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2017 Continuing Education Courses

SR01 Molecular Imaging for Toxicologists Basic Book
AM02 Adding Up Chemicals: Component-Based Risk Assessment of Chemical Mixtures Advanced Book
AM03 Current Principles for Nonclinical Chronic Toxicity/Carcinogenicity Testing of Environmental Chemicals Basic Book
AM04 Navigating Drug-Induced Vascular Injury in Preclinical and Clinical Development of Novel Therapeutics Basic Book
AM05 New Concepts and Technologies in Metals Toxicology Advanced Book
AM06 Reproductive Toxicity: Challenges and Practical Approaches to Determine Risk in Drug Development Basic Book
AM07 Technologies and Applications of Stem Cells for Use in Toxicology Advanced Book
PM08 Detecting Cancer Risk in Drugs: Design, Conduct, and Interpretation of Carcinogenicity Studies for Regulatory Approvals Advanced Book
PM09 Developmental and Reproductive Toxicology (DART) and Risk Assessment of Environmental Chemicals: Applications, Complexities, and Novel Approaches Basic Book
PM10 Emerging Approaches in Genetic Toxicology for Product Development Basic Book
PM11 Extrapolation in the Airways: Strategies to Incorporate In Vivo and In Vitro Data to Better Protect Human Health Advanced Book
PM12 Health-Based Limits for Toxicological Risk Assessment: Setting Acceptable Daily Exposures for Pharmaceutical and Chemical Safety Basic Book
PM13 Read-Across: Case Studies, New Techniques, and Guidelines for Practical Application Basic Book


Molecular Imaging for Toxicologists

Sunrise Mini-Course (SR01) | 7:00 AM to 7:45 AM

Chairperson(s): Aurore Varela, Charles River Laboratories, Senneville, QC, Canada; and David L. Hutto, Charles River Laboratories, Wilmington, MA.

Endorser(s): Toxicologic and Exploratory Pathology Specialty Section

Advanced in vivo imaging techniques such as magnetic resonance, and nuclear and tomographic imaging are the gold standard in several areas of clinical medicine for diagnosis and guided therapy, and play an increasing role in clinical trials, being an integral part of the drug development process. Imaging sciences have known an incredible development during the last decades, and many techniques, such as MRI, PET, SPECT, and X-ray-computed tomography, have become indispensable. The applications of in vivo translational imaging are now extending further into drug discovery and development, and have the potential to considerably accelerate the process, reduce the cost, significantly affect the drug development process, and comply with the 3R. It is important to understand the technologies and their applications and limitations. Imaging technology includes a range of modalities such as magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), in vivo optical imaging, and ultrasound. These noninvasive and quantitative techniques provide not only anatomical evaluation but also functional and molecular information that can access the mechanisms of drug action or its toxicity. The future trends will certainly be in multimodality imaging, combining high sensitivity and molecular techniques with high spatial resolution and morphological techniques. Imaging stands out as one of the most promising translational techniques that can significantly improve decision-making in early phase, to kill compounds that are destined to fail in later phase, and the go/no go decisions can be made earlier based on pertinent information. Imaging technologies can improve the drug development process, not only with the development of safer and effective drugs but also with reducing timelines. Better prediction of toxicology in an earlier stage will certainly limit the large contribution of drug failure for adverse effect in later stage development. Although, imaging has not yet a major place in safety pharmacology and toxicology studies, several applications exist in cardiovascular, neurology, teratology, and reproductive toxicity. Same technologies and the same physiological and pathological parameters can be quantified for both pharmacology and toxicology applications, confirming the role of in vivo imaging as a translational biomarker for both efficacy and safety assessment. This overview provides the opportunity to review fundamentals of molecular imaging, review important applications of imaging in different therapeutics areas, opportunities for decision-making in preclinical phase and challenges of GLP validation, and to actually integrate imaging approaches into safety assessment in drug development.

The Wonderful World of Molecular Imaging: Understand the Technology. Roger Lecomte, Université de Sherbrooke, Sherbrooke, QC, Canada.

Imaging Biomarkers for Decision Making in Drug Discovery. Paul J. McCracken, ICON Plc., Philadelphia, PA.


Adding Up Chemicals: Component-Based Risk Assessment of Chemical Mixtures

Morning Course (AM02) | 8:15 AM to 12:00 Noon

Chairperson(s): Jane Ellen Simmons, US EPA, Research Triangle Park, NC; and Richard Hertzberg, Biomathematics Consulting, Atlanta, GA.

Endorser(s): Mixtures Specialty Section
Occupational and Public Health Specialty Section
Risk Assessment Specialty Section

Component-based methods, while least preferred, are most frequently used to conduct mixtures risk assessments (RA), needing only toxicological information on the individual chemicals or pairs. Inherent in component-based methods are assumptions regarding: toxicological similarity (e.g., dose addition) or independent action; the likelihood or relevance of nonadditive interactions; and the appropriate combined action model. This course covers underlying concepts, inherent assumptions, and uncertainties for mixture assessments. Topics include: guidance from regulatory and advisory bodies for component-based mixtures RA; empirical support and biological understanding for concepts of toxicological similarity and independence; existing and emerging methods, such as grouping chemicals for mixtures RA; influence of study design and data analysis on choice of a combined action model; uncertainties from extrapolation of models to untested dose ranges; conceptual differences of individual risk vs population fraction; consequences of forcing effect measures into a pseudo-risk construct; a rubric of criteria for evaluating usefulness of existing interaction studies; and approaches for reducing the uncertainty of, or incorporating nonadditive interactions into, the RA. Three types of component-based methods are considered, based on: toxicological similarity, independent action, and more complex and hybrid concepts. Step-by-step case studies with different mixtures allow the attendee to work through examples with the instructor. A case study is presented that includes toxicological experimentation and environmental RA for an intentional defined mixture of insecticidal proteins that have been commercialized to enhance efficacy against agricultural pests and combat insect resistance by targeting multiple modes of action. The course will help those who conduct component-based mixtures RA for occupational health and safety, product safety, public health protection, or regulatory decision-making and will appeal to toxicologists who conduct component-based mixtures experiments. Attendees will be equipped to use component-based mixture RA methods and understand their assumptions, advantages, and limitations.

Grouping Chemicals for Assessment and Conducting Assessments with the Hazard Index and Related Methods. Jane Ellen Simmons, US EPA, Research Triangle Park, NC.

Mode of Action, Experimental Design, and Model of Combined Action: Is There a Connection? Christopher J Borgert, Applied Pharmacology and Toxicology, Inc., Gainesville, FL.

The Flip Side: Methods for Independent Action, and Hybrid Methods for Interactions and for Mixed Modes. Richard C. Hertzberg, Biomathematics Consulting, Atlanta, GA.

A Case Study: How Mixture Data are Used in Risk Assessments for Genetically-Engineered Crops Expressing Multiple Insecticidal Traits. Steven L. Levine, Monsanto Company, St Louis, MO.


Current Principles for Nonclinical Chronic Toxicity/Carcinogenicity Testing of Environmental Chemicals

Morning Course (AM03) | 8:15 AM to 12:00 Noon

Chairperson(s): Kristen Ryan, National Toxicology Program/NIEHS, Durham, NC; and Lynea Murphy, The Dow Chemical Company, Midland, MI.

Endorser(s): Carcinogenesis Specialty Section
Regulatory and Safety Evaluation Specialty Section

Chronic toxicity and carcinogenicity testing in rodents is considered the “gold-standard” approach for identifying potential hazards of chemicals and is necessary to inform risk assessment or risk management. The objectives of this course are to provide the basic tools for toxicologists who desire a better understanding of how to assess chemical-related toxicity associated with chronic exposure and subsequent potential risk(s) to humans. The course will begin with an overview of the current practices for conducting chronic toxicity and carcinogenicity studies and provide examples for how integrated testing strategies may aid in refinement of study design/conduct. The next presentation of this course will focus on evaluating rodent pathology in long-term toxicity studies (i.e., what to expect, pathology peer review, and differentiating between age-related or strain-specific findings and chemical-mediated toxicity). Next, an overview of the regulatory requirements for chronic toxicity/carcinogenicity studies will be presented with a discussion of how data inform regulatory decisions with a focus on environmental chemicals. The final presentation in this course will highlight recent advances in identifying and classifying carcinogens, with an emphasis on the development and application of novel approaches and high-throughput data streams in human health hazard assessments. The expected audience includes toxicologists who work in regulated product development (e.g., chemical industries), scientists who may be responsible for monitoring or directing contracted chronic toxicity/carcinogenicity studies, as well as regulators of chemicals in commerce or environmental contaminants.

Introduction and Course Goals. Kristen Ryan, National Toxicology Program/NIEHS, Durham, NC.

Design, Conduct, and Interpretation of Chronic Toxicity/Carcinogenicity Studies: Where We’ve Been and Where We’re Going. Lynea Murphy, The Dow Chemical Company, Midland, MI.

Overview of Pathology for Chronic Toxicity and Carcinogenicity Studies in Rodents. Mark Cesta, Division of the National Toxicology Program, NIEHS, Durham, NC.

Overview of Regulatory Requirements for Chronic Toxicity/Carcinogenicity Testing. Gregory Akerman, US Environmental Protection Agency, Arlington, VA.

Approaches for Evaluating Mechanisms and Incorporating High-Throughput Screening Data in Cancer Hazard Evaluations of Environmental Chemicals. Kate Guyton, International Agency for Research on Cancer, Lyon, France.


Navigating Drug-Induced Vascular Injury in Preclinical and Clinical Development of Novel Therapeutics

Morning Course (AM04) | 8:15 AM to 12:00 Noon

Chairperson(s): Hong Wang, Genentech, South San Francisco, CA; and Bradley Enerson, Pfizer, Groton, CT.

Endorser(s): Cardiovascular Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

Drug induced vascular injury (DIVI) can cause significant delays in or even halt the development of promising new drugs due to the uncertainty in the predictivity of preclinical findings to humans and the lack of validated safety biomarkers for DIVI. Increasing numbers of cross-industry collaboration to explore and validate novel safety biomarkers and imaging technologies are being carried out in preclinical and clinical studies to better enable the development of novel drugs associated with DIVI. When encountering DIVI in preclinical studies, it is important that the toxicologists and pathologists work together to understand the mechanisms, species translatability, and to engage early discussions with the clinicians and Regulatory Agencies to evaluate potential path forward. This CE course is dedicated to provide a systematic training on DIVI. The first presenter will provide an overview on the different mechanisms of DIVI, pathology lesions, clinical manifestation, different tools and novel safety biomarkers available to investigate DIVI, and regulatory consideration. The second and the third presenters will use case examples to discuss common mechanisms of pharmaceuticals- and biotherapeutics-induced DIVI, respectively. Presenters will illustrate common tools and novel technologies that can be used to investigate the mechanisms and preclinical to clinical translation, how to use these data to inform go/no-go decisions, and to support clinical development and registration. Lastly, the final speaker will utilize a fun, interactive working session to challenge the audience to solve DIVI findings real-time, and to engage the audience to consider alternative strategies to enable the development of novel safe and efficacious drugs. The course will be wrapped up with pragmatic points for considerations for the toxicologists when DIVI is observed in preclinical studies.

Drug Induced Vascular Injury: From PDEs to Proteins, How Little Holes Cause Big Problems. James Weaver, US Food and Drug Administration (FDA), Silver Spring, MD.

Inflammation, Hemodynamics and Direct Cellular Toxicity: A Review of Relevant Mechanisms and Derisking Strategies for Small Molecule-Related Vascular Injury. Bradley Enerson, Drug Safety Research and Development, Pfizer, Groton, CT.

Vascular Injury Associated with Biotherapeutics: Mechanisms of Toxicity and Consideration for Risk Assessment. Hong Wang, Development Toxicology, Safety Assessment, Genentech, South San Francisco, CA.

Drug-Induced Vascular Injury: Practical Exercises. Tanja Zabka, Pathology, Safety Assessment, Genentech, South San Francisco, CA.


New Concepts and Technologies in Metals Toxicology

Morning Course (AM05) | 8:15 AM to 12:00 Noon

Chairperson(s): Wei Zheng, Purdue University, West Lafayette, IN; and Michael Hughes, US EPA, Research Triangle Park, NC.

Endorser(s): Mechanisms Specialty Section
Metals Specialty Section
Neurotoxicology Specialty Section

Metals have provided unique challenges to toxicologists because of difficulties in methods of their detection, limited understanding of their mechanisms of action, means of medical intervention, and the connections between human health, animal health, and the ecosystem. A recent incident of drinking water lead exposure in Flint, Michigan bespeaks the social, economic, and ethnic impacts of metal toxicity in general populations. This basic course is intended to introduce the audience with the novel concepts and technologies in metal toxicological research, from mechanistic interpretation to therapeutic intervention, and from innovative technologies in diagnosis and quantification of metal body burden to the concept of “One Health” that integrates ecology, animal health, and human health as a whole system. The Introduction will briefly review the current state of metal-induced toxicities due to worldwide environmental and occupational exposure and state the purposes of this course (Dr. Zheng). The first lecture will introduce the integrative concept of “One Health” that embraces the factors from ecology and the environment to animal and human susceptibility to interpret metal toxicity (Dr. Wise). The second lecture will further extend the concept by providing a concise overview of general disposition (e.g., absorption) and mechanisms of metal toxicity (e.g., direct interaction with functional groups of critical proteins, generation of reactive oxygen species, and alteration of cell signaling pathway) and the integrating these factors on the impact of metals on epigenetics and cancer stem cells (Dr. Hughes). The third lecture will provide an overview of advanced medical imaging modalities such as MRI/MRS, PET, and XRF and their applications. The speaker will use manganese (Mn) as an example to showcase how imaging can be used for early diagnosis of metal toxicities and monitoring of disease progression and therapy (Dr. Dydak). The final lecture will discuss new concepts in clinical treatment of metal toxicities within and beyond the traditional chelation therapy (Dr. Smith). Speakers will discuss these concepts and technologies in the context of metal toxicology with details specific to metals having particular human environmental health relevance, such as lead (Pb), manganese (Mn), cadmium (Cd), arsenic (As) and mercury (Hg). The course will benefit those who desire knowledge on novel mechanistic interpretation of metal toxicities, theories on metal toxicity treatment and intervention, and technical approaches in utilizing widely available imaging technologies that can be used to support research in metal toxicology. As the course introduces concepts and techniques that are equally applicable to other fields, researchers engaged in wider aspects of metal toxicology, such as neurotoxicology, nanotoxicology, carcinogenesis, risk assessment, and occupational health will benefit by attending this course.

Introduction: Current State of Metal Toxicities. Wei Zheng, Purdue University, West Lafayette, IN.

One Health: Integrated Metal Toxicity from Ecology, Environment to Human Health. John P. Wise, University of Louisville, Louisville, KY.

Disposition and Mechanisms of Toxicities of Metals and Metalloids. Michael F. Hughes, US EPA, Research Triangle Park, NC.

Medical Imaging Technologies in Metal Toxicological Diagnosis and Research. Ulrike Dydak, Purdue University, West Lafayette, IN.

Concepts and Recent Advancement in the Treatment of Metal Toxicities. Donald R. Smith, University of California Santa Cruz, Santa Cruz, CA.


Reproductive Toxicity: Challenges and Practical Approaches to Determine Risk in Drug Development

Morning Course (AM06) | 8:15 AM to 12:00 Noon

Chairperson(s): Jeffrey Moffit, Alnylam Pharmaceuticals, Cambridge, MA; and Edward Dere, Brown University, Providence, RI.

Endorser(s): Regulatory and Safety Evaluation Specialty Section
Reproductive and Developmental Toxicology Specialty Section

The goal of this course is intended to provide an overview of reproductive biology, typical mechanisms of toxicity, and provide a path forward to critically evaluate reproductive liabilities for risk/benefit in humans. This course is primarily intended for toxicologists who encounter reproductive toxicity in a drug development setting, but these tools and approaches are equally applicable to assessing consumer products or environmental chemicals. Reproductive toxicity is a major source of compound attrition, representing one of the most difficult toxicities to predict or monitor in humans. The broad description of reproductive toxicity can arise from direct adverse effects on specific reproductive cell types, perturbations in hormonal signaling cascades, or toxicities that may only become evident from adverse effects on the conceptus. Mechanistic insight into reproductive toxicities is often difficult to ascertain, as reproductive tracts are exceedingly complex with many biological unknowns and species-specific differences in biology or maturation. The first two presentations will focus on male and female reproductive toxicity, respectively. These sessions will cover basic reproductive biology, typical types of reproductive toxicity findings, and case studies that provide real-world approaches to developing decision making criteria for evaluating reproductive liabilities. The third talk will describe various in vitro techniques to profile early development candidates for reproductive liabilities or mechanistically investigate toxicities identified in vivo. A final presentation will cover the unique ways in which biologics can cause reproductive toxicities and alternative approaches to investigating these modalities, which differ from small molecules. In summary, this course will give attendees an appreciation for the complexities of reproductive biology, challenges associated with understanding the mechanistic basis of reproductive findings, and provide practical approaches to determining the risk/benefit relationship of these reproductive toxicities.

Introduction. Edward Dere, Brown University, Providence, RI.

Failure to Launch—Challenges and Strategies to Assess Risk in Male Reproductive Toxicity. Jeffrey Moffit, Alnylam Pharmaceuticals, Cambridge, MA.

Female Reproductive Toxicology—Overview of Female Reproductive Biology, Typical Types of Toxicity Pathways/Challenges to Derisking, Case Studies. Kimberly Hatfield, US Food and Drug Administration, Silver Spring, MD.

In Vitro Approaches to Assessing Reproductive Toxicology. Sarah Campion, Pfizer Inc., Groton, CT.
Reproductive Safety Assessment for Biopharmaceuticals. Wendy Halpern, Genentech, South San Francisco, CA.


Technologies and Applications of Stem Cells for Use in Toxicology

Morning Course (AM07) | 8:15 AM to 12:00 Noon

Chairperson(s): Erik Tokar, NTP, NIEHS, Durham, NC; and Aaron Bowman, Vanderbilt University Medical Center, Nashville, TN.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Neurotoxicology Specialty Section
Stem Cells Specialty Section

Stem cells (SCs) biology has been one of the most active areas of research over the last decade. Advances in SC technology are providing exciting opportunities for in vitro modeling in a physiologically-relevant environment that is both consistent and replicable. Indeed, SCs are revolutionizing toxicological research and continue to be an area with tremendous potential for areas including toxicity screening, drug development, and disease pathogenesis. In order to remain at the forefront of these important areas of research, toxicologists must continue to learn and integrate these cutting-edge technologies and applications of SCs into their research. In this course, speakers representing academia, government, and industry will provide diverse viewpoints on the use of SCs in toxicology in both broad and specific contexts. Technologies and potential applications for assorted types of stem cell models (i.e. embryonic, induced pluripotent, multipotent, cancer stem cells, etc.) for various research purposes, including disease modeling, regenerative therapies, drug discovery, and toxicity testing will be described. The first speaker, Dr. Tokar, will provide an updated summary of available SC technology platforms and current protocols. The second speaker, Dr. Moore, will provide examples of how SC resources can be sourced or generated for studies with specific emphasis on genome modifying technology. The third speaker, Dr. Bowman, will provide specific examples of how SC models enable gene x environment interaction and translational environmental health studies with special emphasis the potential for clinical applications. The final speaker, Dr. Kolaja, will close out the session with new microphysiological applications of SC platforms for safety assessment. Overall, this important and timely course will highlight the history, nomenclature, properties, regulation, and derivation of SCs, and the key roles these cells play in the genesis of various human diseases.

The Fundamentals of Stem Cells for Use in Toxicological Research. Erik Tokar, NTP, NIEHS, Durham, NC.

Strategies for Building Better iPSC Models of Human Disease and Development. Jennifer Moore, Rutgers University, Piscataway, NJ.

Patient-Derived Stem Cells As a Translational Model for Molecular Neurotoxicology and Environmental Health Research. Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Applications of Microphysiological Systems and Induced Pluripotent Stem Cell Derived Tissues in Safety Assessment. Kyle L. Kolaja, Celgene, Summit, NJ.


Detecting Cancer Risk in Drugs: Design, Conduct, and Interpretation of Carcinogenicity Studies for Regulatory Approvals

Afternoon Course (PM08) | 1:15 PM to 5:00 PM

Chairperson(s): Owen McMaster, US FDA Center for Drug Evaluation and Research, Silver Spring, MD; and James Popp, Stratoxon LLC, Morgantown, PA.

Endorser(s): Carcinogenesis Specialty Section
Regulatory and Safety Evaluation Specialty Section

Evaluation of the carcinogenic potential of therapeutic agents is a very complex, multi-step process which is conducted only for drugs which meet certain criteria. Recently, ICH has issued a regulatory notice document regarding proposed changes to rodent carcinogenicity testing of pharmaceuticals. This course is designed to provide an overview of the practical aspects of the design, conduct, and interpretation of the US FDA-required carcinogenicity assessments. This course will be useful for students and investigators who have not had recent, hands-on experience conducting such studies, or who would like to update their knowledge of recent advancements in carcinogenicity assessment. The first talk will provide an overview of the current procedures for evaluating the potential carcinogenicity of a drug to be marketed in the US. The second talk will detail the planning, conduct, and interpretation of the two-year rat carcinogenicity study, the cornerstone of many carcinogenicity assessments. The third talk will detail the planning, conduct, and interpretation of studies using the TgrasH2 mouse model to assess cancer risk. The TgrasH2 has become the most widely used alternative to the two-year mouse carcinogenicity study. This talk will also include a discussion of other alternatives to the two-year bioassay and will end with a case study of a TgrasH2 study. The fourth talk will go into the review of the carcinogenicity assessments from the perspective of an US FDA reviewer. This reviewer will describe the point of view of the Pharmacology/Toxicology review, the review division, and that of CDER’s Executive Carcinogenicity Assessment Committee. The fifth talk will discuss an initiative by the ICH S1 Expert Working Group to assess the feasibility of a weight-of-evidence approach as a possible future option for the carcinogenicity testing of pharmaceuticals.

Essentials of Carcinogenicity Testing. Owen McMaster, US FDA Center for Drug Evaluation and Research, Silver Spring, MD.

Specific Aspects and Approaches for Regulatory Evaluation of Pharmaceuticals in 2-Year Rodent Carcinogenicity Studies. James A. Popp, Stratoxon LLC, Morgantown, PA.

The TgrasH2 Assay. Mark Morse, Charles River, Spencerville, OH.

Evaluating Carcinogenicity: The Reviewer’s Perspective. Timothy McGovern, US FDA Center for Drug Evaluation and Research, Silver Spring, MD.

The ICH S1 Carcinogenicity Testing Guideline: Status Report. Todd Bourcier, US FDA Center for Drug Evaluation and Research, Silver Spring, MD.


Developmental and Reproductive Toxicology (DART) and Risk Assessment of Environmental Chemicals: Applications, Complexities, and Novel Approaches

Afternoon Course (PM09) | 1:15 PM to 5:00 PM

Chairperson(s): Heather Lynch, Gradient, Cambridge, MA; and Natasha Catlin, National Toxicology Program, Durham, NC.

Endorser(s): Reproductive and Developmental Toxicology Specialty Section
Risk Assessment Specialty Section

The potential for developmental and reproductive toxicity (DART) is a unique and critical consideration for product safety as well as for the derivation of environmental health criteria and occupational exposure levels (OELs) for chemicals. The establishment of safe levels of exposure that protect against DART effects remains a major challenge, due to factors such as the complexity of human reproductive and developmental processes, unique routes of exposure (e.g., breast milk), sensitive subpopulations (e.g., the fetus and pregnant women), and short duration windows of susceptibility (e.g., the period of organogenesis). The goal of this course is to provide the participant with an introduction to traditional and emerging DART assessment approaches, with a focus on their practical application in safety assessment and policy-making. The first presentation will provide an overview of the biology of the mammalian reproductive system and prenatal/early life development, focusing on physiological and timing-specific vulnerabilities of critical importance to risk assessment (RA). The second presentation will describe standard testing protocols for DART and provide information regarding requirements for industry. The third presentation will expand beyond traditional experimental approaches to assays designed to elucidate the mechanistic aspects of DART effects, including novel in vitro assays, and will discuss key considerations in the interpretation of the biological relevance of DART effects. The fourth presentation will then review the application of DART data to human health risk assessment of environmental chemicals, focusing on the consideration of these data in the derivation of toxicity criteria by US agencies. The final presentation will demonstrate the use of DART RA in industry, describing several practical screening approaches for assessing the potential for DART effects in the workplace. This course will be of broad interest to testing laboratories, general toxicologists, risk assessors, risk managers, industrial hygienists, and others seeking a better understanding of how DART data are generated and applied in hazard and risk assessment.

The Biology of Reproductive and Developmental Toxicity for Risk Assessment. Jodi Flaws, University of Illinois, Urbana, IL.

DART Testing Protocols and Applications Within Industry. Reza Rasoulpour, Dow AgroSciences, Indianapolis, IN.

Targeted Approaches for DART Adverse Outcome Hypothesis Testing. John Rogers, US EPA, Research Triangle Park, NC.

DART Considerations in Regulatory Guidance and Policy: Toxicity Values and Susceptible Populations. Susan Makris, US EPA, Washington, DC.

Application of DART Risk Assessment: Protecting Workers from Chemical Exposures. Heather Lynch, Gradient, Cambridge, MA.


Emerging Approaches in Genetic Toxicology for Product Development

Afternoon Course (PM10) | 1:15 PM to 5:00 PM

Chairperson(s): Jeffrey C. Bemis, Litron Laboratories, Rochester, NY; and Krista L. Dobo, Pfizer Worldwide R&D, Groton, CT.

Endorser(s): Carcinogenesis Specialty Section
Drug Discovery Toxicology Specialty Section

Genetic toxicology is a well-established part of safety testing for product development. Recent advances in methods and technologies, as well as the emergence of new challenges for product development, are changing the type of data that are generated and the way that genetic toxicology data are utilized. The intention of the proposed continuing education session is to highlight the development and application of novel methods and approaches that have the potential to improve well-established safety studies and risk assessment. The focus will be on in vitro/in vivosystems and computational approaches which can be used to support and enhance data required for regulatory submissions and improve human health risk assessment.

The topics covered will be of interest to both genetic toxicology experts, as well as other toxicologists who want to learn about emerging developments in genetic toxicology testing, risk assessment approaches, and how they can be utilized to make informed decisions. The course content will also speak to the importance of in vitro studies in addressing 3R’s initiatives and their increasing role in genetox testing and human risk assessment. It is worth noting that the Course Chair, Jeff Bemis, chaired a similar SOT CE course back in 2011 covering new technologies in genetic toxicology. This will provide an opportunity to revisit some of the forward-looking statements made in that course and where genetic toxicology actually is six years later. Overall, the CE course will deliver comprehensive information on new technologies along with practical examples, so attendees will come away with an understanding of how state-of-the-art approaches can be integrated to benefit their product development activities.

Introduction to Genetic Toxicology in Drug Development. Krista L. Dobo, Pfizer Worldwide R&D, Groton, CT.

Emerging and Established Mutagenicity Assays to Support and Enhance Regulatory Evaluations.
Paul White, Health Canada, Ottawa, ON, Canada.

MOA Screening—Impact on Drug Discovery Decisions and Regulatory Testing Strategies. Zhanna Sobol, Pfizer Worldwide R&D, Groton, CT.

Multiplexed In Vitro Assays for the Determination of Genotoxic Mode of Action. Steven M. Bryce, Litron Laboratories, Rochester, NY.

Application of 3D Models and Other Advancements for the Determination of Genotoxicity in Consumer Products. Stefan Pfuhler, Proctor & Gamble, Cincinnati, OH.

Contribution of Genotoxicity Information and Point of Departure Metrics to Improve Decision Making and Risk Assessment in Drug Development. George Johnson, Swansea University, Swansea, United Kingdom.


Extrapolation in the Airways: Strategies to Incorporate In Vivo and In Vitro Data to Better Protect Human Health

Afternoon Course (PM11) | 1:15 PM to 5:00 PM

Chairperson(s): Marie Fortin, Colgate-Palmolive, Piscataway, NJ; and Madhuri Singal, Reckitt Benkinser, Montvale, NJ.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

The science of safety and risk assessment relies primarily upon the use of data generated with in vivo or in vitro models that significantly differ physiologically from humans. While tremendous leaps have been made in the extrapolation of animal-to-human data for the oral route of exposure, significant gaps remain with respect to the inhalation route. The intrinsic differences between animals and humans are such that even dosimetry is complicated by the intrinsic differences between humans and other animals with respect to anatomy, breathing rate, depth of deposition, gas exchange capacity, and in situ metabolism. While a variety of assumptions are routinely used to provide rough estimates and a greater level of understanding is necessary to ensure that risk is not underestimated. In recent years, financial and ethical concerns have driven substantial efforts to substitute in vitro approaches for animal models; however, this transition comes with greater challenges in developing scientifically sound extrapolations for risk assessment. The fluid mechanics and cellular diversity within the airways has made it difficult to model, and it has become increasingly more difficult for safety and risk assessors to perform their evaluations with a high degree of confidence because they lack robust extrapolation strategies.

The aim of this advanced CE Course is to review the critical differences between humans and common surrogate species and explain approaches to strengthen safety evaluation and risk assessment by integrating complementary in vitro data and leveraging novel in vitro models when in vivo data is not available. While alternative airway models have been previously described, this session will focus on the extrapolation from these models to inform risk assessment. Consideration will be given to gas/vapor and particulate/droplets to provide the breadth necessary to address the different types of exposure that can occur via inhalation and strategies to incorporate the outcomes of alternative testing methods into risk assessment will be presented. By the end of this advanced CE Course, attendees will have a better understanding of how to integrate and utilize in vitro and in vivo data to support the safety evaluation of their products, or for the risk assessment of environmental and occupational exposures that occur via the inhalation route.

Labored Extrapolation: From Data Gasps to a Sigh of Relief. Marie C. Fortin, Colgate-Palmolive, Piscataway, NJ.

Review and Analysis of Species Differences in Respiratory Anatomy. Kent E. Pinkerton, University of California–Davis, Davis, CA.

Using Physiologically Based Pharmacokinetic Modeling and In Vitro Metabolism Data to Conduct Animal-to-Human Extrapolation in Inhalation Dosimetry. Harvey J. Clewell, ScitoVation, LLC, Research Triangle Park, NC.

Leveraging Reconstructed Upper and Lower Airway 3D Models (Human and Rat) for the Safety Assessment of Small Molecules. Samuel Contant, Epithelix, Geneva, Switzerland.

Performing In Vitro to In Vivo Extrapolation (IVIVE) in Humans. Robert Devlin, US Environmental Protection Agency, Chapel Hill, NC.


Health-Based Limits for Toxicological Risk Assessment: Setting Acceptable Daily Exposures for Pharmaceutical and Chemical Safety

Afternoon Course (PM12) | 1:15 PM to 5:00 PM

Chairperson(s): Patricia Weideman, Sakari Consultants LLC, Stratham, NH; and Andrew Maier, University of Cincinnati, Cincinnati, OH.

Endorser(s): Occupational and Public Health Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

Health-based exposure limits (HBELs) have been used for many years to assure safety or assess risks from potential adverse health-related effects arising from exposures to xenobiotics. Acceptable Daily Exposure (ADE) and Permitted Daily Exposure (PDE) are terms referencing assessments that can be considered as the bases for a variety of health-based assessments associated with the development and manufacture of chemicals and pharmaceuticals, industrial and specialty chemicals, consumer products, and other environmental contaminants, including active ingredients and products, process/product impurities, chemical intermediates, extractables, and leachables. ADEs/PDEs have similar overall intent and definition as other HBELs and may also have regulatory implications. Generally the numerous specific HBELs, including ADEs, are based on robust hazard assessments that can be used as the basis for subsequent risk assessments for a variety of situations, including further derivation of occupational exposure limits (OELs) to protect workers who manufacture or process chemicals and pharmaceuticals and the derivation of limits for cleaning validation processes. As an example, the transition to the use of HBELs (i.e. ADEs) to protect product quality of pharmaceuticals has gained industry and regulatory interest and created much effort in the implementation of HBEL concepts on a large scale. In addition, recent regulatory scrutiny and international guidances have focused attention on prevention of cross-contamination in equipment or facilities for which HBELs and industrial hygiene principles have significant impact. Various traditional default approaches (e.g. 10 ppm) have been used historically to manage cross-contamination issues and good manufacturing procedures (GMPs); however, these default approaches have not been based on current health-based risk assessment methods. In contrast to the default approaches, derivation of ADEs includes the use of robust datasets such as those in the pharmaceutical industry. These datasets are generally more complete than those for chemical manufacturing and often include information about mechanism of action, pharmaco- and toxico-dynamics and kinetics, bioavailability, and application of appropriate adjustment factors to better inform hazard and risk decisions. Although toxicological information about industrial chemicals may not be based on human experience and the datasets are constructed differently, these data often offer additional information based on use and experience that are not available for pharmaceuticals. Use of data and methods parallels many aspects of the evolving methods in deriving HBELs for either industrial chemicals or pharmaceuticals. Although ADEs are a step toward better informed science- and health risk-based decisions, the methods used to derive ADEs are complex and are not harmonized among various regulatory constituencies and practitioners. The unique aspects of ADE derivation and application will be highlighted. Using pharmaceuticals as the example, this session will provide background and tools for toxicologists and regulators to better understand the basis, derivation, and application of these unique assessments for protection of human safety as an attempt to provide more consistency in approach and outcomes.

Introduction: Derivation of Health-Based Exposure Limits Using Acceptable Daily Exposure (ADE): Why Now? Patricia Weideman, Sakari Consultants LLC, Stratham, NH.

Regulatory and Industry Trends in Deriving Health-Based Exposure Limits. Robert Sussman, SafeBridge Consultants Inc., New York, NY.

Application of Data-Derived Health Limits Versus Default Limits. Brad Stanard, MedImmune, Gaithersburg, MD.

The Point of Departure As a Central Aspect of ADE Derivation. Joel Bercu, Gilead Sciences, Foster City, CA.

Fine-Tuning the Health-Based Assessment: Applying Adjustment Factors and Use of Pharmacokinetic Data. Bruce D. Naumann, Merck and Co., Inc., Kenilworth, NJ.


Read-Across: Case Studies, New Techniques, and Guidelines for Practical Application

Afternoon Course (PM13) | 1:15 PM to 5:00 PM

Chairperson(s): Kristie Sullivan, Physicians Committee for Responsible Medicine, Oakland, CA; and Mark Cronin, Liverpool John Moores University, Liverpool , United Kingdom.

Endorser(s): Biological Modeling Specialty Section
In Vitro and Alternative Methods Specialty Section
Regulatory and Safety Evaluation Specialty Section

The relationship between structure and activity has been exploited in the hazard characterization of chemicals for several decades, including specifically the practice of “reading across” or applying toxicity data from one or more chemicals to another with a similar structure to fill a data gap. Read-across is currently a useful strategy to increase our understanding of chemical hazard without de novo testing. However, expertise, application, and acceptance of the results of a particular read across vary within and among organizations and geographical regions. There are a number of reasons for this, including regulatory or legislative drivers, an increasing motivation to expand the use of non-testing strategies, and minimal consensus around how to weigh evidence and address and express uncertainty. Recently, multiple stakeholder organizations have contributed to active and robust discussions on read across in a variety of venues in an effort to build consensus around these issues. This course will update participants on those efforts and provide practical guidance for conducting read-across for regulatory use, including across different regulatory regions. Speakers will present experience-driven case studies to share best practices and communicate the state-of the-art for structure-based read-across, while looking ahead at how results from New Approach Methodologies including in vitro, “omics,” and high throughput/content methods may be incorporated into a read across to improve its outcome.

The Regulatory Landscape for Read Across. Kristie Sullivan, Physicians Committee for Responsible Medicine, Washington, DC.

Setting the Stage: Forming a Category Using Chemical Structures to Read Across Toxicological Data. Mark Cronin, Liverpool John Moores University, Liverpool, United Kingdom.

Improving Read Across Using Biological Data and Quality Assessment. Nicole Kleinstreuer, National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), Research Traingle Park, NC.

A Framework to Build Scientific Confidence in Read-Across Results. Grace Patlewicz, Environmental Protection Agency, Research Triangle Park, NC.

ECHA’s Approach to Read Across: The Read-Across Assessment Framework (RAAF). Eric Stilgenbauer, European Chemicals Agency, Helsinki, Finland.

Applying the Read-Across Assessment Framework to Identify and Address Uncertainty. Andrea Richarz, European Commission, Joint Research Centre, Ispra (VA), Italy.

Building a Read-Across from the Ground Up. Sharon Buring Stuard, The Procter & Gamble Company, Cincinnati, OH.