Special Sessions

Plenary Opening Lecture: Signal Transduction Pathways Used by Therapeutic Agents and Drugs of Abuse

Monday Morning, March 16, Time: 8:00 AM–9:00 AM
Exhibit Hall A

Lecturer: Nobel Laureate Paul Greengard, Vincent Astor Professor, The Rockefeller University, New York, NY

Nerve cells communicate with each other through two distinct mechanisms referred to as fast and slow synaptic transmission. A number of components of the two signal transduction pathways have been identified. Fast synaptic transmission occurs via activation by a neurotransmitter of a ligand-gated ion channel. In contrast, slow synaptic transmission occurs via a signal transduction cascade that can be remarkably complex and that usually involves second messengers and/or protein phosphorylation/dephosphorylation reactions. A growing body of knowledge concerning slow signal transduction pathways has been utilized to elucidate the mechanism of action of therapeutic agents used for the treatment of schizophrenia, Parkinsonism, and depression, as well as of drugs of abuse, such as caffeine, cannabis, amphetamine, PCP, and LSD.

Dr. Paul Greengard is the Vincent Astor Professor of Molecular and Cellular Neuroscience at The Rockefeller University and Director of The Fisher Center for Alzheimer’s Research. Greengard received his Ph.D. from Johns Hopkins in 1953. He spent five years in England receiving advanced training at the University of London, at Cambridge University and at the National Institute of Medical Research. Upon his return to the United States, Greengard worked as Director of the Department of Biochemistry at Geigy (now Novartis) Research Laboratories, in Ardsley, New York for eight years. In 1967, he left the pharmaceutical industry to return to academia. From 1968 to 1983 Greengard served as Professor of Pharmacology and Psychiatry at Yale University, at which time he moved to his current position at The Rockefeller University.

Over the years, Greengard’s achievements have earned him many distinguished awards including the Metropolitan Life Foundation Award for Medical Research, The Charles A. Dana Award for Pioneering Achievements in Health, the Ralph W. Gerard Prize in Neuroscience from the Society for Neuroscience, The National Academy of Sciences Award in the Neurosciences, the 3M Life Sciences Award of the Federation of American Societies for Experimental Biology. In the year 2000, Greengard was awarded the Nobel Prize in Physiology or Medicine for his discoveries concerning signal transduction in the nervous system.

He is an Honorary Member of the National Academies of Science in Sweden, Norway, and Serbia and has been the recipient of many honorary degrees. He is a member of the National Academy of Sciences and of the Institute of Medicine of the National Academies.

Leading Edge in Basic Science Award Lecture: The Structural Pervasiveness of Estrogen Activity—Benefits and Risks from the Eclectic Nature of Ligand Binding by the Estrogen Receptor

Monday Morning, March 16, Time: 12:30 PM–1:20 PM
Room 324

Lecturer: John Katzenellenbogen, University of Illinois, Urbana, IL

Estrogens have diverse actions in both reproductive and nonreproductive tissues, and compounds of remarkably diverse structure sources can display estrogenic activity. These structures can be either steroidal or nonsteroidal but are typically phenolic. Estrogens act through estrogen receptors (ERs), ligand-modulated transcription factors that regulate hundreds of genes. When estrogens bind to ERs, they stabilize specific conformations that reflect ligand size and shape, and the rigidified surface features of these complexes serve as docking sites for coregulators that alter the pattern of gene transcription in a cell- and gene-specific manner. Guided by X-ray crystallography, we developed modular, combinatorial approaches to prepare novel nonsteroidal estrogens having high selectivity for the ER subtypes, ER? or ERβ, that are useful as pharmacological probes of receptor function. We have also diversified the three-dimensional structure of ER ligands, obtaining estrogens with unexpected biological selectivities of both fundamental and medical interest, and our strogen-dendrimer conjugates can distinguish nuclear from extranuclear estrogen signaling. We have used estrogens labeled with fluorine-18 to image ER-positive breast tumors by positron emission tomography; this in vivo assessment of ER function is useful in predicting patient benefit from endocrine therapies. Our chemical, biochemical, and structural studies on the ERs and their ligands provide new insights into the broad functions of these receptors in biology and medicine. They also have assisted toxicologists by providing tools for distinguishing the specific receptors and mechanistic pathways through which some endocrine disruptor can act.

SOT/EUROTOX Debate

Monday, March 16, Time: 4:30 PM–5:50 PM
Ballroom I

Motion: Nanotoxicology—Much Ado About Nothing?

Endorsed by:
Society of Toxicology (SOT)
European Societies of Toxicology (EUROTOX)

Debaters:
SOT: Nigel Walker, NIEHS, Research Triangle Park, NC
EUROTOX: Kai Savolainen, Finnish Institute of Occupational Healthreceives, Helsinki, Finland

Each year the SOT Annual Meeting includes a debate that continues a tradition that originated in the early 1990s in which leading toxicologists advocate opposing sides of an issue of great toxicological importance. This year, our debaters will address the proposition: Nanotoxicology Is NOT Much Ado About Nothing.

Nanomaterials are the building blocks of a promising new (nano)technology, and these materials are currently being utilized in such diverse areas as engineering, information technology, and diagnostics. Many of these applications are directly related to the fact that nanomaterials have unique physical-chemical properties compared with their larger counterparts because of their quantum size effects and large surface area. Even though nanomaterials are now routinely produced and commercialized, there is still relatively little known about their biology or potential health impacts. Nanotoxicological studies are intended to determine whether, and to what extent these materials may pose a threat to human beings and the environment. The debate will present some of the challenges to the design, conduct, and interpretation of nanotoxicological studies, with particular emphasis on whether their unique properties contribute to unique toxicological profiles.

Regardless of framework differences and personal convictions, each scientific delegate will present relevant evidence and compelling scientific arguments to persuade and appeal to the response of the audience in order to obtain the approval or refusal of the motion.

In addition to being a featured session at the Annual Meeting, this debate will again take place from September 13–16, 2009, at the 46th Congress of EUROTOX in Dresden, Germany.

The 2009 debate will again take place from September 13–16, 2009 at the 46th Congress of EUROTOX in Dresden, Germany.

Translational Impact Award Lecture: Keap1 One Eye on the Target—Translating Molecular Toxicology into Cancer Prevention

Tuesday, March 17, Time: 8:00 AM–8:50 AM
Room 324

Lecturer: Thomas W. Kensler, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

The development of Nrf2 knockout mice provided the first key insights into the toxicological importance of this transcription factor’s signaling pathway. As examples, Nrf2 knockout mice are more sensitive to acute hepatotoxic, pneumotoxic and neurotoxic challenges. In addition, chemical carcinogenesis is exacerbated in several target organs of knockout mice. Nrf2 regulates the expression of conjugating and antioxidative genes, as well as those affecting glutathione homeostasis, NADPH generation, solute transporters, and proteasome function. Collectively, these genes govern a broad-based adaptive response to environmental toxins and toxicants. Transcription of these genes is activated in response to oxidative and electrophilic stresses, leading to increased stability and nuclear accumulation of Nrf2. In some instances, cysteines on Keap1, a cytoplasmic tether for Nrf2, serve as sensors leading to pathway activation. Of great relevance to disease prevention, this pathway also can be induced by an expanding array of small molecule drugs and natural products including dithiolethiones, isothiocyanates and triterpenoids. These compounds are potent anticarcinogens in animal models and their efficacy is lost in Nrf2 knockout mice, highlighting the central importance of this pathway. Several of these inducers are currently being evaluated in clinical trials for cancer prevention in populations at high risk for environmental carcinogenesis.

NIH Grants Room

Tuesday, March 17, Time: 9:30 AM–4:30 PM
Room 304

Chairperson: Joel G. Pounds, Pacific Northwest National Laboratory, Richland, WA
Sponsored by: Research Funding Committee

NIH program and review staff of the Center for Scientific Review and NIEHS will be available in the NIH Grants Room for individual conversations. Attend the NIH Brown Bag Lunch on Tuesday to make an appointment or check the posted schedule to meet with the NIH staff member who can discuss with you aspects of scientific review or specific grant opportunities. New investigators are especially encouraged to meet with program staff. Handouts will be available.

NIH Brown Bag Lunch

Tuesday, March 17, Time: 12:00 Noon–1:15 PM
Room 301

Chairperson: Joel G. Pounds, Pacific Northwest National Laboratory, Richland, WA
Sponsored by: Research Funding Committee

Bring your lunch and join staff from the NIH Center for Scientific Review (CSR) and the NIEHS program officers for lunch and informal discussions about review and grant opportunities at NIEHS. There will be time for questions and discussion, and you can make arrangements to meet these representatives later in the NIH Grants Room. Bag lunches will be available at a nearby concession for purchase.

Distinguished Toxicology Scholar Award Lecture: Role of Reactive Metabolites, Protein Adducts, Immune System, and Other Susceptibility Factors in Drug-Induced Liver Injury

Tuesday, March 17, Time: 12:30 PM–1:20 PM
Room 324

Lecturer: Lance R. Pohl, National Institutes of Health, Bethesda, MD

Most of my research has been directed towards understanding the mechanisms of drug-induced liver injury (DILI). Early studies involved the development of chemical trapping, radiochemical, and stable isotope techniques for identifying reactive metabolites of chloroform, carbon tetrachloride, inhalation anesthetics, and other xenobiotics as well as providing evidence consistent with a mechanistic role in DILI for protein adducts of reactive metabolites. Then specific antibodies for detecting, purifying, identifying, and exploring the toxicologic consequences of specific protein adducts of hepatotoxic drugs were designed and used. For example, this approach made it possible for us to show that patients diagnosed with inhalation anesthetic-induced liver injury had serum antibodies that reacted with one or more purified endogenous liver proteins that had been the target of reactive trifluoroacetyl halide metabolites of inhalation anesthetics, a finding suggesting that the adaptive immune system may have a pathologic role in liver injury caused by inhalation anesthetics. More recently, we have turned our attention towards uncovering risk factors unrelated to reactive metabolite formation that may have a role in determining the susceptibility of patients to DILI. With the use of a murine model of acetaminophen-induced liver injury (AILI) and several genetically deficient mouse strains, we discovered that endogenous interleukin (IL)-13, IL-10, and IL-4 were hepatoprotectants, whereas IL-6 was either a hepatoprotectant or a hepatoprotoxicant depending on its serum concentration. In contrast, endogenous macrophage-migration inhibitory factor, osteopontin, and NK and NKT cells enhanced AILI. In other studies, Kupffer cells protected against AILI, while endogenous glucocorticoids enhanced AILI, and both of these factors appeared to have a role in preventing drug-protein adducts released from injured hepatocytes from causing allergic reactions by inducing immunological tolerance. Comparisons of the proteomes and transcriptomes of mice that were susceptible or resistant to AILI led to the discovery of numerous other potential risk factors that may contribute to the incidence of DILI. Recent findings suggest that polymorphisms in genes encoding risk factors and/or their receptors uncovered by us and other investigators in animal model studies may contribute to individual susceptibility to DILI. None of the research described here could have been done without the hard work and intellectual contributions made by my students, fellows, and colleagues and the continuous support of the Intramural Research Program of the NHLBI and NIH.

U.S. FDA Advisory Panel Appointments

Wednesday, March 18, Time: 7:30 AM–8:50 AM
Room 310

Chairperson(s): James A. Popp, Stratoxon, LLC., Lancaster, PA and Margaret A. Miller, U.S. FDA National Center for Toxicology Research, Rockville, MD

U.S. Food and Drug (FDA) Advisory Committees are panels of independent, outside experts who advise the agency on regulatory and research questions involving complex medical and scientific issues. FDA relies on Advisory Committees to ensure that FDA programs, products reviewed, and approvals are scientifically sound. A recent review of FDA Advisory Committee membership revealed that toxicologists are not routinely participating in these meeting. Toxicologists have a wealth of knowledge that could impact and improve agency decisions. Recognizing the need to include several disciplines in its decision-making, FDA is working to strengthen the Advisory Committee process by expanding participation of various scientific disciplines. This session will explain the role of FDA Advisory Committees and the rules governing participation on these Committees with a goal of encouraging participation by toxicologist. SOT members involved in FDA Advisory Committees will discuss their experience and provide insight on how to engage in the process.

• Introduction for Advisory Committees at the Food and Drug Administration, Michael Ortwerth, U.S. FDA, ACOMS, Rockville, MD
• Advising the Food and Drug Administration: The Role of the Toxicologist, Jim Riviere, North Carolina State University, Raleigh, NC
• Participating in the Process: How and Why, Margaret A. Miller, U.S. FDA, National Center for Toxicology Research, Rockville, MD

Keynote Medical Research Council (MRC) Lecture: The Ubiquitin Proteolytic System—From Basic Mechanisms through Human Diseases and on to Drug Targeting

Wednesday, March 18, Time: 8:00 AM–8:50 AM
Ballroom I

Lecturer: Nobel Laureate Aaron Ciechanover, The Rappaport Faculty of Medicine and Research Institute,Technion-Israel Institute of Technology, Bat Galim, Haifa, Israel

Dr. Aaron Ciechanover was born in Haifa, Israel in 1947. He received his M.Sc. (1970) and M.D. degrees (1975) from Hadassah and the Hebrew University School of Medicine in Jerusalem and his D.Sc. in biochemistry from the Technion (1981). There, as a graduate student with Dr. Avram Hershko, they discovered the ubiquitin-proteasome system for regulated degradation of intracellular proteins. They demonstrated that covalent attachment of ubiquitin to the target substrate signals it for degradation by a downstream protease. They purified the conjugating enzymes, deciphered their mechanism of action, showed that the system degrades abnormal proteins in cells, and proposed a model according to which polyubiquitination functions as a recognition signal for a specific, downstream protease that degrades the substrate with the release of reusable ubiquitin. Through the years it has become clear that ubiquitinmediated degradation of proteins is central to the regulation of basic cellular processes, including the cell cycle, transcriptional regulation, growth and development, differentiation, apoptosis, receptor modulation, DNA repair, and maintenance of the cell’s quality control. With the multiple substrates targeted and processes involved, it is not surprising that the system has been implicated in the pathogenesis of many diseases, a broad array of malignancies and neurodegenerative disorders among them. This led pharma companies to initiate efforts to develop mechanism-based drugs. One of them to combat multiple myeloma, is already on the market with many more in the pipeline.

Following his graduate studies, Dr. Ciechanover obtained his postdoctoral training (1981–1984) with Dr. Harvey Lodish at the Massachusetts Institute of Technology (M.I.T.) and the Whitehead Institute in Cambridge, Massachusetts, U.S.A. There he studied receptor-mediated endocytosis and deciphered the mechanism of iron uptake by the transferring receptor. In parallel and in collaboration with Drs. Alexander Varshavsky and Daniel Finley, he continued his work on the ubiquitin system. Following his return to Israel in 1984, he joined the Faculty of Medicine of the Technion in Haifa and established his own laboratory where he has continued to contribute significantly to the development of the field via studying, among other subjects, the mechanisms of ubiquitin-mediated regulation of transcription factors and growth promoting factors such as p53, Myc, MyoD, and NF-kB. For his studies that led to the discovery of the ubiquitin system, Dr. Ciechanover, along with Drs. Avram Hershko and Irwin Rose, was awarded the Nobel Prize in Chemistry in 2004. Beforehand, in 2000, he shared the prestigious Albert Lasker Award for Basic Medical Research with Drs. Hershko and Varshavsky, and was awarded in 2003 the Israel Prize for Biological Research, the highest recognition bestowed by the State of Israel. Dr. Ciechanover is a member of the Israeli National Academy of Sciences and Humanities, the Pontifical Academy of Sciences of the Vatican, and the American Philosophical Society. He is a Foreign Fellow of the American Academy of Arts and Sciences, and a Foreign Associate of the National Academy of Sciences of the U.S.A. and its Institute of Medicine.

NIH Grants Room

Wednesday, March 18, Time: 9:00 AM–12:00 NOON
Room 304

Chairperson: Joel G. Pounds, Pacific Northwest National Laboratory, Richland, WA
Sponsored by: Research Funding Committee

NIH program and review staff of the Center for Scientific Review and NIEHS will be available in the NIH Grants Room for individual conversations. Attend the NIH Brown Bag Lunch on Tuesday to make an appointment or check the posted schedule to meet with the NIH staff member who can discuss with you aspects of scientific review or specific grant opportunities. New investigators are especially encouraged to meet with program staff. Handouts will be available.

Soapbox Session

Wednesday, March 18, Time: 12:00 NOON–1:20 PM
Pratty Street Lobby

Chairperson(s): Myrtle A. Davis, National Cancer Institute, Bethesda, MD and Hollie Swanson, University of Kentucky, Lexington, KY

Each speaker will be allowed to address the audience for up to 10 minutes on a topic they have submitted in advance to the session chairpersons from the SOT Scientific Program Committee. Topics can reflect either an area of continuing concern or an issue that has arisen during the meeting, and are expected to be novel, controversial, contrary, and/or unpopular. No projector or computer slide capability will be provided, but speakers can hold up a poster as a visual aid if desired. After each speaker, the audience will have up to five minutes to challenge or support the speaker with questions or comments.

Meet the Director of NIEHS, Linda Birnbaum

Wednesday, March 18, Time: 12:00 NOON–1:20 PM
Room 316

Chairperson(s): Michael P. Holsapple, ILSI Health and Environmental Sciences Institute, Washington, DC

"Meet the Director" is a special 80-minute session where leaders of major federal agencies engage in a panel discussion of emerging trends in toxicology research and funding. This year, the NIEHS and NTP welcomed a new director, Linda Birnbaum. Dr. Birnbaum is a former SOT president and was president-elect of the International Union of Toxicology. This session will give SOT Annual Meeting Attendees an important opportunity to hear about Dr. Birnbaum's plans for leading the NIEHS and NTP. The Director will discuss the Institute's research portfolio including opportunities for non-agency toxicologists. Dr. Birnbaum will set aside time to hear suggestions and answer questions from attendees.

This session will be immediately followed by an update from Antonio Scarpa from the NIH Center for Scientific Review.

Merit Award Lecture: Chemical Hepatocarcinogenesis—Mechanisms, Pathogenesis, and Thresholds

Wednesday, March 18, Time: 12:30 PM–1:20 PM
Ballroom I

Lecturer: Gary M. Williams, New York Medical College, Valhalla, NY

The distinction between DNA-reactive and epigenetic mechanisms of carcinogenicity was conceived in part from extensive findings with hepatocarcinogens in the hepatocyte DNA repair assay for DNA reactivity. These mechanisms were incorporated into understanding of the pathogenesis of liver neoplasia as a multistep process. In the first sequence, neoplastic conversion, hepatocytes are initiated through DNA alteration to form proliferative preneoplastic lesions. In the second sequence, neoplastic development, a variety of cellular and tissue epigenetic alterations facilitate the development of preneoplastic cells into neoplasms. DNA adduct formation is a form of toxicity involving electrophilic molecular alterations, in contrast to many epigenetic effects, which elicit adaptive responses resulting from modulation of basic metabolic processes mediated by receptor binding. Generally, epigenetic carcinogens are accepted as having carcinogenicity thresholds, whereas DNA-reactive carcinogens are assumed not to have thresholds. To investigate the possibility of thresholds for DNA-reactive hepatocarcinogens, the dose-response characteristics of two well studied representatives were investigated. By quantifying key bioindicators of effect, including DNA adduct formation, cytotoxicity, cell proliferation and induction of preneoplastic lesions, evidence was found for nonlinearities and no-effect levels at low doses, supporting the concept of thresholds.

Update from the NIH Center for Scientific Review

Wednesday, March 18, Time: 1:30 PM–2:30 PM
Room 316

Chairpersons: Kenneth S. Ramos, University of Louisville, Louisville, KY and Cheryl Lyn Walker, University of Texas MD Anderson Cancer Center, Smithville, TX

Speaker(s): Antonio Scarpa, National Institutes of Health, Center for Scientific Review, Bethesda, MD

Antonio Scarpa will provide Annual Meeting attendees with an update on important initiatives currently underway at NIH. Dr. Scarpa will also discuss the established Systemic Injury by Environmental Exposure (SIEE) Special Emphasis Panel (SEP) in the Digestive Health Integrative Review Group (IRG). This SIEE SEP will allow NIH grant proposals on toxicology to be reviewed by scientists familiar with the subject matter. This session also will provide an opportunity for a lively discussion of the importance of toxicology in advancing basic research and protecting public health and grants needed to support these efforts.

Issues Session: The 'Vision' for Toxicity Testing in the 21st Century: Promises and Conundrums

Thursday, March 19, Time: 7:30 AM–8:50 AM
Room 309

Chairperson(s): Lois Lehman-McKeeman, Bristol-Myers Squibb Company, Princeton, NJ and Michael Holsapple, ILSI Health and Environmental Sciences Institute, Washington, DC

Endorsed by: SOT Presidential Chain

This special session has been organized by the 2009 Program Committee to build on the success of a special session at the 2008 Annual Meeting that introduced SOT members to three important reports that were published by the National Academy of Science in 2007. While there are many topics and issues of interest to toxicologists, there are only a few that have the potential to have as great an impact on the science of toxicology, as the vision and strategy for 'Toxicity Testing in the 21st Century' developed by the National Research Council (NRC) in 2007. Recent advances in systems biology, testing in cells and tissues, and related scientific fields offer the potential to fundamentally change the way that chemicals are tested for the risks that they may pose to humans. There are clear promises associated with components of the vision, which in many ways are natural extensions of the evolution of our science—including our commitment to the 3Rs: replacement, reduction and refinement; and our desire to integrate state-of-the-art mechanistic, modeling and risk assessment approaches. However, to fully implement the vision, there are also challenges to be identified and obstacles to be overcome. The goals for this special session are to promote open and balanced discussion to enhance the potential for realizing the promises by identifying the challenges and conundrums associated with components of the 'Vision'; and to facilitate the communication of ideas regarding the implications for the future of Toxicology.

• Introduction, Michael Holsapple, ILSI Health and Environmental Sciences Institute, Washington, DC
• Toxicological Sciences Forum Series on the NAS Vision, Lois Lehman-McKeeman, Bristol-Myers Squibb Company, Princeton, NJ
• Toxicity Testing in the 21st Century: Bringing the Vision to Life, Mel Andersen, The Hamner Institute, Research Triangle Park, NC
• Evidence-based Toxicology—The Door for the New Toxicology? Thomas Hartung, Johns Hopkins University, Baltimore, MD
• Application of New Technologies to the Future of Toxicology: The Dose Still Makes the Poison, James Bus, The Dow Chemical Company, Midland, MI
• Open Discussion