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CEd-Tox: SOT Courses Online

SOT and the CE Committee are proud to offer a diverse online continuing education program: CEd-Tox. With the changing economy, we recognize it is more important than ever to keep your skills sharp, learn new techniques, and stay competitive in your field. This program is dedicated to providing such opportunities and resources to the scientific community in order to facilitate professional development beyond the Annual Meeting, as well as provide a low-cost alternative to those who are unable to attend. CEd-Tox offers access to CE slide presentations, audio, and English language transcriptions (for select courses) for 2009–2014 SOT Annual Meetings.

Most courses run approximately three and a half hours and are divided into a brief introduction followed by approximately four 45-minute segments that are viewed individually. Registrants will have 30-day unlimited access to the course(s) beginning on the date of purchase. The course segments are viewed via online streaming audio and slide presentation, and are not downloadable. Selected courses from the 2009—2014 Annual Meetings are currently available.

 

Registration Information

CEd-Tox registration includes 30-day unlimited access beginning on the date of purchase. You will receive a confirmation receipt by email once your registration is complete. This email will include the start date for your 30-day access, as well as account login information, and instructions. Courses are viewed via online streaming of audio and slide presentations and require Internet access.

Annual Meeting CE Course registrants have online access to the specific course(s) course in which they registered.

Fees by Member Type**

SOT Member $75.00
Nonmember $150.00
SOT Retired Member $55.00
SOT Emeritus Member $55.00
Postdoctoral Member FREE
Postdoctoral Nonmember* $45.00
Graduate Student Member FREE
Graduate/Undergraduate Student Nonmember* $22.50
SOT Affiliate $75.00

*Student and Postdoc Nonmembers: Please provide your institution, advisor name, and contact information, as well as a copy of your student ID, via email to SOT Headquarters or fax to 703.438.3113 to ATTN: CE Online. Student or Postdoc status will be verified prior to enrollment at the reduced rate, which may result in a delay in the access start date. Registrants will receive notification once enrollment has been activated.

**Scientists from developing countries, regardless of Member Type, may be eligible for free access to courses. See Global Initiatives PDF icon or Contact SOT Headquarters for more information.

Register—Course Access

If you prefer to register via mail or fax download, and submit this CE Course Online Registration Form. All registrations submitted by fax or hard copy will be processed online by SOT staff and the registrant notified of the access start date.

Mail or Fax Forms to:
Society of Toxicology Continuing Education
ATTN: SOT Online CE
1821 Michael Faraday Drive, Suite 300
Reston, VA 20190
FAX: 703.438.3113

After you register, you will receive an email notification confirming your enrollment, including details on how to access the course. If you did not receive verification of enrollment, please contact us.

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Search for Courses

Search and sort by: course title, topic, or year.
If you know the speaker name, you may also search by speaker.

Course Topic Year
Alternative In Vitro Toxicology Testing for the 21st Century †

Thomas A. Hartung

In Vitro Methods 2012
Applications of Computational Systems Biology for Toxicology*

Thomas A. Hartung

Biological Modeling 2011
Applications of Computational Systems Biology for Toxicology *

Melvin E. Andersen, Qiang Zhang, Jared E. Toettcher, Jason M. Haugh, Sudin Bhattacharya

Molecular Biology 2011
Assessment of OcularToxicity in Toxicology Studies Conducted for Regulatory Purposes †

Margaret Collins, Mark Vezina, Robert Munger, Christopher Murphy, Ken Schafer

Ocular 2010
Basic Embryology and Developmental Toxicity Testing

John M. DeSesso, Kathleen K. Sulik, Kimberley A. Treinen, Reza J. Rasoulpour

Reproductive and Developmental Toxicology 2012
Basic Principles of Human Risk Assessment †

Qiyu (Jay) Zhao, Jeffrey Lewis, John C. Lipscomb, Robinan Gentry, M.E. (Bette) Meek

Risk Assessment 2013
Best Practices for Developing, Characterizing and Applying Physiologically Based Pharmacokinetic Models in Risk Assessment

John C. Lipscomb, Hugh Barton, Kannan Krishnan, George Loizou, Bette Meek, Jos Bessems

Risk Assessment/Safety Assessment 2011
Biodegradable Materials for Tissue Engineering: Applications and Safety Assessment

John P. Fisher

Risk Assessment/Safety Assessment 2011
Combination Products: Toxicology and Regulatory Challenges * ♠

Thinh Nguyen, Jon Cammack, Chandramallika (Molly) Ghosh

Combination Products 2014
Combination Products: Toxicology and Regulatory Challenges *♠

Thinh Nguyen, Jon Cammack, Chandramallika (Molly) Ghosh

Medical Devices 2014
Comparative Biology of the Lung †

Richard Parent, Kent Pinkerton, Jeffrey Tepper, Laura Van Winkle, Gary R. Burleson

Inhalation and Respiratory 2010
Computational and Experimental Aspects of microRNAs in Toxicology ♠

Igor Pogribny, Kai Wang, Susan C. Tilton, Richard J. Brennan, Karol L. Thompson

Molecular Biology 2014
Concepts of Green Chemistry and Its Role in the Identification and Design of Safer Chemicals and Products †

John Warner, Lauren Heine, Thomas G. Osimitz, J. Craig Rowlands, Donald Versteeg

Risk Assessment/Safety Assessment 2012
Current Nonclinical Strategies and Methods for Evaluating Drug-Induced Cardiovascular Toxicity †

Dennis J. Murphy, Derek Leishman, R. Dustan Sarazan, Brian Berridge, John Koerner

Cardiovascular 2011
Current Trends in Genetic Toxicology Testing ♠

B. Bhaskar Gollapudi, Stephen Dertinger, Robert H. Heflich, Matthew J. LeBaron, B. Bhaskar Gollapudi

Regulatory and Safety Evaluation 2014
Cutaneous Toxicity: In Vitro Methods for Toxicity and Safety Evaluation *

Thomas J. Franz, Jeffrey J. Yourick, William G. Reifenrath, Cynthia A. Ryan, John W. Harbell, Marian W. Glynn

Dermal Toxicology 2012
Cutaneous Toxicity: In Vitro Methods for Toxicity and Safety Evaluation *

Thomas J. Franz, Jeffrey J. Yourick, William G. Reifenrath, Cynthia A. Ryan, John W. Harbell, Marian W. Glynn

In Vitro Methods 2012
Dealing with the Data Deluge: A Live Data Discovery and Analysis Course

Marc E. Gillespie, Carolyn J. Mattingly, Teri E. Klein, Susan M. Bello

Molecular Biology 2011
Drug Hypersensitivity Reactions: Risk Assessment and Management *

Franklin Adkinson, Cynthia Ju, Jessica Whritenour, Marija Popovic

Drug Discovery 2011
Drug Hypersensitivity Reactions: Risk Assessment and Management *

Franklin Adkinson, Cynthia Ju, Jessica Whritenour, Marija Popovic

Risk Assessment/Safety Assessment 2011
Epidemiology for Toxicologists: What the Numbers Really Mean ♠

Nancy B. Beck, Michael Goodman, Sorina Eftim, Julie E. Goodman, James S. Bus

Epidemiology 2014
Epigenetics in Toxicology: Introduction, Mechanistic Understanding and Applications in Safety Assessment †

Mayurranjan S. Mitra, James G. Herman, Oliver Hankinson, Kenneth S. Ramos, Dana Dolinoy, Jay I. Goodman

Molecular Biology 2011
Evaluating Toxicity of Engineered Nanomaterials: Issues with Conventional Toxicology Approaches

Srikanth S. Nadadur, Scott McNeil, Chris Vulpe, Frank A. Witzmann, Günter Oberdörster

Nanotoxicology 2011
Inhalation Studies: Challenges and Complexities ♠

Willie J. McKinney, Robert F. Phalen, Gregory L. Baker, Michael J. Oldham, Jack R. Harkema, Mark A. Higuchi

Inhalation and Respiratory 2014
Methodologies in Human Health Risk Assessment ♠

M.E. (Bette) Meek, Qiyu (Jay) Zhao, Hugh A. Barton, John C. Lipscomb

Risk Assessment 2014
Mitochondrial Toxicity: Animal Models and Screening Methods in Drug Development †

James Dykens, Urs A. Boelsterli, Yvonne Will, Toshimori Kitami

Drug Discovery 2010
New Technologies and Approaches in Genetic Toxicology and Their Expanding Role in General Toxicology and Safety Assessment †

Jeffrey C. Bemis, Richard Walmsley, Anthony M. Lynch, B. Bhaskar Gollapudi, Maik Schuler, Lutz Mueller

Risk Assessment/Safety Assessment 2011
Nonclinical Animal Models Enabling Biopharmaceutical Advances in Translational Medicine

Elise M. Lewis, Karen Davis-Bruno, Jacqueline Carleer, Kary E. Thompson, Susan B. Laffan, Kyle L. Kolaja,

Comparative and Veterinary Toxicology 2014
Nonclinical Pediatric Drug Development: Considerations, Study Designs, and Strategies ♠

Thomas M. Monticello, Rakesh Dixit, Sherry J. Morgan, Niels-Christian Ganerup, Vivek Kadambi, John T. Sullivan

Drug Development 2014
Nonclinical Pediatric Drug Development: Considerations, Study Designs, and Strategies ♠

Thomas M. Monticello, Rakesh Dixit, Sherry J. Morgan, Niels-Christian Ganerup, Vivek Kadambi, John T. Sullivan

Reproductive and Developmental Toxicology 2014
Overview and Application of the WHO-IPCS Harmonized Guidance for Immunotoxicity Risk Assessment for Chemicals †

Jeffrey C. Bemis, Richard Walmsley, Anthony M. Lynch, B. Bhaskar Gollapudi, Maik Schuler, Lutz Mueller

Risk Assessment/Safety Assessment 2012
Practical How-To and Pitfalls Associated with Current Epigenetic Studies

Reza John, Chunhua Qin, Barbara F. Hales, Russell S. Thomas, Carmen Marsit

Molecular Biology 2011
Protecting Human Health: Use of Toxicological and Epidemiological Data in Determining Safe Levels for Human Exposure †

Eileen P. Hayes, Daniel L. Costa, Rita Schoeny, Bruce D. Naumann, Timothy J. McGovern

Risk Assessment/Safety Assessment 2011
Quantitative In Vitro to In Vivo Extrapolation: The Essential Element of In Vitro Assay Based Risk Assessment †

Bastiaan Johan Blaauboer, Nynke Kramer, Justin G. Teeguarden

In Vitro Methods 2011
Segment-Specific Renal Pathology for the Non-Pathologist †

Susan G. Emeigh Hart, John Seely, Jim Stolz, Daniela Ennulat

Toxicologic and Exploratory Pathology 2010
Stem Cells in Toxicology (2014) ♠

Richard Parent, Kent Pinkerton, Jeffrey Tepper, Laura Van Winkle, Gary R. Burleson

Stem Cells 2014
Stem Cells in Toxicology † (2012)

Ying Xia, Michael P. Waalkes, Erik J. Tokar, R. Clark Lantz, Kyle L. Kolaja

Toxicologic and Exploratory Pathology 2012
Stem Cells Utility in Toxicology Screening

Manu M. Sebastian, Gabriela Cezar, Stephen Storm, Hirdesh Uppal

Stem Cells 2011
Stress As a Confounding Factor in Toxicology Studies

David Dorman, Nacy Everds, George Foley, Paul Snyder

Stem Cells 2009
The Biology and Toxicology of the Peri- and Post-Natal Development

Christopher J. Bowman, Donald G. Stump, Gary J. Chellman, Sue Marty

Reproductive and Developmental Toxicology 2011
The Practice and Implementation of Neural Stem Cell-Based Approaches to Neurotoxicology (CME)

Aaron B. Bowman, Steven L. Stice, Ellen Fritsche, Timothy J. Shafer

Stem Cells 2013
The Practice and Implementation of Neural Stem Cell-Based Approaches to Neurotoxicology (CME)

Aaron B. Bowman, Steven L. Stice, Ellen Fritsche, Timothy J. Shafer

Mechanisms 2013
The What, When, and How of Nonclinical Support for an IND Submission †

Paul Nugent, Ronald Wange, Dorothy Colagiovanni, Dorothy Colagiovanni, J. Neil Duncan, Drew Rasco

Drug Discovery 2013
Translation of Safety Biomarkers in Drug Discovery and Development

Kay Criswell, Nacy Everds, Denise Bounous, Jennifer Colangelo, Michael R. Blevins

Drug Discovery 2009
Toxic Effects of Metals †

Michael P. Waalkes, Michael F. Hughes, Wei Zheng, Max Costa, Erik J. Tokar

Metals 2013
Toxicology and Risk Assessment of Chemical Mixtures *†

Jane Ellen Simmons, Christopher J. Borgert, Sami Haddad, Moiz Mumtaz

Mixtures 2011
Toxicology and Risk Assessment of Chemical Mixtures *

Jane Ellen Simmons, Christopher J. Borgert, Sami Haddad, Moiz Mumtaz

Risk Assessment/Safety Assessment 2011
Weighing in on Nutrition—Essential Concepts for Toxicologists

Jo Ann S. Carson, Daniel M. Wilson, Angela L. Slitt, Carl L. Keen

Cardiovascular Tox 2013
Weighing in on Nutrition—Essential Concepts for Toxicologists

Jo Ann S. Carson, Daniel M. Wilson, Angela L. Slitt, Carl L. Keen

Foods 2013

* Courses can be categorized under more than one topic
Hard copy course transcription available with registration
CE course ebook is available for the course


Course Descriptions

(click on course title to show/hide description)

Hard copy course transcription available with registration

Alternative In Vitro Toxicology Testing for the 21st Century †

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45 Minute course

Chairperson: Stephen H. Safe, Texas A&M University, College Station, TX

Endorsed by:
Risk Assessment Specialty Section

Over the last two decades, alternatives to animal testing were strongly driven by animal welfare considerations. A culture of organotypic cell models, quality assurance and validation developed, which resulted in a number of novel approaches for regulatory testing. Progress to replace especially the systemic and chronic types of tests has been limited. Novel programs to assess large number of substances such as existing chemicals (REACH and the emerging TSCA reauthorization), nanoparticles or mixtures, as well as new products such as biologicals and cell therapies now add to the need to move to another approach for toxicity testing. Additionally, interest in health effects like endocrine disruption, developmental neurotoxicity, immunotoxicity, obesity, atherosclerosis or childhood asthma require extensive and new types of testing. This is often referred to as Toxicity Testing for the 21st Century (Tox-21c), after the respective NAS vision document from 2007, which has been made US EPA’s toxicity testing strategy in 2009.The central change is moving from apical “black box” animal models to mechanism or pathway of toxicity (PoT). The biotechnology and bioinformatics revolution of recent years has made it possible to develop systems biology, here systems toxicology, approaches. The experiences from the field of alternative methods now prove to be the most important to implement a new regulatory approach. Standardization and validation of cell cultures is crucial for PoT identification as well as the implementation of high-throughput type of tests based on PoT. The first projects to systematically map the entirety of human PoT, the Human Toxome, have started. The validation of these novel tests represents an enormous challenge. It is proposed to follow the role model of evidence-based medicine. For this purpose, the evidence-based toxicology collaboration was started at SOT 2011 and is currently shaping its procedures and governance.

Alternative In Vitro Toxicology Testing for the 21st Century. Thomas A. Hartung, John Hopkins University Center for Alternatives to Animal Testing (CAAT), Baltimore, MD

 

Applications of Computational Systems Biology for Toxicology
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Chairpersons: Melvin E. Andersen, The Hamner Institutes for Health Sciences, Research Triangle Park, NC, and Rory B. Conolly, US EPA, Research Triangle Park, NC

Sponsor: Molecular Biology Specialty Section

Endorsed by:
Biological Modeling Specialty Section

The field of toxicity testing and risk assessment is undergoing a shift from reliance on high-dose animal studies towards increased use of human in vitro systems that promise to provide mechanistic understanding of toxicity for environmentally relevant low-dose exposure. For this fundamental change, toxicologists will need to adopt more integrated experimental and computational approaches to resolve the structures of key signaling pathways, which are composed of functional network motifs, and to understand the consequences of chemical perturbation on the dynamic and steady-state behaviors of these pathways. This course introduces state-of-the-art computational systems biology tools that are being used for organizing and understanding molecular circuits under both physiological and perturbed conditions. A broad overview will first provide a historical context of dose-response studies based on understanding mode of action through cellular pathway perturbation. The course will describe signaling properties of a suite of recurring network motifs, including ultrasensitivity, feedback, and feedforward loops, to appreciate the basic building blocks of complex biochemical pathways and networks. Secondly, focusing on the DNA damage response and cell cycle progression pathways, we will illustrate how these network motifs are organized into molecular circuits to give rise to higher-level cellular functions and if perturbed, how functional aberrations result. Signal transduction networks activated by growth factors are then examined to show how pathway cross-talk and feedback loops define the activation logic of the downstream MAPK, which is a key determinant of cell growth and survival. Finally, we will shows how stochastic gene expression and the resulting non-genetic cell-to-cell variability plays a role in influencing dose response curves using examples such as B cell differentiation and its disruption by dioxin. The course concludes with a short summary and suggestions for applying these computational systems biology tools to future toxicity testing.

Introduction, Melvin E. Andersen, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

Network Signaling Motifs, Qiang Zhang, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

From Dynamics to Decisions: Quantitative Modeling of the Mammalian DNA Damage Response, Jared E. Toettcher, University of California San Francisco, San Francisco, CA

Dynamic Regulation of Growth Factor Signaling Networks, Jason M. Haugh, North Carolina State University, Raleigh, NC

Stochastic Gene Expression and Heterogeneous Cellular Response, Sudin Bhattacharya, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

Assessment of Ocular Toxicity in Toxicology Studies Conducted for Regulatory Purposes †

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Chairperson(s): Margaret Collins, Charles River Laboratories, Reno, NV, and Andrea Weir, Charles River Laboratories, Reno, NV

Sponsor: Toxicologic and Exploratory Pathology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section
Comparative and Veterinary Specialty Section

Ocular toxicity is known to occur following intended or unintended exposure of ocular tissues to xenobiotics. It can occur following local exposure of the eye to an agent or after exposure via oral or other routes of administration. In order to define the risks that pharmaceuticals, pesticides, and other toxic substances pose to the eye, an assessment of ocular toxicity is routinely included in general toxicology studies conducted for regulatory purposes. Because anatomical and physiological differences between species can impact the nature of the ocular effects observed, understanding species differences is important. Although it is possible to detect some ocular effects, such as conjunctivitis, with the naked eye, more sensitive techniques are routinely used to assess ocular toxicity. Slit lamp biomicroscopy and indirect ophthalmoscopy are routinely utilized to more closely evaluate the anterior and posterior chambers of the eye, respectively, during the course of toxicology studies. At the time of necropsy, ocular tissues are collected and processed for histopathological evaluation. More specialized endpoints, such as electroretinography, can be incorporated, as needed. Ocular anatomy and physiology and the assessment of ocular toxicity can be challenging to scientists involved in the safety assessment of pharmaceuticals, pesticides and other agents. This basic course will cover ocular anatomy and physiology in laboratory animals, established methods used to assess ocular toxicity, as well as more novel techniques for toxicity assessment. Examples of ocular toxicity that can occur following different routes of exposure will be discussed.

Introduction and Overview, Margaret Collins, Charles River Laboratories, Reno, NV

Comparative Ocular Anatomy and Physiology in Laboratory Animals, Mark Vezina, Charles River Laboratories, Montreal, Quebec, Canada

Diagnostics in Ocular Toxicology, Robert Munger, Animal Ophthalmology Clinic, Dallas, TX

Diagnostics and Ocular Imaging in the 21st Century, Christopher Murphy, University of California, Davis, CA

Ocular Pathology: Looking at the Eye, Ken Schafer, Vet Path Services, Inc., Greenfield, IN

Basic Embryology and Developmental Toxicity Testing

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Chairpersons: Christopher J. Bowman, Pfizer Worldwide Research and Development, Groton, CT, and Lori A. Dostal, Exponent, Inc., Farmington Hills, MI

Sponsor: Reproductive and Developmental Toxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

Embryonic and fetal development in mammalian species is a complex process which is sensitive to the effects of maternal and environmental factors. The timing of development of the major organ systems varies between humans and other animal species, but the basic biology of development is similar in all species thus allowing extrapolation of animal testing results for xenobiotics to humans. The course will begin by providing an overview that highlights developmental biology from fertilization of the gametes to normal maturation of a full term placenta and fetus including examples of developmental toxicants and teratogens with known modes of action. Subsequently, applied toxicology concepts for evaluation of the potential for bio/pharmaceuticals and chemicals to affect pregnancy and embryo-fetal development will be discussed. Global regulatory strategies and requirements to minimize health effects on women and unborn children will also be addressed. Finally, key information will be presented to provide for a better understanding of the biological and toxicological basis of prenatal developmental toxicity testing and the impact of various outcomes on drug development, chemical use, environmental impact, and human health risk.

Introduction. Lori A. Dostal, Exponent, Inc., Farmington Hills, MI

Implantation, Placentation, and Early Embryonic Development. John M. DeSesso, Exponent, Inc., Alexandria, VA

Demystifying Mammalian Embryogenesis. Kathleen K. Sulik, University of North Carolina, Chapel Hill, NC

The Importance of Developmental Toxicity Testing to Pharmaceutical Development. Kimberley A. Treinen, Merck, Summit, NJ

Navigating Developmental Toxicity Testing of Agricultural Molecules and Industrial Chemicals. Reza J. Rasoulpour, Dow Chemical Company, Midland, MI

Basic Principles of Human Risk Assessment †

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Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Qiyu (Jay) Zhao, US EPA, Cincinnati, OH, and M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Sponsor: Risk Assessment Specialty Section

An overview of the fundamental guiding principles and general methods used in chemical risk assessment will be provided. These principles and methods are addressed in presentations and discussions organized by the four components identified by the National Research Council in the Risk Assessment Paradigm: Hazard Identification and Characterization; Dose- Response Assessment; Exposure Assessment; and Risk Characterization. Guiding principles and key concepts in risk assessment will be illustrated by examples from the literature and sample calculations for dose-response assessment, exposure assessment, and risk characterization will presented.

Introduction to Chemical Risk Assessment. Qiyu (Jay) Zhao, US EPA, Cincinnati, OH.

Hazard Identification and Characterization. Jeffrey Lewis, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ.

Dose-Response Assessment. John C. Lipscomb, US EPA, Cincinnati, OH.

Exposure Assessment. Robinan Gentry, ENVIRON International Corporation, Monroe, LA.

Risk Characterization. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Best Practices for Developing, Characterizing and Applying Physiologically based Pharmacokineti Models in Risk Assessment

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Chairpersons: M.E. (Bette) Meek, University of Ottawa, Ottawa, Ontario, Canada, and John C. Lipscomb, US EPA, ORD/NCEA, Cincinnati, OH

Sponsor: Risk Assessment Specialty Section

Endorsed by:
Biological Modeling Specialty Section

This course is aimed at increasing confidence in the evaluation and application of PBPK models in quantitative health risk assessments, through systematic consideration of relevant criteria for their development and documentation, based on guidance. These principles (Best Practices for PBPK Modeling Applied to Health Risk Assessment) have been recently collected and expanded upon in guidance published by the WHO International Programme on Chemical Safety (2010), and have been the subject of several other peer-reviewed publications. The course comprises lectures describing the link between mode of action, dose-response characterization and risk assessment, and the role of PBPK models in reducing and characterizing uncertainty and variability. The course will present principles for the development, characterization, and communication and criteria for evaluation of PBPK models for risk assessment applications. A novel inclusion will be a projected demonstration of real-time changes in model outcome that depend on choice of model parameter values (e.g., breathing rate, metabolic activity). The demonstration of user-friendly model development software will be demonstrated in the final lecture. This will show the impact of choices for parameter values, and models will be exercised and the results interpreted to produce quantitative values to be used in place of uncertainty factors in health risk assessments.

Toxicokinetics in Risk Assessment, John C. Lipscomb, US EPA, ORD/NCEA, Cincinnati, OH

Developing a PBPK Model, Hugh Barton, Pfizer, Inc., Groton, CT

Characterizing a PBPK Model, Kannan Krishnan, University of Montreal, Montreal, Québec, Canada

Applying PBPK Models in Risk Assessment, George Loizou, Health and Safety Laboratory, Buxton, United Kingdom

Case Study 1, Bette Meek, University of Ottawa, Ottawa, Ontario, Canada

Case Study 2, Jos Bessems, RIVM, Bilthoven, Netherlands

Biodegradable Materials for Tissue Engineering: Applications and Safety Assessment

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Chairpersons: Ronald P. Brown, Center for Devices and Radiological Health (CDRH), US FDA, Silver Spring, MD, and Richard W. Hutchinson, Ethicon Inc., Johnson & Johnson, The Woodlands, TX

Sponsor: Medical Device Specialty Section

Endorsed by:
In Vitro and Alternative Methods Specialty Section

The incorporation of biodegradable materials as a fundamental component in tissue regeneration strategies began in the early 1980’s and continues today. The function of a biodegradable material is to act as a temporary support matrix for transplanted or host cells so as to restore, maintain, or improve tissue. In order for this function to be achieved, biodegradable materials must undergo a number of critical examinations to define their properties. For example, degradation rate, degradation products, and the tissue response to these products must all be characterized. In this presentation we will introduce a number of natural and synthetic biodegradable materials that are commonly considered in regenerative medicine, as well as some recently developed novel materials. The techniques utilized to describe their physical properties and the relationship between physical properties and tissue response will be examined, and advanced techniques for material characterization and toxicological effects will be considered. Finally, the application of these biodegradable materials in tissue engineering strategies will be described.

Biodegradable Materials for Tissue Engineering: Applications and Safety Assessment, John P. Fisher, University of Maryland, College Park, MD

Combination Products: Toxicology and Regulatory Challenges ♠

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

Sponsor(s):
Career Resource and Development Committee
Drug Discovery Toxicology Specialty Section
Medical Device Specialty Section

Therapeutic and diagnostic products that combine drugs, devices, and/or biological elements are termed and regulated by US Food and Drug Administration (US FDA) as combination products. Technological advances continue to merge product types and blur the historical lines of separation among traditional drugs, biologics, and medical devices. Concomitantly, 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 employing ever-evolving collaborative efforts to address the regulatory complexities 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. Trends and strategies for addressing the impact of overlapping technologies and evolving regulatory processes in developing a successful preclinical evaluation program will be highlighted. A regulatory overview of definitions and combination product examples, as well as a high-level review of US FDA’s final rule (effective July 22, 2013), will be included. A primary focus of the course is discussion of approaches in optimizing a preclinical program for a hypothetical drug-device combination product (e.g., a monoclonal antibody packaged in a prefilled syringe). Additionally, regulatory overview of the preclinical evaluation program will be provided. Future trends in combination product therapies will also be highlighted.

Overview of Combination Products. Thinh Nguyen, US FDA Office of Combination Products, Silver Spring, MD.

Overview of a Development Program for a Hypothetical Combination Product. Jon Cammack, AstraZeneca Biologics, Gaithersburg, MD.

Regulatory Overview of Preclinical Assessment of Combination Products. Chandramallika (Molly) Ghosh, US FDA, Silver Spring, MD.

Comparative Biology of the Lung †

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Chairperson(s): Richard Parent, Consultox Ltd., Damariscotta, ME, and Daniel Costa, US EPA, Research Triangle Park, NC

Sponsor: Inhalation and Respiratory Specialty Section

Endorsed by:
Immunotoxicology Specialty Section
Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

All mammals have evolved respiratory structures to ensure that the principal function of the lung, gas exchange, is met under varying physiological conditions. However, this essential function is achieved despite significant differences in the structural organization, cellular composition, and related functions mediated through the respiratory system and across mammalian species. Translational toxicology requires that one understand these innate differences in fundamental respiratory biology if one is to appropriately interpret and extrapolate findings in animal models. On a gross level, the nasal passages, pleural thickness, vascularity, and connective tissue structure vary between species. Quantitative evaluation of the tracheobronchial airway tree demonstrates few consistent features between species. The epithelial cell populations lining the lung differ in cell type, location, and abundance. The metabolic enzymes, cytokines, chemokines, protease, and anti-oxidant potential, although showing some similarities, also demonstrate vast differences. Similarly, basic immunological functions in laboratory animals must be understood and related to those in humans to enable appropriate species translation. We will illustrate many of these fundamental differences, describe methods for making measurements in different species, and most importantly, focus on the fundamentals of appropriate interpretation of study data derived in animals for human use. Attendees will gain a basic understanding of the value and pitfalls extending from these species differences, which will enable improved study design and extrapolation of research data for efficacy, safety pharmacology, and toxicology studies. This course is intended to provide attendees with a basic understanding of lung structure-function relationships and associated immunological and metabolic functions in laboratory animals that will aid in the extrapolation of inhalation or respiratory data to humans.

Introduction, Richard Parent, Consultox Ltd., Damariscotta, ME, and Daniel Costa, US EPA, Research Triangle Park, NC

Comparative Anatomy of Mammalian Respiratory Systems, Kent Pinkerton, University of California, Davis, CA

Interpretation and Limitations in the Assessment of Lung Function in Laboratory Mammals, Jeffrey Tepper, Tepper Nonclinical Consulting, San Carlos, CA

Metabolism and Enzymatic Balance in the Respiratory Tract, Laura Van Winkle, University of California, Davis, CA

Pulmonary Immune Functions Important for Translational Toxicology and Predictive of Risk in Humans, Gary R. Burleson, BRT—Burleson Research Technologies, Inc., Morrisville, NC

Computational and Experimental Aspects of microRNAs in Toxicology ♠

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Theme: Advancing Clinical and Translational Toxicology and Application of Biomarkers

Chairperson(s): Susan C. Tilton, Pacific Northwest National Laboratory, Richland, WA, and Tamara L. Tal, US EPA, Research Triangle Park, NC.

Sponsor(s):
Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section
Molecular Biology Specialty Section

MicroRNAs (miRNAs) are small noncoding RNAs that function as post-transcriptional regulators of gene expression. miRNAs are increasingly recognized for their importance in regulating mechanisms of disease and exposure, including those associated with nervous system development, cardiac function, metabolism and cancer. miRNAs and their transcriptional targets are highly conserved across species. They are also stable in plasma and urine as biomarkers of tissue-specific damage or response. Furthermore, miRNAs are unique in that not only can they be experimentally measured along with their inhibitory effects on transcript and protein levels, but their post-transcriptional regulation can also be computationally predicted based on sequence specificity and conservation across species. Given the overall importance of miRNAs in toxicology, it is necessary to understand both computational and experimental aspects of miRNAs for accurate miRNA quantification and discovery of the functional consequences of their disruption by chemical or drug exposure. The goal of the course is to provide toxicologists with a better understanding of miRNA biology (biogenesis, sequence, structure, function, and species similarities), the experimental and computational resources available for identification and target prediction and how these resources can be leveraged to identify mechanisms and biomarkers of toxicity.

Background on miRNA Biology and Relationship to Toxicology. Igor Pogribny, US FDA-NCTR, Jefferson, AR.

Experimental Methods for Measuring Circulating RNAs. Kai Wang, Institute for Systems Biology, Seattle, WA.

Computational Resources for miRNA Identification, Target Prediction, and Integration of Co-Expressed miRNAs and mRNAs. Susan C. Tilton, Pacific Northwest National Laboratory, Richland, WA.

Network and Pathway Analysis of miRNA Data. Richard J. Brennan, Sanofi, Waltham, MA.

Strategies for Developing miRNA Biomarkers of Toxicity. Karol L. Thompson, US FDA-CDER, Silver Spring, MD.

Concepts of Green Chemistry and Its Role in the Identification and Design of Safer Chemicals and Products †

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Chairpersons: Pamela J. Spencer, Dow Chemical Company, Midland, MI, and John Warner, Warner Babcock Institute for Green Chemistry, Wilmington, MA

Endorsed by:
Molecular Biology Specialty Section

Hazard identification, dose-response characterization, and exposure potential are the underpinning of product safety assessments. These basic principles help regulatory agencies, manufacturers, and formulators determine the conditions for safe use of chemicals, raw materials, and products for a given application to reduce adverse impacts to human health and the environment. Today, as a part of the growing interest in green chemistry, the pendulum is shifting. The large number of companies engaging in sustainability initiatives coupled with increased consumer demand for greener products is driving a new process where impacts of chemical products and processes are included as design criteria. Reducing intrinsic chemical hazards up front is a strategy used in developing safer alternatives to existing chemicals. Thus green chemistry is raising the bar for chemical safety assessments. Our panel of experts will begin with a background of green chemistry, its basic principles, why it is useful and highlight key certification programs/tools used to identify safer alternatives including their methods and criteria with specific emphasis on the Green Screen for Safer Chemicals alternatives assessment tool. There are unique opportunities for toxicologists to assist molecular designers in reducing the intrinsic hazards of their molecules by providing insight into toxicological mechanisms and data that support the application of green chemistry principles in the design of new chemicals and products. To underscore the importance of this issue, we will illustrate how principles of green chemistry are applied in a consumer products and a chemical company. The caveats and challenges will be addressed by using case studies. The exploration of this topical area will provide an understanding of green chemistry, awareness of the tools and programs immediately available and how to access and use them as well as an appreciation for some of the practical challenges associated with implementing principles of green chemistry into product development and assessments of safer alternatives.

Introduction. Pamela J. Spencer, Dow Chemical Company, Midland, MI

Introduction to the Concepts of Green Chemistry and Its Role in the Design of Safer Chemicals and Products. John Warner, Warner Babcock Institute for Green Chemistry, Wilmington, MA

Using Comparative Hazard Assessments: Green Screen for Safer Chemicals, Lauren Heine, Lauren Heine Group LLC, Juneau, AK

Strategies and Methods for Incorporating Green Chemistry into the Design of Chemicals and Products. Thomas G. Osimitz, Science Strategies, LLC, Charlottesville, VA

Application of the Principles of Green Chemistry in a Chemical Company: Overview and Case Studies. J. Craig Rowlands, Dow Chemical Company, Midland, MI

Application of the Principles of Green Chemistry in a Consumers Products Company: Overview and Case Studies. Donald Versteeg, Procter and Gamble Company, Cincinnati, OH

Current Nonclinical Strategies and Methods for Evaluating Drug-Induced Cardiovascular Toxicity †

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Chairpersons: Hong Wang, Genentech Inc., South San Francisco, CA, and Dennis J. Murphy, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA

Sponsor: Cardiovascular Toxicology Specialty Section

Endorsed by:
Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

Cardiovascular (CV) toxicity is among the major causes of withdrawal of drugs or restriction in their labeling and has had an impact on public health and the rising cost of developing new drugs. Early identification and characterization of CV liabilities, better understanding of the predictive values of nonclinical models, and an integrated and iterative approach during drug development could greatly facilitate the development of safe and effective medicines for patients. This course will describe the current in vitro and in vivo methods for evaluation of functional and structural CV liabilities, and discuss the strategies that can be applied at early stages of drug development to help reduce attrition and to avoid unanticipated liabilities at later development stages in either animal studies or in the clinic. Study design and data interpretation will be discussed, as well as the advantages, limitations, and future directions of current methods involving both functional and structural assessments. Specific topics such as integration of functional CV endpoints into repeat-dose toxicity studies, methods for identification and characterization of cardiac arrhythmia, and special considerations for testing oncology and diabetes drugs and biologics will be covered. In addition, case study examples will be provided to highlight how these data can be used to inform decisions at different stages of development. A regulatory perspective on the challenges and gaps of CV safety evaluations and opportunities available to improve the overall CV safety assessment paradigm will also be presented. Overall, this course will provide participants with a broad overview of the types of drug-induced CV liabilities, the current nonclinical strategies and methodologies for early detection of CV liabilities, and a regulatory perspective on the impact of CV toxicity on the drug-development process.

Opening Remarks and Overview of Cardiovascular Toxicity, Dennis J. Murphy, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA

Early Identification of Cardiovascular Functional Liabilities: Role of In Vitro Assays, Derek Leishman, Eli Lilly & Company, Indianapolis, IN

Integrated Assessment of Cardiovascular Functional Liabilities: In Vivo Animal Models, R. Dustan Sarazan, Data Sciences International, St. Paul, MN

Assessment of Cardiovascular Injury: Morphological Evaluations and Biomarkers, Brian Berridge, GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC

A Regulatory Perspective on Drug-Induced Cardiovascular Liabilities: Challenges, Gaps, and Opportunities, John Koerner, US FDA, Silver Spring, MD

Current Trends in Genetic Toxicology Testing

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Theme: Safety Assessment: Mechanisms and Novel Methods

Chairperson(s): B. Bhaskar Gollapudi, Exponent, Midland, MI, and Stephen Dertinger, Litron Laboratories, Rochester, NY.

Sponsor(s): Regulatory and Safety Evaluation Specialty Section

The scientific discipline of genetic toxicology has played an important role in the safety assessment of existing and new chemicals during the past four decades. This field has undergone significant changes during this time, not only in its regulatory applications, but also in the tools and technologies employed to identify adverse events. While the emphasis during the early years was on protecting germ cells and future generations from the deleterious effects of mutagenic agents, the focus shifted in later years towards identifying carcinogenic chemicals through the use of short-term assays. Furthermore, genetic toxicology tended to operate as a standalone discipline, generating qualitative data and placing little importance on dose-response analysis or integration with other toxicology measurements. The field is now in the midst of a sea change. Regulatory requirements across the globe are being harmonized, with emphasis on “3 Rs.” For example, recent changes to ICH and OECD testing guidelines promote the integration of genetic toxicology endpoints (e.g., Comet, micronucleus, and gene mutation) into repeat-dose general toxicology studies. This integrated approach benefits the interpretation of genotoxic findings by placing them in context with other toxicology data, including pharmacokinetics and pharmacodynamics. Additionally, regulatory initiatives such as REACH stress the importance of germ cell effects as part of a comprehensive assessment of genotoxicity. Guidelines for the study of mutations in germ cells of transgenic animals (OECD 488) have recently been finalized. Rapid advances in molecular biology are facilitating the integration of genomic biomarkers into standard toxicology studies to identify various classes of genotoxic agents (DNA reactive and DNA nonreactive). Finally, genetic toxicology is moving from a qualitative science to the quantitative assessment of dose-responses including the identification of point-of-departure (PoD) metrics to extrapolate effects to realistic human exposure levels. The course is designed to provide a comprehensive overview of recent changes and newly established practices in the field with emphasis on their application in safety assessments.

Introduction. B. Bhaskar Gollapudi, Exponent, Midland, MI.

Integration of Genetic Toxicology Endpoints Into Repeat Dose Studies. Stephen Dertinger, Litron Laboratories, Rochester, NY.

Resurgence of Transgenic Animals in Genotoxicity Testing. Robert H. Heflich, US FDA-NCTR, Jefferson, AR.

Approaches to Genetic Toxicology Testing in the Era of Genomics. Matthew J. LeBaron, The Dow Chemical Company, Midland, MI.

Quantitative Assessment of Dose-Response in Genetic Toxicology Studies. B. Bhaskar Gollapudi, Exponent, Midland, MI.

Cutaneous Toxicity: In Vitro Methods for Toxicity and Safety Evaluation

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Chairpersons: William G. Reifenrath, Stratacor Inc., Richmond, CA, and Cynthia A. Ryan, Procter & Gamble Company, Cincinnati, OH

Sponsor: Dermal Toxicology Specialty Section

Endorsed by:
In Vitro and Alternative Methods Specialty Section

Skin is the largest external organ and serves as a living, dynamic protective envelope surrounding the body. As such, it is constantly exposed to environmental hazards, including hazardous compounds; these exposures account for a major portion of all reported industrial illnesses. Skin exposures may also occur from pharmaceuticals or consumer products that are intentionally applied. In vitro methods are important as a first step to estimate skin permeation, and the potential of skin irritation and sensitization for compounds or mixtures of compounds that are directly toxic to the skin or systemically toxic. In exploration of these issues we will provide an overview of the current status of in vitro models for cutaneous toxicity safety evaluations and the regulatory requirements for establishing the nonclinical safety of dermal drug products. This important topic has relevance to toxicologists involved in safety evaluations and risk assessments for chemicals that contact the skin.

Use of the Excised Human Skin Model for Percutaneous Risk Assessment. Thomas J. Franz, Cetero Research, Fargo, ND

Direct Comparison of In Vitro and In Vivo Dermal Absorption of Several Chemicals. Jeffrey J. Yourick, US FDA, Laurel, MD

Specialized Procedures for Lipophilic and Semi-Volatile Compounds and Their Influence on Comparative In Vitro—In Vivo Skin Absorption. William G. Reifenrath, Stratacor, Inc., Richmond, CA

Skin Sensitization: Underlying Mechanisms, Hazard Identification, and a Quantitative Risk Assessment Approach. Cynthia A. Ryan, Procter & Gamble Company, Cincinnati, OH

Skin Irritation: In Vitro Models. John W. Harbell, Mary Kay Inc., Dallas, TX

US Regulatory Requirements for Establishing the Nonclinical Safety of Dermal Drug Products. Marian W. Glynn, Dow Pharmaceutical Sciences, Petaluma, CA

Dealing with the Data Deluge: A Live Data Discovery and Analysis Course

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Chairpersons: Marc E. Gillespie, Saint Johns University, Jamaica, NY, and Susan M. Bello, Jackson Laboratory, Bar Harbor, ME

Sponsor: Molecular Biology Specialty Section

Endorsed by: N/A

Using Web based resources and tools to gain novel scientific insights and advance your research is a significant step for all researchers. As the pace of science accelerates, experimental technologies continue to evolve and the quantity of data increases. With the evolution in biological research comes an increasing reliance on database resources and computational analysis tools to parse and integrate this growing mass of biological data. The field of toxicology is not exempt from these challenges. In this course, representatives from a diverse group of data resources have joined their efforts to present a unique series of hands-on tutorials. The tutorials follow a hypothetical researcher through the various stages of experimental design and data analysis, demonstrating how the different workshop resources can be used to facilitate all steps of the research process. Participants will identify orthologous biological information across different species; identify biological trends (pathway, function, phenotype, xenobiotic interactions) within a submitted data set; investigate an individual data set with online resources, identifying supplementary information available across multiple data sets; and gain hands on experience with formatting and submitting data to a diverse set of online data resources.

Today toxicologists must select appropriate model organisms, manage abundant high-throughput data, understand legacy data, and develop pathway-based understanding of environmental factors influencing biological systems. Mastery of these concepts improves toxicity prediction while providing insights into environmentally influenced diseases and phenotypes. A clear understanding of the diverse online data resource aims and limitations equips the researcher with the best combination of resources to effectively address their questions.

NOTE:  This was a unique “hands on” interactive course presented at the 2011 Annual Meeting. AM04 course attendees brought their own laptop computers as well as their own Internet network connection. The interactive nature of this course may be lost for those viewing the course online

Reactome Knowledgebase, Marc E. Gillespie, Saint Johns University, Jamaica, NY

Comparative Toxicogenomics Database (CTD), Carolyn J. Mattingly, Mount Desert Island Biological Laboratory, Salisbury Cove, ME

PharmGKB, Teri E. Klein and Li Gong, Stanford University Medical Center, Stanford, CA

Mouse Genome Informatics Database, Susan M. Bello, Jackson Laboratory, Bar Harbor, ME

Drug Hypersensitivity Reactions: Risk Assessment and Management

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Chairpersons: Marija Popovic, Eli Lilly & Company, Indianapolis, IN, and Jessica Whritenour, Pfizer Global Research and Development, Groton, CT

Sponsor: Immunotoxicology Specialty Section

Endorsed by: N/A

Drug hypersensitivity reactions are not a common problem in drug development; however, when they do occur they can have a significant impact on the drug candidate’s developmental success. Drug hypersensitivity reactions are usually discovered in Phase II or III clinical trials, or in the post-marketing phase. Once allergic reactions are observed in patients, one needs to determine if the reaction is mediated by an immune response to the drug, or another mechanism. There are a few ex vivo diagnostic methods that can be used to identify immune-mediated reactions, but one needs to be aware of the limitations and advantages of each approach. In vitro methods, or animal models presently being developed to predict drug’s potential to trigger hypersensitivity reaction in the patient population are being developed, but at present, they have significant limitations. Risk management strategies may include selection of patient populations based on the HLA haplotype. This course is intended as an introduction for those with limited background in the area of hypersensitivity, or allergic reaction to drugs. The focus of the course will be on systemic hypersensitivity reactions (drug administered orally or parenterally) and will include discussions both on drugs that are small molecules and biologics.

Clinical Overview: Description of the Types of Drug Hypersensitivity Reactions, Franklin Adkinson, Johns Hopkins University, Baltimore, MD

Mechanisms of Drug Hypersensitivity Reactions: Types I-IV Mechanisms, Hapten, PI, and Danger Hypotheses, Cynthia Ju, University of Colorado Denver, Aurora, CO

Pseudoallergic and Anaphylactoid Drug Hypersensitivity Reactions, Jessica Whritenour, Pfizer Global Research and Development, Groton, CT

Predictive Testing: Different Animal Models and Future Possibilities, Marija Popovic, Eli Lilly & Company, Indianapolis, IN

Epidemiology for Toxicologists: What the Numbers Really Mean ♠

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Theme: New Science and Perspectives Surrounding Environmental and Occupational Exposures

Chairperson(s): Nancy B. Beck, American Chemistry Council, Washington, DC, and Julie E. Goodman, Harvard School of Public Health and Gradient, Cambridge, MA.

Sponsor(s):
Occupational and Public Health Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

Twenty-first Century risk assessment relies on data from multiple lines of evidence. High quality human epidemiology data are generally preferred for regulatory decision-making, but the body of evidence often includes animal toxicity, in vitro, in silico, animal dosimetry, and human exposure data. The quality of individual epidemiology studies can be highly variable and dependent on study design as well as other critical factors that sometimes cannot be controlled for. For risk assessors to fully understand the implications of epidemiology evidence, they must understand how the overall integration of toxicity and mechanistic data with human epidemiology findings facilitates science-informed decision-making. A sufficient understanding of the epidemiology data is a necessary starting point for appropriately integrating all the available information. The course is geared towards the toxicologist who is trying to determine how to appropriately evaluate, use, and integrate epidemiology data in a weight-of-evidence evaluation or risk assessment. Attendees first will be given a basic overview of epidemiology, with a focus on different epidemiology study designs and their strengths and weaknesses. Attendees will also gain an understanding of exposure assessment and biomonitoring, and how this information is used and evaluated in epidemiology studies. Additional learning objectives of the course: How to determine when an association may be supportive of a causal relationship and what confidence intervals mean; how to use trend information; how to evaluate and understand adjustments that are made for potential confounding factors; and how to evaluate several epidemiology studies on the same topic, particularly in light of available toxicity and mechanistic data. Finally, attendees will learn to integrate all types of data streams with a real example. Attendees will leave the course with a stronger understanding of how to interpret and use epidemiology data in their weight-of-evidence analyses and risk assessments, and how epidemiology can help inform regulatory decision-making.

Setting the Stage. Nancy B. Beck, American Chemistry Council, Washington, DC.

Overview of Epidemiologic Studies. Michael Goodman, Emory University, Atlanta, GA.

Exposure Assessment and Biomonitoring in Epidemiologic Studies. Sorina Eftim, George Washington University School of Public Health and Health Services and ICF International, Fairfax, VA.

When an Association Indicates Causation. Julie E. Goodman, Harvard School of Public Health and Gradient, Cambridge, MA.

A Case Study Showing How Toxicology Complements Epidemiology for Informing Human Risk. James S. Bus, Exponent, Midland, MI.

Epigenetics in Toxicology: Introduction, Mechanistic Understanding, and Applications in Safety Assessment †

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Chairpersons: Mayurranjan S. Mitra, Washington University School of Medicine, St. Louis, MO, and Thomas Sussan, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD

Sponsor: Molecular Biology Specialty Section

Endorsed by:
Carcinogenesis Specialty Section
Cardiovascular Toxicology Specialty Section
Mechanisms Specialty Section

Epigenetics refers to molecular mechanisms that cause heritable changes in gene expression without altering the DNA sequence. The most widely studied epigenetic mechanisms encompass DNA methylation, histone modifications, and gene regulation by non-coding RNAs, such as microRNAs. Typically, these mechanisms are required for normal cellular development and differentiation; however, perturbations in them can lead to diseases, notably cancer. Increasing evidence suggest that environmental factors such as diet, stress, and exposure to radiation and xenobiotics can induce heritable changes in the epigenetic status, potentially affecting the health of the present and future generations. Importantly, the long-term and life-threatening consequences of environment/chemical-induced changes in epigenetics, makes this field a critical area for future exploration by toxicologists. The course will begin by introducing the fundamental concepts of epigenetics and reviewing the various underlying mechanisms. Methods to assess epigenetic changes will be discussed, followed by a discussion of the role of DNA cytosine methylation in the regulation of carcinogen-inducible CYP450 genes. Mechanistic understanding of the role of microRNAs in the regulation of cellular toxicity and the influence of environment on epigenetics that cause developmental effects will also be presented. Finally, the future of epigenetics in toxicology and its potential applications for safety assessment will be discussed. Students as well as toxicologists working in academia, federal and pharmaceutical industries, and researchers interested in mechanistic toxicology will benefit from taking this course.

Introduction, Mayurranjan S. Mitra, Washington University School of Medicine, St. Louis, MO

Introduction and Overview of Epigenetics, James G. Herman, The Johns Hopkins School of Medicine, Baltimore, MD

Role of Epigenetics in the Regulation of Carcinogen-Metabolizing Enzymes, Oliver Hankinson, University of California Los Angeles, Los Angeles, CA

Retroelements and MicroRNAs in the Epigenetic Regulation of Cellular Differentiation, Proliferation, and Toxicity, Kenneth S. Ramos, University of Louisville, Louisville, KY

Epigenetic Gene Regulation: Linking Early Developmental Environment to Adult Disease, Dana Dolinoy, University of Michigan, Ann Arbor, MI

What We Need to Know Prior to Incorporating an Epigenetic Evaluation into Safety Assessments, Jay I. Goodman, Michigan State University, East Lansing, MI
Evaluating Toxicity of Engineered Nanomaterials: Issues with Conventional Toxicology Approaches

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Chairpersons: Srikanth S. Nadadur, NIEHS-DERT, Research Triangle Park, NC, and Frank A. Witzmann, Indiana University School of Medicine, Indianapolis, IN

Sponsor: Nanotoxicology Specialty Section

Endorsed by:
Cardiovascular Toxicology Specialty Section
In Vitro and Alternative Methods Specialty Section
Inhalation and Respiratory Specialty Section

Engineered nanomaterials (ENMs) have become an integral part of numerous consumer products, cosmetics, building materials, medical devices, therapeutic agents, and environmental remediation. Global demand for nanomaterials and nano-enabled devices has been projected to surpass $3.1 trillion by 2015. The widespread use of nanotechnology-derived products presents opportunities for intentional and unintentional exposure to ENMs. The size and size-dependent novel physical and chemical properties that make ENMs unique compared to micro-scale products of similar chemical composition makes it difficult to determine their interaction with biological matrices. The recent flood of toxicology literature without proper physical and chemical characterization of ENMs proposes adverse to no health effects for certain common ENMs such as carbon nanotubes and metal oxide nanoparticles. The course will provide an overview of the issues facing nanotechnology that the scientific community must grapple with in regard to predicting toxicity and biological outcomes associated with nanoscale properties and the need to identify and integrate novel approaches for safety of ENMs. To begin, focus will be placed on the importance of incorporating physical and chemical characteristics of ENMs in interpreting biological data; high throughput in vitro approaches using multiple parameters to classify ENMs toxicity profile will then be covered. Altered proteomic profiles in a model in vitro system to understand molecular alterations will be explored. Finally, the interpretation of data from in vivo studies using inhalational routes of exposure will be discussed. The goal of this course is to encourage both the novice and the toxicologist trained in conventional toxicity assessment to think outside the box to design rational toxicology studies in evaluating the safety of ENMs that are currently in use, and to develop models to predict potential toxicity of second and third generation ENMs.

Engineered Nanomaterials (ENMs) Toxicity Evaluation: Issues with Conventional Approaches, Srikanth S. Nadadur, NIEHS-DERT, Research Triangle Park, NC

Importance of Integrating Physicochemical Characterization Information in Toxicity Assessment of Engineered Nanomaterials, Scott McNeil, National Cancer Institute, Bethesda, MD

Emergence of High Content Screening for Assessment of Nanotoxicity,Chris Vulpe, University of California Berkeley, Berkeley, CA

Proteomic Profiling of the Biological Effects of Engineered Nanomaterial Exposure Using In Vitro Models, Frank A. Witzmann, Indiana University School of Medicine, Indianapolis, IN

Correlating In Vitro and In Vivo Nanotoxicity: Limitations and Challenges, Günter Oberdörster, University of Rochester Medical Center, Rochester, NY

Inhalation Studies: Challenges and Complexities ♠

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Theme: New Science and Perspectives Surrounding Environmental and Occupational Exposures

Chairperson(s): Gregory L. Baker, Battelle, West Jefferson, OH, and Willie J. McKinney, Altria Client Services, Richmond, VA.

Sponsor(s): Inhalation and Respiratory Specialty Section

The successful execution of animal inhalation studies (e.g., acute, subchronic, and chronic) present many challenges and complexities not encountered with other routes of exposure. Five inhalation study challenges will be addressed: 1) Comparison of methods of exposure and potential impact on inhalation studies; 2) Using various test materials, generating simple atmospheres (e.g., exposures to gases, nanoaerosols, bioaerosols, micron-sized aerosols) and mixtures (e.g., semivolatile compounds and particles, tobacco smoke); 3) selection of the appropriate animal species (e.g., species specific dosimetry); 4) incorporating standard and novel toxicological endpoints; 5) deciding which regulatory guidance document or specifications (e.g., US EPA, US FDA, OECD, and NTP) to follow. The diversity of presenters’ backgrounds (government, contract research organization, industry, and academic), and depth of experience, will provide a broad and rich resource for the participants.

Introduction. Willie J. McKinney, Altria Client Services, Richmond, VA.

Comparison of Whole Body vs. Nose-Only Exposure. Robert F. Phalen, University of California Irvine, Irvine, CA.

Test Materials for Inhalation Studies. Gregory L. Baker, Battelle, West Jefferson, OH.

Inhalation Studies—Test Subjects and Dose Predictions. Michael J. Oldham, Altria Client Services, Inc., Richmond, VA.

Toxicological Endpoints in Inhalation Studies. Jack R. Harkema, Michigan State University, East Lansing, MI.

Regulatory Guidance for Inhalation Studies. Mark A. Higuchi, US EPA, Research Triangle Park, NC.

Methodologies in Human Health Risk Assessment ♠

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Theme: Enhancing Strategies for Risk Assessment

Chairperson(s): Qiyu (Jay) Zhao, US EPA, Cincinnati, OH, and M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Sponsor(s):
Biological Modeling Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

This course provides an overview of more advanced aspects of chemical risk assessment, following up from a successful CE course on basic principles offered at the Annual Meeting in 2013. This new course will focus on methodologies, which incorporate increased use of biological and chemical specific data as a basis to provide more accurate estimates of risk. In addition, it will address evolving areas such as problem formulation as a basis to better target toxicity testing and tailor assessments to the needs of risk management. The course will feature presentations and discussions focusing on the value of mode of action analysis for characterization of hazard, the fundamental tenets of physiologically based pharmacokinetic (PBPK) model development and implementation, use of benchmark dose (BMD) models to identify points of departure, and use of chemical specific adjustment factors to address inter- and intraspecies uncertainty and variability. The principles and key components of these methodologies will be illustrated with applied case examples from the regulatory risk assessment arena.

An Overview of Advanced Aspects of Risk Assessment. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Mode of Action Analysis. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Benchmark Dose Modeling. Qiyu (Jay) Zhao, US EPA, Cincinnati, OH.

Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling. Hugh A. Barton, Pfizer, Inc., Groton, CT.

Nondefault Uncertainty Factor Values. John C. Lipscomb, US EPA, Cincinnati, OH.

Mitochondrial Toxicity: Animal Models and Screening Methods in Drug Development †

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Chairperson(s): Yvonne Will, Pfizer Global Research and Development, Groton, CT, and Carlos Palmeira, University of Coimbra, Coimbra, Portugal

Sponsor: Drug Discovery Toxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

Mitochondria produce almost all the energy in cells, but also chronically expose the cell to cytotoxic free radicals. Mitochondrial disease and toxicity is a rapidly advancing field and the consequences of mitochondrial impairment should be appreciated by scientists in all disciplines. It is estimated that more than 75 diseases and metabolic disorders are attributable, at least in part, to mitochondrial dysfunction. Mitochondrial dysfunction can lead to many different pathologies of the liver, heart, muscle, kidney, and CNS through diverse mechanisms. Numerous widely prescribed therapeutics can undermine mitochondrial function by interfering with DNA replication or expression, and more acutely, by uncoupling or inhibiting oxidative phosphorylation, leading to organ dysfunction and damage. In addition, numerous environmental agents can contribute to diseases and toxicity through modifications of mitochondrial function, leading for example to Parkinson’s Disease and Autism. This course will review fundamental concepts of mitochondrial biology and the many different mechanisms by which xenobiotics interfere with mitochondrial function. Both common and novel in vitro screening approaches will be described, as well as in vivo animal models used to study mitochondrial-mediated toxicities and pathologies, with an emphasis on both their utility and limitations. The course will also introduce Structure-Activity Relationship and systems biology approaches to reveal common factors and novel mechanisms of mitochondrial toxicity. Upon completion of this course, participants will have a deeper understanding of how xenobiotics can alter the basic biochemistry and physiology of mitochondria, how minute changes in mitochondrial processes translate into complex toxicities, organ pathologies, and diseases, as well as a basic understanding of how to study mitochondria and mitochondrial dysfunction.

Mitochondrial Function and Dysfunction in Disease and Drug-Induced Toxicity, James Dykens, Pfizer Global Research and Development, Sandwich, United Kingdom

Animal Models of Mitochondria-Mediated Drug Toxicity, Urs A. Boelsterli, University of Connecticut School of Pharmacy, Storrs, CT

In Vitro Approaches to Assess Mitochondria-Mediated Drug Toxicity and Possible Biomarker Development: Advantages and Limitations, Yvonne Will, Pfizer Global Research and Development, Groton, CT

Integrated Mitochondrial and Nuclear Genomic Regulation of Oxidative Phosphorylation in the Study of Mitochondrial Toxicity and Function, Toshimori Kitami, Broad Institute of MIT and Harvard University, Cambridge, MA

New Technologies and Approaches in Genetic Toxicology and Their Expanding Role in General Toxicology and Safety Assessment †

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Chairpersons: Jeffrey C. Bemis, Litron Laboratories, Rochester, NY, and Jennifer C. Sasaki, Johnson & Johnson, Raritan, NJ

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
In Vitro and Alternative Methods Specialty Section

For decades, genetic toxicology and the “genetox battery” have been a well-established part of safety testing for pharmaceuticals and other chemical agents. Recent advances in experimental methodologies are contributing to a change in the way that genetic toxicology data are generated and incorporated in the disciplines of toxicology and safety testing. The intention of this course is to illustrate the broader impact that new genetic toxicology approaches are having on drug/chemicals safety assessment and human risk analysis. The structure of the course will provide examples of (1) Early discovery/high-throughput genotoxicity screening of chemical entities; (2) Integration of genetic toxicology assays with repeat-dose in vivo toxicology studies; and (3) New approaches for genotoxicity risk assessment, and conclude with an update on genotoxic impurity management strategies for pharmaceuticals. Speaker presentations will illustrate how genotoxicity testing is evolving from a hazard identification based-discipline to an integrated approach that may ultimately yield quantitative information that can be used for human risk assessment.

This course should be of interest to experienced genetic toxicologists as well as those involved in general toxicology who want to learn about how incorporation of new genotoxicity methods can improve test predictivity, lower costs, reduce animal use, and may ultimately be applied to human risk assessment

Introduction, Jeffrey C. Bemis, Litron Laboratories, Rochester, NY

High-Throughput Genetic Toxicity Screening Assays in Discovery Research & Development, Richard Walmsley, Gentronix, Ltd., and The University of Manchester, United Kingdom

The In Vitro Micronucleus Assay in Mammalian Cells: A High Content Assay, Anthony M. Lynch, GlaxoSmithKline, Hertfordshire, United Kingdom

Genetic Toxicity and Thresholds: State of the Science, B. Bhaskar Gollapudi, The Dow Chemical Company, Midland, MI

Integration of Genetic Toxicology Endpoints into Repeat-Dose Toxicity Studies, Maik Schuler, Pfizer PGRD, Groton, CT

Risk Assessment of Genotoxic Impurities in Pharmaceuticals, Lutz Mueller, Hoffmann La Roche, Inc., Basel, Switzerland

Nonclinical Animal Models Enabling Biopharmaceutical Advances in Translational Medicine ♠

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Theme: Advancing Clinical and Translational Toxicology and Application of Biomarkers

Chairperson(s): Thomas M. Monticello, Amgen Inc., Thousand Oaks, CA, and Vivek Kadambi, Millennium, Cambridge, MA.

Sponsor(s):
Clinical and Translational Toxicology Specialty Section
Comparative and Veterinary Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

A fundamental theme in drug discovery and nonclinical development is the utilization of appropriate animal models that are predictive for efficacy or adverse events in humans administered a novel biopharmaceutical. The accurate prediction of human adverse effects using nonclinical animal toxicology studies remains a major goal in drug development and relies on appropriate animal models. Essential attributes for an appropriate animal model include similar target distribution, target pharmacology, systemic pharmacokinetics, metabolism, and distribution to those of humans. Utilization of the most appropriate animal model aligns with the 2011 US FDA Strategic Plan to advance regulatory science and modernize toxicology in order to enhance product safety and develop better models of human adverse responses. The Preclinical Safety Leadership Group (PSLG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is creating a contemporary industry-wide database to determine accuracy with which the interpretation of nonclinical safety assessments in animal models correctly predicts human risk. The course will present considerations for the selection of an appropriate animal model for nonclinical safety, the use of animal models of disease in safety testing, emerging use of the minipig in safety testing, data from an industry-wide nonclinical to clinical translational database, and the use of animal safety data in the design and conduct of clinical trials. Output from the course will help identify advances and remaining gaps in the utilization of animal models in biopharmaceutical development.

Introduction. Thomas M. Monticello, Amgen Inc., Thousand Oaks, CA.

What Constitutes a Relative Animal Model in Translational Medicine? Rakesh Dixit, MedImmune Inc., Gaithersburg, MD.

Use of Animal Models of Human Disease for Nonclinical Safety Assessment of Pharmaceuticals. Sherry J. Morgan, Abbvie, North Chicago, IL.

The Minipig As a Nonrodent Species in Nonclinical Safety Testing and Where Are We Now? Niels-Christian Ganerup, Ellegaard Göttingen Minipigs A/S, Dalmose, Denmark.

Nonclinical to Clinical Translational Safety Database Initiative. Vivek Kadambi, Millennium, Cambridge, MA.

Utilization of Nonclinical Animal Data in the Conduct of Human Clinical Trials. John T. Sullivan, Amgen Inc., Thousand Oaks, CA.

Nonclinical Pediatric Drug Development: Considerations, Study Designs, and Strategies ♠

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Theme: Safety Assessment: Mechanisms and Novel Methods

Chairperson(s): Kary E. Thompson, Bristol-Myers Squibb Company, New Brunswick, NJ, and Elise M. Lewis, Charles River Laboratories, Horsham, PA.

Sponsor(s): Reproductive and Developmental Toxicology Specialty Section

Although nonclinical and clinical testing needs for drugs for pediatric populations have been discussed for more than 40 years, there is no default approach to evaluating safety in this age group. Over the last decade there has been a heightened awareness of the differences between the pediatric and adult patient, and these differences are being addressed by the pharmaceutical and healthcare industries, as well as the governmental and regulatory bodies that sanction the development and testing of drugs for children. As regulatory demands evolve for nonclinical safety assessments in juvenile animals, industry leaders are developing innovative ways to meet the regulatory expectations and to overcome the challenges associated with pediatric drug development. Many practical issues regarding nonclinical testing in immature animals have been surmounted, using novel and/or adapted approaches. There are considerations related to the differences in regional guidelines (US FDA, EU, and Japan), therefore development of appropriate information for submission to worldwide agencies is critical. History and experience provide the best scientific arguments as to why juvenile animals can be useful. There are numerous examples of drugs that have identified findings in various species, including information regarding kinetic and toxicity differences that highlight considerations regarding nonclinical testing models. Additionally, there are unique challenges associated with nonclinical juvenile toxicity testing for biopharmaceuticals, including selection of appropriate animal models, immunogenicity, dose selection (toxicity vs. pharmacology), and relevant endpoints. Developing a juvenile animal program requires an appreciation of the complexity of the nonclinical strategies to enable pediatric trials and an overview of the historical perspective and the current approaches to evaluating safety during this unique period of life.

Introduction. Elise M. Lewis, Charles River Laboratories, Horsham, PA.

US FDA Regulatory Perspective on Pediatric Product Development. Karen Davis-Bruno, US FDA, Silver Spring, MD.

EU Pediatric Regulation (EC) No 1901/2006: Impact on Nonclinical Development Plans. Jacqueline Carleer, Belgian Federal Agency for Medicines and Health Products, Brussels, Belgium.

Nonclinical Strategies to Support Pediatric Trials. Kary E. Thompson, Bristol-Myers Squibb Company, New Brunswick NJ.

Juvenile Toxicity Studies: What Can We Do? Susan B. Laffan, GlaxoSmithKline, King of Prussia, PA.

Biologics Juvenile Toxicity Testing: Exploring Options to Address the Challenges. Gary J. Chellman, Charles River Laboratories, Reno, NV.

Overview and Application of the WHO-IPCS Harmonized Guidance for Immunotoxicity Risk Assessment for Chemicals †

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Chairpersons: Andrew A. Rooney, NIEHS, Research Triangle Park, NC, and Henk Van Loveren, National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands

Sponsor: Immunotoxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

The WHO/IPCS harmonized guidance document is the first compressive guidance document for risk assessment in toxicology. Immunotoxicity risk assessment of chemicals is an evaluation of the potential for unintended effects of chemical exposure on the immune system. These effects manifest as four principal types of immunotoxicity which are categorized as immuno—suppression and stimulation, autoimmunity, and sensitization. We will provide an overview of the methods used to detect and characterize immunotoxicity and the potential consequences of unintended immunomodulation. It is well established that xenobiotic-related immunosuppression can lead to reduced resistance to infections and certain neoplastic diseases. Exposure to xenobiotics has been shown to be associated with development or worsening of autoimmune disease. It has been established that xenobiotics can elicit hypersensitivity responses directly as an allergen, or they can enhance the induction or severity of allergic sensitization to pollen or dust mites. The determination of risk associated with immunostimulation may be more difficult, but unexpected stimulation should not be disregarded as it may result in nonspecific inflammation or the skewing of normally protective immune responses to favor induction or exacerbation of autoimmunity and hypersensitivity. The fundamental concepts of risk assessment as they apply to the evaluation of immunotoxicity as well as the application of the guidance will be highlighted. We will begin by reviewing case studies which include data that focuses on different areas of immunotoxicity—suppression, sensitization, and autoimmunity. The studies will demonstrate application of the guidance, particularly the development of weight of evidence conclusions from the available data. Finally, we will illustrate that risk assessment for a given chemical should consider the full range of immune effects for that chemical, and data should be evaluated separately for evidence of suppression, stimulation, autoimmunity, and sensitization.

Overview of the WHO/IPCS Harmonized Guidance for Immunotoxicity Risk Assessment for Chemicals. Henk Van Loveren, National Institute of Public Health (RIVM), Bilthoven, Netherlands

Immunotoxicity Risk Assessment. Andrew A. Rooney, NIEHS, Research Triangle Park, NC

Assessment of Immunosuppression, Immunostimulation, and Autoimmunity. Robert W. Luebke, US EPA, Research Triangle Park, NC

Assessment of Sensitization and Allergic Response. Peter Griem, Symrise AG, Holzminden, Germany

Case Study 1: Lead. Michael I. Luster, West Virginia University School of Medicine, Morgantown, WV

Case Study 2: Halogenated Platinum Salts. Peter Griem, Symrise AG, Holzminden, Germany

Case Study 3: Mercury. Andrew A. Rooney, NIEHS, Research Triangle Park, NC

Practical How-To and Pitfalls Associated with Current Epigenetic Studies (Advanced)

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Chairpersons: Reza John Rasoulpour, The Dow Chemical Company, Midland, MI, and Chunhua Qin, Merck & Co., Inc., West Point, PA

Sponsor: Molecular Biology Specialty Section

Endorsed by:

The study of toxicant-induced epigenetic modifications is greatly expanding in complexity and scope as new tools of measuring these changes become available. Fundamental questions (e.g., how best to quantify changes) become enigmatic with DNA methylation, histone modifications, and microRNA epigenetic modifications that can affect imprinted, coding, non-coding, and global regions of the genome. Understanding these questions is important in interpreting species/strain-specific responses. This advanced course is a practical guide to techniques used in epigenetic research with respect to toxicology for in vivo/ex vivo screening of rodent models, post-fertilization, embryos, developmental biology, and human disease states. Topics range from advancements in techniques to screening strategies and tools, and include techniques to correlate epigenetic changes to gene expression and apical end points, use of imprinted genes as biomarkers, and profiling DNA methylation in human population-based research. For screening tools to determine species-specific responses, a variety of novel technologies will be analyzed such as epigenomic profiling of DNA methylation in mouse tumors, pyrosequencing to examine the activity of endogenous retroviruses (e.g., IAP), and assays to explore miRNA and histone modification changes. In addition, cutting edge techniques such as deep sequencing technologies of bisulfite-converted DNA will be discussed as these have enabled the characterization of methylation changes at the genome level; however, the significant challenge in using this technology is dealing with the massive amount of information obtained and making sense of the observed methylation changes. Scientists in academia, industry, and government will leave this course with an understanding of the strengths and weaknesses of available epigenetic tools, how these tools can be best used in screening and mode-of-action experiments, as well as insight into future potential of mechanistic epigenetic toxicology.

Screening Tools and Approaches for Methylation Analysis of Imprinted Genes, Reza John Rasoulpour, The Dow Chemical Company, Midland, MI

Profiling Epigenetic Changes in Rodent Tumor Models, Chunhua Qin, Merck & Co., Inc., West Point, PA

Evaluating Epigenetic Changes in Germ Cells and Early Embryos, Barbara F. Hales, McGill University, Montreal, Québec

Evaluating Epigenetic Changes Using Bisulfite Deep Sequencing, Russell S. Thomas, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

Population-Based DNA Methylation Profiling in Exposure-Related Disease, Carmen Marsit, Brown University, Providence, RI

Protecting Human Health: Use of Toxicological and Epidemiological Data in Determining Safe Levels for Human Exposure †

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Chairpersons: Eileen P. Hayes, EP Hayes Toxicology Services LLC, Longmont, CO and Terry Gordon, New York University School of Medicine, Tuxedo Park, NY

Sponsor: Occupational and Public Health Specialty Section

Endorsed by: N/A

Toxicological and epidemiological data are the basis for risk assessment processes used to determine acceptable levels of exposure. This is the case for the general public who may be exposed to pollutants via ambient air and/or drinking water, for workers who may be exposed to chemicals in the workplace, and for patients who may have exposure to both active pharmaceutical ingredients (API) and impurities that may be present in the product. The goal of this course is to provide students with an understanding of the regulatory background and the practical application of both toxicological and epidemiological information in setting exposure levels considered to be protective of public health. The objectives of this course are 1) to describe the regulatory requirements that underlie development of acceptable levels of exposure for either the general population or select populations (workers, patients) via the media described above; and 2) to describe the evaluation of toxicological and epidemiological data in determining acceptable levels of exposure. Case studies of representative compounds will illustrate the processes. The US Environmental Protection Agency (US EPA) has well-defined processes for establishing both National Ambient Air Quality Standards (NAAQS) under the Clean Air Act and drinking water Maximum Contaminant Levels (MCLs) under the Safe Drinking Water Act. The Occupational Health and Safety Administration (OSHA) promulgates permissible exposure limits (PELs) for the workplace. The American Conference of Government Industrial Hygienists (ACGIH), a non-profit, non-governmental organization publishes Threshold Limit Values (TLVs) that are used globally by many public and private-sector employers to protect the health of their employees. Additionally, many employers have established programs to derive acceptable levels of workplace exposure for compounds not specifically regulated by government agencies. Acceptable identification, reporting, and safety thresholds for impurities in drug products are governed under guidance documents issued by the International Committee on Harmonization (ICH), the US Food and Drug Administration and the European Medicines Agency. The course will highlight legal and customary definitions of “acceptable risk,” as well as risk assessment methods for evaluating data to estimate risk levels under these programs. The regulations and/or guidances will be detailed and approaches used to comply with them will be described. This course will begin with a description methods underlying US EPA actions to protect the general public, i.e., establishment of NAAQS and MCLs. The course will then detail requirements, guidance, and processes to protect specific populations, i.e., workers and patients. In each case representative examples will be used to illustrate the processes. The application of toxicological and epidemiological data in these programs will be described.

Introduction, Eileen P. Hayes, EP Hayes Toxicology Services LLC, Longmont, CO

Clean Air Regulation: Science and the Process, Daniel L. Costa, US EPA-ORD, Research Triangle Park, NC

Drinking Water Regulation: Science and the Process, Rita Schoeny, US EPA, Washington, DC

Setting Occupational Exposure Limits, Bruce D. Naumann, Merck & Co., Inc., Whitehouse Station, NJ

Qualification of Impurities in Drug Products, Timothy J. McGovern, SciLucent, LLC, Herndon, VA

Quantitative In Vitro to In Vivo Extrapolation: The Essential Element of In Vitro Assay Based Risk Assessment †

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Chairpersons: Harvey J. Clewell, III, The Hamner Institutes for Health Sciences, Research Triangle Park, NC, and Bastiaan Johan Blaauboer, Utrecht University, Utrecht, Netherlands

Sponsor: Risk Assessment Specialty Section

Endorsed by:
Biological Modeling Specialty Section
In Vitro and Alternative Methods Specialty Section
Nanotoxicology Specialty Section

There is increasing recognition of the need to use efficient approaches to assess the risk assessment of high numbers of chemicals in a short time. The reliance on approaches consisting of animal experimentation has its drawbacks in terms of ethical, economical, and—not least—scientific limitations in assessing risks in a high-throughput mode. The quantitative interpretation of toxic effects of compounds in in vitro studies, using in silico approaches such as systems biological descriptions of toxicity pathways and physiologically based pharmacokinetic modeling (PBPK), are a necessary component of the National Academy of Sciences vision on toxicity testing in the 21st Century. The limited studies performed with this approach to date have shown that good predictions for the risk of the use of chemicals can be made. However, a number of limitations have also become clear and more standardization of methods is needed before implementation of quantitative in vitro-in vivo extrapolations (QIVIVE) in risk assessments can be achieved.

In this course, the following elements of the approach for assessing risks on the basis of in vitro toxicity data will be discussed:

  • How can we improve the applicability of in vitro methods by determining the real concentrations that come into contact with the cells in vitro, both for chemical compounds and for particles?
  • How can we effectively and efficiently integrate the metabolism of compounds, for clearance as well as for bioactivation?
  • How can we provide a flexible and yet robust scheme for integrating the different elements in a high-throughput environment?

The Use of In Vitro Metabolism Data and Biokinetic Modeling to Conduct QIVIVE for Chemicals, Bastiaan Johan Blaauboer, Utrecht University, Utrecht, Netherlands

Characterizing Free Test Chemical Concentration During In Vitro Toxicity Assays, Nynke Kramer, Utrecht University, Utrecht, Netherlands

Particokinetic Modeling to Support QIVIVE for Particle Toxicity Assays, Justin G. Teeguarden, Pacific Northwest National Laboratory, Richland, WA

QIVIVE

Segment-Specific Renal Pathology for the Non-Pathologist †

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Chairperson(s): Debie Hoivik, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, and Susan G. Emeigh Hart, Auxilium Pharmaceuticals, Inc., Malvern, PA

Sponsor: Toxicologic and Exploratory Pathology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

The structural and functional complexity of the kidney uniquely predisposes it to be a sensitive target organ for a number of toxicants. By taking a segment-specific approach to the kidney, participants will gain a broad understanding of structure and function, spontaneous changes, the utility of biomarkers for injury, and morphological changes associated with injury. The different segments of the nephron will be reviewed. Species and gender-related differences in renal structure and function will be emphasized, especially where these contribute to differences in nephrotoxic responses. These differences need to be considered when determining the relevance of findings seen in animal studies to humans. We will review some of the more commonly noted spontaneous lesions and their overall incidences, variance by strain (rodents) and age, all of which can impact study outcome. Lesions such as renal amyloidosis in the mouse and chronic progressive nephropathy in the rat are just two examples of spontaneous lesions which may adversely impact the outcome of a study or may be enhanced by chemical administration, often complicating findings and interpretation. Representative examples of segment-specific morphological changes that occur as a direct response to toxicant exposure will be provided, focusing on those changes evident in laboratory animals used for regulatory testing of new chemical entities. For each morphological change, a corresponding control will be provided to clearly depict the nature of the change. Finally, when choosing a biomarker to monitor for kidney effects, it is critical to understand the utility and limitations of traditional and novel serum and urinary markers of renal injury. Participants will gain a broader perspective on selection and implementation of biomarkers, particularly of the newer urinary markers which provide insight into segment specificity or mechanisms of nephrotoxic injury. Moreover, the participants will understand the specificity of each biomarker as a predictor of injury for specific parts of the nephron.

The Kidney: Anatomic and Physiologic Features of Mechanistic Relevance, Susan G. Emeigh Hart, Auxilium Pharmaceuticals, Inc., Malvern, PA

Spontaneous and Background Changes in Laboratory Animals, John Seely, Experimental Pathology Laboratories, Inc., Research Triangle Park, NC

Renal Toxicant Induced Lesions by Nephron Segment, Jim Stoltz, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Biomarkers of Renal Injury, Daniela Ennulat, GlaxoSmithKline, King of Prussia, PA

Stem Cells in Toxicology (2014) ♠

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Theme: Biomarkers for Exposure Assessment, Safety Evaluation, and Translational Medicine

Chairperson(s): Erik J. Tokar, NIEHS, Research Triangle Park, NC, and Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Sponsor(s): Stem Cells Specialty Section

Stem cells are revolutionizing toxicological research and remain an area with tremendous potential. Recently, research on stem cells has generated tremendous public and professional interest. However, some areas of toxicological research have lagged behind in the integration of stem cells as a concept in toxicant-induced disease etiology. We will describe the utility and suitability of the assorted types of stem cell models (i.e. embryonic, fetal, progenitor, induced pluripotent, immortalized stem cell lines, etc.) for various research purposes, including disease modeling, drug discovery and toxicity testing in order to describe the potential applications of stem cells in toxicological research. This important overview of stem cells will highlight their nomenclature, properties, and their roles in the genesis of various diseases.

Introduction. Erik J. Tokar, NIEHS, Research Triangle Park, NC.

The Concepts and Methods for Stem Cells. Erik J. Tokar, NIEHS, Research Triangle Park, NC.

Stem Cells in Carcinogenesis. Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Applications of Stem Cells for Toxicology and Regenerative Medicine, Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Stem Cells in Safety Testing. Kyle L. Kolaja, Cellular Dynamics International, Montclair, NJ.

Stem Cells in Toxicology † (2012)

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Chairpersons: Michael P. Waalkes, NIEHS, Research Triangle Park, NC, and Erik J. Tokar, NIEHS, Research Triangle Park, NC

Sponsor: Stem Cells Specialty Section

Endorsed by:
Biotechnology Specialty Section
Carcinogenesis Specialty Section
Reproductive and Developmental Toxicology Specialty Section

Stem cells are revolutionizing toxicological research and remain an area with tremendous potential. Recently, research on stem cells has generated tremendous public and professional interest. However, some areas of toxicological research have lagged behind in the integration of stem cells as a concept in toxicant-induced disease etiology. We will describe the utility and suitability of the assorted types of stem cell models (i.e. embryonic, fetal, progenitor, induced pluripotent, immortalized stem cell lines, etc.) for various research purposes, including disease modeling, drug discovery and toxicity testing in order to describe the potential applications of stem cells in toxicological research. This important overview of stem cells will highlight their nomenclature, properties, and their roles in the genesis of various diseases.

The Concepts and Methods for Stem Cells. Ying Xia, University of Cincinnati, Cincinnati, OH

Stem Cells in Carcinogenesis. Michael P. Waalkes and Erik J. Tokar, NIEHS, Research Triangle Park, NC

Stem Cells and Regenerative Medicine. R. Clark Lantz, University of Arizona, Tucson, AZ

Stem Cells in Safety Testing. Kyle L. Kolaja, Hoffmann-La Roche, Inc., Nutley, NJ

Stem Cells Utility in Toxicology Screening

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Chairpersons: Manu M. Sebastian, Columbia University, New York, NY, and Zaher A. Radi, Pfizer Global Research and Development, Cambridge, MA

Sponsor: Society for Toxicologic Pathology
Toxicologic and Exploratory Pathology Specialty Section

Endorsed by: N/A

The development of toxicological screening tools for evaluating toxicity of new drug candidates has been a major focus in the pharmaceutical industry. Human embryonic stem (hESC) cells and induced pluripotent stem (iPS) cells and their lineage cells can be used as tools to predict developmental and other toxicities of drug candidates since several of the human biochemical pathways are active in these cells. In addition, stem cells can also be used to help in the mechanistic understanding of how a specific class of compounds leads to toxicity. Participation in this course will provide a basic overview of the utility of stem cells in drug discovery and update toxicologists on a variety of stem cells applications as screening tool for evaluating toxicity in multiple organ systems, thereby giving toxicologists a better understanding of the potential practical application of these in vitro methods for safety and risk assessment.

Introduction: Stem Cells As Tools for Toxicology Screening, Manu M. Sebastian, Columbia University, New York, NY

Metabolomics of Human Embryonic Stem Cells and Predictive Biomarkers of Developmental Toxicity, Gabriela Cezar, University of Wisconsin, Madison, WI

Stem Cells and Mice with Humanized Livers: New Tools for Drug Metabolism and Toxicology, Stephen Strom, University of Pittsburgh Medical School, Pittsburgh, PA

Using Embryonic Stem Cell Models to Profile Potential Developmental Toxicants, E. Sidney Hunter III, US EPA, Research Triangle Park, NC

Stem Cells in Preclinical Drug Development, Hirdesh Uppal, Genentech, Inc., South San Francisco, CA

 

Stress As a Confounding Factor

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Chairperson(s): Katie Sprugel, Amgen, Seattle, WA, and Nancy Everds, Amgen, Seattle, WA

Sponsor: Toxicologic and Exploratory Pathology Specialty Section

Endorsed by:
Immunotoxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section
Women in Toxicology Special Interest Group

Stress can confound the interpretation of toxicity studies. The biology of stress includes complex interrelationships between neurologic and endocrine pathways. Stressors can have effects on in-life, clinical pathology, endocrine, and immune system parameters. Effects on any of these systems may be observed during a toxicity study. The challenge in toxicology is to differentiate between primary test article-related changes and secondary changes related to stress. This differentiation is fundamental to the assessment of stress in the regulatory environment. Understanding the pathophysiology of major systems impacted by stress and the potential range of responses is key to assessing the contribution of stress to study findings. Effects of stress in animals and humans, including potential biomarkers, will be discussed. Key references for the understanding of stress-related findings will be provided.

Introduction, Katie Sprugel, Amgen Inc., Seattle, WA

Neurohormonal Aspects of Stress, David Dorman, North Carolina State University, Raleigh, NC

Stress and Clinical Pathology, Nancy Everds, Amgen Inc., Seattle, WA

Stress and Endocrine Organs, George Foley, Schering-Plough, Summit, NJ

Stress and the Immune System, Paul Snyder, Purdue University, West Lafayette, IN

The Biology and Toxicology of the Peri- and Post-Natal Development

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Chairpersons: Gregg D. Cappon, Pfizer Global Research and Development, Groton, CT, and Gary J. Chellman, Charles River Laboratories, Reno, NV

Sponsor: Reproductive and Developmental Toxicology Specialty Section

Endorsed by: N/A

The susceptibility to toxicity of organ systems during in utero and post-natal development is a concern for both drugs and environmental chemicals. While developmental toxicity can be manifested by death, structural abnormalities, and altered growth, alterations in the functional competence are of special concern during post-natal development. The primary focus in the past has been on functional toxicity to the CNS and reproduction, but the potential for developmental exposure to impact function of other systems such as the cardiovascular, respiratory, immune, endocrine, and digestive systems is now widely recognized. This basic course will begin with a review of post-natal development of major organ systems in humans and how those developmental processes might translate to sensitive periods for toxicity. Focus will be placed on study designs for evaluation of pharmaceuticals during the pre- and post-natal development period and designs for juvenile animal toxicity studies to support pediatric drug development. Next, designs will be presented for assessment of post-natal and juvenile toxicity studies in non-human primates, a rapidly expanding area given the increase in biopharmaceutical research. The course will wrap up with a discussion of multigenerational studies used to assess potential toxicity of environmental chemicals. Attendees will leave this course with an appreciation of the complex biology of pre- and post-natal development periods and an overview of current approaches to evaluating safety during this period.

Post-natal Maturation of Major Organ Systems, Christopher J. Bowman, Pfizer Inc., Groton, CT

Post-natal and Juvenile Toxicity Studies: Basic Study Designs and Practical Approaches, Donald G. Stump, WIL Research Laboratories LLC, Ashland, OH

Post-natal and Juvenile Toxicity Studies in Non-Human Primates, Gary J. Chellman, Charles River Laboratories, Reno, NV

One and Two-Generation Studies for Assessment of Environmental Chemicals, Sue Marty, The Dow Chemical Company, Midland, MI

The Practice and Implementation of Neural Stem Cell-Based Approaches to Neurotoxicology, Jointly Sponsored by: UAMS College of Medicine and SOT

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CME AM06 Course Flyer PDF icon

Jointly Sponsored by: University of Arkansas for Medical Sciences College of Medicine and SOT

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CME Task Force: John G. Benitez, MD, MPH (Chair), Dori R. Germolec, PhD (Council Contact), Martin A. Philbert, PhD, Kenneth S. Ramos, MD, PhD, Dr. Richard Y. Wang, MD

Chairperson(s): Timothy J. Shafer, US EPA, Research Triangle Park, NC, and Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Sponsor: Neurotoxicology Specialty Section

Endorsed by:
Mechanisms Specialty Section
Metals Specialty Section
Reproductive and Developmental Toxicology Specialty Section
Stem Cells Specialty Section

The availability and use of human pluripotent stem cells (hPSC) and human neural stem cells (hNSC) for toxicology has dramatically increased in the past decade. hNSC are powerful tools for toxicologists and can provide tissue that would otherwise be unobtainable. This includes a renewable source of neural tissue from the same genetic stock that is not transformed or derived from a tumor, a source of normal human nervous system tissue, and sources of nervous system tissue from patients with clinical disease. However, culture and differentiation of hNSC are unique from culture of primary or transformed neural tissue. The course will bring together experts in the culture of various types of neural stem cells, including embryonic human derived neural stem cells, neurospheres, and neural cells derived from hPSC. Each expert will discuss the basic approaches to culturing different types of hNSC, including propagation of the cells in a progenitor status, as well as protocols for differentiation of the cells into different types of neurons. Pitfalls that are both common to the different models as well as unique ones will be described. The goal of the course is to provide the student with knowledge regarding different types of neural stem cell cultures, the techniques to successfully culture and differentiate these models, and application of these model systems to neurotoxicology. The course will conclude with an examination of appropriate outcome measures and discuss the possibility of personalized neurotoxicological assessment.

Accreditation and AMA Designation Statement

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship 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 3.25 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 stem cell research and neural stem cell based approaches to neurotoxicology, neurology and regenerative medicine.

Statement of Need, Overall Purpose, and Learner Objectives

The novel technology of applying human stem cell models to research in environmental health and medicine means that the challenges and possibilities of this research was not covered in didactic training of most practitioners; this course will provide

  • an overview of the field;
  • applications of the technology to human disease;
  • an understanding of the pros and cons of this research to enhance the ability of physicians to respond to questions regarding this topic from patients.

Basic background information on the use of appropriate controls and methodologies will be provided to facilitate and improve understanding of the reasonable or practical applications of this technology in answering questions about human disease.

At the conclusion of this activity, participants will acquire an understanding of the application of neural stem cell based approaches to neurotoxicology.

Specifically, participants will be able to

  • understand the use of neurospheres as 3D cultures for developmental neurotoxicity testing;
  • identify neurotoxicity tests and mechanistic-based toxicology approaches using human neural stem cells.

This will ultimately help physicians explain stem cell research and treatments based on stem cell research to their patients.

Disclosure Statement

It is the policy of the University of Arkansas for Medical Sciences (UAMS) College of Medicine to ensure balance, independence, objectivity, and scientific rigor in all sponsored or jointly sponsored educational activities. All individuals who are in a position to control the content of the educational activity (course/activity directors, planning committee members, staff, teachers, or authors of CME) must disclose all relevant financial relationships they have with any commercial interest(s) as well as the nature of the relationship. Financial relationships of the individual’s spouse or partner must also be disclosed, if the nature of the relationship could influence the objectivity of the individual in a position to control the content of the CME. The ACCME describes relevant financial relationships as those in any amount occurring within the past 12 months that create a conflict of interest. Individuals who refuse to disclose will be disqualified from participation in the development, management, presentation, or evaluation of the CME activity.

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, 2013.

Introduction. Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Cultural and Neural Differentiation of Human ESC-Derived Neural Cells. Steven L. Stice, University of Georgia and ArunA Biomedical, Inc., Athens, GA.

Neurospheres As 3D Cultures for Developmental Neurotoxicity Testing. Ellen Fritsche, Leibniz Research Institute of Environmental Medicine, Düsseldorf, Germany.

Break

Culture and Differentiation of hPSC-Derived Neurons and the Promise of Personalized Toxicology. Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Neurotoxicity Test Development and Mechanistic-Based Toxicology Using hNSC. Timothy J. Shafer, US EPA, Research Triangle Park, NC.

The What, When, and How of Nonclinical Support for an IND Submission †

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Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT, and Dorothy Colagiovanni, N30 Pharmaceuticals, LLC, Boulder, CO.

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
Cardiovascular Toxicology Specialty Section
Drug Discovery Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

The initiation of dosing of human subjects in a Phase 1 clinical trial represents the culmination of years of drug development, and immediately preceding the start of dosing, months of work to prepare and submit the Investigational New Drug (IND) application (or Clinical Trial Application (CTA)). A critical part of the submission dossier is the sections that describe the nonclinical data and interpretation that underwrite the clinical plan; specifically, the results of studies in pharmacology, pharmacokinetics, and toxicology, and their integration into a coherent argument that justifies the clinical starting dose, escalation of dose, and “stopping criteria” to be used in the clinical trial. The objective of the course is to elucidate the path to a successful IND/CTA submission by outlining what needs to be done (concentrating principally on the toxicology and safety pharmacology studies), the timeline and order of activities, and the presentation of the data and its integration into a coherent risk assessment to support introduction of the investigational compound into the clinic. The focus will be the content of the Nonclinical Overview (NCO), which represents an integrated detailed summary of the nonclinical studies conducted to support the clinical plan for first-in-human (FIH) dosing. The course will address the expectations of the two main “customers” for the NCO: the US FDA pharmacology/toxicology reviewer evaluating the data to determine if it supports the safety considerations of the clinical plan, and the clinician designing the clinical protocol and conducting the FIH trial.

Introduction. Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT.

Overview of the Nonclinical Toxicology Support for Clinical Trials. Paul Nugent, Pfizer Worldwide Research and Development, Groton, CT.

The IND Review Process from the Perspective of the Nonclinical Reviewer. Ronald Wange, US FDA, Silver Spring, MD.

Toxicology Studies in Drug Development and Their Contribution to the NCO. Dorothy Colagiovanni, N30 Pharmaceuticals, LLC, Boulder, CO.

The Content of the Nonclinical Overview (NCO). J. Neil Duncan, Pfizer Worldwide Research and Development, Groton, CT.

Clinical Perspective on the NCO. Drew Rasco, South Texas Accelerated Research Therapeutics (START), San Antonio, TX.

Toxicology and Risk Assessment of Chemical Mixtures †

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Chairpersons: Jane Ellen Simmons, US EPA, Research Triangle Park, NC, and Christopher J. Borgert, Applied Pharmacology Toxicology, Inc., Gainesville, FL

Sponsor: Mixtures Specialty Section

Endorsed by:
Biological Modeling Specialty Section
Occupational Health and Public Health Specialty Section

Assessment of the safety and risk of environmental chemicals, pharmaceuticals, consumer and personal care products, pesticides, and food additives increasingly requires consideration of the potential pharmacological and toxicological interactions that might occur as these agents are encountered as mixtures by patients, consumers, and through environmental exposures (e.g., mixtures present in air, water, soil). Both toxicological evaluations and risk assessments of mixtures of chemicals are complex due to the potential pharmacokinetic and pharmacodynamic mechanisms that might result in nonadditive interactions. While greater than expected toxicity is of most concern for environmental exposures, both less than and greater than additive toxicity are of pharmacological concern. Toxicological evaluation of chemical mixtures necessitates study designs, methods of analysis, and limits on interpretation not required for single chemicals. This course will cover the fundamentals of study design and data analysis for mixtures that apply to all classes and categories of chemicals encountered by humans and animals, regardless of market application. The objectives of this course are to 1) describe the basic principles that underlie modern concepts of the toxicology and risk assessment of chemical mixtures; 2) survey the basic tools and techniques needed to design, conduct, analyze and interpret experimental data with defined or complex mixtures of chemicals; and 3) review the guidance, underlying assumptions, and techniques used in risk assessment of chemical mixtures. This course will be of interest to experimentalists who wish to conduct studies on mixtures that are meaningful for evaluation of risk as well as safety and risk assessors who must evaluate and apply data on mixtures and interactions in assessments.

Basic Principles of Additivity Underyling Methods, Designs, and Techniques for Evaluation of Mixtures, Jane Ellen Simmons, US EPA, Research Triangle Park, NC

The Intersection of Design and Interpretation of Mixtures Data, Christopher J. Borgert, Applied Pharmacology Toxicology, Inc., Gainesville, FL

Pharmacokinetic and Pharmacodynamic Mechanisms of Interactions in Mixtures, Sami Haddad, Université de Montreal, Montreal, Québec

Applications of Mixtures Data in Health Risk Assessment, Moiz Mumtaz, CDC-ATSDR, Atlanta, GA

Toxic Effects of Metals †

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Theme: Regulatory Science: Advancing New Approaches for Hazard Identification and Risk Assessment

Chairperson(s): Michael P. Waalkes, NIEHS, Research Triangle Park, NC, and Michael F. Hughes, US EPA, Research Triangle Park, NC.

Sponsor: Metals Specialty Section

Endorsed by:
Risk Assessment Specialty Section
Mechanisms Specialty Section
Neurotoxicology Specialty Section
Stem Cells Specialty Section

Human exposures to metals are a daily occurrence because of their natural presence in the environment—their uses in production of many commercial products—are byproducts of energy production and are found in many hazardous waste sites. The objective of the course is to highlight the fundamentals of metals toxicology. Metals have unique chemical and physical properties that distinguish them from organic-based chemicals. Even though some metals are essential to life, overexposure to these and other metals may result in a toxic effect in one or more organ systems. Upon exposure, metals may be absorbed, distributed throughout the systemic circulation, metabolized, and eliminated. The response of an organism following exposure to metals may be protective (e.g., induction of the metal-binding protein metallothionein), or toxicological by several mechanisms including oxidative stress. Key organ systems such as the central nervous system, the vascular system, as well as the skeleton system are affected by metals including manganese, lead, aluminum, and others. Accumulation of metals in bone has recently gained renewed interest as an eventual source of internal exposure. Noninvasive methods such as neutron activation are now being used to quantitate bone metal levels. Metals can influence gene expression, signal transduction, and epigenetics. Various toxic and carcinogenic metals such as arsenic and chromium alter the epigenetic program in cells; these effects on DNA methylation, histone tail modifications, and microRNA may be involved in metal-induced toxicity. Metals are known to cause cancer by several proposed mechanisms, including oxidative stress and the cancer stem cell hypothesis. Recent evidence suggests that developmental exposure to metals may affect stem cell population dynamics, which could result in adult onset of cancer. Overall, this is intended to be a basic course on metals toxicology, and is ideal to those who desire knowledge on the health effects of metals and useful tools used in metals toxicology research.

Introduction. Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Essentials of Metals Toxicology. Michael F. Hughes, US EPA, Research Triangle Park, NC.

Metal-Induced Organ Systems Toxicities. Wei Zheng, Purdue University, West Lafayette, IN.

Mode of Metals Toxicities: Example of Epigenetics. Max Costa, New York University School of Medicine, Tuxedo Park, NY.

Metals in Carcinogenesis and Developmental Origins of Adult Disorders. Erik J. Tokar, NIEHS, Research Triangle Park, NC.

Translation of Safety Biomarkers in Drug Discovery and Development (Advanced)

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Chairperson(s): Kay Criswell, Pfizer Global Research and Development, Groton, CT, and Jennifer Colangelo, Pfizer, Inc., Groton, CT

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
Comparative and Veterinary Specialty Section
Drug Discovery Toxicology Specialty Section

Several major areas prove problematic in translating animal data/biomarkers to humans. This course focuses on translational issues in hematology, clinical chemistry, protein and peptide assays. It concludes with a risk assessment presentation summarizing the realities of implementing the overall process in defining human relevance of safety and efficacy from preclinical data. Preclinical data gathered in laboratory animals is required by regulatory agencies to determine safety in humans prior to marketing of new products. Species-specific differences in routine and esoteric serum biomarkers make the relevance of findings in animals difficult to interpret. Knowledge in this area is beneficial to the safe conduct of clinical trials and the inclusion of relevant biomarkers as effective safety and efficacy endpoints during new product development. Research scientists, industry scientists, laboratory personnel, and pathologists interested in biomarker development, translation, execution and applications from preclinical through clinical trials may be interested. The difference between data obtained in preclinical and clinical circumstances will be covered in this course. Therefore, it may be of interest to anyone in a preclinical research setting through those engaged in clinical trials, as well as those evaluating the safety of industrial chemicals. Course objectives include identification of potential relevance or non-relevance of animal-based hematologic and clinical chemistry biomarkers to humans, identification of methods of overcoming species-specific problems in protein and peptides biomarkers, and understanding human relevance of animal data and the impact of biomarker utilization on speed and decision-making.

Translation of Safety Biomarkers: Introduction, Kay Criswell, Pfizer Global Research and Development, Groton, CT

Does Preclinical Hematology Predict Human Safety? Nancy Everds, Amgen Inc., Seattle, WA

Translation of Clinical Chemistry Biomarkers: Pitfalls and Solutions, Denise Bounous, Bristol-Myers Squibb, Princeton, NJ

Overcoming the Problem of Species-Specific Proteins and Peptides in Assay Development, Jennifer Colangelo, Pfizer Global Research and Development, Groton, CT

Connecting the Dots to Define Human Relevance to Preclinical Data: Implementing Techniques to Enhance Speed of Delivery and Decision Making, Michael R. Bleavins, Michigan Technology and Research Institute, Ann Arbor, MI

Weighing in on Nutrition—Essential Concepts for Toxicologists

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Theme: Molecular Basis of Genetic Variability and Susceptibility to Toxicants

Chairperson(s): Daniel M. Wilson, The Dow Chemical Company, Midland, MI, and Angela L. Slitt, University of Rhode Island, Kingston, RI.

Sponsor: Food Safety Specialty Section

Endorsed by:
Cardiovascular Toxicology Specialty Section
Ethical, Legal, and Social Issues Specialty Section
Mechanisms Specialty Section
Women in Toxicology Special Interest Group

There has been an exponential increase in the attention focused on the potential role of nutrition in reducing the risk for numerous health complications, ranging from birth defects to age-associated vascular disease. Underscoring the above is the increasing number of presentations and publications related to this subject, and hallmarks such as the recently revamped Food Pyramid into a Plate Icon. Chronic nutritional diseases are accepted to be a current crisis in our society; three nutrition-related diseases alone, obesity, Metabolic Syndrome, and Type 2 Diabetes, afflict over one-third of the American population. To better understand the components and etiology of nutritional diseases, it’s essential for toxicologists to be well versed in the science of nutrition. A comprehensive understanding of nutrition has broad applications in toxicology, especially considering that many of us have roles in investigating the safety of nutrients, food additives or food ingredients, studying nutritional disease, or designing and interpreting preclinical or clinical studies wherein the need to consider and understand nutritional homeostasis is essential. The potential for intersection of normal nutritional metabolic pathways with adverse outcome pathways is becoming even more important to delineate. This course on general nutrition, the biochemistry of nutritional pathways, the essential role of vitamins, the channeling of nutrients such as carbohydrates, proteins and fats, cellular and molecular details of nutrition, and nutritional aspects of development and reproduction, will heighten awareness of their importance in human and animal health at multiple levels. The focus will be on relevant information, starting with an introduction to nutrition, followed by a review of biochemical and metabolic reactions in nutrition, with an emphasis on their relation to toxicology. How the nutritional status of a woman can modulate the developmental toxicity of a number of diverse toxicants, including alcohol, will be presented, along with a seminar describing the tools and applications of molecular and genetic models of nutritional disease.

Introduction. Daniel M. Wilson, The Dow Chemical Company, Midland, MI

Nutrition 101. Jo Ann S. Carson, University of Texas Southwestern, Dallas, TX.

The Biochemistry of Nutrition. Daniel M. Wilson, The Dow Chemical Company, Midland, MI.

Studying Nutritional Disease in Rodent and Cell-Based Models: Proper Selection of Molecular and Systemic Endpoints. Angela L. Slitt, University of Rhode Island, Kingston, RI.

Nutrition and Pregnancy. Carl L. Keen, University of California Davis, Davis, CA.


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