
1769 AUTISM: GENETIC, EPIGENETIC, AND
ENVIRONMENTAL FACTORS INFLUENCING NEURAL
NETWORKS.
I. N. Pessah. Department of Molecular and Biological Sciences, University of
California Davis, Davis, CA.
Our current knowledge about how genetic, epigenetic, and environmental factors
contribute to autism susceptibility is ever changing. From a toxicologist’s perspective,
the identity of defective genes and signaling pathways linked to autism provide
important clues about exposures to environmental chemicals that influence autism
susceptibility, severity, and/or treatment outcomes. One fundamental way by which
heritable genetic vulnerabilities can amplify the adverse effects triggered by environmental
exposures is if both factors (genes x environment) converge to dysregulate
the same signaling systems at critical times of development. Thus, we will review
current knowledge of genetic contributions to autism risk, and present new
SOT 2011 ANNUAL MEETING 379