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2015 Continuing Education Courses

SR01 New Horizons in Chemical Carcinogenesis: Advances in Mode of Action and Mechanism of Cancer Pathogenesis Basic Book
AM02 An Introduction to the Exposome Basic Book
AM03 Demystifying Mixtures: From Study Design Selection to Risk Assessment Application Basic Book
AM04 Safety Evaluation of CNS Administered Therapeutics—Study Design, Dose Routes, and Data Interpretation Basic Book
AM05 The Future of Developmental and Reproductive Toxicology—Building a Bridge to the Animal Free Zone Advanced Book
AM06 The New World of Cancer Immunotherapy: Challenges in Bench to Bedside Translation Basic Book
AM07 Toxicology and Regulatory Considerations for Combination Products Basic Book
PM08 Advances in Safety Assessment of Medical Devices Basic Book
PM09 Interpretation of Cardiovascular Safety Data in Toxicology Studies Advanced Book
PM10 Is Synthetic Biology the Future of Toxicology? Advanced Book
PM11 Skeletal System Endocrinology and Toxicology Basic/CME Book
PM12 Strategies in Investigative Toxicology in a Pharmaceutical Setting Basic Book
PM13 Toxicogenomics Meets Regulatory Decision-Making: How to Get Past Heat Maps, Network/Pathway Diagrams, and “Favorite” Genes Advanced Book

New Horizons in Chemical Carcinogenesis: Advances in Mode of Action and Mechanism of Cancer Pathogenesis

SR01—CE Basic

Chairperson(s): James E. Klaunig, Indiana University, Bloomington, IN; and Udayan M. Apte, University of Kansas Medical Center, Kansas City, KS.

Endorser(s):
Carcinogenesis Specialty Section

The ability of chemicals to cause cancer is an end point with a deep impact on public health. Understanding the mode of action of chemical carcinogens is critical for risk assessment of the chemicals. The mechanisms by which chemicals can cause cell transformation and neoplastic growth have been central to the discipline of toxicology. It is now apparent that the previous simplistic view that chemicals interact with DNA, induce a mutation which results in the formation of a neoplasm is incomplete. Chemical modulation of metabolism, nuclear receptors, gene expression, DNA repair processes, immune surveillance, inflammation, cell to cell communication and changes in target cell function and structure, and their ability to activate stem/progenitor cells, contribute to the formation of preneoplastic cells and their progression to the malignant state. The multitude of changes in the target cell and its microenvironment must be considered in applying mode of action analysis to potential carcinogenic human risk. Besides the estrogen, CAR, PPAR, and AHR receptors, other nuclear receptors, including HNF4a, TR, Nur77, and LXR previously not associated with cancer pathogenesis, appear to play a critical role in the formation and progression of cancer. While the role of these receptors in metabolic processes and differentiation has been known, new studies indicate these proteins are central in cancer pathogenesis either via their canonical or non-canonical actions driven by chemical exposure. This course will review our current level of understanding of chemical carcinogenesis as well as discussing some new frontiers that have implications in cancer pathogenesis from chemical exposure.

Part 1: Mode of Action and Mechanism of Cancer Pathogenesis. James E. Klaunig, Indiana University, Bloomington, IN.

Part 2: New Horizons in Chemical Carcinogenesis: Advances in MOA. Udayan M. Apte, University of Kansas Medical Center, Kansas City, KS.

 

An Introduction to the Exposome

AM02—CE Basic

Theme: Strategies for Exposure and Risk Assessments

Chairperson(s): Gary W. Miller, Emory University, Atlanta, GA; and Martyn T. Smith, University of California Berkeley, Berkeley, CA.

Endorser(s):
Mixtures Specialty Section
Postdoctoral Assembly
Risk Assessment Specialty Section

The exposome has been defined as the totality of our exposures throughout our lifetime. Such a definition defies measurement making it less than useful as a scientific construct. More recently, the concept of the exposome has evolved to represent a measurable entity that encompasses our complex exposures and how our bodies respond to such exposures. The addition of the biological response component to the definition of the exposome positions the field of toxicology to make major contributions to the field. By providing an intellectual foil to the genome-centric framework in biomedical research, the exposome has the potential to elevate the importance of the environment in scientific circles and promote a framework that faithfully integrates the importance of the environment in health and disease. This course will introduce the attendees to the concept of the exposome, explain how it can be used to advance toxicological research by providing a clear translational output, and explain some of the innovative approaches being used to measure the exposome. In order for the exposome to become a useful concept it will be necessary to: (1) capture and quantify the complex exposures, (2) identify and quantify the diverse biological responses, and (3) to integrate these disparate datasets with advanced conceptual thinking and innovative bioinformatic and mathematical approaches. This course was designed to address these three objectives in an informative and interactive setting.

The Exposome: Introduction and Implications for Toxicology. Gary W. Miller, Emory University, Atlanta, GA.

Exposure Pathways, Biomarkers and the Exposome: Predictions, Insight, and Uncertainty. John F. Wambaugh, US EPA, Research Triangle Park, NC.

The Blood Exposome. Martyn T. Smith, University of California Berkeley, Berkeley, CA.

Exposome Bioinformatics: EWAS and Beyond. Chirag J. Patel, Harvard Medical School, Boston, MA.

 

Demystifying Mixtures: From Study Design Selection to Risk Assessment Application

AM03—CE Basic

Theme: Strategies for Exposure and Risk Assessments

Chairperson(s): Jane Ellen Simmons, US EPA, Research Triangle Park, NC; and Cynthia V. Rider, NIEHS, Research Triangle Park, NC.

Endorser(s):
Mixtures Specialty Section
Occupational and Public Health Specialty Section
Risk Assessment Specialty Section

Assessing chemical mixture toxicity is often considered an intractable problem. Difficulty increases for complex mixtures as much of their composition is typically unknown. Although mixtures toxicology and risk assessment (RA) are more complex than for single chemicals due to potential interactions, significant advances have been made in recent years. As a number of experiments are designed poorly from a mixtures perspective, this course will provide coherent strategies for design, analysis of mixtures experiments for robust conclusions, and data that are useful in mixtures RA. Key principles and concepts underlying modern mixtures toxicology, RA, legislation, policy and guidance in the United States and other nations will be reviewed. Guidance based on data quality will be provided for application of either whole mixture or component-based RA approaches. Whole mixture RA discussions will include recent research on methods to determine whether mixtures are sufficiently similar such that toxicity information for one mixture can be used to estimate the toxicity of another. Most mixtures RAs are component-based and a number of approaches will be illustrated—highlighting key differences. Those include the hazard index (HI), target organ HI, interaction weighted HI, and index-chemical based (relative potency factor and toxic equivalency factor) approaches. This course emphasizes recent advances and will be of value to experimentalists wanting to conduct mixture studies meaningful for evaluation of risk or safety, and risk assessors who evaluate mixtures data and apply mixtures RA methods.

Regulatory Drivers and Available Resources. Moiz Mumtaz, CDC, ATSDR, Atlanta, GA.

Berenbaum and Beyond: Concepts and Theories Underlying Mixtures Research and Cumulative Risk Assessment. Cynthia V. Rider, NIEHS, Research Triangle Park, NC.

Designing the Good, Eliminating the Bad and the Ugly. Jane Ellen Simmons, US EPA, Research Triangle Park, NC.

Data Quality Assessment and Whole Mixture Assessments (Mixture of Concern, Sufficiently Similar Mixture, Group of Similar Mixtures). Glenn Rice, US EPA, Cincinnati, OH.

Component-Based Additivity Approaches: Benefits and Uncertainties. Richard Hertzberg, Emory University, Atlanta, GA.

 

Safety Evaluation of CNS Administered Therapeutics—Study Design, Dose Routes, and Data Interpretation

AM04—CE Basic

Theme: Safety Assessment Approaches for Product Development

Chairperson(s): Brian R. Vuillemenot, Genentech, Inc., South San Francisco, CA; and Sven H. Korte, Covance Laboratories GmbH, Muenster, Germany.

Endorser(s):
Biotechnology Specialty Section
Neurotoxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

Many diseases affecting the central nervous system (CNS) are inadequately treated by traditional systemic delivery methods, partly because of the inability of large molecules to bypass the blood-brain barrier. Delivery of large molecules, cells, and other novel therapies directly to the central nervous system via direct parenchymal injection/infusion or catheterization into the intrathecal and/or ventricular spaces overcomes this obstacle and delivers the therapeutics close to the target region. Clinical experience using direct CNS administration of compounds for pain relief and chemotherapy has grown over the past decades, suggesting the same approach can be applied to the treatment of degenerative and inherited disorders. Administration of drugs directly into the brain or cerebrospinal fluid (CSF) may involve some risk, including reaction of the spinal cord or brain tissue adjacent to the device. The preclinical studies used to evaluate the safety of CNS administered compounds must differentiate between the effects of the delivery method, the therapy, and the combination. Reliable, well-characterized animal models for CNS administration of test articles have been developed which enable nonclinical development of these potential therapeutics. This course will discuss the technical challenges of preclinical intrathecal studies, design of studies and nonclinical programs, evaluation of results, and considerations for special endpoints in the studies. The course is targeted to pathologists, toxicologists, administrators, and regulatory personnel who may need to design, conduct, or review these complicated but increasingly worthwhile investigations.

Development of CNS Administered Biologics: Overview, Challenges, and a Case History. Brian R. Vuillemenot, Genentech, Inc., South San Francisco, CA.

Procedures of Intrathecal Drug Delivery and CSF Sampling in Juvenile Nonhuman Primate Studies. Sven H. Korte, Covance Laboratories GmbH, Muenster, Germany.

Intraparenchymal CNS Delivery. Robert B. Boyd, Northern Biomedical Research, Inc., Spring Lake, MI.

Morphologic Assessment of Studies Involving Direct Delivery to the CNS. Mark T. Butt, Tox Path Specialists, LLC, Frederick, MD.

Translation of Nonclinical Intrathecal Data to the Clinic. Teresa L. Wright, Shire, Lexington, MA.

 

The Future of Developmental and Reproductive Toxicology—Building a Bridge to the Animal Free Zone

AM05—CE Advanced

Webcast Registration

Theme: Safety Assessment Approaches for Product Development

Chairperson(s): Reza J. Rasoulpour, Dow AgroSciences, Indianapolis, IN; and Patrick Allard, University of California Los Angeles, Los Angeles, CA.

Endorser(s):
Regulatory and Safety Evaluation Specialty Section
Reproductive and Developmental Toxicology Specialty Section

In this new age of predictive toxicity, adverse outcome pathways, and replacements for traditional testing designs, the world of developmental and reproductive toxicology is the final frontier. The sheer complexity of a developing mammalian embryo/fetus coupled to, and dependent upon, maternal care to follow the predesigned path towards normal development still holds many mysteries. In the past several years, there have been breakthroughs in our thinking of developmental and reproductive toxicology alternative assays that now take what was once inconceivable to something that is merely on the horizon. The course focus will be to explore several different examples utilizing novel model system approaches to predict reproductive and developmental toxicity endpoints. The course will include an introductory overview on the history of this area and the unique challenges upon finding alternatives for reproductive and developmental assays. Fundamental developmental processes including the roundworm, C. elegans, as a model organism for prediction of germline toxicities, will be presented. The course will explore alternative vertebrate models and gain insight on the opportunities and challenges with the popular zebrafish as an alternative model for evaluating developmental toxicity and novel downstream safety assessment applications. The course will conclude with presentations on how different alternative assays such as whole embryo culture, zebrafish, and embryonic stem cells can be coupled together to develop a fingerprint to predict developmental toxicity and a presentation on about how the interrogation of different developmental pathways can be combined with computational approaches to develop virtual developmental and reproductive toxicity platforms, such as the virtual embryo. Scientists at multiple levels (graduate students to very experienced scientists) in academia, government, or industry who are interested in learning the current state of the science for developmental and reproductive toxicity assessment are encouraged to attend this course. Course learning objectives are (1) The current state of the science for different approaches in understanding potential for developmental and reproductive toxicity; (2) unique challenges and opportunities that exist within the developmental and reproductive toxicity assessment area compared to other disciplines within toxicology; (3) the pros and cons of utilizing single model species tools versus combining multiple species for predictive assays; and (4) steps that are underway for the longterm replacement of these studies with approaches in bioprofiling combined with computational modeling.

Introduction and Overview. Reza J. Rasoulpour, Dow AgroSciences, Indianapolis, IN.

Utilizing C. elegans As a Predictive Model for Germline Disruption. Patrick Allard, University of California Los Angeles, Los Angeles, CA.

Alternative Development Toxicity Assessment Using Zebrafish—Routine Safety Assessment and Applications. Douglas Fort, Fort Environmental Laboratories, Stillwater, OK.

Combining Rodent Whole Embryo Culture, Zebrafish, and Embryonic Stem Cell Assays to Generate Predictive Signatures. Karen Augustine, Bristol-Myers Squibb Company, Pennington, NJ.

Building Cellular Pathways for the Future—The Virtual Embryo. Thomas B. Knudsen, US EPA, Research Triangle Park, NC.

 

The New World of Cancer Immunotherapy: Challenges in Bench to Bedside Translation

AM06—CE Basic

Webcast Registration

Theme: Advancing Clinical and Translational Toxicology

Chairperson(s): Rodney Prell, Genentech Inc., South San Francisco, CA; and Rafael A. Ponce, Amgen, Seattle, WA.

Endorser(s):
Biotechnology Specialty Section
Immunotoxicology Specialty Section

The concept of harnessing the immune system to eradicate cancer has been a long-term goal in immunology and oncology. After years of disappointment, the field of cancer immunotherapy (CIT) has gained a strong foothold with the recent approval of two immunotherapies (ipilimumab and sipuleucel-T); and encouraging data emerging from clinical trials testing checkpoint inhibitors, chimeric antigen T cells, oncolytic vaccines, and other modalities. This intensifying effort to identify new CIT targets and/or develop new modalities to harness the immune system presents new challenges for assessing nonclinical safety to support clinical development. For nonclinical safety assessment, understanding the threshold between desired immunological activity (desired pharmacology), and the potential for exaggerated immunologic stimulation is paramount in the clinical dose selection and identifying biomarkers for patient monitoring. Therefore CIT drug development may require creative models and study designs that incorporate extensive immune monitoring that has not been routinely included when testing conventional cancer therapeutics. The course objective is to provide a general overview of the field of cancer immunotherapy, highlight the unique challenges for CIT drug development, and generate discussion with regards to assessing the unique challenges of developing this new oncology therapeutics to ensure patient safety. Presenters will introduce the concept of cancer immunotherapy and summarize the current landscape of the field of CIT drug development, including the various pathways and modalities currently under development, and discuss the scientific limitations of conventional models for evaluating the pharmacology of novel immunotherapeutics, as well as the promise of novel models that may improve translatability of results to the clinical setting. The course will look into the challenges for nonclinical safety assessment of cancer immunotherapy molecules. Case studies from different CIT modalities will illustrate the challenges. Unique clinical challenges of developing CIT molecules, and the regulatory perspective on the need for nonclinical, clinical and regulatory scientists to partner to ensure patient safety when developing CIT molecules, will also be presented.

Introduction into the Transformative World of Cancer Immunotherapy. Rodney Prell, Genentech Inc., South San Francisco, CA.

Developing Novel Nonclinical Models to Improve CIT Drug Development.Keith A. Bahjat, Providence Cancer Center, Portland, OR.

Ipilimumab Nonclinical Safety Assessment: Lessons Learned. Helen G. Haggerty, Bristol-Myers Squibb, New Brunswick, NJ.

Clinical Perspective: Approaches and Challenges to CIT Development. Willem Overwijk, MD Anderson Cancer Center, Houston, TX.

Approaches and Challenges for Cancer Immunotherapy from a Regulatory Perspective. Stacey Ricci, US FDA, Silver Spring, MD.

 

Toxicology and Regulatory Considerations for Combination Products

AM07—CE Basic

Theme: Safety Assessment Approaches for Product Development

Chairperson(s): Jon N. Cammack, AstraZeneca Biologics, Gaithersburg, MD; and Chandramallika (Molly) Ghosh, US FDA, Silver Spring, MD.

Endorser(s):
Drug Discovery Toxicology Specialty Section
Medical Device and Combination Product Specialty Section
Regulatory and Safety Evaluation Specialty Section

Therapeutic and diagnostic products that combine drugs, devices, and/or biological elements are termed, and regulated by the US FDA, as combination products. Technological advances continue to merge product types and blur the historical lines of separation between traditional drugs, biologics, and medical devices. Further, the increasing use of absorbable platforms adds another level of complexity to the development and regulation of certain combination products. US FDA’s medical product centers, the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH), are utilizing evolving collaborative efforts in order to address the regulatory challenges of combination products. Because combination products involve components that would normally be developed and regulated under different types of processes and policies, and frequently submitted to different US FDA Centers, these products raise challenging development, regulatory, and review management questions. Differences in these pathways for each combination product type can impact the processes for all aspects of product development and management, especially preclinical testing, but also, clinical investigation, marketing applications, manufacturing and quality control, adverse event reporting, promotion and advertising, and post-approval modifications. The 2014 Sunrise Combination Products CE course introduced the emerging topic; the 2015 CE course will provide in-depth detail on the evolving regulatory processes in developing a successful preclinical evaluation program. In addition to examples of product development scenarios (including drug/biologic-device and antibody drug conjugate combination products), US FDA will provide a reviewer perspective on key program considerations.

Regulatory Overview of Combination Products: Introduction, Definitions, Terms, High-Level Review of New FDA GMP Rules. Thinh Nguyen, US FDA, Silver Spring, MD.

Preclinical Development Challenges for a Hypothetical Drug Pump. Kelly P. Coleman, Medtronic, Inc., Minneapolis, MN.

Case Study of a Preclinical Development Program for a mAb Pre-Filled Syringe Biologic-Device Combination Product. Jon N. Cammack, AstraZeneca Biologics, Gaithersburg, MD.

Considerations for Preclinical Development of Antibody-Drug Conjugates. Matthew Dieter, AbbVie, Chicago, IL.

FDA Reviewer Perspective—Considerations for Bench, Biocompatibility, and Animal Testing of Absorbable Drug-Eluting Stents. Jennifer L. Goode, US FDA, Silver Spring, MD.

 

Advances in Safety Assessment of Medical Devices

PM08—CE Basic

Theme: Safety Assessment Approaches for Product Development

Chairperson(s): Niranjan S. Goud, Boston Scientific Corp., Spencer, IN; and Ron Brown, US FDA, Silver Spring, MD.

Endorser(s):
Association of Scientists of Indian Origin Special Interest Group
Medical Device and Combination Product Specialty Section
Risk Assessment Specialty Section

Medical devices used in the diagnosis and treatment of various diseases are manufactured from polymeric materials and metal alloys, each of which may be associated with safety concerns for the patient. The aim of this course is to provide an outline of the various in vitro, in vivo, and in silico methodologies for the safety assessment of medical devices and to discuss how risk assessment approaches can be used in the biological evaluation process for medical devices. Presentations will provide an overview of the biocompatibility test methods recommended by ISO 10993, US Pharmacopeia, and ASTM and will include examples of test failures and how to resolve them without compromising patient safety. The course will begin with a broad overview of the approaches used to evaluate the biological safety of medical devices. Following the introductory talk, there will be presentations on two high-profile and toxicologically important topics, the potential health risks associated with the use of metallic hip implants, and approaches to evaluate the biological safety of plastic dental materials. One challenge in conducting toxicological risk assessments of compounds released from medical device materials is when there are no adequate toxicity data for these compounds. The course will conclude with a presentation that provides practical guidance on the derivation of exposure limits for leachable chemicals released from medical devices when only limited toxicity data are available. This course should be of broad interest to toxicologists and health care professionals involved in evaluating patient risks to new treatment modalities, and in particular to toxicologists involved in evaluating the safety of medical devices and combination products containing drugs or biologics.

Methods in Assessing the Biocompatibility of Medical Devices. Niranjan S. Goud, Boston Scientific Corporation, Spencer, IN.

The Use of Plastic Materials in Dentistry—An Issue of Concern? Jon E. Dahl, Nordic Institute of Dental Materials, Oslo, Norway.

Risk Assessment of Orthopedic Implants—Case Study of Metal-on-Metal Hip Prosthesis. Whitney V. Christian, Cardno ChemRisk, Pittsburgh, PA.

Derivation of Tolerable Intake Values for Compounds with Limited Toxicity Data. Ron Brown, US FDA, Silver Spring, MD.

 

Interpretation of Cardiovascular Safety Data in Toxicology Studies

PM09—CE Advanced

Webcast Registration

Theme: Safety Assessment Approaches for Product Development

Chairperson(s): John J. Kremer, Covance Laboratories Inc., Madison, WI; and Hong Wang, Genentech Inc., South San Francisco, CA.

Endorser(s):
Cardiovascular Toxicology Specialty Section
Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

The value of integrating cardiovascular (CV) safety evaluation into general toxicology studies has been increasingly recognized in drug development for both pharmaceutical and biotechnology-derived products. These combined study approaches offer a unique opportunity to gain a holistic understanding of drug-related functional, biochemical, and morphological changes in the context of proper pharmacokinetic/ pharmacodynamic (PK/PD) data. Past courses have focused on the best practices, including study design and execution for integrating CV endpoints into toxicology studies. This course will provide a comprehensive and detailed discussion on the interpretation of CV findings as part of a toxicology study. For example, how are CV functional data interpreted (e.g. heart rate, blood pressure, electrocardiogram, contractility) as compared to traditional endpoints (e.g. pathology)? Is a physiological finding (e.g. a decrease in contractility) a primary effect or a compensatory effect to other changes? Is it due to a direct CV effect or secondary to drug-related toxicity? How/when should a CV finding be interpreted as a “hazard” versus “adverse”? What are the potential mechanisms for toxicity? How do I utilize the holistic data to design the next steps? How does surgically implanted instrumentation affect or potentially confound a pathology evaluation? The course will start with outlining the questions and focus on how these assessments are used and interpreted in this emerging paradigm of combined CV/toxicology studies. The target audience consists of toxicologists who may have limited exposure to CV or safety pharmacology data or are looking to expand their knowledge in this area. By the end of this symposium, the audience should better understand the considerations and strategies in integrating CV/toxicology studies as well as real-world case-studies (or best practices) for interpretation of these data for drug safety assessment.

Study Design Considerations to Improve Cardiovascular Safety Assessment.  John J. Kremer, Covance Laboratories Inc., Madison, WI.

Hemodynamic Data: Toward Maximal Information Extraction. Bari Olivier, Michigan State University, East Lansing, MI.

Pathologist Viewpoint on Mapping Physiological Data to Other Indices of Toxicity Including Histopathology. Wendy Halpern, Genentech, Inc., South San Francisco, CA.

Doxorubicin in NHPs: A Case Study in Using Multiple Parameters to Assess CV Function As Part of a Toxicology Study. Michael Engwall, Amgen, Thousand Oaks, CA.

 

Is Synthetic Biology the Future of Toxicology?

PM10—CE Advanced

Theme: Safety Assessment Approaches for Product Development

Chairperson(s): Saber M. Hussain, US Air Force, Wright-Patterson AFB, OH; and Dan Huh, University of Pennsylvania, Philadelphia, PA.

Endorser(s):
In Vitro and Alternative Methods Specialty Section

One frequent critique of traditional in vitro study design is lack of functional correlation between a submerged cellular monolayer and a full organ or tissue system. However, scientists do agree that during preliminary toxicological screening, when little is known regarding the behavior of a new molecule, simple in vitro models coupled with basic toxicological endpoints are critical for generating a baseline response and determining future actions. Currently, there a significant discrepancy exists between in vitro and in vivo correlations. One approach to bridge this gap is through the development of enhanced in vitro systems to more closely mimic an accurate physiological environment. When examining a physiological system, two key components to be addressed are (1) the three dimensional aspect of an organ or tissue and the cell to cell communication that occurs within this structure; and (2) the dynamic environment that flows in and around the tissue, arising from the cardiovascular system. Early improvements in traditional in vitro designs explored co-cultures that included immune cells, the addition of dynamic media flow, and three dimensional matrices (though limited studies have combined multiple of these variables). The focus of the course is to evaluate the current trends in synthetic biology that are advantageous to enhanced in vitro design. One major focus will be on current organ-on-a-chip research, which incorporates cell to cell communication coupled with dynamic flow of media or air, depending on cell type. In addition, since inhalation is a predominant route of toxicological exposure, this course will explore the design of an artificial nose that represents inhalation and the ability of a compound to cross the olfactory bulb in an effort to predict a neurotoxicity risk.

Introduction. Saber M. Hussain, US Air Force, Wright-Patterson AFB, OH.

A Human Breathing Lung-on-a-Chip for Toxicology Studies. Dan Huh, University of Pennsylvania, Philadelphia, PA.

Developing Microengineered Models of Liver Toxicology. Salman R. Khetani, Colorado State University, Fort Collins, CO.

Microvascular Systems on a Chips. Kapil Pant, CFD Research Corporation, Huntsville, AL.

Development of Artificial Respiratory Device for Nanomaterial Toxicity. Lei Kerr, Miami University, Miami, OH.

 

Skeletal System Endocrinology and Toxicology

PM11—CE Basic/CME

Theme: Safety Assessment Approaches for Product Development

Jointly Provided by University of Arkansas for Medical Sciences College of Medicine and SOTSee Continuing Medical Education Courses for details.

CME Task Force: Richard Y. Wang, MD (Chair), William D. Atchison, PhD, John G. Benitez, MD, MPH Michael Kosnett, MD, Melissa McDiarmid, MD, MPH, Martin A. Philbert, PhD, Kenneth S. Ramos, MD, PhD, Gary Rankin, PhD, John A. Wisler, PhD, DABT

Chairperson(s): Alan M. Hoberman, Charles River Laboratories, Horsham, PA; and Susan Y. Smith, Charles River Laboratories, Senneville, QC, Canada.

Endorser(s):
Clinical and Translational Toxicology Specialty Section
Immunotoxicology Specialty Section
Reproductive and Developmental Toxicology Specialty Section

The skeleton has traditionally been considered within the framework of two tenets: A hard structure for protection of the organism, and a major reservoir for the maintenance of serum calcium. Bone remodeling, the process of remaking our skeleton every decade, reinforces that structure/function correlate. However emerging evidence suggests the skeleton is intimately related to other organ systems including but not limited to organs involved in energy metabolism, reproductive system, immune system, central nervous system and muscle, through paracrine, endocrine and neural networks. The goal of this course is to explore these interactions further and highlight the importance of including skeletal evaluations in juvenile and standard toxicology studies and their relevance to humans and clinical trials. In addition, an overview of bone biology and the appropriate techniques for assessment of changes in bone will be provided. The presentations will focus on bone biology, its growth during infancy and childhood and the regulatory systems involved in the maintenance of bone quality during adulthood; the techniques available for bone evaluations in toxicology studies; why bone has recently been accepted as an endocrine system and what the functions of hormones secreted from bone are; and explore the complex relationships unfolding between bone and the different biological systems and the implications in drug development.

Accreditation and AMA Designation Statement

This activity has been planned and implemented in accordance with the Requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of The University of Arkansas for Medical Sciences (UAMS) College of Medicine and the Society of Toxicology (SOT). The UAMS College of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The UAMS College of Medicine designates this live activity for a maximum of 3.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Target Audience

Medical Doctors, health professionals, and researchers with an interest in the importance of the skeletal system in juvenile and standard toxicology studies, and their relevance to humans and clinical trials.

Overall Purpose

Emerging evidence suggests the skeleton is intimately related to other organ systems, such as those involved with the reproductive system, energy metabolism, immune system, and central nervous system. Thus, there is a need to explore these interactions and highlight their importance in toxicology studies, and to humans and clinical trials.

The course will discuss the importance of the skeletal system in juvenile and standard toxicology studies, and their relevance to humans and clinical trials.

Special Needs: We are committed to making this CME activity accessible to all individuals. If you need auxiliary aid(s) or service(s) as identified in the Americans with Disabilities Act, or have a dietary restriction, please describe your needs on the registration form. Most requests can be accommodated if notification is received by March 1, 2015.

Introduction. Susan Y. Smith, Charles River Laboratories, Senneville, QC, Canada.

Primer on Bone Biology: Cells, Matrix, and Mineral in Skeletal Modeling and Remodeling. Marc D. McKee, McGill University, Montréal, QC, Canada.

State of the Art Assessment of Bone Tissue in Preclinical Studies. Aurore Varela, Charles River Laboratories, Montréal, QC, Canada.

Bone As an Underappreciated Endocrine System. Clifford Rosen, Maine Medical Center Research Institute and Tufts University, Scarborough, ME.

The Cross Talk between Bone and Other Biological Systems. Rana Samadfam, Charles River Laboratories, Montréal, QC, Canada.

 

Strategies in Investigative Toxicology in a Pharmaceutical Setting

PM12—CE Basic

Theme: Safety Assessment Approaches for Product Development

Chairperson(s): Damir Simic, Janssen R&D (Johnson & Johnson), Spring House, PA; and Mausumee Guha, Medivation—Toxicology, San Francisco, CA.

Endorser(s):
Drug Discovery Toxicology Specialty Section
Molecular and Systems Biology Specialty Section
Risk Assessment Specialty Section

Investigative toxicology is a broad discipline encompassing multiple tools and strategies to help generate and test hypotheses as part of target safety assessments and derisking efforts in support of discovery and development programs. In most pharmaceutical and biotechnology companies, investigative toxicology exists as either a stand-alone lab, or the function is embedded within various support groups. Discovery and development programs that call upon investigative toxicology to manage safety liabilities and facilitate understanding of toxicity issues face a number of challenges. These include adequate communication across stakeholders, steep learning curves, identification of clear deliverables that require resource prioritization and constantly shifting interests. This “best practices” session will highlight steps on how to overcome such challenges by focusing on three key functions: (1) designing testable hypothesis, (2) communication of the meaningful experimental findings, and (3) proposing rationales and decision processes for the timely resolution of the issue(s). Specifically, best practices will be highlighted in relation to the stage of the program within the R&D pipeline. The presenters will focus on optimal investigative toxicology strategies applicable during target safety evaluation, lead optimization, pre-IND, IND, late stages of the compound development and life cycle management, with case examples. The utility of tools such as genomics, RNAi, metabolomics, in vitro assays and informatics for the integration of supportive data (e.g. clinical chemistry, histopathology, TK and biomarkers), and application of communication tools such as MindMaps will be discussed. Finally, a regulatory perspective on the utility, impact, and practical considerations of submitting investigative toxicology studies to regulatory authorities to assess clinical risk will be presented.

A Roadmap to Effective Investigative Toxicology Safety Assessment, De-Risking, and Communication. Damir Simic, Janssen R&D (Johnson & Johnson), Spring House, PA.

Integrating Investigative Toxicology in the Early-Drug Discovery Space. Dong U. Lee, Genentech, Inc., South San Francisco, CA.

Optimizing Compound Safety during the Lead Development to FIH Stage. Bart A. Jessen, Pfizer, Inc., San Diego, CA.

Investigating Mechanisms of Toxicity of Pharmaceuticals during Late Stage Development and Life-Cycle Management. Mausumee Guha, Medivation—Toxicology, San Francisco, CA.

A Regulatory Perspective on Investigative Toxicology. Janice A. Lansita, Tox Strategies, Baltimore, MD.

 

Toxicogenomics Meets Regulatory Decision-Making: How to Get Past Heat Maps, Network/Pathway Diagrams, and “Favorite” Genes

PM13—CE Advanced

Webcast Registration

Theme: Strategies for Exposure and Risk Assessments

Chairperson(s): Ivan Rusyn, Texas A&M University, College Station, TX; and Russell S. Thomas, US EPA, Research Triangle Park, NC.

Endorser(s):
Biological Modeling Specialty Section
Molecular and Systems Biology Specialty Section
Risk Assessment Specialty Section

Toxicogenomics is a mature field which provides invaluable information on the molecular events preceding or accompanying toxicity; however, most traditional use of gene expression and other ‘omic data in toxicology is largely the same as it was ten years ago: The mode-of-action analysis, classification/prediction, and biomarker discovery. As the technological advances keep driving costs down and information content and reproducibility up, the toxicogenomics data has begun to be used more widely in the human health assessments of chemicals, and will likely be one of the crucial information sources for next-generation of risk assessment decisions. Given the general familiarity of the toxicologists with high-dimensional transcriptional profiling data and major traditional ways in which such data are analyzed, presented and interpreted, this course is designed to demonstrate how the toxicogenomics data can become a key element in hazard identification, dose-response analysis and selection of scientifically-justifiable uncertainty factors. By superimposing the opportunities that are now afforded by both traditional and high-throughput genomics data onto the human health assessment paradigm, this course will be informative to the risk assessment practitioners and the toxicology research community, and increase the scientific impact of the fundamental toxicology studies.

Human Health Risk Assessment: Where Do Toxicogenomics Data Fit? Q. Jay Zhao, US EPA, Cincinnati, OH.

Gene Expression Profiling for Regulatory Decision-Making: Many Genes or Many Samples? David Gerhold, NIH, Bethesda, MD.

Hazard Identification and Toxicogenomic Data: Read-Across Using High-Dimensional Biological Data. Ivan Rusyn, Texas A&M University, College Station, TX.

Quantitative Dose-Response Analysis with Toxicogenomics Data. Russell S. Thomas, US EPA, Research Triangle Park, NC.

Gene Expression and Genetic Variability. Fred A. Wright, North Carolina State University, Raleigh, NC.