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2005 Continuing Education Courses

The Continuing Education Program offers a widerange 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.


Fundamentals of Nanotechnology: Chemistry, Exposure, Health/Environmental Assessments, and Societal Impacts

Sunrise MiniCourse 1 BASIC

Chairperson(s): David B. Warheit, DuPont Haskell Laboratory, Newark, DE.

Endorsed by:
Ethical Legal and Social Issues SS
Inhalation SS*
Occupational and Public Health SS
Risk Assessment SS

Nanotechnology is an emerging multidisciplinary science that deals with the creation and use of molecules a few billionths of a meter in size. Assessing the potential hazards of the nanomaterials in this technology, and the products constructed from nanoparticulates is an emerging area in toxicology and health risk assessment. The development of toxicity data sets and exposure assessments for various nanoparticles and nanomaterials is ongoing and evolving as new particles, materials and exposure methodologies are developed. A related issue in toxicology and risk assessment is the extent to which nanoparticle toxicity can be extrapolated from existing toxicology databases for macro and microscale particletypes. Additional information needs that are being addressed include the environmental and biological fate, transport, persistence, and transformation, as well as the recyclability and overall sustainability of manufactured nanoparticles. This sunrise lecture is designed to be a basic primer on the fundamental chemistry and physics of engineered nanostructures. The understanding of the composition of and source generation of particles becomes fundamentally more important when one considers that the surfaces or surface coatings may comprise > 50% composition of small nanoparticles (< 30 nm), and herein will lie the interactions of nanoparticles with cells. Future studies likely will demonstrate that method of particle synthesis, surface coatings, aggregation potential, surface charge, and shape may be as or more important than particle size in modifying biological/toxicological effects. Methods to form materials such as singlewalled carbon nanotubes, fullerenes, quantum dots, nanocrystalline ceramics (e.g., titania), and nanometals will be reviewed. For each material class, the essential properties and applications will be outlined. The tutorial will conclude with a discussion of the actual applications of these high performance materials and projections for the industry growth over the next decade.

  • The Basics of Engineered Nanomaterials for Toxicologists or Tutorial: The Fundamental Chemistry and Physics of Engineered Nanostructures, Vicki L. Colvin, Rice University, Houston, TX.

Dose Considerations for In Vitro Studies

AM02 Basic

Chairperson(s): John B. Morris, University of Connecticut, Storrs, CT, and JeanClare Seagrave, Lovelace Respiratory Research Institute, Albuquerque, NM.

Endorsed by:
In Vitro SS
Inhalation SS*
Risk Assessment SS
Student Advisory Committee (SAC)

Technological advances have made possible the investigation of the cellular effects of air pollutants through variety of in vitro approaches. However, in order to be relevant to human health effects following ambient exposures, these methods must accurately model biologically relevant exposure pathways, doses and responses. This continuing education course will provide both theoretical and practical information on appropriate dose selection and dosage techniques for in vitro studies of air pollutant toxicity. The first presentation will cover the basic concepts of vapor dosimetry including the roles of partitioning, chemical reactivity and local metabolism. Specific information on regional respiratory deposition in laboratory animals and humans and its relevance to cellular microdosimetry will be provided. The second presentation will include specific examples of in vitro approaches with a focus on microdosimetric considerations for reactive gases; in particular the potential biological impacts of surface lining layers and their constituents will be emphasized. Basic concepts of size specific regional particle deposition and clearance will be covered in the third presentation. Specific information on regional respiratory deposition efficiencies in laboratory animals and humans and its relevance to cellular microdosimetry will be provided. The final presentation will describe specific examples of in vitro approaches on particle toxicity with a cellular dosimetric comparison of effects observed in vitro compared to those in vivo. Overall the course is aimed at providing information not only on the importance of employing in vivo dosimetric considerations in designing in vitro studies, but also with providing a firm conceptual foundation for the selection of relevant doses for such work.

  • Dosimetric Considerations for Vapors and Gases, John B. Morris, University of Connecticut, Storrs, CT.
  • In Vitro Systems for Studies of Reactive Gases, Edward Postlethwait, University of Alabama at Birmingham, Birmingham, AL.
  • Dosimetric Considerations for Particles, Richard B. Schlesinger, Pace University, Pleasantville, NY.
  • In Vitro Systems for Studies of Particles, JeanClare Seagrave, Lovelace Respiratory Research Institute, Albuquerque, NM.

Developmental Toxicology Studies: Design, Interpretation, and Risk Assessment

AM03 Basic

Chairperson(s): Joseph F. Holson, WIL Research Laboratories, Inc, Ashland, OH and Ronald D. Hood, RD Hood & Associates, Toxicology Consultants, Tuscaloosa, AL.

Endorsed by:
Reproductive and Developmental Toxicology SS*
Risk Assessment SS

Developmental toxicity studies are among the most complex and challenging in the field of toxicology. They entail multiple and interrelated endpoints and systems that are rapidly changing in characteristics and in their responses to toxic insults over time. These studies inherently generate large data sets. However, because of the decline in relevant training programs, data from developmental toxicity studies are often managed or interpreted by individuals with limited backgrounds in these fields. Although published regulatory agency guidance is available, this course will extend such guidance by presenting in detail current study designs, procedures for study evaluation, and case studies. Lectures will cover fetal endpoints including mortality, growth, visceral exams and skeletal exams, as well as endpoints of maternal toxicity and their relationship to developmental toxicity. Developmental toxicity will be viewed in a broad context, including aspects of postnatal development and multigenerational effects. Proper analysis of developmental toxicity data requires specific statistical considerations, and these will be presented. Finally, putting together all the data from such studies for human risk assessment will be discussed. Considerations of design flexibility, endpoint sensitivities, and use of mode of action analysis and confirmatory studies will be included. Thus, the course will present key information required for understanding the biological and toxicological bases of findings from developmental

  • Evaluation of Fetal Weight, External and Visceral Anomalies in Developmental Toxicity Studies, Donald G. Stump, WIL Research Laboratories, Inc, Ashland, OH.
  • Overview of Developmental Toxicity Study Designs, Endpoints Sensitivities, Statistical Power, Variability, and Use of Historical Control Data, Joseph F. Holson, WIL Research Laboratories, Inc, Ashland, OH.
  • Evaluation of Skeletal Endpoints in Developmental Toxicity Studies, John M. Rogers, U.S. EPA, Research Triangle Park, NC.
  • Use of Developmental Toxicity Data in Risk Assessment, Susan L. Makris, U.S. EPA, Washington, DC.

Clinical Pathology—The Granddaddy of Biomarkers

AM04 Basic

Chairperson(s): Thomas Monticello, SanofiAventis, Bridgewater, NJ and Gail Walter, Gail Walter Consultants, Kalamazoo, MI.

Endorsed by:
Comparative and Veterinary SS
Regulatory and Safety Evaluation SS
Risk Assessment SS
Student Advisory Committee (SAC)
Toxicologic & Exploratory Pathology SS*

Research for novel biomarkers of toxicity continues to grow at a rapid pace. While biomarkers of tissue injury have a long history in the discipline of clinical pathology, the full value of these preclinical datasets are oftentimes under and/or over interpreted by scientists not extensively trained in this discipline. This basic course will emphasize current practices in clinical pathology utilized in drug discovery and preclinical safety studies and will also highlight advances in more novel biomarkers of toxicity. Basic interpretation of clinical pathology parameters will be presented in addition to factors to consider with respect to animal model, study design and the assays themselves. Examples of hepatic biomarkers and more recently identified biomarkers of toxicity will be highlighted. The applicability and pitfalls of utilizing reference ranges will be discussed, as will the approach in determining biological relevance of results versus statistical significance. Finally, regulatory perspectives on complete datasets and data interpretation will be addressed. This course is intended for the general toxicology community to improve their understanding of clinical

  • Clinical Pathology Techniques in Discovery, Safety Assessment and Biomarker Development, Laurie O’Rourke, Novartis, East Hanover, NJ.
  • Coping with Multiple Masters: The Fine Art of Balancing Clinical Pathology and Toxicology in Preclinical Drug Development, Gail Walter, Gail Walter Consultants, Kalamazoo, MI.
  • Avoiding Pitfalls in the Interpretation of the Hemogram and other Clinical Pathology Assays Conducted for Toxicology Testing, Nancy Everds, Dupont Haskell Laboratory, Newark, DE.
  • Regulatory Perspectives on Clinical Pathology Data Analysis, Kenneth Hastings, CDER, U.S. FDA, Rockville, MD.

Immunology for Toxicologists

AM05 Basic

Chairperson(s): Ian Kimber, Syngenta Central Toxicology Laboratory, Macclesfield,Cheshire, United Kingdom and Dori R. Germolec, National Institute for Environmental Health Sciences, Research Triangle Park, NC.

Endorsed by:
Immunotoxicology SS*
Risk Assessment SS

The adaptive immune system 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 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 a variety of forms, those of greatest significance for toxicologists being skin sensitization and allergic contact dermatitis, allergic sensitization of the respiratory tract, food allergy and idiosynctratic allergic drug reactions. Finally, xenobiotics have been implicated in the induction or exacerbation of autoimmune reactions and autoimmune disease. This course will provide a grounding in fundamental and clinical aspects of immunology, and will describe the basic elements immunotoxicity, allergy and autoimmunity. The objective is deliver an accessible guide to the immune system and immunotoxicology for general

  • An Introduction to Immunology: Fundamental and Clinical Aspects, Ian Kimber, Syngenta Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom.
  • Elementary Immunotoxicology, Robert House, DynPort Vaccine Company, Frederick, MD.
  • Allergy and Allergic Disease, MaryJane Selgrade, U.S. EPA, Research Triangle Park, NC.
  • Autoimmunity and Autoimmune Disease, Dori R. Germolec, National Institute for Environmental Health Sciences, Research Triangle Park, NC.

Evaluation of Cardiac Drug Toxicity in Pharmaceutical Discovery ad Development

AM06 (Repeats as PM 12) BASIC

Chairperson(s): Brian Short, Allergan, Irvine, CA and Y. J. Kang, University of Louisville, Louisville, KY.

Endorsed by:
Comparative and Veterinary SS
HESI Biomarkers Technical Committee
Mechanisms SS
Regulatory and Safety Evaluation SS
Student Advisory Committee (SAC)

The heart is an important potential target organ to evaluate in nonclinical and clinical studies during drug development as well as a therapeutic site of action for many cardiovascular diseases. There are examples in almost every therapeutic class of drugs that produced unanticipated cardiotoxicity leading to market withdrawal or cessation of development. Toxicologists are an integral part of an interdisciplinary group, including physiologists, pharmacologists, pathologists, clinicians, and regulators, which assess cardiac safety. As such, toxicologists play a critical role in the screening of pharmaceutical agents for cardiotoxicity as well as in establishing an adequate margin of safety and working basis for monitoring therapeutic endpoints and clinical safety of trial participants. The goal of this continuing education course is to illustrate the integration of physiology, pharmacology, toxicology, and pathology of the heart addressing both recent scientific advances and practical knowledge in pharmaceutical company setting. This course will cover in vitro and in vivo models of druginduced cardiac injury and recent advances in biomarkers of cardiac injury to improve the strategy for detection and nonclinical and clinical monitoring of drugrelated cardiotoxicity. This CE course will provide current understanding of the physiology of the heart with a focus on normal and druginduced disturbances in cardiac electrophysiology and cardiac function, as well as testing strategies for assessing potential cardioactive drug candidates prior to entry into clinical trials. It will also cover basic and advanced knowledge of pathology of the heart, including a review of cardiac pathological evaluation, and provide case examples of the integration of physiological and pathological parameters and risk assessment to humans. Biochemical, cellular and molecular mechanisms of cardiac toxicity, including recent work in experimental animal studies and novel approaches directed toward understanding mechanisms of druginduced cardiac injury, cardiomyopathy and cardiac hypertrophy will be presented. Finally, biomarkers of druginduced cardiac injury will be discussed. This will include a review of the findings of the Expert Working Group on Biomarkers of DrugInduced Cardiac Toxicity, an indepth look at serum troponins, and related work currently in progress under the ILSIsponsored Subcommittee on the Development and Application of Biomarkers of Toxicity.

  • Physiological Basis for Cardiac Drug Toxicity and Evaluation, Robyn L. Phelps, Allergan, Irvine, CA.
  • Integrating Cardiac Pathology into Drug Discovery and Development, Calvert Louden, AstraZeneca Pharmaceuticals, Wilmington, DE.
  • Mechanisms of DrugInduced Cardiotoxicity, Y. J. Kang, University of Louisville, Louisville, KY.
  • Biomarkers of DrugInduced Cardiac Toxicity, Malcolm J. York, GlaxoSmithKline, Ware, Hertfordshire, United Kingdom.

International Harmonization of Technical Requirements for Conducting NonClinical Safety Studies of Human Pharmaceuticals: Guidelines, Case Studies, and Challenges

AM07 (Repeats as PM 13) BASIC

Chairperson(s): Rakesh Dixit, Merck Research Laboratories, West Point, PA.

Endorsed by:
Carcinogenesis SS*
Regulatory & Safety Evaluation SS
Risk Assessment SS

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 to standardize and harmonize technical requirements for the worldwide marketing approval of human pharmaceuticals. The six party ICH comprises the regulatory agencies and researchbased pharmaceutical industrial organizations from three major geographical areas, the United States, the European Union and the Japan. The major goals of the ICH process are to minimize unique regional requirements, reduce the duplication of nonclinical toxicology and clinical testing requirements, and to accelerate the global development, registration and marketing of human pharmaceuticals in a costeffective manner. Under Safety topics (nonclinical safety), 15 major guidelines have been harmonized and implemented through three major global regulatory agencies. These include guidelines on technical requirements for genotoxicity, toxicity, carcinogenicity, reproductive and development toxicity, biotechnology safety, toxicokinetics, safety pharmacology and joint safety and efficacy. This course is designed to provide a thorough understanding of the rationale behind ICH guidelines and the utility of the ICH guidelines in accelerating and global harmonization of safety evaluation of pharmaceuticals. The presentations will also highlight case studies with detailed examples, and experience in conducting nonclinical ICH safety studies. The presentations will also discuss the challenges, and problems encountered due to the differences in the interpretation, and the acceptance of the ICH Guidelines by the practicing regulatory organizations, reviewers and the traditional practices of specific geographical areas.

  • Guidelines on Genotoxicity Testing: Case Studies, Study Interpretation and Challenges, Sheila Galloway, Merck Research Laboratories, West Point, PA.
  • Developmental and Reproductive Toxicology Testing: Case Studies Study Interpretation and Challenges, Maureen Fesuton, SanofiSynthelabo, PA.
  • Chronic Toxicity, Carcinogenicity and Toxicokinetics Guidelines: Case Studies and Challenges, Rakesh Dixit, Merck Research Laboratories, West Point, PA.
  • U.S. FDA's Experience and Guidance Related to ICH Safety Guidelines, David JacobsonKram, U.S. FDA, Rockville, MD.

Male Reproductive Hazard Identification and Risk Assessment

PM 08 ADVANCED

Chairperson(s): Michael W. Conner, Theravance, Inc., South San Francisco, CA and Robert E. Chapin, Pfizer, Inc., Groton, CT.

Endorsed by:
Reproductive and Developmental Toxicology SS
Regulatory and Safety Evaluation SS
Toxicologic & Exploratory Pathology SS

In the preclinical development of pharmaceuticals, there are numerous opportunities to observe effects on the male reproductive system. There are relevant endpoints in both routine repeateddose toxicity studies and in the developmental and reproductive toxicity studies. In recent years methods for identification of male reproductive injury have expanded well beyond the traditional endpoints of fecundity in rodent fertility studies and routine microscopic examination of testes in repeateddose and reproductive toxicity studies. There is an expectation, for instance, that pathologists will examine testes with knowledge of and reference to the stages of the seminiferous epithelium. Assessment of number, motility and frequency of morphological abnormalities in epidydimal sperm has become routine in rodent fertility studies. Recently, some emphasis has also been placed on identification of biomarkers for testicular injury. The next steps following identification of a signal are ill defined. The purpose of this continuing education course is to address what types of signals are commonly observed and to present a rationale for interpreting these data with regard to risk assessment for volunteers and patients. The speakers in this course will place an emphasis on case studies and will provide their proposals for subsequent preclinical and/or clinical investigations. We will deal with the issue of reversible vs. irreversible injury, and review the latest data on the differences between these two. We will hear case reports on investigative mechanistic studies and when they are best pursued, and the course will close with a review of the considerations that should be addressed when riskassessing male reproductive findings.

  • Early Signal Identification, Dianne Creasy, Huntingdon Life Sciences, East Millstone, NJ.
  • Signals in Primates—Reversible and Irreversible Injury, Kim Boekelheide, Brown University, Providence, RI.
  • Further Characterization of Male Reproductive Injury—Case Studies, Patrick J. Wier, GlaxoSmithKline, King of Prussia, PA.
  • Safety Assessment for Male Reproductive Injury, Robert E. Chapin, Pfizer, Groton, CT.

Development and Interpretation of Toxicokinetic Data

PM 09 ADVANCED

Chairperson(s): John Lipscomb, U.S. EPA/ORD, Cincinnati, OH and Jos Bessems, TNO, Zeist, Netherlands.

Endorsed by:
Regulatory and Safety Evaluation SS
Risk Assessment SS*
Student Advisory Committee (SAC)

Drug development and environmental health risk assessment activities are based on knowledge of chemical disposition and tissue interactions, that may be separately considered as toxicokinetics (TK) and toxicodynamics (TD). Each activity is initiated with valuation of basic toxicity information, including characterizing effective doses and the doseresponse relationship identifying critical organs, tissues and processes; examining metabolic characteristics and the toxic nature of metabolites. Each activity culminates with the assessment of TK and TD relative to the concentration/doseresponse relationship. This basic continuing education course is intended for the general toxicologist desiring to increase the use of TK data to build compound dossiers, and to address the needs of scientists designing toxicity and pharmacokinetic studies, preclinical and clinical studies, and conducting safety and/or risk assessments. Four lectures will be presented; content will address the design, conduct and evaluation of studies to inform an understanding of chemical disposition and effectiveness in the biological system. Instruction will be given on the considerations of doses and concentrations used in wholeanimal toxicity and ADME studies and in in vitro investigations; the biochemical basis of chemical metabolism and the considerations and assumptions necessary to interpret metabolism findings; best use of TK data to inform doses intended for use in TD studies; extrapolations of effective doses between and among species through the use of default and chemicalspecific uncertainty/adjustment factors; available guidance on uncertainty factor derivation for human health risk assessment; overview of PBPK modeling and its application to extrapolations of dose, route and duration, between and among species; and the basis and results of choice of classical or PBPK modeling for drug development and risk assessment.

  • Use of ADME Data in Toxicity Study Design, Jos Bessems, TNO, Zeist, Netherlands.
  • Combining Toxicokinetic and Toxicodynamic Data for Application in Drug Development, Rakesh Dixit, Merck Research Laboratories, West Point, PA.
  • Use of Compound Specific and General Kinetic Data in Human Risk Assessment, John Lipscomb, U.S. EPA / ORD, Cincinnati, OH.
  • Physiologically Based Pharmacokinetic Modeling, Hugh Barton, Research Triangle Park, NC.

Phototoxicity: Current Concepts, Experimental Designs, and Regulatory Expectations

PM 10 Basic

Chairperson(s): Joseph Tigner, Purdue Pharma L.P., Ardsley, NY and Vincent A. Murphy, P&G Pharmaceuticals, Inc., Cincinnati, OH.

Endorsed by:
Regulatory and Safety Evaluation SS*
Risk Assessment SS

Exposure to solar ultraviolet and visible radiation produces acute and chronic skin damage. Chemicals, including pharmaceutical agents, may exacerbate such effects following topical or systemic exposure. The aim of phototoxicological testing is to predict the likelihood of such events using various in vivo and in vitro models. The purpose of this course is to familiarize toxicologists with the basic concepts of phototoxicological testing. This is especially important in light of recent U.S. and European regulatory guidances relating to photosafety testing. The program will describe the comparative anatomy, physiology, and basic photobiology of the skin, the basic principles and experimental designs used in phototoxicity testing in nonclinical species and people as well as in vitro models. The course will also address the most recent regulatory guideline

  • Effect of Light on the Structure and Function of Skin, J.F. Nash, The Procter & Gamble Co., Cincinnati, OH.
  • Phototoxicity, Photocarcinogenicity, and Photoallergy, Study Designs and Issues, P. Donald Forbes, Argus ResearchCharles River, Horsham, PA.
  • Drug Phototoxicity in Humans: A Randomized Controlled Trial Methodology, James Ferguson, Dundee, Scotland.
  • CDER/FDA Photosafety Guidance for Industry, Abigail Jacobs, U.S. FDA/CDER, Rockville, MD.

Something Old, Something New; Traditional and Novel

PM 11 Basic

Chairperson(s): Susan Emeigh Hart, AstraZeneca Pharmaceuticals, Wilmington, DE and Syril Pettit, ILSI Health and Environmental Sciences Institute (HESI), Washington, DC.

Endorsed by:
Risk Assessment SS
Toxicologic & Exploratory Pathology SS*

Because the kidney is an important target organ of toxicity, there is a need for sensitive, specific and noninvasive assays that can be used to detect lowlevel, potentially reversible renal injury in both animal toxicology studies and the clinical setting. Most of the available techniques do not allow identification of the segment(s) of the kidney affected by a toxicant. Better understanding of the pathophysiology of nephrotoxic processes, combined with information arising from genomic, proteomic and molecular biologic assessment of the effects of nephrotoxic chemicals has led to the identification of several promising new candidates that might serve as sensitive, segmentselective biomarkers of nephrotoxicity that can be applied readily in both the preclinical and clinical settings with adequate testing and validation. This basic CE course will provide an overview of renal structure and function, discuss the appropriate use and limitations of traditional clinical pathology assessment of renal injury, and describe the processes necessary for appropriate validation and subsequent regulatory acceptance of a novel biomarker. The final two speakers will describe the novel biomarker candidates under consideration by the Nephrotoxicity Working Group of the ILSIHESI Technical Committee on the Development and Application of Biomarkers of Toxicity. The first of these will provide an overview of novel biomarkers for proximal tubular injury while the second will discuss the pathophysiology of renal papillary necrosis and how it relates to the identification of novel biomarkers

  • Technical and Regulatory Issues in Biomarker Selection and Validation, James T. MacGregor, Toxicology Consulting Services, Arnold, MD.
  • Classical Clinical Pathology Approaches to the Assessment of Renal Structure and Function, Denise Bounous, BristolMeyers Squibb Company, Princeton, NJ.
  • Emerging Biomarkers of Renal Proximal Tubular Injury, Ernie Harpur, SanofiSynthelabo Research, Malvern, PA.
  • Emerging Biomarkers of Renal Papillary Necrosis, Susan Emeigh Hart, AstraZeneca Pharmaceuticals, Wilmington, DE.

Evaluation of Cardiac Drug Toxicity in Pharmaceutical

PM 12 (Repeats as AM 06) BASIC

Chairperson(s): Brian Short, Allergan, Irvine, CA and Y. J. Kang, University of Louisville, Louisville, KY.

Endorsed by:
Comparative and Veterinary SS
HESI Biomarkers Technical Committee
Mechanisms SS
Regulatory and Safety Evaluation SS

The heart is an important potential target organ to evaluate in nonclinical and clinical studies during drug development as well as a therapeutic site of action for many cardiovascular diseases. There are examples in almost every therapeutic class of drugs that produced unanticipated cardiotoxicity leading to market withdrawal or cessation of development. Toxicologists are an integral part of an interdisciplinary group, including physiologists, pharmacologists, pathologists, clinicians, and regulators, which assess cardiac safety. As such, toxicologists play a critical role in the screening of pharmaceutical agents for cardiotoxicity as well as in establishing an adequate margin of safety and working basis for monitoring therapeutic endpoints and clinical safety of trial participants. The goal of this continuing education course is to illustrate the integration of physiology, pharmacology, toxicology, and pathology of the heart addressing both recent scientific advances and practical knowledge in pharmaceutical company setting. This course will cover in vitro and in vivo models of druginduced cardiac injury and recent advances in biomarkers of cardiac injury to improve the strategy for detection and nonclinical and clinical monitoring of drugrelated cardiotoxicity. This CE course will provide current understanding of the physiology of the heart with a focus on normal and druginduced disturbances in cardiac electrophysiology and cardiac function, as well as testing strategies for assessing potential cardioactive drug candidates prior to entry into clinical trials. It will also cover basic and advanced knowledge of pathology of the heart, including a review of cardiac pathological evaluation, and provide case examples of the integration of physiological and pathological parameters and risk assessment to humans. Biochemical, cellular and molecular mechanisms of cardiac toxicity, including recent work in experimental animal studies and novel approaches directed toward understanding mechanisms of druginduced cardiac injury, cardiomyopathy and cardiac hypertrophy will be presented. Finally, biomarkers of druginduced cardiac injury will be discussed. This will include a review of the findings of the Expert Working Group on Biomarkers of DrugInduced Cardiac Toxicity, an indepth look at serum troponins, and related work currently in progress under the ILSIsponsored Subcommittee on the Development and Application of Biomarkers of Toxicity.

  • Physiological Basis for Cardiac Drug Toxicity and Evaluation, Robyn L. Phelps, Allergan, Irvine, CA.
  • Integrating Cardiac Pathology into Drug Discovery and Development, Calvert Louden, AstraZeneca Pharmaceuticals, Wilmington, DE.
  • Mechanisms of DrugInduced Cardiotoxicity, University of Louisville, Louisville, KY.
  • Biomarkers of DrugInduced Cardiac Toxicity, Malcolm J. York, GlaxoSmithKline, Ware, Hertfordshire, United Kingdom.

International Harmonization of Technical Requirements for Conducting NonClinical Safety Studies of Human Pharmaceuticals: Guidelines, Challenges

PM 13 (Repeats AM 07)

Chairperson(s): Rakesh Dixit, Merck Research Laboratories, West Point, PA.

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 to standardize and harmonize technical requirements for the worldwide marketing approval of human pharmaceuticals. The six party ICH comprises the regulatory agencies and researchbased pharmaceutical industrial organizations from three major geographical areas, the United States, the European Union and the Japan. The major goals of the ICH process are to minimize unique regional requirements, reduce the duplication of nonclinical toxicology and clinical testing requirements, and to accelerate the global development, registration and marketing of human pharmaceuticals in a costeffective manner. Under Safety topics (nonclinical safety), 15 major guidelines have been harmonized and implemented through three major global regulatory agencies. These include guidelines on technical requirements for genotoxicity, toxicity, carcinogenicity, reproductive and development toxicity, biotechnology safety, toxicokinetics, safety pharmacology and joint safety and efficacy. This course is designed to provide a thorough understanding of the rationale behind ICH guidelines and the utility of the ICH guidelines in accelerating and global harmonization of safety evaluation of pharmaceuticals. The presentations will also highlight case studies with detailed examples, and experience in conducting nonclinical ICH safety studies. The presentations will also discuss the challenges, and problems encountered due to the differences in the interpretation, and the acceptance of the ICH Guidelines by the practicing regulatory organizations, reviewers and the traditional practices of specific geographical areas.

  • Guidelines on Genotoxicity Testing: Case Studies, Study Interpretation and Challenges, Sheila Galloway, Merck Research Laboratories, West Point, PA
  • Developmental and Reproductive Toxicology Testing: Case Studies Study Interpretation and Challenges, Maureen Fesuton, SanofiSynthelabo, PA.
  • Chronic Toxicity, Carcinogenicity and Toxicokinetics Guidelines: Case Studies and Challenges, Rakesh Dixit, Merck Research Laboratories, West Point, PA.
  • U.S. FDA's Experience and Guidance Related to ICH Safety Guidelines, David JacobsonKram, U.S. FDA, Rockville, MD.