Scientific Program Overview (dates and times)
Lecturer: Doris Taylor, Texas Heart Institute, Houston, TX.
Cardiovascular disease (CVD) is the number one cause of death in the United States. However, few treatments for CVD provide a means to regain full cardiac function with no long-term side effects. Novel tissue-engineered products may provide a way to overcome the limitations of current CVD therapies by replacing injured myocardium with functioning tissue or by inducing more constructive forms of endogenous repair. Dr. Taylor will discuss some of the factors that must be considered in the development of tissue-engineered products and review the methods currently being investigated to generate more.
Lecturer: Joan Nichols, University of Texas Medical Branch, Galveston, TX.
We have learned a great deal about respiratory tract and lung physiology or pathophysiology of disease from the study of animal disease models, tissues from patients isolated at autopsy or growth of monoclonal human cell populations in two dimensional (2D) cultures. Animal models, mainly mice, have been widely used in research and although animal models can simulate human disease they never fully mirror all aspects of human immune response or pathophysiology of disease. Because of this many drug treatments and vaccines developed solely using animal models have been ineffective when used in patient care. Recent advances in microfabrication technology, microfluidics, and tissue engineering have provided a new approach to the development of human 3D tissue culture models which enable production of robust long-lived human tissue analogs. Use of these models along with more complex 3D human organ culture models, containing multiple cell phenotypes, provides a more reasonable approximation of what occurs in the dynamic in vivo microenvironment of human tissues. Microfluidic supported 3D respiratory tract and lung models are currently being used as advanced human testing platforms for evaluating drug response or drug toxicity, hopefully reducing the cost of drug development. Human tissue models may also provide a mechanism for development of personalized medical care based on testing of drugs on a patient’s own cells or engineered tissues in the future.
Chairperson(s): John B. Morris, Society of Toxicology Vice President; University of Connecticut, Storrs, CT.
Lecturers: Linda Birnbaum, NIEHS, Research Triangle Park, NC; and Pamela McInnes, NCATS, Bethesda, MD.
This important session will provide an informal venue for meeting attendees to have a candid and open discussion with two key leaders of federal organizations with missions to protect and improve public health: Dr. Linda Birnbaum, PhD, Director, National Institute of Environmental Health Sciences (NIEHS), NIH, and Dr. Pamela McInnes, DDS, Deputy Director, National Center for Advancing Translational Sciences (NCATS), NIH. The entire session will be devoted to a question-and-answer format concerning scientific directions and priorities for NIEHS and NCATS including funding priorities and outlooks, and training opportunities. As NIEHS and NCATS are partners in the Tox21 initiative a focus will be upon the utility and future of high throughput testing. Dr. Birnbaum has served as the Director of the National Institute of Environmental Health Sciences and the National Toxicology Program since 2009. Dr. McInnes was appointed deputy director of NCATS in January 2014.
Chairperson(s): Patricia E. Ganey, Michigan State University, East Lansing, MI, and Mumtaz Iscan, Ankara University, Ankara, Turkey.
SOT Debater: Thomas M. Monticello, Amgen, Inc., Thousand Oaks, CA.
EUROTOX Debater: Ruth Roberts, ApconiX Ltd, Alderley Edge, United Kingdom.
|Endorser(s):||Society of Toxicology (SOT)
European Societies of Toxicology (EUROTOX)
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 significant toxicological importance. This year, our debaters will address the proposition: Preclinical (Safety) Toxicology Testing Predicts the Clinical Outcome.
Preclinical safety testing of new drug candidates is a crucial step in pharmaceutical drug development and is a highly controlled process based on specific regional and global regulatory agency criteria Preclinical toxicology testing includes a sequential series of in silico, in vitro, and in vivo toxicology studies prior to first in human (FIH) clinical trials. Specifically, data on genotoxicity, general toxicology and safety/secondary pharmacology are generated, and then used to characterize potential safety risks for humans by identifying tolerated doses and target organs of toxicity. These studies are also used to identify potential safety biomarkers to be used in the context of dose and exposure, informing clinicians of appropriate monitoring and also the potential for reversibility after a dose free period. Although preclinical toxicology studies are a regulatory requirement, there has been debate recently that has questioned their utility in evaluating human safety risks. On the one hand, toxicities noted in patients may differ from those noted in animals, questioning the relevance of the animal studies, advocating instead for alternative models such as the “organ/tissue on a chip.” This is consistent with the concept introduced by Russell and Burch for the 3Rs; reduction, refinement and replacement in animal experimentation. On the other hand, preclinical animal toxicology studies may play an important role in predicting toxic dose and exposure, even if the dose limiting toxicities in animals and humans differ. The debaters will discuss the state of the science on preclinical safety testing and whether it can predict clinical outcome.
Regardless of framework differences and personal convictions, each scientific debate 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 SOT Annual Meeting in New Orleans, Louisiana, this debate will again take place (with the debaters taking the reverse positions) in Istanbul, Turkey during the 52nd Congress of the European Societies of Toxicology (2016 EUROTOX Annual Congress), September 4–7, 2016.
Lecturer: Stephen Skaper, University of Padua, Padua, Italy.
One of the more important recent advances in neuroscience research is the understanding that there is extensive communication between the immune system and the central nervous system (CNS). Proinflammatory cytokines play a key role in this communication. The emerging realization is that glia and microglia, in particular, (which are the brain’s resident macrophages), constitute an important source of inflammatory mediators and may have fundamental roles in CNS disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to proinflammatory signals released from other non-neuronal cells, principally those of immune origin. Mast cells are of particular relevance in this context. These immune-related cells, while resident in the CNS, are capable of migrating across the blood-spinal cord and blood-brain barriers in situations where the barrier is compromised as a result of CNS pathology. Emerging evidence suggests the possibility of mast cell-glia communication and opens exciting new perspectives for designing therapies to target neuroinflammation by differentially modulating the activation of non-neuronal cells normally controlling neuronal sensitization, both peripherally and centrally. This presentation will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells, in particular, and the possibility that mast cell-microglia crosstalk may contribute to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerate disease progression, as well as promote pain transmission pathways.
Lecturer: Alan I. Faden, University of Maryland School of Medicine, Baltimore, MD.
It has long been claimed that prior traumatic brain injury (TBI) increases the subsequent incidence of Alzheimer’s disease (AD). However, recent larger epidemiological studies indicate a relationship to subsequent dementia but not to AD. There is also a well-recognized association between repeated mild TBI and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread attention in relationship to high contact sports. The term chronic traumatic encephalopathy (CTE) has been used to define a “specific” entity marked by neurobehavioral changes and deposition of phosphorylated tau protein. Less well appreciated with regard to post-traumatic neurodegeneration is the role of sustained neuroinflammation, even though this association has been recognized pathologically for decades. More recent experimental work, as well as clinical neuroimaging studies, has underscored the relationship between chronic neuroinflammation and progressive brain neurodegeneration in a number of disorders including TBI, while providing mechanistic support. Manifested by extensive microglial and astroglial activation, chronic traumatic brain inflammation (CTBI), or perhaps better termed chronic traumatic inflammatory encephalopathy (CTIE), appears likely to be the most important cause of post-traumatic neurodegeneration and related cognitive decline in terms of prevalence. Perhaps even more critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable weeks to months after the initiating insult(s).
Lecturer: Robin J.M. Franklin, Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent stem cells contributing to regeneration of the injured CNS. This process can occur with remarkable efficiency in multiple sclerosis (MS), and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in MS, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. There is now compelling evidence that ageing is the major contributor to the declining efficiency of remyelination and that this is largely due to a failure of stem cell differentiation. This talk will review recent studies we have undertaken aimed at obtaining a detailed understanding of the mechanisms of regulating differentiation during remyelination and hence identifying novel therapeutic targets.
The Society of Toxicology (SOT) and the Japanese Society of Toxicology (JSOT) are delighted to jointly sponsor a mini-symposium on a topic of mutual interest: Metal toxicity. Each Society has selected from among its membership a true leader in the field to provide their perspectives on recent advances in this area. The SOT invited speaker, Michael Ashner, will discuss his work on manganese toxicity, and the JSOT invited speaker, Yoshito Kumagai, will discuss his work on methylmercury. Together they will provide state of the art insights into the biochemical/molecular toxicity of these two ubiquitous toxic metals.
Manganese Neurotoxicity: From Worms to Human Neonates, Lecturer: Michael Aschner, Albert Einstein College of Medicine, Bronx NY.
Role of Reactive Sulfur Species in Detoxification of Methylmercury: Phase Zero Reaction for Electrophile Trapping and Detoxification, Lecturer: Yoshito Kumagai, University of Tsukuba, Tsukuba, Japan.
Lecturer: Melvin Andersen, The Hamner Institutes for Health Sciences, Research Triangle Park, NC.
Instead of postdoctoral work on shark hemoglobin, military service plunked me down in a laboratory assessing the toxicity of chemicals found onboard nuclear submarines. The new life was bewildering. Why did we use probit analyses for dose response; why the logarithm of inhaled concentration as a measure of dose; what’s the relationship expected between inhaled concentration and chemical in tissue or between the amount of chemical and response? These questions came to mind based on training in modeling small and large molecule kinetics, but received no ready answers. My career, through another six positions working with many talented colleagues, provided opportunities to use quantitative modeling tools to look at these and other aspects of dose-response relationships. This retrospective examines my experience using quantitative models for understanding dose-response relationships. The talk touches on pharmacokinetics, pharmacodynamics ad new directions in cell-pathway based models. The main lessons of a long career are that models require us to state our ideas clearly and quantitatively and then to see if our ideas are correct or in need of revision. The use of these models repeatedly shows that it is even more important to know our ideas are wrong than simply to think they might be right.
Lecturer: Cheryl Lyn Walker, Texas A&M Institute of Biosciences and Technology, Houston, TX.
The epigenome has long been recognized as an important target and read out of toxicants that modulate gene expression, with the initial focus on cytosine methylation of DNA, later on chromatin modifications that comprise the “histone code,” and most recently noncoding RNAs. While much of the language of epigenetics has been elucidated, pathways by which environmental and toxic insults “reprogram” the epigenome are still being uncovered, with many exciting discoveries being made that promise to open new frontiers in toxicological research. In the area of cell metabolism, new insights are being made in understanding how hypoxia and TCA cycle enzymes regulate the activity of TET enzymes that oxidize 5-metylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), the so called “sixth-base,” to reprogram the DNA methylome. We are also discovering that the cell’s epigenetic machinery is vulnerable to environmental exposures, especially during development. Even brief early life exposures can alter the epigenome and reprogram gene expression in a manner that persists across the life course. Finally, a new picture is emerging that epigenetic “readers, writers, and erasers” have important non-chromatin targets, and that perturbations affecting these enzymes can have far reaching impact beyond the epigenome itself, directly modifying, and regulating, transcription factors, cell signaling pathways, and the cytoskeleton.
Lecturer: I. Glenn Sipes, University of Arizona, Tucson, AZ.
In the early 1970s the role of bioactivation as an initiating event in chemical-induced injury became increasingly apparent. Results of a variety of studies with bromobenzene and chloroform demonstrated that a CYP-450 catalyzed oxidative reaction converted these chemicals to reactive intermediates that covalently bound to hepatic proteins (marker of bioactivation). The degree of binding correlated with the extent of hepatic injury. Subsequently, CCl4 and the inhalation anesthetic, halothane, were shown to undergo CYP-450 catalyzed reduction to radicals that bound to lipids and proteins. Based on this reductive pathway, the first reproducible animal model of halothane induced liver injury was developed. Although bioactivation was the critical initiating event for these and other chemicals, it became apparent that subsequent immune mediated events were required for the progression to necrotic liver injury. Potentiation of CCl4-induced liver injury by vitamin A pretreatment of rats was shown to result from vitamin A activation of Kupffer cells, the resident macrophage of the liver. Similarly, the inherent sensitivity of F344 rats, as compared to SD rats, to chlorobenzene-induced liver injury results from a more robust oxidative stress in the livers of F344 rats, mediated in part by Kupffer cells. Injury of non-hepatic tissues by chemicals can be caused by reactive metabolites produced in situ or by the liver. The unique susceptibility of the mouse ovary to 4-vinylcyclohexene is explained by its enhanced capacity to form (via CYP-450) the more reactive metabolite, vinylcyclohexane diepoxide, and by a reduced capacity to detoxify this diepoxide (via epoxide hydrolase). These are just a few examples of an area of research that has a rich history, is now central to our discipline and has launched many, many scientific careers.
Lecturer: Richard Beger, NCTR, US Food and Drug Administration, Jefferson, AR.
Acetaminophen (APAP) overdose is both clinically relevant and a good model for the development of new translational biomarkers. APAP is primarily metabolized by CYP2E1 to form the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) which can bind to cysteine residues of proteins and form APAP-protein adducts. APAP adducts in humans and rodents have been shown to correlate with ALT levels. ‘Omics technologies (microRNA profiling, proteomics and metabolomics) have been employed to discover translational phenotype response biomarkers of APAP-induced liver injury in biofluids from nonclinical studies. These potential translational ‘omics biomarkers of liver injury have been evaluated using clinical samples from healthy and APAP overdose patients. Data supporting the use of microRNAs as biomarkers for DILI using APAP will be presented. Metabolomics approaches have been used to discover that long-chain acylcarnitines and bile acids were significantly altered in blood from APAP-treated rodents. Increases in long-chain acylcarnitines may represent mitochondria injury and associated reduced β-oxidation capacity. Data show that glycine and taurine conjugated bile acids appear to be sensitive determinants of APAP-induced liver injury. Overall, exciting progress in the development of novel translational omics and protein adducts biomarkers of hepatotoxicity has been made using biofluid samples from humans and rodents with APAP-induced liver injury.