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2012 Continuing Education Courses

SR01 Alternative In Vitro Toxicology Testing for the 21st Century Basic
AM02 Applications of Biomarkers in the Assessment of Health and Disease Advanced
AM03 Basic Embryology and Developmental Toxicity Testing Basic
AM04 Cutaneous Toxicity: In Vitro Methods for Toxicity and Safety Evaluation Advanced
AM05 Frontiers and Applications in Predictive Toxicology: In Silico Methods for Risk Assessment, Toxicology, and Metabolism Basic
AM06 Overview and Application of the WHO-IPCS Harmonized Guidance for Immunotoxicity Risk Assessment for Chemicals Basic
AM07 Stem Cells in Toxicology Basic
PM08 Concepts of Green Chemistry and Its Role in the Identification and Design of Safer Chemicals and Products Basic
PM09 Innate Immunity and Its Relevance to Toxicology Basic
PM10 MicroRNAs in Biology and Toxicology Basic
PM11 Regulatory Sciences: Preclinical Drug Development from Small Molecules to Biologics Basic
PM12 Specialized Techniques for Dose-Response Assessment and Risk Assessment of Chemical Mixtures Advanced
PM13 The Use of Physiologically-Based Pharmacokinetic Modeling to Inform Early Life Sensitivity to Chemical Toxicity Advanced

Alternative In Vitro Toxicology Testing for the 21st Century

SR01—CE Basic

Chairperson: Stephen H. Safe, Texas A&M University, College Station, TX

Endorsed by:
Risk Assessment Specialty Section

Over the last two decades, alternatives to animal testing were strongly driven by animal welfare considerations. A culture of organotypic cell models, quality assurance and validation developed, which resulted in a number of novel approaches for regulatory testing. Progress to replace especially the systemic and chronic types of tests has been limited. Novel programs to assess large number of substances such as existing chemicals (REACH and the emerging TSCA reauthorization), nanoparticles or mixtures, as well as new products such as biologicals and cell therapies now add to the need to move to another approach for toxicity testing. Additionally, interest in health effects like endocrine disruption, developmental neurotoxicity, immunotoxicity, obesity, atherosclerosis or childhood asthma require extensive and new types of testing. This is often referred to as Toxicity Testing for the 21stCentury (Tox-21c), after the respective NAS vision document from 2007, which has been made US EPA’s toxicity testing strategy in 2009.The central change is moving from apical “black box” animal models to mechanism or pathway of toxicity (PoT). The biotechnology and bioinformatics revolution of recent years has made it possible to develop systems biology, here systems toxicology, approaches. The experiences from the field of alternative methods now prove to be the most important to implement a new regulatory approach. Standardization and validation of cell cultures is crucial for PoT identification as well as the implementation of high-throughput type of tests based on PoT. The first projects to systematically map the entirety of human PoT, the Human Toxome, have started. The validation of these novel tests represents an enormous challenge. It is proposed to follow the role model of evidence-based medicine. For this purpose, the evidence-based toxicology collaboration was started at SOT 2011 and is currently shaping its procedures and governance.

Alternative In Vitro Toxicology Testing for the 21st Century. Thomas A. Hartung, John Hopkins University Center for Alternatives to Animal Testing (CAAT), Baltimore, MD

Applications of Biomarkers in the Assessment of Health and Disease

AM02—CE Advanced

Chairpersons: Vishal S. Vaidya, Harvard Medical School, Boston, MA, and Donna L. Mendrick, US FDA, Jefferson, AR

Sponsor: Drug Discovery Toxicology Specialty Section

Endorsed by:
Association of Scientists of Indian Origin Special Interest Group
Disease Prevention Task Force
Risk Assessment Specialty Section

Biomarkers serve as quantitative measures of chemical exposures and biologically effective doses, early warning signals of biologic effect, predict outcome in a patient with disease, and identify who will respond to an intervention and whether the intervention is working. The current era of scientific discovery has brought seemingly limitless opportunities for improvements in medical care. Translational biomarkers that can be measured in blood or urine in both experimental animals and man are of particular interest. Given the importance to the clinical, pharmaceutical, and regulatory communities motivated by more specific and timely diagnoses, early intervention and safer therapies, clinically useful biomarkers have evolved over time, reflecting the scientific and technologic progress made over the centuries. An increasing number of clinically relevant tests and procedures are available to estimate organ injury and guide treatment. The use of molecular signals in the assessment of health and disease is not new; however, the concept of what constitutes a useful biomarker has evolved considerably in the past two to three decades given the advanced enabling technologies, deeper molecular understanding of disease, and the advent of a regulatory framework for biomarker qualification. Our panel experts will highlight the potential of these molecular signals over a wide variety of applications spanning preclinical-clinical safety and disease monitoring in therapeutic and environmental exposures pertaining to cancer, lung, heart, and kidney disease. Coordinated efforts at biomarker discovery and validation as well as technologies for biomarker measurement will help ensure that the ultimate goal of safer drugs, a cleaner environment, and improved patient outcomes is realized.

Introduction. Donna L. Mendrick, US FDA, Jefferson, AR

Discovering Cancer Biomarkers: From Diagnosis and Prognosis through Therapy. Marsha A. Moses, Children’s Hospital-Boston, Harvard Medical School, Boston, MA

Advanced Molecular Biomarkers in Understanding Lung Exposure Biology. David E. Christiani, Harvard School of Public Health, Boston, MA

Biomarkers of Cardiac Dysfunction—Beyond Troponins. James R. Turk, Amgen, Inc., Thousand Oaks, CA

Kidney Safety Signal: From Identification to Point of Care Testing. Vishal S. Vaidya, Harvard Medical School, Boston, MA

Basic Embryology and Developmental Toxicity Testing

AM03—CE Basic

Chairpersons: Christopher J. Bowman, Pfizer Worldwide Research and Development, Groton, CT, and Lori A. Dostal, Exponent, Inc., Farmington Hills, MI

Sponsor: Reproductive and Developmental Toxicology Specialty Section

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

Embryonic and fetal development in mammalian species is a complex process which is sensitive to the effects of maternal and environmental factors. The timing of development of the major organ systems varies between humans and other animal species, but the basic biology of development is similar in all species thus allowing extrapolation of animal testing results for xenobiotics to humans. The course will begin by providing an overview that highlights developmental biology from fertilization of the gametes to normal maturation of a full term placenta and fetus including examples of developmental toxicants and teratogens with known modes of action. Subsequently, applied toxicology concepts for evaluation of the potential for bio/pharmaceuticals and chemicals to affect pregnancy and embryo-fetal development will be discussed. Global regulatory strategies and requirements to minimize health effects on women and unborn children will also be addressed. Finally, key information will be presented to provide for a better understanding of the biological and toxicological basis of prenatal developmental toxicity testing and the impact of various outcomes on drug development, chemical use, environmental impact, and human health risk.

Introduction. Lori A. Dostal, Exponent, Inc., Farmington Hills, MI

Implantation, Placentation, and Early Embryonic Development. John M. DeSesso, Exponent, Inc., Alexandria, VA

Demystifying Mammalian Embryogenesis. Kathleen K. Sulik, University of North Carolina, Chapel Hill, NC

The Importance of Developmental Toxicity Testing to Pharmaceutical Development. Kimberley A. Treinen, Merck, Summit, NJ

Navigating Developmental Toxicity Testing of Agricultural Molecules and Industrial Chemicals. Reza J. Rasoulpour, Dow Chemical Company, Midland, MI

Cutaneous Toxicity: In Vitro Methods for Toxicity and Safety Evaluation

AM04—CE Advanced

Chairpersons: William G. Reifenrath, Stratacor Inc., Richmond, CA, and Cynthia A. Ryan, Procter & Gamble Company, Cincinnati, OH

Sponsor: Dermal Toxicology Specialty Section

Endorsed by:
In Vitro and Alternative Methods Specialty Section

Skin is the largest external organ and serves as a living, dynamic protective envelope surrounding the body. As such, it is constantly exposed to environmental hazards, including hazardous compounds; these exposures account for a major portion of all reported industrial illnesses. Skin exposures may also occur from pharmaceuticals or consumer products that are intentionally applied. In vitro methods are important as a first step to estimate skin permeation, and the potential of skin irritation and sensitization for compounds or mixtures of compounds that are directly toxic to the skin or systemically toxic. In exploration of these issues we will provide an overview of the current status of in vitro models for cutaneous toxicity safety evaluations and the regulatory requirements for establishing the nonclinical safety of dermal drug products. This important topic has relevance to toxicologists involved in safety evaluations and risk assessments for chemicals that contact the skin.

Use of the Excised Human Skin Model for Percutaneous Risk Assessment. Thomas J. Franz, Cetero Research, Fargo, ND

Direct Comparison of In Vitro and In Vivo Dermal Absorption of Several Chemicals. Jeffrey J. Yourick, US FDA, Laurel, MD

Specialized Procedures for Lipophilic and Semi-Volatile Compounds and Their Influence on Comparative In Vitro—In Vivo Skin Absorption. William G. Reifenrath, Stratacor, Inc., Richmond, CA

Skin Sensitization: Underlying Mechanisms, Hazard Identification, and a Quantitative Risk Assessment Approach. Cynthia A. Ryan, Procter & Gamble Company, Cincinnati, OH

Skin Irritation: In Vitro Models. John W. Harbell, Mary Kay Inc., Dallas, TX

US Regulatory Requirements for Establishing the Nonclinical Safety of Dermal Drug Products. Marian W. Glynn, Dow Pharmaceutical Sciences, Petaluma, CA

Frontiers and Applications in Predictive Toxicology: In Silico Methods for Risk Assessment, Toxicology, and Metabolism

AM05—CE Basic

Chairpersons: Christopher A. Reilly, University of Utah, Salt Lake City, UT, and Sneha Bhatia, Research Institute for Fragrance Materials, Inc., Woodcliff Lake, NJ

Sponsor: In Vitro and Alternative Methods Specialty Section

Endorsed by:
Food Safety Specialty Section
Molecular Biology Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

With the integration of open source programs, in silico tools, and bioinformatics, the role of the computer continues to transform daily activities and work for the modern scientist. Furthermore, the call for reduced animal testing in toxicity evaluation has led to an expansion of in silico resources, quantitative structure-activity relationship (QSAR) programs, chemoinformatics systems, and predictive metabolism tools. Regulatory authorities, pharmaceutical, chemical, and food industries are actively using such tools in the safety evaluations of novel drug candidates, food additives, environmental contaminants and consumer products. We will begin by providing a basic introduction to various in silico tools, specifically predictive toxicology and metabolism platforms, and how their algorithms compute results and influence the decision process. A composed set of didactic lectures will be used to introduce the basic concepts and activities surrounding the use of in silico tools in ADME/Tox and safety studies. In follow-up participants will be provided with a brief summary of various platforms with practical tutorials of the computational toxicology platforms discussed.

Introduction to Computational Toxicology. Sneha Bhatia, Research Institute for Fragrance Materials, Inc., Woodcliff Lake, NJ

Computational Models for Predicting Human Toxicities. Sean Ekins, Collaborations in Chemistry, Inc., Fuquay-Varina, NC

Computational Approaches to the Prediction of Metabolism and the Simulation of Metabolic Pathways. Tony Long, Lhasa Limited, Leeds, United Kingdom

Computational Safety Analysis for Regulatory Decision-making and Research at FDA. Luis G. Valerio, Jr., US FDA, Silver Spring, MD

Computational Approaches: Linking Chemical Exposures and Human Disease. Dale E. Johnson, Emiliem, Inc., Emeryville, CA and University of California Berkeley, Berkeley, CA

Predictive Toxicology Platforms: Tools for the Trade? Eugene Ahlborn, Givaudan Flavors, Cincinnati, OH

Overview and Application of the WHO/IPCS Harmonized Guidance for Immunotoxicity Risk Assessment for Chemicals

AM06—CE Basic

Chairpersons: Andrew A. Rooney, NIEHS, Research Triangle Park, NC, and Henk Van Loveren, National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands

Sponsor: Immunotoxicology Specialty Section

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

The WHO/IPCS harmonized guidance document is the first compressive guidance document for risk assessment in toxicology. Immunotoxicity risk assessment of chemicals is an evaluation of the potential for unintended effects of chemical exposure on the immune system. These effects manifest as four principal types of immunotoxicity which are categorized as immuno—suppression and stimulation, autoimmunity, and sensitization. We will provide an overview of the methods used to detect and characterize immunotoxicity and the potential consequences of unintended immunomodulation. It is well established that xenobiotic-related immunosuppression can lead to reduced resistance to infections and certain neoplastic diseases. Exposure to xenobiotics has been shown to be associated with development or worsening of autoimmune disease. It has been established that xenobiotics can elicit hypersensitivity responses directly as an allergen, or they can enhance the induction or severity of allergic sensitization to pollen or dust mites. The determination of risk associated with immunostimulation may be more difficult, but unexpected stimulation should not be disregarded as it may result in nonspecific inflammation or the skewing of normally protective immune responses to favor induction or exacerbation of autoimmunity and hypersensitivity. The fundamental concepts of risk assessment as they apply to the evaluation of immunotoxicity as well as the application of the guidance will be highlighted. We will begin by reviewing case studies which include data that focuses on different areas of immunotoxicity—suppression, sensitization, and autoimmunity. The studies will demonstrate application of the guidance, particularly the development of weight of evidence conclusions from the available data. Finally, we will illustrate that risk assessment for a given chemical should consider the full range of immune effects for that chemical, and data should be evaluated separately for evidence of suppression, stimulation, autoimmunity, and sensitization.

Overview of the WHO/IPCS Harmonized Guidance for Immunotoxicity Risk Assessment for Chemicals. Henk Van Loveren, National Institute of Public Health (RIVM), Bilthoven, Netherlands

Immunotoxicity Risk Assessment. Andrew A. Rooney, NIEHS, Research Triangle Park, NC

Assessment of Immunosuppression, Immunostimulation, and Autoimmunity. Robert W. Luebke, US EPA, Research Triangle Park, NC

Assessment of Sensitization and Allergic Response. Peter Griem, Symrise AG, Holzminden, Germany

Case Study 1: Lead. Michael I. Luster, West Virginia University School of Medicine, Morgantown, WV

Case Study 2: Halogenated Platinum Salts. Peter Griem, Symrise AG, Holzminden, Germany

Case Study 3: Mercury. Andrew A. Rooney, NIEHS, Research Triangle Park, NC

Stem Cells in Toxicology

AM07—CE Basic

Chairpersons: Michael P. Waalkes, NIEHS, Research Triangle Park, NC, and Erik J. Tokar, NIEHS, Research Triangle Park, NC

Sponsor: Stem Cells Specialty Section

Endorsed by:
Biotechnology Specialty Section
Carcinogenesis Specialty Section
Reproductive and Developmental Toxicology Specialty Section

Stem cells are revolutionizing toxicological research and remain an area with tremendous potential. Recently, research on stem cells has generated tremendous public and professional interest. However, some areas of toxicological research have lagged behind in the integration of stem cells as a concept in toxicant-induced disease etiology. We will describe the utility and suitability of the assorted types of stem cell models (i.e. embryonic, fetal, progenitor, induced pluripotent, immortalized stem cell lines, etc.) for various research purposes, including disease modeling, drug discovery and toxicity testing in order to describe the potential applications of stem cells in toxicological research. This important overview of stem cells will highlight their nomenclature, properties, and their roles in the genesis of various diseases.

Stem Cells in Toxicology. Erik J. Tokar, NIEHS, Research Triangle Park, NC

The Concepts and Methods for Stem Cells. Ying Xia, University of Cincinnati, Cincinnati, OH

Stem Cells in Carcinogenesis. Michael P. Waalkes and Erik J. Tokar, NIEHS, Research Triangle Park, NC

Stem Cells and Regenerative Medicine. R. Clark Lantz, University of Arizona, Tucson, AZ

Stem Cells in Safety Testing. Kyle L. Kolaja, Hoffmann-La Roche, Inc., Nutley, NJ

Concepts of Green Chemistry and Its Role in the Identification and Design of Safer Chemicals and Products

PM08—CE Basic

Chairpersons: Pamela J. Spencer, Dow Chemical Company, Midland, MI, and John Warner, Warner Babcock Institute for Green Chemistry, Wilmington, MA

Endorsed by:
Molecular Biology Specialty Section

Hazard identification, dose-response characterization, and exposure potential are the underpinning of product safety assessments. These basic principles help regulatory agencies, manufacturers, and formulators determine the conditions for safe use of chemicals, raw materials, and products for a given application to reduce adverse impacts to human health and the environment. Today, as a part of the growing interest in green chemistry, the pendulum is shifting. The large number of companies engaging in sustainability initiatives coupled with increased consumer demand for greener products is driving a new process where impacts of chemical products and processes are included as design criteria. Reducing intrinsic chemical hazards up front is a strategy used in developing safer alternatives to existing chemicals. Thus green chemistry is raising the bar for chemical safety assessments. Our panel of experts will begin with a background of green chemistry, its basic principles, why it is useful and highlight key certification programs/tools used to identify safer alternatives including their methods and criteria with specific emphasis on the Green Screen for Safer Chemicals alternatives assessment tool. There are unique opportunities for toxicologists to assist molecular designers in reducing the intrinsic hazards of their molecules by providing insight into toxicological mechanisms and data that support the application of green chemistry principles in the design of new chemicals and products. To underscore the importance of this issue, we will illustrate how principles of green chemistry are applied in a consumer products and a chemical company. The caveats and challenges will be addressed by using case studies. The exploration of this topical area will provide an understanding of green chemistry, awareness of the tools and programs immediately available and how to access and use them as well as an appreciation for some of the practical challenges associated with implementing principles of green chemistry into product development and assessments of safer alternatives.

Introduction. Pamela J. Spencer, Dow Chemical Company, Midland, MI

Introduction to the Concepts of Green Chemistry and Its Role in the Design of Safer Chemicals and Products. John Warner, Warner Babcock Institute for Green Chemistry, Wilmington, MA

Using Comparative Hazard Assessments: Green Screen for Safer Chemicals, Lauren Heine, Lauren Heine Group LLC, Juneau, AK

Strategies and Methods for Incorporating Green Chemistry into the Design of Chemicals and Products. Thomas G. Osimitz, Science Strategies, LLC, Charlottesville, VA

Application of the Principles of Green Chemistry in a Chemical Company: Overview and Case Studies. J. Craig Rowlands, Dow Chemical Company, Midland, MI

Application of the Principles of Green Chemistry in a Consumers Products Company: Overview and Case Studies. Donald Versteeg, Procter and Gamble Company, Cincinnati, OH

Innate Immunity and Its Relevance to Toxicology

PM09—CE Basic

Chairpersons: Wendy J. Freebern, Bristol-Myers Squibb, North Brunswick, NJ, and Jacintha M. Shenton, MedImmune, Inc., Cambridge, United Kingdom

Sponsor: Immunotoxicology Specialty Section

The innate immune system is the host’s first line of defense against infection. Thus, knowing the what, why, how, and when of innate immune function assessment in toxicology evaluations is important. This course will introduce the components of the innate immune system and its role in host defense, discuss clinical observations resulting from inhibition or stimulation of innate immune function in non-clinical species, provide case examples where understanding intentional or inadvertent effects on innate immune function has had utility in toxicity testing, and explain the what and how of innate immune measurements and the gaps in capabilities thereof. Innate immunity assessments to be discussed include bacterial killing assays and an array of macrophage, neutrophil, and natural killer cell activity assessments which will be described within the context of various target organs, animal models, and toxicology programs. In addition, investigating innate immune function on a molecular level through evaluating cell signaling molecules and regulated expression of anti-microbial peptides, chemokines, and cytokines will be discussed. In closing, the application of innate immunity testing in the clinic and translatability of non-clinical findings to the clinic will be examined. This course should be of broad interest to toxicologists with the desire to learn about the innate immune system and how innate immune evaluations can be applied to toxicology testing. In addition, the course will appeal to scientists whom are interested in learning methodologies of innate immune function testing and applicability thereof.

Innate Immunity and Its Relevance to Toxicology: An Introduction. Jacintha M. Shenton, MedImmune, Inc., Cambridge, United Kingdom

Not Just a Physical Barrier: Cellular and Molecular Innate Immune Defense Mechanisms of the Epidermis. Jamie J. Bernard, Rutgers University, Piscataway, NJ

The Why, When, What and How of Macrophage and Neutrophil Function Testing in Drug Development. Wendy J. Freebern, Bristol-Myers Squibb, North Brunswick, NJ

Accessing Natural Killer Cell Activity in Non-Clinical Toxicity Studies. Christina Satterwhite, Charles River Laboratories, Reno, NV

Innate Immunity in Drug-Induced Liver Injury. Cynthia Ju, University of Colorado, Aurora, CO

Translating Non-Clinical Innate Immune Testing into the Clinic. Wendy J. Komocsar, Eli Lilly and Company, Indianapolis, IN

MicroRNAs in Biology and Toxicology

PM10—CE Basic

Chairpersons: Neelakanteswar Aluru, Woods Hole Oceanographic Institution, Woods Hole, MA, and Carmen J. Marsit, Dartmouth Medical School, Hanover, NH

Sponsor: Molecular Biology Specialty Section

MicroRNAs (miRNAs) constitute a critically important class of non-coding, small RNAs, which post-transcriptionally regulate gene expression. miRNAs are approximately 18-24 nucleotides (nt) in length, that regulate gene expression by binding to 3'untranslated regions (UTR), coding sequences or 5'UTR of target messenger RNAs (mRNAs), and leading to inhibition of translation or mRNA degradation. It is estimated that miRNAs regulate approximately 30% of the human protein-coding genome. miRNAs control the expression of genes involved in several biological processes, including apoptosis, proliferation, differentiation, and metastasis. Given the prominent role miRNAs play in organismal function, it is not surprising that the aberrant expression of miRNAs can lead to a wide range of human diseases and disorders, including cancer, neurodegenerative diseases, diabetes and a variety of cardiovascular and hepatic disorders. In addition to contributing to the underlying cause of a particular disease, miRNAs can also represent potential therapeutic targets and diagnostic biomarkers. The recent discovery of circulating miRNAs are promising biomarker candidates since they can be detected from readily attainable blood samples. On account of the critical role that miRNAs play in biological function and the diverse range of applications in which miRNA analysis is of value, significant effort has been invested over the past decade to develop new detection methods. We will provide an overview of existing and emerging tools for miRNA analysis, with particular emphasis placed on the current state of the art and important developments in this emerging field.

Overview of MicroRNA Quantification Methods. Neelakanteswar Aluru, Woods Hole Oceanographic Institution, Woods Hole, MA, and Carmen J. Marsit, Dartmouth Medical School, Hanover, NH

MicroRNA Functions in Stress Responses. Anthony Leung, John Hopkins University, Bloomberg School of Public Health, Baltimore, MD

Evaluating the Toxicological Role of MicroRNAs During Development. Robert L. Tanguay, Oregon State University, Corvallis, OR

MicroRNAs in Cancer, Stephen H. Safe, Texas A&M University, College Station, TX

MicroRNA Profiling in Population-Based Studies of Exposure-Related Health Outcomes, Carmen J. Marsit, Dartmouth Medical School, Hanover, NH

Regulatory Sciences: Preclinical Drug Development from Small Molecules to Biologics

PM11—CE Basic

Chairpersons: Tao Wang, Novartis Pharmaceuticals, Emeryville, CA, and David McGuinn, US FDA, Silver Spring, MD

Sponsor: Biotechnology Specialty Section

Endorsed by:
Immunotoxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section
Women in Toxicology Special Interest Group

Drug development is a highly regulated but science-driven process from early discovery to marketing. Once the drug candidate has been discovered, preclinical safety evaluations are required to ensure the safety of the drug during clinical trials, ultimately bridging the gap between drug discovery and marketing. The preclinical development of four types of drugs, small molecular-weight drugs, biologics, oligonucleotide-based therapeutic drugs and antibody drug conjugates (ADCs), will be illustrated to emphasize the cross-functional nature of regulatory sciences. In exploration of this important topic, we will begin with a focus on small molecular-weight drug candidates, which require a sliding scale for the degree of development from relatively minimal regulatory requirements for oncology drug development to the much more stringent requirements for the development of drugs for non-life threatening conditions and chronic treatment. Next the focus will shift to large molecule biologics and will provide illustrations of the unique challenges the regulatory safety assessment and clinical development that biologic drug candidates present. Our panel of experts will then focus on oligonucleotide-based therapeutics since many of the overarching oligonucleotide class-based properties have been well established, but there remain unique considerations for each subclass of oligonucleotide. This talk will discuss the preclinical development of oligonucleotide-based therapeutic drugs, including antisense, siRNA, immunostimulatory and aptamer applications. At last this course will also cover ADCs, which are comprised of monoclonal antibodies (biologics) conjugated with drugs or cytotoxins (small molecules). Standard approaches for preclinical safety evaluation of each of the individual components of these conjugates may not always be necessary. The regulatory expectations for this class of therapeutics are continuing to be defined. We will illustrate the safety assessment challenges and development strategies associated with certain ADCs.

Regulatory Sciences: Preclinical Drug Development from Small Molecules to Biologics. Tao Wang, Novartis Pharmaceuticals, Emeryville, CA

The Preclinical Development of Low Molecular Weight Drugs—Comparison of Oncology and Non-Oncology Indications. David McGuinn, US FDA, Silver Spring, MD

Safety Assessment and Clinical Development of Biopharmaceuticals. James D. Green, Boehringer Ingelheim Pharmaceuticals, Inc., Sudbury, MA

Development of Oligonucleotide Therapeutics and Its Toxicological Considerations. Page Bouchard, Novartis Institutes for BioMedical Research, Cambridge, MA

Development Strategies and Safety Assessment of Antibody Drug Conjugates. Kimberly A. Stickland, Biogen Idec., Inc., San Diego, CA

Specialized Techniques for Dose-Response Assessment and Risk Assessment of Chemical Mixtures

PM12—CE Advanced

Chairpersons: Jane Ellen Simmons, US EPA, Research Triangle Park, NC, and Michael J. DeVito, NIEHS, Research Triangle Park, NC

Sponsor: Mixtures Specialty Section

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

A variety of methods are available for chemical mixtures risk assessment. A key step is careful consideration of data quantity and quality to guide the type of assessment done. Whole mixture methods will be summarized that, after considering data quality and quantity, do not differ from single chemical methods. The principal uncertainty for “sufficiently similarity” is ascertaining that two mixtures are sufficiently similar so that one may be used as a surrogate of another. Two approaches for a group of similar mixtures will be reviewed, comparative potency and geographic site-specific assessment. The course will focus on component-based methods (toxic equivalency factors, relative potency factors, binary weight of evidence, hazard index, target-organ toxicity hazard index, interaction-based hazard index) as they are the most frequently performed mixtures assessments. They use single-chemical toxicity and exposure data, with possibly some toxicity information on defined mixtures of the chemicals of interest. For each method (whole mixture and component-based), the presenter will describe data requirements, assumptions and limitations and illustrate the application by example. Upon conclusion, students will be able to navigate the risk assessment flow chart, have an understanding of the assumptions, limitations and uncertainties underlying the presented approaches, and be able to either apply the presented methods to their own data, or consult more knowledgeably with risk assessors. The methods and approaches are applicable to the diverse universe of mixtures, including those found in air, water, soil and food and apply to environmental, industrial, pharmaceutical, intentional and accidental mixtures. The course will be useful to toxicologists as understanding how their data are used to assess risk will enable the design and conduct of more meaningful and useful multi-pollutant experiments. Additionally, understanding underlying assumptions will foster design and conduct of experiments to replace assumptions with evidence-based understanding.

Risk Assessment Methods for Whole Mixtures. Jane Ellen Simmons, US EPA, Research Triangle Park, NC

Beyond Relative Potencies: Uncertainties in the Application of TEFs in Risk Assessment. Michael J. DeVito, NIEHS, Research Triangle Park, NC

Using Dose Addition: Hazard Index, Target Organ Toxicity Hazard Index and the Interaction-Weighted Hazard Index. Richard C. Hertzberg, Biomathematics Consulting, Atlanta, GA

The Use of Binary Weight of Evidence to Characterize Chemical Interactions for Risk Assessment. Moiz Mumtaz, ATSDR, Atlanta, GA

The Use of Physiologically-Based Pharmacokinetic Modeling to Inform Early Life Sensitivity to Chemical Toxicity

PM13—CE Advanced

Chairpersons: Harvey J. Clewell, The Hamner Institutes for Health Sciences, Research Triangle Park, NC, and Miyoung Yoon, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

Endorsed by:
Regulatory and Safety Evaluation Specialty Section

A major challenge in assessing potential susceptibility to environmental chemicals during in utero and postnatal development is uncertainty regarding the actual exposure in the target subpopulation. We will demonstrate the value of PBPK modeling in quantitative health risk assessments for infants and children by providing a scientifically sound tool to predict the target tissue dose in the young. A thorough understanding of dynamic changes in physiological and biochemical factors is essential to predict the target tissue exposure during development. Factors that influence the kinetic behavior of chemicals in early life include ontogeny in metabolizing enzymes, changes in transporter expression, maturation of biological barriers such as the blood brain barrier, differential growth of tissues, and distinct exposure patterns compared to adults. PBPK modeling provides a means to integrate these factors in the proper context and thus reduce uncertainty in conducting risk/safety assessment for early life. The presentations will provide an overview of pharmacokinetic factors affecting early life sensitivity and two case studies of PBPK approaches for gestation/lactation and childhood exposures, plus a demonstration of how PBPK modeling of development can be used to evaluate neonatal epidemiological results. The course participants will get in depth understanding of the value of PBPK modeling in addressing issues of potential sensitivity in infants and children and the possible application scenarios of this valuable tool.

Physiological and Pharmacokinetic Factors Affecting Early Life Sensitivity to Chemical Exposures. Rebecca A. Clewell, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

PBPK Modeling of Manganese Exposures during Gestation and Lactation. Miyoung Yoon, The Hamner Institutes for Health Sciences, Research Triangle Park, NC

Modeling of Pyrethroid Exposures in Early Life. Rogelio Tornero-Velez, US EPA, Research Triangle Park, NC

Use of PBPK Models of Perfluorinated Compounds to Evaluate Whether Epidemiologic Associations are Due to Reverse Causality. Matthew P. Longnecker, NIEHS, Research Triangle Park, NC