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2009 Continuing Education Courses

The Continuing Education Program offers a wide range of courses that cover state-of-the-art 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.

SR01 Topics in Ethics: Conflict of Interest—Real or Imagined?—PBDEs As a Case Study Basic
AM02 Free Radicals for Toxicologists—From the Basics to Inflammation and Disease Basic
AM03 Characterizing Modes-of-Action and Their Relevance in Assessing Human Health Risks Basic
AM04 Evaluation of Toxicity to Male and Female Reproductive Systems: Biology, Study Design and Data Interpretation Basic
AM05 Immunology for Toxicologists Basic
AM06 Principles and Applications of Toxicokinetics Basic
AM07 Translation of Safety Biomarkers in Drug Discovery and Development Advanced
PM08 Free Radicals for Toxicologists—From the Basics to Inflammation and Disease Basic
PM09 Characterizing Variability and Uncertainty with Physiologically-Based Pharmacokinetic Models Basic
PM10 Current Approaches in Mixture Risk Assessment Basic
PM11 How Similar is Similar and How Relevant is Relevant? Considerations in the Design of a Predictive Development Program for Biotherapeutics Basic
PM12 New Frontiers in Metal Toxicology: Genetic Susceptibility, Early Diagnosis, and Related Biological Indices Advanced
PM13 Stress As a Confounding Factor in Toxicology Studies Basic

Topics in Ethics: Conflict of Interest—Real or Imagined?—PBDEs As a Case Study

SR01—CE Sunrise

Chairperson(s): Steven G. Gilbert, Institute of Neurotoxicology & Neurological Disorders, Seattle, WA and Philip Wexler, National Library of Medicine, Bethesda, MD

Sponsor: Ethical, Legal, and Social Issues Special Interest Group

Endorsed by:
Education Committee
Regulatory and Safety Evaluation Specialty Section

Throughout their professional lives, most toxicologists will confront an array of issues beyond the strictly scientific ones they have trained for. These may range across topics such as animals in research, human subject research, investigational and reporting bias, and conflict of interest concerns. The interdisciplinary nature of toxicology, its sometimes tangled regulatory framework, and implications for public safety and health, make policy considerations perhaps more relevant than they are for other sciences. Toxicologists, therefore, need to be braced for an array of ethical, legal, and social challenges, and to learn how to sensibly address allegations of conflict of interest or bias while practicing their science. This course will examine, through a case study related to polybrominated diphenyl ethers (PBDEs), the consequences of alleging conflict of interest or bias. In August, 2007 the EPA dismissed Deborah Rice from its PBDE review panel in compliance with a request from the American Chemistry Council, and expunged her comments from the official record. Dr. Rice had previously expressed her views about PBDE’s dangers as part of work with the Maine government. The EPA’s rationale was "the perception of a potential conflict of interest." This incident highlights the challenge of a scientist holding a scientifically credible opinion about an issue prior to review by an expert panel (on which he/she is serving) assigned to assess the same issue. Under what circumstance does a position become a conflict of interest or bias? The practical and ethical issues raised in staffing scientific review panels affects scientists and policy makers. Course time will be provided for a discussion of conflict of interest and an examination of related incidents. Students will be provided with a selected list of Web resources related to the ethical issues under discussion.

The Relevance of Ethics to Science and Toxicology, Steven G. Gilbert, Institute of Neurotoxicology and Neurological Disorders, Seattle, WA

Case Study of PBDE Review and Allegations of Conflict of Interest, Deborah C. Rice, Maine Center for Disease Control and Prevention, Augusta, ME

Audience Discussion with Panel, Deborah Rice, Steven Gilbert and, Philip Wexler

Free Radicals for Toxicologists—From the Basics to Inflammation and Disease (repeats as PM08)

AM02—CE Basic

Chairperson(s): Lin L. Mantell, St. John’s University College of Pharmacy, Queens, NY and Judith T. Zelikoff, New York University School of Medicine, Tuxedo, NY

Sponsor: Immunotoxicology Specialty Section

Endorsed by:
Inhalation and Respiratory Specialty Section
Occupational and Public Health Specialty Section

The production of reactive oxygen species/reactive nitrogen species (ROS/RNS) has long been recognized to not only serve as a biomarker for oxidative stress, but also significantly contribute to the pathogeneses of various inflammatory tissue injuries and diseases. The emphasis of this course will be placed on an in-depth, state of the art review of the relationship among free radicals, immunologically-related inflammatory responses and environmental exposures and diseases. At the conclusion of this session, the participants will be able to describe the basic concepts of free radicals as they relate to immune-mediated events, better understand the production of reactive oxygen/nitrogen species (ROS/RNS) from both inflammatory responses and exposure to environmental toxicants, and realize the impact of ROS/RNS on normal physiological responses and pathological processes.

The Basics of Free Radicals, Garry Buettner, University of Iowa, Iowa City, IA and Society for Free Radical Biology and Medicine

Reactive Metabolites of Oxygen and Nitrogen in Inflammation: The Good and the Bad, Matthew Grisham, Louisiana State University Health Sciences Center, Shreveport, LA

Metal Induced Oxidants and Anti-Oxidants: Agents that Regulate and Dysregulate Immune Cell Activities, Michael A. Lynes, University of Connecticut, Storrs, CT

Free Radical Generation from Exposure to Particulate Air Pollutants and the Inflammatory Response, Andy Ghio, U.S. EPA, Chapel Hill, NC

Summary, Lin L. Mantell, St. Johns University, College of Pharmacy, Queens, NY/The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY

Characterizing Modes-of-Action and Their Relevance in Assessing Human Health Risks

AM03—CE Basic

Chairperson(s): Stephen S. Olin, ILSI Research Foundation, Washington, DC and Samuel M. Cohen, University of Nebraska Medical Center, Omaha, NE

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
Carcinogenesis Specialty Section
Risk Assessment Specialty Section

Determining the mode(s)-of-action of a toxicant is the goal of many toxicology studies, and these data are often used in risk assessment. This course will present a systematic approach to characterizing the mode(s)-of-action (MOA) of toxicants and will lead participants through the application of a framework for evaluating the relevance of an animal mode-of-action in assessing human risk. A brief introduction to the history and significance for risk assessment of MOA/human relevance analysis will lay the foundation for this course, with the first presentation providing the basic concepts involved in application of the MOA/human relevance framework. Subsequent presentations will demonstrate the application of the framework through selected case studies with both cancer and non-cancer endpoints. Case studies will examine issues such as multiple endpoints with shared or different MOAs, the extension of the framework to dose-response analysis, and the effect of lifestage on the analysis. The objective of the case studies is to show clearly how the framework analysis is done, to illustrate the importance of a systematic evaluation of the available data, and to provide course participants with the tools to begin applying the MOA/human relevance framework in their own work.

The Development and Significance of Mode-of-Action/Human Relevance Analysis, Samuel M. Cohen, University of Nebraska Medical Center, Omaha, NE

Framework for Characterizing Modes-of-Action in Animals and Humans, Alan Boobis, Imperial College, London, United Kingdom

A Mode-of-Action/Human Relevance Analysis for Thyroid Disruption and Its Relationship to Cancer and Neurodevelopmental Effects, Kevin M. Crofton, U.S. EPA, Research Triangle Park, NC

Cytotoxicity, Carcinogenicity, and Dose-response and the Mode-of-Action/Human Relevance Framework, M. E. (Bette) Meek, University of Ottawa, Ottawa, Ontario, Canada

Evaluation of Toxicity to Male and Female Reproductive Systems: Biology, Study Design and Data Interpretation

AM04—CE Basic

Chairperson(s): Kok Wah Hew, Takeda Global Research & Development Center, Inc., Lake Forest, IL and Barry S. McIntyre, Schering Plough Research Institute, Summit, NJ

Sponsor: Reproductive and Developmental Toxicology Specialty Section

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

The objectives of this course are to provide the basic tools for toxicologists who desire a better understanding of how to assess toxicant-related effects on animal reproduction and the subsequent potential risk(s) to human reproduction. The anticipated audience includes toxicologists who work in regulated product development (e.g., pharmaceutical, chemical, and pesticide industries), as well as scientists who may be responsible for monitoring contracted reproductive toxicity studies so that they can understand the subject sufficiently to work with study directors (i.e., study design and interpretation of study results). Reproductive toxicity studies assess multiple interrelated endpoints in the male and female reproductive systems. In order to properly design, conduct, and interpret these studies, a broad knowledge of male and female reproductive organ development, anatomy, physiology, and endocrinology is required. Using this as a starting point, the overall designs of reproductive toxicity studies for regulatory submissions, and subsequent application of these data to assess potential risk in humans will be discussed. Additional presentations will provide an overview of the anatomy and physiology of the male and female reproductive systems, respectively, as well as endocrine regulation of these systems. This course will include an overview of the study designs to evaluate toxicity to male and female reproductive systems based on current regulatory guidelines. The course will conclude with case studies of reproductive toxicity data, subsequent interpretation, and how these results are being used to assess potential risks to human reproduction. In summary, upon completion of this course, the attendee will have an appreciation for the key information required for the design of reproductive toxicity studies and interpretation of reproductive toxicity data and will be able to provide guidance for risk assessment in reproductive toxicity evaluation.

Male Reproductive System: Anatomy, Physiology, and Endocrine Regulation, Kim Boekelheide, Brown University, Providence, RI

Female Reproductive System: Anatomy, Physiology, and Endocrine Regulation, Anthony R. Scialli, Sciences International Inc., Alexandria, VA

Reproductive Toxicity Testing: Study Designs and Toxicity Endpoints, Barry S. McIntyre, Schering Plough Research Institute, Summit, NJ

Reproductive Toxicity Testing: Data Interpretation and Risk Assessment, Donald G. Stump, WIL Research Laboratories, LLC, Ashland, OH

Immunology for Toxicologists

AM05—CE Basic

Chairperson(s): Ian Kimber, University of Manchester, Manchester, United Kingdom and Raymond Pieters, IRAS Utrecht University, Utrecht, Netherlands

Sponsor: Immunotoxicology Specialty Section

The adaptive immune response that is found in mammals comprises a dedicated interacting system of tissues, cells and molecules that work in concert to provide specific immune responses and host resistance to pathogenic microorganisms and transformed cells. Specific immunity is supplemented by, and works in harmony with, the phylogenetically more ancient innate immune system. Immunotoxicology describes the study of adverse health effects that may result from the interaction of xenobiotics with one or more components of the immune system. Such health effects may take a variety of forms. These include frank immunotoxicity where there is a functional impairment of the immune system. The concern here is that compromised immune function may translate into an increased susceptibility to infectious and/or malignant disease. A second potential consequence of the interaction of chemicals or proteins with the immune system is allergy: defined as the adverse health effects that may arise from the stimulation of a specific immune response. Allergic disease may take one of several forms, those of greatest significance for toxicologists being skin sensitization and allergic contact dermatitis, allergic sensitization of the respiratory tract, food allergy, and idiosyncratic drug reactions. Finally, xenobiotics have also been implicated in the induction or exacerbation of autoimmune responses and autoimmune disease. This basic grade course will provide a firm grounding in fundamental and clinical aspects of immunology, and will describe the basic elements of immunotoxicity, allergy and autoimmunity in view of the interaction between innate and adaptive immunity. The objective is to deliver an accessible guide to the immune system and immunotoxicology for general toxicologists.

An Introduction to Immunology: Fundamental and Clinical Aspects, Ian Kimber, University of Manchester, Manchester, United Kingdom

Elementary Immunotoxicology, Robert House, Dynport Vaccine Company-LLC, Frederick, MD

Allergy and Allergic Disease, MaryJane Selgrade, U.S. EPA, Research Triangle Park, NC

Autoimmunity and Autoimmune Disease, Raymond Pieters, IRAS, Utrecht University, Utrecht, Netherlands

Principles and Applications of Toxicokinetics

AM06—CE Basic

Chairperson(s): Michael J. Bartels, Dow Chemical, Midland, MI and Charles Timchalk, Batelle Pacific Northwest Laboratories, Richland, WA

Sponsor: Biological Modeling Specialty Section

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

Toxicokinetic (TK) data play an important role in chemical risk assessments. Chemical risk assessments are increasingly incorporating consideration of the mode of action (MOA) of the chemically-induced toxicity. Increasing reliance on MOA in such evaluations in turn requires increasingly detailed information regarding the active chemical moiety (parent compound or metabolite) and relevant target tissue dose metrics. This course will begin by providing background on the need for and role of toxicokinetic data in risk assessments. This presentation will include a discussion of the interaction between ev aluation of MOA and toxicokinetic data and the role of such data in both interspecies and high to low dose extrapolations in risk assessment. We will go on to describe basic principles of pharmacokinetics from both the classical and physiologically-based approaches. The presentation will provide the conceptual and mathematical basis for developing a better understanding of pharmacokinetics and how pharmacokinetic analyses are conducted. In addition, we will address elements of the design of toxicokinetic experiments, conducted as part of subchronic/chronic toxicity studies. This presentation will include standardized approaches for TK sampling and data analysis. Finally, the presenters will provide examples of the integration of toxicokinetic data into current risk assessments, including the incorporation of human biomonitoring data in the evaluation of chemical exposures and risks.

Why is an Understanding of Toxicokinetics Important? James S. Bus, Dow Chemical, Midland, MI

Basic PK Principles, Sean M. Hays, Summit Toxicology, Lyons, CO

Toxicokinetic Study Design, Shakil A. Saghir, Dow Chemical, Midland, MI

Application of Quantitative Toxicokinetic Data in Health Risk Assessment, John C. Lipscomb, U.S. EPA, Cincinnati, OH

Translation of Safety Biomarkers in Drug Discovery and Development

AM07—CE Advanced

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 assays 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: identification of potential relevance or non-relevance of animalbased 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 in Drug Discovery and Development: Introduction,
Kay Criswell, Pfizer Global Research and Development, Groton, CT

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

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

Overcoming the Problems 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 Decisions and Decision Making, Michael R. Bleavins, Michigan Technology and Research Institute, Ann Arbor, MI

Free Radicals for Toxicologists—From the Basics to Inflammation and Disease

PM08—CE Basic

Chairperson(s): Lin L. Mantell, St. John’s University College of Pharmacy, Queens, NY and Judith T. Zelikoff, New York University School of Medicine, Tuxedo, NY

Sponsor: Immunotoxicology Specialty Section

Endorsed by:
Inhalation and Respiratory Specialty Section
Occupational and Public Health Specialty Section

The production of reactive oxygen species/reactive nitrogen species (ROS/RNS) has long been recognized to not only serve as a biomarker for oxidative stress, but also significantly contribute to the pathogeneses of various inflammatory tissue injuries and diseases. The emphasis of this course will be placed on an in-depth, state of the art review of the relationship among free radicals, immunologically-related inflammatory responses and environmental exposures and diseases. At the conclusion of this session, the participants will be able to describe the basic concepts of free radicals as they relate to immune-mediated events, better understand the production of reactive oxygen/nitrogen species (ROS/RNS) from both inflammatory responses and exposure to environmental toxicants, and realize the impact of ROS/RNS on normal physiological responses and pathological processes.

The Basics of Free Radicals, Garry Buettner, University of Iowa, Iowa City, IA and Society for Free Radical Biology and Medicine

Reactive Metabolites of Oxygen and Nitrogen in Inflammation: The Good and the Bad, Matthew Grisham, Louisiana State University Health Sciences Center, Shreveport, LA

Metal Induced Oxidants and Anti-Oxidants: Agents that Regulate and Dysregulate Immune Cell Activities, Michael A. Lynes, University of Connecticut, Storrs, CT

Free Radical Generation from Exposure to Particulate Air Pollutants and the Inflammatory Response, Andy Ghio, U.S. EPA, Chapel Hill, NC

Summary, Lin L. Mantell, St. Johns University, College of Pharmacy, Queens, NY/The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY

Characterizing Variability and Uncertainty with Physiologically-Based Pharmacokinetic Models

PM09—CE Basic

Chairperson(s): Hugh A. Barton, U.S. EPA, Research Triangle Park, NC and Gunnar Johanson, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

Sponsor: Biological Modeling Specialty Section

Endorsed by:
Risk Assessment Specialty Section

As pharmacokinetic (PK) models are increasingly applied in risk and safety assessments, it is critical to improve the characterization of variability and uncertainty. Variability describes real differences among individuals arising from external exposure pathways, diet, health status, genetics, and other factors that contribute to differences in internal exposures or tissue dosimetry. Absent perfect knowledge, there are uncertainties arising from a range of sources including experimental error, that can impact confidence in model predictions. Physiologically-based pharamacokinetic (PBPK) models provide a biologically motivated description of processes influencing the absorption, distribution, metabolism, and excretion of endogenous compounds or xenobiotics. PBPK models rely on a wide range of in vitro and in vivo data to estimate parameter values and demonstrate the predictive capabilities of the models. This course will describe characterization of variability and uncertainty using PBPK models from a number of perspectives. The range of PBPK model structures and their applications in risk and safety assessment will be presented. How to approach characterizing uncertainty in the presence of variability will be described. Data from humans can be analyzed using PBPK models to characterize PK variability. Finally, linking variations in external exposure pathways with PK variability provides methods to characterize human dosimetry for use in risk assessments or interpretation of biomonitoring data.

Pharmacokinetic Models—What are They and What are They Used For? Hugh A. Barton, U.S. EPA, Research Triangle Park, NC

Relating Data and Models to Characterize Parameter and Prediction Uncertainty, R. Woodrow Setzer, U.S. EPA, Research Triangle Park, NC

Use of Human Experimental Data in PBPK Modeling of Population Variability, Gunnar Johanson, Karolinska Institute, Stockholm, Sweden

Variability in Exposure and Internal Dosimetry Assessed with PBPK Models, Cecilia Tan, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

Current Approaches in Mixture Risk Assessment

PM10—CE Basic

Chairperson(s): Moiz Mumtaz, CDC Agency for Toxic Substances & Disease Registry, Atlanta, GA and Christopher J. Borgert, Applied Pharmacology and Toxicology Inc., Gainesville, FL

Sponsor: Mixtures Specialty Section

Endorsed by:
Inhalation and Respiratory Specialty Section
Occupational and Pubic Health Specialty Section
Risk Assessment Specialty Section

Human exposure to combinations of chemicals and drugs is an everyday reality of life. There is tremendous interest in scientific and regulatory tools for evaluating the joint toxic action of chemicals and drugs in mixtures. This course will provide and overview on the methods and tools reflective of the current state of knowledge in the area of mixture risk assessment, as well as illustrative, real-life examples of their application to risk assessment. We will begin with an introduction to the various approaches to mixture risk assessment and illustrate the use of these methods to assess risks associated with human exposure to contaminants in selected hazardous waste sites. The course will then describe the process of cumulative risk assessment of pesticides, highlighting the use of pharmacokinetic, pharmacodynamic and relative potency factors in the process. The development and application of relative potency factor approach to evaluate safety of mixtures of drugs will also be addressed. Finally, we will discuss the current approaches and tools for assessing the role of interactions in mixture risk assessment, with particular emphasis on the use of physiologically-based pharmacokinetic (PBPK) models. Course participants will be provided with data evaluation strategies, data sets from real world examples, exercise results, and discussion of uncertainty pertaining to the application of various mixtures procedures. The intended audience for this course will be experimentalists, modelers, epidemiologists and risk assessors interested in the assessment of health risks associated with human exposure to chemical and/or drug mixtures.

Assessing Risk from Chemical Mixtures at Hazardous Waste Sites, Moiz Mumtaz, ATSDR, Atlanta, GA

Cumulative Risk Assessment of Pesticides, Anna B. Lowit, U.S. EPA, Washington, DC

Relative Potency Factors in Drug Safety Assessment, Christopher J.Borgert, Applied Pharamcology and Toxicology Inc., Gainesville, FL

Assessing the Role of Interactions in the Risk Assessment of Chemical Mixtures, Kannan Krishnan, Université de Montréal, Montreal, Quebec, Canada

How Similar is Similar and How Relevant is Relevant? Considerations in the Design of a Predictive Development Program for Biotherapeutics

PM11—CE Basic

Chairperson(s): Laura Andrews, Genzyme, Framingham, MA and Leigh Ann Burns-Naas, Pfizer Global Research and Development, San Diego, CA

Sponsor: Comparative and Veterinary Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

Preclinical development programs that are designed to support the safe clinical use of biopharmaceuticals have considerations that are very different from programs designed to support the development of small molecule drugs. In particular, with more and more targeted therapeutics being developed a traditional development program is becoming more and more difficult. While the ICH S6 guidance continues to drive the program decisions more often than not a different approach is warranted due to species specificity and paucity of relevant animal models. To design a predictive non clinical program that will support not only first in human dosing but also eventual approval of the therapeutic is becoming more complex. Assuring safety in humans is the first and foremost task of a well designed program but assuring safety and application to specific patient populations is also essential to the targeted therapeutic products. Topics to be addressed in this course will include general pathology and physiology issues between species that might contribute to species selection/interpretation, utility of tissue cross reactivity to determine relevant species, considerations into the development of a homologous protein (from bench to beast), development and characterization of animal models as relevant species (including KO animals and models of disease), and additionally what to do if nothing is 'relevant'. The course attendee will learn key concepts in the considerations for designing a predictive program for a biotherapeutic product.

Understanding Comparative Phyiology and Pharmacology, Frank Geoly, Pfizer, Groton, CT

How Similar is Similar: Understanding the Impact of Homologous or Surrogate Protein Development, Jeanine Bussiere, Amgen, Thousand Oaks, CA

How Relevant is Relevant: Understanding the Utility and Impact of Using Transgenic Models and Animal Models of Disease, Joy Cavagnaro, Access BIO, Boyce, VA

Intergration of Concepts into Roadmaps for Development of Novel Biotherapeutics, Laura Andrews, Genzyme, Framingham, MA

New Frontiers in Metal Toxicology: Genetic Susceptibility, Early Diagnosis, and Related Biological Indices

PM12—CE Advanced

Chairperson(s): Wei Zheng, School of Health Sciences Purdue University, West Lafayette, IN and Michael P. Waalkes, NCI at NIEHS, Research Triangle Park, NC

Sponsor: Metals Specialty Section

Endorsed by:
Mechanisms Specialty Section
Neurotoxicology Specialty Section
Occupational and Public Health Specialty Section

Physical and chemical properties of many toxic metals are common in their tendency to donate electrons, their resistance to biotransformation and their similarity in physical sizes and electrical charges. Yet human responses to metal insults are not uniform such that metal-caused diseases may manifest in a particular population and spare in others. Thus, the inherited individual susceptibility must be taken into account when developing strategies for risk assessment or treatment becomes necessary. In many clinical cases, the signs and symptoms of metal intoxication are subtle and imperceptible. Because of these, clinically well defined metal diseases, such as lead-induced learning deficit or manganese-caused parkinsonism, are usually diagnosed too late for an effective therapeutic intervention. Thus, a reliable biomarker of a particular type of metal diseases, developed either based on injuries in biochemical and physiological functions or alterations in cellular signal pathways, bears a quintessential importance in metal toxicological research. This advanced course is intended to address the biological indices of metal toxicities from the angle of individual genetic susceptibility for early diagnosis. The course will provide an overview on metal-related biomarkers established from animal and human studies and the application of these biomarkers, such as lead, in risk assessment. Recent advancement in understanding the genetic susceptibility that contributes to metal-induced toxicities will then be discussed. Manganese will be used as an example to explore novel ideas to use integrated biomarkers combining exposure indices with biological outcomes. Finally, the course will illustrate an innovative way to explore metal biomarkers by targeting at metal interaction with the cellular signal pathways. The course will survey these new frontiers in metal toxicological research by providing details specific to 'hot' metals, such as lead, manganese, arsenic and mercury. The intended audience for this course are those who desire an advanced introduction to mechanisms of metal toxicities, an advanced knowledge on metal-gene interaction and risk assessment, and an advanced technical approach in developing a useful biomarker for metal intoxication. The course will be of interest to others engaged in wider aspects of metal toxicology, neurotoxicology, carcinogenesis, risk assessment, and occupational health.

Introduction: Principles of Metal Toxicology, Curtis D. Klaassen, University of Kansas, Kansas City, KS

Biomarkers of Metal Intoxication: How Predictive Are Exposures of Adverse Effects?, Deborah A. Cory-Slechta, University of Rochester, Rochester, NY

Genetic Susceptibility Underlying Metal-Induced Toxicities, Jie Liu and Michael P. Waalkes, NCI at NIEHS, Research Triangle Park, NC

A Single Parameter Combining Multiple Bio-Indices As a New Approach to Discover Biomarkers of Metal Toxicities: A Case Study with Manganese, Wei Zheng, Purdue University, West Lafayette, IN

Cell Signal Pathways Targeted by Toxic Metals, Michael J. McCabe, University of Rochester, Rochester, NY

Stress As a Confounding Factor in Toxicology Studies

PM13—CE Basic

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.

Stress As a Confounding Factor in Toxicology Studies: Introduction, Katie Sprugel, Amgen, Seattle, WA

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

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

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

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