x



Share this page.

2002 Continuing Education Courses

The Continuing Education Program offers a widerange 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.


Use of Laser Capture Microdissection (LCM) in Molecular Toxicology Research

Sunrise Mini Course01 Basic

Governor’s A

Speaker: Jeffrey I. Everitt, CIIT Centers for Health Research, Research Triangle Park, NC.

Endorsed by:
The Molecular Biology Specialty Section
The Toxicologic and Exploratory Pathology Specialty Section

Laser capture microdissection (LCM) is a recently developed technique that allows one to rapidly procure morphologically defined cell populations from sections of heterogenous tissues using direct visualization. This technique has greatly expanded the ability of the toxicologist to conduct molecular analyses on a wide array of specific target cells and tissues of interest. Cells obtained by microdissection have been used as a source of genomic DNA, the isolation of mRNA amenable to reverse transcription polymerase chain reaction (RTPCR), and the generation of expression libraries. LCM has been combined with cDNA microarray hybridization techniques and proteomic methods to provide new and exciting approaches for combining gene expression with traditional morphological methods. This seminar will review microdissection methods and equipment and discuss the utility of LCM in toxicology studies.

A Practical Approach to Blood and Lymphoid Tissue (BLT) in Toxicology Assessments

AM02 Basic

Presidential B

Chairpersons: JoAnn C. L. Schuh, Applied Veterinary Pathobiology, Bainbridge Island, WA and Lynda Lanning, BioReliance, Rockville, MD.

Endorsed by:
The Toxicologic and Exploratory Pathology Specialty Section

Blood, bone marrow, thymus, spleen, lymph nodes and mucosaassociated lymphoid tissue are a complicated, but important interactive system of tissues and cells modulated directly and indirectly by xenobiotics. Evaluation of blood and lymphoid tissues (BLT) has always been part of a standard histopathology and toxicology screen, but advanced evaluations of BLT are becoming increasingly important to the rapidly changing fields of immunotoxicology and immunotherapeutic development. The objective of this basic course is to provide contemporary information on the pathophysiology of BLT useful to individuals in regulatory and research areas of toxicology. This course will review important features of i) basic anatomy, function, and evaluation of blood and blood forming organs, ii) anatomy and function of lymphoid tissues and their component parts, iii) terminology, iv) general and toxic immunomodulation, and v) pathophysiology (neoplastic and nonneoplastic responses). Species, sex and age specific differences that may affect the design and outcome of studies, and techniques used to evaluate BLT will be discussed. A practical understanding of the anatomy, terminology, and toxicologic pathology associated with BLT, will aid toxicologists in making proper interpretation of treatmentrelated changes in safety and efficacy studies, and in communicating this information between disciplines, within teams and to regulatory agencies.

  • Practical Approaches to BLT: Finding Them, Collecting Them, and Analyzing Them, Lynda Lanning, BioReliance, Rockville, MD.
  • Bare Bones Blood and Bone Marrow, Gregg Travlos, NIEHS, Research Triangle Park, NC.
    Essential Lymph Nodes, Peter Mann, Experimental Pathology Labs., Inc., Research Triangle Park, NC.
  • Thymic and Splenic Splendor, Michael Leach, BASF, Worcester, MA.
  • Lymphoid Aggregates of Mucosal and Nonlymphoid Tissues, JoAnn C., L. Schuh, Applied Veterinary Pathobiology, Bainbridge Island, WA.

Alterations in Gene Expression as a Mechanism of Toxicant Action

AM03 Advanced

Governor’s A

Chairperson: Ronald N. Hines, Medical College of Wisconsin, Milwaukee, WI.

Endorsed by:
The Molecular Biology Specialty Section
The Regulatory and Safety Evaluation Specialty Section
The Reproductive and Developmental Specialty Section

Over the last several years, it has become apparent that many environmental toxicants exert their effects by the activation or disruption of specific signaling pathways, ultimately resulting in alterations in gene expression. With the completion of the human genome project and the advent of many powerful new technologies, there has been a revolution in our understanding of these mechanisms on the molecular level. This continuing education course will review our current state of knowledge regarding toxicantinduced alterations in gene expression and also identify future directions and research opportunities. The first speaker will focus on our current understanding of the mechanism(s) whereby four receptors, i.e., the Ah receptor (AhR), the Constitutive Androstane Receptor (CAR), the Pregnane X Receptor (PXR), and the Peroxisome Proliferator Activated Receptor (PPAR), mediate the toxicity of four broad classes of chemicals. In contrast to these specific receptor mechanisms, metals exert their toxicity through both stressresponse pathways, as well as specific metalresponsive transcription factors. The second speaker will focus on our current understanding of these pathways of toxicant action. The third speaker will review the many exciting discoveries in our understanding of how toxicants alter gene expression during specific windows of development and thereby exert their teratogenic effects. Finally, the fourth speaker will discuss the role of tissueselective transcription factors on the expression of xenobiotic metabolizing enzymes and how this process impacts toxicant susceptibility. As an advanced course, this curriculum should appeal to toxicologists whose research is in or immediately peripheral to this focus area, but who are interested in gaining a better understanding of the overall subject and its future direction.

  • ReceptorMediated Toxicant Action, Qiang Ma, CDC/NIOSH, Morgantown, WV.
  • MetalInduced Alterations in Gene Expression, Glen K. Andrews, University of Kansas Medical Center, Kansas City, KS.
  • Alterations in Gene Expression as a Mechanism of Teratogenesis, Philip E. Mirkes, University of Washington, Seattle, WA.
  • Role of TissueSelective Transcription Factors in Regulating Xenobiotic Metabolizing Enzymes, Ronald N. Hines, Medical College of Wisconsin, Milwaukee, WI.

Integrating Toxicologic Pathology into Compound Evaluation and Risk Assessment

AM04 Basic

Governor’s B

Chairpersons: Douglas C. Wolf, USEPA, Durham, NC and Jerry F. Hardisty, Experimental Pathology Laboratory, Research Triangle Park, NC.

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

Pathology endpoints are the central response around which human health risk assessment is determined. This course is designed for the general toxicology community to gain an understanding of the basics of toxicologic pathology. Toxicologic pathology encompasses the study of changes in tissue morphology that help define the risk of exposure to xenobiotics. The first presentation will review the basics of pathology studies including tissue processing, pathology review, standard techniques, and efforts being made to standardize the conduct, review, and reporting of pathology studies which are important for appropriate interpretation of data. Other speakers will discuss the structural and functional aspects of the liver and kidney and the general concepts of mechanisms of injury, species and sex differences, background and induced lesions, which are necessary for appropriate risk characterization. The liver is the most common target for xenobioticinduced adverse effects and the kidney has a central role in filtration, metabolism, and excretion and is frequently a site of toxic injury. Correlating clinicopathology with morphologic and functional alterations is necessary for full understanding of adverse effects. Finally, diagnostic terminology, study data relative to cancer bioassay findings, the steps in tumor development, and their relevance to human health risk will be presented.

  • The Pathologist and Pathology Data—the Art and the Craft, Jerry F. Hardisty, Experimental Pathology Laboratory, Research Triangle Park, NC.
  • Integrating Liver Pathology into Toxicity Evaluation, Richard T. Miller, GlaxoSmithKline, Research Triangle Park, NC.
  • Integrating Kidney Pathology into Toxicity Evaluation, Jeffrey I. Everitt, CIIT Centers for Health Research, Research Triangle Park, NC.
  • Interpreting the Pathology from Chemical Carcinogens for Risk Assessment, Douglas C. Wolf, USEPA, Durham, NC.

Basic Principles and Protocols in Molecular Toxicology

AM05 (repeats as PM 13) Basic

Presidential E

Chairpersons: William B. Mattes, Pharmacia, Kalamazoo, MI and John W. Davis, II, Schering Plough Research Institute, Lafayette, NJ.

Endorsed by:
The Molecular Biology Specialty Section

Many of the mechanisms through which xenobiotics affect tissues or cells occur at the molecular level. Over the past ten or fifteen years the use of molecular techniques to dissect mechanisms of toxicity has grown greatly. These techniques are used to identify growth regulatory pathways, alterations in gene and/or protein expression, as well as proteinDNA and proteinprotein interactions. Accordingly, there has been an explosion in the number of reagents and kits that are commercially available. While these kits and reagents have facilitated the detection of mechanisms of toxicity, a basic understanding of the methods used is just as important. This course will detail a number of basic techniques currently in use in an attempt to give a researcher new to this area information as to which tools may be most relevant with regards to their specific research area. Presentations will include the practical considerations when setting up a given technique as well as references that will help the investigator trouble shoot these systems. Finally, actual data will be shown in an effort to demonstrate the kinds of information that can be obtained by these experiments and the ways in which this information can be interpreted and used to develop hypothesisdriven research. This is a basic level course intended to introduce to the researcher the tools and references that are available to him or her.

  • Basic Protocols and Principles in Nucleic Acid Manipulation, Mary K. Walker, University of New Mexico, Albuquerque, NM.
  • Using Polymerase Chain Reaction in Molecular Toxicology, Jack P. Vanden Heuvel, Penn State University Center for Molecular Toxicology, University Park, PA.
  • Design, Construction and Use of Reporter and Expression Vectors, Michael S. Denison, University of CaliforniaDavis, Davis, CA.
  • Basic Techniques in Detecting Proteins and Protein: Protein Interactions, John W. Davis, II, Schering Plough Research Institute, Lafayette, NJ.

Two-Stepping through Toxicogenomics: A Basic Primer

AM06 Basic

Presidential A

Chairpersons: Mary Jane Cunningham, Molecular Mining Corporation, Kingston, Ontario, Canada and Timothy Zacharewski, Michigan State University, East Lansing, MI.

Endorsed by:
The In Vitro Specialty Section
The Mechanisms Specialty Section
The Risk Assessment Specialty Section

Toxicogenomics as used here is broadly defined as gene and protein expression technologies and their application to addressing pertinent issues of toxicology. This basic course will start with an overview of how genomics and proteomics came into existence. Different microarray formats will be covered including cDNA, oligonucleotide, fiber optic, and highthroughput versions of gene expression microarrays as well as a broad overview on proteomics and data analysis. Several landmark papers will be discussed showing how genomics and proteomics can be applied. An indepth presentation will follow detailing how to set up and run your own microarrays and will cover array manufacture, sample preparation, array hybridization and scanning, and image analysis. In addition, setting up and running 2D protein gels will be discussed as well as their interpretation using mass spectroscopy. With all of these technologies, complex data sets are generated and the final presentation will discuss alternative statistical and bioinformatic methods which can be used to analyze the data.

  • Genomics and Proteomics: History and Application to Toxicology, Mary Jane Cunningham, Molecular Mining Corporation, Kingston, Ontario, Canada.
  • Gene Expression Microarrays: The DoItYourself Guide, Timothy Zacharewski, Michigan State University, East Lansing, MI.
  • Elements and Functions of a Toxicoproteomics Lab.,
    B. Alex Merrick, NIEHS, Research Triangle Park, NC.
  • Various Data Analysis Formats for Gene and Protein Expression Methods, Roland Somogyi, Molecular Mining Corporation, Kingston, Ontario, Canada.

Challenges in Development of Anticancer Drugs

AM07 Basic

Presidential C

Chairpersons: Vijayapal Reddy, Eli Lilly and Company, Greenfield, IN and Adaline Smith, National Cancer Institute, Rockville, MD.

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

Preclinical and clinical drug development for anticancer drugs differ from other pharmaceuticals, because of the lifethreatening nature of the disease. Treatment with anticancer drugs at clinically efficacious doses usually induces serious side effects, but often less threatening to patients than their disease. The design of preclinical toxicology studies for anticancer drugs is intended to identify a safe clinical starting dose, characterize toxicities that may be encountered in human clinical trial, and determine whether these toxicities are reversible, manageable, and predictable. This basic course will focus on different aspects of preclinical and clinical anticancer drug development. The first speaker will present differences in the preclinical drug development philosophy between different classes of anticancer drugs (e.g., cytotoxic, immunomodulators, and modulatory drugs). The second speaker will discuss the prediction of human tolerated dose using in vitro hematotoxicity tests and the integration of this knowledge into preclinical modeling and toxicology. The third speaker will focus on regulatory considerations for preclinical development of anticancer drugs. The fourth speaker will discuss the clinical development of anticancer drugs. The final speaker will review the special preclinical and clinical regulatory issues associated with the development of biologics for the treatment of cancer. This basic drug development course is targeted to government, biotechnology and pharmaceutical toxicologists, as well as physicians and general toxicologists with an interest in cancer chemotherapy.

  • Preclinical Development Philosophy between Different Classes of Anticancer Drugs, Joseph E. Tomaszeski, National Cancer Institute, Bethesda, MD.
  • Myelotoxic Effects of Anticancer Drugs on Human, Canine, and Murine Myeloid Progenitor Cells Using In Vitro Hematotoxicology Assays, Ralph E. Parchment, Karmanos Cancer Institute, Detroit, MI.
  • Regulatory Considerations for Preclinical/Clinical Development of Anticancer Drugs, John K. Leighton USFDA, Rockville, MD.
  • Clinical Development of Anticancer Drugs, John Wright, National Cancer Institute, Bethesda, MD.
  • Preclinical and Clinical Regulatory Issues Associated with the Development of Biologics, Alexandra Worobec, USFDA, Rockville, MD.

Incorporation of Pharmacokinetic and Pharmacodynamic Data into Risk Assessments

AM08 Advanced

Governor’s C

Chairpersons: John C. Lipscomb, USEPA/ORD/NCEA, Cincinnati, OH and Lynne Haber, Toxicology Excellence for Risk Assessment, Cincinnati, OH.

Endorsed by:
The Biological Modeling Specialty Section
The In Vitro Specialty Section
The Risk Assessment Specialty Section

The increasing attention to chemicalspecific mechanistic data in human health risk assessments should encourage researchers and programmers to identify and develop riskrelevant information. Recently, guidance for replacing default uncertainty factors with adjustment factors based on chemicalspecific data has been made available. This course will investigate recent and emerging approaches to metabolism, pharmacokinetics, and pharmacodynamics with respect to producing data adequate for inclusion in human health risk assessments, and methods to use such data in risk assessment. Physiologicallybased pharmacokinetic (PBPK) modeling has developed riskrelevant information, but the "validation" of these models for some chemicals in humans may be problematic. In some instances, the best available data may be generated in vitro and in silico and require extrapolation to the in vivo setting. PBPK models then become attractive and can be used to estimate riskrelevant, mechanisticallyrelated PK outcomes, and variance thereof, when adequate biochemical and physiologic/anatomic information are incorporated. Human interindividual variance is presently addressed in the uncertainty factors (UFH) used to derive safe levels of exposure. The quantification of human variance through in vivo, in vitro, and in silico approaches will be presented. This will include the evaluation of genetic and environmental modulation of biochemical individuality (e.g., polymorphisms and coexposures) and their impact on tissue dosimetry and agerelated differences in humans.

  • Overview/Introduction: Pharmacokinetics, Uncertainty Factors and the Risk Assessment Process, John C. Lipscomb, USEPA /ORD/NCEA, Cincinnati, OH.
  • Guidance for Adequacy of Data as a Basis for Development of CompoundSpecific Adjustment Factors, Bette Meek, Health Canada, Ottawa, Ontario, Canada.
  • In Silico Approaches for PBPK Modeling and Estimation of Interindividual Variance, Kannan Krishnan, University of Montreal, Montreal, Quebec, Canada.
  • In Vitro to In Vivo Extrapolations of Metabolic Rate Constants and their Use in PBPK Modeling, Gregory L. Kedderis, CIIT Centers for Health Research, Research Triangle Park, NC.
  • Use of PBPK Modeling to Evaluate Implications of Human Variability, Harvey Clewell, ENVIRON Corporation, Ruston, LA.

Toxicology of Naturally Occurring Toxins—Don’t Mess with Mother Nature!

PM09 Basic

Governor’s B

Chairperson: Frederick W. Oehme, Comparative Toxicology LaboratoriesKansas State University, Manhattan, KS and Robert W. Coppock, Alberta Research Council, Vegreville, AB, Canada.

Endorsed by:
The Comparative and Veterinary Specialty Section
The Food Safety Specialty Section
The Toxicologic and Exploratory Pathology Specialty Section

Natural toxins are generally not recognized for their true importance. The benign perception that nature is all healing is contradicted by the numerous but often little appreciated public risks from contact with venomous animals and use of plants as herbal remedies. Lack of understanding these hazards produces a false sense of societal security. To update the SOT membership about the range, potency, and mechanisms of action of poisons found in nature, this basic course will illustrate the chemical risks, compositions, mechanisms of action, effects and effective therapies for animal venoms, growing plants, and herbal products. Each speaker is a nationally recognized expert in their presentation's themes. Drs. Wallace and Peterson recognize and manage snake, reptile, and arthropod envenomations in their daily toxicology practices. Poison Center director, Dr. Furbee, overviews repeated exposures to poisonous plants with a working knowledge of each plant's poisonous principle(s). Dr. Kois west coast laboratory deals with the variety of toxicology events from herbal products. Each speaker will provide personal experiences and the characteristics, toxicologic mechanisms and effects of specific intoxications, alerting toxicologists more familiar with sterile and urban environments with the circumstances and dangers afforded by Mother Nature. This unique continuing education course gives insight into the living dangers around us by providing current toxicological knowledge about these everyday lifestyle hazards. "Naturally Occurring Toxins" will be timely, of wide professional and public interest, and certainly stimulating to our broad audience.

  • Rattlesnake and Gila Monster Envenomations, Kevin L. Wallace, Good Samaritan Regional Medical CarePhoenix, Phoenix, AZ.
  • Venomous Arthropods, Michael E. Peterson, Reid Veterinary Hospital, Albany, OR.
  • Plant Poisons, Brent Furbee, Indiana Poison Center, Indianapolis, IN.
  • Herbal Toxicity, Richard Ko, California Department of Health Services, Sacramento, CA.

Regulation of Drug and ChemicallyInduced Apoptotic Cell Death: New In Vivo Perspectives

PM10 Advanced

Presidential B

Chairpersons: Sid D. Ray, Long Island University, Brooklyn, NY and Stephen B. Pruett, Louisiana State University Medical Center, Shreveport, LA.

Endorsed by:
The Molecular Biology Specialty Section

Apoptosis is a natural consequence in vivo, and there is now substantial evidence that apoptosis plays an important role in the toxic effects of a number of drugs and chemicals. Although it is a naturallyorchestrated selflimiting program, a vast majority of the investigators employ in vitro models to interpret in vivo mechanisms. While in vitro assays are relatively sensitive, specific, and reliable, an ongoing question is the reproducibility of such mechanisms in complex in vivo systems. Therefore, one of the primary goals of this course is to discuss coherently numerous proposed pathways that regulate this cell suicidal process and test their feasibility in in vivo models. The overall objectives of this CE course are: (i) an overview of role of apoptosis during target organ toxicities (cardiotoxicity, hepatotoxicity, nephrotoxicity, and immunotoxicity), (ii) a broad review of mechanisms of action of targetorgan specific apoptogenic drugs and chemicals; and (iii) a discussion of mechanisms that regulate apoptosis at the organ, cellular, sub cellular, and molecular levels. Since oxidative stress, caspases, caspaseactivated DNAse, reactive oxygen species, mitochondrial, and cell cyclerelated events are known to modulate this process, their contributory roles will be a brief part of the curriculum. The concepts gained from this course will be useful to teachers and researchers involved in target organ toxicology, biochemical toxicology, general toxicology, carcinogenesis, molecular toxicology, and mechanistic toxicology.

  • Drug and Chemicallyinduced Apoptotic and AntiApoptotic Mechanisms in the Liver and Kidneys In Vivo, Sid D. Ray, Long Island University, Brooklyn, NY.
  • Apoptosis and Cardiotoxicity: Signaling Mechanisms, James Kang, University of Louisville, Louisville, KY.
  • Apoptosis in Immunotoxicology: Roles of Caspases, Stephen B. Pruett, Louisiana State University Medical Center, Shreveport, LA.
  • Apoptosis and Cell Cycle Control: Recent Advances, Nelu Jena, WhiteHead Institute, MIT, Cambridge, MA.

Internal Dosimetry: Measurement of DNA Damage as an Indicator of Internal Exposure to Genotoxicants

PM11 Advanced

Presidential A

Chairperson: Barbara S. Shane, Integrated Laboratory Systems, Research Triangle Park, NC.

Endorsed by:
The Carcinogenesis Specialty Section
The Environmental Mutagen Society
The Epidemiology Specialty Section

Large molecular weight chemical carcinogens, including polycyclic aromatic hydrocarbons, aromatic and heterocyclic amines, and aflatoxins, are encountered in the ambient environment, the work place and in our food supply. These carcinogens usually require metabolic activation before becoming adducted to DNA. The covalent DNA adducts which are formed, often termed "bulky" adducts, distort the conformation of the DNA helix and are typically removed from the DNA by nucleotide excision repair. However, some proportion of these adducts are not repaired and following cell division can result in a mutation. Other promutagenic events (malondialdehydeDNA adducts) occur as the result of oxidative damage resulting from endogenous metabolic processes and exposure to xenobiotics that initiate a lipid peroxidation cascade. A third type of DNA damage results from agents that induce strand breaks or crosslinking. The first two talks will discuss the spectrometric, immunochemical, and postlabelingbased approaches that can be used to measure both bulky adducts and those caused by lipid peroxidation products. The third talk will describe the single cell gel (Comet) assay that is used to measure strand breaks, alkalilabile sites, and crosslinking. The final talk will focus on the consequence of DNA damage, namely mutations, particularly those found in infants and young children. The measurement of these mutations using the Tlymphocyte cloning assay that quantifies the mutant frequency (MF) of the HPRT gene will be described. This course will be suitable for those toxicologists that are interested in the latest techniques used to measure DNA damage and how these endpoints can be used as an internal dosimeter for epidemiological monitoring of human populations.

  • Human Biomonitoring for DNA Adducts Induced by Xenobiotic Carcinogens of Large Molecular Weight, Miriam Poirier, National Institutes of Health, Bethesda, MD.
  • Measurement of DNA Damage by Lipid Oxidation Products in People, Lawrence Marnett, Vanderbilt University Medical Center, Nashville, TN.
  • Single Cell Gel (Comet) Assay to Measure DNA Damage in Humans, Raymond Tice, Integrated Laboratory Systems, Durham, NC.
  • The Analysis of HPRT Mutations During the Late Stages of Fetal Development and Childhood as a Biomarker for Leukemogenesis in Infants and Children, Barry Finette, University of Vermont, Burlington, VT.

Toxicity Profiling of Genes and Proteins by Toxicologists: Advanced Topics in Toxicogenomics

PM12 Advanced

Governor’s A

Chairpersons: B. Alex Merrick and Darlene Dixon, NIEHS, Research Triangle Park, NC.

Endorsed by:
The Mechanisms Specialty Section
The Toxicologic and Exploratory Pathology Specialty Section

Chemical toxicity profiling using gene expression technologies will soon become more accessible to practicing toxicologists through contract, industrial, and academic core facilities. It is anticipated that gene expression data for many compounds will begin to appear in preclinical drug evaluations, new drug applications, and environmental risk assessment documents as well as basic toxicology research. Although many toxicologists have an understanding of genomics and proteomics, the best use of their applications, attendant bioinformatics, and associated databases still present a challenge. This advanced course is aimed at research and industrial toxicologists to better familiarize them with gene expression technologies at the transcript and protein level. The course is structured around four areas, genomics, genoinformatics, proteomics, and proteoinformatics. Experts in each area will cover the latest technological advances, specific applications and how to relate and interpret the high toxicogenomic information density with bioinformatic tools and relevant databases.

  • Toward Construction of a Transcript Profile Database Predictive of Chemical Toxicity, Chris Corton, CIIT Centers for Health Research, Research Triangle Park, NC.
  • The ToxicoInformatics Challenge in Genomics Database Development and Functional Interpretation of Data, Pierre Bushel, NIEHS, Research Triangle Park, NC.
  • Proteomics: Applications and Opportunities in Toxicology, Frank A. Witzmann, Indiana University School of Medicine, Indianapolis, IN.
  • Proteome BioKnowledge Library: Curated Protein Information for Functional Proteomics, Susan Rabatin, Applied Biosystems, Santa Fe, NM.

Basic Principles and Protocols in Molecular Toxicology

PM13 (repeat of AM 5) Basic

Presidential E

Chairpersons: William B. Mattes, Pharmacia, Kalamazoo, MI and John W. Davis, II, Schering Plough Research Institute, Lafayette, NJ.

Endorsed by:
The Molecular Biology Specialty Section

Many of the mechanisms through which xenobiotics affect tissues or cells occur at the molecular level. Over the past ten or fifteen years the use of molecular techniques to dissect mechanisms of toxicity has grown greatly. These techniques are used to identify growth regulatory pathways, alterations in gene and/or protein expression, as well as proteinDNA and proteinprotein interactions. Accordingly, there has been an explosion in the number of reagents and kits that are commercially available. While these kits and reagents have facilitated the detection of mechanisms of toxicity, a basic understanding of the methods used is just as important. This course will detail a number of basic techniques currently in use in an attempt to give a researcher new to this area information as to which tools may be most relevant with regards to their specific research area. Presentations will include the practical considerations when setting up a given technique as well as references that will help the investigator trouble shoot these systems. Finally, actual data will be shown in an effort to demonstrate the kinds of information that can be obtained by these experiments and the ways in which this information can be interpreted and used to develop hypothesisdriven research. This is a basic level course intended to introduce to the researcher the tools and references that are available to him or her.

  • Basic Protocols and Principles in Nucleic Acid Manipulation, Craig B. Marcus, University of New Mexico College of Pharmacy, Albuquerque, NM.
  • Using Polymerase Chain Reaction in Molecular Toxicology, Jack P. Vanden Heuvel, Penn State University Center for Molecular Toxicology, University Park, PA.
  • Design, Construction and Use of Reporter and Expression Vectors, Michael S. Denison, University of CaliforniaDavis, Davis, CA.
  • Basic Techniques in Detecting Proteins and Protein: Protein Interactions, John W. Davis, II, Schering Plough Research Institute, Lafayette, NJ.

Strategies and Issues in NonClinical Development of Intravenous Infusion Drug Products

PM14 Basic

Presidential C

Chairpersons: William Halliwell, ScheringPlough Research Institute, Lafayette, NJ and George Lulham, JTIMacdonald Corp., Toronto, Ontario, Canada.

Endorsed by:
The Regulatory and Safety Evaluation Specialty Section
The Reproductive and Developmental Specialty Section

A large number of pharmaceutical and biotechnology products intended for administration by intravenous infusion in the clinic have entered into nonclinical development during the past decade. Many of these have shown early success in the clinic and subsequently required additional safety evaluation. Nonclinical testing has also utilized the intravenous route to avoid issues associated with short drug halflife or poor absorption that preclude using more traditional clinical dosing routes. Additionally, continuous infusion studies are conducted with noninfusion drugs to control blood levels, such as fetal/neonatal exposure, for mechanistic studies. As a result, the use of intravenous infusion for nonclinical studies has increased steadily over the past number of years. There are unique design, conduct, and interpretation issues associated with this route of drug administration as a tool in evaluating product safety. Toxicologists and regulators in pharmaceutical/biotech product development are increasingly likely to be involved in designing, conducting, interpreting, and assessing mechanisms of toxicity for nonclinical safety programs using the intravenous infusion route. The goal of this course is to explore the scientific and technical challenges associated with the use of continuous and intermittent intravenous infusion in drug development. The utility and special considerations of this treatment route for reproductive studies of intravenously infused drug products and noninfusion products where there may be a need to achieve specific systemic exposures will also be addressed.

  • Scientific, Technical and Design Considerations in the Conduct and Interpretation of Infusion Toxicology Studies, Glenn Washer, ClinTrials BioResearch, Ltd., Senneville (Montreal), Quebec, Canada.
  • The Design and Conduct of a Safety Evaluation Program for Eptifibatide, a Clinically Approved Inhibitor of Platelet Aggregation, William Halliwell, ScheringPlough Research Institute, Lafayette, NJ.
  • Conduct of Reproduction Toxicity Studies by Continuous Intravenous Infusion, KokWah Hew, Purdue Pharma L.P., Ardsley, NY.
  • Scientific Challenges in Drug Development Using Continuous Intravenous Infusion, Joy A. Cavagnaro, Access BIO, Leesburg, VA.

Current Approaches for Validation and Regulatory Acceptance of Novel Test Methods

PM15 Basic

Governor’s C

Chairpersons: Sidney Green, Howard University College of Medicine, Washington, DC., Leonard M. Schechtman, USFDA, NCTR, Rockville, MD and William S. Stokes, NIEHS, Research Triangle Park, NC.

Endorsed by:
The In Vitro Specialty Section

New technologies such as toxicogenomics are providing a mechanistic basis for the improvement of existing toxicity testing methods and for the development of new improved methods. The new and revised methods may be faster, more economical, and reduce animal use. In order for regulatory authorities and industries to embrace methods that incorporate new technologies, there must be an effective process for determining their scientific validity and acceptability for regulatory use. Enactment of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Authorization Act of 2000 established ICCVAM as a permanent committee, and requires federal agencies to determine that methods are valid for their proposed use prior to their adoption. Federal regulatory agencies have implemented processes to consider the applicability and acceptability of ICCVAMrecommended methods, and to inform the regulated community of their decisions. A parallel organization has been established in the European Union (European Center for the Validation of Alternative Methods, ECVAM). Five methods have successfully completed the ICCVAM and ECVAM evaluation/validation processes and have been adopted by regulatory authorities. International acceptance of new methods is an essential prerequisite for widespread use. This course will review new initiatives by national and international authorities to achieve acceptance of new and revised toxicological testing methodologies. Also, current issues relevant to validation and regulatory acceptance will be addressed. This course is targeted for toxicologists and scientists involved in developing, validating, or using toxicological test methods to meet national and international regulatory testing requirements. The course is particularly relevant as differential gene expression is rapidly being applied to new and existing test methods to identify more sensitive and specific decision criteria.

  • The Role of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and the NTP in the Regulatory Acceptance of New and Revised Test Methods, William S. Stokes, NIEHS, Research Triangle Park, NC.
  • The FDA Process for Consideration of ICCVAM Recommended Test Methods, Leonard M. Schechtman, USFDA, NCTR, Rockville, MD.
  • The EPA Process of Considering ICCVAM Recommended Test Methods, Karen Hamernik, USEPA, Washington, DC.
  • The Validation and Acceptance of Alternative Methods in the European Union, Andrew Worth, European Centre for the Evaluation of Alternative Methods, Varese, Italy.
  • The Role of OECD in Achieving International Acceptance of Harmonized Test Guidelines, Herman Koeter, Organisation for Economic Cooperation and Development, Paris, France.