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Preliminary Program

Scientific Sessions

 

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Monday, March 13

9:30 AM to 12:15 PM

Symposium Sessions
Early-Life Inorganic Arsenic Exposures and Later-in-Life Effects

Symposium | 9:30 AM to 12:15 PM

Chairperson(s): Janice Lee, US EPA, Research Triangle Park, NC; and Rebecca Fry, University of North Carolina Chapel Hill, Chapel Hill, NC.

Endorser(s): Metals Specialty Section
Occupational and Public Health Specialty Section
Reproductive and Developmental Toxicology Specialty Section

Arsenic (As) contamination from geologic, anthropogenic, and food origins is an increasing concern for the US and globally. There is increasing evidence that early life exposure to As affects fetal and child health, as well as development and health later in life. In addition to developmental neurotoxicity, there is evidence that other organs and functions may be susceptible during development after exposure to As. This symposium will highlight the current state of research of As and its role in life stage susceptibility. Discussions will include how early life exposure to As increases the risk of mortality, neurocognitive impairment, altered immune function, and adverse pregnancy outcomes. A putative adverse outcome pathway (AOP) for developmental effects and the impact of As on the proposed key events will be discussed. The session will also attempt to address the mechanism of actions (MOA) by which As could induce or exacerbate these disease endpoints during a critical window of susceptibility. The United States Environmental Protection Agency (US EPA) Integrated Risk Assessment System (IRIS) is currently developing a new inorganic As assessment that considers life stage susceptibility. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.

Introduction. Janice Lee, US EPA, Research Triangle Park, NC.

Mortality Associated with Early Life Exposure to Arsenic. Craig Steinmaus, California Environmental Protection Agency, Berkeley, CA.

Neurocognitive Impairment Due to Early Life Arsenic Exposure. Joseph Graziano, Columbia University Mailman School of Public Health, New York, NY.

Long-Term Effects of Early-Life Arsenic Exposure on Immunity and Disease Risk. Fenna Sillé, University of California Berkeley, Berkeley, CA.

Adverse Pregnancy Outcomes Associated with Arsenic Exposure. Margaret Karagas, Geisel School of Medicine at Dartmouth, Lebanon, NH.

Building AOPs for Arsenic-Induced Developmental Outcomes for Improved Risk Assessment. Rebecca Fry, University of North Carolina Chapel Hill, Chapel Hill, NC.

Organs-on-a-Chip, Tissue Bioprinting, and 3D Cultures: Next Generation Models for Toxicology in the 21st Century

Symposium | 9:30 AM to 12:15 PM

Chairperson(s): Shaun McCullough, US EPA, Chapel Hill, NC; and Emma Bowers, University of North Carolina, Chapel Hill, NC.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Mechanisms Specialty Section
Molecular and Systems Biology Specialty Section

Toxicity testing is a cornerstone for risk assessment in applications ranging from product development to the regulation of environmental pollutants; however, the vast majority of toxicity data has been collected in animal models. While the extrapolation of toxicity data from animal models to humans is imperfect due to differences in anatomy and physiology, these traditional models are used because they represent whole-organism biology that is not well replicated by in vitro methods. In recent years, concerns over high cost, long study duration, and ethical considerations have led to increasing pressure to Replace, Reduce, and Refine the use of animal models in toxicity testing. Institution of the “Three Rs” has propelled the use of in vitro systems to characterize the cellular and molecular mechanisms underlying biological changes associated with toxicant exposure. While cell lines have been the workhorses of in vitro toxicology studies for decades, their utility comes at the cost of concerns about their ability to reliably mirror the responses of their in vivo counterparts. The increased availability of primary cells and the ability to generate induced pluripotent stem cells (iPSC) has opened the door to the development of the next generation of in vitro models. The combination of these newly available cell types and advances in cell culture methods has led to the establishment of three-dimensional organoids, bioprinted tissues, and microphysiological systems (“organs-on-a-chip”) that all have great potential to revolutionize the role of in vitro models in toxicity testing.  By incorporating features that are absent from current cell culture models, such as cell-cell interactions, three-dimensional architecture, and mechanophysiological cues, these systems provide greater physiological relevance for the future of molecular, mechanistic, and high-throughput toxicology studies. By incorporating these aspects of the native environment within parent tissues, these next generation in vitro systems have the potential to reduce the reliance on animal models by dramatically increasing the relevance of in vitro models in toxicology research. The goal of this workshop is to examine applications of next generation in vitro models in molecular and mechanistic toxicology studies. To achieve this, we will bring experts together to discuss the development of these models and their current use in toxicity studies. We will answer questions such as: What are the benefits and challenges facing the use of next generation in vitro models in toxicology research? Can iPSC-derived mini-brains effectively model neurotoxicity in pesticide exposures? How can heart-on-a-chip and 3D bioprinted liver tissue be used as screening tools for the toxicity of pharmacologic agents? Does the incorporation of multicellular architecture and mechanophysiological cues impact toxicity of tobacco and e-cigarette exposures in vitro? What are the perspectives from government and industry on the integration of these models in toxicology and drug discovery research? Following the session attendees will have a better understanding for the benefits, challenges, and applications of next generation in vitro models, and how both government and industry envision their role in the future of toxicity testing.

Introduction. Shaun McCullough, US EPA, Chapel Hill, NC.

21st Century Cell Culture for 21st Century Toxicology. Thomas Hartung, Johns Hopkins University, Baltimore, MD.

Organs-on-a-chip: Microphysiological Platforms as In Vitro Models of Cardiac and Adipose Tissue. Peter Loskill, Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Stuttgart, Germany.

Human Small Airway-on-a-Chip: Applications in Comparing Tobacco and E-Cigarette Exposures. Kambez Benam, Harvard University, Boston, MA.

Utilization of Bioprinted Human Liver Tissues for Toxicology Applications and Disease Modeling. Rhiannon Hardwick, Organovo, San Diego, CA.

Adopting Microphysiological Systems (MPS), or Tissue Chips, as a Research Tool for Drug Development. Kristin Fabre, AstraZeneca, Waltham, MA.

Translational Control in Disease Progression and Xenobiotic-Mediated Toxicity

Symposium | 9:30 AM to 12:15 PM

Chairperson(s): Thomas Baker, Eli Lilly, Indianapolis, IN; and James Stevens, Eli Lilly, Indianapolis, IN.

Endorser(s): Molecular and Systems Biology Specialty Section

Proper translational control of mRNA to protein has shown to play an essential role for a variety of physiological functions, including development, regulation of cell growth, and metabolic function. Currently, two major regulatory pathways have been described to control the rate of protein synthesis: one via the mammalian target of rapamycin (mTOR); and a second through eukaryotic initiation factor 2 (eIF2) kinases. While the mTOR pathway responds primarily to growth signals and changes in nutrient content, eIF2 kinases respond to an array of cellular stresses, including ultraviolet irradiation and misfolded proteins in the endoplasmic reticulum. Both the mTOR and eIF2 kinase pathways directly affect translational control through modulating distinct components involved in translational initiation. However, this same translational machinery, which maintains homeostasis, is often aberrant during the disease pathogenesis, resulting in abnormalities such as enhanced oncogenic potential, neurodegeneration, and metabolic dysfunction. Translational inhibitors are currently being investigated for therapeutic intervention, but modulation of biological pathways that control translation initiation have been implicated in toxicities associated with a variety of xenobiotics. To better apply novel techniques and approaches toward mechanistic toxicity, systems biology, and drug discovery, it is critical to understand the key intracellular signaling events and pathologic consequences of modulating translation. We provide an overview of groundbreaking advances in the understanding of how mTOR and eIF2 kinases, key regulators of translational control, play a role in health and disease at the molecular level, and bridge this knowledge to current applications of risk assessment and translational toxicology. The speakers, representing perspectives from industry to academia, will provide mechanistic insight into the pathogenesis of disease and drug-induced toxicities associated with altered translational control as well as provide guidance toward drug safety. We briefly introduce translational control’s relationship to toxicity and pathogenesis of disease, followed by a discussion on novel mechanistic insights into differential signaling pathways, which activate mTORC1 through unique amino acid sensing. We will then discuss mTOR inhibition and the signaling cascade resulting from reactive oxygen species (ROS) toxicity as an adaptive response to control redox homeostasis through selective autophagy of peroxisomes. Next we will transition from translational control by mTOR to eIF2 kinases. Translational control by eIF2 kinases have been identified in numerous disease states and drug related toxicities. With this, we will discuss novel translation mechanisms of GCN2 activation as an adaptive response in the skin following UV irradiation, which will be followed by discussions on the role of ER stress in the progression of liver disease, such as nonalcoholic steatohepatitis and drug induced liver injury, linking hepatocelullar death to inflammation for approaches of risk management. At the conclusion of this symposium, participants will have a good understanding of the role translational control plays in various disease states as well as approaches for elucidating mechanism of toxicity for various drugs and xenobiotics.

Introduction. Thomas Baker, Eli Lilly, Indianapolis, IN.

Differential Regulation of mTORC1 by Amino Acids. Jenna Jewell, University of Texas Southwestern Medical Center, Dallas, TX.

A New Look at an Old Machine: New Cellular Targets for the Cell’s Translational Machinery. Cheryl Walker, Baylor College of Medicine, Houston, TX.

Translational Control and the eIF2 Kinase Pathway in Health and Disease. Dan Spandau, Indiana University School of Medicine, Indianapolis, IN.

ER Stress Regulates a Biological Network Driving the Pathogenesis of Liver Disease. Jeffrey Willy, Eli Lilly, Indianapolis, IN.

The Role of ER Stress in Progression of NAFLD to NASH. Randal Kaufman, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.

Workshop Sessions
Cross-Industry and Regulatory Approach for the Identification and/or Qualification of Novel Safety Biomarkers of Drug-Induced Vascular Injury (DIVI)

Workshop | 9:30 AM to 12:15 PM

Chairperson(s): Deidre Dalmas, GlaxoSmithKline, King of Prussia, PA; and Nicholas King, Critical Path Institute, Predictive Safety Testing Consortium, Tucson, AZ.

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

Drug-induced vascular injury (DIVI) in nonclinical toxicology studies is a challenging safety issue that can lead to significant delays in the drug development process and/or result in project termination due to lack of sensitive, specific, and/or effective translational biomarkers, and an incomplete understanding of predictivity of nonclinical models for clinical risk. In nonclinical species, DIVI has been observed with numerous structurally and pharmacologically diverse compounds. Despite individual efforts across industry, mechanism(s) by which DIVI damage occurs to blood vessels is still not completely understood. Because the issue is too complex to be solved by individual companies working in isolation and with limited resources, the Predictive Safety Testing Consortium’s (PSTC) Vascular Injury Working Group (VIWG), and the Safer and Faster Evidence-Based Translation (SAFE-T) Consortium, have been working individually and jointly to identify non-invasive translational biomarkers of DIVI. This will address the question of human relevance using panels of nonclinical and clinical biomarkers that underpin histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) common across species, including humans that can detect the onset, progression, and reversibility of DIVI irrespective of the mechanism of injury. A panel of circulating candidate protein biomarkers that can differentiate rodents with evidence of DIVI from vehicle-treated rats has been developed by the PSTC VIWG. Similarly, the SAFE-T consortium has demonstrated a panel of circulating protein biomarkers that are shared or have shared biology to those identified by the VIWG and may distinguish between patients with vascular disease/injury and healthy volunteers. In addition, the PSTC VIWG and SAFE-T Consortium have developed key outputs required for the qualification of clinical and nonclinical safety biomarkers, and have jointly developed a translational approach to qualify new vascular safety biomarkers for use in clinical drug development research. This session will highlight the industry and regulatory perspective on nonclinical DIVI, its impact on the drug development process, and evolution of the regulatory processes for biomarker qualification. It will showcase the progress of each consortium toward development of novel assays for vascular injury, the collaborative, cross-industry translational approach developed by the PSTC VIWG and SAFE-T Consortium towards qualification of the candidate DIVI biomarkers, and innovative in vitro and non-invasive approaches currently being utilized to assist in the identification/prediction of DIVI.

Drug-Induced Vascular Injury and Impact on Drug Development: Industry Perspective. Heath Thomas, Experimental Pathology Laboratories, Inc. (EPL) NorthEast, Collegeville, PA.

Drug-Induced Vascular Injury: Biomarker Qualification and Impact on Regulatory Review and Decision-Making. James Weaver, US FDA, Sliver Spring, MD.

Nonclinical and Clinical Drug-Induced Vascular Injury: Output of the Preclinical Safety Testing Consortium Vascular Injury Working Group and Safer and Faster Evidence-based Translation Consortium. Tanja Zabka, Genentech, Inc., South San Francisco, CA.

Utility of Flow-Based 3D In Vitro Models to Investigate Mechanisms of DIVI in Drug Discovery. Matthew Brock, Genentech, Inc., South San Francisco, CA.

Novel Integration of Off-Target Screening, Genomic, and Cardiovascular Risk Assessment Strategies for Prediction of Nonclinical Drug-Induced Vascular Injury. Deidre Dalmas, GlaxoSmithKline, King of Prussia, PA.

Vascular Imaging of Matrix Metalloproteinase Activity as an Informative Nonclinical Biomarker of Drug-Induced Vascular Injury. Raymond Gonzalez, Merck Research Laboratories, West Point, PA.

Panel Discussion. Deidre Dalmas, GlaxoSmithKline, King of Prussia, PA.

Fit for Purpose: Using Computational Models for Risk

Workshop | 9:30 AM to 12:15 PM

Chairperson(s): John Wambaugh, US EPA, Research Triangle Park, NC; and Nisha Sipes, NTP/NIEHS, Research Triangle Park, NC.

Endorser(s): Biological Modeling Specialty Section
In Vitro and Alternative Methods Specialty Section
Molecular and Systems Biology Specialty Section

The aim of this workshop is to discuss the development, acceptance, and use of fit for purpose computational models for risk assessment applications. In fields ranging from chemical toxicology to health and property reinsurance, decision makers frequently face data gaps when analyzing risk. Some critical data gaps can be successfully bridged using fit for purpose computational models, which are defined as much by what is omitted as what is included in the model.  Examples of these models include quantitative structure activity (QSAR) models for specific hazards and environmental fate, pharmacokinetic models of chemical disposition, toxicodynamic models for effect, and exposure models. This workshop brings together a panel of experts with first-hand experience ranging from constructing computational models included in screening-level tools, such as EPI Suite, to risk-based decision making using predictive models. Presenters will provide examples of the application of fit for purpose models in the environmental and pharmaceutical arenas, how uncertainties are defined in these models, and what are the strengths and limitations of the models in the particular decision context. Discussions will encompass a broad range of computational models (from physico-chemical properties to human population risk assessment) and chemicals (including pharmaceuticals and environmental exposures) in risk applications. Presenters will also discuss objectives, approaches, technologies, knowledge gaps, and suggestions for future research, with an emphasis on lessons learned. The last presentation will provide unique commentary on the use of computational models and risk in corporate reinsurance. This workshop is designed to appeal to a broad audience interested in using or understanding computational methods to elucidate and predict toxicological outcomes for risk assessment. The workshop concludes with a panel discussion on new computational tools that could or should be used for the study of chemical risk.

Introduction: Occam’s Razor. John Wambaugh, US EPA, Research Triangle Park, NC.

Development and Application of Computational Tools to Support Chemical Exposure and Risk Assessment. Jon Arnot, ARC Arnot Research and Consulting, University of Toronto Scarborough, Toronto, ON, Canada.

Population Based Risk Assessment. Lesa Aylward, Summit Toxicology, Falls Church, VA.

Drug Development in the 21st Century. Hugh Barton, Pfizer, Groton, CT.

An Intuitive Approach toward Predicting Human Risk with the Tox21 10k Library. Nisha Sipes, NTP/NIEHS, Research Triangle Park, NC.

Calculating Risk on the Really Large Scale with Less than Ideal Information. Ryan Hansen, Gen Re (General Reinsurance Corporation), Stamford, CT.

Scientific, Regulatory, and Safety Considerations for Probiotics and Microbiome Targeted Therapeutics

Workshop | 9:30 AM to 12:15 PM

Chairperson(s): Lois Haighton, Intertek Scientific and Regulatory Consultancy, Mississauga, ON, Canada; and Andrea Wong, Council for Responsible Nutrition, Washington, DC.

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

Advances in the understanding of relationships between gastrointestinal microbiota and human health outcomes have stimulated much research in the field of probiotics and therapeutics that target the microbiome. The global demand for this product class has seen significant recent growth due largely to genomic advances that have made it possible to more accurately characterize individual microbial strains and the gut microbiome as a whole. Probiotics are being proposed for use as functional ingredients in foods and beverages, dietary supplements, animal feed, medical foods, and drug products, with each category subjected to different regulatory requirements for the demonstration of safety. The guidelines are not harmonized, neither across the different product categories, or between different jurisdictions; thus, the relevant regulatory path can be difficult to navigate. Similar to probiotics, the required regulatory path and associated safety requirements for microbiome targeted therapeutics, such as Fecal Microbiota Transplants, single strain commensal therapies, or small molecule approaches, differ greatly by product type. The safety assessment of microbials for use as live probiotic cultures requires additional hazard characterization beyond that which can be provided by the standard battery of toxicity testing studies applied to chemicals, since the physiological and pathological interactions between microorganisms and their “hosts” are often highly species-specific. Advances in genome sequencing techniques have allowed for vast improvements in the regulatory oversight of consumer products containing microbial ingredients and have highlighted the importance of understanding strain level genomic differences. Just as the probiotic or microbiota-modulating effects of two closely related strains may differ, so too will their safety profiles. Recommended safety evaluation procedures for probiotics have been discussed in general terms with a number of guidance documents available from different authoritative and regulatory bodies (e.g., US FDA, EFSA, FAO/WHO). Recently, however, a more comprehensive safety decision tree has been proposed, which aims to aid in the harmonization of these guidelines and promote the continued development of safe microbial cultures intended for human consumption. The objectives of this workshop are to discuss and highlight the following: (1) Current regulations in the US and other global jurisdictions that apply to the use of probiotics and provide clarity regarding acceptable claims for such products; (2) Health Canada’s model approach to streamlining the regulation of probiotics as Natural Health Products; (3) The recent development of a decision tree to assist in the safety evaluation of novel microbial cultures intended for consumption by humans and animals; (4) The US FDA’s genomic science-based approach to improve the safety and regulatory oversight of foods and dietary supplements containing live microbial ingredients; and (5) Approaches utilized to target and improve the health of the microbiome, including Fecal Microbiota Transplants, and the regulatory challenges associated with microbiome targeted therapeutics. All speakers will participate in a panel discussion following the last presentation.

Understanding the Safety Requirements and Regulatory Hurdles of Different Product Classes Containing Probiotics. Alexandra Lobach, Intertek Scientific & Regulatory Consultancy, Mississauga, ON, Canada.

Health Canada’s Natural Health Product Monograph for Probiotics: A Streamlined Model. Solange Henoud, Lallemand Health Solutions Inc., Montreal, QC, Canada.

Development and Application of a Safety Decision Tree to Assess the Safety of Probiotics. Michael Pariza, University of Wisconsin-Madison, Madison, WI.

Genomic Approaches to Characterizing Live Microbial Ingredients in Foods for Improved Safety and Regulatory Oversight. Christopher Elkins, US FDA, Laurel, MD.

Scientific and Regulatory Challenges to Measuring the Health of the Microbiome and in the Development of Targeted Therapeutic Agents. John Eid, Whole Biome, Inc., San Francisco, CA.

Platform Sessions
  • Investigating Mode of Action in Chemical Carcinogenesis
  • Ozone and Inflammation

9:30 AM to 12:45 PM

Poster Sessions
  • Carcinogenesis I
  • Carcinogenesis II
  • Developmental and Juvenile Toxicity
  • Epidemiology and Public Health
  • Epigenetics
  • Liver: In Vitro and In Silico Approaches
  • Mixtures
  • Nanotoxicology: In Vivo
  • Neurotoxicology: Metals—Cd, Pb, and Others
  • Neurotoxicology: Metals—Mercury
  • Receptors, Gene Regulation, and Signaling Reproductive Toxicology

12:30 PM to 1:50 PM

Roundtable Session
Bias and Conflict of Interest in Conducting Research and Risk Assessments: Perspectives from Academia, Government, Industry, and Others

Roundtable | 12:30 PM to 1:50 PM

Chairperson(s): Kun Yi, Syngenta Crop Protection, LLC, Greensboro, NC; and Jaqueline Patterson, University of Cincinnati, Cincinnati, OH.

Endorser(s): Ethical, Legal and Social Issues Specialty Section
Regulatory and Safety Evaluation Specialty Section

Charges or claims of conflict of interest (COI) are made with increasing frequency with regard to suspicion that personal employment, associations, or funding sources will interfere with the ability of a scientist to objectively conduct or interpret studies, and/or serve on peer review or advisory panels. A frequent concern is funding sources. As public funding for scientific research decreases and becomes more competitive, researchers are seeking funding from other sources (e.g. non-profit organizations, special interest groups, industry, foundations, and advocacy groups). How can we address these concerns in a way that makes best use of the data and talents of all? COI is generally defined as a personal financial interest that interferes with the individual’s ability to perform objectively. The National Academies (2003) define conflict of interest as “any financial or other interest which conflicts with the service of the individual because it (1) could significantly impair the individual’s objectivity, or (2) could create an unfair competitive advantage for any person or organization.…The term ‘conflict of interest’ means something more than individual bias. There must be an interest, ordinarily financial, that could be directly affected…” In addition, “questions of lack of objectivity and bias ordinarily relate to views stated or positions taken that are largely intellectually motivated or that arise from the close identification or association of an individual with a particular point of view or the positions or perspectives of a particular group. Some potential sources of bias, however, may be so substantial… (e.g., where one is totally committed to a particular point of view, and unwilling, or reasonably perceived to be unwilling, to consider other perspectives or relevant evidence to the contrary).” SOT has developed definitions and guidance for members regarding COI, bias, and advocacy (www.toxicology.org/about/vp/coi.asp). This roundtable session will begin with a philosopher of science examining three philosophical criteria for objectivity in science: transparency, reproducibility, and critical review. This will be followed by scientists from various sectors (government, contract research organization (CRO), academia, private sector, and scientific society) who will reflect upon COI and potential for bias in their professional work (e.g. interpretation and application of their work), and how one might mitigate or manage biases and conflicts of interest. Speakers will address questions such as: How are affiliation (e.g., industry, NGO, consultant) and funding source (e.g., government, foundation, industry) viewed when evaluating potential conflicts of interest and bias? Do (or how might?) funding sources influence study design, reporting of data, and interpretation? How can concerns regarding COI and bias on peer review and advisory panels be managed with reviewers, editors, and publishers? How can bias and conflict of interests be minimized? Can systematic review approaches help to minimize effects of bias/COI? Is GLP an effective tool to address consistency and transparency? Do standardized/validated test guidelines provide solutions to address consistency, reproducibility, and transparency? Can transparency be satisfied with requirements for raw data availability? Is it practical to call for blinding or double-blinding experimental studies? How do we deal with publication bias? Conflict of interest and bias are on-going issues in toxicology research and use of study results. It is important to recognize possible sources of COI and bias and develop ways to mitigate the potential effects. This session will provide an opportunity for participants to discuss openly issues around conflict of interest, and how COI and bias might affect scientists’ work, as well as their integrity and credibility.

Introduction. Kun Yi, Syngenta Crop Protection, LLC, Greensboro, NC.

Key Philosophical Criteria for Objectivity in Science: Transparency, Reproducibility, and Critical Review. Kevin Elliott, Michigan State University, East Lansing, MI.

Bias and Funding Sources: A Perspective from the Private Sector. Richard Becker. American Chemistry Council, Washington, DC.

An Academic’s Perspective on COI and Bias. Norbert Kaminski, Michigan State University, East Lansing, MI.

Managing COI and Bias in a CRO Setting. Pragati Sawhney Coder, Charles River Laboratories, Ashland, OH.

Inherent and Acquired Biases in Interpreting Toxicological Data for Regulatory Risk Assessment. Rita Schoeny, US EPA (Retired), Washington, DC.

Informational Sessions
Advances in Preclinical Safety Testing: Progress in Implementation of ICH Guidances

Informational | 12:30 PM to 1:50 PM

Chairperson(s): Kenneth Loveday, Biogen, Cambridge, MA; and Michael Graziano, Bristol-Myers Squibb, Princeton, NJ.

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

New strategies and approaches for preclinical safety testing are progressing at a rapid pace. The International Conference on Harmonisation (ICH), which consists of drug regulatory authorities from Europe, Japan, United States, Switzerland, and Canada, along with regional pharmaceutical trade associations, is responsible for generating standardized scientific and technical aspects of pharmaceutical product development and registration. ICH has clearly recognized a need to revise several existing safety guidances and develop new ones based on evolving science. The Preclinical Safety Leadership Committee (DruSafe) in the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) provides technical and scientific support in the development of these safety guidances. DruSafe also promotes an awareness of, and facilitates discussions on, implementation issues. This session will feature speakers from EMA and pharmaceutical companies to review progress, implementation issues, and scientific considerations and contributions for several new and revised ICH Guidances including: ICH S1—Rodent Carcinogenicity Studies for Human Pharmaceuticals. In 2013, ICH initiated a project to evaluate the ability of sponsors and drug regulatory authorities (DRAs) to use a weight-of-evidence approach for carcinogenicity assessments as an alternative to conducting 2-year rat studies, when appropriate. This presentation will review the status of the project, and provide a DRA assessment on opportunities to build better alignment on the predictions between sponsors and DRAs, with a focus on the value of pharmacology data. Successful implementation of this approach will result in a reduction in unnecessary rat carcinogenicity studies; ICH M7—Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. This guideline focuses on potential mutagenic impurities, which are classified into one of five risk categories. This presentation will describe key elements of the guideline and highlight areas where issues in implementation may arise; Update on Proposed Revisions to ICH S5(R3)—Correlation of In Vitro and In Vivo Assays of Developmental Toxicity. The objectives of this revision are to align ICH S5 with recommendations in other safety guidances, to provide better rationale for species and dose selection (including human exposure data), and to offer recommendations on integrating in vitro teratogenicity and non-mammalian in vivo testing strategies with in vivo mammalian embryo-fetal development (EFD) studies; ICH S11—Nonclinical Safety Testing in Support of Development of Pediatric Medicines. An ICH Expert Working Group has been convened to develop a harmonized guidance document for nonclinical development of pediatric medicines. In this session, aspects of juvenile animal studies that proved to be of most value for clinical development will be identified, with a goal of achieving world-wide harmonization on when juvenile animal studies are needed, and provide value for safe use of pharmaceuticals in pediatric populations.

Introduction. Kenneth Loveday, Biogen, Cambridge, MA.

ICHS1: Rodent Carcinogenicity Studies for Human Pharmaceuticals. Jan Willem van der Laan, EMA, Utrecht, Netherlands.

ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. Elizabeth Martin, AstraZeneca, Cheshire, United Kingdom.

Update on Proposed Revisions to ICH S5 (R3): Correlation of In Vitro and In Vivo Assays of Developmental Toxicity. Paul Andrews, Eisai, Woodcliff Lake, NJ.

ICH S11: Nonclinical Safety Testing in Support of Development of Pediatric Medicines. Doug Keller, Sanofi, Bridgewater, NJ.

 

Supporting Open Data in Toxicology

Informational | 12:30 PM to 1:50 PM

Chairperson(s): George Woodall, US EPA, Research Triangle Park, NC; and Gary Miller, Emory University, Atlanta, GA.

Endorser(s): Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section
Specialty Section Collaboration and Communication Group

The goals of the session are to provide basic conceptual frameworks to increase open access to toxicological data, encourage cross-discipline collaboration, link existing toxicological research data with computational toxicology and Tox21, and ensure long-term sustainability for toxicological data resources into the future. The move toward open data has increased across all scientific disciplines for several years. In Toxicity Testing in the 21st Century, the NAS recommended development of data management infrastructure “to enable broad data-sharing across academic, government, industry, and NGO sectors and institutions.” A February 2013 Memorandum from the Office of Science and Technology Policy (Executive Office of the President of the United States) ordered Federal Agencies to make data they create publicly available. SOT has made several forays into this topic, including a CCT Session in May 2012, “Building for Better Decisions,” and a roundtable session at SOT 2015 discussing the barriers to sharing toxicological data. In this session, we will move beyond the barriers to investigate what resources have been built, what needs to be developed to accommodate all subdisciplines of toxicology, and ensure sustainability into the future. We will discuss areas of common cause with other sciences, strategies to tap existing open data infrastructure, leverage across knowledge domains, and identify strategies to avoid redundancy. Key aspects also include developing authoritative reference standards (a common lexicon) to ensure clarity and avoid ambiguity in communicating complex datasets across disciplines; common metadata and data format standards to ensure efficient interoperability; moving beyond chemical-specific toxicity models (e.g., Adverse Outcome Pathways) as a strategy to protect proprietary data and still contribute to the open data model; ensuring existing legacy data are not lost; and planning for long range data curation. Speakers and panelists have been recruited to represent a broad range of disciplines (policy-makers, information scientists, journal editors, and toxicologists) and types of organizations (government, academia, industry, and NGOs). Likewise, this session is relevant to the full range of subdisciplines within toxicology, as represented by the Specialty Sections within SOT, which generate toxicological data (dose-response, hazard ID, mechanistic, etc.) and those which use such data in cross-discipline analysis, regulatory decisions, or risk assessments. Outcomes expected from the session are a set of recommendations for basic conceptual frameworks to increase open access to toxicological data; strategies to encourage cross-discipline collaboration; approaches for linking legacy study data to computational toxicology and the Tox21 initiative; and methods to ensure longterm sustainability and access to toxicological data. Note: The views expressed in this abstract are those of the authors and do not necessarily represent the views or policies of the US EPA.

Introduction. George Woodall, US EPA, Research Triangle Park, NC.

Open Data in Biomedical Science: Policy Drivers and Recent Progress. Ronald Hines, US EPA, Research Triangle Park, NC.

Creating a Common Vocabulary to Enable Data Sharing and Integration. Carolyn Mattingly, North Carolina State University, Raleigh, NC.

Building Infrastructure to Support Data Sharing and Interoperability. Lynn Yarmey, Research Data Alliance/US, Boulder, CO.

Hidden in Plain Sight: The Value and Importance of Unpublished Data. Timothy Pastoor, Pastoor Science Communications, Greensboro, NC.

The Health and Environmental Research Online (HERO) Database: Real-World Application for Risk Assessment. John Vandenberg, US EPA, Research Triangle Park, NC.

 

1:15 PM to 4:30 PM

Poster Sessions
  • Bioinformatics and Tox Databases
  • Cytochrome P450
  • Endocrine Toxicology
  • Hepatotoxicity
  • Nanotoxicology: In Vitro
  • Neurodegenerative Diseases
  • Neurotoxicology: Metals—Manganese
  • Neurotoxicology: Microelectrode Arrays (MEAs)
  • Pharmacogenomics
  • Stem Cell Biology and Toxicology

2:00 PM to 4:45 PM

Symposium Sessions
Cell Health and Mechanistic Assays for the In Vitro Prediction of DILI

Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Yvonne Will, Pfizer, Groton, CT; and Dominic Williams, AstraZeneca, Cambridge, United Kingdom. 

Endorser(s): Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section
Risk Assessment Specialty Section

The current test systems employed by the pharmaceutical industry are poorly predictive of drug-induced liver injury (DILI); in particular, idiosyncratic DILI cannot be predicted in animal systems. This session seeks to address this issue through outlining liver cell heath assays that are fit for purpose, and also outline the development of innovative preclinical test systems, which are both mechanism-based and of physiological, pharmacological, and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis, and mathematical systems analysis has been adopted to evaluate existing models, and develop new models that can provide validated test systems, with respect to the prediction of specific forms of DILI and further elucidation of mechanisms that relate to idiosyncratic DILI. The approach encompasses completely characterised cell lines, well-defined, and physiologically stable hepatocytes, multi-cell type in vitro models and animal models. Triangulation of human, in vitro and animal data is providing a fundamental understanding of how drugs can harm the liver, and how this relates to the idiosyncratic response. The objectives of this symposium: 1. Define the application and limitations of current and novel test systems and provide an improved panel of in vitro “best practice assays” for predicting DILI in the human population during drug development; 2. Explore and understand the relationship between in vitro assay signals and DILI in vivo, in preclinical test species, and in man; 3. Enhance shared understanding, between academia, pharma, and regulatory agencies, of the value and limitations of new and existing approaches for DILI hazard identification and risk assessment.

Introduction. Dominic Williams, AstraZeneca, Cambridge, United Kingdom.

The Importance of Defining the Physiological, Pharmacological, and Toxicological Phenotype of In Vitro Test Systems. Kevin Park, University of Liverpool, Liverpool, United Kingdom.

HepaRG Cell-Model for Drug Discovery and Research. Richard Weaver, Servier, Paris, France.

Novel 3D Hepatic Models for Prediction of Enzyme Inducibility, Long-Term Drug Toxicity, and Drug Action in Healthy and Diseased States. Magnus Ingelman-Sundberg, Karolinska Institutet, Stockholm, Sweden.

Systems Microscopy Approaches in Unraveling and Predicting DILI. Bob van der Water, Leiden University, Leiden, Netherlands.

The Development and Validation of High Content Biology for Use as a Pharmaceutical Industry Hepatotoxicity Screen. Mikael Persson, Astrazeneca, Gothenburg, Sweden.

Circadian Rhythms in Air Pollution-Induced Pulmonary and Cardiovascular Disorders: A Race against the Clocks

Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Petra Haberzettl, University of Louisville, Louisville, KY; and Martin Young, University of Alabama at Birmingham, Birmingham, AL.

Endorser(s): Cardiovascular Toxicology Specialty Section
Inhalation and Respiratory Specialty Section

Exposure to air pollution has emerged as one of the leading causes of death world-wide. The World Health Organization (WHO) estimates that every year exposure to air pollution causes 7 million premature deaths. Extensive epidemiological studies have shown that exposure to polluted air increases the risk of pulmonary and cardiovascular diseases as well as metabolic disorders; however, the underlying pathophysiological mechanisms have remained elusive. Air pollution exposure affects pulmonary, cardiac, and vascular functions that follow circadian rhythmicity and increases the risk for pulmonary and cardiovascular events that follow diurnal patterns. Recent studies have shown that exposures to air pollution disrupt pulmonary and cardiovascular molecular circadian clocks, changes circadian blood pressure pattern, and exacerbates the cardiometabolic effects of dyssynchrony (misaligned circadian rhythm). This symposium will highlight this research, identifying the circadian clocks and rhythms as a novel target of air pollution exposure, and will compare the effects of air pollution on circadian rhythmicity with circadian rhythm disruption induced by other stressors such as ischemia, virus infections and diabetes. The circadian rhythm—defined as physiological, mental, and behavioral changes following a 24 h cycle—controls fundamental physiology, cellular and molecular processes, such as blood pressure, cell division, and DNA-repair that regulate physiological homeostasis. Circadian rhythmicity is regulated by external signals such as light, temperature, food, or physical activity, called Zeitgeber. However, the normal circadian rhythmicities of these environmental factors are disrupted by our modern lifestyle choices. Recent reports suggest that urbanization, accompanied by migration to more polluted areas (with light and air pollution), and our modern 24 hour lifestyle (35% adults sleep less than the recommended 7–8 hours) contributes to the development of pulmonary, cardiovascular, and metabolic disorders. For instance, circadian dyssynchrony, the misalignment between the central clock (supra chiasmatic nucleus, SCN) in the hypothalamus and peripheral clocks by the disturbing the light cycle (e.g. due to changes in sleep/wake pattern, jet lack, or shift work) has been described to increase the risk of developing metabolic and cardiovascular disease. Although the central pacemaker, the SCN has long been considered the primary regulator of circadian rhythm the discovery of clock gene expression, and function in peripheral tissues has challenged this dogma. Peripheral circadian clocks play a critical role in optimizing the organization of cellular function in the lungs, and are directly involved in metabolic homeostasis and cardiovascular function. The studies presented in this symposium will illustrate the importance of different peripheral circadian clocks in the development of pulmonary, cardiovascular, and metabolic disorders, and will provide evidence that exposure to different air pollution disrupt peripheral circadian clocks and circadian rhythm in pulmonary and cardiovascular tissues similar to the circadian misalignment induced by other stressors such as ischemia, virus infections, and diabetes. The specific presentations of this symposium will show that: 1) Peripheral circadian clocks in cardiomyocytes modulate the responsiveness of the heart to physiologic stimuli (e.g., insulin) and pathologic stresses (e.g., ischemia/reperfusion); 2) Peripheral circadian clock disruption in the lungs by environmental tobacco smoke exposure or influenza infection contributes to the pathophysiology and toxicology of chronic airway diseases and their exacerbation in mice; 3) Peripheral circadian clocks in vascular smooth muscle cells contribute to the disruption of blood pressure circadian rhythm in diabetic db/db mice; 4) Circadian blood pressure pattern are altered by exposure to second hand tobacco smoke and its constituent benzo-a-pyrene (BaP) in rats; and 5) Peripheral circadian clocks in the lungs and aorta are disrupted by the exposure to fine particulate air pollution, and that fine particulate air pollution exposure exacerbates metabolic injury in circadian dyssynchrony. In summary, this symposium will provide novel aspects and new mechanistic insights to understand the adverse health effects originating from air pollutant exposure, and our modern lifestyle in association with circadian clock and rhythm disturbances.

Introduction. Petra Haberzettl, University of Louisville, Louisville, KY.

Clock Control of Cardiovascular Physiology and Pathophysiology. Martin Young, University of Alabama at Birmingham, Birmingham, AL.

Inhaled Toxicants and Influenza Virus-Mediated Molecular Clock Disruption in Lung Toxicology or Pathobiology. Irfan Rahman, University of Rochester Medical Center, Rochester, NY.

Blood Pressure Circadian Rhythm. Ming Gong, University of Kentucky, Lexington, KY.

Second Hand Tobacco Smoke and Benzo-a-pyrene Increase Arterial Stiffness and Alter Circadian Blood Pressure Patterns Associated with Systemic Inflammation and Oxidative Stress. Lynn Weber, University of Saskatchewan, Saskatoon, SK, Canada.

Fine Particulate Matter (PM2.5) Exposure-Induced Clock Disruption and Its Possible Contribution to the Cardiometabolic Effects of Dyssynchrony. Petra Haberzettl, University of Louisville, Louisville, KY.

Lifespan Neuroimmunotoxicology: Age-Dependent Neuroimmune Dyshomeostasis Caused by Pollutants, Pathogens, and Psychoactive Substances

Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Nick Filipov, University of Georgia, Athens, GA; and Vic Johnson, Burleson Research Technologies, Inc., Morrisville, NC.

Endorser(s): Immunotoxicology Specialty Section
Neurotoxicology Specialty Section

Interactions between the immune and nervous systems are critical to overall health and wellness. These interactions are dynamic and vary throughout life, in part due to the age-dependent plasticity of these two complex and dispersed organ systems. In addition, early in development, the maternal immune system contributes to both normal and abnormal brain development of the offspring. Perturbation of neuroimmune interactions and cross talk underlies a deluge of neurological disorders and diseases, ranging from neurodevelopmental disorders, such as Autism Spectrum Disorder, to neurodegenerative diseases like Parkinson’s, Multiple Sclerosis and Alzheimer’s, the latter considered a disease of the elderly. Evidence indicates that exogenous exposures to a variety of pressures such as stress, xenobiotics, including psychoactive substances, and infection can result in neuroimmune dyshomeostasis that is a core component in the etiology of many neurological disorders. Age and developmental stage are already recognized as key toxicity modifiers due to age-dependent differences in metabolism or barrier, i.e., blood-brain barrier, presence, and structure. However, perturbation of the integrity of the neuro-immune axis by environmental factors within the context of age is only a recent focus of investigation, and is largely underappreciated by the toxicology community. The goal of this symposium is to highlight the importance of considering age and developmental stage in neuroimmunotoxicology by providing examples of neuroimmune dyshomeostasis caused by pollutants, pathogens, and psychoactive substances when exposures take place at different stages of life.

An Introduction to Neuroimmune Dyshomeostasis: The Game Changes as We Develop and Age. Vic Johnson, Burleson Research Technologies, Inc., Morrisville, NC.

Environmental Influences Early in Life Impact the Neuroimmune Axis: Focus on Autism-Like Neurodevelopmental Disorders. David Lawrence, Wadsworth Center, New York State Department of Health, Albany, NY.

Neuroimmune Interactions and Drugs of Abuse: Overview of Marijuana Compounds with a Focus on Critical Exposure Windows. Barbara Kaplan, Mississippi State University, Mississippi State, MS.

Microglia and the Neuroinflammation Hypothesis of Air Pollution in Adult Mice and Rats. Michelle Block, Indiana University School of Medicine/Stark Neuroscience Research Institute, Indianapolis, IN.

Neuroimmunology of the Aged: Interactions with Pathogens Contributing to Neuroimmune Dyshomeostasis. Rodney Johnson, University of Illinois, Urbana, IL.

Workshop Sessions
Bispecific Molecules: Nonclinical and Clinical Development Challenges

Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Pedro Del Valle, US FDA, Silver Spring, MD; and Patricia Ryan, MedImmune, LLC, Gaithersburg, MD.

Endorser(s): Biotechnology Specialty Section
Immunotoxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

Bispecific antibodies combine antigen‐recognizing elements into a single molecule and are able to bind to two or more targets. This design was described more than 30 years ago, and it addresses the fact that more than one pathway is often present in many diseases. Initial challenges in the development of bispecific antibodies included inefficient designs, manufacturing problems, immunogenicity, undesirable toxicity liabilities, and shorter half‐life that hampered their development but provided many lessons learned. New molecular engineering technologies that incorporates high-throughput methods for quantitative analysis are generating alternatives for selection of bispecific antibodies formats that can be grouped as 1) bispecific fragments, 2) bispecific IgG (BsIgG), 3) appended IgG, 4) bispecific fusion proteins, and 5) bispecific antibodies conjugates. Discussion of engineering strategies for the production of a large matrix of bispecific antibodies will illustrate the technological developments in manufacturing that have occurred in recent years. Bispecific antibodies are being developed for treatment of solid tumors and hematologic malignancies, for virus neutralization, for treatment of inflammatory diseases, gene mediated therapy, and for immunodiagnostic applications. While different bispecific antibodies formats widened the potential therapeutic applications of the molecules, they also introduced hurdles for nonclinical toxicology programs to characterize toxicity liabilities and identify target organs of toxicity to enable clinical trials. For example, both targets are often not present in healthy animals or they are not present in a manner similar to humans. That is the case of blinatumomab, the first bispecific antibody approved in the US. It is a bispecific T cell‐engaging (BiTE®) format against CD3xCD19 composed only of the variable regions of antibodies that are connected by flexible linker peptides. Blinatumomab lacks an Fc region resulting in a smaller size molecule relative to a mAb, leading to enhanced tissue penetration but conferring short serum half‐life that requires administration by continuous infusion. No neurological toxicities were observed in non‐terminal toxicology studies, still life‐threatening neurological toxicities occurred in patients. The current generation of BiTE® constructs is fully human in sequence and cross‐reacts with NHPs. Discussion of strategies for nonclinical assessment, including target liability assessment for defining a safe clinical starting dose and for mimicking the clinical dosing regimen for various BiTE® constructs, will explain the challenges faced during the development of this type of bispecific antibody. BsIgGs retain Fc‐mediated effector functions such as antibody‐dependent cell mediated cytotoxicity, complement‐dependent cytotoxicity, and antibody‐dependent cellular phagocytosis. Modifications to the Fc to minimize those effector functions can also be incorporated depending on the intended target; some bispecific antibodies are designed for membrane bound targets; for example, to bring T or natural killer cells in close proximity to malignant cells promoting activation of immune effector cells for tumor cell destruction. Others are being designed to interact with two different disease mediators neutralizing two different signaling cascades through inactivation either on the level of the receptor or on the ligands, proliferation, or inflammatory processes. In most cases of bispecific antibodies redirecting T cells to tumor cells, integrated safety assessments relies on MABEL approaches for defining a FIH starting dose. Though MABEL approaches based on in vitro assays can define a safe starting dose for a FIH trial, it may take a long time to define a therapeutic dose to be tested in subsequent trials. A retrospective analysis of available data is important to understand limitations of current paradigms for FIH. When one of the targets is not present in animal models, safety pharmacology assessments provided limited information of undesirable pharmacodynamic properties. Generation of bispecific constructs that cross-react with animal models would be important to understand bispecific antibodies attributes such as mechanism of action, pharmacokinetics, and immunogenicity that influence nonclinical development strategies. The talks in this workshop are designed to spark discussion about the nonclinical programs for the development of different bispecific antibodies formats, the hurdles encountered for toxicity testing, and how toxicologists sorted them out to advance bispecific antibodies successfully in clinical development, and the regulatory challenges the Agency faces. This workshop will aid toxicologists with a better understanding of bispecific antibodies applications, the characteristics of different bispecific formats and their toxicity liabilities, and alternative strategies for toxicity testing to adequately assess the safety profile for patients.

Historical Perspectives of Bispecific Antibodies. Pedro Del Valle, US FDA, Silver Spring, MD.

Bispecific Antibodies: Strategies, Considerations, and Challenges. Christoph Spiess, Genentech, Inc., San Francisco, CA.

Nonclinical Characterization of Blinatumomab and Its Translation into the Clinic. Benno Rattel, AMGEN Research (Munich) GmbH, Munich, Germany.

Strategies for Nonclinical Safety Assessment of Bispecific mAbs. Cliff Sachs, MedImmune, LLC, Gaithersburg, MD.

Bispecific Antibody Constructs: A Retrospective Examination of Nonclinical Data. Haleh Saber, US FDA, Silver Spring, MD.

Controversies in Pesticide Toxicology

Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Allister Vale, School of Biosciences, University of Birmingham, Birmingham, United Kingdom; and Martin Wilks, Swiss Centre for Applied Human Toxicology, University of Basel, Basel, Switzerland.

Endorser(s): Clinical and Translational Toxicology Specialty Section
Neurotoxicology Specialty Section
Occupational and Public Health Specialty Section

Neonicotinoids block postsynaptic nicotinic acetylcholine receptors (nAChRs) and their specificity for insect nAChR is several hundred times greater than for vertebrate nAChR. It would be expected, therefore, that the features of human neonicotinoid poisoning would be less severe than nicotine poisoning, but after a substantial ingestion this is not the case. Bees can be exposed to neonicotinoids when foraging on seed treated crops and as a result of dust expelled into the environment from drilling machines. Both laboratory studies and semifield experiments have shown that sublethal neonicotinoid exposure can affect many aspects of pollinator behavior and physiology, though responses vary between bee species and by type of exposure. For another class of insecticides, the organophosphorus chemicals, there is substantial controversy as to whether neurobehavioral changes can occur in humans as a consequence of acute poisoning and after low level exposure to these insecticides. The evidence base is relatively scarce for the former and extensive for the latter, but in both cases the results are not convincing and are conflicting. In most studies, assessment of exposure is vague and, given the variability of farmer exposures, chemicals other than anticholinesterases might account for the observed effects. Severe cholinergic overstimulation causing hypoxia and convulsions may lead to permanent neurobehavioral deficits, but such conditions are often unreported. The choice of controls is also critical when deficits on visual attention, visuomotor speed, and motor dexterity are detected in those workers previously poisoned when compared with those never poisoned. Also measurements of red cell AChE activity are rarely performed, hampering the understanding of the underlying mechanism(s). While the variable presence of more susceptible individuals, possibly due to polymorphisms of metabolic profiles, may account for these differing results, it is unclear what the potential mechanisms could be. Another controversy that has been debated for many years is whether pesticide exposure is a causative factor in neurodegenerative disease. So far, possible underlying mechanisms are not well understood, and epidemiological evidence linking its etiology with long-term/low-dose exposure to specific pesticides is limited. A potential source of bias in many epidemiological studies that rely on self reports is the absence of specific exposure assessments since pesticides are often grouped together in questionnaires, despite the fact that their mechanisms of action are very different. The European Food Safety Authority (EFSA) has proposed the concept of the OECD Adverse Outcome Pathways to describe different putative mechanisms underlying Parkinson’s Disease that may be be linked ultimately to specific pesticides. Although this provides a scientific rationale for the processes that may lead to a final outcome of neurodegeneration, it is not yet clear that it will allow the establishment of cause-effect relationships since it relies on heterogenous data from different sources (human epidemiology, animal, in vitro) and of different quality. The final controversy in this session concerns glyphosate, a broad spectrum herbicide currently with the highest production volumes of all pesticides. It is used in more than 750 different products for agriculture, forestry, urban, and home applications. The International Agency for Research on Cancer (IARC) Working Group classified glyphosate as “probably carcinogenic to humans” (Group 2A) in 2015. In making this overall evaluation, the Working Group noted that mechanistic and other relevant data support the classification of glyphosate in Group 2A. In addition to limited evidence for the carcinogenicity of glyphosate in humans and sufficient evidence for the carcinogenicity of glyphosate in experimental animals, the Working Group were of the view that there is strong evidence that glyphosate can operate through two key characteristics of known human carcinogens, and that these can be operative in humans. The European registration renewal assessment, published by EFSA in October 2015, was the first comprehensive regulatory scientific assessment conducted after the publication of the IARC monograph, and used the classification criteria for chemicals adopted under the United Nation Globally Harmonised System (UNGHS). Based on the same evidence base regarding epidemiological studies, and broader evidence regarding carcinogenicity in animals and genotoxicity, EFSA has concluded that glyphosate is unlikely to be genotoxic or pose a carcinogenic threat to humans.

Introduction. Allister Vale, University of Birmingham, Birmingham, United Kingdom.

Neonicotinoid Insecticides: Safe for Humans, but Toxic to Bees? Allister Vale, School of Biosciences, University of Birmingham, Birmingham, United Kingdom.

Do Neurobehavioral Changes Occur in Humans as Long-lasting Consequences of Acute Poisoning with Organophosphorus Insecticides and after Low Level Exposures to Anticholinesterase Agents? Marcello Lotti, Università degli Studi di Padova, Padova, Italy.

Pesticides and Neurodegenerative Disease: Is There a Causal Link? Martin Wilks, Swiss Centre for Applied Human Toxicology, University of Basel, Basel, Switzerland.

Is Glyphosate a Probable Human Carcinogen? Yes! Ivan Rusyn, Texas A&M University, College Station, TX.

Is Glyphosate a Probable Human Carcinogen? No! Daniele Court-Marques, European Food Safety Authority (EFSA) Pesticides Unit, Parma, Italy.

Improving Public Health through Innovations in Exposure Science

Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Cecilia Tan, US EPA, Durham, NC; and Alicia Paini, Joint Research Centre, Ispra, Italy.

Endorser(s): Mixtures Specialty Section
Reproductive and Developmental Toxicology Specialty Section
Women in Toxicology Special Interest Group

In the traditional risk assessment paradigm, exposure science is relegated to a supporting role, providing an exposure estimate for comparison with hazard-based guidance values to determine whether there may be an unacceptable risk to public health. More recently, exposure science has transformed into a distinct discipline that complements toxicology as a means to understand the relationship between exposures to chemical mixtures and multiple health effects. This transformation is driven by advances in, for example, analytical methods, biomarker discovery, computational capabilities and algorithms, remote and on-person sensors, and geographic information systems. These major innovations in exposure science provide novel data streams that can revolutionize toxicity testing strategies and conventional risk assessment. For example, large numbers of chemicals are being detected at ever-lower concentrations in environmental and biological samples, providing relevant exposure information to be integrated into toxicity testing strategies. Novel biomarkers are being developed to expand our understanding of exposures, early biological effects, and susceptibility, and to allow for the exploration of contributions from both chemical and non-chemical stressors to adverse health outcomes. This workshop will introduce numerous innovative tools to enable better characterization of human exposures to mixtures of chemicals, including 1) a non-targeted approach to identify chemical signatures in house dust; 2) a laser ablation method for reconstructing early lifestage exposures to chemicals and essential nutrients using deciduous teeth; 3) the use of low-cost air sensors to collect air pollutant data for individuals; and 4) a biomonitoring study to examine the potential role of various estrogens in disruption of normal endocrine functions in pregnant women. In addition to exposure characterization, exposure data can be integrated with hazard information obtained from in vitro toxicity screening assays and/or disease outcomes found in epidemiologic studies to provide insight into the complex relationship between multiple exposures and multiple health outcomes. The last presentation will introduce a framework for organizing data and information emerging from exposure science research, along with tools to further the application of systems-based approaches for improving public health. Following the presentations, there will be a 20- minute open discussion among workshop presenters and attendees to explore strategies to raise awareness in the conventional toxicology community of these innovative exposure-based approaches. The overarching goal of this workshop is to initiate discussions about the utility of these novel approaches in exposure science, together with advancements in toxicity testing strategies, in order to improve public health assessment. Disclaimer: Although this abstract was reviewed by US EPA and approved for publication, it may not necessarily reflect official Agency policy.

Transitioning Toxicological Research with Innovative Exposure Science and Tools. Alicia Paini, Joint Research Centre, Ispra, Italy.

Innovative Screening Methods to Identify Chemical Exposure Signatures and Linkages to Toxicity: Case Study with House Dust. Julia Rager, ToxStrategies, Austin, TX.

Uncovering Prenatal and Early Childhood Windows of Susceptibility to Environmental Chemicals Using Teeth. Manish Arora, Icahn School of Medicine at Mount Sinai, New York, NY.

Understanding of Air Pollution-Related Health Impacts Using Sensor Technologies. Edmundo Seto, University of Washington, Seattle, WA.

Aggregate Exposures and Adverse Outcome Pathways for Estrogen Mimics: Can the Frameworks and Emerging Exposure Data Help Focus Public Health Research on the Most Relevant Exposures? Justin Teeguarden, Pacific Northwest National Laboratory, Richland, WA.

A Conceptual Framework to Advance Exposure Science Research and Complement the Adverse Outcome Pathway Framework. Stephen Edwards, US EPA, Durham, NC.

Modernizing Toxicological Risk Assessment for Compounds Released from Pharmaceutical, Consumer, Medical Device, and Combination Products: Alternative Tools and Methods

Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Richard Hutchinson, Johnson & Johnson, Somerville, NJ; and Alan Hood, US FDA, Silver Spring, MD.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Medical Device and Combination Product Specialty Section
Regulatory and Safety Evaluation Specialty Section

The potential toxicological effects of compounds released from medical devices and combination products are a patient safety concern for both device manufacturers and regulatory stakeholders. This session will address the need to advance methods for the toxicological risk assessment of compounds released from medical devices and combination products, and will explore opportunities for modernizing the risk assessment approaches for these compounds. This session is intended to generate a dialogue for recent advancements from a variety of industry and non-industry initiates in the development, acceptance, and application of alternative tools that complement or replace in vivo testing. The session focuses on two areas of toxicological risk assessment: hazard assessment, and risk characterization. The session begins with modernizing hazard assessment through systematic review using objective, reproducible methods that transparently document scientific judgments and the scientific basis of hazard identification conclusions. Then, recent insights on assigning Cramer classification to compounds that can be used as guidance and improvement of in silico tools will be presented. Computational tools, such as QSAR models and Read-Across, to predict the toxicity of compounds lacking experimentally-derived toxicity data and the use of these predicted toxicity values will be discussed. The final topic is a semi-quantitative risk evaluation matrix to determine the amount and rigor of component testing that may be necessary and appropriate to establish that the component is suitable for its intended use. Academic/industry/consulting toxicological risk assessors and regulatory affairs representatives who have an interest in recent advancements in toxicological risk assessment in medical devices, combination, and consumer products should consider attending this workshop.

Introduction. Alan Hood, US FDA, Silver Spring, MD.

Evaluation of the Potential Immunotoxicity Associated with Exposure to Perfluorooctanoic Acid (PFOA) with a Systematic Review Framework. Andrew Rooney, V. Walker, A. Boyles, K. Thayer, NIEHS-NTP, Research Triangle Park, NC.

Advancing Understanding of Cramer Classification with Adverse Outcome Pathway (AOP). K. Li, Amgen, Thousand Oaks, CA.

A Practical Guidance for Cramer Class Determination. Jie Shen, Eli Lilly and Company, Indianapolis, IN.

Modernizing Toxicological Risk Assessment for Medical Devices Using ISO 10993 Standards. Ron Brown, US FDA, Silver Spring, MD.

The Development of a Risk Evaluation Matrix for Polymeric Materials and Components Used in the Manufacture of Pharmaceuticals and BiopharmaceuticalsMichael Eakins, Eakins & Associates, East Windsor, NJ.

Platform Sessions
  • Multi-Omic Connections in Chemical Toxicity
  • Reproductive Toxicology

Tuesday, March 14

9:30 AM to 12:15 PM

Symposium Sessions
Cardiopulmonary Consequences of Gestational Toxicant Exposure: Getting to the Heart of the Matter

Symposium | 9:30 AM to 12:15 PM

Chairperson(s): Lynette Rogers, The Ohio State University, Columbus, OH; and Phoebe Stapleton, Rutgers University, Piscataway, NJ.

Endorser(s): Cardiovascular Toxicology Specialty Section
Reproductive and Developmental Toxicology Specialty Section
Women in Toxicology Special Interest Group

Xenobiotic exposures affect the maternal and/or in utero environment resulting in impairments in fetal development. During the period of rapid fetal growth, underdeveloped cardiovascular systems are especially vulnerable to their environment. Furthermore, fetal exposures can evoke changes in epigenetic signatures that result in permanent modifications in gene expression. This symposium will focus on the intersection between maternal and fetal exposure and the developing cardiovascular system. Speakers will provide data from three common exposures: nanomaterials; particulate matter or air pollution (PM 2.5); and nicotine. The current findings related to susceptible gestational windows for cardiovascular development and epigenetic, transcriptomic, and toxicokinetics changes in vascular physiology and cardiac function will be presented. The impact of these exposures is of major concern for regulatory agencies, as the developing fetus is more susceptible to environmental or personal exposures than are adults. In response to these concerns, new concepts in predictive modeling and risk assessment associated with fetal exposures will be presented as future avenues of research within developmental toxicology. Finally, current applications using the adverse outcome pathway framework (ToxCast library) for risk assessment in embryonic vascular disruption and developmental defects will be presented. The topics discussed will provide the state of the art information on effects of maternal toxicant exposure on cardiovascular deficits in the offspring which are of concern to clinicians and basic scientists, as well as government and pharmaceutical regulatory agencies. In summary, this symposium seeks to address the significant threats to cardiovascular health that are associated with fetal/perinatal exposures, and offer new insights into the predictive, mechanistic, and risk assessment strategies in developmental toxicology.

Introduction. Lynette Rogers, The Ohio State University, Columbus, OH.

Altered Maternal and Placental Vascular Responses following Acute Nanomaterial Administration. Christopher Wingard, Brody School of Medicine at East Carolina University, Greenville, NC.

Alterations in the Cardiovascular Epigenome after Prenatal Engineered Nanomaterial Exposures. Timothy Nurkiewicz, West Virginia University, Morgantown, WV.

Fetal Cardiac Function and Related Heath Parameters are Altered by Maternal Exposure to Ambient Particulate Matter during Specific Gestational Exposure Windows in a Mouse Model. Judith Zelikoff, New York University School of Medicine, Tuxedo, NY.

Cardiovascular Risk Factors following Fetal and Neonatal Exposure to Nicotine. Alison Holloway, McMaster University, Hamilton, ON, Canada.

Advancements in Cardiopulmonary Toxicology and Developmental Risk Assessment for Product Safety Assessment. Reza Rasoulpour, Dow AgroSciences, Indianapolis, IN.

Adverse Outcome Pathway (AOP) Framework for Embryonic Vascular Disruption and Developmental Defects. Thomas Knudsen, US EPA, Research Triangle Park, NC.

Contribution of Gene Transcription to Spontaneous Mutation and Genotoxic Outcomes

Symposium | Innovations in Toxicological Sciences Session | 9:30 AM to 12:15 PM

Chairperson(s): Robert Schiestl, University of California Los Angeles, Los Angeles, CA; and Joanna Klapacz, The Dow Chemical Company, Midland, MI.

Endorser(s): Carcinogenesis Specialty Section

All organisms sustain a certain number of background mutations as a result of cellular processes or interactions with their environment. The significant source of spontaneous mutation, arising from normal DNA metabolism, is contributed by mispairing of bases during DNA replication. As DNA metabolic processes of transcription, replication, and repair are not temporally separated, one process has the potential to influence the occurrence and outcome of another. In fact, recent research in the area of genetic instability has demonstrated that the process of gene transcription alone can elevate DNA damage load and genetic modifications. Transcription unwinds DNA strands, potentially sensitizing the untranscribed strand to react with endogenous and exogenous agents. Thus, the understanding of background spontaneous mutation, including that arising from transcription, can be a critical aspect of understanding point-of-departure metrics of DNA-reactive agents. Genetic instability is also a hallmark of carcinogenesis, and cells from patients carrying mutations conferring cancer prone phenotypes show a higher level of genetic instability. To better understand how transcription influences genetic instability, various researchers have constructed and validated different genetic assays in model organisms, including, bacteria, yeast, human culture cells, and even in in vivo mouse models, to study the generality and occurrence of transcription-associated mutagenesis (TAM). Using the highly inducible promoter systems in model organisms, it has been documented that high levels of transcription are associated with elevated mutation and recombination rates. In the case of TAM, the level of mutagenesis was shown to be directly proportional to the level of transcription, and the direction of replication fork movement relative to that of RNA polymerase. Molecular mechanisms have also been elucidated by which cells can solve transcription-replication conflicts to prevent genome instability and will be discussed during the symposium. The role of RNA-DNA hybrids in these conflicts, their role in modulating chromatin structure, and epigenetic modifications will also be addressed to explain how they can lead to chromosome breakage, fragility, and contribute to background DNA damage levels and even disease.

Introduction. Robert Schiestl, University of California Los Angeles, Los Angeles, CA.

Transcription-Associated Mutagenesis Contributes to Background Gene Mutation. Joanna Klapacz, The Dow Chemical Company, Midland, MI.

Ames Assay Negative Carcinogens Cause DNA Deletions Preferentially in Transcribed DNA. Robert Schiestl, University of California Los Angeles, Los Angeles, CA.

Proceed with Caution: Removal of Transcription-Associated Supercoils Can Be Hazardous to Genome Integrity. Sue Jinks-Robertson, Duke University Medical Center, Durham, NC.

Coordinated Action of RNA-Binding Factors and Chromatin Remodeling to Prevent Genome Instability. Andres Aguillera, CABIMER-Universidad de Sevilla, Sevilla, Spain.

Workshop Sessions
Incorporating In Vitro Reproductive and Developmental Assays into Regulatory Risk Assessment

Workshop | 9:30 AM to 12:15 PM

Chairperson(s): Suzanne Fitzpatrick, US FDA, College Park, MD; and Elaine Faustman, University of Washington, Seattle, WA.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Regulatory and Safety Evaluation Specialty Section
Reproductive and Developmental Toxicology Specialty Section

Reproductive and developmental hazards are an important public health risk. Toxicology testing plays a fundamental role in characterizing these potential risks. However, most of the toxicology tools used for regulatory assessment of potential reproductive and developmental toxicants rely on high-dose animal studies and default extrapolation procedures and have remained relatively unchanged for decades, despite the scientific revolutions of the past half century. New predictive models are needed to gain a better understanding of reproductive and developmental toxicity mechanisms at multiple levels of biological organization, including genes, proteins, pathways, and cell/organ function. Assessing safety is particularly challenging in the reproductive/developmental toxicology field due to the reproductive cycle’s complexity and unusually long time frame for testing. Several promising new in vitro assays for reproductive and developmental endpoints have been developed that could address important questions such as species-specific toxicity and endocrine effects, while promising faster and more efficient toxicity testing with the use of less animals. Regulatory toxicologists must decide how these methods can be used for regulatory assessment. This workshop will be an opportunity for all stakeholders to discuss how to gain confidence in the results of these new models for reproductive and developmental testing. The workshop will discuss some new promising in vitro models and proposals on how these new tests can be incorporated into regulatory risk assessment. A panel of the speakers and additional federal regulatory scientists will then review challenges presented in the talks, and outline how to move forward to use these models in regulatory assessments.

Introduction. Suzanne Fitzpatrick, US FDA, College Park, MD.

A Review of In Vitro Developmental Toxicology Assays and Potential Applications in Regulatory Developmental Toxicology Testing. Karen Augustine, Bristol-Myers Squibb Company, Pennington, NJ.

Testicular Cells Co-Culture as an Alternative Model for Male Reproductive Toxicity. Elaine Faustman, University of Washington, Seattle, WA.

Qualifying New In Vitro Tools for Use in a Regulatory Risk Assessment. Suzanne Fitzpatrick, US FDA, College Park, MD.

Reimagining Evaluation of Human Pharmaceutical Reproductive Risk. Christopher Bowman, Pfizer Inc, Groton, CT.

An Integrated European Program Driving Mechanism-Based Toxicity Testing and Risk Assessment for the 21st Century. Marcel Leist, University of Konstanz, Konstanz, Germany.

Panel Discussion. Suzanne Fitzpatrick, US FDA, College Park, MD.

Opportunities for Read-Across Development and Application Using QSAR Approaches

Workshop | 9:30 AM to 12:15 PM

Chairperson(s): Richard Becker, American Chemistry Council, Washington, DC; and Grace Patlewicz, US EPA, Research Triangle Park, NC.

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

Read-across is a data gap filling technique used within analogue and category approaches for regulatory purposes. Although there has been considerable experience applying these techniques for regulatory programs, acceptance remains context dependent and reliant on expert assessment. Recent activities, including those led by Cosmetics Europe, and separately by the European Chemicals Agency (ECHA), have developed conceptual frameworks to identify and document sources of uncertainty. Addressing uncertainties using mechanistic information within Adverse Outcome Pathways (AOPs) is still in its infancy; although several case studies have been developed, their success and uptake remains dependent on subjective assessment. Currently, there are no objective metrics to evaluate the performance or quantify the uncertainties in read-across predictions. This is in sharp contrast to (Q)SARs (which are underpinned by the same principles), where measures of performance are specified as one of the (Q)SAR validation principles. This raises the question of whether there are learnings and approaches that can be drawn from this related field that could be exploited to enhance read-across, and in doing so, transition away from expert assessment. Research to develop read-across predictions of toxicity (qualitatively or quantitatively, e.g. benchmark dose or NOAELs) using similarity weighted activity of nearest neighbors based on chemistry and/or bioactivity descriptors (akin to a local QSAR model) are being investigated. Opportunities also exist to derive read-across predictions within local domains using other chemoinformatics techniques, from systematically identifying and evaluating source analogues, characterizing analogues with relevant mechanistic information to using machine learning techniques. This workshop will discuss opportunities of moving from expert-driven approaches to systematic read-across prediction by exploiting informatics. Methods to quantify uncertainty, combine different types of information, and thereby to reduce the uncertainty, will also be discussed.The workshop will comprise a series of highly focused presentations that will provide an update of the state of the science for traditional read-across, and demonstrate opportunities for using informatics approaches in selecting and characterizing analogues, objectively evaluating read-across predictions, and assessing performance. The session is intended to foster discussion between practitioners of read-across and other modeling approaches, and investigators and regulators across environmental, industrial, consumer products, and pharmaceutical toxicology at the same time as articulating the practical value of the read-across methodologies being developed in enhancing human and environmental risk assessment.

Introduction. Grace Patlewicz, US EPA, Research Triangle Park, NC.

Current Progress with Expert Driven Read-Across in the Regulated Community: Practical Experiences Using Glycol Ethers. Nicholas Ball, The Dow Chemical Company, Horgen, Switzerland.

Read-Across at the Crossroads of Chemoinformatics and Regulatory Science. Chihae Yang, Altamira and Molecular Networks, Columbus, OH.

Reproducible Read-Across Evaluations Based on SAR Information. Emilio Benfenati, Mario Negri Institute, Milan, Italy.

Quantifying Uncertainty in Read-Across Assessment: An Algorithmic Approach. Grace Patlewicz, US EPA, Research Triangle Park, NC.

Using Quantitative Predictions of Continuous Toxicity Values in Read-Across. Jessica Wignall, ICF International, Fairfax, VA.

Focused Discussion and Wrap-Up. Richard Becker, American Chemistry Council, Washington, DC.

Informational Session
Thresholds of Toxicological Concern: 21st Century Safety Assessment

Informational | 9:30 AM to 12:15 PM

Chairperson(s): Heli Hollnagel, Dow Europe GmbH, Horgen, Switzerland; and Kristi Muldoon-Jacobs, US FDA, College Park, MD.

Endorser(s): Regulatory and Safety Evaluation Specialty Section

Safety assessment is the evaluation of a chemical to ensure that exposure from its use is acceptable within the current risk analysis paradigm. Typically, this involves an evaluation of chemical-specific toxicity data from animal studies, to derive acceptable levels of exposure. As analytical methods improve, more and more chemicals are detected in our environment for which chemical specific exposure levels can be estimated, but toxicology data is lacking. The Concept of the Threshold of Toxicological Concern (TTC) uses the principles of chemical grouping and read-across to screen chemicals at low levels of exposure for prioritization of follow-up testing. The approach considers chemical structure, metabolism, and animal toxicity data to establish generic chronic exposure thresholds below which there is no appreciable health risk. At the same time, scientists are striving to identify methods and approaches capable of achieving the NAS vision to Refine, Replace and Reduce animal testing, whilst improving the efficiency of low tier evaluations. Within that context, the TTC approach should be evaluated against emerging methods such as: computational approaches, in vitro methods, and individual chemical read-across, to predict systemic repeat-dose toxicity. This session is laid out to review the scientific basis of the TTC concept and the areas of ongoing improvements, such as database updates, the derivation of internal TTCs, and updates to the structural groupings used in TTC. This status quo will also be challenged by looking at if, and how, the TTC approach can be advanced into the 21st century.  Sufficiently large databases with information from in vivo toxicology studies are a crucial foundation for the TTC concept. The thresholds for potential carcinogens were derived from a dataset originally build in the 1980s from the UC Berkeley Cancer Potency Database. The thresholds for non-cancer endpoints were developed in the 1990s from the Munro dataset of repeated dose studies. Since then, different smaller projects have confirmed the robustness of the thresholds in general, and for specific endpoints, by demonstrating that updates to study subsets or addition of new data did not result in relevant changes. However, the datasets serving as the basis of the current TTC values are partly outdated and do not necessarily represent all types of chemical structures. One major effort to expand the structural domain of the TTC dataset for non-cancer endpoints with chemicals related to cosmetics has just been concluded by the COSMOS/ILSI Europe project. For the cancer potency TTC dataset, an ILSI Europe Expert Group is developing a framework for evaluation of cancer bioassay and genotoxicity data, to lay out how the cancer TTC thresholds could be refined despite the challenges of predicting cancer mechanism of action, human relevance of tumor findings, and potency based on often scant data. The current TTCs are representative of external oral exposures. Recently, the development of TTCs based on internal exposure, such as chemical concentration in blood, has been proposed, with the particular advantage that they could be used in risk assessment for non-oral routes of exposure. Examples will be presented of the use of PBPK modeling to derive internal concentrations for chemicals in the existing TTC database, which is the first step towards developing internal TTCs. The TTC approach relies on grouping chemicals using the Cramer et al. 1978 Decision Tree (DT), which was developed 40 years ago to provide a tool to prioritize orally ingested substances based on their chemical structure. Combining knowledge of structure, metabolism, and toxicity, a sequence of yes/no questions were devised that leads to the assignment of a substance to one of three classes of toxic concern. Given the scientific knowledge accumulated since 1978, the DT is overdue for an update. The session will discuss current work to develop more refined DT questions, which leads to an increased number of six classes of toxic concern, aimed at more accurate allocation of a broad range of structures to toxicity classes with appropriate thresholds. Rapid progress in the development of in vitro and in silico methods is giving rise to alternative approaches, which could make the current TTC approach redundant. The volume of data being generated by Tox21 methods, allied with the development of adverse outcome pathways and their respective molecular initiating and other key events, is providing opportunities for molecular read-across, including (Q)SAR, which should be more accurate that conventional approaches based on in vivo toxicity data. The session will examine whether Tox21 data could be used to develop TTCs, and if abandoning the TTC approach would result in an unnecessary limitation in available risk assessment strategies.

Introduction: What Exactly Is TTC, and How Is It Used? Kristi Muldoon-Jacobs, US FDA, College Park, MD.

Updating the TTC Cancer Potency Database and the Cosmetic-Related Substance Database. Heli Hollnagel, Dow Europe GmbH, Horgen, Switzerland.

The Application of Physiologically Based Pharmacokinetic (PBPK) Modeling to Support the Derivation of Internal Thresholds of Toxicological Concern (TTCs). Harvey Clewell, ScitoVation, Research Triangle Park, NC.

The Application of an Updated Cramer, et al. Decision Tree to Food Ingredient Safety Assessment. Szabina Stice, US FDA, College Park, MD.

TTC in the Times of Tox21. Alan Boobis, Imperial College London, London, United Kingdom.

Platform Sessions
  • Chemical and Biological Weapons
  • Endocrine Toxicology
Mechanisms of Toxicity: SPC Highlights Emerging Scientists

Platform | 9:30 AM to 12:15 PM

Chairperson(s): Patricia Ganey, Michigan State University, East Lansing, MI; and Saber Hussain, US Air Force Research Laboratory, Dayton, OH.

Endorser(s): Scientific Program Committee

Identification, Confirmation, and Replication of Novel Non-Invasive MicroRNA Biomarkers to Detect Kidney Fibrosis in Humans. Mariana Cardenas Gonzalez, Harvard Medical School, Boston, MA.

Deficiencies in Mitochondrial Fission and Fusion Sensitize C. elegans to Arsenite-Induced Mitochondrial Dysfunction. Anthony Luz, Duke University, Durham, NC.

Effect on Cadmium-on-Stem Cell Population in Human Renal Proximal Tubular Cells. Swojani Shrestha, University of North Dakota, Grand Forks, ND.

Towards the Development of a Quantitative Adverse Outcome Pathway for Thyroperoxidase Inhibition: Thyroid Hormone Disruption and Neurodevelopmental Deficits. Iman Hassan, US EPA, Research Triangle Park, NC.

Characterization of the Modes of Action of Thiocyanate on the Thyroid Hormones Levels Using a Mechanistic Dose-Response Model. Marie-Emilie Willemin, US FDA/NCTR, Jefferson, AR.

Non-Dioxin-Like Polychlorinated Biphenyls Modify Gap Junctions to Specifically Disturb Human Neural Crest Cell Migration. Johanna Nyffeler, University of Konstanz, Konstanz, Germany.

A Mixture of 18 Anti-Androgens at Concentrations below Individual Chemical Effect Levels Produces Reproductive Tract Malformations in the Male Rat. Justin Conley, US EPA, Research Triangle Park, NC.

Prenatal Phthalate Mixture Exposure Adversely Affects Female Reproduction in Mice. Changqing Zhou, University of Illinois, Urbana, IL.

Comparison and Analysis of Toxcast Data with In Vivo Data for Food-Relevant Compounds Using the Risk21 Approach. Alexandra Turley, Michigan State University, East Lansing, MI, and ILSI-North America, Washington, DC.

Intraneuronal Delivery of a Single Domain Antibody Prevents Death to Lethal Doses of BoNT/A in a Murine Model of Botulism. Edwin Vazquez-Cintron, US Army Medical Research Institute of Chemical Defense, Edgewood, MD.

 

9:30 AM to 12:45 PM

Poster Sessions
  • Dose-Response Assessment and Toxicity Reference Value Derivation
  • Exposure Assessment and Biomonitoring
  • Immunotoxicology
  • Kidney
  • Metals I: Arsenic and Lead
  • Neurotoxicology: General Neurotoxicity
  • Non-Pharmaceutical Safety Assessment
  • Ocular Toxicology
  • Oxidative Injury and Redox Biology
  • Pharmaceutical Safety: Drug Development
  • Pharmaceutical Safety: Drug Discovery
  • Tobacco Products

 

1:15 PM to 4:30 PM

Poster Sessions
  • Biomarkers
  • Biotransformation
  • Cell Death Mechanisms
  • Chemical and Biological Weapons
  • Genetic Toxicity
  • Medical Devices
  • Metals II: Cadmium and Mercury
  • Metals III: Various Metals and Mixtures
  • Nanoparticle Exposure, Dosimetry, and In Silico Modeling
  • Regulation and Policy
  • Skin
  • The Developmental Basis of Adult Disease

 

2:00 PM to 4:45 PM

Symposium Sessions
Big Data, Meet Chemical Carcinogenesis! Are There New Solutions for an Old Problem?

Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Udayan Apte, University of Kansas Medical Center, Kansas City, KS; and James Klaunig, Indiana University, Bloomington, IN.

Endorser(s): Carcinogenesis Specialty Section

The ability of chemicals to cause cancer is a highly relevant end point with a significant public health impact. Determining the mechanisms by which chemicals modulate normal cellular pathways to induce neoplastic transformation and growth is central to the discipline of toxicology. New data obtained via development of new animal models combined with high-throughput ‘omics technologies has revolutionized the way we identify modes of action (MOA). These new “Big Data”-assisted technologies have highlighted several novel molecular targets involved in chemical carcinogenesis and changed our understanding of MOA. Development of molecular networking tools has revealed novel gene networks that regulate neoplastic growth secondary to chemical exposure. A completely unbiased adverse outcome pathway analysis is yet another approach that can revolutionize understanding the mechanisms of chemical carcinogenesis. Despite several key advances, major challenges remain in employing the new systems biology based big data techniques to chemical carcinogenesis research. This symposium will bring together scientists bringing  “Big Data” methodologies to the chemical carcinogenesis field. The new frontiers of using data analytics to study chemical carcinogenesis and the challenges ahead will be discussed.

Introduction. James Klaunig, Indiana University, Bloomington, IN.

Mode of Action in Chemical Carcinogens: Setting the Baseline. James Klaunig, Indiana University, Bloomington, IN.

Integrating Toxicogenomics Data into Adverse Outcome Pathways for Cancer. Chris Corton, US EPA, Research Triangle Park, NC.

Warburg-Like Differential Gene Expression and Metabolic Reprogramming during Progression of Cancer Pathogenesis: Lesson Learned from Liver Cancer Studies. Timothy Zacharewski, Michigan State University, East Lansing, MI.

NGS Reveals Novel Targets and MOA in Chemical Carcinogenesis. Udayan Apte, University of Kansas Medical Center, Kansas City, KS.

Chemically-Induced Neuroinflammation and “Sickness Behavior” Disorders

Symposium | 2:00 PM to 4:45 PM

Chairperson(s): James O’Callaghan, CDC-NIOSH, Morgantown, WV; and G. Jean Harry, NIEHS/NIH, Research Triangle Park, NC.

Endorser(s): Immunotoxicology Specialty Section
Neurotoxicology Specialty Section

Neuroinflammation is a dominant theme in contemporary neuroscience. This is not surprising given the number of neurological disease states, e.g. Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, where neuroinflammation has been implicated. Thus, a clear association has emerged among neurodegenerative disorders, and the elaboration of proinflammatory cytokines and chemokines in the CNS, the core feature of the neuroinflammatory condition. While neuroinflammation often occurs in association with damage to neurons and glia, it also can occur in the absence of neurodegeneration, e.g. where elevated concentrations of proinflammatory cytokines are seen with systemic infection. In these circumstances, neuroinflammation is associated with sickness behavior, i.e. a constellation of symptoms manifested in loss of appetite, fever, muscle pain, fatigue, and cognitive problems. Typically, sickness behavior accompanies an inflammatory response that resolves with time, with gradual restoration to homeostasis. However, chronic sickness behavior syndromes can also occur, and may be instigated or exacerbated by chemical exposures, both from the environment and pharmaceuticals. In this symposium, we bring together two junior investigators and two senior investigators to provide an overview of the central/peripheral immune system interactions that can contribute to the sickness behavior condition, and present recent preclinical and clinical data, as well as data from experimental models, on three sickness behavior disorders: Chemobrain, Gulf War Illness, and Chronic Fatigue. These presentations serve as examples of the chronic neuroinflammatory condition as an important chemical exposure issue, with implications beyond the disorders and exposures to be presented. The goal of the symposium is to provide a framework for considering alterations in the normal inflammatory response of the nervous system as a basis for complex neurological and physiological disorders that can be initiated or exacerbated by chemical or pharmaceutical exposure.

Introduction. G. Jean Harry, NIEHS/NIH, Research Triangle Park, NC.

Overview of Neuroinflammation and Sickness Behavior. Christopher McPherson, NIEHS/NIH, Research Triangle Park, NC.

Chemobrain. Cobi Heijnen, University of Texas MD Anderson Cancer Center, Houston, TX.

Gulf War Illness. Lindsay Michalovicz, CDC-NIOSH, Morgantown, WV.

Chronic Fatigue. Nancy Klimas, Nova Southeastern University, Fort Lauderdale, FL.

Panel Discussion. James O’Callaghan, CDC-NIOSH, Morgantown, WV.

Emerging Concepts in Nonclinical Development of Immuno-Oncology Agents: Enabling Translation of Nonclinical Pharmacology and Safety Information to First-in-Human Clinical Trials

Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Vijayapal Reddy, Eli Lilly and Company, Indianapolis, IN; and Jacqueline Kinyamu-Akunda, Novartis Institute for Biomedical Research, East Hanover, NJ.

Endorser(s): Comparative and Veterinary Specialty Section
Immunotoxicology Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

Immunotherapy is a fast growing area of new pharmaceuticals in oncology, the success of which is evidenced by the recent approval of a number of immune modulators and numerous others in development. Immuno-oncology (IO) agents target suppressive signals that prevent the development of an immune response and activate the immune system to help fight cancer. The breadth of immune targets is expanding rapidly; consequently, new challenges in nonclinical assessment have emerged, including a lack of appropriate animal models to assess efficacy and safety; differences in sensitivities of various animal species to immune modulators; safety issues in humans not predicted by nonclinical testing; and limited knowledge of the translatability of data from nonclinical species to humans. This session will provide attendees with practical knowledge for approaches to evaluate the safety of novel immune modulatory agents, with an emphasis on assessments to support first-in-human clinical trials. The first speaker will give an overview of nonclinical assessment of immune therapies, discuss considerations for target safety, challenges in identifying the right models for nonclinical testing, and highlight alternative approaches where no appropriate animal models exist. The second speaker will expand further on mouse models relevant to efficacy and safety, with a focus on the pathological characteristics of humanized mouse models. The third speaker will discuss examples of selection of appropriate animal species for nonclinical studies, and considerations for the starting dose in first-in human studies based on nonclinical safety and efficacy studies. The fourth speaker will highlight the challenges in translating nonclinical information to first-in-human and early clinical trials with respect to pharmacology and safety. Finally, the last speaker will discuss regulatory aspects and considerations of the safety evaluation to support human clinical trials.

Introduction. Vijayapal Reddy, Eli Lilly and Company, Indianapolis, IN.

Preclinical Models for Immunotherapies: Considerations for On-Target Safety. Laura Johnson, University of Pennsylvania, Philadelphia, PA.

Looking Beyond Cytokines: A Pathology Perspective on Humanized Immune System Models. Daniel Weinstock, Janssen R&D, Spring House, PA.

Critical Endpoints in Safety Studies Supporting Immuno-Oncology Agents. Rakesh Dixit, Medimmune (a member of AstraZeneca Group), Gaithersburg, MD.

Translating Preclinical Data for Immunotherapeutic Agents to the Design of First in Human Oncology Trials—Challenges and Opportunities. Randi Isaacs, Novartis Institute for Biomedical Research, East Hanover, NJ.

Regulatory Perspectives on Nonclinical Safety Evaluation of Immune-Oncology Agents. John Leighton, US FDA, Silver Spring, MD.

Lost in Translation: Bringing the Real World to In Vitro Data

Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Michelle Embry, ILSI Health and Environmental Sciences Institute, Washington, DC; and Todd Gouin, Unilever, Milton Keynes, United Kingdom.

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

Recent advances in high-throughput in vitro assays provide opportunities for improved mechanistic understanding of toxicity for chemical safety assessment, and ultimately for reduced animal testing. In order to expand the utility of in vitro bioassay data for human and environmental systems, a “translation” of information obtained in vitro to in vivo systems, commonly referred to as in vitro to in vivo extrapolation (IVIVE), is required. Methods that more explicitly and quantitatively translate information from in vitro test systems to in vivo systems, as well as reliable approaches that quantifiably link external exposures to internal exposures corresponding to target sites, will foster confidence in the acceptance of the emerging high-throughput data streams for applications in hazard and risk assessment. Despite the advances in IVIVE, toxicokinetic (TK) models, and understanding of key processes such as absorption, distribution, metabolism, and excretion (ADME) processes, there are still outstanding issues that must be addressed before these in vitro methods can reliably be applied for hazard-based and risk-based assessment. Recent developments have improved characterization of exposure in vitro, including the development of modelling tools that calculate the concentration of chemicals in various test and environmental systems (e.g., humans), based on system and chemical-specific properties. Advances in analytical chemistry, such as passive dosing, solid phase micro-extraction (SPME), gas and liquid chromatography, and mass spectrometry, provide tools that could be applied to in vitro systems to better understand and control in vitro exposure of both the parent chemical and metabolites. Improved quantification of in vitro exposure-response relationships, in combination with better understanding of the physiological mode of action of a chemical, represent better quality input data for use within mechanistic toxicokinetic and physiologically-based pharmacokinetic models. This session will communicate cross-disciplinary advances in the development, evaluation, and application of quantitative tools that help link the external and internal exposures with exposure-response relationships, allowing for a more robust real world translation, application, and acceptance of emerging high-throughput data streams for hazard and risk assessment.

Introduction. Todd Gouin, Unilever, Milton Keynes, United Kingdom.

Dosemetrics in In Vitro Repeated Dosing Toxicity Assays and Other Complex Assays. Nynke Kramer, Utrecht University, Utrecht, Netherlands.

Utilizing Mass Balance Modeling for the Assessment of Internal Exposure in Cell-Based Bioassays. Beate Escher, UFZ-Helmholtz Centre for Environmental Research, Leipzig, Germany.

QVIVE Approaches to Evaluate Interindividual Toxicokinetic Variability. Barbara Wetmore, US EPA, Research Triangle Park, NC.

High-Throughput PBPK: Evaluating EPA’s Open-Source Data and Tools for Dosimetry and Exposure Reconstruction. John Wambaugh, US EPA, Research Triangle Park, NC.

Evaluation of Pharmacokinetic Models for In Vitro to In Vivo Extrapolation (IVIVE) of High-Throughput Toxicity Screening Data. Lisa Sweeney, Naval Medical Research Unit Dayton, Wright Patterson AFB, OH.

MiRNAs As Translational Biomarkers of Kidney Injury

Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Jean-Charles Gautier, Sanofi, Alfortville, France; and Rounak Nassirpour, Momenta Pharmaceuticals Inc., Cambridge, MA.

Endorser(s): Drug Discovery Toxicology Specialty Section
Molecular and Systems Biology Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

Biomarker monitoring for kidney injury remains a challenge in both preclinical and clinical settings. There is a critical need for sensitive, specific, translatable, and non-invasive biomarkers of renal toxicity to diagnose nephron segment specific injury. MicroRNAs (miRNAs) are attractive biomarker candidates for kidney injury because they are stable in urine, are conserved across species, and relatively easy to measure. Additionally, due to their proposed tissue-specific or at least kidney-enriched expression, miRNAs released into the urine could indicate the specific location of cellular damage. Thus, miRNAs may constitute an attractive alternative to proteins as kidney safety biomarkers. Several efforts are currently underway to identify tissue-specific or pathology-specific miRNA patterns for drug-induced kidney injury from urine samples across species in the context of consortia—namely the Health and Environmental Sciences Institute (HESI) and the Predictive Safety Testing Consortium (PSTC). The goal of this symposium is to provide an overview of the methodology and best practices, together with the most recent results obtained to assess cellular specificity of urinary miRNA biomarkers along with identification of cross-species concordance. Information also will be provided on how the miRNA urinary biomarkers compare with other novel kidney protein biomarkers that have already been discovered. The symposium will begin with a detailed background on miRNA biogenesis and function, and how they relate to kidney injury. This will be followed by presentation of original data showing identification of sensitive, specific, and mechanistic miRNAs to detect acute kidney injury and chronic kidney disease in humans. The third presentation will address site specificity aspects relative to kidney injury affecting proximal and distal tubules in rodent models. The fourth presentation will further explore the utility of miRNAs as biomarkers of tubular kidney injury in larger animals. Finally, the fifth presentation will provide recent results obtained on miRNAs as biomarkers of glomerular injury in both rats and non-human primates.

Introduction. Jean-Charles Gautier, Sanofi, Alfortville, France.

Introduction to miRNAs with Emphasis on Kidney Development and Pathophysiology. Christos Argyropoulos, University of New Mexico School of Medicine, Albuquerque, NM.

Urinary miRNA Biomarkers for Kidney Diseases in Humans. Vishal Vaidya, Harvard Medical School, Boston, MA.

Investigation of Urinary miRNAs Associated with Tubular Segment Specific Injury to the Nephron in Rodents. Jean-Charles Gautier, Sanofi, Alfortville, France.

Translation of Tubular Injury Kidney miRNA Biomarkers to Large Mammalian Species. Eric McDuffie, Janssen Research & Development, LLC, San Diego, CA.

Urinary miRNAs as Biomarkers of Glomerular Injury in Rats and Nonhuman Primates. Rounak Nassirpour, Momenta Pharmaceuticals Inc., Cambridge, MA.

Workshop Sessions
Low-Dose Non-Monotonic Responses

Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Suzanne Fitzpatrick, US FDA, College Park, MD; and Michael Dourson, TERA Center, University of Cincinnati, Cincinnati, OH.

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

There is a growing gap and disagreements among scientists regarding the interpretation and relevance of some research findings on low-dose non-monotonic dose response relationships, and how best to use these data for determining human health risk in a regulatory setting. Greater understanding is needed regarding research and data related to low-dose effects and the use of risk-based approaches to evaluate risk using studies finding non-monotonic dose-response curves. This session will address several key issues, including what is meant by low-dose and non-monotonic, identification of critical effect, and the concept of hormesis. The challenge of current epigenetic findings is to determine where in the risk assessment spectrum these effects lie, and whether current risk assessment methods can are adequate to address them.

Introduction. Suzanne Fitzpatrick, US FDA, College Park, MD.

Harmonizing Terminology: Concepts of “Low-Dose” and Non-Monotonic Dose Response in Toxicological Research and Regulatory Science. Sue Yi, Syngenta, Greensboro, NC.

Examples of Discovery Science: Epigenetic Changes That May Impact the Judgment of Critical Effect. Shuk-mei Ho, University of Cincinnati College of Medicine, Cincinnati, OH.

Hormesis: What It Means for Toxicology and Risk Assessment. Edward Calabrese, University of Massachusetts, Amherst, MA.

The Ability of Current Studies to Detect (or Not) Non-Traditional Effects. Alan Boobis, Imperial College, London, United Kingdom.

Strengths and Weaknesses of Low-Dose Observations and Their Relevance to Human Exposures and Risk Assessment. Rita Schoeny, US EPA (Retired), Washington, DC.

Safety or Prediction?  What Is the Future of Regulatory Toxicity Testing?

Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Douglas Keller, Sanofi US LLC, Bridgewater, NJ; and Thomas Hartung, Johns Hopkins University, Baltimore, MD.

Endorser(s): Clinical and Translational Toxicology Specialty Section
Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

In 1944, the US FDA recommended a standard battery of safety pharmacology and toxicity tests for drugs in development, and the earlier passage of the Food, Drug and Cosmetic Act mandated testing of drugs for safety before they were introduced into commerce. This Act and its subsequent changes were largely the result of the Elixir Sulfanilamide and other drug safety tragedies, ushering in the era of standardized toxicity testing in animals that continues to this day. The battery of tests has been updated and expanded in response to emerging experience with novel chemical entities and endpoints of concern.The performance of nonclinical testing in pharmaceutical development has been quite good when considering that the objective is to minimize harm to human volunteers and patients (safety) by identifying potential target organs, and providing a monitoring and exposure framework. Overall, there is a 70–80% negative predictive value for whole animal tests in predicting whether a clinical adverse event will occur or not. However, prediction of specific target organ toxicities is not as robust. Within this framework, the impact of animal testing to inform human safety can be quantitated, and data will be presented for both the discovery and development phases of pharmaceutical research. While testing on animals remains the regulatory requirement for pharmaceuticals, the accumulated knowledge regarding toxicity mechanisms and pathways gathered over the past 40 years could provide the basis for additional information that could streamline the approach for predicting human toxicity with a reduction in animal use. The 2007 NAS report on Toxicity Testing in the 21st Century initiated a major push in the direction of predictive toxicity testing, but how it can be implemented is a subject of debate. Despite the level of enthusiasm for non-animal safety testing, there remains little evidence that this can approach can be confidently implemented to ensure human safety. Nevertheless, the integration of mechanistic and pathway information, along with exposure data (or prediction), into computational models may provide the systems toxicology basis for prediction of effects, in addition to the absence of effects, leading to broader use of these processes in nonclinical research. With successful development and validation of these high-content information processes, the need for extensive guidelines on animal testing may be reduced, instead relying on the biological information gained in vitro and in silico to design targeted in vivo safety testing. Presenters in this session will discuss several aspects of the current drug development paradigm and how animal testing is being used to inform patient safety, efforts to improve toxicity testing with mechanistic data and human cells, and regulatory approaches/implications of a change in paradigm towards more in vitro data and modeling. A 30-minute discussion period will be held at the conclusion of the session.

Introduction. Douglas Keller, Sanofi, Bridgewater, NJ.

The History and Performance of Nonclinical Safety Testing in Pharmaceutical Research and Development. Thomas Jones, Eli Lilly, Indianapolis, IN.

Pre-Development Attrition of Pharmaceuticals: How to Identify the Bad Actors Early. Sherry Ralston, AbbVie, North Chicago, IL.

Nonclinical-Clinical Correlation of Adverse Effects in Pharmaceutical Development. Thomas Monticello, Amgen, Thousand Oaks, CA.

Systems Toxicology: The Final Goal of the Emerging New Approach Methods. Thomas Hartung, Johns Hopkins University, Baltimore, MD.

FDA Efforts to Enhance Safety Testing of Pharmaceuticals. Karen Davis-Bruno, US FDA (CDER), Silver Spring, MD.

Platform Session
  • Particulate Matter and Cardiovascular Impairment

 

5:00 PM to 6:20 PM

Education-Career Development Session
Careers for Toxicologists at Primarily Undergraduate Institutions: Everything You Need to Know About the Job, Hiring Process, and Strategies for Success in Teaching and Research
Education-Career Development | 5:00 PM to 6:20 PM

Chairperson(s): Karen Stine, Auburn University at Montgomery, Montgomery, AL; and Wade Powell, Kenyon College, Gambier, OH.

Endorser(s): Career Resource and Development Committee
Education Committee
Postdoctoral Assembly

Primarily Undergraduate Institutions (PUIs) offer a substantial proportion of the available tenure-track faculty positions in the life sciences. For toxicologists interested in careers that combine research and teaching, a PUI can provide an excellent setting for interdisciplinary research collaborations and the opportunity to introduce undergraduate students to toxicology, in both the classroom and the laboratory. But the process of preparing for, finding, interviewing for, and launching a PUI career differs in terms of strategy and approach from that for a faculty position at a research university, often leaving graduate students and postdoctoral trainees with few role models and limited information on where to start to pursue this career path. This session brings together PUI toxicologists at different career stages to discuss the roles available for toxicologists in traditional academic undergraduate-oriented departments, and to provide advice on how to strategically navigate the competitive job market for tenure track positions at PUIs. Strategies also will be offered for laying the groundwork for success in the critical first few years on the job. The topics discussed will include: (1) a broad overview of the job responsibilities and expectations for PUI tenure-track faculty members; 2) what to expect from the hiring and interview process, and how toxicologists can prepare and present themselves as qualified candidates for PUI positions; (3) strategies, tools, and resources for achieving early successes in both the research and teaching aspects of the job. The session will conclude with a panel discussion, giving postdocs and graduate students considering this career option the opportunity to further explore these topics and others that were not explicitly covered.

Introduction. Karen Stine, Auburn University at Montgomery, Montgomery, AL.

Is a Career at a PUI Right for You? An Overview of Expectations and Opportunities on the Career Path at Primarily Undergraduate Institutions. Karen Stine, Auburn University at Montgomery, Montgomery, AL.

Navigating the Hiring Process. Larissa Williams, Bates College, Lewiston, ME.

Launching and Maintaining a Successful Undergraduate Research Program.Wade Powell, Kenyon College, Gambier, OH.

Teaching Toxicology: Preparing Future Faculty for the Toughest Job You’ll Ever Love. Christine Curran, Northern Kentucky University, Highland Heights, KY.


Wednesday, March 15

9:30 AM to 12:15 PM

Symposium Sessions
Investigating Metabolic Diseases Using Integrated ‘Omics Approaches
Symposium | 9:30 AM to 12:15 PM

Chairperson(s): Samantha Snow, US EPA, Durham, NC; and Jessica Sapiro, University of Arizona, Wayne State University, Clawson, MI.

Endorser(s): Graduate Student Leadership Committee
Molecular and Systems Biology Specialty Section
Postdoctoral Assembly

The combination of the general population living longer, consuming a Western diet rich in saturated fats, and leading a sedentary lifestyle, among other risk factors, has led to the prevalence of metabolic diseases worldwide. For example, it is estimated that 20–25% of the US population have fatty liver disease, and approximately 35% of US adults have metabolic syndrome. Advances in next generation DNA sequencing, RNASeq methods, and novel mass spectrometry tools have provided access to large amounts of data that are able to be deciphered using computational approaches and new statistical methods to generate new hypotheses. Since the building blocks of a cell (DNA, RNA, proteins, metabolites) do not work in isolation and must orchestrate functions across global networks, it is important to utilize these molecular tools to understand biological functions in an entire system. The goal of this symposium is to demonstrate the use of different ‘omics technologies as a tool to decipher possible mechanisms in the development of toxicant exposure-induced metabolic diseases. The first two speakers will present data using toxicogenomics and proteomics tools, respectively, in liver disease. The remaining four speakers will take an integrative approach combining multiple technologies (i.e. redox-based proteomics, transcriptomics, metabolomics, ChIP sequencing, epigenomics, lipidomics) in the setting of metabolic dysfunctions. Using ‘omics applications in these settings will enhance understanding of known molecular mechanisms involved in metabolic diseases, aid in identifying undiscovered pathways underlying adverse health effects, and further develop integrated models to identify risk factors to improve human health.

Introduction. Samantha Snow, US EPA, Durham, NC.

Using Publicly Available Toxicogenomics Data to Identify Absorption, Distribution, Metabolism, and Excretion (ADME) Genes Relevant to Steatosis. Samuel Suarez, US EPA, Durham, NC.

Chronic Alcohol Consumption Alters Mitochondrial Protein Hyperacetylation and Induces Hepatic Oxidative Stress. Mohammed Assiri, University of Colorado Denver Skaggs School of Pharmacy, Denver, CO.

Redox Proteomics for the Detection of Protein Cysteine- and Protein Network-Mediated Mechanisms of Toxicity. Joshua Chandler, Emory University School of Medicine, Atlanta, GA.

Elucidation of Hepatic Metabolic Reprogramming in AhR-Mediated NAFLD through the Integration of Complementary ‘Omic Datasets. Rance Nault, Michigan State University, East Lansing, MI.

Epigenomic and Lipidomic Techniques Used to Identify Non-Alcoholic Fatty Liver in Mice Perinatally Exposed to Bisphenol A and High Fat Diets. Elizabeth Marchlewicz, University of Michigan, Ann Arbor, MI.

Whole-Genome Bisulfite Sequencing Provides Insights into Metabolic Dysfunction in Male Mice Exposed In Utero to Bisphenol A. Suzanne Martos, John Hopkins University, Baltimore, MD.

The Skin As a Metabolic and Immune-Competent Organ: Implications for Pharmaceutical Development and Safety Assessment
Symposium | 9:30 AM to 12:15 PM

Chairperson(s): Yoshiro Saito, MHLW, Kamiyoga, Japan; and Jeanine Bussiere, Amgen, Inc., Thousand Oaks, CA.

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

One of the most important recent advances in the study of cutaneous adverse drug reactions is the understanding that the skin is both a metabolically and immunologically competent organ. Recent mechanistic insights into the ability of the skin to serve as a protective barrier with limited drug biotransformation ability, yet highly active immune function, has provided insight into the biological capability of the skin. While the immune response of the skin to drugs is quite different from that of the liver due to evolutionary conditioning, it frequently occurs in response to various drug classes and manifests as a spectrum of hypersensitivity reactions. The skin is a common site of adverse and even idiosyncratic drug reactions; drug-specific T cells, as well as involvement of an adaptive immune response, appear to be key mechanistic drivers in the scenarios. Association of other factors such as HLA polymorphisms may play a significant role for particular drugs. The purpose of this symposium is to integrate emerging findings into proposed mechanisms of drug metabolism and immunity in the skin that are likely responsible for rashes and other local allergic responses. Although the focus will be on toxicology, current information about genetic associations and novel mechanisms with drugs such as immunotherapies and immune checkpoint inhibitors will be incorporated. The unique biological aspects of the skin, and current issues and implications on drug development, will be discussed. Lastly, current methodologies cannot predict cutaneous adverse drug reactions, and this symposium aims to highlight the recent data to support various mechanisms of drug-induced skin reactions, and the implications for predictive clinical safety.

Introduction. Jeanine Bussiere, Amgen Inc., Thousand Oaks, CA.

Introduction to the Skin as a Target for Immune-Mediated Drug Hypersensitivity (What Are the Issues We’re Seeing in the Clinic/Patients). Yoshiro Saito, MHLW, Kamiyoga, Japan.

The Nevirapine Idiosyncratic Adverse Drug Reaction Model to Understand Cutaneous Immunology and Screening Methods. Amy Sharma, Amgen, Inc., South San Francisco, CA.

Drug Metabolism and Immune Responses in the Skin. Jack Uetrecht, University of Toronto, Toronto, ON, Canada.

Towards the Development of a Novel T Cell Priming Assay to Screen for Skin Sensitization Potential. Dean Naisbitt, University of Liverpool, Liverpool, United Kingdom.

Molecular Interaction between Drugs and HLA/TCR in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Shuen-lu Hung, National Yang-Ming University, Taipei, Taiwan.

Workshop Sessions
3D Cell Platforms to Advance Toxicological Sciences
Workshop | 9:30 AM to 12:15 PM

Chairperson(s): Peggy Guzzie-Peck, Janssen Pharmaceutical Company, Chalfont, PA; and Brian Berridge, GlaxoSmithKline, Research Triange Park, NC.

Endorser(s): Drug Discovery Toxicology Specialty Section
In Vitro and Alternative Methods Specialty Section
Mechanisms Specialty Section

Microphysiological and 3 dimensional (3D) model systems represent a compelling and provocative technological advancement for improving current in vitro static, cell-based models with the potential to more accurately recapitulate organ function, and therefore better predict in vivo toxicological mechanisms, improve compound selection during lead optimization, and enable “personalized toxicology” assessments using patient-derived iPS cells in these systems. Development of these platforms is being funded by DARPA and NIH NCATS, and includes collaboration with pharmaceutical companies with the intent to improve the clinical relevance of translational research and become less reliant on traditional animal model-based studies of safety. However, significant challenges, including qualification/validation of these models and scalability, remain to fully integrate these models in drug development. This workshop will provide insights into the evolution of these platforms with “real world” experiences of the evaluation and use of “organ-on-a-chip” (microphysiological) and organoid (3D) platforms from the pharmaceutical industry perspective. This will include discussions on the need for validation/qualification for specific context of use, examples of applications for screening or investigating the underlying mechanisms of target organ toxicity, and the experiences gained regarding advantages, disadvantages, challenges, and limitations of these platforms.

Microphysiological Systems in Drug Development—Evolving a Paradigm. Lorna Ewart, AstraZeneca, Saffron Walden, United Kingdom.

Organs-on-Chips: 3D Microphysiological Systems for Understanding Mechanism of Action in Drug Discovery and Development. Geraldine Hamilton, Emulate, Inc., Boston, MA.

Human-on-a-Chip Systems for Mechanistic Toxicology Investigations. James Hickman, University of Central Florida, Orlando, FL.

A Human “Kidney-on-a-Chip” Microphysiological System for Assessing Nephrotoxicity. Jonathan Himmelfarb, University of Washington, Seattle, WA.

An Industry Perspective on New and Emerging In Vitro Models for Assessing Hepatotoxicity Risk in Drug Discovery. Will Proctor, Genentech, Inc, South San Francisco, CA.

Challenges and Novel Approaches Evaluating Developmental and Reproductive Toxicity of Biotherapeutics
Workshop | 9:30 AM to 12:15 PM

Chairperson(s): Christopher Bowman, Pfizer, Groton, CT; and Joy Cavagnaro, Access BIO, Boyce, VA.

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

Biotherapeutics can present unique challenges and opportunities for developmental and reproductive safety testing compared to small molecules. The ICH S6 guideline that governs these molecules provides useful principles and detailed guidance when designing safety studies. It states that the specific study design and dosing schedule can be modified for many reasons including: our understanding of species specificity; the nature of the product; the mechanism of action; immunogenicity; pharmacokinetics; pharmacodynamics; and embryo-fetal exposure. Because these considerations can differ widely among different biotherapeutics, unique product-specific studies must be designed not only for the specific characteristics of the molecule, but also the suitability of relevant test systems. For instance, biotherapeutics are often more specific with fewer off-target effects and less ability to pass into the fetus; however, specificity can limit the species available for in vivo testing, as can issues with immunogenicity.  In addition, the target patient population and the risk/benefit balance can impact the amount and extent of safety testing. These presentations will include how ICH S6 and other guidance documents, as well as best practices and recent experience, shape the development of biotherapeutics, including monoclonal antibodies and oligonucleotides. As experience with biotherapeutics is relatively limited compared to small molecules, our knowledge is evolving rapidly. In order to adhere to everchanging regulatory expectations, minimize the use of animals, and improve the performance of developmental and reproductive safety assessment/toxicology, innovative strategies using a combination of animal models and study designs are currently being developed and applied by many companies. The talks in this workshop are designed to summarize the current regulatory landscape and to showcase recent examples addressing these regulatory needs, and answering relevant biological questions associated with safety.

Experience and Challenges Presented by Developmental and Reproductive Toxicology of Biotherapeutics. Christopher Bowman, Pfizer, Inc., Groton, CT.

Alternate Embryofetal Toxicity Assessments of Anti-Cancer Biopharmaceuticals. LaRonda Morford, Eli Lilly, Indianapolis, IN.

Mechanism-Based DART Risk Assessment for Biopharmaceuticals Blocking the PD 1/PD-L1 Pathway. Danuta Herzyk, Merck Research Laboratories, West Point, PA.

Case-by-Case Approach for Assessing DART Risk of Oligonucleotide-Based Therapies. Joy Cavagnaro, Access BIO, Boyce, VA.

Thinking Beyond DART Studies for Risk Assessment of Biotherapeutics. Pedro Del Valle, US FDA-CDER, Silver Spring, MD.

Circulatory Mechanisms Underlying the Systemic Effects of Inhaled Nanoparticles and Complex Combustion Mixtures: Common Pathways for Diverse Toxicants
Workshop | 9:30 AM to 12:15 PM

Chairperson(s): Matthew Campen, University of New Mexico, Albuquerque, NM; and Andrew Ottens, Virginia Commonwealth University, Richmond, VA.

Endorser(s): Cardiovascular Toxicology Specialty Section
Inhalation and Respiratory Specialty Section
Nanotoxicology Specialty Section

Numerous studies highlight that inhaled agents may cause systemic health effects, including cardiovascular, neural, and renal diseases, yet the mechanisms underlying this relationship remain uncertain and highly contentious. Most inhaled xenobiotics are confined to the lung. Inhaled gases are metabolized and particulates are largely removed to the gut by mucociliary action, with only trace concentrations attaining extrapulmonary compartments; however, systemic pathophysiological outcomes of inhaled pollutants are routinely reported. Recent findings show that pulmonary toxicity can cause production and release of novel biomolecules into the blood, with downstream implications for vascular cell activation and extrapulmonary inflammation. Progress in this area provides not only knowledge with which to protect public health from environmental and occupational hazards, but also informs the basis of comorbidities in complex inflammatory clinical conditions, such as metabolic syndrome and cardiorenal disease. This workshop will highlight the latest evidence for lipid, protein, and metabolite modification in response to a diverse array of inhaled agents and the transduced effect, such modifications on the vasculature, brain, and other major organ systems.

Introduction. Matthew Campen, University of New Mexico, Albuquerque, NM.

Evidence for Mechanistic Specificity Driving Pulmonary Particulate Exposure-Induced Cardiovascular Dysfunction. Aaron Erdely, NIOSH, Morgantown, WV.

Nanomaterial Inhalation-Induced Serum Biomarkers Associated with Extrapulmonary Microvascular Dysfunction. Timothy Nurkiewicz, West Virginia University, Morgantown, WV.

Discriminatory Circulating Peptides from Different Inhalation Exposures—Biomarker and Cerebrovascular Implications. Andrew Ottens, Virginia Commonwealth University, Richmond, VA.

Early Endothelial Bioactivity of Serum after Diesel Exhaust Inhalation: A Driver of Latent Impairment in Left Ventricular Pressure in the Heart? Aimen Farraj, US EPA, Research Triangle Park, NC.

Vascular Effects after Exposure to Particles: Systematic Literature Review and Plasma Bioactivity in Carbon Black Exposed ApoE Knockout Mice. Peter Moller, University of Copenhagen, Copenhagen, Denmark.

Increasing the Utility and Acceptance of Chemical Specific Adjustment Factors—International Experience
Workshop | 9:30 AM to 12:15 PM

Chairperson(s): Bette Meek, University of Ottawa, Ottawa, ON, Canada; and Richard Brown, World Health Organization, Geneva, Switzerland.

Endorser(s): Biological Modeling Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

The application of chemical-specific toxicokinetic (TK) or toxicodynamic (TD) data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared to the use of traditional default uncertainty factors. This workshop will summarize the state of the science since the introduction of the WHO/IPCS guidance on chemical-specific adjustment factors (CSAF) in 2005, including the impact of more recent guidance, such as the IPCS guidance on physiologically-based pharmacokinetic modeling (PBPK), and the US EPA guidance on data-derived extrapolation factors. The session also illustrates how CSAF principles complement ongoing research initiatives to develop more innovative testing and assessment strategies based on additionally evolving frameworks to consider Adverse Outcome Pathways/mode of action and combined exposures. A summary of lessons learned from an analysis of approximately 100 case studies identified in the literature and information provided by regulatory agencies globally illustrates the nature of evolution of CSAF in regulatory application.  It also identifies associated challenges, including adequacy of supporting data and assessments in which CSAF were considered but not adopted. Based on this analysis, recommendations for relevant interdisciplinary research and engagement are included.  The session ends with a panel discussion on enhancing uptake of CSAF in chemical risk assessment, including an opportunity for the audience to discuss principal aspects with representatives from key stakeholder groups. Researchers, biological modelers, and risk assessors interested in increasing their knowledge concerning the application of relevant toxicological data to reduce uncertainty associated with interspecies differences or human variability will find this session of interest. The content of the session is also relevant to regulators interested in expanding their knowledge of the scope of application and nature of supporting data considered most valuable in the development of CSAF over the last couple of decades.

Introduction. Richard Brown, World Health Organization, Geneva, Switzerland.

Analysis of International Experience on CSAFs and Potential Path Forward. Bette Meek, University of Ottawa, Ottawa, ON, Canada.

Data-Derived Extrapolation Factors, Modes of Action, and Target Tissues. John Lipscomb, US EPA, Cincinnati, OH.

Harmonization of Chemical-Specific Adjustment Factors (CSAFs) with Other Recent Research Efforts—Adverse Outcome Pathways (AOP) and Mode of Action (MOA) Frameworks. Alan Boobis, Imperial College, London, United Kingdom.

Analysis of the Value and Challenges to Deriving Chemical-Specific Adjustment Factors (CSAF) and Other Data-Derived Factors in Quantitative Risk Assessment. Virunya Bhat, NSF International, Ann Arbor, MI.

Panel Discussion: Enhancing Uptake in Risk Assessment. Mathieu Valcke, Quebec National Institute of Public Health (INSPQ), Montreal, QC, Canada.

Measurement and Prediction of Chemicals in Consumer Products
Workshop | 9:30 AM to 12:15 PM

Chairperson(s): John Wambaugh, US EPA, Research Triangle Park, NC; and Kristin Isaacs, US EPA, Research Triangle Park, NC.

Endorser(s): Mixtures Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

In many cases, no exposure data are available for placing possible chemical hazard within a relevant human exposure context. The aim of this workshop is to bring experts from industry, academia, and government together to discuss existing and emerging methods for characterizing chemicals in various categories of consumer products (e.g., cosmetics, cleaning products, building materials, and food contact materials). The presence of chemicals in such “near field” sources has been shown to be a key driver of high exposure levels in Centers for Disease Control (CDC) National Health and Nutrition Survey (NHANES) biomonitoring data. Information on chemical constituents of products, while only a prerequisite, provides heuristics for estimating human exposure. New high-throughput measurement strategies that combine high-resolution mass spectrometry with chemo-informatics data could enable rapid forensic analysis of chemicals present in these products. In addition, government requirements for product testing and new industry initiatives are providing additional inventories of chemicals present in products due to either intentional inclusion or contamination. These new data sources, in concert with data-driven or mechanistic modeling approaches, can elucidate potential human exposures to thousands of commercial chemicals and reduce uncertainty in modeling approaches. For example, new models have been developed to predict from chemical structure the probable functional roles in products where that information is unavailable. The new data can also provide methods to address specific case studies on chemicals in imported products or products manufactured from recycled materials. Although thousands of chemicals have undergone high-throughput screening for bioactivity as a surrogate for hazard, corollary approaches for estimating exposure are sorely needed to understand potential risks. The first talk in this session will briefly summarize the current state of the field, including the integration and linkage of exposure information with toxicological information in support of risk-based chemical evaluation, and the current need for new information on consumer products. This presenter will then describe new data sources for identifying markers of potential chemical exposure. The next three presentations will address interpreting these and other data in terms of real world human exposures, respectively, from the academic, industry, and regulatory points of view. The final presenter, from the Consumer Product Safety Commission, will address the use of exposure information in consumer product risk assessment and the need to address emerging consumer technologies. Speakers will discuss objectives, approaches, technologies, knowledge gaps, and suggestions for future research; a panel discussion will follow the concluding presentation. This workshop will be of high interest to a broad audience interested in the assessment of the safety of both individual chemicals and mixtures that result from consumer product exposures. Presenters will consider: What is the potential for new rapid forensic measurement techniques for characterizing substances in consumer products (formulations, articles, building materials, food contact materials)?  How can modeling approaches that consider chemical structure and/or chemical use information add value to rapid forensic measurement data?  How should consumer product chemicals be categorized in terms of their use or properties for informing read-across in terms of exposure pathways and sources?  What efforts exist or are being initiated to manage, inventory, or quantify chemicals used in products from manufacturing source through supply chain to finished product?  How can consumer product chemical inventories (both ingredients and contaminants) inform aggregate or cumulative exposure-based risk assessments?  Ultimately, how can improved exposure estimates for chemicals in consumer products be integrated with different types of toxicological information to support frameworks for risk-based chemical evaluation and decision-making?

Introduction. John Wambaugh, US EPA, Research Triangle Park, NC.

Consumer Product Data from the EPA’s Exposure Forecasting (ExpoCast) Project. John Wambaugh, US EPA, Research Triangle Park, NC.

Integrated Model Framework for Assessing Exposure to Consumer Products. Deborah Bennett, University of California, Davis, Davis, CA.

Aggregate Exposure Assessment for the Safety Evaluation of Fragrance Materials. Cian O’Mahony, Creme Global, Dublin, Ireland.

Prediction of Chemical Function: Model Development and Application. Kristin Isaacs, US EPA, Research Triangle Park, NC.

US Consumer Product Safety Commission Approaches to Estimating Chemical Exposures from Consumer Products. Treye Thomas, US Consumer Product Safety Commission, Bethesda, MD.


 

9:30 AM to 12:45 PM

Poster Sessions
  • Air Pollution
  • Air Pollution: Particulate Matter
  • Animal Models
  • Clinical and Translational Toxicology
  • Developmental Neurotoxicity
  • Disposition/Pharmacokinetics
  • Food Safety and Nutrition
  • Liver 1: Mechanisms and Translational Biomarkers
  • Liver 2: Mechanisms and Translational Biomarkers
  • Nanotoxicology: Carbon-Based Nanomaterials
  • Natural Products
  • Persistent Organic Pollutants
  • Pesticides Respiratory Toxicology

 

12:30 PM to 1:50 PM

Roundtable Sessions
Designing a Carcinogenic Mode-of-Action Research Program Useful for Regulatory Decision Making: Challenges and Lessons Learned
Roundtable | 12:30 PM to 1:50 PM

Chairperson(s): James Klaunig, Indiana University, Bloomington, IN; and Angela Lynch, ToxPlus Consulting, Haymarket, VA.

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

In 2001, the World Health Organization’s International Programme on Chemical Safety (IPCS) published the Conceptual Framework for evaluating an (animal) Mode of Action (MOA) for Chemical Carcinogenesis. The framework provided an approach to principles commonly used for evaluating mode of action, and outlined elements to be considered when deciding whether available experimental data support a particular mode of action. In 2006, the document was updated to include a Framework for Analyzing the Relevance of a Cancer MOA for Humans. In addition, the US EPA published a framework for determining a mutagenic mode of action for carcinogenicity using the 2005 Guidelines for Carcinogen Risk Assessment and supplemental guidance for assessing susceptibility from early-life exposures to carcinogens. The International Agency for the Research on Cancer (IARC) identified and published determination of human relevancy criteria for a-2 urinary globulin (a2u) MOA for male-specific rat kidney tumors. The US EPA and NTP ostensibly follow IARC’s lead when evaluating chemicals for this particular MOA. However, criteria and guidance for collecting and interpreting MOA data from authorities for other genotoxic and epigenetic MOA are limited. Currently no validated guideline studies or guidance from regulatory authorities are available for MOA research design. The lack of such information creates scientific challenges in initiating MOA research programs that lead to data useful to make regulatory decisions, and can lead to the inefficient use of research funds and animals. This session explores the challenges of generating MOA data deemed acceptable by regulatory authorities to determine whether experimentally induced genotoxic or epigenetic carcinogenesis is relevant to humans. The speakers and invited panelists will participate in a discussion on utilization of MOA in regulatory assessment. Questions for the panel will include those generated from the audience, as well as the following: What additional guidance from regulatory agencies can be provided to help define the extent of MOA research necessary to address human relevancy? How much MOA data is enough?  Is there a point at which enough data exist to make a regulatory decision about human cancer risk?  And, how should epidemiology data, and what types of epidemiology data, be considered in the MOA framework?

The IPCS Framework and How It Is Used to Initiate a MOA Research Plan. Angela Lynch, ToxPlus Consulting, Haymarket, VA.

Current Status and Regulatory Challenges for Ongoing CYP 2F2 MOA Research. George Cruzan, Tox Works, Bridgeton, NJ.

Evaluation of Modes of Action for Rodent Liver Tumor Formation by CAR and PPARα Activators. Brian Lake, CXR Biosciences, Dundee, United Kingdom.

Regulatory Perspective: How Do Regulatory Authorities Currently Utilize MOA Data to Make Decisions about Human Relevancy? Anna Lowit, US EPA, Arlington, VA.

Panel Discussion/Q&A. James Klaunig, Indiana University, Bloomington, IN.

Herbo-Metallic Mixtures in Traditional Medicines
Roundtable | 12:30 PM to 1:50 PM

Chairperson(s): J. Christopher States, University of Louisville, Louisville, KY; and Jie Liu, Zunyi Medical College, Zunyi, China.

Endorser(s): American Association of Chinese in Toxicology Special Interest Group
Metals Specialty Section
Mixtures Specialty Section

Metals are ubiquitous in our lives; people are exposed to metals through the food we eat, the water we drink, the polluted air we breathe, and the medicines we take. Some metals are essential to human health such as zinc (Zn), copper (Cu), and iron (Fe), while other metals are of serious toxicological concern such as lead (Pb), cadmium (Cd), mercury (Hg), and the metalloid arsenic (As). Medicinal metals include platinum (Pt)-derived anticancer drugs, lithium carbonate as antimanics, aluminum hydroxide as antacids, and herbo-metallic mixtures with a long history of use in traditional medicines. In traditional medicines, metals often undergo specific processing procedures (e.g., heating, grinding). The addition of “processed” metals to herbal mixtures is thought to assist the efficacy, or reduce toxicity, in a given remedy. The goal of this session is to bring to light the history of use, toxicological consequences, and risk assessment considerations for metals in complex botanical mixtures common to traditional medicines around the world. We will start with historical aspects of arsenic-containing mixtures as cancer chemotherapeutics, which are still used today.  Next, we will discuss progress in assessing complex botanical mixtures for toxicity, and incorporating comparisons of biological responses in addition to chemistry in evaluating mixture efficacy and toxicity. Finally, we will discuss the current status of herbo-metal mixtures used in Ayurverdic medicines, Tibetan medicines, and Chinese medicines. Throughout this discussion, we will consider how metals in traditional medicines differ from nominally related metals in the environment based on their interactions with the botanical matrix, effects of processing, and differences in disposition. The rationale for including metals in traditional remedies, and their interactions with drugs, remains a topic of great interest. The beneficial effects of herbo-metallic mixtures often go hand-in-hand with toxicity, and appropriate evaluation of herbo-metallic mixtures is needed. Presentations will highlight the latest science on traditional medicines and complex botanical mixtures and discuss areas that require further investigation. Expected outcomes: 1) herbo-metallic mixtures, rather than individual pure compounds, should be a research strategy for traditional medicines; 2) metals used in traditional medicines are different from environmental pollutants, for example, HgCl2 and MeHg, and are never included in traditional remedies; thus, chemical form of metals matters; 3) the disposition, pharmacology, toxicology of herbo-metallic mixtures should be considered to balance the benefits and risks.

Introduction. J. Christopher States, University of Louisville, Louisville, KY.

Arsenic in Cancer Chemotherapy: A Historical Perspective. J. Christopher States, University of Louisville, Louisville, KY.

Understanding Chemical and Biological Similarity across Complex Mixtures in Hazard Characterization of Botanical Dietary Supplements. Cynthia Rider, NIEHS-NTP, Research Triangle Park, NC.

Clinical and Toxicological Aspects of Ayurvedic Medicinal Remedies with High Levels of Heavy Metals. Madhusudan Soni, Soni & Associates Inc, Vero Beach, FL.

Traditional Tibetan Medicine Zuotai: Mercury Chemical Speciation Transformation in Gastro-Intestinal Tract. Lixin Wei, Chinese Academy of Sciences-CAS, Xining, China.

Chemical Forms of Metals Are a Major Determinant of Metal Toxicity and Therapeutic Effects in Traditional Medicines. Jie Liu, Zunyi Medical College, Zunyi, China.

Informational Sessions
Communicating Toxicology to the Public
Informational | 12:30 PM to 1:50 PM

Chairperson(s): Philip Wexler, National Library of Medicine, Bethesda, MD; and Sidharta Ray, Manchester University College of Pharmacy, Fort Wayne, IN.

Endorser(s): Education Committee
Ethical, Legal, and Social Issues Specialty Section
Specialty Section Collaboration and Communication Group

The general public is expressing an increasing need and desire to learn about scientific issues affecting their daily lives. At the same time, scientists are recognizing the importance of making their work engaging and understandable to general audiences. Many educational efforts are aimed at training toxicologists and the K–12 community about toxicological principles. The non-homogenous general public, though, tends to be an overlooked audience. Much of what they learn these days about toxicology is “catch as catch can” via not always reliable, and sometimes misleading, sources. Print and broadcast media, the Internet, and social networking offer mixed results tools for finding credible news and information about chemical hazards and safety. Efforts to enhance the public’s understanding of science, toxicology included, may be considered among the last frontiers of science communication, which goes hand in hand with science education. Innovative approaches are beginning to appear to allow toxicologists to communicate more effectively about the nature and impact of their work to non-specialists with differing levels of existing technical knowledge, public officials, the media, potential funders, and colleagues in other disciplines. This informational session will explore a variety of recent approaches taken to inform the public about toxicology and chemical risk. The Toxicology Education Foundation (TEF) is an organization which recognized, early on, the importance of addressing public needs and concerns. To that end, a TEF presentation will address their new project of developing a series of YouTube videos to reach audiences with concise and practical information related to chemical safety and risk. A second talk will describe efforts by the chemical industry vis a vis the American Chemistry Council, to relate safety, hazard, and risk to the public. The Agency for Toxic Substances and Disease Registry has recently released a unique eBook, The Story of Health, which is the topic of another presentation, which takes a multi-factorial approach, including environmental and toxicological determinants, to explaining disease causation. Following this, a presentation will focus on Toxipedia, a Wiki-based online site, offering an encyclopedic approach to toxicological topics, including science, risk, hazards, and regulations, for general audiences. The final talk will describe a series of programs held in conjunction with previous SOT Annual Meetings to bring toxicology to the public in less conventional, non-academic settings, including public affairs institutes, public libraries, science cafes, department stores, and pubs. This session will enable attendees to gain a better grasp of how toxicological research and, more generally, information concerning potential chemical hazards, is perceived by various public audiences. The target audience for the session itself encompasses toxicologists of various persuasions seeking approaches that can be used to make their research clear and engaging to people with limited science and technical backgrounds. It cuts across and should be of value to a broad array of toxicological sub-disciplines. Finally, it will encourage more toxicologists to communicate their own work and related information on toxics in a scientifically accurate and understandable fashion, and describe existing efforts and tools which can serve as models for presenting similar information to the public.

Introduction. Philip Wexler, National Library of Medicine, Bethesda, MD.

The Toxicology Education Foundation: Enabling Public Interest with YouTube. Jeffrey Jenkins, Oregon State University, Corvallis, OR.

Communicating Information on Chemical Safety. Nancy Beck, American Chemistry Council, Washington, DC.

Presenting Environmental Health Content to a Variety of Audiences Using Case Stories. Brian Tencza, Agency for Toxic Substances and Disease Registry, Atlanta, GA.

Toxipedia: An Online Toxicology Encyclopedia for the Public. Steven Gilbert, Institute of Neurotoxicology & Neurological Disorders, Seattle, WA.

Opportunities for Unconventional Public Engagement about Toxicology. Philip Wexler, National Library of Medicine, Bethesda, MD.

Data Science to Generate Toxicity Signatures
Informational | 12:30 PM to 1:50 PM

Chairperson(s): Jane Bai, US FDA, Silver Spring, MD; and Ravi Iyengar, Icahn School of Medicine at Mount Sinai, New York, NY.

Endorser(s): Cardiovascular Toxicology Specialty Section

Adverse events associated with the use of therapeutically efficacious drugs remain a serious problem. Rare adverse events are generally identified in animal and clinical studies, both of which are expensive. It would be useful and cost-effective if there were cell-based signatures that could predict toxicity in animal models and humans. LINCS (Library of Integrated Network Cellular Signatures), a NIH Common fund program, has funded DToxS (Drug Toxicity Signature Generation Center) center (www.dtoxs.org) to develop cellular signatures for drug toxicity. The center has been operational since September 2014. The DToxS center is currently focused on experimentally-gathering transcriptomic and proteomic signatures of cancer drugs that can cause cardiac adverse events. Future studies include generation of signatures for hepatotoxicity and peripheral neuropathy. For cancer drugs, the DtoxS center uses primary cardiomyocytes differentiated from induced pluripotent stem cells from healthy human subjects. Data are gathered using mRNASeq and discovery-based proteomics. Both the raw and the processed data are posted on the website as they are generated and are freely available. All released data pass extensive quality control measures, and are accompanied by metadata as well as SOPs. Users can download both high-throughput molecular data and the results of initial computational analyses, such as ranked lists of differentially expressed genes/proteins, relevant cellular subnetworks, and enriched cellular processes. The molecular signatures are linked to clinical data on adverse event propensity using data from FAERS and academic medical center EMRs. The raw and processed data and the signature lists are freely available for further analyses. The purpose of the session will be to introduce and familiarize researchers in toxicology with the large-scale data that is being gathered by the DToxS center. The session will describe currently available datasets for cardiotoxicity associated with cancer drugs as a prototype, and how these can be accessed and downloaded. The session will also take the audience though the types of computational analyses that can be performed on these data sets with publicly available computational tools to identify differences between drugs and between drug responses in individuals. As these freely available datasets analyses can be downloaded and used for further analyses, this session will conclude with a discussion of how the resource can be best exploited for the development of mechanistic research projects.

Translational Data Science for Predictive Assessment of Cardiac Contractility-Related Toxicity. Jane Bai, US FDA, Silver Spring, MD.

Transcriptomics Data and Signatures for Protein Kinase Inhibitor Responses of Cardiomyocytes. Marc Birtwistle, Icahn School of Medicine at Mount Sinai, New York, NY.

Exploiting Cellular Data to Infer Toxicity Mechanisms. Shankar Subramaniam, University of California at San Diego, San Diego, CA.

Ensuring Rigor and Reproducibility of Drug Toxicity Signatures. Ka Yee Yeung-Rhee, Institute of Technology at the University of Washington, Seattle WA.

Historical Highlights Session
NIEHS Superfund Research Program: A History of Cutting-Edge Science and Innovative Technologies
Historical Highlights | 12:30 PM to 1:50 PM

Chairperson(s): Danielle Carlin, NIEHS, Research Triangle Park, NC; and Rebecca Fry, University of North Carolina-Chapel Hill, Chapel Hill, NC.

Endorser(s): Metals Specialty Section
Mixtures Specialty Section
Molecular and Systems Biology Specialty Section

The National Institute of Environmental Health Sciences (NIEHS) Superfund Hazardous Substance Basic Research and Training Program (SRP) is a critical player in the national effort to protect human health and the environment from hazardous substances. The Program funds a wide range of university-based and small business research to address public health concerns related to hazardous substances in the environment. SRP takes a problem solving, solution-oriented approach that combines laboratory, field, and population-based studies to improve our understanding of and minimize the health effects associated with exposures to contaminants. Created by the same legislative framework that created the US Environmental Protections Agency’s (US EPA) Superfund hazardous waste remediation program and the Center for Disease Control and Prevention’s Agency for Toxic Substances and Disease Registry (ATSDR), the SRP’s role is to support science-based decision making by elucidating the basic principles underlying hazardous substance toxicity and risk. SRP-funded researchers are focusing on the health effects of individual contaminants, as well as complex chemical mixtures, determining relevant chemical exposures, identifying developmental windows of susceptibility, analyzing patterns in toxicologic data to assess risks to human health presented by hazardous substances, and development of tools to facilitate assessment of exposure and mitigation of toxicity. The Program’s central goal is to understand and break the link between chemical exposure and disease. This session will highlight the scientific findings from the SRP’s extramural community over the past 30 years, as well as ongoing state-of-the-art science, which includes a focus on various chemical classes (e.g. metals, PCBs, PAHs), mixtures, and emerging contaminants. We will also discuss future scientific areas of interest to the Program and how the Program will continue to support the understanding of hazardous substance toxicity and risk to exposure to hazardous substances and relevant mixtures.

NIEHS Superfund Research Program: A History of Cutting-Edge Science and Innovative Technologies. William Suk, NIEHS, Research Triangle Park, NC.

Systems Toxicology Approaches to Understand the Harms of Toxic Metals in Vulnerable Populations. Rebecca Fry, University of North Carolina-Chapel Hill, Chapel Hill, NC.

Integrating New Research Models to Understand and Mitigate the Adverse Effects of PAH Mixtures. Robert Tanguay, Oregon State University, Corvallis, OR.

Novel Methods for Detection and Prevention of Emerging Superfund Contaminants. Stephania Cormier, University of Tennessee Health Sciences Center, Memphis, TN.

Emerging Prevention Paradigms with Nutrition: The Impact of the NIEHS SRP. Bernhard Hennig, University of Kentucky, Lexington, KY.

 

1:15 PM to 4:30 PM

Poster Sessions
  • Alternatives to Mammalian Models I: Liver, Ocular, and Skin Alternatives
  • Alternatives to Mammalian Models II
  • Autoimmunity/Hypersensitivity
  • Cardiovascular and Hemodynamics toxicity
  • Ecotoxicology
  • Education, Ethical, Legal, and Social Issues
  • General Toxicology
  • Inflammation in Disease
  • Inflammation: Methods and Mechanisms
  • Nanotoxicology: General
  • Neurotoxicology: Pesticides
  • Quantitative Systems Toxicology Risk Assessment Strategies and Applications

 

2:00 PM to 4:45 PM

Symposium Sessions
Enhancing the Clinical Benefit of Cancer Drugs: Toxicity As a Therapeutic Target
Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Syril Pettit, HESI, Washington, DC; and Brian Berridge, GlaxoSmithKline, King of Prussia, PA.

Endorser(s): Cardiovascular Toxicology Specialty Section
Clinical and Translational Toxicology Specialty Section
Immunotoxicology Specialty Section

Recent advances in cancer drug therapy have significantly contributed to survivability in cancer patients.  Clinical protocols that are increasingly including more targeted therapies, or leveraging the patient’s own immune response, are benefiting patients that previously had very little hope.  But, cancer treatment has been an area where we have tolerated toxic liabilities (both acute and delayed effects) more than any other class of pharmaceuticals.  These liabilities include cardiovascular toxicity, peripheral nerve deficits, cognitive dysfunction, respiratory disease, and immune-inflammatory reactions. These liabilities come at incredible cost to the patients (with respect to quality of life as well as adherence to treatment) and the healthcare system overall.  These effects are not limited to a single drug class, and are associated with both traditional oncologic therapies as well as novel targeted therapies.  The translational toxicology research community has the opportunity to benefit patients and survivors with generation of translational data on biomarkers of toxicity, by defining mechanism of action, and investigating novel dosing and protective strategies.  This session will provide preclinical, clinical, translational, and patient perspectives on the need to address those liabilities to not only increase survivability, but also improve post-cancer quality of life.

Introduction. Syril Pettit, HESI, Washington, DC.

An Overview of Cancer Drug-Related Toxicity. Charles Cleeland, MD Anderson Cancer Center, Houston, TX.

Identifying and Mitigating the Toxic Effects of Novel Immunotherapies. Laura Cappelli, Johns Hopkins School of Medicine, Baltimore, MD.

Balancing Toxicity and Efficacy: Perspective from a Researcher Who Is Also a Patient. Jamie Holloway, Independent Consultant, Arlington, VA.

There Are Solutions: Efforts to Mitigate and Manage Cancer Drug-Related Cardiotoxicities. Steven Lipshultz, Children’s Hospital of Michigan, Detroit, MI.

Opportunities, Hurdles, and Networks to Spur Research on Toxicity As a Therapeutic Target for Cancer Drugs. Syril Pettit, HESI, Washington, DC.

Increasing Confidence in Safety Assessment Decisions: The Inclusion of Metabolism in Toxicity Testing Strategies
Symposium | 2:00 PM to 4:45 PM

Chairperson(s): Miyoung Yoon, ScitoVation, LLC, Research Triangle Park, NC; and Stephen Ferguson, NTP/NIEHS, Research Triangle Park, NC.

Endorser(s): Biological Modeling Specialty Section
In Vitro and Alternative Methods Specialty Section
Risk Assessment Specialty Section

Numerous international research programs are attempting to improve efficiency and human relevance in chemical safety assessments. A fundamental change occurring in toxicity testing to this end is the use of human cell-based in vitro assays, in conjunction with emerging predictive computational tools, to move away from animal-based risk assessment strategies and toward safety assessments. Available in vitro and in silico methods are emerging, but require considerable improvements to increase predictivity of in vivo effects in response to chemical exposures. In addition, accurate characterization of the chemical exposure profiles in culture models is critical to make risk-based decisions using these new in vitro tools beyond hazard characterization. Biokinetics, metabolism in particular, has to be addressed to increase our confidence in risk-based decisions using animal-free, cell based toxicity assays on potential risks of chemical exposure to human safety beyond hazard characterization. This session will highlight the importance of considering metabolism and biokinetics and discuss the strategies to best incorporate kinetics and metabolism into the in vitro-based safety testing framework. The first presentation will cover the recent advances in in vitro hepatocyte culture and computational modeling approaches to improve the predictivity of human metabolism. A few applications and examples of these advanced in vitro and in silico tools will be presented in the context of human safety assessment. The importance of addressing metabolite-mediated effects to ensure confidence in high-throughput screening-based prioritization will be demonstrated through a case study on the application of in silico molecular tools to complement in vitro screening assays. The case of the estrogen receptor binding and potency assays will be presented. An update will follow on the research efforts currently being made in the Tox21 program to address xenobiotic metabolism under higher throughput assay platforms. The audience will then have an opportunity to learn about the case study results highlighting the importance of considering metabolism to improve the predictive power of in vitro toxicity assays, as well as the work-flow of using metabolism and biokinetics in the integrated testing strategies. Critical needs and challenges in integrating biokinetics and biodynamics in repeated exposure studies in vitro will be presented based on the outcomes from recent EU research efforts.

Predicting Human Metabolism Using a Combination of In Vitro Experimental and Computational Modeling Approaches to Support Chemical Safety Decisions. Miyoung Yoon, ScitoVation, LLC, Research Triangle Park, NC.

Complementing In Vitro Screening Assays with In Silico Molecular Chemistry Tools to Examine Potential In Vivo Metabolite-Mediated Effects. Cecilia (Yu-Mei) Tan, US EPA, Research Triangle Park, NC.

Incorporating Improved Physiological Relevance, Xenobiotic Metabolism, and Data-Rich Assay Approaches into Tox21 (Phase III). Stephen Ferguson, NTP, NIEHS, Research Triangle Park, NC.

In Silico Predictions and In Vitro Experimental Results of Toxicity as Part of an Integrated Testing Strategy. Bas Blaauboer, Utrecht University, IRAS, Utrecht, Netherlands.

Consideration of Biokinetics and Metabolism in Repeated Dosing In Vitro Toxicity Assays. Emanuela Testai, Istituto Superiore di Sanità, Rome, Italy.

Novel In Vitro and In Silico Platforms for Modeling Developmental and Reproductive Toxicity
Symposium | Innovations in Toxicological Sciences Session | 2:00 PM to 4:45 PM

Chairperson(s): Thomas Knudsen, US EPA, Research Triangle Park, NC; and Nicole Kleinstreuer, NIEHS, Research Triangle Park, NC.

Endorser(s): Biological Modeling Specialty Section
In Vitro and Alternative Methods Specialty Section
Reproductive and Developmental Toxicology Specialty Section

Recent progress in systems toxicology and synthetic biology have paved the way to new thinking about in vitro/in silico modeling of developmental processes and toxicities, both for embryological and reproductive impacts. Novel in vitro platforms, such as 3D organotypic culture models, engineered microscale tissues, and complex microphysiological systems (MPS), together with computational models and computer simulation of tissue dynamics, lend themselves to integrated testing strategies for predictive toxicology. As these methodologies continue to evolve, for the purposes of effects assessment, they must be integrally tied to maternal/fetal physiology and toxicity of the developing individual across early life stage transitions, from fertilization to birth, puberty, and beyond. This symposium will focus on how the novel technology platforms can help now and in the future, with in vitro/in silico modeling of complex biological systems for developmental and reproductive toxicity issues, and translating systems models into integrative testing strategies. The symposium is based on three main organizing principles: (1) that novel in vitro platforms with human cells configured in nascent tissue architectures with native microenvironments yield mechanistic understanding of developmental and reproductive impacts of drug/chemical exposures; (2) that novel in silico platforms with high-throughput screening (HTS) data, biological models of complex adaptive systems, and chemical structure information, yields predictive understanding of developmental and reproductive impacts of drug/chemical exposures; and (3) that a combination of technologies is necessary for analytical (to understand) and theoretical (to predict) application for probing the relevant biological processes and toxicological mechanisms to inform safety assessments. After a brief introduction, the first two presentations will cover reproductive issues: a novel MPS to recreate the ovarian axis in vitro using iPSC technology in a linked microfluidics environment that provides a 3-dimensional support system mimicking the complexity of human in vivo physiology; and pathway-based computational models that integrate HTS data from orthogonal assays to measure nuclear hormone receptor pathways and performance-based approaches to appropriately validate them for regulatory decision-making. The second two presentations will cover embryological issues: a novel in vitro platform (Brain MAPs) designed and synthetically engineered to instruct morphogenesis from human neural stem cells (hNSCs) and print microscale arrays of organoids for phenotype-specific, quantitative high-throughput developmental neurotoxicity studies; and computer models structured to simulate complex cell signaling networks in a heuristic framework that translates ToxCast HTS data into predictions of developmental toxicity. The final presentation will address the integration of results from novel in vitro/in silico models with chemical/exposure information for developmental and reproductive safety assessment. Models combining in vitro data from synthetic human tissue architectures, coupled with in silico models inspired by biological understanding from animal studies, yield mechanistic understanding of developmental and reproductive impacts of drug/chemical exposures. A combination of in vitro/in silico approaches is necessary for predictive understanding of toxicological processes and informing safety assessments.

Introduction. Thomas Knudsen, US EPA, Research Triangle Park, NC.

Microphysiological Modeling of the Female Reproductive Tract. Shuo Xiao, University of South Carolina, Columbia, SC.

Pathway Based Models to Predict Developmental and Reproductive Toxicities. Nicole Kleinstreuer, NIEHS/NTP/NICEATM, Research Triangle Park, NC.

Brain Model for Analysis of Developmental Pathways. Randolph Ashton, University of Wisconsin, Madison, WI.

Computer Simulation of Developmental Processes and Toxicities. Thomas Knudsen, US EPA, Research Triangle Park, NC.

Combining Cheminformatics and In Vitro/In Silico Models for Developmental and Reproductive Toxicity Assessment. George Daston, Procter & Gamble Co., Cincinnati, OH.

Workshop Sessions
Anesthetics, Analgesics, and Ionizing Radiation: Balancing Utility and Safety in Pregnant Women, Infants, and Children
Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Henrik Viberg, Uppsala University, Uppsala, Sweden; and William Slikker, US FDA-NCTR, Jefferson, AR.

Endorser(s): Clinical and Translational Toxicology Specialty Section
Neurotoxicology Specialty Section
Specialty Section Collaboration and Communication Group

Use of anesthesia, analgesia, and ionizing radiation (IR) in pregnant women, neonates, toddlers, and children is sometimes necessary therapeutically, surgically, or to relieve pain and/or painful procedures. Despite safety concerns, to refrain from use of these agents may be unethical, inhumane, and potentially harmful to normal development. Yet, accumulating data from animal models have recently shown that exposure to anesthetic and analgesic agents, such as ketamine, sevoflurane, and paracetamol, during critical periods of development causes neurotoxicity, manifested as neuronal cell death, synaptic remodeling, and altered morphology of the developing brain, and subsequently result in long-term deleterious effects, including cognitive deficits. Possible mechanisms of action for these functional effects includes changes in several different systems, for example GABAergic neurons, NMDA-receptors, endocannabinoid system, and neurotrophic factors, and in different parts of the brain, e.g. hippocampus and cerebral cortex. Despite these agents being physically and chemically different, developmental neurotoxic effects have similarities. Also, IR has been proposed to induce developmental neurotoxic effects, during early postnatal development, both in humans and in experimental animals. These behavioral effects are similar to those induced by anesthesia and analgesia, when exposure occurs during a critical period of perinatal life. Furthermore, IR can interact with ketamine in the induction of developmental neurotoxicity, making it important to find ways to prevent these effects, and some compounds, e.g. melanin and clonidine, have been put forward to have these effects. Because of the necessity of anesthetics and analgesics, millions of children are exposed to these agents on an annual basis worldwide, with 5 million episodes of anesthesia yearly in the United States alone. The results from animal models are corroborated by epidemiological studies indicating neurotoxic effects, including delayed motor development and increased risk for developing attention-deficit/hyperactivity disorder (ADHD)-like behavior problems or hyperkinetic disorders (HKDs) in children, after developmental exposure to the analgesic agent paracetamol (acetaminophen). This is a multidisciplinary session and attendees will gain knowledge about functional defects observed in humans and experimental animals, as well as possible mechanisms of action, common and specific, behind these developmentally induced disorders. Fundamental researchers, clinicians, and regulators will be informed of the full spectrum of anesthetic/analgesic-induced developmental neurotoxic effects in animal models, and early data gathered from epidemiological studies in children.

Introduction. Henrik Viberg, Uppsala University, Uppsala, Sweden.

Epidemiological and Experimental Findings Concerning Developmental Exposure to Anesthetic Agents. Vesna Jevtovic-Todorovic, University of Colorado School of Medicine, Denver, CO.

Developmental Neurotoxic Effects of Paracetamol (Acetaminophen) in an Animal Model. Gaetan Philippot, Uppsala University, Uppsala, Sweden.

Interaction between the Anesthetic Agent Ketamine and Gamma-Radiation Exacerbate Neurotoxicological Defects. Sonja Buratovic, Uppsala University, Uppsala, Sweden.

Pathways to Anesthetic-Induced Neurotoxicity and Prevention in the Developing Nervous System. William Slikker, US FDA-NCTR, Jefferson, AR.

Panel Discussion. Thomas Jones, Eli Lilly and Company, Indianapolis, IN.

Data Standardization Across ‘Omic Platforms in Regulatory Toxicology
Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Weida Tong, US FDA-NCTR, Jefferson, AR; and Timothy Gant, Centre for Radiation, Chemical and Environmental Effects, Oxfordshire, United Kingdom.

Endorser(s): Molecular and Systems Biology Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

Molecular events associated with the effects of chemical, biological, and physical agents on biological systems can be globally determined using ‘omic high-throughput technologies. These technologies are playing a major role in the generation of new knowledge and understanding in mechanisms of toxicity. However, use and application of these technologies has been slower in hazard identification and regulatory risk assessment. This slow uptake has been associated with technical issues of data quality and reproducibility. Although such challenges still exist, the main challenge now is achieving consistency in data processing and biological interpretation. Consistent methods and agreed frameworks and processes for collection/curating, processing, analyzing, and interpreting data are paramount to support regulatory assessments. Consensus amongst stakeholders including industry, academia, and regulatory agencies on this issue will provide guidance and confidence on how ‘omic technologies can be applied in regulatory decision-making.  To that end, this workshop will propose transparent frameworks and suitable processes to provide a baseline and confidence on the application of ‘omics in regulatory decision making, with a specific emphasis on data analysis and interpretation in risk assessment. Challenges and issues in the regulatory application of ‘omic data will be addressed in the context of status and future direction for developing objective protocols for the analysis, interpretation, and reporting of ‘omic results. The presenters will give their views on a path forward with time for the audience to respond and discuss. The session will be of interest to bioinformaticians, research toxicologists, and regulators alike, and will welcome input from all of these sectors.

Introduction. Weida Tong, US FDA-NCTR, Jefferson, AR.

Towards Developing a Framework for Using New Technologies in Next Generation Risk Assessment and Decision Making. Alan Poole, ECETOC, Brussels, Belgium.

Quality Assurance of ‘Omics Technologies Considering GLP-Like Requirements. Ben Ravenzwaay, BASF SE, Ludwigshafen, Germany.

Transcriptomics Data Analysis: Lessons Learned from the FDA-Led Community-Wide Consortium Effort. Weida Tong, US FDA-NCTR, Jefferson, AR.

Analyzing Data: Towards Developing a Framework for Transcriptomics and Other “Big Data”Analysis for Regulatory Application. Timothy Gant, Chemical and Environmental Effects, Public Health England, Oxfordshire, United Kingdom.

Standardization in Metabolomics—The Current Effort and Future Directions. Hector Keun, Imperial College London, London, United Kingdom.

Is There a Concern for Neurotoxicity from Replacement Organophosphorus Flame-Retardants?: Insights Using Molecular Approaches, Systems Biology, and Human Exposure
Workshop | 2:00 PM to 4:45 PM

Chairperson(s): Helena Hogberg, Johns Hopkins University, Baltimore, MD; and Mamta Behl, NTP, NIH, Research Triangle Park, NC.

Endorser(s): Molecular and Systems Biology Specialty Section
Neurotoxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

The global flame retardants (FR) consumption has surpassed 2 million tons and yet is expected to increase in order to meet international flammability standards. FRs are widely used in products such as upholstered furniture, electrical devices, baby products, textiles, and plastic, where the potential exposure is high. Especially, the use of FR in baby products and the exposure to children are of concern, as the developing brain is much more vulnerable to environmental perturbation than the brain of an adult. Prior to 2005, polybrominated diphenyl ethers (PBDEs) were the primary FRs used in the US. PBDEs have been banned in Europe and phased out in the US due to several health issues, specifically concerns for developmental neurotoxicity (DNT) following exposure in infants and children, and have now been replaced by organophosphorus FRs (OPFRs). However, there is limited information on potential health effects of these novel replacements. This is of concern, as the OPFR resembles organophosphate pesticides that are well known to induce neurotoxicity. In fact, there are in vitro data demonstrating neurotoxicity and developmental toxicity of many OPFRs. At this time it is not clear if these effects are observed at concentrations relevant to human exposure. Epidemiology studies show that metabolites of OPFRs are detected in the urine in more than 93% of infants at much higher concentrations than in adults. This workshop will begin with addressing current flammability standards and issues relating to the use of FRs in household products. Presenters will then address latest findings on in vitro and alternative species using a wide range of models (e.g. human and rodents cell lines, 3D cell cultures, and zebrafish) and methods (e.g. neurite outgrowth, electrical activity, transcriptomics, metabolomics, and behavioral studies). In addition, limited rat in vivo data will presented. The relevance of these findings will be discussed based on the observation of human exposure to OPFR. The main goal of the workshop is to shed light and discuss the current status of OPFRs, specifically related to DNT and neurotoxicity, and to link human exposures with findings in experimental models using point of departure methods and in vitro in vivo extrapolation. Attendees will gain national and international perspective from academia, government, and industry. The introduction will present the agenda of the workshop, including the overall goals, speaker line up, and the intended outcome. Dr. Behl will introduce the current status of the replacement OPFRs and their potential concern for DNT. The first presenter will describe current flammability standards and how FRs may be used in consumer products to meet these standards. The exposure, toxicity concerns, and data gaps for OPFRs will be discussed. The second presenter will report on the neurotoxicity observed in different in vitro cell lines using a variety of cellular and molecular endpoints. The data will be discussed in perspective to the in vivo study by the group showing that FRs were not detected in the brain and did not induce appreciable neurotoxicity in exposed neonate rat pups. Gaps in both the in vitro and in vivo studies will be discussed. The third presenter will then present DNT effects using organotypic cell cultures that better mimic the in vivo situation than traditional monolayer cultures. This study evaluates longer exposure time during development and goes more in mechanistic depth to describe pathways of toxicity of some OPFRs. The next presentation will discuss the actual human exposure of OPFRs, with focus on children and the presence of OPFRs in baby products. The research has showed that the urinary metabolites of these OPFRs are commonly detected in the US population, raising the concern of exposure. The final presenter will summarize by discussing how a battery of in vitro tests using different models and endpoints targeting different closely inter-related molecular pathways for developmental and DNT can be used in determining a point of departure for prioritizing compounds for further in vivo testing. It will then compare the in vitro findings with in vivo data in rodents (gene expression and functional end-points) to truth the data, and will highlight the need for a “systems biology” approach while determining a point of departure value.  It will finally link in vitro and rodent data to human exposure using in vitro/in vivo extrapolations (IVIVE) to provide some insight on margins of safety.

Introduction. Helena Hogberg, Johns Hopkins University, Baltimore, MD.

Flame Retardants in Consumer Products: Background and Current Standards. Melanie Biggs, Consumer Product Safety Commission, Rockville, MD.

In Vitro and Ex Vivo Neurotoxicity Assessment for Prioritization and Risk Assessment of Alternative Flame Retardants. Remco Westerink, Utrecht University, Utrecht, Netherlands.

Pathway Evaluation of the Developmental Neurotoxicity of Organophosphorus Flame-Retardants. Helena Hogberg, Johns Hopkins University, Baltimore, MD.

Children’s Exposure to Organophosphate Flame Retardants: Are They a Better or Worse Replacement for PBDEs? Heather Stapleton, Duke University, Durham, NC.

Putting It into Perspective: Relating Experimental Data to Human Exposure—Is Neurotoxicity Really a Concern? Mamta Behl, NTP, NIH, Research Triangle Park, NC.

 

5:00 PM to 6:20 PM

Roundtable Session
Implementing Developmental Thyroid Toxicity Guidance into Practice: What’s Working, What’s Not, and How Can We Do Better?
Roundtable | 5:00 PM to 6:20 PM

Chairperson(s): Abby Li, Exponent Health Science, San Francisco, CA; and Steffen Schneider, BASF, Ludwigshafen, Germany.

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

Thyroid hormone is essential for normal brain development both in the fetus and the neonate. In humans, thyroid function is not fully engaged until week 20 of gestation; in rodents, it is day 17. Chemicals that change circulating levels of thyroid hormone can be associated with neurobehavioral disorders and alterations in neurological development. Because of the complexity of brain development and its behavioral manifestations, it is important to target testing strategies based on the putative mode of action to focus time and resources on the critical endpoint(s) of concern. In 2015, US EPA OPP and OECD included thyroid measurements as part of new toxicity testing data requirements. US EPA has included comparative thyroid measures as part of Tier 2 testing for some pesticides as part of the Endocrine Disrupter Screening Program.  Guidance for this study includes thyroid histopathology and serum hormone measurements (T4, T3 and TSH) for Gestation Day (GD) 20 dams and fetuses, offspring at postnatal day (PND) 4, and dams and offspring on PND 21 (www.epa.gov/sites/production/files/2015-06/documents/thyroid_guidance_assay.pdf). OECD added thyroid measurements to reproductive and developmental screening tests (OECD 421, 422), including thyroid hormone measurements in pups at PND 13, adult males at the end of reproductive period, and, if available, PND 4 pups and dams at day 13 of lactation.  As more new studies with developmental thyroid endpoints are being conducted in response to these 2015 requirements, technical and regulatory issues have arisen regarding the variability and sensitivity of the hormone measurements in rat fetus and pups at different ages. In addition, there are questions on how to interpret the thyroid hormone data within the context of thyroid physiology and brain development. While there might be greater agreement on the clinical features that may be considered adverse following severe impacts on the thyroid system, there is greater uncertainty and disagreement regarding the appropriate point of departure for more modest effects. This roundtable brings together academic, industry, and government scientists to share knowledge, experience, and perspective from these recently conducted studies to address technical issues, discuss data interpretation, and collectively develop a perspective that can inform future work. The session will begin with a brief introduction of the current guideline recommendations and regulatory need to address developmental thyroid toxicity (DTT). This first presenter will also discuss how DTT data can be used to determine a point of departure and/or the magnitude of uncertainty factors used in risk assessments. The next three presentations initially will be asked to take contrasting scientific positions with data to illustrate the issues raised. These presenters include scientists who are on the forefront of conducting or sponsoring studies according to US EPA guidance and OECD 421/422 requirements, and an academic expert on developmental thyroid toxicity. During the balance of the time, these same speakers will be asked to step back from their positions and consider solutions and approaches that will improve implementation and interpretation of developmental thyroid toxicity studies. To set the tone for the discussion, the last speaker will argue the stated position with data, and then discuss data that supports a contrasting position. This roundtable is timely and provides a forum for constructive cross-communication with the goal of improving laboratory capabilities and safety evaluations for developmental thyroid toxicity.

Guideline Recommendations and Problem Formulation for Risk Assessment of Environmental Chemicals. Susan Makris, US EPA NCEA, Arlington, VA.

Implementing Developmental Thyroid Guidelines into Practice: A Survey of Current Capabilities and Challenges. Steffen Schneider, BASF SE, Ludwigshafen, Germany; and Leah Zorilla, Bayer CropScience, Durham, NC.

Minor Perturbations in Thyroid Assays Should Not Be Assumed to Be Adverse Due to Variability, Species Differences, and Compensatory Feedback. Sue Marty, The Dow Chemical Company, Midland, MI.

Any Measurable Change in Perinatal Thyroid Hormone Can Affect Brain Development, and There Are Sensitive Measures to Detect These Changes. Thomas Zoeller, University of Massachusetts, Amherst, MA.

Discussion: What’s Working, What’s Not, and How Can We Improve Implementation and Interpretation of Developmental Thyroid Toxicity Studies? Abby Li, Exponent Health Sciences, San Francisco, CA.

Informational Session
Addressing Rigor and Transparency in Research and Journal Publications
Informational | 5:00 PM to 6:20 PM

Chairperson(s): Sally Darney, NIEHS, Research Triangle Park, NC; and Nancy Beck, American Chemistry Council, Washington, DC.

Endorser(s): Graduate Student Leadership Committee
Postdoctoral Assembly
Specialty Section Collaboration and Communication Group

Driven by changes throughout the research and user community, increased efforts are being directed to insuring scientific rigor and transparency in both the conduct and publication of toxicological and environmental health research. Up front, funding agencies are adding criteria for rigor and reproducibility as an integral part of a grant application. At the end of the pipeline, regulatory agencies are honing their requirements for using data in risk assessment and regulatory decision making. In between, journals are playing an increasingly important role in these efforts with the dual goals of publishing highly credible science, and making it more accessible and discoverable within the broad community of scientists and research users. This session will explore the many challenges inherent in achieving rigor and reproducibility from the perspective of researchers, information specialists, and journal editors, while highlighting the availability of new tools and approaches for addressing them. Of broad interest across all SOT specialty sections, special interest groups, and disciplines in toxicology, public health, and risk assessment, the session starts with an overview of established reporting guidelines (such as ARRIVE for animal studies), and introduces new initiatives to foster openness and transparency, the use of valid and appropriate statistics, and the acceptance of data quality standards. Next, the audience will hear about how the NIH is developing innovative programs and tools to enable all domains of biomedical research to become more data-centric and open, and to make all types of research products more “discoverable” and useable. In this new biomedical science, not only publications, but other objects, such as data, software, workflows, and identifies (of investigators, grant numbers, reagents, etc.) will be digital, as well as findable, accessible, interoperable, reusable, and citable. The editors-in-chief of Environmental Health Perspectives (EHP) and Toxicological Sciences (ToxSci) will add their insights on how this information revolution is impacting journal submission guidelines, peer review policies, and data access requirements. For example, ToxSci recently launched a partnership with the Dryad Digital Depository, which enables investigators to make their underlying data available to peer reviewers, and later to the broader community once the paper is accepted. In addition to toxicology studies, EHP publishes research findings derived from exposure and ecosystem modeling, as well as epidemiological approaches that integrate biological, social, and environmental determinants of health. These fields face their own unique challenges in making data accessible (while protecting human subjects) and suitable for meta-analyses when data cut across spatial scales and human populations. A discussion period at the end of the session will enable audience members to share their experiences using these new data access tools and responding to the challenge of ensuring reproducibility in their research and publishing endeavors.

Introduction. Sally Darney, NIEHS, Research Triangle Park, NC.

From Research to Publishing: Guidelines for Rigor and Transparency. Nancy Beck, American Chemistry Council, Washington, DC.

NIH and the Changing Ecosystem of Science, Publishing, and Scholarship. Mike Huerta, NIH, Bethesda, MD.

Making Data Accessible: Perspectives from an Investigator and Editor. Gary Miller, Emory University, Atlanta, GA.

Interdisciplinary Challenges for Rigor and Reproducibility in Environmental Health Research. Sally Darney, NIEHS, Research Triangle Park, NC.

Bioinformatics Tools for Accelerated Hypothesis Generation and Mechanistic Insights
Informational | 5:00 PM to 6:20 PM

Chairperson(s): Susan Bello, Mouse Genome Informatics (MGI), Bar Harbor, ME; and Marc Gillespie, St. John’s University, New York, NY.

Endorser(s): Biological Modeling Specialty Section
Molecular and Systems Biology Specialty Section

There are a wide range of freely available, web-based bioinformatics resources and tools for hypothesis generation and data analysis. Finding and picking the best tool for a specific research question can be challenging and time consuming. A tool or resource may be used to investigate gene function, identify genes sharing common features (pathway, expression pattern, phenotypes), narrow candidate gene lists, and find gene, protein, or compound interactions. Selecting a tool or resource requires at least some understanding of the design, function, and limits of the tool. To generate reliable results, researchers need to understand what types of data are integrated, how those types of data are integrated, how to access the data, and what sorts of outputs may be produced. This session features four resources representing different types of freely available, internet-based, bioinformatic resources, followed by a practical example of use of these types of tools in a research program. Mouse Genome Informatics (informatics.jax.org), the premier international database resource for the laboratory mouse, will demonstrate the use of the Human-Mouse: Disease Connection portal to leverage mouse and human phenotype data in candidate gene analysis. Reactome (reactome.org) is a free, open-source, manually curated, and peer reviewed human pathway database. Reactome’s intuitive bioinformatics tools for data visualization and interpretation will be used to analyze gene expression, small molecule (metabolite data), and cancer gene sets. ToxCast provides a significant amount of chemical bioactivities (data for nearly 2,000 chemicals and over 450 gene targets), many not found in the literature, with findings implicating gaps in knowledge about chemical effects on biological systems. GeneWeaver (geneweaver.org) facilitates the integration of functional genomics resources, and will show how to combine user submitted data with data from public resources to gain novel insights into the biomolecular basis of toxicological effects. The session will conclude with case studies centered on the practical applications of toxicogenomics databases in nonclinical safety assessment, including species selection, cross species comparison around organ toxicity, and immunomodulation in nonhuman primates. At the end of this session, participants will have an understanding of how to make use of each resource, and which bioinformatic tools will accelerate their research.

Introduction. Marc Gillespie, St. John’s University, Jamaica, NY.

Using Mouse Genome Informatics’ Human-Mouse: Disease Connection Tool in Candidate Gene Analysis. Susan Bello, Mouse Genome Informatics (MGI), Bar Harbor, ME.

Using Reactome as a Foundation for Adverse Outcome Pathway (AOP) Identification. Marc Gillespie, St. John’s University, New York, NY.

Integration of Heterogeneous Functional Genomics Data in GeneWeaver.org with Applications in Toxicology. Elissa Chesler, The Jackson Laboratory, Bar Harbor, ME.

ToxCast Data Expands Universe of Chemical-Gene Interactions. Sean Watford, National Center for Computational Toxicology, US EPA, Chapel Hill, NC.

Applications of Toxicogenomics Database in Nonclinical Safety Assessment. Jing Yuan, Boehringer Ingelheim Pharmaceutical, Ridgefield, CT.

Education-Career Development Session
Mastering Soft Skills to Advance Your Scientific Career
Education-Career | 5:00 PM to 6:20 PM

Chairperson(s): Karilyn Sant, University of Massachusetts, Amherst, MA; and Samantha Snow, US EPA, Chapel Hill, NC.

Endorser(s): Career and Resource Development Committee
Graduate Student Leadership Committee
Postdoctoral Assembly

The overwhelming majority of the typical training experience focuses upon doing excellent science and identifying a career path. However, without a bit of personality, even trainees with the most exceptional resume may not stand out in a saturated applicant pool. Soft skills are often ignored in training, but can have a huge impact on the amount of success one obtains throughout their career. This session is designed to bring charismatic leaders in the field to discuss the non-scientific attributes that have contributed to their success, and also the qualities they seek out when identifying candidates for their organizations. Presentations will focus on: (1) how to network effectively; (2) how to present oneself in a professional environment using proper body language and etiquette; and (3) effective communication, leadership, and management skills. These interactive presentations will utilize demonstrations when applicable, and will be followed by a panel of young toxicologists who have successfully mastered these soft skills to transition from trainee to professional across the sectors. These discussions will be highly relevant to all student and postdoctoral attendees, as well as senior toxicologists who want to improve the professional training of mentees. This session will stimulate a discussion about underserved aspects of professional development, and enable trainees to learn and implement an essential skill set which will improve professional relationships throughout their careers.

Introduction. Karilyn Sant, University of Massachusetts Amherst, Amherst, MA.

Networking Effectively to Gain Traction for Your Science. Ruth Roberts, ApconiX, Alderley Edge, United Kingdom.

First Impressions Matter: Etiquette for the Professional. Martin Philbert, University of Michigan, Ann Arbor, MI.

Reflections on a Personal Journey: Learning to Become a Scientific Leader. Ronald Hines, US EPA, Research Triangle Park, NC.

Early-Career Scientist Panel Discussion. Shaun McCullough, US EPA, Chapel Hill, NC.

Early-Career Scientist Panel Discussion. Bethany Hannas, DOW Chemical Company, Midland, MI.

Early-Career Scientist Panel Discussion. Jonathan Shannahan, Purdue University, West Lafayette, IN.

 

Thursday, March 16

8:30 AM to 11:15 AM

Symposium Sessions
Evaluating the Reproductive and Developmental Effects of Botanical Dietary Supplements
Symposium | 8:30 AM to 11:15 AM

Chairperson(s): Kembra Howdeshell, NIEHS/NTP, Research Triangle Park, NC; and Cynthia Rider, NIEHS/NTP, Research Triangle Park, NC.

Endorser(s): Food Safety Specialty Section
Mixtures Specialty Section
Reproductive and Developmental Toxicology Specialty Section

Use of botanical dietary supplements is widespread, with approximately 18% of adults in the US reporting use of natural products, including botanical dietary supplements. Many diverse botanical products are marketed for their purported support of reproductive health, from black cohosh for gynecological and menopausal issues, to maca for male enhancement. There is a public perception that “natural” products (i.e., derived from plants or fungi) are safer than pharmaceuticals. However, there is often inadequate data to support the safety of these products. There are many factors that raise concerns about potential reproductive and developmental effects of botanical dietary supplements. Primarily, several plant or fungi constituents have well-characterized endocrine activity, such as genistein from soy and the mycotoxin zearalenone. In addition to these biologically-active constituents, numerous reports have documented adulteration of botanicals with pharmaceutical compounds or structurally-related analogs. Contributing to the difficulty in characterizing potential reproductive and developmental effects of botanical dietary supplements is the fact that they are complex mixtures that can vary significantly depending on source material and manufacturing processes. Therefore, inconsistent results in animal studies of toxicity or clinical trials for efficacy can be expected based on differences in product composition. Finally, botanical dietary supplements are regulated under the Dietary Supplement Health and Safety Act, which treats botanical ingredients that were on the market prior to its 1994 passage as food, which is assumed to be safe. Instead of requiring pre-market safety assessment, there is a reliance on adverse effect reporting, which is particularly problematic for identifying reproductive and developmental consequences that can manifest years after exposure. In this session, speakers will address different aspects of evaluating the reproductive and developmental effects of botanical dietary supplements. The session will begin with a presentation on applying rigorous evaluation methods to measure efficacy, toxicity, and chemopreventive potential of botanicals traditionally associated with treatment of menopausal symptoms. Next, speakers will present specific cases of identifying and characterizing reproductive and developmental effects of botanicals or their constituents. A discussion of adulterants with reproductive and developmental implications will follow. Finally, screening methods for rapid identification of reproductive and developmental toxicity of botanicals will be addressed. A multi-faceted discussion of botanicals and associated reproductive and developmental endpoints will help guide future research and inform public health decisions on this important topic.

Introduction. Kembra Howdeshell, NIEHS, Research Triangle Park, NC.

Botanicals as Natural Alternatives to Traditional Pharmaceuticals for Women’s Reproductive Health. Judy Bolton, University of Illinois Botanical Research Institute, Chicago, IL.

Evaluation of Reproductive Health Effects for the Caffeine in an Energy Shot. Mary Hixon, Gradient, Acton, MA.

Embryo-Fetal Toxicity in the Rat and Rabbit as a Result of Dietary Supplement Exposure: Vinpocetine as a Case Study. Natasha Catlin, NIEHS/NTP, Research Triangle Park, NC.

Screening of Male Enhancement Supplements for the Presence of Undeclared Drug Products. Connie Gryniewicz-Ruzicka, US FDA/CDER, St. Louis, MO.

An Industry’s Approach to Testing the Safety of Botanicals. Karen VanderMolen, New Chapter Inc./The Procter & Gamble Company, Brattleboro, VT.

In Vitro and Alternative Methods in Ocular Toxicology: The “Eyes” Have It
Symposium | Innovations in Toxicological Sciences Session | 8:30 AM to 11:15 AM

Chairperson(s): Mercedes Salvador-Silva, Alcon a Novartis Company, Fort Worth, TX; and Chris Somps, Pfizer, Inc., Groton, CT.

Endorser(s): In Vitro and Alternative Methods Specialty Section
Ocular Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section

Advanced tissue engineering and microfluidics technologies are providing new opportunities for more predictive in vitro ocular models, including three-dimensional (3D) tissue culture, self-forming organoids, and organ-on-a-chip models. These exciting technologies promise better, more physiologically and structurally relevant, models of the human eye, which will improve predictions of ocular toxicity. The goal of the session is to bring together experts from the pharmaceutical and biotechnology industries, academic institutions, as well as government agencies, to discuss current uses and future challenges of in vitro models for ocular toxicity, and safety assessment of drugs, chemicals, and cosmetics, as well as environmental toxins and medical device materials. The current state of these advanced techniques, the unique issues confronting their development and application, and challenges for validation and regulatory acceptance, will be discussed. This session will start with a broad overview of in vitro ocular safety assessment models, including internationally recognized and validated in vitro ocular irritant models, and their application for cosmetic, pharmacology, and medical device safety assessments. The second speaker will summarize regulatory efforts associated with the development, validation, and international acceptance of alternative in vitro methods for prediction of ocular toxicology, and will discuss the current hurdles and challenges regarding validation and acceptance of alternative methods for ocular toxicity prediction. The third and fourth speakers will describe examples of novel 3D and organ-on-a-chip models, and their application to the physiology and pathophysiology of glaucoma, tear production, and dry eye. The final speaker will discuss the current state and challenges of using stem cells to generate of 3D retinal organoids, and the potential use of organoids for retinal disease models, drug development, and ocular toxicity assessments. Attendees will learn about the 1) the development of complex, physiologically relevant in vitro ocular models for assessing ocular toxicity; 2) the challenges and critical decision points that influence the use of alternative methods for in vitro toxicology; 3) the strengths/limitations, predictive capacity, reproducibility, and sensitivity of the alternative methods presented and; 4) the challenges associated with in vitro model validation and clinical translation.

Introduction. Mercedes Salvador-Silva, Alcon a Novartis Company, Fort Worth, TX.

Alternative Methods for Ocular Toxicology Testing. Frank Barile, St. John’s University, Queens, NY.

Gaining Acceptance of Alternative Approaches for the Assessment of Serious Eye Damage/Eye Irritation. João Barroso, EURL ECVAM/Systems Toxicology Unit–IHCP, European Commission Joint Research Centre, Ispra (VA), Italy.

Bioengineering 3D Human Ocular Conventional Outflow Tract Models. Karen Torrejon, Glauconix, Inc., Albany, NY.

Microengineered Physiological Biomimicry: Human Organ-on-Chips. Dan Huh, University of Pennsylvania, Philadelphia, PA.

Structure and Composition of Human Pluripotent Stem Cell-Derived 3D Retinal Structures: Potential Tools for Studying Outer Retinal Toxicity. David Gamm, University of Wisconsin School of Medicine and Public Health, Madison, WI.

Quantitative Systems Toxicology for Chemical Safety Assessment
Symposium | 8:30 AM to 11:15 AM

Chairperson(s): Bob van de Water, Leiden University, Leiden, Netherlands; and Richard Paules, NIEHS, Research Triangle Park, NC.

Endorser(s): Mechanisms Specialty Section
Molecular and Systems Biology Specialty Section

The past years have seen major progress in both bioinformatics and systems biology approaches to extract relevant biological information from ‘omics data, as well as the integration of such data in computational biology approaches for safety assessment. This work also has strongly influenced the toxicological community to translate these systems biology findings and methods into approaches that can find ultimate application in chemical safety testing strategies. Different levels of systems biology are envisioned. Firstly, the integrated interpretation of large scale ‘omics datasets allows for the identification of common denominators that can explain and/or predict adverse events, preferably human. Such systems approaches offer great value in risk assessment because they allow an individual observation to be placed in the context of an entire system. To be effective, models must encompass the multiple scales of complexity of biological systems, e.g. from cells to tissues and organs, as well as the multiple dimensions of biological responses, e.g. time, dose, etc. High throughput and high content technologies provide the large amounts of data necessary to create multi-scale and multi-dimensional systems models. Secondly, these large datasets together with our rapidly improving understanding of cell biological processes in health and disease, has created the opportunities to re-create biology in silico through mathematical biological modeling. In the latter case these models can be populated in a quantitative way with cell biological experimental data. Both systems biology approaches conceptually fit with the Adverse Outcome Pathway (AOP) framework, with the firm advantage of making such AOP models now computable. In this symposium, we will discuss these different approaches and the opportunities for future safety testing strategies.

Introduction. Bob van de Water, Leiden University, Leiden, Netherlands.

Systems Biology Strategies for Translational Risk Assessment Using Gene Expression Networks. James Stevens, Eli Lilly, Indianapolis, IN.

Implementing Approaches for Moving Tox21 towards Quantitative Systems Toxicology. Richard Paules, NIEHS, Research Triangle Park, NC.

Quantitative and Functional Assessment of the Dynamics of Toxicological Key Events in Safety Testing. Bob van de Water, Leiden University, Leiden, Netherlands.

Computational Cellular Stress Systems Models to Define the Tipping Point between Adaptive Cellular Capacity and Adverse Outcomes: Implications for Safety Decision Making. Alistair Middleton, Unilever, Colworth, United Kingdom.

In Silico Dynamics: Computer Simulation in a Virtual Embryo. Thomas Knudsen, US EPA, Research Triangle Park, NC.

Concluding Remarks and Wrap-Up. Richard Paules, NIEHS, Research Triangle Park, NC.

The Next Technology Wave: Biosensors, Extreme Computing, and Organ Chips for Predicting Cardiovascular Toxicity
Symposium | Innovations in Toxicological Sciences Session | 8:30 AM to 11:15 AM

Chairperson(s): Anthony Bahinski, GlaxoSmithKline, King of Prussia, PA; and Amy Kim, H3 Biomedicine, Cambridge, MA.

Endorser(s): Cardiovascular Toxicology Specialty Section
Drug Discovery Toxicology Specialty Section
In Vitroand Alternative Methods Specialty Section

Development of safe and effective drugs is currently hampered by the poor predictive power of existing preclinical animal models that often lead to failure of drug compounds late in their development after they enter human clinical trials. Given the tremendous cost of drug development and the long timelines involved, major pharmaceutical companies and government funding agencies are now beginning to recognize a crucial need for new technologies that can quickly and reliably predict drug cardiovascular safety and efficacy in humans in preclinical studies, and approaches to integrate these novel technologies within regulatory science and use. This symposium will highlight innovative approaches to developing much-needed new toxicological methods for evaluation of cardiotoxicity, and the role that regulatory agencies such as the US FDA have in developing criteria and potential guidance for qualifying these new testing methods. The symposium brings together key experts from the fields of high performance computing using a human heart electrophysiological model, optical electrophysiology to assess arrhythmogenicity, gene editing developing human-induced isogenic pluripotent stem cell models, fluorescent protein biosensors, and Organ Chips developing a 3-dimensional AngioChip. They will highlight and discuss the advantages and challenges inherent in new innovative tools being applied towards identification and characterization of cardiotoxicity. Lastly, the process of qualifying new testing methods into use as a drug development tool will be discussed by the US FDA.

Introduction. Anthony Bahinski, GlaxoSmithKline, King of Prussia, PA.

Towards Predictive Biology with Extreme Computing. Frederick Streitz, HPC Innovation Center, Lawrence Livermore National Laboratory, Livermore, CA.

Optical Electrophysiology for Probing Arrhythmogenic Risk in Human iPSC-Derived Cardiomyocytes. Kit Werley, Q-State Biosciences, Cambridge, MA.

Human Genome and Tissue Engineering For Cardiac Disease Modeling. Luke Judge, University of California, San Francisco, San Francisco, CA.

Applying Fluorescent Protein Biosensors in Microphysiological Systems. D. Lansing Taylor, University of Pittsburgh, Pittsburgh, PA.

AngioChip: Vascularization Platform for Organ-on-a-Chip Engineering and Direct Surgical Anastomosis. Milica Radisic, University of Toronto, Toronto, ON, Canada.

Advancing FDA Regulatory Science through Innovation. Suzanne Fitzpatrick, US FDA, College Park, MD.

Workshop Sessions
Biological Advances to Help Navigate the Nonclinical Safety Assessment Strategy in Cancer Immunotherapy: Utility, Limitations, and Future Direction
Workshop | 8:30 AM to 11:15 AM

Chairperson(s): Robert Li, Genentech, South San Francisco, CA; and Jacintha Shenton, Janssen, Philadelphia, PA.

Endorser(s): Biotechnology Specialty Section
Immunotoxicology Specialty Section

Therapeutically harnessing the immune system to kill cancer cells is arguably the most significant advance in the treatment of cancer in the past several years.  Novel immunotherapies recently approved by the US Food and Drug Administration (US FDA) include two checkpoint inhibitors targeting PD-1, a bispecific T cell redirector targeting CD19, and one oncolytic viral therapy. These drugs have led to long-term responses in a subset of patients that had failed prior therapies. As exciting as these achievements are, tremendous efforts are being invested in the field to increase the proportion of patients benefiting from these therapies. For example, identification of new molecules involved in immune tolerance to cancer cells and their application in immunotherapy as single agents, or in combination to enhance clinical efficacy, are actively being pursued. In addition, there are a multitude of other strategies under investigation, including novel T cell redirectors, genetically-modified T cell therapies, and cancer vaccines. In fact, more than half of the current cancer clinical trials include some form of immunotherapy, many of which are investigating possible combination strategies.  In parallel with this paradigm shift in therapeutic options for cancer, safety-related questions are also raised in terms of how to design/tailor nonclinical safety assessment for clinically relevant hazard identification and risk management.The objective of this scientific session is to 1) provide a general overview of the field of cancer immunotherapy (CIT): the current status and the future direction driven by the advances in cancer immunology (e.g. new checkpoints) and bioengineering platforms (e.g. hexamer vs. monomer); 2) highlight the unique challenges in safety assessment for CIT drug development; and 3) promote discussion in regard to assessing the unique challenges of developing these new oncology therapeutics to ensure patient safety.

Introduction. Robert Li, Genentech, South San Francisco, CA.

The Biology of Cancer Immunotherapy. Brendan Curti, Earle A. Chiles Research Institute, Portland, OR.

The Utility and Limitations of Conventional Animal Models in CIT Safety Assessment. Gautham Rao, Genentech, South San Francisco, CA.

Nonclinical Safety Assessment of a P-Cadherin-Specific T Cell-Recruiting Bispecific Molecule for Cancer. Cris Kamperschroer, Pfizer, Groton, CT.

Cytokines, T Cell Homeostasis, and Safety Risk: Lessons from CAR T Cell Therapeutics. Rafael Ponce, Juno, Seattle, WA.

The Use of Pharmacology in Nonclinical Safety Evaluation of Cancer Immunotherapeutics. Whitney Helms, US FDA, Washington, DC.

Microparticles and Exosomes in Cardiopulmonary System-Stem Cell and Microenvironment Regulation by Toxicants
Symposium | 8:30 AM to 11:15 AM

Chairperson(s): Irfan Rahman, University of Rochester, Rochester, NY; and Daniel Conklin, University of Louisville, Louisville, KY.

Endorser(s): Carcinogenesis Specialty Section
Cardiovascular Toxicology Specialty Section
Inhalation and Respiratory Specialty Section

Exosomes are membrane bound extracellular microvesicles that are loaded with a variety of bioactive molecules capable of directly regulating target cells by delivering bioactive components to alter the distal cells. Microparticles (MPs) and exosomes are released from different cell types such as epithelial, fibroblasts, endothelial (MPs or exosomes), tumor cells, and stem cells, including immune inflammatory cells in pulmonary andcardiovascular system. Recent data suggested that environmental agents, PM2.5, inhaledoxidants/toxicants, including cigarette smoke, profibrotic agents, and carcinogens can affect the secretion of exosomes. Exosomes can function as endocrine signal mediators to target cell phenotype. Exosomes released from target cells may have toxicological impact on a paracrine via an intercellular communication in cardiovascular, lung, liver, and circulatory systems. Emerging studies of mesenchymal stem cells (MSC )-derived exosomes show promising therapeutic and beneficial effects. For example, mitochondrial-derived vesicles can encapsule bioenergetics, which are transported from MSCs to damaged cells. This session will unravel the specific cell-type that is responsible for enriched circulating exosome markers/signatures in toxicology and the pathogenesis of systemic diseases. Intercellular communication, tissue repair vesicles, immunemodulatory effects, biomarkers, nomenclatures and technological advances, and toxicological impact on exosomes and MPs research will also be presented Overall, the workshop will present the novel findings on development of novel exosome signatures as biomarkers, toxicological end points by toxicants, and beneficial effects via stem cells in systemic toxicity and diseases. This includes toxicological perspectives of exosomes and microvesicles, e.g. agents and actions bytoxicants creating microenvironment forsystemic or organ toxicity in cardiopulmonarysystems, microenvironment, and toxicantsinduced injuries.

Introduction. Irfan Rahman, University of Rochester, Rochester, NY.

The Biology and Function of Exosomes in Microenvironment. Raghu Kalluri, University of Texas MD Anderson Cancer Center, Houston, TX.

Endothelial Microparticles are Associated with PM2.5 Exposure: Implications for Cardiovascular Events. Tim O’Toole, University of Louisville, Louisville, KY.

Cellular Microparticles and Exosomes in Stress Responses and Inhaled Toxicant-Induced Pulmonary Diseases. Luis Ortiz, University of Pittsburgh, Pittsburgh, PA.

Characterization of Microparticles and Exosomes in Toxicological and Lung Injurious Responses. Irfan Rahman, University of Rochester, Rochester, NY.

Exosome Biogenesis: Models, Predictions and Results in Toxicity. Stephen Gould, Johns Hopkins University School of Medicine, Baltimore, MD.

New Findings on Pyrethroid Developmental Neurotoxicity: An Alternate Approach to Charactering Age-Related Differences to Hazard Identification
Workshop | 8:30 AM to 11:15 AM

Chairperson(s): Charles Vorhees, Cincinnati Children’s Research Foundation & University of Cincinnati, Cincinnati, OH; and Derek Gammon, FMC Corp., Ewing, NJ.

Endorser(s): Neurotoxicology Specialty Section
Reproductive and Developmental Toxicology Specialty Section

The neurotoxicity of Type I and Type II pyrethroids in adult rats has been investigated for many years and the principal mechanism of action on voltage-sensitive sodium channels (VSSC) is well established. By contrast, there is relatively little published data on the developmental effects of these compounds, on potential sex differences, on their long-term effects, or on neurotransmitter systems. This is important because household pyrethroid use has increased following restriction of organophosphorus insecticides. The prevailing view is that these compounds have no long-term effects, but new evidence suggests this may not be the case. Recent data also demonstrate that early exposure can affect neurotransmitter systems. There are also newer data showing differences as a function of age and sex and these differences depend on the type of pyrethroid and dose. The purpose of this workshop is to bring forward new data on the above topics with deltamethrin (Type II) and permethrin (Type I) as examples for effects on voltage-gated ion channels, startle, locomotor activity, learning and memory, and their relationship to brain and plasma concentrations. The relative sensitivity of young vs. adult animals, the long-term effects of early exposure, pharmacokinetics, and sex effects, provide new insights into these compounds. This is timely because the US EPA has pyrethroids under review and has noted need for data to better characterize effects in children. The workshop will begin with a presentation that will lay the foundation for how Type I and Type II pyrethroids affect VSSC and other ion channels in different species. The presenter will also describe atypical (Type III) pyrethroids that have mixed effects. This will be followed with a presentation that will show new data on the pharmacokinetics of deltamethrin and permethrin in young rats. The next talk will present new data on the effects of deltamethrin exposure on sodium channel expression and glutamate release. This will be followed with a presention on new data on early versus adult effects of deltamethrin and permethrin on acoustic startle, and of deltamethrin on learning and memory. As a conclusion, the panel will be joined by California EPA scientist Dr. Poorni Iyer who, along with Dr. Gammon, will lead a discussion of the implications of the new data for hazard characterization for protecting children and place the data in context.

Effects of Pyrethroids on Voltage-Sensitive Ion Channels. Derek Gammon, FMC Corp., Ewing, NJ.

Lack of Age-Dependent Differences in Pyrethroid Internal Dosimetry at Low Exposure Levels. James Bruckner, University of Georgia, Athens, GA.

Developmental Deltamethrin Exposure Causes Long-Term Downregulation of Nav Protein and Reduced Neurotransmitter Release. Jason Richardson, Northeast Ohio Medical University, Rootstown, OH.

Developmental Effects of Pyrethroids on Acoustic Startle and on Learning and Memory. Charles Vorhees, Cincinnati Children’s Research Foundation & University of Cincinnati, Cincinnati, OH.

Panel Discussion. Poorni Iyer, California EPA, Sacramento, CA.


 

8:30 AM to 11:45 AM

Poster Sessions (Including Late-Breaking Poster Session)
  • Alternatives to Mammalian Models III
  • Biological Modeling
  • Emerging Technologies
  • Systems Toxicology

Late-Breaking Poster Session supplement will be available early March 2017

 

Continuing Education (CE)



2017 Continuing Education Courses

All courses will be held at the Baltimore Convention Center. Please check the signage in the Registration area and at the CE Booth for room assignments. Note: Your course materials are available outside of the room immediately prior to the course (they are not available at the Registration area). If you have your course ticket, go directly to the assigned course room. If you have not received your course ticket or have not registered, please check in at Registration on Saturday afternoon/evening or on Sunday morning. If you have misplaced your ticket, please go to the CE Booth (open 6:30 am–5:30 pm on Sunday, March 12, 2017) near the course classrooms.

Sunday, March 12

7:00 AM to 7:45 AM

SR01 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, Eisai AiM Institute, Andover, MA.

8:15 AM to 12:00 Noon

AM02 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.

AM03 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.

AM04 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.

AM05 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.

AM06 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.

AM07 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.

1:15 PM to 5:00 PM

PM08 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.

PM09 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.

PM10 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.

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

MOA Screening—Impact on Drug Discovery Decisions and Regulatory Testing Strategies. Maik Schuler, Pfizer PGRD, Groton/New London, CT.

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

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

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.

PM11 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.

PM12 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.

PM13 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.

 

Featured Sessions

Daily Plenary Session: Data Science

Monday, March 13, 8:00 AM to 9:20 AM

Systems Approaches to Drug Efficacy and Toxicity in an Era of Big Data

Lecturer: Peter Sorger, Harvard Medical School, Boston, MA.

The development of new therapeutic drugs is fundamental to improving human health, but the process is challenged by rising costs and a high rate of failure. New and better technology and big data are often put forward as the solutions to these problems. However, I will discuss laboratory and clinical studies showing that some of the fundamental concepts in pharmacology and toxicology are ripe for reinvention. Increasing data on the impact of cell-to-cell variability and temporal variation in cellular physiology motivates new ways of thinking about seemingly simple concepts such as drug dose-response. Better understanding of sources of variation in laboratory and clinical data should also improve our ability to identify robust biomarkers of therapeutic and adverse effects.

I will argue that big data and data science are essential but insufficient: correct interpretation of empirical data in biomedicine hinges on theories about mechanism. I will discuss these theories, with reference to cytotoxic and targeted anti-cancer therapies, and studies of drug response in cell culture, animal models, and human clinical trials. New pharmacological principles derived from such studies are being developed into practical algorithms and open-source software as a means to improve target qualification, lead molecule optimization, and early phase clinical trials. The hoped for outcome: better drugs at a cost society can afford.

 

Open Ecosystems for Understanding Toxicities and Adverse Events

Lecturer: Lara Mangravite, Sage Bionetworks, Seattle, WA.

The presentation will address the use of collaborative approaches for the gathering, sharing and interpretation of health data. This will include the use of remote sensor-based data collection approaches to capture fluctuations in health relative to medication and disease—and the consideration of how these could be used to track adverse events.

Merit Award Lecture

Monday, March 13, 12:30 PM to 1:20 PM

Cell Proliferation and Carcinogenesis: Bad Luck and the Environment

Lecturer: Samuel M. Cohen, University of Nebraska Medical Center, Omaha, NE.

Cancer develops because of multiple permanent genetic errors arising in a single stem cell, a clonal disease. Every time DNA replicates, spontaneous mistakes can occur. Thus, the risk of cancer can be increased by either directly damaging DNA each time it replicates (DNA reactive) or increasing the number of DNA replications (cell proliferation), or both. Some have indicated that the “spontaneous” errors that occur during DNA replication are the basis for cancer being due to “bad luck,” and are the cause of most cancers. However, it is well-known that numerous environmental factors can increase the risk of cancer. This dilemma is readily resolved by realizing that the number of stem cells and the rate of their proliferation can be markedly influenced by the environment. Over the course of more than a 50 year career in carcinogenesis research, I have been actively involved in research on DNA reactive carcinogens (nitrofurans, aromatic amines, nitrosamines) and non-DNA reactive carcinogens (saccharin, PPARγ agonists, arsenicals, others). Based on the fundamentals of carcinogenesis, a mode of action (MOA) approach, and the accumulated knowledge of carcinogenesis in animals and humans, carcinogenic risk can be readily evaluated today without utilizing the two-year bioassay.

Meet the Directors: A Conversation with Linda S. Birnbaum and Robert J. Kavlock

Monday, March 13, 1:30 PM to 2:30 PM

Chairperson(s): Patricia E. Ganey, Society of Toxicology Vice President; Michigan State University, East Lansing, MI.

Panelists: Linda S. Birnbaum, NIEHS, Research Triangle Park, NC; and Robert J. Kavlock, US EPA, Washington, DC.

This important session will provide an informal venue for meeting attendees to have a candid and open discussion with two key leaders of federal organizations with missions to protect and improve public health: Dr. Birnbaum, Director, National Institute of Environmental Health Sciences (NIEHS), NIH, and Dr. Kavlock, Deputy Assistant Administrator for Science at the Office of Research and Development for the US EPA. The entire session will be devoted to a question-and-answer format concerning scientific directions and priorities for NIEHS and EPA including funding priorities and outlooks, and training opportunities.

SOT/EUROTOX Debate

Monday, March 13, 4:45 PM to 6:00 PM

Toxicology Testing of Drug Combinations Does Not Add Significant Value to Human Risk Evaluation Beyond What Is Known for the Individual Agents

Chairperson(s): Leigh Ann Burns Naas, Gilead Sciences Inc., Foster City, CA; and Heather Wallace, University of Aberdeen, Aberdeen, United Kingdom.

SOT Debater: Kenneth L. Hastings, Hastings Toxicology Consulting LLC, Mount Airy, MD.

EUROTOX Debater: Phil Bentley, Toxicodynamix International LLC, Hendersonville, NC, and Basel, Switzerland.

Endorser(s): Society of Toxicology (SOT)
European Societies of Toxicology (EUROTOX)

Each year the SOT Annual Meeting includes a debate that continues a tradition that originated in the early 1990s in which leading toxicologists advocate opposing sides of an issue of significant toxicological importance. This year, our debaters will address the proposition: Toxicology Testing of Drug Combinations Does Not Add Significant Value to Human Risk Evaluation Beyond What is Known for the Individual Agents. The use of innovative drug combinations—both large and small molecule—in clinical development is increasing. The objective is often to increase efficacy by targeting multiple pathways for the same disease, to improve safety by being able to lower doses of one or more drugs, or to provide more convenient/acceptable therapies to patients. As the number of these clinical combinations rises, there is an increasing need to evaluate their nonclinical safety. At the heart of this evaluation is the question regarding the need for actual animal testing. Global regulatory guidance has provided a framework for the nonclinical safety evaluation of combination products, which considers the need for testing based on such things as the potential for PK or PD interactions, overlapping toxicology profiles, extent of toxicology characterization of the individual agents and their margins of safety, human clinical experience with the individual agents, and the stage of clinical development of each agent. The guidance applies not only to fixed dose combinations but co-packaged and co-use as well. Unless there is clinical experience with the combination and that combination involves two late stage (Phase 3, Marketed) entities, nonclinical repeat dose toxicity studies up to 90 days are recommended. This broad recommendation is inconsistent with the principles of the 3Rs for reduction, refinement, and replacement in animal experimentation. Conversely, the potential for unexpected safety events with novel, targeted therapies is a clear clinical concern. The debaters will discuss the evidence regarding whether the information gathered in nonclinical combination studies provides clear benefit in the overall risk evaluation for clinical combinations.

Regardless of framework differences and personal convictions, each scientific debate delegate will present relevant evidence and compelling scientific arguments to persuade and appeal to the audience in order to obtain the approval or rejection of the motion. In addition to being a featured session at the SOT Annual Meeting in Baltimore, Maryland, this debate will again take place (with the debaters taking the reverse positions) in Bratislava, Slovak Republic, during the 53rd Congress of the European Societies of Toxicology (2017 EUROTOX Annual Congress), September 10–13, 2017.

Daily Plenary Session: Precision Medicine

Tuesday, March 14, 8:00 AM to 9:20 AM

Pharmacogenomics of Drug Toxicity in Cancer: Making the Case for Precision Medicine

Lecturer: Jun J. Yang, St. Jude Children’s Research Hospital, Memphis, TN.

Elucidation of the genetic basis for inter-patient variability in drug toxicity not only reveals important biology of a drug’s mechanism of action but also provides critical knowledge that enables risk-adapted treatment individualization. This is particularly relevant in cancer where chemotherapy is often associated with severe acute toxicities and debilitating long-term side effects. Therefore, the narrow therapeutic index of anti-leukemic drugs provides a compelling rationale for improvements in evidence-based precision medicine approaches. Focusing on acute lymphoblastic leukemia as a model disease, our pharmacogenomics research identifies genetic factors associated with response and toxicity of a wide range of common anti-cancer drugs, from which we then develop genetics-guided individualized therapy. For example, inherited deficiency in detoxification enzymes TPMT and NUDT15 predisposes children with leukemia to severe thiopurine-induced myelosuppression and preemptive dose adjustment based on gene genotype effectively minimizes host toxicity without compromising anti-cancer efficacy of this class of drugs. In fact, there is a rapidly-growing number of medications for which pharmacogenomic variants can directly guide treatment choice and/or dosing strategy. At the forefront of precision medicine, pharmacogenomics hold particularly great promise to transform medical practice with more efficacious and safer therapies across diseases.

 

The Role of Precision Medicine in Closing the Innovation Gap

Lecturer: Richard Barker, University of Oxford, Oxford, United Kingdom.

The tremendous recent advances in basic bioscience are not translating as effectively and affordably as they should into health benefit for patients and positive change in healthcare delivery. The presentation will analyze and illustrate this phenomenon and the threat it represents to the long-term sustainability of biomedical innovation. It will also propose changes to both the innovation process and the environment in which it operates, highlighting the golden thread of precision medicine—vital to the potential to make major changes in innovation productivity. The talk will draw on the speaker›s recent experience launching the UK’s Precision Medicine Catapult.

Daily Plenary Session: Keynote Medical Research Council (MRC) Lecture

Wednesday, March 15, 8:00 AM to 9:20 AM

The Exposome: Challenges and Opportunities

Lecturer: Paul Elliott, Imperial College, London, United Kingdom.

National and international variations in disease rates, and temporal trends—for example, the remarkable and rapid declines in coronary heart disease mortality in many countries over recent years, point to the overwhelming importance of environmental factors in risk of chronic diseases. The new developments in ’omics technologies, new sensor technologies and exposure assessment methods, provide an unprecedented opportunity to make real advances in understanding the links between environmental stressors, health and disease. Recently the exposome concept has been proposed as a means to gain greater understanding of the interaction between the environment and the host. The exposome captures the totality of internal (biochemical) and external exposures (and their biological imprints) from a variety of sources including chemical and biological agents, gut microbial and lifestyle/psychosocial factors, over the life course. The idea is that these factors interact at a cellular and systems level to generate molecular signatures of health or disease, providing new insights into disease etiopathogenesis that can inform both preventive strategies and new treatments. The metabolic signature can be assessed through ’omic technologies and biomarkers, encompassing a wide range of molecules, including small molecule metabolites in blood or urine (metabolomics), and downstream changes in gene expression levels and regulation (transcriptomics, epigenomics, proteomics). Metabolomics in particular is a powerful and innovative approach that captures in high-resolution direct signatures of the end products of metabolic pathways associated with a wide range of physiological and pathophysiological processes. This lecture will present some recent applications of the exposome approach, including use of the Metabolome-Wide Association Study (MWAS) concept, and discuss how these ideas may be taken forward in the future.

Distinguished Toxicology Scholar Award Lecture

Wednesday, March 15, 12:30 PM to 1:20 PM

Dioxins and the Ah Receptor: Synergy of Discovery

Lecturer: Linda S. Birnbaum, NIEHS, Research Triangle Park, NC.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the prototype for a family of structurally related compounds which have a common mechanism of action, a common spectrum of biological responses, and are environmentally and biologically persistent. A plethora of effects have been reported in people, wildlife, and domestic animals since chloracne was first described in 1899. In the laboratory, species from all vertebrate classes have been used to study the pharmacokinetics, mechanisms of action, and toxic effects of dioxins. Primary activation of the aryl hydrocarbon (Ah) receptor has shown to be a necessary, but not sufficient, mediator of dioxins’ toxic effects. Toxicology studies laid the groundwork for understanding of the Ah receptor as a key regulatory protein in development and differentiation, in stem cells, in the immune system, in cancer and heart disease, in eye and skin health, etc. Through the study of dioxins, the scientific community has learned a great deal about the Ah receptor and the basic helix-loop-helix family of transcription factors. Thus, we pause to ask: When would we have “discovered” the Ah receptor if we had not studied dioxins?

Translational Impact Award Lecture

Wednesday, March 15, 5:00 PM to 5:50 PM

Development of a Clinical Diagnostic Test for Acetaminophen Liver Injury

Lecturer: Laura P. James, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, AR.

Acetaminophen is the most widely used drug in the US and in many European countries for the treatment of pain and fever. The drug is also recognized to be a major cause of acute liver failure and acute liver injury in the US. The role of metabolic activation as an initiating event in acetaminophen liver injury in animal models is well recognized. Currently available approaches for the diagnosis of acetaminophen liver injury in the clinical setting are inadequate. Quantitation of blood-based acetaminophen protein adducts through high performance liquid chromatography with electrochemical detection has characterized adduct levels relative to acetaminophen exposure. Adduct levels greater than 1.0 nmol/mL are both sensitive and specific for acetaminophen liver injury. Development and proof-of-concept testing of a rapid, lateral flow assay for acetaminophen protein adducts shows that semi-quantitative detection of blood based adducts in the clinical setting can be used in the future to identify patients with acetaminophen liver injury.

Society of Toxicology and Japanese Society of Toxicology Mini-Symposium

Wednesday, March 15, 5:00 PM to 6:20 PM

The Society of Toxicology (SOT) and the Japanese Society of Toxicology (JSOT) are delighted to jointly sponsor a mini-symposium on a topic of mutual interest: Drug-induced liver injury. Each Society has selected from among its membership a true leader in the field to provide their perspectives on recent advances in this area.

Cytotoxic Interaction of Cytokines with Drugs That Cause Idiosyncratic Liver Injury

Lecturer: Robert A. Roth, Michigan State University, East Lansing, MI.

Idiosyncratic, drug-induced liver injury (IDILI) continues to limit the use of efficacious drugs and cause serious morbidity and mortality in sensitive patients. Although much remains unknown about mechanisms by which these adverse reactions arise, evidence in people and animal models points to an activated immune system as critical to the pathogenesis. For several drugs, specific HLA polymorphisms are associated with risk for IDILI in human patients. For other drugs, animal models based on immune system activation have provided evidence of a role for inflammatory cytokines. For example, a murine model in which mice were sensitized and challenged with halothane resulted in hepatitis associated with interferon-gamma (IFNg) production. Similarly, in mice undergoing an acute inflammatory episode, trovafloxacin enhanced the appearance of tumor necrosis factor-alpha (TNF) and IFNg in the plasma. In vitro, trovafloxacin amplified the production of TNF in macrophages activated by LPS. In addition, in a human hepatocyte cell line (HepG2), TNF interacted with trovafloxacin to cause cell death, and IFNg enhanced this response. Likewise, in rats, chlorpromazine interacted with an inflammatory episode caused by LPS, resulting in liver injury, and in vitro, TNF interacted with chlorpromazine to cause cytotoxicity. Similar results were found with diclofenac, a nonsteroidal anti-inflammatory drug that has caused IDILI in humans. These drugs cause nonlethal cell stress of various sorts that resulted in activation of mitogen-activated protein kinases (MAPKs). Indeed, each of the above-mentioned drug-TNF interactions was associated with activation of C-jun N-terminal kinase (JNK), and JNK inhibition abolished the drug-TNF interaction. Moreover, the cytotoxic drug-TNF interactions were enhanced by IFNg exposure. These and other results suggest that drug-induced cell stress and its interaction with cytokines such as TNF and IFNg can lead to prolonged activation of JNK and perhaps other MAPKs, resulting in death of hepatocytes. Such cytotoxic drug-cytokine interaction could provide the basis for an assay to aid in preclinical identification of drug candidates with IDILI potential.

 

Establishment of a Novel Cell-Based Assay for Drug-Induced Liver Injury (DILI) Potential Considering Immune- and Inflammation-Related Factors

Lecturer: Tsuyoshi Yokoi, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Drug-induced liver injury (DILI) is one of the leading causes of failure in drug development and post-marketing drug withdrawal. Although some preclinical in vitro evaluation of hepatotoxic potential of drugs by utilizing hepatic cell death or cellular stress as markers have been developed, their predictive ability is low. To establish a cell-based system for the assessment of DILI, it is necessary to better understand its mechanism including alterations in gene expression using animal models of DILI. Using in vivo mouse DILI models of hepatotoxic (acetaminophen, dicloxacillin, flutamide, halothane, and diclofenac) and non-hepatotoxic (ampicillin, bicalutamide, isoflurane, and ibuprofen) drugs, we found that the hepatic mRNA levels of immune factors including S100A8, S100A9, “NATCH, LRR, and pyrin domain-containing protein 3” (NLRP3), IL-1β, and the receptor for advanced glycation endproducts (RAGE) were commonly increased in hepatotoxic drug-administered mice. To clarify whether these five biomarkers can be applied to a cell-based screening system. We found that the total sum score of gene expression levels of S100A8, S100A9, RAGE, and IL-1β mRNA in HL-60 cells and NLRP3 mRNA in K562 cells incubated with and without human liver microsomes (HLM), could identify drugs at high risk for hepatotoxicity. These results raised the possibility that an in vitro assay considering immune- and inflammation-related factors could improve the prediction of clinical DILI. Because liver microsomes do not fully reflect the in vivo nature of liver, we next applied HepaRG cells that express drug-metabolizing enzymes comparable to primary human hepatocytes to a cell-based assay. HepaRG or HepG2 cells were treated with 96 drugs with different DILI risks. An area under the receiver operating characteristic curve (ROC-AUC) was calculated to evaluate the predictive performance of the mRNA levels as markers to discriminate DILI risk. The expression of IL-8 in HL-60 cells treated with conditioned media from HepaRG cells (HL-60/HepaRG) exhibited the highest ROC-AUC value of 0.758. An integrated score calculated from the levels of S100A9, IL-1β, and IL-8 more precisely determined the DILI risks than individual gene expression did. Collectively, we developed a novel cell-based assay system for risk assessment of DILI and suggested that this assay has a potential utility in screening for DILI in preclinical drug development.

Events and Activities

Events listed below are being held in the Baltimore Convention Center unless otherwise noted.


View All Recurring Events Student and Postdoctoral Scholars Regional Chapter Special Interest Group Specialty Section Career Events

Undergraduate Diversity Program

Saturday, March 11 to Monday, March 13

Hilton Baltimore Hotel

Chairperson(s): Judith T. Zelikoff, New York University School of Medicine, Tuxedo Park, NY; and Kimberly Hodge-Bell, Monsanto Company, St. Louis, MO.

Hosted by: Committee for Diversity Initiatives (CDI)

(Open to CDI Travel Awardees)

Students and faculty advisors were selected from a national pool of applicants to participate in the Undergraduate Diversity Program. The program begins Saturday evening with networking within mentoring groups, an introduction to toxicology, and the CDI Reunion, a celebration including current and past program participants and organizers. See Sunday Undergraduate Education Program for a description of the activities on Sunday. On Monday, these students participate in Scientific Sessions, visit Poster Sessions, attend the In Vitro Lecture and Luncheon, continue to network with graduate students, postdoctoral scholars, and career toxicologists, and conclude this concentrated exposure to the discipline of toxicology and possibilities inherent in the pursuit of graduate studies in the biomedical sciences.

SCHEDULE (Events are held in the Hilton Baltimore Hotel unless otherwise noted.)

Saturday, March 11
(Open to CDI Travel Awardees and Invited Guests)

  5:00 PM–5:15 PM   Registration for Students with Committee on Diversity Initiatives Travel Awards   Holiday Ballroom 1
  5:15 PM–7:30 PM   Opening Event
Chairs: Judith T. Zelikoff, PhD, New York University School of Medicine, Tuxedo Park, NY; and Kimberly Hodge-Bell, PhD, DABT, Monsanto Company, St. Louis, MO.
   
  6:45 PM–7:30 PM   Are You Curious and Ask Questions? Do You Want to Help People? Toxicology Might Be for You! An Introduction to Toxicology
Antonio T. Baines, PhD, 1993 Program Alumnus, North Carolina Central University, Durham, NC.
   
  7:30 PM–8:30 PM   Committee on Diversity Initiatives Reunion
Open to all, especially invited are those previously involved in CDI activities.
   
  7:35 PM–7:40 PM   2017 Perry J. Gehring Diversity Student Travel Award Recognition

   
  7:40 PM–8:30 PM   Networking    
 

Sunday, March 12
(Open to CDI Travel Award Recipients, Mentors, and Organizers and Undergraduates who register for the Sunday Undergraduate Education Program)

  8:00 AM–12:00 Noon   Toxicology Presentations
Chairs: Judith T. Zelikoff, PhD, New York University School of Medicine, Tuxedo Park, NY; and Kimberly Hodge-Bell, PhD, DABT, Monsanto Company, St. Louis, MO.
  Holiday Ballroom 1
    8:05 AM–8:10 AM   Welcome
John B. Morris, PhD, SOT President, University of Connecticut, Storrs, CT.
   
    8:10 AM–8:55 AM   Drug Discovery Toxicology, A Paradigm Shift for Pharma
Yvonne Will, PhD, Pfizer Inc., Groton, CT.
   
    9:00 AM–9:45 AM   The Toxic Sins of Our Ancestors
Patrick Allard, PhD, University of California Los Angeles, Los Angeles, CA.
   
    9:55 AM–11:00 AM   Interactive Presentation Forensic Toxicology Overview
Michael J. McCabe, PhD, Robson Forensic Inc., Lancaster, PA.
   
    11:05 AM–11:55 AM   Human Health and Risk Assessment
Marquea D. King, PhD, US Environmental Protection Agency, Washington, DC.
   
  12:00 Noon–12:40 PM   Lunch and Networking

   
  12:55 PM–1:55 PM   Breakout Sessions for Students:
What Is Graduate School and What Can I Expect? A Graduate Student Perspective How to Get into Graduate School: An Academic Advisor’s Perspective

  Key Rooms 9–12
  12:55 PM–1:55 PM   Breakout Session for Advisors:
Tips for Advising Prospective Graduate Students or How to Get Your Students Accepted to Graduate School

  Calloway A
  2:05 PM–2:55 PM   Career Roundtable: Opportunities in Toxicology

  Key Rooms 9–12
  3:00 PM–5:00 PM   Open Time with Academic Toxicology Program Directors and Internship Sponsors

  Key Balloom 7
   
  SOT Annual Meeting Events
  5:15 PM–6:30 PM   Awards Ceremony   Convention Center, Ballroom III
  6:30 PM–7:30 PM   Welcome Reception   Convention Center, Hall A
  7:30 PM–9:00 PM   Student/Postdoctoral Scholar Mixer   Holiday Ballroom 4
 

Monday, March 13
(Open to CDI Travel Award Recipients, Mentors, and Organizers)

  8:00 AM–9:20 AM   Plenary Lecture: Data Science
Peter Sorger, PhD, Harvard Medical School, Boston, MA; and Lara Mangravite, PhD, Sage Bionetworks, Seattle, WA.
  Convention Center, Hall A
  9:30 AM–11:05 AM   Groups Attend Annual Meeting Sessions and Posters    
  11:30 AM–1:00 PM   In Vitro Lecture and Luncheon for Students
Anthony Bahinski, MBA, PhD, GlaxoSmithKline, King of Prussia, PA.
  Holiday Ballroom 1
  1:15 PM–3:10 PM   Groups Attend Annual Meeting Sessions and Posters    
  3:30 PM–4:30 PM   Career Presentation Getting Started: Steps on the Way to a Science Career in Academia, Industry, or Government
Myrtle A. Davis, DVM, PhD, NIH/NCI, Bethesda, MD.
  Holiday Ballroom 1
  3:30 PM–4:30 PM   Host Mentor and Peer Mentor Meeting

  Calloway A
  4:30 PM–5:00 PM   Program Closing Session
Judith T. Zelikoff, PhD, CDI Co-Chair, New York University School of Medicine, Tuxedo Park, NY.
  Holiday Ballroom 1

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Sunday Undergraduate Education Program

This flyer promotes all of the Annual Meeting activities for undergraduate students.

Sunday, March 12, 8:00 AM to 5:00 PM

Hilton Baltimore Hotel

Chairperson(s): Judith T. Zelikoff, New York University School of Medicine, Tuxedo Park, NY; and Kimberly Hodge-Bell, Monsanto Company, St. Louis, MO.

Hosted by: Committee for Diversity Initiatives (CDI)

Endorser(s): Education Committee
Undergraduate Education Subcommittee

(Open to CDI Travel Award Recipients, Mentors, and Organizers and Undergraduates who register for the Sunday Undergraduate Education Program)

Undergraduates participate in this special introduction to topics in various toxicology disciplines, including an opportunity to explore and interpret data. Students discuss with graduate students and academic program directors how to submit strong graduate school applications and succeed in graduate school, as well as learning the merits of specific graduate programs. They also network with SOT mentors and toxicologists in various employment sectors to become more familiar with what life is like in different career paths in toxicology.

SCHEDULE (Events are held in the Hilton Baltimore Hotel unless otherwise noted.)

Sunday, March 12

  8:00 AM–12:00 Noon   Toxicology Presentations
Chairs: Judith T. Zelikoff, PhD, New York University School of Medicine, Tuxedo Park, NY; and Kimberly Hodge-Bell, PhD, DABT, Monsanto Company, St. Louis, MO.
  Holiday Ballroom 1
    8:05 AM–8:10 AM   Welcome
John B. Morris, PhD, SOT President, University of Connecticut, Storrs, CT.
   
    8:10 AM–8:55 AM   Drug Discovery Toxicology, A Paradigm Shift for Pharma
Yvonne Will, PhD, Pfizer Inc., Groton, CT.
   
    9:00 AM–9:45 AM   The Toxic Sins of Our Ancestors
Patrick Allard, PhD, University of California Los Angeles, Los Angeles, CA.
   
    9:55 AM–11:00 AM   Interactive Presentation Forensic Toxicology Overview
Michael J. McCabe, PhD, Robson Forensic Inc., Lancaster, PA.
   
    11:05 AM–11:55 AM   Human Health and Risk Assessment
Marquea D. King, PhD, US Environmental Protection Agency, Washington, DC.
   
  12:00 Noon–12:40 PM   Lunch and Networking

   
  12:55 PM–1:55 PM   Breakout Sessions for Students:
What Is Graduate School and What Can I Expect? A Graduate Student Perspective How to Get into Graduate School: An Academic Advisor’s Perspective

  Key Rooms 9–12
  12:55 PM–1:55 PM   Breakout Session for Advisors:
Tips for Advising Prospective Graduate Students or How to Get Your Students Accepted to Graduate School

  Calloway A
  2:05 PM–2:55 PM   Career Roundtable: Opportunities in Toxicology

  Key Rooms 9–12
  3:00 PM–5:00 PM   Open Time with Academic Toxicology Program Directors and Internship Sponsors

  Key Balloom 7
   
 

SOT Annual Meeting Events

  5:15 PM–6:30 PM   Awards Ceremony   Convention Center, Ballroom III
  6:30 PM–7:30 PM   Welcome Reception   Convention Center, Hall A
  7:30 PM–9:00 PM   Student/Postdoctoral Scholar Mixer   Holiday Ballroom 4
           

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Awards Ceremony Music

Sunday, March 12, 4:45 PM to 5:15 PM

Performed by Luke Brindley

Luke Brindley is a critically acclaimed singer/songwriter and fingerstyle guitarist. He tours nationally and has a dynamic live show. Along with his brothers, he owns Jammin Java, a premier music venue in Virginia presenting the finest local, regional, and nationally touring acts.

Awards Ceremony

Sunday, March 12, 5:15 PM to 6:30 PM

Please join the Awards Committee, in conjunction with SOT Council, the Board of Publications, and the Education Committee, as we honor distinguished scientists at our prestigious SOT Awards Ceremony. At the ceremony, SOT Awards are presented, as well as a number of grants, fellowships, and other honors for cutting-edge and novel research. Please refer to the Awards and Fellowships section of the SOT website for complete details at www.toxicology.org/awards.

Welcome Reception

Sunday, March 12, 6:30 PM to 7:30 PM

The Welcome Reception is a great opportunity to renew friendships and to make new acquaintances. Please join the Society in this kick-off of the Annual Meeting.

25-Year (Or More) Member Reception

Sunday, March 12, 7:00 PM to 8:00 PM

If you have been a member of the Society of Toxicology for 25 years or more, please join your colleagues in recognition and celebration of your contributions to the Society. Be sure to wear your membership anniversary pin.

Student/Postdoctoral Scholar Mixer

Sunday, March 12, 7:30 PM to 9:00 PM
Hilton Baltimore Hotel

(Ticket Required) 

Hosted by: Graduate Student Leadership Committee (GSLC)

This opportunity is for all students and postdoctoral scholars to gather, meet new colleagues, and reestablish relationships in an informal atmosphere at the beginning of the meeting. Learn about being involved in SOT by speaking with student leaders at the SOT component group posters. The GSLC Outstanding Leadership Award is presented during this event. Tickets are obtained at no cost by registering for the Mixer of the Annual Meeting Registration Form. Ticket and meeting badge are required. Complimentary refreshments and a cash bar will be available.

Global Gallery of Toxicology

Monday, March 13 to Wednesday, March 15, 9:15 AM to 4:30 PM
Representative Attended Poster Session—Monday, March 13, 11:45 AM to 12:15 PM

Adjacent to the SOT Pavilion in the ToxExpo Exhibit Hall

Toxicology societies from around the world are invited to participate in the Global Gallery of Toxicology. Now in its fifth year, posters of these sister societies will be prominently displayed during the meeting, showcasing their formation, key accomplishments, strategic initiatives, and activities. The goal of SOT and of all these societies is to increase the reliance of international decision-makers on the science of toxicology and to advance human health and disease prevention. For more information about participating in the Global Gallery, please contact Kevin Meritt (Tel: 703.438.3115) by January 6, 2017.

Regional Chapter, Special Interest Group, and Specialty Section Posters

Monday, March 13 to Wednesday, March 15, 9:15 AM to 4:30 PM
Representative Attended Poster Session—Monday, March 13, 11:45 AM to 12:15 PM

Adjacent to the SOT Pavilion in the ToxExpo Exhibit Hall

Dedicated poster space is available for the SOT Regional Chapters, Special Interest Groups, and Specialty Sections during the 2017 SOT Annual Meeting. Visit this poster area to learn more about the activities and opportunities presented by these SOT groups.

Global Collaboration Coffee

Monday, March 13, 9:30 AM to 11:30 AM

IUTOX invites all Global Gallery participants and representatives of societies from around the world to the Global Collaboration Coffee hosted by SOT. This event offers an opportunity for scientific leaders to connect and gain a better understanding of the initiatives of societies around the world. Following the coffee, attendees will adjourn together to the Global Gallery. To participate in the Global Collaboration Coffee or the Global Gallery, please contact Kevin Meritt (Tel: 703.438.3115).

Trainee Discussion with Plenary Session Presenters: Drs. Sorger and Mangravite

Monday, March 13, 9:45 AM to 10:45 AM

Rooms 304/305

(Ticket Required; Limited Seating) 

Lecturers: Peter Sorger, Harvard Medical School, Boston, MA; and Lara Mangravite, Sage Bionetworks, Seattle, WA.

Drs. Sorger and Mangravite will both meet informally for discussion with graduate students and postdoctoral scholars after their Plenary Session. Registration is limited to SOT graduate student and postdoctoral members.

In Vitro Toxicology Lecture and Luncheon

Monday, March 13, 11:30 AM to 1:00 PM
Human Organs-on-Chips Testing—Strengths and Challenges

Hilton Baltimore Ballroom 4

(Ticket Required) 

Chairperson(s): Barbara L. Kaplan, Mississippi State University, Mississippi State; Mindy Reynolds, Washington College, Chestertown, MD; Deb Hoivik, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT; and Alison Sanders, Icahn School of Medicine at Mount Sinai, New York, NY.

Lecturer: Anthony Bahinski, GlaxoSmithKline, King of Prussia, PA.

Supported by: An educational grant from the Colgate-Palmolive Company

Hosted by: Education Committee

The goal of the In Vitro Toxicology Lecture series is to feature important research using in vitro and alternative techniques to study basic mechanisms and to illustrate how these test methods benefit animal welfare by refining, reducing, and replacing animal use whenever it is feasible. Undergraduate students, graduate students, postdoctoral scholars, and recipients of Colgate-Palmolive awards are among the guests at the In Vitro Toxicology Lecture and Luncheon. Students and postdoctoral scholars register for $10 (nonrefundable) via the Annual Meeting registration.

Dr. Bahinski will discuss the potential for human organs-on-chips to provide better predictive power over existing preclinical animal models that often lead to failure of drug compounds late in their development. Organs-on-Chips are microfluidic cell culture devices that contain hollow micrometer-sized chambers inhabited by living cells that recreate the specialized multicellular architectures, tissue-tissue interfaces, physicochemical microenvironments and vascular perfusion necessary to recapitulate organ-level physiology in vitro. These biomimetic devices provide a window on human physiology as they enable real-time, high-resolution microscopic imaging as well as analysis of biochemical, genetic and metabolic activities of living cells when they are positioned within the context of functional tissue and organ units. These microsystems could potentially further our understanding of disease etiology and fill the critical need for improved model systems to predict efficacy, safety, bioavailability, and toxicology outcomes for candidate compounds. Luncheon participants will discuss a case study involving this new approach. Lunch service is available for those who arrive before 11:45 am.

Undergraduate Educator Network Meeting

Monday, March 13, 2:00 PM to 3:00 PM

Chairperson(s): Kristine L. Willett, University of Mississippi, University, MS.

Endorser(s): Education Committee
Undergraduate Education Subcommittee

The Education Committee and the Undergraduate Education Subcommittee are hosting the Undergraduate Educator Network Meeting for all faculty involved in the teaching of toxicology to undergraduates, trainees thinking about teaching, and for those interested in including toxicology at the undergraduate level. Hear an update on initiatives for undergraduate faculty, provide your input, and discuss shared interests. The hour-long meeting will be followed with
networking time.

Platform Session: Mechanisms of Toxicity: SPC Highlights Emerging Scientists

Tuesday, March 14, 9:30 AM to 12:15 PM

Room 310

Chairperson(s): Patricia Ganey, Michigan State University, East Lansing, MI; and Saber Hussain, US Air Force Research Laboratory, Dayton, OH.

New for the 2017 Annual Meeting: The Scientific Program Committee selected ten abstracts authored by students or postdocs that were of a particular high quality, on a variety of topics, in order to spotlight these young emerging toxicologists. We invite you to attend this Platform session to support your fellow students and postdocs.

Endorser(s): Scientific Program Committee

Identification, Confirmation, and Replication of Novel Non-Invasive MicroRNA Biomarkers to Detect Kidney Fibrosis in Humans. Mariana Cardenas Gonzalez, Harvard Medical School, Boston, MA.

Deficiencies in Mitochondrial Fission and Fusion Sensitize C. elegans to Arsenite-Induced Mitochondrial Dysfunction. Anthony Luz, Duke University, Durham, NC.

Effect on Cadmium-on-Stem Cell Population in Human Renal Proximal Tubular Cells. Swojani Shrestha, University of North Dakota, Grand Forks, ND.

Towards the Development of a Quantitative Adverse Outcome Pathway for Thyroperoxidase Inhibition: Thyroid Hormone Disruption and Neurodevelopmental Deficits. Iman Hassan, US EPA, Research Triangle Park, NC.

Characterization of the Modes of Action of Thiocyanate on the Thyroid Hormones Levels Using a Mechanistic Dose-Response Model. Marie-Emilie Willemin, US FDA/NCTR, Jefferson, AR.

Non-Dioxin-Like Polychlorinated Biphenyls Modify Gap Junctions to Specifically Disturb Human Neural Crest Cell Migration. Johanna Nyffeler, University of Konstanz, Konstanz, Germany.

A Mixture of 18 Anti-Androgens at Concentrations below Individual Chemical Effect Levels Produces Reproductive Tract Malformations in the Male Rat. Justin Conley, US EPA, Research Triangle Park, NC.

Prenatal Phthalate Mixture Exposure Adversely Affects Female Reproduction in Mice. Changqing Zhou, University of Illinois, Urbana, IL.

Comparison and Analysis of Toxcast Data with In Vivo Data for Food-Relevant Compounds Using the Risk21 Approach. Alexandra Turley, Michigan State University, East Lansing, MI, and ILSI-North America, Washington, DC.

Intraneuronal Delivery of a Single Domain Antibody Prevents Death to Lethal Doses of BoNT/A in a Murine Model of Botulism. Edwin Vazquez-Cintron, US Army Medical Research Institute of Chemical Defense, Edgewood, MD.

Trainee Discussion with Plenary Session Presenters: Drs. Yang and Barker

Tuesday, March 14, 9:45 AM to 10:45 AM

Rooms 304/305

(Ticket Required; Limited Seating)  

Lecturers: Jun J. Yang, St. Jude Children’s Research Hospital, Memphis, TN; and Richard Barker, University of Oxford, Oxford, United Kingdom

Drs. Yang and Barker will both meet informally for discussion with graduate students and postdoctoral scholars after their Plenary Session. Registration is limited to SOT graduate student and postdoctoral members.

Postdoctoral Assembly Luncheon

Tuesday, March 14, 12:00 Noon to 1:15 PM

(Ticket Required) 

Chairperson(s): Gabriel Knudsen, NCI, Research Triangle Park, NC.

Hosted by: Postdoctoral Assembly

The Postdoctoral Assembly (PDA) Luncheon is a casual event that encourages engagement and networking among postdoctoral scholars. Finishing up a discussion from your morning poster session? Leaving early to set up a poster or attend another meeting? That’s no problem; stop in when you can! Enjoy a buffet lunch while networking with others, including PDA officers, Postdoctoral Representatives, and SOT Councilors. This is the time for postdocs to relax, celebrate achievements, and have fun. At 12:45 pm, there will be a short program, which will include recognition of the Best Postdoctoral Publication Award recipients and the welcoming of the 2016–2017 PDA officers. Door prizes add even more fun to this lively event. Postdocs should reserve a ticket for $10 when registering for the Annual Meeting.

Career Exploration through Speed Informational Interviews

Tuesday, March 14, 1:20 PM to 2:40 PM

(Ticket Required) 

Chairperson(s): Natasha Caitlin, NIEHS-NTP, Research Triangle Park, NC; Alexandra Noël, Louisiana State University, Baton Rouge, LA; Co-Chairs: Gabriel Knudsen, NCI, Research Triangle Park, NC; Samantha McNeal, University of South Carolina, Columbia, SC; Daniel Spade, Brown University, Providence, RI; and Christopher Stewart, MPI Research, Mattawan, MI.

Hosted by: Postdoctoral Assembly
Toxicologists of African Origin

Endorser(s): Career Resource and Development Committee

Do you find yourself wondering what your career options are in the field of toxicology? Then this is the event for you! This career development special event is designed for graduate students and postdocs who want to gain insight into the different career sectors in toxicology. Groups of three trainees will rotate through a series of approximately eight-minute discussions with career representatives from academia, government, and industry. Trainees can ask the career representatives questions about their background, career path, the hiring process in their company/sector, and other aspects of identifying and pursuing career interests.

This session will provide an informal opportunity to gain insight about different employment sectors in toxicology through candid discussions in a casual setting. Graduate students and postdocs are encouraged to sign up for this event when they registering for the Annual Meeting, as registration will be limited to maximize the opportunity for small group discussion with career representatives.

Undergraduate Student Meeting

Tuesday, March 14, 3:30 PM to 4:45 PM

CC Room 330

Chairperson(s): Karen E. Stine, Auburn University at Montgomery, Montgomery, AL, and Kristine L. Willett, University of Mississippi, University, MS.

Hosted by: Education Committee
Undergraduate Education Subcommittee

Undergraduate students are encouraged to participate in an informal meeting to talk about shared interests related to career paths in toxicology, discuss undergraduate tox-related activities, and to provide feedback to the Undergraduate Education Subcommittee. Most of the meeting will be devoted to small group interaction with graduate students and postdoctoral scholars who can provide perspective and answer questions about toxicology graduate programs.

SOT Annual Business Meeting

Tuesday, March 14, 4:45 PM to 6:15 PM

SOT Members are invited and encouraged to attend the 56th SOT Annual Business Meeting. The agenda includes discussion of plans for next year, a financial summary, and a review of the 2016–2017 accomplishments.

Tox ShowDown

Tuesday, March 14, 7:30 PM to 9:00 PM

Hilton Baltimore Hotel

Chairperson(s): Phil Wexler, NIH-NLM, Bethesda, MD.

This is the sixth year of the Tox ShowDown, the toxicological quiz game par excellence. Three teams of three contestants each—the Endocrine Disruptors, the Free Radicals, and the Toxic Metabolites—battle each other to answer questions wholly, partially, or remotely related to toxicology. Topics cover the gamut, including the role of toxicology in history, current events, arts, culture, and society, not to mention science. The event features a cash bar and is a great opportunity to see how many questions you can answer correctly, while enjoying a good laugh. As always, there will be prizes for all participants and audience door prizes.

Trainee Discussion with Medical Research Council (MRC) Lecturer: Dr. Elliott

Wednesday, March 15, 9:45 AM to 10:45 AM

Room 304

(Ticket Required; Limited Seating)  

Lecturer: Paul Elliott, Imperial College, London, United Kingdom.

Dr. Elliott will meet informally for discussion with graduate students and postdoctoral scholars after his Keynote MRC Lecture. Registration is limited to SOT graduate student and postdoctoral members.

Poster Tours for Trainees

Monday, March 13 to Wednesday, March 15, Time Varies by Group

Meet at the Poster Tour Board in the Pratt Street Lobby near registration.

Hosted by: Postdoctoral Assembly

The Postdoctoral Assembly (PDA) organizes Poster Tours for Trainees for graduate students and postdoctoral scientists to participate in a one-hour, guided poster tour with an expert toxicologist. These small group tours provide the opportunity for trainees to take part in critical evaluation of cutting-edge toxicology methods and research findings and network with an expert toxicologist. Recruitment of individuals interested in being poster tour guides will begin in early December. Graduate student and postdoctoral scholar sign-up will open in early 2017. Details for each group will be distributed to the participants in advance of the meeting.

Chat with an Expert

Monday, March 13 to Thursday, March 16, Time Varies by Group

Meet at the Chat with an Expert Poster Board in the Pratt Street Lobby near Registration.

Hosted by: Graduate Student Leadership Committee (GSLC)

The purpose of Chat with an Expert is to provide graduate students and postdoctoral scholars with the opportunity to network informally with well-established toxicologists while obtaining career advice and meeting new colleagues. Small groups are composed by matching research interests of students and postdocs with those of an expert. The expert for each group identifies a time and a place for an informal meeting, and the group meets at the Chat with an Expert Poster before proceeding to the meeting location. This program also includes opportunities for postdocs to host informal meetings with graduate students. Expert registration is currently open. Graduate student/postdoc registration will open in early 2017. Details for each group meeting will be sent to participants in advance of the meeting.

Expert Registration

 

Regional Chapter Events

Monday, March 13

7:30 AM–8:00 AM

Central States Regional Chapter Meeting/Breakfast

7:30 AM–8:00 AM | B & O American Brasserie  

12:15 PM–2:00 PM

Mid-Atlantic Regional Chapter Business Meeting and Networking Luncheon

12:15 PM–2:00 PM | The Pratt Street Ale House  

4:45 PM–6:15 PM

Allegheny-Erie, Michigan, and Lake Ontario Regional Chapters Joint Reception

4:45 PM–6:15 PM | Hilton Baltimore   Ruth

5:30 PM–7:30 PM

Pacific Northwest Regional Chapter Reception

5:30 PM–7:30 PM | Phillips Seafood  

6:00 PM–10:00 PM

Southeastern Regional Chapter and University of Georgia Interdisciplinary Toxicology Program Reception

6:00 PM–10:00 PM | Luna Del Sea  

Tuesday, March 14

12:15 PM–2:00 PM

Northeast Regional Chapter Student Luncheon

12:15 PM–2:00 PM | Hilton Baltimore   Key Ballroom 9

6:00 PM–7:30 PM

Lone Star and South Central Regional Chapters Joint Mixer

6:00 PM–7:30 PM | The James Joyce Pub  

6:00 PM–10:00 PM

Southern California and Mountain West Regional Chapters Joint Reception

6:00 PM–10:00 PM | Ripley's Believe It or Not!  

6:30 PM–9:00 PM

National Capital Area Regional Chapter and John Hopkins University Joint Reception/Mixer

6:30 PM–9:00 PM | Pratt Street Ale House  

7:30 PM–10:30 PM

Northern California Regional Chapter Reception

7:30 PM–10:30 PM | Tir Na Nog Irish Bar and Grill  

Wednesday, March 15

12:00 PM–1:30 PM

Regional Chapter Collaboration and Communication Committee (RC4) Meeting

12:00 PM–1:30 PM | CC   Room 330

5:00 PM–6:30 PM

Ohio Valley Regional Chapter Reception

5:00 PM–6:30 PM | Pratt Street Ale House  

Special Interest Group Events

Monday, March 13

6:45 AM–7:45 AM

Women in Toxicology Special Interest Group Executive Committee Meeting

6:45 AM–7:45 AM | Hilton Baltimore   Mencken

12:00 PM–1:30 PM

Special Interest Group Collaboration Group Meeting

12:00 PM–1:30 PM | CC   Charles Street VIPSuite

4:45 PM–5:45 PM

Association of Scientist of Indian Origin Special Interest Group Career Talk with Toxperts

4:45 PM–5:45 PM | Hilton Baltimore   Peale

5:00 PM–9:00 PM

American Association of Chinese in Toxicology Special Interest Group Distinguished Chinese Toxicologist Lectureship Award and Reception

5:00 PM–9:00 PM | Hyatt Regency Baltimore   Constellation Ballroom A

5:30 PM–8:00 PM

Toxicologists of African Origin Special Interest Group Annual Reception

5:30 PM–8:00 PM | Inner Harbor Cruise  

6:30 PM–8:30 PM

Korean Toxicologists Association in America Special Interest Group Meeting/Reception

6:30 PM–8:30 PM | Pratt Street Ale House  

7:00 PM–9:30 PM

Association of Scientists of Indian Origin Special Interest Group Reception

7:00 PM–9:30 PM | Hilton Baltimore   Peale

Tuesday, March 14

12:15 PM–1:30 PM

American Association of Chinese in Toxicology Special Interest Group Career Development Workshop

12:15 PM–1:30 PM | CC   Room 302

6:15 PM–8:15 PM

Hispanic Organization of Toxicology Special Interest Group Reception and Awards Ceremony

6:15 PM–8:15 PM | Maryland Art Place  

Wednesday, March 15

12:15 PM–1:15 PM

Hispanic Organization of Toxicology Special Interest Group Mentoring Activity

12:15 PM–1:15 PM | CC   Room 341

5:00 PM–7:00 PM

Women in Toxicology Special Interest Group Reception

5:00 PM–7:00 PM | Hilton Baltimore   Holiday Ballroom 3

Specialty Section Events

Monday, March 13

6:30 AM–8:00 AM

Clinical and Translational Toxicology Specialty Section Officers Meeting

6:30 AM–8:00 AM | CC   Room 341

Dermal Toxicology Specialty Section Officers Meeting

6:30 AM–8:00 AM | CC   Room 341

Drug Discovery Toxicology Specialty Section Officers Meeting

6:30 AM–8:00 AM | Light Street Cafe  

Immunotoxicology Specialty Section Officers Meeting

6:30 AM–8:00 AM | CC   Room 341

In Vitro and Alternative Methods Specialty Section Officers Meeting

6:30 AM–8:00 AM | CC   Room 341

Mechanisms Specialty Section Officers Meeting

6:30 AM–8:00 AM | CC   Room 341

Neurotoxicology Specialty Section Officers Meeting

6:30 AM–8:00 AM | CC   Room 341

Regulatory and Safety Evaluation Specialty Section Officers Meeting

6:30 AM–8:00 AM | CC   Room 341

Risk Assessment Specialty Section Officers Meeting

6:30 AM–8:00 AM | CC   Room 341

7:00 AM–8:00 AM

Food Safety Specialty Section Officers Meeting

7:00 AM–8:00 AM | Miss Shirley's Cafe  

Reproductive and Developmental Toxicology Specialty Section Officers Meeting

7:00 AM–8:00 AM | CC   Room 311

12:00 PM–1:30 PM

Specialty Section Collaboration and Communication Group Meeting

12:00 PM–1:30 PM | CC   Room 330

12:15 PM–1:45 PM

Risk Assessment Specialty Section Mentoring Event

12:15 PM–1:45 PM | CC   Room 343

12:15 PM–2:00 PM

Comparative and Veterinary Specialty Section Meeting/Luncheon

12:15 PM–2:00 PM | Fogo de Chão  

Toxicologic and Exploratory Pathology Specialty Section Meeting/Luncheon

12:15 PM–2:00 PM | Fogo de Chão  

4:45 PM–5:45 PM

Immunotoxicology Specialty Section Mentoring Event

4:45 PM–5:45 PM | Hilton Baltimore   Key Ballroom 9

5:00 PM–6:00 PM

Medical Device and Combination Product Specialty Section Coffee Q&A Mentoring Event

5:00 PM–6:00 PM | Hilton Baltimore   Key Ballroom 5

6:00 PM–7:30 PM

Drug Discovery Toxicology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 8

Immunotoxicology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 9

Inhalation and Respiratory Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 6

Medical Device and Combination Product Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 5

Metals Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 11

Nanotoxicology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 7

Risk Assessment Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Holiday Ballroom 4

6:00 PM–8:00 PM

Food Safety Specialty Section Meeting/Reception

6:00 PM–8:00 PM | Pratt Street Ale House  

7:30 PM–9:00 PM

In Vitro and Alternative Methods Specialty Section Networking Event

7:30 PM–9:00 PM | Sheraton Inner Harbor   Chesapeake Ballroom 1

Tuesday, March 14

12:15 PM–1:45 PM

Ethical, Legal, and Social Issues Specialty Section Meeting/Luncheon

12:15 PM–1:45 PM | CC   Room 341

In Vitro and Alternative Methods Specialty Section Meeting/Luncheon

12:15 PM–1:45 PM | Hilton Baltimore   Holiday Ballroom 4

12:15 PM–2:00 PM

Biotechnology Specialty Section Mentoring Event

12:15 PM–2:00 PM | Hilton Baltimore   Key Ballroom 11

12:30 PM–1:30 PM

Carcinogenesis Specialty Section Officers Meeting

12:30 PM–1:30 PM | CC   Room 311

6:00 PM–7:30 PM

Biological Modeling Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 9

Biotechnology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 11

Dermal Toxicology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 7

Mechanisms Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 6

Regulatory and Safety Evaluation Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 5

Reproductive and Developmental Toxicology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Holiday Ballroom 4

Stem Cells Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 8

Wednesday, March 15

6:30 AM–8:00 AM

Regulatory and Safety Evaluation Specialty Section Breakfast: First-in-Man Clinical Trials—Recent Experiences in Europe

6:30 AM–8:00 AM | CC   Room 324

12:15 PM–1:15 PM

Molecular and Systems Biology Specialty Section Mentoring Event

12:15 PM–1:15 PM | Fogo de Chão  

12:15 PM–1:45 PM

Cardiovascular Toxicology Specialty Section Meeting/Luncheon

12:15 PM–1:45 PM | CC   Room 302

Drug Discovery Toxicology Specialty Section Mentoring Event

12:15 PM–1:45 PM | CC   Room 305

Occupational and Public Health Specialty Section Meeting/Luncheon

12:15 PM–1:45 PM | CC   Room 324

6:00 PM–7:30 PM

Carcinogenesis Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 5

Clinical and Translational Toxicology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 8

Mixtures Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 9

Molecular and Systems Biology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 11

Neurotoxicology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 6

Ocular Toxicology Specialty Section Meeting/Reception

6:00 PM–7:30 PM | Hilton Baltimore   Key Ballroom 7

Satellite Meetings

Each year, SOT endorses several Satellite Meetings that are held in conjunction with the Annual Meeting. Satellite Meetings are organized around scientific topics related to toxicology and will be held in and around the Baltimore area. Proposals for a Satellite Meeting should be sent by email to Heidi Prange to the attention of Patricia Ganey, SOT vice president and Scientific Program Committee chair.

Requests approved by January 10, 2017, will be published in the Program. All requests must be received by January 27, 2017.

Metabolic Syndrome and Associated Diseases: From the Bench to the Clinic
(SOT Contemporary Concepts in Toxicology [CCT] meeting)

Saturday, March 11, 8:45 AM to 5:30 PM

Baltimore Convention Center, Room 314

(Separate Registration Required)

Hosted by: SOT Metabolic Syndrome CCT Organizing Committee

This conference will examine current knowledge on metabolic diseases, including developmental aspects and challenges in therapeutic strategies for associated diseases. It also will include a poster session and time devoted to a discussion of mechanisms thought to play important roles in the syndrome/diseases and provide insight into drugs and environmental agents thought to influence them.

Visit the SOT website to register for this CCT meeting, view the agenda, and find abstract submission information.


Horizons and Challenges in Organotypic Culture Models for Predictive Toxicology

Saturday, March 11, 9:00 AM to 5:00 PM

Baltimore Convention Center, Room 310
Hosted by: Barbara Klieforth, US EPA, Washington, DC; William L. Murphy, University of Wisconsin, Madison, WI; and M. Shane Hutson, Vanderbilt University, Nashville, TN.

Purpose of the Meeting: The ability to create microphysiological organotypic culture models provide an opportunity for a paradigm shift and the advancement of alternative, more public health relevant and efficient toxicity testing methods. These Organotypic Culture Models for Predictive Toxicology (OCM-PTs) will be faster, less costly, and more scientifically robust than many currently available methods. Refined assessment models of how organs and tissues respond to environmental chemicals, coupled with the rigorous requirements of contemporary toxicology screening, will be critical to informing implementation of the Frank R. Lautenberg Chemical Safety for the 21st Century Act, the amended Toxic Substances Control Act. The development of OCM-PTs are complicated by their highly interdisciplinary nature. New directions, challenges, and needs will be discussed in order to bridge the research disciplines needed to move the cutting-edge science on OCM-PTs forward. 

Sessions will be held with young investigators from the OCM-PT Centers at the University of Wisconsin (Human Models for Analysis of Pathways Center), Vanderbilt University/University of Pittsburgh (the Vanderbilt-Pittsburgh Resource for Organotypic Models for Predictive Toxicology), University of Washington (the University of Washington Predictive Toxicology Center), Texas A&M/North Carolina State University (the Cardiotoxicity Adverse Outcome Pathway Center), and their collaborators in the Chemical Safety for Sustainability Program at the US Environmental Protection Agency.

SCHEDULE

  8:00 AM–9:00 AM   Poster set up and display
  9:00 AM–9:10 AM   Welcome and Introduction
Jeff Frithsen, US EPA Chemical Safety for Sustainability National Program Director
  9:10 AM–9:30 AM   Status of OCM-PT Co-Operatives with VTM Research
Tom Knudsen, US EPA/NCCT
  9:30 AM–10:30 AM   Mammary Development and Breast Cancer
Moderator: Jill Franzosa, US EPA/CSS
  10:30 AM–11:30 AM   Novel Bioengineering Platforms for Developmental Toxicity
Moderator: Sid Hunter, US EPA/NHEERL
  11:30 AM–12:45 PM   Cardiovascular Development and Toxicity 
Moderator: Barbara Klieforth, US EPA/NCER
  12:30 PM–1:45 PM   Lunch Break and Poster Viewing
  1:45 PM–3:00 PM   Paired Microphysiological Systems and Integrative Simulation
Moderator: Tom Knudsen, US EPA/NCCT
  3:00 PM–5:00 PM   Attended Poster Session

Full Agenda 
Registration: Open registration. No fee to register and attend.

For more information on this Satellite Meeting, contact Barbara Klieforth.

Updates on Activities Related to 21st Century Toxicology and Related Efforts: Invited Presentations and Open Microphone

Thursday, March 16, 12:30 PM to 4:00 PM

The Lord Baltimore Hotel

Organized by: The Center for Alternatives to Animal Testing (CAAT)and The Human Toxicology Project Consortium, and The Human Toxome Project

If you’re planning to attend the Society of Toxicology (SOT) Annual Meeting in Baltimore this March, please join the Center for Alternatives to Animal Testing (CAAT), The Human Toxicology Project Consortium (HTPC), and The Human Toxome Project Consortium for our annual satellite meeting on 21st century toxicology activities and related efforts. The satellite meeting provides an informal setting in which interested stakeholders can update each other on these important topics.

The meeting will feature a number of invited presentations but also leave time for an “open microphone” segment in which participants are welcome to give brief presentations on germane topics, with or without a few slides.

SCHEDULE
  12:30 PM   Box Lunch (for pre-registered participants)

Welcome
Thomas Hartung, Johns Hopkins University
  1:00 PM   Invited Speakers (10 minute presentations each followed by 5 minutes of discussion)
      ToxCast Update
Russell Thomas, US Environmental Protection Agency
      EDSP21 Update
Stanley Barone, US Environmental Protection Agency
      Tox21 Update
Richard Paules, US National Toxicology Program
      TT21C Update
Rebecca Clewell, ScitoVision
      NICEATM Update
Warren Casey, NICEATM
      EU Tox-Risk Update
Michael Schwarz, University of Tuebingen
      Evidence-Based Toxicology Update
Katya Tsouin, EBT Johns Hopkins
      CAAT’s Read-Across Initiative and Human Toxome-Related Activity Update
Thomas Hartung, Johns Hopkins
      Human Toxicology Project Consortium Update
Catherine Willett, HTPC
  3:15 PM   Open microphone for additional presentations and discussion
  4:00 PM   Adjourn

Please register for the satellite meeting by email Jamie DeRita at your earliest convenience. Box lunches will be available to those who have pre-registered.

Read-Across in the 21st Century

Friday, March 17, 12:30 PM to 4:00 PM

The Lord Baltimore Hotel/The Baltimore Theater

Organized by: The Center for Alternatives to Animal Testing (CAAT)

If you’re planning to attend the Society of Toxicology (SOT) Annual Meeting in Baltimore this March, please join the Center for Alternatives to Animal Testing (CAAT) for our satellite meeting on read-across in the 21st century toxicology. The satellite meeting provides an informal setting in which interested stakeholders can update each other on these important topics.

The meeting will feature several invited presentations, but also leave time for an “open microphone” segment in which participants are welcome to give brief presentations on germane topics, with or without a few slides.

SCHEDULE
  10:00 AM   Welcome
Thomas Hartung, Johns Hopkins University
  10:30 AM   Invited Speakers (30 minute presentations each followed by 10 minutes of discussion)
Dr. Yamada, NIHS
Dr. Huuskonen or Eric Stilgenbauer, ECHA
  12:00 Noon   Box Lunch (for those who have pregistered)
  1:00 PM   TBA, Health Canada
Dr. Verloo, EFSA
TBA, NICNAS
  2:00 PM   Coffee Break
  2:45 PM   Open microphone for additional presentations and discussion
  3:45 PM   Session Wrap Up
  4:00 PM   Adjourn

Please register for the satellite meeting by email Jamie DeRita at your earliest convenience. Box lunches will be available to those who have pre-registered.

Fun Run

Fun Run sponsorship opportunities available.

Tuesday, March 14, 6:30 AM

Camden Yards