51st Annual Meeting & ToxExpo - Society of Toxicology

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Society of Toxicology 2012 Scientific Symposia Breast Cancer As a Multifactorial Disease: Interaction of Genetics, Life Stage, and the Environment Monday, March 12, 2:00 PM to 4:45 PM Chairperson(s): David L. Eaton, University of Washington, Seattle, WA, and Joyce S. Tsuji, Exponent, Inc., Bellevue, WA. Sponsor: Carcinogenesis Specialty Section Endorsed by: Disease Prevention Task Force Mechanisms Specialty Section Occupational and Public Health Specialty Section Reproductive and Developmental Toxicology Specialty Section Women in Toxicology Special Interest Group Despite decades of research into its causes and treatments, breast cancer remains the most common invasive cancer and the second leading cause of cancer mortality for women in the United States. Known risk factors include genetic mutations; birth weight and stature; timing of breast development, child bearing, lactation, and senescence; body fat; and physical inactivity. Some common external, environmental risk factors include radiation, hormone therapy, diet, alcohol, and perhaps smoking and shift work/circadian rhythm disruption. Several environmental chemicals have also been implicated in the etiology of breast cancer. Although toxicological studies indicate potential hazards through endocrine disruption and even some hormone independent mechanisms, strong epidemiological evidence is largely lacking. Animal bioassays for breast and other types of cancer typically assess each chemical independently, and exposure periods usually do not include potentially sensitive windows of susceptibility, such as in utero, the neonatal period, puberty, or menopause. Nevertheless, emerging epigenetic data support the concept that exposure during sensitive early life stages when the mammary gland is developing can result in developmental reprogramming of breast cells, thereby increasing breast cancer risk later in life. Similarly, stimulation of breast cell division later in life by endocrine-active agents may increase mutation rates or promote tumors at a life stage in which DNA repair is waning. This important topic explores the complex interaction among the potential contributors to breast cancer risk in follow up to the 2011 report of the Institute of Medicine Committee on Breast Cancer and the Environment (funded by Komen for the Cure). • Gene-Environment Interactions in Breast Cancer Risk. Mary-Claire King, University of Washington, Seattle, WA. • The Complex Etiology of Breast Cancer: A Life-Course Approach. Robert Hiatt, University of California, San Francisco, CA. • Early-Life Exposures to Endocrine-Active Chemicals Promotes Breast Cancer Risk Later in Life. Linda Birnbaum, NIEHS, Research Triangle Park, NC. The Thematic Track information can be found on pages 8–9. • Dietary and Occupational Disruption of Endocrine Signaling: Implications for Breast Cancer Risk. Helmut Zarbl, Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Princeton, NJ. • Environmental Epigenomics: Developmental Reprogramming of Cancer Susceptibility. Cheryl Walker, University of Texas MD Anderson Cancer Center, Smithville, TX. • New Directions for Future Research on Environmental Influences on Breast Cancer. Joyce Tsuji, Exponent, Inc., Bellevue, WA. Evaluation of Ocular Safety in the Development of New Drugs Monday, March 12, 2:00 PM to 4:45 PM Chairperson(s): Brian J. Christian, Covance Inc., Verona, WI, and James N. Ver Hoeve, University of Wisconsin, Madison, WI. Sponsor: Ocular Toxicology Specialty Section Endorsed by: Biotechnology Specialty Section Regulatory and Safety Evaluation Specialty Section Interest in the research and development of therapies for age-related ocular disease has increased as the size of the aging population grows. In recent years significant advances in treating ocular disease have been developed such as the application of antineovascular drugs, previously used in oncology, for use in treating vascular disease of the eye. The development of sustained release formulations has similarly expanded the application of therapies for anterior segment ocular disease to diseases of the posterior segment. The eye poses a unique challenge to drug development as a consequence of the anatomic and physiologic barriers to drug access to intraocular targets. The complexity of the structure and function of the eye, the need to use nonroutine, specialized safety evaluation techniques, and the important role of vision in normal function, all add to the challenges faced by both ocular toxicologists and regulatory agencies. The focus of this session will be to highlight key ocular safety assessment techniques commonly used to evaluate the anterior (i.e., multiple corneal evaluation methods) and posterior (i.e., electroretinography) segments of the eye. Data will be presented that demonstrate how the techniques may be applied in a nonclinical safety evaluation setting. In addition, case studies detailing the development of a protein biologic and a sustained release formulation for posterior segment disease will provide attendees with examples of safety assessment strategies as well as the challenges that may be encountered. Finally, pertinent issues in the assessment of ocular safety from the perspective of the regulatory agency will be presented, along with discussion of the drug development implications of selected findings. • Assessment of Corneal Toxicity. Henry Edelhauser, Emory University, Atlanta, GA. Thematic Session 72 SOT’s 51 st Annual Meeting
San Francisco, California The Thematic Track information can be found on pages 8–9. • Electroretinography in Ocular Safety Assessment: Vigabatrin Retinal Toxicity. James N. Ver Hoeve, University of Wisconsin, Madison, WI. • Safety Assessment Strategies and Challenges for Developing Intravitreally Administered Biologics. Vladimir Bantseev, Genentech, Inc., San Mateo, CA. • Practical Encounters in Intravitreal Nonclinical Safety— The Retisert Experience. Mary Richardson, Bausch & Lomb, Rochester, NY. • Regulatory Perspectives of Contemporary Issues in Ocular Toxicology. Wiley Chambers, US FDA, Silver Spring, MD. Characterizing Toxic Modes of Action and Pathways to Toxicity Molecular Basis for Prevention of Cardiotoxicity Monday, March 12, 2:00 PM to 4:45 PM Chairperson(s): Qin M. Chen, University of Arizona, Tucson, AZ, and Y. James Kang, University of Louisville, Louisville, KY. Sponsor: Cardiovascular Toxicology Specialty Section Endorsed by: Drug Discovery Toxicology Specialty Section Mechanisms Specialty Section Molecular Biology Specialty Section Cardiac toxicity is an increasing concern for chemo, radiation, and gene targeting therapies. The overlapping molecular pathways of cardiac protection versus cancer cell growth, and cardiac energy metabolism versus underlying causes of diseases such as obesity or diabetes pose threats to new drug development against these diseases. Whereas anthracyclines, such as doxorubicin, are well known for inducing cardiotoxicity manifested by arrhythmia and chronic cardiomyopathy, the monoclonal antibody trastuzumab (Herceptin) targeting the epidermal growth factor receptor for cancer therapy induces apoptosis and hypertrophy of cardiomyocytes, leading to dilated cardiomyopathy. Small molecular kinase inhibitors, such as imatinib (Gleevec), cause cardiotoxicity due to induction of apoptosis of cardiomyocytes. While kinase inhibitors and gene targeting therapy have tremendous potential for pharmacological treatment of cancer and other diseases, finding the signaling pathways and genes that can protect against cardiotoxicity is an emerging issue. Thus, in exploration of this important topic, we will discuss the ways in which the heart can be protected from tissue injury by addressing signaling molecules, unique genes, and nutritional factors. • Cardiotoxicity of Chemotherapeutic Drugs: Clinic Presentation and Treatment. Joseph Alpert, University of Arizona, Tucson, AZ. Symposia • Cardiotoxicity of Kinase Targeted Therapeutics. Thomas Force, Thomas Jefferson University, Philadelphia, PA. • Mitochondrial Aldehyde Dehydrogenase 2, Nitroglycerin, and Myocardial Injury. Daria Mochly-Rosen, Stanford University, Stanford, CA. • Nrf2 and GILZ As Molecular Targets for Cardiac Protection. Qin M. Chen, University of Arizona, Tucson, AZ. • Hypoxia-Inducible Factor-1 in Cardiac Toxicity and Regeneration. Y. James Kang, University of Louisville, Louisville, KY. Nanoparticles for Drug Delivery: Interactions with the Immune System Monday, March 12, 2:00 PM to 4:45 PM Chairperson(s): Sandra Casinghino, Pfizer, Inc., Groton, CT, and Marina A. Dobrovolskaia, SAIC-Frederick Inc., Frederick, MD. Sponsor: Immunotoxicology Specialty Section Endorsed by: Nanotoxicology Specialty Section Nanotechnology holds great promise for targeted drug delivery. Unique chemical and physical properties of nanomaterials may lead to improvements in delivery technology in several ways. Examples include increasing the solubility of poorly soluble drugs, increasing efficacy and safety by delivering drugs directly to diseased tissues, and potentially decreasing costs by achieving therapeutic efficacy despite administration of lower doses of drugs. Many publications have discussed the toxicology of environmental and occupational nanomaterials, but more information is needed regarding nanoparticles designed for parenteral administration. These nanoparticles may present unique issues due to recognition by the innate immune system and downstream effects on adaptive immunity. Interactions with the immune system may result in premature clearance before payload delivery, disseminated intravascular coagulation-like toxicities, inflammation, anaphylaxis, and decreased resistance to infection or tumors. Nanoparticles are a very broad and diverse class of biomaterials, and there are significant gaps in our knowledge of the mechanisms by which nanoparticles interact with the immune system. Recognition by immune cells is influenced by many factors, including direct interaction of nanoparticles with red blood cell proteins as well as proteins of the complement and coagulation systems. Therefore nanomaterials may need to be screened for hematocompatibility and complement activation prior to preclinical in vivo studies. Investigation of nanomaterial effects on the function of immune cells, such as phagocytes and lymphocytes, is also important, and development of in vitro assays that are predictive of in vivo observations is critical. Further work is needed to elucidate which chemical and physical properties of nanoparticles are responsible Scientific up-to-date information at www.toxicology.org 73 Thematic Session
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Monday, March 12 8:00 AM-9:00 AM PL
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9:00 AM-12:30 PM Poster Sessions
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Clinical Toxicology from Bedside to
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Appreciates the Generous 51st Annua
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