The discipline of applied genetic toxicology relies primarily on in vitro and in vivo technologies, some of which have been in use for more than 30 years. Though technological advances have led to high-throughput analyses (e.g. Ames II, flow cytometric analyses of micronuclei), development of in vivo assays applicable to all tissues that could be used as follow-up assays (i.e., Comet assay, gene mutations in transgenic animals), pathway analyses (genomic evaluations), and in silico approaches (QSAR), the regulatory testing battery remains unchanged: 1) an in vitro test for gene mutation in bacteria, 2) an in vitro cytogenetic or micronucleus assay with mammalian cells or an in vitro mouse lymphoma thymidine kinase (tk) assay, and in some cases, 3) an in vivo test for chromosomal damage using rodent hematopoietic cells. Though genetic damage is frequently assessed as a key event(s) in the progression of cancer, toxicologists recognize that a wide spectrum of human health effects may be caused by genetic damage.
Our understanding of molecular biology has increased exponentially in recent years, particularly in areas such as epigenetics, miRNA, and genetic structure. Technologies and tools are also being developed in fields outside of genetic toxicology such as 3D tissue cultures, organ cultures, stem cells, and imaging. The purpose of this workshop is to consider the impact that our improved understanding of biology and new technologies might have on our ability to perform genetic toxicology studies to yield information that is more relevant to human hazard and risk assessment for genetic damage. By bringing together expertise from both within and outside the discipline of genetic toxicology, it is hoped that productive discussions can be held to define ways of bridging genetic toxicology to other disciplines, and to identify potential synergies that would result in new approaches to inform more accurate genotoxicity risk assessment.
Tuesday, April 24, 2012
Overview of ILSI Health and Environmental Sciences Institute
Dr. James Kim, HESI
Genetic Toxicology: Why thinking outside the box? Overview, rationale and objectives of the workshop
Dr. Véronique Thybaud, Sanofi
Session 1
Alternative experimental models to improve genetic toxicity testing
Dr. Marilyn Aardema, BioReliance
Overview of the use of 3-dimensional tissue constructs for genotoxicity testing
Dr. Stefan Pfuhler, Procter & Gamble
Development of in vitro toxicity tests using hepatocytes differentiated from human stem cells
Dr. Seiichi Ishida, National Institutes of Health Science, Japan
Humanized models in toxicology and their applications to hazard characterization and risk assessment
Darrell Boverhof, The Dow Chemical Co.
Session 2
Biomarkers of epigenetic changes and their applicability to genetic toxicology
Dr. Bhaskar Gollapudi, The Dow Chemical Co.
A new paradigm for epigenetic control of cell phenotype: Dynamic reprogramming of tRNA modifications and ribosomes controls selective translation of stress response proteins
Dr. Peter Dedon, Massachusetts Institute of Technology
Epigenomics and impact for drug safety sciences
Dr. Jennifer Marlowe, Novartis
Epigenetic traits as biomarkers of carcinogenesis
Dr. Igor Pogribny, U.S. Food and Drug Administration, NCTR
MIR-34 prevents in vivo lung tumor initiation and progression in the therapeutically resistant KRAS;TRP53 mouse model
Dr. Andrea Kasinski, Yale University
Workshop: recap of previous day
Dr. James Kim, HESI
Session 3
New technologies and approaches
Ms. Kristine Witt, National Institute of Environmental Health Sciences
Imaging as an approach to safety assessment
Dr. Bill Slikker, U.S. Food and Drug Administration, NCTR
The Tox21 strategy for detecting genotoxicants
Dr. Ray Tice, National Institute of Environmental Health Sciences
The behavior of genomic signatures of genotoxicity: Effect of dose level and exposure duration
Dr. Scott Auerbach, National Institute of Environmental Health Sciences
Wrap-up: Discussion and next steps
Dr. Bhaskar Gollapudi, The Dow Chemical Co.
hesi@hesiglobal.org
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