x



Share this page.

2010 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 Biological Pathway Analysis: An Introduction to the Pathway Knowledge Bases for Toxicological Research Basic
AM02 Biologicals: Introduction to Drug Development Basic
AM03 Comparative Biology of the Lung Basic
AM04 Cytokines: Balancing Therapeutic Utility and Immune System-Mediated Toxicities Basic
AM05 Nuclear Receptors: Role in Chemical Mode-of-Action and Targets for Toxicity Testing Basic
AM06 Predictive Power of Novel Technologies (Cells to ‘Omics): Promises, Pitfalls, and Potential Applications Basic
AM07 Reproduction and Regulatory Impact Basic
PM08 Assessment of Ocular Toxicity in Toxicology Studies Conducted for Regulatory Purposes Basic
PM09 Gene-Environment Interactions Influence Cytokine Biology in Immunotoxicity and Disease: Genomic, Genetic, and Epigenetic Perspectives Advanced
PM10 Mitochondrial Toxicity: Animal Models and Screening Methods in Drug Development Basic
PM11 ICH Initiatives for Conducting Pharmaceutical Preclinical Safety Studies: New and Revised Guidelines and Challenges Advanced
PM12 Segment-Specific Renal Pathology for the Non-Pathologist Basic
PM13 Technologies and Tools for Toxicity Testing in the 21st Century Basic

Biological Pathway Analysis: An Introduction to the Pathway Knowledge Bases for Toxicological Research

SR01—CE Sunrise

Chairperson(s): Marc E. Gillespie, St. John’s University, Queens, NY

Sponsor: Molecular Biology Specialty Section

Endorsed by:
N/A

Genomic and proteomic datasets are a complex but information rich resource. Toxicology is expanding to new omics-based technologies to identify important gene and protein expression changes. A critical step in such studies is the analysis of the data set to derive reasonable mechanistic meaning and testable hypothesis. Additionally, the use of genomic and proteomic approaches to identify new lead molecules for biologically relevant targets is rapidly expanding. A challenge for scientists is how to properly and effectively incorporate high-throughput omics technologies into their research programs. This course will present practical cases demonstrating how the Reactome pathway analysis tools can be used to identify relevant biological pathways within large and immensely complex data sets derived from multiple high-throughput technology platforms. The course will begin with an overview of how genomic and proteomic data sets are generated including, but not limited to, microarray gene expression data, mass-spectrometry data, protein interaction data, and RNAi screening. All of these methods share a common endpoint, the generation of large datasets that the toxicologist must analyze without prior knowledge of a reasonable mechanistic basis or outcome. Often the analysis of such data can be biased by focusing on known genes and pathways. The creation of new knowledge bases, often called pathway databases, incorporates information on protein, gene, and literature databases to facilitate the identification of relevant schemes using combinations of data, resulting in predictions that more closely approximate biological networks. The course will review how available knowledge bases such as Reactome and PharmGKB can be used to interrogate large and complex datasets to identify the contributions of specific pathways in a given biological response to toxicant exposure.

Biological Pathway Analysis: An Introduction to the Pathway Knowledge bases for Toxicological Research, Marc E. Gillespie, St. John’s University, Queens, NY

Biologicals: Introduction to Drug Development

AM02—CE Basic

Chairperson(s): James D. Green, Biogen Idec, Inc., Cambridge, MA, and Laura Andrews, Genzyme Corporation, Framingham, MA

Sponsor: Regulatory and Safety Evaluation Specialty Section

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

Toxicologists and other preclinical scientists have developed an extensive experience base with a wide range of product classes of biologics over the last two decades. These product classes include: proteins, monoclonal antibodies, vaccines, cell therapies, gene therapy products, peptides, and oligonucleotides. These product classes are diverse in origin and are manufactured by a variety of production methods. For example, host cells (e.g., E coli, yeast, CHO cells) are used in the production of antibodies and proteins; various solid and liquid state chemical syntheses have been used for the production of peptides, siRNA's and oligonucleotides, and a variety of vectors (e.g., retrovirus, AAV) have been used to produce gene therapy products. The historical information that has set the ground work for current practices will be reviewed and important global regulatory requirements will be identified that should be considered collectively when designing the battery of nonclinical safety studies. Unique considerations for each of these product classes will be highlighted as well as the timing of the considerations. Emphasis will be placed on two distinct phases; in particular, those that occur prior to the conduct of human clinical trials and those that occur during clinical development. The course will be an integrated discussion of the scientific, risk/benefit, and regulatory considerations that should be considered for the development and human testing of biotherapeutics. We intend to address evolving regulatory requirements in each specific product area and, as appropriate, discuss important differences from the development of small molecule drugs. Students with little or no experience in this area, as well as toxicologists working in pharmaceutical drug development will benefit from taking this course.

Introduction, James D. Green, Biogen Idec, Inc., Cambridge, MA

Principles for Development of Monoclonal Antibodies and Related Forms, Randy Soltys, Genentech Inc., South San Francisco, CA

Principles for Development of Proteins, Shawn M. Heidel, Eli Lilly & Company, Greenfield, IN

Principles for Development of Novel Biologics: siRNA, Oligonucleotides, Anti-Sense, and Aptamers, Arthur A. Levin, Carlsbad, CA

Principles for Development of Vaccines, Cell and Gene Therapies, and Blood Products (CBER-Regulated Products), Timothy MacLachlan, Genzyme Corporation, Framingham, MA

Comparative Biology of the Lung

AM03—CE Basic

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

Sponsor: Inhalation and Respiratory Specialty Section

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

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

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

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

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

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

Cytokines: Balancing Therapeutic Utility and Immune System-Mediated Toxicities

AM04—CE Basic
Target Area: Cytokine Biology

Chairperson(s): Lynne A. LeSauteur, Charles River Laboratories, Montreal, Quebec, Canada, and Rafael Ponce, Amgen, Inc., Seattle, WA

Sponsor: Immunotoxicology Specialty Section

Endorsed by:
N/A

Direct and indirect modulation of cytokines via therapeutics, either increasing or decreasing cytokines, is a central factor in the success of current therapies targeting cancer, autoimmunity, inflammation, and infection. However, nonclinical and clinical data demonstrate that these therapies can overwhelm compensatory mechanisms designed to protect the host, resulting in toxicity. The therapeutic benefits and potential toxicities can be best understood through an understanding of the central role of cytokines in modulating cellular function. To address these specific issues, we will define the central toxicities and syndromes that have been identified as arising from cytokine-mediated immunomodulation; establish the immunological basis for these toxicities using in-depth exploration where possible, including useful biological markers that can inform clinicians and toxicologists; develop an understanding of cytokine modulation in the treatment of cancer, autoimmunity, inflammation, and infection; and identify deficiencies in current toxicological practice for predicting certain immune system-mediated risks arising from cytokine-mediated immunomodulation in humans. Finally, we will explore specific case studies where these principles have been applied to reinforce these central concepts.

Introduction, Lynne A. LeSauteur, Charles River Laboratories, Montreal, Quebec, Canada

Cytokine Modulation: The Yin and the Yang, Rafael Ponce, Amgen, Inc., Seattle, WA

Immunomodulators That Inhibit Cytokines, Helen Haggerty, Bristol-Myers Squibb, Syracuse, NY

Immunomodulators That are Pro-Inflammatory Cytokines, Dennis Miller, Zymogenetics, Inc., Seattle, WA

Cytokine Storms: Its Not Nice to Fool with Mother Nature, Chris Horvath, Taligen Therapeutics, Cambridge, MA

Nuclear Receptors: Role in Chemical Mode-of-Action and Targets for Toxicity Testing

AM05—CE Basic
Theme: Cell Signaling

Chairperson(s): Chris Corton, U.S. EPA, Research Triangle Park, NC, and Jack Vanden Heuvel, Pennsylvania State University, University Park, PA

Sponsor: Molecular Biology Specialty Section

Endorsed by:
Drug Discovery Toxicology Specialty Section

Nuclear receptors (NR) are one of the most abundant classes of transcriptional regulators in animals and function as ligand-activated transcription factors. They provide a direct link between signaling molecules and transcriptional responses that impact diverse functions including development, metabolic homeostasis, and reproduction. NR are not only promising pharmacological targets but can be activated inappropriately by environmentally relevant chemicals leading to a broad spectrum of adverse effects. Thus the intent of this basic course is to provide an overview of the biology of nuclear receptors, the pathways and modes-of-action of a subset of nuclear receptors involved in chemical toxicity, and strategies for screening chemicals for nuclear receptor interactions as well as placement in mode-of-action categories. To begin with, we will cover the structure, function and general mechanisms of activation as well as basic biological roles of NR that are targets of xenobiotics in different tissues and cell types. We will then explore the role of nuclear receptors in both augmenting and suppressing chemical carcinogenesis, which will include a summary of mode-of-action and human relevance of those NR (CAR, PPAR, PXR, RXR) commonly associated with liver cancer. Following this summary, the adverse effects of xenobiotics on the endocrine system associated with activation or modulation of estrogen, androgen, and thyroid hormone receptors will be addressed. Finally, both the primary and secondary screening strategies to define effects of chemicals on NRs and the pathways that mediate their adverse effects will conclude this course. The intended audience for this course includes those who desire a basic knowledge of the state of the science of nuclear receptors in chemical mode-of-action and strategies for accelerating the placement of chemicals into mode-of-action pathways. The course will be of interest to many who are engaged in wider aspects of carcinogenesis, reproductive biology and risk assessment.

Introduction, Chris Corton, U.S. EPA, Research Triangle Park, NC, and Jack Vanden Heuvel, Pennsylvania State University, University Park, PA

The Structure and Function of Nuclear Receptors, Jack Vanden Heuvel, Pennsylvania State University, University Park, PA

Role of Nuclear Receptors in Chemical Carcinogenesis, Chris Corton, U.S. EPA, Research Triangle Park, NC

Role of Nuclear Receptors in Endocrine Disruption, Stephen Safe, Texas A&M University, College Station, TX

Nuclear Receptors and High-Throughput Screening, Keith Houck, U.S. EPA, Research Triangle Park, NC

Predictive Power of Novel Technologies (Cells to ‘Omics): Promises, Pitfalls, and Potential Applications

AM06—CE Basic

Chairperson(s): Srikanth S. Nadadur, NIEHS, Research Triangle Park, NC, and Mary Jane Cunningham, Nanomics Biosciences, Cary, NC

Sponsor: Molecular Biology Specialty Section

Endorsed by:
Inhalation and Respiratory Specialty Section
Mechanisms Specialty Section

Advances in the disciplines of cell and molecular biology have led to the development of novel biotechnologies capable of generating “global molecular profiles” for in situ toxicological assessment. These technologies should accelerate our understanding of molecular basis for potential toxicity and susceptibility. Both theoretical and practical information on these emerging high-throughput technologies, their applicability, interpretation, and integration to gain a more comprehensive understanding of cellular responses to chemical/toxicant stress will be provided. To begin, our focus will be the potential utility of laser capture micro-dissection in isolating specific cell populations for toxicological assessment at the level of RNA and proteins, followed by the ongoing evolution of gene expression profiling approaches from “toxicogenomics” to systems biology. To adequately cover this topic area, an overview of proteomic technologies in analyzing the protein interactions and downstream signaling mediators involved in toxic response pathways will be presented, as well as an examination of the capabilities of high-throughput technologies for identifying single nucleotide polymorphisms (SNPs) and their predictive value for characterizing underlying genetic susceptibilities to toxicants. Finally, we will address the high-throughput technologies available to identify genome-wide epigenetic alterations, and interpreting the role of epigenetic alterations in health, disease, and toxicant-induced biological outcomes. This course, while basic, aims to educate toxicologists on the array of ever growing technologies available to gain a comprehensive understanding of the underlying mechanisms mediating biological response. The goal is to move towards a better and reliable prediction and extrapolation of toxic responses. For the scientists, technical, and regulatory staff involved in various stages of compound development or regulation, this course should be a nice refresher.

Introduction: Integration is the Way to Go, Srikanth S. Nadadur, NIEHS, Research Triangle Park, NC

Gene Expression Profiling for Toxicity Assessment Using Systems Biology, Mary Jane Cunningham, Nanomics Biosciences, Cary, NC

Integrating Transgenic Animal Models and Laser Capture Microdissection Applications with "Micro-Omic"-Based Analyses for In Vivo Toxicological Assessments, Kevin L. Dreher, NHEERL, ORD, U.S. EPA, Research Triangle Park, NC

Clinical Proteomics: Mapping Molecular Networks in Clinical Specimens Using Reverse Phase Protein Microarrays, Emauel F. Petricoin, George Mason University, Manassas, VA

The Role of DNA Variation in Human Drug Response, Steven P. Hamilton, University of California, San Francisco, CA

Epigenome Profiling: Mapping Epigenetic Alterations in Health and Disease, Steven A. Belinsky, Lovelace Respiratory Research Institute, Albuquerque, NM

Reproduction and Regulatory Impact

AM07—CE Basic

Chairperson(s): Robert E. Chapin, Pfizer Global Research & Development, Groton, CT, and Jeffrey S. Moffit, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

Sponsor: Reproductive and Developmental Toxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

Most new compounds destined for commerce, and all compounds intended for human consumption, need to be assessed for developmental and reproductive toxicity (DART). However, the underlying biology can be confusing because the jargon employed by the cognoscenti can be impenetrable and the implications of findings in these studies are often difficult to appreciate quickly. Our panel will begin this course with an open dialogue designed to lift the veil of uncertainty around many of these issues. After a quick review of some of the key biology, we will touch on the characteristic study designs which generate the necessary data. A point of focus will have the panel examine the typical effects seen in adults and juveniles, and what impact these can have on the registration and use of the compound in Europe and the U.S., respectively. Although the focal point for this course will be on environmental compounds, the final presentation will highlight drug candidates and how reproductive or developmental findings affect their journey to the marketplace. It is our goal to leave students with a better understanding of the impacts that reproductive or developmental findings have on the registration and use of environmental and pharma compounds.

Basic Biology and Study Designs, Chad Blystone, NIEHS/NTP, Research Triangle Park, NC

The Regulatory Impact of Reproductive Development: The European Perspective, Aldert Piersma, RIVM, Bilthoven, Netherlands

The Regulatory Impact of Reproductive Findings: The U.S. Perspective, Vicki Dellarco, U.S. EPA, Washington, DC

The Impact of DART Findings on Drug Candidates, Tracey Zoetis, Scilucent, Herndon, VA

Assessment of Ocular Toxicity in Toxicology Studies Conducted for Regulatory Purposes

PM08—CE Basic

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

Sponsor: Toxicologic and Exploratory Pathology Specialty Section

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

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

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

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

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

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

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

Gene-Environment Interactions Influence Cytokine Biology in Immunotoxicity and Disease: Genomic, Genetic, and Epigenetic Perspectives

PM09—CE Advanced

Chairperson(s): Berran Yucesoy, CDC/NIOSH, Morgantown WV, and Victor J. Johnson, CDC/NIOSH, Morgantown WV

Sponsor: Immunotoxicology Specialty Section

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

Cytokines are key signaling and effector molecules that regulate many aspects of host response to exogenous stressors. To date, animal and human studies have identified individual and interacting effects of cytokines at different stages in the pathogenesis of chronic inflammatory and immune-mediated diseases. Animal studies utilizing gene knock-out and transgenic animals and expression microarrays have identified disease-related cytokine networks. Human studies using various genome screening efforts have also uncovered potential candidate genes for disease development and progression. Cytokine genes and their receptors are highly polymorphic and variations in these genes have been associated with the course of and susceptibility to a variety of diseases including infectious, inflammatory, and autoimmune. In addition, epigenetic changes including altered DNA methylation and histone acetylation can control cytokine gene expression by changing the transcription-permissive nature of chromatin structure. Environmental factors are known to modify the direction and magnitude of disease risk in an environment-specific manner. In this respect, genetic association studies have identified interactions between cytokine gene variations and environmental/occupational exposures as shown in the case of silicosis and asthma. In addition, recent studies demonstrated that environmental exposures might alter methylation states of key cytokines genes supporting an epigenetic gene-environment interaction. This course will address aspects of the current state of knowledge with respect to genomic, genetic, and epigenetic approaches in the investigation of cytokine genes associated with occupational and environmental-related diseases.

Exploring Gene-Environment Interactions and the Role of Cytokines in Occupational Allergic Respiratory Disease: Whole-Genome Expression and Beyond, Victor J. Johnson, CDC/NIOSH, Morgantown, WV

Influence of Cytokine Gene Variations on Chronic Inflammatory/Immune Diseases: Importance of Gene-Environment Interactions, Berran Yucesoy, CDC/NIOSH, Morgantown, WV

Genetic Regulation of Cytokines in Risk of Beryllium Sensitization and CBD: A Model for Gene-Environment Interaction, Lisa A. Maier, National Jewish Health, Denver, CO

Environmental Exposures Interact with the Epigenome Altering Gene Regulation and Disease Risk, Randy L. Jirtle, Duke University Medical Center, Durham, NC

Mitochondrial Toxicity: Animal Models and Screening Methods in Drug Development

PM10—CE Basic

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

Sponsor: Drug Discovery Toxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

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

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

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

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

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

ICH Initiatives for Conducting Pharmaceutical Preclinical Safety Studies: New and Revised Guidelines and Challenges

PM11—CE Advanced

Chairperson(s): Tao Wang, Novartis Pharmaceuticals Corporation, Emeryville, CA, and David McGuinn, U.S. FDA, Silver Spring, MD

Sponsor: Regulatory and Safety Evaluation Specialty Section

Endorsed by:
Carcinogenesis Specialty Section
Reproductive and Developmental Toxicology Specialty Section
Women in Toxicology Special Interest Group

In recent years, the International Conference of Harmonization (ICH) Expert Working Groups have been developing new guidelines and revising some of the existing guidelines on preclinical safety requirements. Some of the important recent initiatives include new guidance, ICH S9, for preclinical evaluation of anticancer pharmaceuticals, revision of ICH M3 guidance that addresses the timing of preclinical studies in relation to various stages of clinical development, and new guidelines on genotoxicity testing (ICH S2) that replaces and combines the ICH S2A and S2B guidelines. Over the past decade, substantial experience regarding preclinical safety evaluation of biologics (ICH S6) has been gained and based on this experience revision of S6 is underway. The latest rationale behind the new initiatives at ICH will be discussed, while a panel of experts will present new developments and key challenges in each of the areas mentioned above and will provide expert commentary and perspective on the potential impact on preclinical safety evaluation programs these guidelines may have. Case studies will be used to highlight detailed examples, experience in conducting non-clinical ICH safety studies, and the acceptance of the ICH guidelines by the practicing regulatory organizations and reviewers. Our panel experts have years of experience in preclinical toxicology testing from either an industry or regulatory perspective. In addition, several have represented the United States on the ICH Expert Working Groups, and participated in writing or revising these ICH guidelines. This panel will be available to answer questions that will allow the participant to obtain valuable information on this topic.

Introduction, Tao Wang, Novartis Pharmaceuticals Corporation, Emeryville, CA

Fundamentals of Nonclinical Drug Development, David McGuinn, U.S. FDA, Silver Spring, MD

Preclinical Development of Oncology Therapeutics: An Industry Perspective, Daniel Lapadula, Novartis Pharmaceuticals Corporation, East Hanover, NJ

Use of Genotoxicity and Carcinogenicity Data in U.S. FDA Center for Drug Evaluation and Research, David Jacobson-Kram, U.S. FDA, Silver Spring, MD

Nonclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals: FDA Regulatory Perspective on the ICH S6 Guidance and Updates, Anne M. Pilaro, U.S. FDA, Silver Spring, MD

Segment-Specific Renal Pathology for the Non-Pathologist

PM12—CE Basic

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

Sponsor: Toxicologic and Exploratory Pathology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

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

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

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

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

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

Technologies and Tools for Toxicity Testing in the 21st Century

PM13—CE Basic
Theme: Toxicity Testing in the 21st Century

Chairperson(s): Robert Kavlock, U.S. EPA, Research Triangle Park, NC, and Dan Wilson, Dow Chemical Company, Midland, MI

Sponsor: In Vitro and Alternative Methods Specialty Section

Endorsed by:
Risk Assessment Specialty Section

Toxicology testing has traditionally been associated with defined and tiered testing around dedicated endpoints (i.e., acute, reproductive and developmental, chronic and cancer, etc.). Over time, validated surrogates or refined alternatives for some of the end-points have come into acceptance for screening and international regulatory use. Coinciding with the release of the NAS report on Toxicity Testing in the 21st Century: A Vision and a Strategy, a dedicated and rapid shift towards use of more non-whole animal testing is underway. Also, in vitro methods are expected to play a major role under REACH and to address the European Union-wide ban on animal use in cosmetics development. Inherent in this shift is a necessary understanding of the critical aspects of cellular, metabolic, and genetic functions effected in response to chemical and drug-induced toxicity as well the dose-response attributes of the responses. Towards this end, elaboration of predictive toxicity pathways by integration of information from in vitro assays, surrogate organisms, ‘omics technologies, in silico approaches, and bioinformatics is ongoing. A review of how the classic approaches for toxicity testing are evolving into sophisticated molecular/mechanistic based approaches and the nature and implementation of in vitro high-throughput screening assays, with some mention of implementation of informatics approaches will be addressed. Further insight into how the information will be considered in the context of animal use, testing prioritization, dose-response considerations, and human health risks will be explored. This basic course should be of interest to classically trained toxicologists and investigators and regulators wanting to understand the latest technologies and tools that will be the necessary repertoire for card-carrying mammalian toxicologists.

From the Land of Classical Mammalian Toxicology and Pathology to the Land of In Vitro, Molecular, Genomics, and Other Tools, Kevin Morgan, sanofi-aventis, Research Triangle Park, NC

Considerations When Utilizing High-Throughput Technologies and Cells of Different Target Organs to Evaluate Toxicity Endpoints of Large Sets of Test Chemicals, Jon Inglefield, Emergent Biosolutions, Gaithersburg, MD

Whole Genome Technologies: Integrating Knowledge from Complex Sources, Pathways, and Systems into Toxicology, Douglas A. Bell, NIEHS-NIH, Research Triangle Park, NC

New Tools—How Do They Affect the Bottom Line? Paul Price, Dow Chemical Company, Midland, MI