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2007 Continuing Education Courses

The Continuing Education Program offers a wide range of courses that cover stateoftheart knowledge in toxicology, as well as new developments in toxicology and related disciplines. Courses can be applied toward certifying and licensing board requirements and may also be used for recertification with the American Board of Toxicology (ABT). Both basic and advanced course topics are offered. The basic course is intended to provide a broad overview of an area or to assist individuals in learning new techniques or approaches. The advanced course is intended to be of interest to individuals with previous knowledge of the subject or already working in the field.

*The Primary Specialty Section (SS) or Regional Chapter (RC) Endorser

SR01—REACH: A New Framework for the Regulation of Chemicals

Jennifer Galvin, ConocoPhillips, Bartlesville, OK and E. Spencer Williams, ChemRisk Houston, TX

Endorsed by:
Food Safety Specialty Section
Occupational and Public Health Specialty Section
Regulatory and Safety Evaluation Specialty Section*
Risk Assessment Specialty Section

The European Commission (EC) is increasing its regulation of chemicals through a comprehensive new program known as REACH (Registration, Evaluation, and Authorization of Chemicals). The legislation, which is based on the precautionary principle, shifts the burden from government to industry to prove that chemicals can be used safely before they are marketed. As a part of this new system, manufacturers and importers of chemicals will be required to submit hazard, use, and risk data for many substances manufactured in or imported into the EU. Chemicals which exist in preparations or as part of articles sold in the marketplace will also be subject to these regulations. Thus, while REACH is a European regulation, it will impact manufacturers worldwide. A key aspect of the program is the requirement to submit data concerning the physicochemical properties, toxicity, and environmental effects of those chemicals. Registration will be mandatory before a new chemical can be marketed, as well as to keep an existing chemical on the market, and chemicals of greatest concern will be subject to formal authorization procedures much like pharmaceuticals. The amount of information required for registration will be proportional to the production or imported volumes. Chemicals that are classified as carcinogenic, mutagenic, toxic to reproduction, persistent, or bioaccumulative may be banned entirely if the manufacturer cannot demonstrate that risks associated with the chemical can be controlled.

REACH will impact the global chemicals industry and their downstream users. The estimated costs to industry for complying with REACH have been reported to be as high as $64 billion (€50 billion). Chemicals produced in quantities greater than 1000 tons, as well as the most toxic chemicals, will have to be registered within 3 years of the regulation entering into force, and all chemicals over 1 ton must be registered within 11 years. Compliance with this regulation will require significant toxicology and laboratory resources.

Navigating the New EU REACH Regulation
Michele Dastin van Rijn, U.S. Department of State, Brussels, Belgium

REACH: A Primer for Toxicologists
E. Spencer Williams, ChemRisk, Houston, TX

REACH: Implementation and Industry Actions
Mike Penman, ExxonMobil Petroleum & Chemical, Machelen, Belgium

AM02/PM08—Concepts, Methods and Applications of Discovery, and Investigative Toxicology

John Davis, II, Pfizer Global Research & Development, Chesterfield, MO and Drew A. Badger, Allergan, Inc., Irvine, CA

Endorsed by:
Drug Discovery Specialty Section*

Drug development is a long, complex and expensive process. Typical development timelines are between 10 and 15 years with attrition rates that are often too high for companies to sustain productive pipelines. Investigational and discovery toxicology are extensions of the field of general toxicology, created to fulfill the growing need for generating higher throughput, integrative, and predictive toxicological information, in an effort to reduce attrition at later stages of drug development. These novel ideas have begun to be employed more frequently and it is widely anticipated that this will pave the way for future drug testing paradigms. This course will provide first an overview of the role of toxicology in discovery units including a description of how the discovery toxicologist can support nonclinical drug development. The next lecture will cover in vitro methods and interpretation of cytotoxicity. Following this, an iterative approach to derisking strategies of QT prolongation will be discussed. The forth speaker will discuss strategies to partner with pharmacology colleagues to probe and understand toxicology. The course will conclude with a lecture discussing emerging technologies that hold nearterm potential for improving drug safety evaluation. By the conclusion of this course it is anticipated that the attendees will be able to better assess which approaches would be most appropriate for their organization.

Discovery and Investigational Toxicology: An Evolving Paradigm
John Davis, II, Pfizer Global Research & Development, Chesterfield, MO and Drew A. Badger, Allergan, Inc., Irvine, CA

Methods and Applications of Predictive Cytotoxicity
James M. McKim, CeeTox Corporation, Kalamazoo, MI

Preclinical QT Screening Methods and Interpretation
Jill V. SteidlNichols, Pfizer Global Research & Development, La Jolla, CA

Partnering with Pharmacology to Probe Toxicology
Bruce D. Car, Bristol Myers Squibb Company, Princeton, NJ

Emerging technologies — Applications in Investigative Toxicology
Kyle L. Kolaja, Roche Palo Alto, Palo Alto, CA

AM03/PM09—Genomics: From Novice to Expert, From Challenges to Promises

Banalata Sen, U.S. EPA, Research Triangle Park, NC and Susan Hester, U.S. EPA, Research Triangle Park, NC

Endorsed by:
Mechanisms Specialty Section
Molecular Biology Specialty Section
Women in Toxicology (WIT) Specialty Section*

Microarrays, when used properly, can be a powerful tool for genomics research. The complexity of the technology provides numerous challenges and potential pitfalls to the uninitiated. The FDA has developed guidelines for submission of genomics data and the EPA has guidelines for submission under development. It is becoming increasingly necessary for toxicologists in many fields, including regulatory review, to have some level of understanding of the design and interpretation of microarray based studies. The ability to utilize this technology and generate reproducible results requires a detailed understanding of the process. The first presentation will focus on the design considerations of a successful microarray experiment. In a typical microarray experiment, lists of significant differentially expressed genes are created. The common task faced by any researcher is to translate these gene lists into a better understanding of the biological phenomenon involved. The second presentation will discuss the use of various bioinformatic tools for data mining. From drug discovery, to a better understanding of the disease process, to unraveling the toxicity profile of unknown chemicals, genomics offers many promises. The second half of the course will highlight the applications and limitations of this emerging technology in disease and toxicity profiling. The third presentation will focus on the use of microarray in disease outcome prediction. The final presentation will examine the potential of genomics in evaluating toxicity and identifying biomarkers. This course is aimed at providing investigators contemplating or pursuing studies in differential gene expression, and practicing toxicologists involved in data interpretation for safety assessment and regulation, valuable knowledge of experimental design, sample processing, data analysis, and an understanding of the scope and limitations of this powerful tool.

Quality Analysis in Toxicogenomic—Design Considerations for Efficient and Effective Microarray Studies
Jeff Tucker, National Institute of Environmental Health Sciences, Research Triangle Park, NC

Beyond the Gene List—Annotation, Clustering, Sample Class Discovery
Pathway Analysis, Susan Hester, U.S. EPA, Research Triangle Park, NC

Disease Outcome Prediction Using Gene Expression Microarraysndpoints
Herbert Auer, Columbus Children's Research Institute, Columbus, OH

Toxicogenomics for Toxicity Evaluation and Biomarker Identification
Hisham Hamadeh, Amgen, Inc., Thousand Oaks, CA

AM04—Allergy and Allergic Disease: A Primer for Toxicologists

Ian Kimber, Syngenta, Macclesfield, Cheshire and G. Frank Gerberick, Procter & Gamble Company, Cincinnati, OH

Endorsed by:
Immunotoxicology Specialty Section*

Allergy to chemicals and proteins is an important health issue, and some forms of allergy are increasingly prevalent diseases. Moreover, there is no doubt that skin sensitization represents the most common manifestation of immunotoxicity in humans. Allergy may take a variety of forms, those of greatest relevance to toxicology being allergic contact dermatitis resulting from skin sensitization, respiratory allergy and occupational asthma associated with both proteins and chemicals, gastrointenstinal and systemic allergic responses caused by food proteins, and a variety of local and systemic adverse reactions to drugs where allergic reactions are frequently implicated. The purpose of this Continuing Education course is to explore, in the context of toxicological sciences, and following a general introduction to the principles of allergy, each of the four main types of allergic disease mentioned above. In each case clinical manifestations of disease, biological mechanisms, and approaches available for toxicological evaluation will be described. This basic Level course will be of value to immunotoxicologists, and also to those with interests in respiratory, skin and gastrointestinal toxicology, occupational medicine, the development of approaches to hazard characterization, and risk assessment.

Introduction to Allergy and Skin Sensitization/Allergic Contact Dermatitis
Ian Kimber, Syngenta, Macclesfield, Cheshire

Allergy of the Respiratory Tract
Jean F. Regal, University of Minnesota Medical School, Duluth, MN

Food Allergy
Gregory S. Ladics, The DuPont Company, Wilmington, DE

Drug Allergy
Kenneth L. Hastings, USFDA, Rockville, MD

AM05—Fundamentals of Human Health Risk Assessment with a Case Study Approach

Teresa Leavens, CIIT Centers for Health Research, Research Triangle Park, NC and Jennifer OrmeZavaleta, U.S. EPA, Corvallis, OR

Endorsed by:
Biological Modeling Specialty Section
Regulatory and Safety Evaluation Specialty
Risk Assessment Specialty Section*

This course will provide a general overview of the process of human health risk assessment to educate students and post doctorates interested in careers in risk assessment and researchers interested in how their work can impact and strengthen the science upon which the assessments are based. Risk assessment is used by toxicologists to estimate the likelihood of an adverse event from exposure to a hazardous agent. In 1983 the National Academy of SciencesNational Research Council published: Risk Assessment in the Federal Government: Managing the Process in which the process of risk assessment was clearly outlined into 4 components including hazard identification, doseresponse assessment, exposure assessment, and risk characterization. This course will focus on each of these 4 components and will use vinyl chloride, especially the U.S. EPA IRIS assessment, as a case study to illustrate the development and application of the 4 components. The presentations will cover historical studies incorporated into hazard identification including acute, subchronic, and chronic animal assays as well as epidemiology studies, in vitro assays, predictive models, and genomics research. Information will also be presented on determination of the modeofaction from non tumor data, and how it may guide and direct the assessment process to reduce uncertainty in extrapolating effects. Various methods of doseresponse assessment will be presented including statistical and mechanistic models used to extrapolate effects among doses and species. Available exposure factor data, exposure modeling tools, biomonitoring data, and potential sources of variability and uncertainty in exposure assessment will be highlighted. The final component, risk characterization, will address statistical and biological issues, such as appropriate models and target populations, as well as connect the process of risk assessment with risk management.

Teresa Leavens, CIIT Centers for Health Research, Research Triangle Park, NC

Hazard Identification
Gary Foureman, U.S. EPA, Research Triangle Park, NC

DoseResponse Assessment
Harvey Clewell, III, CIIT Centers for Health Research, Research Triangle Park, NC

Exposure Assessment
Elaine CohenHubal, U.S. EPA, Research Triangle Park, NC

Risk Characterization
Michael Gargas, The Sapphire Group, Inc., Beavercreek, OH

AM06—Toxicology and Molecular Biology of Tissue Repair

Harihara Mehendale, University of Louisiana Monroe, Monroe, LA and Chris Corton, U.S. EPA, Research Triangle Park, NC

Endorsed by:
Carcinogenesis Specialty Section
Mechanisms Specialty Section*
Molecular Biology Specialty Section

After chemical exposure, injury may progress unabated leading to tissue and organ dysfunction and failure, or regress leading to recovery. When recovery occurs, tissue injury resolves as a result of cell division, restored tissue architecture, structure and function. The molecular biology of these events, and their dynamic relationships to progression or regression of tissue injury are of significant mechanistic interest, because risk of adverse effects from chemical exposure should consider not only the level of tissue damage but the dynamics of recovery from that damage. In addition, interventional therapeutic opportunities may be developed through this understanding. These dynamic events apply to acute injuries such as ischemiareperfusion, drug or toxicantinduced necrosis, or chronic tissue injuries. The first lecture will cover the sequential events that occur during tissue regeneration using recent genomic analyses of the partial hepatectomy model and other models of tissue regeneration. The second lecture will describe various models of liver injury, doseresponse relationships and modulations of injury and progression leading to hepatic failure, and regression of injury leading to recovery from injury. The third lecture will cover the cellular and biochemical changes associated with renal injuries, and how injury initiated by drugs, toxicants, and ischemiareperfusion may progress leading to renal failure. Both renal as well as hepatic injury and tissue repair models will be discussed in the context of modulation by disease, dose, duration of ischemia before reperfusion, and nutritional factors. The last lecture will cover the role of the dynamic events of tissue destruction and restoration focusing on hydrolysis of extracellular matrix components by activated matrix metalloproteinases in preparation for restoration of tissue architecture. The role of angiogenesis in restoring extracellular matrix, cell mobility and placement are dynamic and critical events needed in reestablishing tissue homeostasis.

Toxicology and Molecular Biology of Tissue Repair
Chris Corton, U.S. EPA, Research Triangle Park, NC

Genomics of Tissue Repair
Linda Greenbaum, University of Pennsylvania School of Medicine, Philadelphia, PA

Progression and Regression of Hepatic Injury
Harihara Mehendale, University of Louisiana Monroe, Monroe, LA

Models and Mechanisms of Renal Injury and Repair
Joseph Bonventre, Harvard Institutes of Medicine, Boston, MA

Dynamics and Mechanisms of Matrix Remodeling
Rama Khokha, Ontario Cancer Institute, Toronto, Ontario, Canada

AM07—The Biology and Toxicology of the Peri- and Post-Natal Development

Diana J. AuyeungKim, Charles River Laboratories, Reno, NV and Robert E. Chapin, Pfizer Global Research & Development, Groton, CT

Endorsed by:
Regulatory and Safety Evaluation Specialty Section
Reproductive and Developmental Toxicology Specialty Section*
Risk Assessment Specialty Section

The period of postnatal development has always been of societal, scientific, and regulatory concern. This concern is heightened by the growing literature which shows that exposures and health status in early (prenatal and postnatal) life can have significant health consequences much later in life; in humans, this may mean 5060 years later. This basic course will begin with a review of the recent data showing the connection between earlylife events and laterlife health, and move on to a discussion of the comparative developmental biology of rodents and humans. The third talk will describe regulatory and tailored study designs which address perinatal exposures and adult outcomes and discuss endpoint selection. The last speaker will address the issues and challenges of data interpretation and regulatory action. Attendees will take home an appreciation of the complex biology, the length of the health trajectory that is set up by very early exposures, and the challenges of dealing with these issues from a regulatory perspective.

Recent Understandings of the Impacts of EarlyLife Exposures
Leila W. Jackson, Case Western Reserve University School of Medicine, Cleveland, OH

The Comparative PostNatal Maturation of Rats and Humans
Gregg D. Cappon, Pfizer Global Research & Development, Groton, CT

Study Designs and Data Interpretation
Rochelle Tyl, RTI International, Research Triangle Park, NC

Regulatory Interpretation and Risk Assessment/Risk Management
Susan L. Makris, U.S. EPA, Washington, DC

PM10—Toxicological Evaluation of Chemical and Drug Mixtures

Christopher Borgert, Applied Pharmacology and Toxicology Inc., Gainesville, FL and Kannan Krishnan, Universite de Montreal, Montreal, Quebec, Canada

Endorsed by:
Biological Modeling Specialty Section
Mixtures Specialty Section*
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

Drugs, consumer and personal care products, pesticides, environmental chemicals, and foods are often assessed for safety and risk without extensive consideration of numerous 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). Such assessments are complex due to the potential pharmacokinetic and pharmacodynamic mechanisms that underlie interactions in mixtures, necessitating 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 uses of chemicals, regardless of market application. The first presentation will cover the basic principles underlying componentbased and whole mixture techniques as well as study designs available for evaluating the toxicity of mixtures. The second presentation will review the concepts for evaluating data on mixtures, including data on binary and higher order interactions, and will apply those concepts to various examples from the published scientific literature. The third talk will focus on the pharmacokinetic and pharmacodynamic mechanisms of interactions among drugs and chemicals. The final talk will present the current approaches and guidance for conducting risk assessment of chemical mixtures and safety assessment of drug combinations. The course will be of interest to experimentalists who wish to conduct studies on mixtures that are more probative and relevant for safety and risk assessment, as well as for safety and risk assessors who must evaluate and apply data on mixtures and interactions in assessments.

Methods, Designs and Techniques for Evaluation of Mixtures
Jane Ellen Simmons, U.S. EPA, Research Triangle Park, NC

Interpretation of Mixtures Data — Case Studies of the Good, the Bad and the Ugly
Christopher Borgert, Applied Pharmacology and Toxicology Inc., Gainesville, FL

Pharmacokinetic and Pharmacodynamic Mechanisms of Interactions in Mixtures
Kannan Krishnan, Universite de Montreal, Montreal, Quebec, Canada

Application of Mixtures Data in Health Risk Assessment of Chemicals and Safety Assessment of Drugs
Moiz Mumtaz, CDC Agency for Toxic Substances & Disease Registry, Atlanta, GA and Alexander Constan, Infinity Pharmaceuticals, Cambridge, MA

PM11—Physiologically Based Pharmacokinetic Modeling for Risk Assessment Applications

Hugh A. Barton, US Environmental Protection Agency, Research Triangle Park, NC and Justin G. Teeguarden, Pacific Northwest National Laboratory, Richland, WA

Endorsed by:
Biological Modeling Specialty Section*
Risk Assessment Specialty Section
Pharmacokinetics is a key step in mechanistically based risk assessments, linking chemicals exposures with the mode of action leading to toxicity. Physiologically based pharmacokinetic (PBPK) modeling is one approach for incorporating pharmacokinetics into risk assessment, particularly quantitative doseresponse analyses. This course will guide the student through the PBPK modeling process, from model development through the use of the modeling results in risk assessment. The basic principals of PBPK model development will be described, focusing on the range of different model structures that have been developed to address compounds with a variety of physicochemical characteristics, toxicological properties, and exposure pathways. Models for endocrine active compounds will be described to illustrate issues of serum protein and receptor binding and modeling in vitro and in vivo systems. Characterizing variability of the human population can be incorporated in PBPK models using distributions of physiological and chemicalspecific parameters (e.g., metabolism)and Monte Carlo methods. Bayesian statistical approaches implemented with Markov Chain Monte Carlo analyses and maximum likelihood methods will be described as these have been the major approaches to characterizing uncertainty in model estimated dose metrics. Qualitative and quantitative evaluations of PBPK models are a critical step in their application in risk assessments. A variety of risk assessment applications (e.g., routetoroute extrapolations, derivation of references concentrations/doses and cancer unit risks) will be presented including an overview of EPA's new document describing approaches for the use of PBPK modeling in regulatory risk assessment.

The Wide World of Pharmacokinetic Models and How They Are Built
Hugh A. Barton, U.S. EPA, Research Triangle Park, NC

PBPK Modeling of Endocrine Active Compounds in Vivo and in Vitro
Justin G. Teeguarden, Pacific Northwest National Laboratory, Richland, WA

Characterizing Uncertainty and Variability in PBPK Models
Harvey J. Clewell, CIIT Centers for Health Research, Research Triangle Park, NC

Applications of PBPK Models in Risk Assessment
Robert S. DeWoskin, US Environmental Protection Agency, Research Triangle Park, NC

PM12—Protein Therapeutics: Assessment and Impact of Immunogenicity on Study Design and Interpretation

Yanli Ouyang, USFDA, Silver Spring, MD and Lynne LeSauteur, Charles River Laboratories, Senneville, Quebec, Canada

Endorsed by:
Immunotoxicology Specialty Section*
Regulatory and Safety Evaluation Specialty Section

Immunogenicity is a unique and significant safety and efficacy concern in developing protein therapeutics and could have significant impact on safety, pharmacokinetics, and efficacy. Antierythropoietin (EPO) antibodieselicited pure red cell aplasia has highlighted the significant impact of immunogenicity on human safety of protein therapeutics. Immunogenicity is also a critical issue in designing and interpreting animal toxicity studies. The purpose of this basic CE course is to highlight important aspects of immunogenicity including an overview of current FDA regulation with regards to nonclinical and clinical immunogenicity assessment. Specifically, the course will address what makes protein therapeutics potentially immunogenic, and how an antibody response is produced. The development and validation of common methods used to detect an antibody response will be presented by describing development/optimization parameters and validation criteria for immunogenicity assays, followed by case studies describing antibody screening approaches, and total and neutralizing antibodies determination. This course will also review the current practice in immunogenicity evaluation in animal models and recent development of new animal models. The consequences of immunogenicity will be discussed using specific case studies highlighting safety evaluation, risk assessment, potential clinical consequence and the impact of immunogenicity on designing and interpreting toxicity studies. With the current drug development approach on targeted therapeutics, protein therapeutics are becoming increasingly important. Immunogenicity is a challenge for anyone involved in immunotoxicity research and in the research and development of protein therapeutics.

What Makes Protein Therapeutics Potentially Immunogenic and How to Detect and Characterize Immunogenicity
Daniel Wierda, Eli Lilly & Company, Greenfield, IN

How to Measure Immunogenic Response: Method Development, Assay Validation and Sample Analysis
Deborah FincoKent, Pfizer, Inc., Groton, CT

How to Use Animal Models to Evaluate Immunogenicity
Robert House, DynPort Vaccine Company LLC, Frederick, MD

Safety Evaluation of Immunogenicity, Clinical Consequences of Immunogenicity and Risk Assessment
Susan Kirshner, USFDA, Bethesda, MD

PM13—Rodent Imaging Overview for the Toxicologist

Kathleen Gabrielson, Johns Hopkins University, Baltimore, MD and Robert Maronpot, National Institute of Environmental Health Sciences, Research Triangle Park, NC

Endorsed by:
Comparative and Veterinary Specialty Section*
Drug Discovery Specialty Section
Mechanisms Specialty Section
Toxicologic & Exploratory Pathology Specialty Section

In the last decade, in vivo imaging methods have become established tools in basic science research. This course is designed to provide a general overview of imaging modalities utilized in basic science with applications to drug discovery and toxicological research. This review will focus on five imaging modalities including: MR, PET, SPECT, optical and ultrasound. Each speaker will give a basic overview of the modality and present specific examples relevant to drug discovery and toxicological research. In this review, several applications of MRI, Magnetic Resonance Spectroscopy and Electron Paramagnetic Resonance in oncology, cardiovascular disease and morphological phenotyping during toxicological studies will be described. PET and SPECT imaging of radioactively labeled compounds will be reviewed in the setting of drug discovery and toxicological research. The application of the multimodality imaging scanners will also be discussed. These multimodalities studies provide comprehensive evaluation that enables the toxicologist to study structure, function, in tandem with distribution and metabolism of radioactively labeled drugs. PET imaging of gene expression during pharmacology studies will be reviewed. Optical imaging will be reviewed in the context of imaging gene expression in transgenic mice engineered with gene promoters from enzymes (CYP1A2 or CYP3A4) driving luciferase expression. Signal transduction pathway discovery in toxicological research will be discussed using optical imaging in transgenic mice with a Smadresponsive luciferase reporter. Ultrasound imaging will be overviewed using applications of toxicity and drug discovery in cardiovascular and cancer mouse models. Following completion of this workshop, attendees should have basic understanding of the various imaging modalities and applications to drug discovery and toxicological research.

Overview: Applicability/Feasibility of Rodent Imaging for the Toxicologist
Kathleen Gabrielson, Johns Hopkins University, Baltimore, MD

Magnetic Resonance Imaging
Robert Maronpot, National Institute of Environmental Health Sciences, Research Triangle Park, NC

Positron Emission Tomography and Single Photon Emission Computed Tomography
Benjamin Tsui, Johns Hopkins University, Baltimore, MD

Optical Imaging
Pamela Contag, Xenogen Corporation, Alameda, CA

Ultrasound Imaging
Kathleen Gabrielson, Johns Hopkins University, Baltimore, MD