Continuing Education Courses in Developing Countries

IUTOX sponsors training courses worldwide and, in the last few years; these have been conducted in Argentina, Chile, China, Estonia, Finland, Georgia, India, Mexico, Slovenia and South Africa.

Lecturer Funding for National Meetings in Developing Countries

A major activity of IUTOX is to support and enhance toxicology education especially within countries in which toxicology is underrepresented. The work relates strongly to the mission of IUTOX and does much to enhance international cooperation and interaction. The IUTOX Education Commission is pleased to provide the following guidelines on the programmes that are supported and the mechanisms whereby support can be obtained. We very much encourage applications for support from those countries who may benefit from this input into National Society meetings or workshops.

Guidelines for Support to Member Societies

Purpose:
The purpose of this initiative is to enhance the development of toxicology in these counties through the provision of education and transfer of expertise from those countries in which toxicology is more advanced. Each year, IUTOX can provide limited support in the form of lectures from experts in a range of toxicology areas for inclusion in National Toxicology Society Meetings in countries in which toxicology is underrepresented.

Eligible activities include:

• Support of a visiting delegate to assist in workshops aimed at formation of new local toxicology societies.

• Support of visiting lecturer(s) to contribute to education courses, lectures and symposia associated with National meetings of a) an existing member society b) organisations that show potential for development into a National Toxicology Society.

• Programmes will only be supported if the Scientific Programme of the entire meeting/workshop can be seen, amended if necessary, and approved by IUTOX.

Level of Support for Programmes:

Historically, each CE course has cost around $3000-$5000. It is therefore anticipated that an "average" programme might provide one or two speakers/contributors and generally two CE courses plus one workshop contribution per year.

Nature of Topics:

The topics of any presentations should be linked closely to the nature of the scientific meeting and the specific needs of the country (including an address in the language of the host country if possible). The speaker list should be identified by the Education Commission members in consultation with any relevant funding body. Two deadlines for applications per year will operate (June 1st and December 1st).

CE Material On-Line

Toxicology Resources: IUTOX has coordinated the translation of a number of toxicology resources into Spanish for free download from the IUTOX Web site.These include: Toxicologia Avanzada; Toxicologia Fundamental; and IUPAC Material Natural and Anthropogenic Environmental Oestrogens.

Previous IUTOX CE Courses

From EUROTOX (2001)

1. Good laboratory practice (GLP)– The conduct of toxicological investigations under GLP and what it entails for the toxicologist

Introduction: GLP and its intentions
The GLP Study-Differentiating studies from experiments
Standard Operating Procedures-Some critical points, The Study Plan-Guiding the experiments and their chronology
Records and Documentation-How to manage data and results
Conclusions-What does a study director have to observe

2. Animal models of immunotoxicity

Host resistance models
Models for skin allergy
Models for respiratory allergy
Models for food allergy

 

3. Methods for culturing epithelial cells and toxicological applications

Primary cultures of epithelial cells : Introduction
Collagen gel cultures of hepatocytes and their use in metabolism-linked toxicity studies
Methods for culturing epithelial cells from the intestinal and urinary tract

 

From ICT IX (2001)

4. A biotechnology platform for toxicology

Consists of two sessions; Tools in toxicology A and Tools in toxicology B. Session A covers technologies that range from selecting an in vitro system for toxicity testing through to what is toxicogenomics whereas B develops the newer technologies further and looks at 3D proteomics for fast protein identification, bioinformatics and how we can synergise the new technologies.

5. Risk assessment  

Consists of two sessions; Basic elements of risk assessment followed by New issues in risk assessment methodologies. The aim of this course is to present the risk assessment process from a multidisciplinary scientific and practical point of view.

 

From SOT (2001)

6. Sunrise Mini-Course: Genomic technologies applied to toxicology (Basic)

Genomic technologies, originally brought into the pharmaceutical industry as target discovery tools, are providing the toxicologist with a means to understanding toxic mechanisms. These tools, including microarray hybridization, real-time PCR, plate screening technologies, and large-scale sequencing, are being used to identify and eliminate toxic liabilities at an earlier stage. When combined with traditional safety evaluation methods, these genomic approaches also improve the predictive value of preclinical studies for determining human risk. This basic course will be of interest to all toxicologists who wish to integrate genomic technologies into their practice of toxicology.

 

7. Web Resources for Toxicologists (Basic)

Internet Web resources in toxicology are widespread and growing in number. This basic course will highlight the major Web databases and other sites of relevance to the toxicology community. One major focus of the course will be the National Library of Medicine's (NLM) toxicology, environmental health, and chemical nomenclature files residing on its TOXNET system. New Web interfaces have simplified searching and made it more powerful and efficient. Among the TOXNET databases which will be discussed are the Hazardous Substances Data Bank, the Integrated Risk Information System, the Chemical Carcinogenesis Research Information System, GENE-TOX, USEPA s Toxics Release Inventory, the TOXLINE database of nearly 3 million bibliographic references and the ChemIDplus database of chemical identification/nomenclature. Additional NLM resources such as PubMed, MEDLINEplus, and the directory of organizations, DIRLINE, will also be covered, as will links and additional information available through the Toxicology and Environmental Health Information Program's Web site. Other government sites and databases sponsored by agencies such as USEPA, ATSDR and NIEHS, will also be reviewed, as will those of international organizations. Finally, relevant Web resources from commercial vendors, academic institutions, and non-profit groups will be considered. The instructional format will include PowerPoint presentations and on-line Web demonstrations, while handouts and exercises for participants to work through back at their offices will help reinforce the principles learned. This course will provide a knowledge of the current Web-based toxicology information infrastructure that is critical to the work of practicing toxicologists.

Web-Based Toxicology Resources from the National Library of Medicine
Web-Based Toxicology Resources from USEPA and other Government Agencies
Web-Based Toxicology Resources Available Commercially

 

8. Ocular Toxicity: Assessment Methods and Mechanisms (Basic)

Ocular toxicity, induced by environmental toxicants or therapeutic drugs, is a well-recognized and common concern in the industrial workplace and home. Ocular toxicity produced by candidate compounds has frequently presented hurdles for the successful development of novel pharmaceutical agents. The objectives of this course are to briefly review (1) ocular toxicants and their sites and mechanisms of action; (2) methods for assessment of ocular toxicity on a clinical, structural, and cellular level; and (3) basic scientific approaches to understanding specific examples of lenticular and retinal toxicity. The first speaker will review the comparative ocular anatomy and physiology of the commonly utilized animal models and describe assessment methodologies in terms of application and indication. The second lecture will be a broad survey of classic ocular toxicants, including both direct-acting compounds and systemic agents. The final two speakers will provide information regarding assessment methodologies for toxic insult to lenticular and retinal tissues. These presentations will include specific ñreal-worldî examples where ocular toxicants were identified and systematically investigated at the structural, functional, biochemical, and clinical level to determine their site and mechanism of action. This basic course should be of interest to individuals seeking to familiarize themselves with classical ocular toxicants, those dealing for the first time with challenges regarding assessment of ocular toxicity of novel compounds and to toxicologists using the retina as a model system for the central nervous system.

Fundamentals of Ocular toxicity
From Cornea to Optic Nerve: An Overview of Ocular Toxicants and Their Targets
Toxic Injuries to the Crystalline Lens
The Retinotoxic Effects of Inorganic Lead

 

 

9. Risk assessment for metals (Advanced)

Risk assessment for metals presents unique challenges to the toxicologist. These challenges include the appropriate interpretation of genotoxic data with respect to dose-response relationships (e.g., some carcinogenic metals are genotoxic via indirect mechanisms), the need to consider lifetime exposures in the development of physiologically-based pharmacokinetic (PBPK) models for some metals and consideration of background exposures in making risk management decisions for metals. This advanced course will explore key features of risk assessment for metals, specifically mode of action for carcinogenesis, bioavailability, PBPK models, dose-response models and risk management considerations. The course will demonstrate how advances in understanding mechanisms of metal toxicity can lead to improvements in risk assessment, with emphasis on several well-studied metals such as lead, cadmium, and arsenic. The objectives of this advanced course are to impart knowledge of specific mechanisms involved in metal-carcinogenicity, uptake of metals from the environment, modeling of the distribution and disposition of metals in the body and how such data may be used in risk assessment and risk management.

Mechanisms of Metals Carcinogenesis: Relationship to Risk Assessment
Metals Bioavailability
Dose-Response Model for Metals
Physiologically Based Pharmacokinetic Models for Metals
Some Risk Assessment Considerations in Risk Management of Metals

 

 

10. Choosing tools for toxicogenomics: A primer for the research scientist (Basic)

Toxicogenomics is the science of studying gene expression following toxic insult. Novel technologies in this rapidly growing field now empower investigators to evaluate changes in gene expression on a genome-wide scale enabling new approaches for exposure assessment, prediction of pathophysiologic outcomes, and evaluation of novel therapeutic interventions. This course will address practical aspects of choosing the technical platform most likely to effectively address specific questions posed by individual investigators and will discuss relative merits and deficiencies of these approaches. Emerging techniques in data analysis and strategies for evaluating data derived from multiple platforms will be discussed. This basic level course is intended to assist investigators new to the subject in choosing the microarray technology best suited to their research and resources, and to introduce scientists to emerging techniques in microarray data analysis.

Custom Array Construction: Use and Pitfalls
Querying the Environmental Genome
Tools for Evaluation of the Oxidant Responses
High-Throughput Gene Expression Analysis Using MicroSAGE Libraries and 96-Capillary DNA Sequencer

 

11. Liver toxicology (Basic)

The liver has long been recognized as a target organ for xenobiotic-induced toxicity due to its central role in metabolic disposition. Recently, various pharmaceutical and environmental compounds have been shown to produce idiosyncratic or species-specific hepatotoxicity. These findings highlight the importance of understanding mechanisms of toxicity in order to properly assess risk. This basic course will include the physiology of liver function, recent examples of unexpected hepatotoxicity, regulation of hepatocellular proliferation, role of nonparenchymal cells in hepatotoxicity and the use of in vitro systems to predict in vivo cytolethality and toxicokinetics. The goals of the course are to cover new concepts of liver injury in vitro and/or in vivo. An underlying theme will be recent developments in the understanding of mechanisms involved in hepatotoxicity. This course will be of interest to scientists working in the areas of carcinogenesis, molecular biology, in vitro models, risk assessment and mechanisms.

Liver Physiology and Mechanisms of Hepatotoxicity
Regulation of Hepatocyte Survival and Proliferation
Role of Non-Parenchymal Cells in Hepatotoxicity
In Vitro/In Vivoi comparisons of Cytolethality and Toxicokinetics  

12. Nutraceuticals/functional foods — Safety and regulatory issues (Basic)

Nutraceuticals or functional foods are being rapidly developed, outpacing the development of both sound science and rational regulation. The end result is that these new entities appear unbound by the constraints and testing generally required of new chemical entities. Case studies of nutraceuticals that have been through safety testing and brought to the market will be presented as a guide for the development and regulation of these products in the future. This basic course will discuss the US and global issues related to the science and regulation of functional food products and will explore their characterization as food, pharmaceutical, or other category for regulatory purposes. The mechanisms for safety assessment and regulation of functional foods or nutraceuticals will be explored.

Overview-European/Global Perspective
Scientific Issues
Regulatory Issues in the US A
Strategic Approach to the Safety and Efficacy Assessment of Functional Foods

 

13. Receptors and signal transduction in environmental toxicology (Basic)

Many environmental chemicals are toxic by virtue of their ability to interact with specific hormone receptors, many of which act as transcription factors. Important classes of environmental contaminants that act via receptor-mediated mechanisms include the planar halogenated aromatic hydrocarbons (PHAHs) and hormonally active agents (HAAs or endocrine disruptors). Many of the receptors through which these compounds act have been extensively characterized in rodents. Understanding the diversity and function of such receptors in fish and wildlife is critical to understanding mechanisms of toxicity in these species; however, the comparative biology of these proteins in non-mammalian species is poorly known. This course will present an overview of the comparative biochemistry of two multi-gene families of receptors and transcription factors: the bHLH-PAS family (including the aryl hydrocarbon receptors, hypoxia-inducible factors, and associated proteins) and the nuclear/steroid receptor family (including receptors for steroids, peroxisome proliferators, thyroid hormones, retinoids, and many other natural and synthetic chemicals). Presentations will focus on the current understanding of these receptors and signaling pathways in fish and wildlife. Methods and approaches for studying these pathways will also be discussed. Topics will include the Ah receptor and bHLH-PAS family, ARNT-dependent signaling pathways, estrogen and androgen receptors and nuclear orphan receptors.

Introduction and Overview
The Ah Receptor and bHLH-PAS Gene Family
What ARNT Is and Aint, Implications in Environmental Signal Transduction
Estrogen, Androgen, and Progestin Receptors
Nuclear Orphan Receptors: Finding a Home

 

14. Novel in vivo genotoxicity assays: developing trends for pharmaceutical and environmental applications (Basic)

While in vitro assays are commonly used to determine genotoxic potential for chemicals and environmental agents, an ongoing question is the effect of such agents on genetic endpoints in vivo. Regulatory guidelines often require studies that monitor chromosomal damage following acute dosing in rodents. With the advent of recent technology, genetic damage in vivo can also be monitored as an adjunct endpoint in either descriptive or investigational toxicology studies. This course will introduce several such assays and their mechanistic bases. The first talk will briefly introduce the background for acute genotoxicity assays described in current regulations, and then describe the options that are developing for genotoxicity assays as part of non-acute studies. The next talk will describe one of the most common in vivo endpoints, the micronucleus assay, and then introduce recent technology that allows rapid monitoring of this endpoint in rats and mice, even in peripheral blood. The next two lectures will focus on the application of transgenic loci as in vivo markers of experimental and environmental genotoxicity, both in mammalian and non-mammalian species, particularly with regard to improvements over the last few years.Finally, in vivo models focusing on endogenous loci that can monitor environmental contaminants, particularly genotoxins, will be discussed. The course will be appropriate as a basic course for those interested in current trends in investigating genotoxicity end points in vivo.

Mechanistic aspects of regulatory genetox tests and the interface with in vivo testing
Development approaches to in vivo micronuclei testing
Current status of transgenic animal mutation model
Current status of mutation models with endogenous loci
Models for detecting environmental genotoxicity

 

15. Neurotoxicology of metals: Causes and consequences (Basic)

Metals that are transported across the brain barrier systems can exert profound toxic effects on the central nervous system (CNS). Alterations in neurochemical and neurophysiological regulatory processes can lead to substantial neurological disorders. The first lecture will discuss the organization of the CNS and classifications of metal-induced neurotoxicities. Subsequent lectures will highlight specific cellular/subcellular structures and biochemical/molecular pathways of the CNS that are targeted, as established through the use of cell culture and animal models, by using a specific metal as an example. Speakers will discuss current issues and controversies related to human risks resulting from exposure to metals. The course will serve as an introduction to those who desire an expanded knowledge of the functional anatomy/physiology of the CNS and the impact of neurotoxic metals on these systems. This presentation will be of interest to others engaged in wider

Introduction
Brain structure, function, and barriers: implications for metal neurotoxicity
Disposition-related neuronal responses: maganese neurotoxicity from cns transport to molecular interactions
Age-dependent neuronal responses: difference in mechanism an outcome of methylmercury neurotoxicity
Cell type-specific neuronal responses: differential sensitivities of neurons and neuroglia to low-level lead exposure  

16. Development and use of transgenic animal models in toxicology (Advanced)

This advanced course will provide an overview of methodologies for conventional and conditional gene knockout systems and the application of the resulting transgenic animal models in toxicology. The recent ability to inactivate specific genes in mice has significantly accelerated our understanding of molecular, cellular and even behavioral aspects of normal and disease processes, and the mechanisms of toxicity of exogenous and endogenous compounds. Gene targeting technology in mice by homologous recombination has become an important method to generate loss-of-function of genes in a predetermined locus. A number of gene knockouts has given unexpected results, in part due to the irreversible alteration of chromosomal DNA that results from the use of this technology. Modification of the basic technology now provides additional choices for more specific manipulations of the mouse genome. This includes conditional cell or tissue-specific gene targeting, dominant negative strategies, gene knockin technology and development of double knockout animal models. Tissue-specific knockout models should be extremely valuable in studying mechanisms of target-organ toxicity mediated by chemicals. Overall, these sophisticated methods of making genomic alterations should continue to provide a unique opportunity to create animal models for studying mechanisms of toxicity and to extrapolate these studies to human risk assessment.

Techniques in gene targeting
Knockouts, knockins, and conditional knock-out technologies
Application of genetically engineered mouse models in toxicology and carcinogenesis
Transgenic approaches in inflammation

 

17. Food allergy and intolerance (Basic)

Food allergy is an important health issue. Nearly 1-2% of the adult population has IgE antibody-mediated food allergies, with the prevalence in children being closer to 5%. There is a need to assess the risks of sensitization associated with genetically modified food, infant food and dietary supplements. This basic course will introduce the concepts of food allergy and will identify the concerns associated with the development of new food products. In addition, clinical aspects of food allergy will be discussed, and the cellular and molecular mechanisms which result in sensitization will be considered in detail. Finally, current regulatory approaches to food allergy and intolerance will be reviewed.

Food allergy: clinical aspects
Food allergy: immunological mechanisms and toxicological aspects
Genetically modified foods and food allergy
Food allergy: regulatory aspect

 

18. Environmental bioindicators: useful tools for assessing at-risk populations

This basic course will discuss the advantages and disadvantages of currently recognized biomonitoring systems, and explore well-established markers of chemical injury that are used for exposure and risk assessment in an ecotoxicological setting. Speakers will provide information concerning the expertise required to perform biomonitoring studies, the strengths and weaknesses associated with each approach and how each parameter rates in comparison to other commonly-used predictive endpoints. The final speaker will bring into light how exposure assessment fits into the ecotoxicology risk assessment paradigm and possible extrapolation to humans. The course is designed to provide familiarity with the principles of biomonitoring and provide insight into bioindicators/biomarkers of current interest to risk assessors and regulatory agencies. Information gained in this course will be of interest to a diverse audience including environmental toxicologists, immunotoxicologists, risk assessors and molecular biologists.

Overview
Exposure assessment: advantages and limitations for ecological risk assessment
Exposure assessment through biomonitoring
Biomarkers of endocrine disruption in oviparous vertebrates
Immune response alterations in fish as biomarkers of pollutant exposure/effects
Molecular markers for assessing pollutant exposure

 

19. Prediction of human toxicity and metabolic fate of drugs using in vitro systems

In vitro methods in the evaluation of hepatic metabolism, drug-drug interactions and drug toxicity are rapidly emerging as powerful strategies for addressing concerns regarding drug safety assessment. The human-based in vitro experimental systems include the human colon carcinoma cell line Caco-2 cells for intestinal absorption and human liver systems (microsomes, hepatocytes, liver slices) for drug metabolism, drug-drug interactions and toxicity. These experimental systems allow one to generate human-specific data which may not be available from nonhuman laboratory animals during the preclinical phase of drug development. The major challenge is to accurately predict human drug properties based on in vitro data. This course will review the strengths and limitations of the in vitro, human-based model systems commonly used. The theoretical considerations and examples of successes and failures behind current strategies in the prediction of in vivo human drug absorption, metabolic stability, drug-drug interaction potential and toxicity, based on in vitro data, will be discussed. The approaches discussed may also be applicable towards the evaluation of the toxicological effects of industrial and environmental exposure of humans to xenobiotics. This course is targeted towards toxicologists, pharmacokineticists and regulatory scientists from industry, academia and government who are interested in the application of in vitro approaches to predict the impact of drug and chemical exposure in humans.

Overview: In Vitro Experimental Systems for the Evaluation of Drug Bioavailability
Prediction of Bioavailability
Prediction of Hepatic Clearance
Prediction of Hepatotoxicity
Prediction of Drug-Drug Interactions: Quantitative or Qualitative?

 

20. Stress kinases, nf-kb and caspases: pathways in chemical-induced cell survival and death (Advanced)

Toxicology is changing rapidly and radically due to the advances in our understanding of the cellular signal transduction events elicited by endobiotics and xenobiotics. The challenge lies in the interpretation of these signaling events in terms of the biological relevance. For example, cellular responses to environmental stimuli or insults can result in either a change in homeostasis as a consequence of expression of survival genes or in cell death as a consequence of expression of death-related genes. This advanced course will focus on the role of stress kinases and the NF-B pathways leading to gene expression during cell survival and on the stimulation of the mitochondria-cytochrome C-caspases pathway leading to apoptotic cell death. The goal of the course is to introduce participants to the role of mitochondria, Bcl2, and cytochrome C in xenobiotic-induced apoptosis, the role of MEKK stress kinase proteins and xenobiotic-induced MAPK and caspase activation in cell life and death and the nature and importance of Ah receptor interaction with NF-B in the mechanism of dioxin toxicity. This information will be of importance in assessing the potential risks of environmental toxicants in cellular injury, as well as in pre-clinical toxicological screening of potential drug candidates.

The Role of Mitochondria, Bc12, and Cytochrome C in Xenobiotic-Induced Apoptosis
Xenobiotic-Induced MAPK and Caspase Activation in Cell Life and Cell Death
The Role of MEKK Proteins in Cellular Signal Transduction Pathways
Ah Receptor and NF-kB Interactions, a Potential Mechanism for Dioxin Toxicity  

21. Improving risk assessment for human developmental defects: the promise of recent advances in developmental biology and genomics

Current approaches to assess risk for human developmental defects rely on the use of generic default assumptions largely because of the lack of mechanistic information available on chemicals. Recent advances in developmental biology and genomics hold great promise for improving risk assessment because they provide opportunities for understanding the underlying mechanisms of developmental toxicants. This course will explore how several of these recent advances might be applied to developmental toxicology and risk assessment. Specific topics include: 1) the use of model organisms (C. elegans, Drosophilia, zebrafish and mouse) to study toxicant-induced perturbation of evolutionarily conserved molecular targets and pathways of development that can lead to adverse developmental outcomes; 2) how those model organisms might be used to improve quantitative risk assessment through understanding toxicokinetic and toxicodynamic differences among species; 3) how information from functional analyses of human genome sequences might be used to understand variability in responses to developmental toxicants; and 4) how this new information might be integrated into a comprehensive assessment of human risk. It is anticipated that the primary audience for this course would be scientists working in the areas of developmental toxicology and risk assessment. Others likely to be interested include scientists with interests in areas such as in vitro methodology, mechanisms and molecular biology. This course is especially timely due to the release of the National Academy of Science report on the use of mechanistic data from developmental biology and the human genome project to improve the scientific basis for developmental risk toxicity assessment.

Introduction Using mechanistic Data from Developmental and molecular Biology for Developmental Toxicity Risk Assessment Using Functional Genomics to Understand Human Variability in Responses to Toxicants Novel Conserved Cell Signaling Pathways in Developmental Biology: Implications for use in Developmental Toxicology Toxicokinetic and Toxicodynamic Consideration in Using Cell Signaling Pathway Data for Developmental Toxicity  

SOT(2002)

22. Use of laser capture microdissection (lcm) in molecular toxicology (Basic)

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 (RT-PCR), 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.

 

23. A practical approach to blood and lymphoid tissue (blt) in toxicology assessments (basic)

Blood, bone marrow, thymus, spleen, lymph nodes and mucosa-associated 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 non-neoplastic 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 treatment-related 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
Bare Bones Blood and Bone Marrow
Essential Lymph Nodes thymic and Splenic Splendor
Lymphoid Aggregates of mucosal and Nonlymphoid Tissues

 

24. Alterations in gene expression as a mechanism of toxicant action (Advanced)

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. The proposed continuing education course is designed to review our current state of knowledge regarding toxicant-induced 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 stress-response pathways, as well as specific metal-responsive 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 tissue-selective 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.

Receptor-Mediated Toxicant Action
Metal-Induced Alterations in Gene Expression
Alterations in Gene Expression as a mechanism of Terotogenesis
Role of Tissue-Selective Transcription Factors in Regulating Xenobiotic Metabolizing Enzymes

 

25. Integrating toxicologic pathology into compound evaluation and risk assessment (basic)

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 xenobiotic-induced 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
Integrating Liver Pathology into Toxicity Evaluation
Integrating Kidney Pathology into Toxicity Evaluation
Interpreting the Pathology from Chemical Carcinogens for Risk Assessment

 

26. Basic principles and protocols in molecular toxicology

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 protein: DNA and protein:protein 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 hypothesis-driven 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
Using Polymerase Chain Reaction in Molecular Toxicology
Design, Construction and Use of reporter and Expression Vectors
Basic Techniques in Detecting Proteins and Protein: Protein Interaction  

27. Two-stepping through toxicogenomics: a basic primer

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 high-throughput 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 in-depth 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
Gene Expression Microarrays: The Do-It-Yourself Guide
2D Protein Gels and Interpretation by Mass Spectroscopy
Various Data Analysis Formats for Gene and Protein Expression Methods

  28. Challenges in development of anticancer drugs (Basic)

Preclinical and clinical drug development for anticancer drugs differ from other pharmaceuticals, because of the life-threatening 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
Myelotoxic Effects of Anticancer Drugs on Human Canine and Murine Myeloid Progenitor Cells using In Vitro Hematotoxicology Assays
Regulatory Considerations for Preclinical/Clinical Development of Anticancer Drugs
Clinical Development of Anticancer Drugs
Preclinical and Clinical Regulatory Issues Associated with the Development of Biologics

 

29. Incorporation of pharmacokinetic and pharmacodynamic data into risk assessments (Advanced)

The increasing attention to chemical-specific mechanistic data in human health risk assessments should encourage researchers and programmers to identify and develop risk-relevant information. Recently, guidance for replacing default uncertainty factors with adjustment factors based on chemical-specific 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. Physiologically-based pharmacokinetic (PBPK) modeling has developed risk-relevant 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 risk-relevant, mechanistically-related 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 co-exposures) and their impact on tissue dosimetry and age-related differences in humans.

Overview/Introduction: Pharmacokinetics, Uncertainty Factors and the Risk Assessment Process guidance for Adequacy of Data as a Basis for Development of Compound-Specific Adjustment Factors
In Silico Approaches for PBPK Modeling and Estimation of Interindividual Variance
In Vitro to In Vivo Extrapolations fo Metabolic Rate Constants and their Use in PBPK Modeling Use of PBPK Modeling to Evaluate Implications of Human Variability

 

30. Toxicology of naturally occurring toxins-don't mess with mother nature! (Basic)

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. Characteristics, toxicologic mechanisms and effects of specific intoxications will be provided 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
Venomous Arthropods
Plant Poisons
Herbal Toxicity

 

31. Regulation of drug and chemically-induced apoptotic cell death: new in vivo perspectives (Advanced)

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 naturally-orchestrated self-limiting 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 target-organ 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, caspase-activated DNAse, reactive oxygen species, mitochondrial, and cell cycle-related 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 Chemically-induced Apoptotic and Anti-Apoptotic Mechanisms in the Liver and Kidneys In Vivo
Apoptosis and Cardiotoxicity: Signaling Mechanisms
Apoptosis in Immunotoxicology: Roles of Caspases
Apoptosis and Cell Cycle Control: Recent Advances

 

32. Internal dosimetry: measurement of dna damage as an indicator of internal exposure genotoxicants (Advanced)

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 pro-mutagenic events (malondialdehyde-DNA 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 postlabeling-based 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, alkali-labile 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 T-lymphocyte 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
Measurement of DNA Damage by Lipid Oxidation Products in People
Single Cell Gel (Comet) Assy to Measure DNA Damage in Humans
The Analysis of HPRT Mutations During the Late Stages of Fetal Development and Childhood as a Biomarker for Leukemogenesis in Infants and Children

 

33. Toxicity profiling of genes and proteins by toxicologists: advanced topics in toxicogenomics (Advanced)

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
The ToxicoInformatics Challenge in Genomics Database Development and Functional Interpretation of Data
Proteomics: Applications and Opportunities in Toxicology
Proteome BioKnowledge Library: Curated Protein Information for functional Proteomics

 

34. Basic principles and protocols in molecular toxicology (Basic)

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 protein:DNA and protein:protein 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 hypothesis-driven 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
Using Polymerase Chain Reaction In Molecular Toxicology
Design, Construction and use of Reporter and Expression Vectors
Basic Techniques in Detecting Proteins and Protein: Protein Interactions

 

35. Strategies and issues in non-clinical development of intravenous infusion drug products (Basic)

A large number of pharmaceutical and biotechnology products intended for administration by intravenous infusion in the clinic have entered into non-clinical development during the past decade. Many of these have shown early success in the clinic and subsequently required additional safety evaluation. Non-clinical testing has also utilized the intravenous route to avoid issues associated with short drug half-life or poor absorption that preclude using more traditional clinical dosing routes. Additionally, continuous infusion studies are conducted with non-infusion drugs to control blood levels, such as fetal/neonatal exposure, for mechanistic studies. As a result, the use of intravenous infusion for non-clinical 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 non-clinical 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 non-infusion 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
The Design and conduct of a Safety Evaluation Program for Eptifibatide, a Clinically Approved Inhibitor of Platelet Aggregation conduct of Reproduction Toxicity Studies by Continuous Intravenous Infusion
Scientific Challenges in Drug Development Using Continuous Intravenous Infusion

 

36. Current approaches for validation and regulatory acceptance of novel test methods (Basic)

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 ICCVAM-recommended 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
(ICCV AM) and the NTP in the Regulatory Acceptance of New and Revised Test Methods
The FDA Process for Consideration of ICCV AM Recommended Test Methods
The EPA Process of Considering ICCV AM Recommended Test Methods
The Role of ECV AM for Validation and Regulatory Acceptance of New and Revised Test Methods in the European Union
The Role of OECD in Achieving International Acceptance of Harmonized Test Guidelines