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Scientific Sessions

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Monday, March 12

9:15 AM to 12:00 Noon

Advanced Imaging and Microscopy for Retinal Disease and Toxicity

S IAT  Symposium/Innovations in Applied Toxicology Session

Chairperson(s):

Melva Rios Blanco, Allergan, Irvine, CA; and Donald Fox, Robson Forensic Inc., Philadelphia, PA.

Primary Endorser:

Ocular Toxicology Specialty Section

Other Endorser(s):

Clinical and Translational Toxicology Specialty Section
Neurotoxicology Specialty Section


The three major challenges in the study of acquired and innate diseases, as well as drugs and toxicants that affect the retina in man and experimental animals, are: difficulty in early noninvasive detection of decreased visual function and/or loss with conventional tools and techniques; determination of the cellular site(s) and mechanism(s) of action; and monitoring of progression and/or repair following different treatment/therapeutic regimens. Advances in ocular imaging techniques, for man and experimental animals, provide the ability to noninvasively image individual retinal cells, the optic nerve, and retinal vasculature in living eyes. These new noninvasive techniques enable the clinician and scientist to detect, monitor, and treat retinal disease and injury earlier; to visualize the site of action with greater specificity; and to follow the progress of treatment longitudinally. Moreover, the visualization and determination of the cellular, subcellular, and ultrastructural site and mechanisms of injury in retinas from donated human eyes and experimental animals require a variety of different sophisticated imaging techniques. These newer noninvasive and experimental techniques are readily applicable to the study of drugs and toxicants that produce pathophysiological alterations similar to known retinal and neurodegenerative diseases, or that exacerbate such existing conditions. The objective of the session is to present state-of-the-art research approaches to clinical and experimental animal model imaging and their utility in toxicological research and to show how the obtained data can be utilized for translational research. The presentations will cover the study of different cell populations within the retina and of the supporting vascular networks. Each presentation will share the fundamental aspects of the retina and imaging modalities employed in their work. The first speaker will demonstrate the utility of various optical coherence tomography (OCT) techniques and adaptive optics (AO) to assess morphological and functional changes associated with glaucoma disease progression and treatment in experimental models and evaluation of changes in the retinal nerve fiber layer for early detection. The second speaker will show the utility of AO techniques coupled to advanced imaging techniques to precisely deliver visual stimuli to individual photoreceptors, such that visual function and retinal structure can be studied with cellular resolution in normal and diseased retinas. The third speaker will describe a combination of microscopic techniques from the cellular to ultrastructural to three-dimensional sub-structural levels that elucidate mechanisms of mitochondrial-mediated retinotoxicity in both human and experimental animals. The final speaker will present research focused on the role of hematopoietic stem cells (HSCs) in the physiological and pathological vascular repair in the retina and the utility of imaging and other techniques to study this phenomenon in experimental animals. Overall, the session will accomplish three goals. First, it will introduce and educate the scientific community on the use of state-of-the-art approaches to noninvasive ocular imaging for the early detection, assessment, progression, and treatment of retinal and vascular damage in man and experimental animals. Second, it will enhance the understanding of retinal sites and mechanisms of action of injury. Third, it will provide a basis for determining the translatability of experimental data to humans. The session will be of interest to basic scientists, clinicians, and researchers engaged in drug development and testing.


Introduction. Melva Rios Blanco, Allergan, Irvine, CA.

Cellular and Structural Imaging Techniques in Glaucoma Diagnosis and Treatment. Stuart McKinnon, Duke University, Durham, NC.

Adaptive Optics Imaging to Study Retinal Degeneration and Response to Treatment. Jacque Duncan, University of California San Francisco, San Francisco, CA.

Mitochondria-Mediated Retinotoxicity: Determining Pathophysiological Mechanisms Using Multifaceted Image Analysis and Biochemical Techniques. Donald Fox, Robson Forensic, Inc., Philadelphia, PA.

"Seeing" iPSCs in the Retina during Retinal Repair. Maria Grant, University of Alabama Birmingham, Birmingham, AL.

Cancer Risk Assessment of PAH Mixtures: Current and Future Directions

S Symposium

Chairperson(s):

M. Margaret Pratt, US EPA, Washington, DC; and Cynthia Rider, NIEHS, Research Triangle Park, NC.

Primary Endorser:

Mixtures Specialty Section

Other Endorser(s):

Carcinogenesis Specialty Section


The cancer risk posed by exposures to polycyclic aromatic hydrocarbons (PAHs) has long been a public health concern. The two-year rodent cancer bioassay remains the definitive source of information employed for cancer risk assessment, and using such conventional approaches, the US Environmental Protection Agency (US EPA) is actively working to address the need for an updated and expanded document that serves as the agency’s approach for assessing cancer risk from exposure to PAH mixtures. However, the time and resources required to perform two-year rodent bioassays for the range of environmental PAH mixtures are significant and serve as a disincentive to the development of these kinds of data. Recent trends in toxicology and risk assessment offer opportunities to explore less costly and more rapid alternative approaches using non-apical endpoints for estimating the cancer risk posed by PAH mixtures; however, alternative approaches require critical evaluation to ensure that they represent an improvement from the current approach. The approaches that will be discussed in this session include PAH whole mixtures risk assessment, component-based approaches, use of shorter-term in vitro and in vivo assays to provide cancer-relevant data, and a greater focus on adverse outcome pathways to understand cumulative risk. This will be followed by a panel discussion of the merits of these alternative approaches and what steps are needed to move toward validation. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.


PAH RPF Mixtures Cancer Risk Estimation: Implementing Peer Review Recommendations. M. Margaret Pratt, US EPA, Washington, DC.

In Vitro Screening to In Vivo Testing of Polycyclic Aromatic Hydrocarbons at the National Toxicology Program. Cynthia Rider, NIEHS, Research Triangle Park, NC.

The Genetic Toxicity of Complex Mixtures of Polycyclic Aromatic Hydrocarbons: Evaluating the Dose-Additivity Assumption Using a Transgenic Mouse Model. Paul White, Heath Canada, Ottawa, ON, Canada.

Mechanism-Based Classification of PAH Mixtures to Predict Carcinogenic Potential. Susan Tilton, Oregon State University, Corvallis, OR.

Use of Non-Apical Assay Data in an Integrated Approach to Testing and Assessment of Chemical Mixtures in the Environment: The Advent of Adverse Outcome Pathway Footprinting. Jason Lambert, US EPA, Cincinnati, OH.

Novel Insights on Chemical-Induced Immunotoxicity: Microvesicles and microRNA Dysregulation

S Symposium

Chairperson(s):

Emanuela Corsini, University of Milan, Milan, Italy; and Stacey Anderson, NIOSH, Morgantown, WV.

Primary Endorser:

Immunotoxicology Specialty Section


Eukaryotic cells contain extracellular organelles named microvesicles (e.g., exosomes, nanovesicles) that are released into the microenvironment. Microvesicles and their main content microRNAs are believed to play a central role in many physiological and pathological processes, including inflammation, autoimmunity, atherosclerosis, and cancer. miRNAs, a class of non-protein-coding RNA molecules negatively regulating mRNA translation, have been shown to be involved in several cellular processes, and their role in toxicology is emerging. The miRNA-mediated coordinated control of gene expression has been shown to be crucial in immunity, promoting and finely regulating appropriate immune responses. Both microRNA and microvesicles are a very promising tool in identifying early alterations induced by chemical exposure, which can revolutionize both monitoring and toxicological assessment. The aim of this session is to provide novel insights on the mechanisms of action of immunotoxic compounds focusing on microRNA and microvesicles. Recently, differential expressions of miRNAs and association with several immunologic and inflammatory disorders have been reported, which have important implications in immunotoxicology assessment. miRNAs can influence regulatory mechanisms of inflammation in both inducing and contrasting acute and chronic inflammation. In addition, research on microvesicles also is an emerging and developing field. Studies available to date identified several exposures or lifestyle factors able to modify the trafficking of microvesicles, including air pollutants, cigarette smoke, and oxidative stress. The first speaker will guide the audience into the world of microRNAs from discovery to their role in physiological and pathological conditions, with emphasis on tumors and immunosurveillance, to their use as biomarkers. The second speaker will present data showing influences of environmental exposures on EV-encapsulated RNAs and potential links with several adverse health outcomes, including immunotoxicity. The last two speakers will focus on the role of microRNAs in allergic phenomena, both in humans and in experimental models. Challenges, limitations, and opportunities in this emerging field in environmental health sciences will be discussed.


Introduction. George Calin, University of Texas, Houston, TX.

Effects of Environmental Exposures on Microvesicles Release and Their Contents. Andrea Baccarelli, Columbia University, New York, NY.

Circulating microRNAs and Prediction of Airway Hyperresponsiveness. Kelan Tantisira, Harvard Medical School, Boston, MA.

microRNA in Experimental Models of Chemical Sensitization. Stacey Anderson, NIOSH, Morgantown, WV.

Toxicological Implication of Copper in Neurodegenerative Diseases

S Symposium

Chairperson(s):

Masashi Kitazawa, University of California Irvine, Irvine, CA; and Wei Zheng, Purdue University, West Lafayette, IN.

Primary Endorser:

Metals Specialty Section

Other Endorser(s):

Neurotoxicology Specialty Section


Copper (Cu) is an essential transition metal and required for many normal physiological functions, including energy production, free radical scavenging, connective tissue production, iron mobilization, and neurotransmission. However, excessive intake due to occupational or environmental exposure to divalent Cu(II) has been implicated as a risk for various human diseases. When administered, almost all Cu ions are bound to ceruloplasmin (Cp), and the remainder, non-Cp bound Cu (labile Cu), is bound to albumin, transcuprein, various peptides, and amino acids in plasma. For its chemical reactivity, the plasma level of free Cu is tightly controlled by the above-mentioned Cu-binding proteins. Recent studies have clearly indicated that environmental exposure to Cu in adults accelerates cognitive decline and may increase the risk of developing Alzheimer’s disease (AD)-like neuropathology by elevating non-ceruloplasmin-bound Cu in plasma. This session will bring together the experts who are actively engaging in investigating chemistry of Cu in biological systems, Cu neurotoxicity, and its underlying cellular and molecular mechanisms to discuss the toxicological implications of Cu in neurodegenerative diseases. After a brief introduction of Cu in health and human diseases, the first speaker will highlight the mechanisms by which Cu is transported in and out of the brain through the blood-brain barrier (BBB) and blood-CSF barrier and how the altered Cu transport processes in brain barriers may cause Cu dysregulation, leading to Parkinsonian disorders (PD). The second speaker will present new evidence that Cu controls MMP activity and CLUT-1 levels and how these changes lead to BBB dysfunction in the aged brain in conjunction with the role of Cu in regulating the endothelial lipoprotein receptor-related protein 1 (LRP1) as one possible mechanism increasing the risk for AD. The third speaker will further expand the subject by addressing the immunomodulatory and multifactorial influences of Cu on Aß clearance in the brain and how microRNAs play a critical role in the Cu-mediated down-regulation of LRP1 in the endothelial cells. The fourth speaker will focus on the unique structural chemistry of Cu in its interaction with Aß and how copper positions within the fibrillary structure of Aß and promotes its assembly by using highly sophisticated nanoscience technology. The final speaker will introduce the role of Cu in adult neurogenesis in the subventricular zone. New data unveiling the mechanism by which Cu regulates the critical steps leading to migration and differentiation of neural stem cells in the SVZ-rostral migratory stream pathway, and possible implication in the involvement of Cu in PD, also will be presented. Overall, this session will present the latest findings on the structural, genetic, cellular, and molecular mechanisms of Cu neurotoxicity linking neurodegenerative diseases such as AD and PD. The session will capture the broad interest of those engaged in toxicological research of neurodevelopment and neurodegenerative diseases, neuroscience, neurotoxicology, metal biology, and nanoscience.


Regulation of Copper Homeostasis by the Brain Barrier Systems: Implications in Neurodegenerative Diseases. Andrew Monnott, Cardno-ChemRisk, San Francisco, CA.

Brain Capillary Copper and the Accumulation of CNS Proteins Associated with Neurodegeneration and Dementia. Rashid Deane, University of Rochester, Rochester, NY.

Multifactorial Role of Copper Toxicity on Modulating Amyloid-Beta Clearance Via microRNA and Inflammation. Masashi Kitazawa, University of California Irvine, Irvine, CA.

Amyloid-Copper Complexes and Approaches to Heterogeneity in Biological Systems. Paul Weiss, University of California Los Angeles, Los Angeles, CA.

Does Copper Play a Role in Adult Neurogenesis in Subventricular Zone? Wei Zheng, Purdue University, West Lafayette, IN.

Understanding the Molecular Mechanisms of Zika Virus Reproductive and Developmental Toxicity

S Symposium

Chairperson(s):

Pedro Del Valle, US FDA, Silver Spring, MD; and Elena Hernandez-Ramon, NIH, Bethesda, MD.

Primary Endorser:

Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):

Biotechnology Specialty Section
Clinical and Translational Toxicology Specialty Section


Zika virus (ZIKV) is related to the Yellow fever, West Nile, Japanese encephalitis, and Dengue fever viruses, all classified under the genus Flavivirus that belongs to the family Flaviviridae. Symptoms of infection may include a rash, itching, fever, muscle pain, conjunctivitis, nausea, vomiting, and headaches. ZIKV was isolated from a rhesus macaque in the Zika forest in Uganda in 1947, from mosquitos in 1948 in Africa, from Asian countries in the 1960s, and reached the Americas in 2015. Outbreaks have been reported in Micronesia (2007), French Polynesia (2014), and Brazil (2015). By January 2016, autochthonous cases of ZIKV were reported in more than 50 countries in South, Central, and North America, and the Caribbean, with more than 35,000 cases of the mosquito-borne disease in the United States. ZIKV in pregnant women is reported to cause a wide spectrum of fetal malformations, collectively called congenital Zika syndrome (CZS), that include microcephaly, absent or poorly developed brain structures, retinal damage, hearing deficits, and impaired growth. This session will explore recent findings that have begun to link ZIKV infection with male testicular damage and potential human male infertility and with congenital malformations, microcephaly, and other brain malformations and birth defects. The session also will include an integral discussion of pre-clinical trials and the role of vector control approaches to reduce/prevent ZIKV infection. The introduction will include a brief overview of the ZIKV infection during outbreaks, with emphasis on the current status of the outbreak in the Americas. ZIKV is primarily spread by the daytime-active female Aedes aegypti mosquito, and several mechanisms of ZIKV replication and tissue tropism are being investigated. Evidence that ZIKV requires the ubiquitin-proteasome system for replication and the hijacking of the host ubiquitin system will be discussed. Understanding the molecular mechanisms of replication is critical to identifying existing or developing new drugs that can prevent or stop viral infection. ZIKV can spread from mother to child during pregnancy or at delivery. Infection during pregnancy is reported to cause CZS; scientists in Brazil used pregnant SJL mice to provide evidence that the Brazilian ZIKV strain crosses the placenta, infects fetuses, and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, resulting in impaired neurodevelopment. Research continues to further understand the mechanisms of fetal infection and pathogenesis to identify prevention methods, as the cases of newborns with congenital malformations rise. ZIKV infection also is spread by sexual transmission, especially from symptomatic men to women through the semen. A male mouse model of ZIKV infection was developed by scientists at Washington University in St. Louis to show that ZIKV destroys testicular germ cells, which results in reduction of testosterone levels, inhibin B levels, sperm count, and fertility. The potential impact of the virus on the reproductive health of infected men is unclear, and further research is needed. The US Zika pregnancy registry reported that from 2016 to August 2017, there were 1,784 completed pregnancies with or without birth defects, of which there were 91 liveborn infants and eight pregnancy losses with birth defects, all with laboratory evidence of possible ZIKV infection. The international concern for the fast emergence of ZIKV infection prompted global efforts to find solutions for the ZIKV threat. Approaches include testing current antiviral treatments, developing new drugs, developing vaccines, and implementing vector control strategies. A limited number of drugs and antiviral compounds have been identified using the drug re-purposing screen approach, though drug development has not progressed as fast as expected. Vaccine development for ZIKV has advanced rapidly, capitalizing on previous vaccine development programs for similar diseases like West Nile, Chikungunya, Dengue, and Ebola. Vector control strategies have included a wide-range of mosquito-control methods, such as personal protective measures, breeding environment reduction and larval control, and biological and chemical adulticides measures. Speakers will show that further understanding of the underlying mechanisms of infection and reproductive and developmental toxicity will aid in the design of potential therapies to prevent birth defects; timely implementation of vector control strategies may be effective in the prevention and reduction of ZIKV infection.


Introduction: A Brief Overview of Zika Virus Infection and Current Magnitude of Infection. Pedro Del Valle, US FDA, Silver Spring, MD.

The Role of the Host Ubiquitin System in Zika Virus Replication and Tissue Tropism. Ricardo Rajsbaum, University of Texas Medical Branch, Galveston, TX.

Zika Congenital Syndrome in Murine Experimental Model. Jean Pierre S. Peron, University of São Paulo, São Paulo, Brazil.

Mouse Model of Zika Virus Infection in Testis and Its Potential Relevance to Mechanism of Infection in Human Testis and Male Infertility. Prabagran Esakky, Washington University School of Medicine in St. Louis, St. Louis, MO.

Protective Efficacy of Multiple Vaccine Platforms against Zika Virus Challenge in Rhesus Monkeys. Rafael Larroca, Harvard Medical School, Boston, MA.

Integrated Pest Management: A Multifaceted Approach to Vector Control. Elizabeth Mendez, US EPA, Washington, DC.

Assessing the Dose of Particles in Toxicological Studies: Advances in Dosimetry Models for In Vitro and In Vivo Applications in Light of Risk Assessment

W Workshop

Chairperson(s):

Flemming Cassee, Rijksinstituut voor Volksgezondheid en Milieu (RIVM) and University of Utrecht, Bilthoven, Netherlands; and Justin Teeguarden, Pacific Northwest National Laboratory, Richland, WA.

Primary Endorser:

Inhalation and Respiratory Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Risk Assessment Specialty Section


Emerging hybrid, experimental/computational approaches to cellular dosimetry can be used by particle toxicologists to accurately calculate the delivered dose to cells for various particles and under different in vitro experimental conditions as a function of exposure time. Likewise, in vivo lung dosimetry models allow researchers to estimate the delivered particle dose in any region of the respiratory system, as well as study the implications of particle properties and breathing parameters for diverse animal species. Moreover, knowing the deposited dose also will facilitate the extrapolation from experimental animals (rat, mouse, rabbit, pig, and monkey) to humans of all ages. Most importantly, incorporating such dosimetric methodologies in the study design enables particle toxicologists to bring in vitro and in vivo doses to the same scale, an important step towards the development and validation of in vitro cellular screening assays.


Introduction: Needs for In Vitro Modeling for Risk Assessment. Justin Teeguarden, Pacific Northwest Laboratory, Richland, WA.

Advances in In Vitro Particle Dosimetry Continuum to Assess the Dose Based on Concentrations. Philip Demokritou, Harvard T.H. Chan School of Public Health, Boston, MA.

Demonstration: A Standardized, Integrated Methodology across the ENM Dispersion Preparation-Colloidal Characterization-Cellular Dosimetry. Glen Deloid, Harvard T.H. Chan School of Public Health, Boston, MA.

Modeling the Dose (Rate) in Rodents and Humans Including Demonstrations. Flemming Cassee, National Institute for Public Health and the Environment (RIVM) of the Netherlands and University of Utrecht, Bilthoven, Netherlands.

Defining the Dose of Particles in Toxicological Studies: Applications of Advances in In Vitro and In Vivo Dosimetry Models in Risk Assessment. Günter Oberdörster, University of Rochester, Rochester, NY.

Fate of Inhaled Particle-Gas Mixture in the Respiratory Tract. Bahman Asgharian, Applied Research Associates, Raleigh, NC.

Predicting Drug-Induced Cholestatic Injury in Humans

W Workshop

Chairperson(s):

James McKim, Western Michigan University Homer Stryker M.D. School of Medicine and IONTOX, Kalamazoo, MI; and Mathieu Vinken, Vrije Universiteit Brussel, Brussels, Belgium.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Mechanisms Specialty Section


Drug-induced liver injury is a major reason of failure during the premarketing and postmarketing phases of drug development. Being responsible for more than 50% of all cases of acute liver failure worldwide, drug-induced liver injury is equally of high clinical concern. As such, up to 40% of drug-induced liver injury patients present a cholestastic liver insult pattern. Cholestasis is derived from the Greek words chole and stasis meaning bile and halting, respectively, and denotes any situation of impaired bile secretion with concomitant accumulation of noxious bile acids in the liver or systemic circulation. Drug-induced cholestasis typically, though not uniquely, starts by inhibition of one or more drug transporters directly leading to bile acid retention in the liver. This triggers a deteriorative response associated with oxidative stress, inflammation, and cell death. In parallel, an adaptive response is initiated, which is aimed at restricting bile acid synthesis and influx, while promoting bile acid efflux. In fact, these mechanisms have been embedded recently in an adverse outcome pathway construct in order to further facilitate predictive toxicology. Several additional key events in drug-induced cholestatic liver injury have been identified, including endoplasmic reticulum stress and mitochondrial impairment. Simultaneously, a number of human-based in silico (e.g., DILIsym), ex vivo (e.g., precision-cut liver slices), and in vitro (e.g., sandwich cultures of human hepatocytes and two-compartment systems) models have been introduced to mechanistically study drug-induced cholestatic injury. Such alternative animal-free models are cordially welcomed, not only because of ethical reasons, but also given the fact that preclinical animal models are not adequate predictors of human drug-induced liver injuries due to interspecies differences in bile acid profiles, transport, and regulation. These non-animal methods, especially when combined, are able to accurately and quantitatively predict drug-induced cholestatic liver injury, thus emphasizing their overall clinical relevance.


’Omics-Based In Vitro Verification of an Adverse Outcome Pathway of Cholestatic Liver Injury. Mathieu Vinken, Vrije Universiteit Brussel, Brussels, Belgium.

Mechanistic Modeling of Cholestasis: Clinical Relevance. Kim Brouwer, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Precision-Cut Liver Slices as Model for Drug-Induced Cholestasis. Geny Groothuis, University of Groningen, Groningen, Netherlands.

Prediction of Cholestatic Hepatotoxicity: Integration of Transporter Regulation and Adaptive Response. Kenneth Brouwer, Qualyst Transporter Solutions LLC, Durham, NC.

An Integrated In Vitro Organ Platform to Evaluate Cholestasis. James McKim, Western Michigan University Homer Stryker M.D. School of Medicine and IONTOX, Kalamazoo, MI.

Toxicology's Next Grand Challenge: Embracing Exposure Science for Effective Public Health Protection

W Workshop

Chairperson(s):

Claire Terry, Dow AgroSciences, Indianapolis, IN; and Timothy Gant, Public Health England, Chilton, United Kingdom.

Primary Endorser:

Risk Assessment Specialty Section

Other Endorser(s):

Occupational and Public Health Specialty Section
Regulatory and Safety Evaluation Specialty Section


The human health risk assessment paradigm is changing, and one important aspect of this is the focus upon the exposure element of risk assessments. To date, the greater weight has generally been on hazard in the risk assessment process, with exposure being considered retrospectively. The result is the expenditure of considerable time, effort, and resources on acquiring hazard information that ultimately is not always required to reach conclusions on the safety of a chemical. Scientists have been working to develop exposure and risk assessment methods and tools to change this paradigm; however, a limiting factor is that exposure assessments are specific to the chemical use pattern/scenario, and this can lead to “silos” in approaches and knowledge. This session aims to bring together different sectors (agrochemicals, consumer products, industrial chemicals) and regulators who need exposure data and leverage approaches across these sectors. The scene will be set by the first two presenters, who will describe their vision for integrating advanced exposure science into public health assessment. The next three presentations will focus on approaches and techniques, with case studies, used in the exposure science of chemicals. Current and innovative methods (for example, in silico methods, toxicokinetics, PBPK, IVIVE, biomonitoring data) and their potential application to regulatory frameworks will be discussed. This session aims to provide a forum for academic researchers, industry scientists, and regulators to present and discuss recent advances in the area of exposure assessment for chemicals. The session will conclude with charge questions for discussion by the panel and audience members and will identify key areas/topics/gaps that should be considered further.


Introduction. Claire Terry, Dow AgroSciences, Indianapolis, IN.

Advancing Exposure’s Profile in Providing the Context for Toxicity Testing and Risk Assessment. Jennifer Orme-Zavaleta, US EPA, Research Triangle Park, NC.

The Goals of Exposome Research and Examples from Europe. Paulo Vineis, Imperial College London, London, United Kingdom.

The Importance of Exposure Considerations in Safety Assessment. Andrew Scott, Unilever, Surrey, United Kingdom.

Application of the Aggregate Exposure Pathway and Adverse Outcome Pathway Frameworks to Advance Cumulative Risk Assessment by Integrating Human Health and Ecological Endpoints. David Hines, US EPA, Washington, DC.

How Exposure-Based Refinements Can Benefit the 3Rs. Fiona Sewell, NC3Rs, London, United Kingdom.


12:10 PM to 1:30 PM

Changes to the Common Rule Regulations and Implications for Human Research

IS  Informational

Chairperson(s):

Michael Madden, US EPA, Chapel Hill, NC; and Daniele Wikoff, ToxStrategies, Asheville, NC.

Primary Endorser:

Clinical and Translational Toxicology Specialty Section

Other Endorser(s):

Ethical, Legal, Forensics, and Societal Issues Specialty Section


The regulations that govern research involving human subjects are known as the “Common Rule” because they are shared in common by 18 federal departments and agencies that conduct and support such research [The US Food and Drug Administration is not a signatory to the Common Rule]. These regulations have not changed substantively since 1981. During that time, the research they cover has evolved considerably, with new scientific techniques and new ethical challenges that do not always fit well under the established structure. These include an evolving concept of what constitutes identifiable information and biospecimens, techniques such as whole genome sequencing, and concerns over commercialization and informed consent. A six-year rulemaking process began in 2011, with a preliminary draft notice release and more than 3,000 public comments received. This process culminated in the publication of a revised final rule on January 19, 2017. The majority of changes will take effect in January 2018, bringing sweeping changes for scientists and their institutions, funding agencies, and the Institutional Review Boards (IRBs) that oversee this work. This informational session will review the reasons for change, the rulemaking process, and the major changes in the revised regulations with a presentation by the US Environmental Protection Agency representative on the Interagency Working Group that crafted the new Common Rule. The daily experiences of implementing the Common Rule changes in a timely manner into human subject research at an academic institution and areas where the new rule is not clear will be shared by a presenter with the Office of Clinical Research at the University of Texas Health Science Center at San Antonio (UT Health San Antonio). UT Health San Antonio has several IRB authorization agreements with nearby institutions, such as Brooke Army Medical Center and the Southwest Research Institute, to serve as the single IRB of record for collaborative research. Potential issues with implementation of the new rule with studies at collaborative sites will be presented. A third speaker from the National Institute of Envioronmental Health Sciences IRB will discuss the potential impact of the new Common Rule on the submission and implementation of grant applications and also will provide insights on possible upcoming changes in the National Institutes of Health processes for human studies. This session will present extremely important ethics information for those who perform research with human subjects, including industry, government, and academia, and will facilitate discussions about applicability of the changes to current research and potential research designs and submissions. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.


Introduction. Michael Madden, US EPA, Chapel Hill, NC.

Revising the Common Rule: What Is It, How Did We Get Here, and Where Are We Going? Daniel Nelson, US EPA, Chapel Hill, NC.

Implementing the Changes in the Common Rule at an Academic Medical Center. Kimberly Summers, University of Texas Health Science Center at San Antonio, San Antonio, TX.

NIH Human Subject Research: Changes, Challenges, and Expectations. Kimberly Gray, NIEHS, Durham, NC.

Management of Toxic Wastes in Africa: Challenges and Opportunities

IS  Informational

Chairperson(s):

Abdel-Razak Kadry, US EPA, Washington, DC; and Bernard Gadagbui, University of Cincinnati, Cincinnati, OH.

Primary Endorser:

Toxicologists of African Origin Special Interest Group


Africa is the world’s second largest and second most populous continent, with a population of 1.2 billion people. In spite of its vast natural resources, Africa faces endemic poverty, food insecurity, and pervasive underdevelopment, with almost all countries lacking the human, economic, and institutional capacities to effectively and sustainably develop and manage their resources. In Africa, use of chemicals has taken a central stage in improving health, agriculture, mining, education, research, and many industrial processes. While African countries are heavy users of industrial chemicals, there is an absence of effective chemical waste management systems, as well as chemical safety education and rigorous enforcement of safety regulations. This absence has the potential to contribute to the exposure of a large portion of the population to toxic chemicals. Users and non-users of chemicals risk exposure to toxic chemicals as a result of ignorance of the risks, failure to employ protective measures, and ineffective implementation and enforcement of safety regulations of these chemicals. It was, thus, not surprising when the World Health Organization published alarming findings in 2014 of the results of a survey of 40 African countries on chemicals of public health risk concern and their management. Many chemicals of public health concern that are banned, controlled, or withdrawn in the developed countries are still in use or shipped for disposal to Africa. These hazardous and toxic wastes pose risks to nearby water, soil, and air and have the potential to cause serious environmental and human health impacts. In addition, there are thousands of tons of industrial waste, containing hazardous chemicals, that are improperly discharged or emitted into the environment. In many African countries, industrial waste in liquid form is usually discharged into sewer systems or rivers as effluent, while solid waste is either dumped in landfills or pits within workplace premises or close to residential areas. In addition, international illegal dumping remains a prevalent issue in chemicals management in Africa. Many African countries lack appropriate, cost-effective, and economically viable technology for chemical waste recycling and disposal. The survey reported the absence of sanitary landfills in some African countries. The future of waste management in Africa is brighter than the present state. While many developing countries have no dedicated hazardous landfill disposal facilities, a few countries (for example, South Africa, Egypt, and Ethiopia) have hazardous landfill disposal facilities. The effectiveness of disposal practices in some cities in these countries could be transferred to other African countries. In light of the circumstances described above, this session will bring attention to the status of hazardous and toxic waste management in Africa and the potential to harness resources for effective management of such wastes on the continent. This will be accomplished by presentations by a number of African experts in the area of toxicology and toxic waste disposal. The following topics will be discussed within the context of the problem: 1) scope and status of hazardous and toxic waste problems in Africa; 2) challenges, including geographical, that keep Africa behind the developed world in toxic waste disposal and management; 3) the public health implications from the failure of proper toxic waste disposal in Africa; 4) case studies of successful toxic waste disposal in some African countries and methods to transfer the success to other developing countries; and 5) lessons learned, mitigation strategies, strategic planning, networking, and partnering opportunities. The outcome of the session will be a report detailing strategic planning strategies and recommendations from the presenters and participants in the session. The leaders of Toxicologists of African Origin Special Interest Group and its sister organization the African Society for Toxicological Sciences will play a role in planning, facilitating, and disseminating the recommendations to scientists in Africa and the African governments.


The Adverse Health Effects Associated with Living in the Vicinity of Toxic Waste Dump Sites in Africa. Salah Soliman, Alexandria University, Alexandria, Egypt.

Management of Toxic Waste in Ghana: Challenges and Opportunities. Edith Clarke, FZ Safety and Health Centre, Accra, Ghana.

Toxic Waste Management in Cameroon. Asongalem Acha, University of Buea, Buea, Cameroon.

Solid Waste Management in Sub-Saharan Africa: Our Experience in the Kingdom of Swaziland. Sameer Sakallah, Global Biotechnology Solutions, Chantilly, VA.

Mining Industry and Water Contamination in South Africa: Recommended Remediation Approaches. Mary Gulumian, National Institute for Occupational Health, Johannesburg, South Africa.

Panel Discussion/Q&A Darryl Hood, Ohio State University, Columbus, OH.

Moving Beyond Theory to the Use of Systematic Review to Support Regulatory Decision Making for Evidence-Based Risk Assessment

IS  Informational

Chairperson(s):

Daniele Wikoff, ToxStrategies, Asheville, NC; and Katya Tsaioum, Johns Hopkins Bloomberg School of Public Health Evidence-Based Toxicology Collaboration, Watertown, MA.

Primary Endorser:

Food Safety Specialty Section

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section


The use of systematic review and evidence-based methodologies in toxicology and risk assessment have evolved from theory to practice. This informational session seeks to provide an overview of the landscape of the use of systematic review in regulatory decision making. Recognizing that there are many efforts to advance the science in this arena, this session will focus on efforts specifically associated with risk-based practices, such as development of health-based benchmarks (e.g., acceptable daily intakes, reference doses, etc.) rather than characterization of potential hazard (e.g., likelihood to be a hazard to humans for a given health outcome). Tools and frameworks initially developed for the field of medicine have been adapted for application to toxicological research questions, and in many cases, new tools have been developed. The presentations will describe how the regulatory practitioners have addressed the challenges of toxicological data relative to that of medicine. Examples will include addressing challenges in evaluating exposures vs. interventions, multi-endpoint vs. single-endpoint outcomes, well-defined diseases or conditions, complex data that is often not in humans (but rather in experimental animal studies or in vitro studies) vs. randomized controlled trials in humans, and evaluation of mixtures vs. pure substances. Beyond evaluation of individual studies and qualitative characterizations of hazards, approaches to integrate data in the context of risk—to be evaluated on a common metric, to develop health based-benchmarks—have been developed and applied. These concepts must be balanced with the rigor of a systematic review, a component which translates into time and resources. It is anticipated that this session will provide practical information for toxicologists and risk assessors and facilitate an understanding of how systematic review is being utilized in support of risk-based chemical assessments. Notably, speakers also will highlight how systematic review provides additional rigor and transparency, as well as relevance, of the process in decision making for regulated chemicals.


An Introduction to the Integration of Systematic Review to Support Development of Health-Based Toxicity Values in Chemical Risk Assessments. Daniele Wikoff, ToxStrategies, Asheville, NC.

Systematic Review in Support of Chemical Risk Assessment at the EFSA. Elisa Aiassa, European Food Safety Authority (EFSA), Parma, Italy.

Operationalizing Pragmatic Systematic Review in Support of Chemical Risk Assessment at the US EPA. Kristina Thayer, US EPA, Washington, DC.

Guidelines for Performing Systematic Reviews in the Developmentof Toxicity Factors. Heather Reddick, Texas Commission on Environmental Quality, Austin, TX.

Summary of Global Efforts and Remaining Opportunities to Advance the Field. Katya Tsaioun, Johns Hopkins Bloomberg School of Public Health Evidence-Based Toxicology Collaboration, Watertown, MA.


1:45 PM to 4:30 PM

Adipocyte Toxicology and Obesogens

S  Symposium

Chairperson(s):

Supriya Kulkarni, Yale University, New Haven, CT; and Laura Armstrong, Rutgers, The State University of New Jersey, Piscataway, NJ.

Primary Endorser:

Stem Cells Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Mechanisms Specialty Section


The obesity epidemic and associated co-morbidities are becoming an increasing concern to public health. Obesity can be generally defined by excess storage of lipids in adipose tissue. Central adipose tissue content directly correlates with the development of metabolic syndrome and cardiovascular complications that alter adipose tissue metabolism. Adipose tissue is not only a storage depot for triglycerides, but is a metabolically active organ that is responsible for the release of energy to tissues, such as liver and skeletal muscle, by hormonal-signaling pathways. In addition to lipid metabolism and mobilization, adipose tissue is intricately involved in glucose homeostasis and, therefore, contributes overall to the maintenance of systemic energy balance. It is suggested that adipose tissue plays an important role in the development of obesity-related diseases, thus requiring greater knowledge and understanding of adipose tissue development, signaling pathways, and identification of roles in systemic diseases. Current toxicological findings implicate a role for multiple persistent environmental chemicals, such as phthalates, tributyltin (TBT), and Di-(2-ethylhexyl) phthalate (DEHP) in promoting adiposity. Increases in adiposity are attributed to dysregulation of various metabolic pathways via genetic/epigenetic alterations, as well as contributing environmental factors. Recent studies have demonstrated accumulation of persistent environment toxicants due to their lipophilicity in adipose tissue, making adipocytes and preadipocytes targets of toxicity. Many of these studies have established the diverse mechanisms by which “obesogens” promote adiposity. Overall, toxicants appear to have direct and indirect effects on adipose tissue homeostasis and adipose tissue dysfunction, a key characteristic of obesity and hallmark of metabolic disease. Many compounds have been identified via high-throughput screening programs focusing on target-specific binding. These programs include ToxCast, Tox21, and, more recently, the Endocrine Disruption Screening Program. Prioritizing these chemicals for further in vivo research is essential due to the number of identified chemicals by these programs. Discerning the cellular and molecular endpoints and physiological outcomes of these chemicals is paramount in toxicological research. The objective of this symposium is to present an overview of the effect of obesogens or endocrine-disrupting chemicals on adiposity. Future research is warranted to contribute to understanding the crosstalk between adipose and other metabolically important tissues (liver, skeletal muscle, intestine) and the overall contribution to a growing obesity epidemic in both adults and children worldwide. In utero exposure outcomes to TBT pertaining to the development of a “thrifty genotype” and phthalate exposure effects on adipocyte differentiation and maturation will be discussed, demonstrating the importance of adipocyte development. The major adipocyte regulator PPARγ can be induced by environmental ligands favoring white adipocyte development, while dichlorodiphenyltrichloroethane exerts its effects on brown adipose tissue and the inhibition of thermogenesis, demonstrating the diversity of adipose tissue function. Adipose tissue is responsive to endocrine disruptors; therefore, it is important to also understand the sex-dependent differences in human adipose function and distribution. Lastly, the implications of adipocyte research in regards to regulatory standards and the testing of compounds for adipogeneic properties must be optimized and standardized utilizing specific assays that can correlate to and/or identify obesogens. Medium-throughput assays with greater relevance to downstream cellular outcomes in context to PPARγ and glucocorticoid signaling could be the future of prioritizing adipogeneic compounds for risk assessment. The speakers will introduce the overall importance of adipose tissue homeostasis for human health and the contribution of environmental toxicants to its dysregulation.


Introduction. Supriya Kulkarni, Yale University, New Haven, CT.

Prenatal Obesogen Exposure Leads to a Transgenerational Thrifty Phenotype in Mice. Bruce Blumberg, University of California Irvine, Irvine, CA.

Plasticizer-Induced Changes in Adipocyte Differentiation and Function. Vassilios Papadopoulos. University of Southern California, Los Angeles, CA.

Environmental PPARγ Ligands: Inducers of White, but Not Brite, Adipogenesis. Jennifer Schlezinger, Boston University School of Public Health, Boston, MA.

Sex and Depot Differences in Adipocyte Biology. Susan Fried, Icahn School of Medicine at Mount Sinai, New York, NY.

Evidence That the Pesticide DDT and Its Metabolite DDE Are Obesogens. Michele La Merrill, University of California Davis, Davis, CA.

Screening ToxCast and Tox21-Prioritized Chemicals for Mechanistic Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis. Chad Deisenroth, US EPA, Durham, NC.

Alternative Testing Strategies for Nanomaterials and Ultrafine Particles

S  Symposium

Chairperson(s):

Monita Sharma, PETA International Science Consortium Ltd., London, United Kingdom; and Justin Teeguarden, Pacific Northwest National Laboratory, Richland, WA.

Primary Endorser:

Inhalation and Respiratory Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Risk Assessment Specialty Section


Inhalation represents the primary route of exposure to aerosolized nanomaterials (NMs) and ultrafine particles in humans. The increasing use of NMs in consumer-based products warrants a thorough evaluation of their biological impacts and a need to test a large number of different types of NMs. Due to the substantive time, cost, and animals required to conduct traditional in vivo toxicity tests, there is much interest in developing human-relevant strategies that are less reliant on the use of animals to assess the toxicity of these materials for various risk assessment applications. This session will include presentations on in vitro systems that are currently being used to assess the inhalation toxicity of nanomaterials and ultrafine particles. Additionally, presenters will discuss the parameters that are critical to consider while designing in vitro systems and which facilitate their interpretation and application in risk assessment, including the following: dosimetry, aerosol generation and exposure, appropriate cell types, and identification of relevant endpoints. Contribution of adverse outcome pathways (AOPs) to experimental and regulatory toxicology of NMs and strategies for the development of AOPs, as well as associated issues and limitations, also will be discussed. By discussing the aforementioned parameters, this session will provide an insight into the factors that should be considered to increase the ability of in vitro methods to predict human outcomes, eventually leading to their use in regulatory decision making.


Introduction. Monita Sharma, PETA International Science Consortium Ltd., London, United Kingdom.

Integrated In Vitro-In Vivo Models for Nanomaterial and Ultrafine Particle Toxicity Testing: Moving from a Screening Hazard Tool to Predictive Models for In Vivo Adverse Effects. Todd Stueckle, NIOSH, Morgantown, WV.

Predictive 3D Lung Models to Assess the Toxicity of Inhaled Nanoparticles. Barbara Rothen-Rutishauser, University of Fribourg, Fribourg, Switzerland.

Contemporary Considerations in Engineered Nanomaterial Characterization, Aerosol Generation, and Exposure. Christie Sayes, Baylor University, Waco, TX.

An Integrated Methodology across the Dispersion Preparation-Colloidal Characterization-Cellular Dosimetry Continuum for Engineered Nanomaterials. Philip Demokritou, Harvard T.H. Chan School of Public Health, Boston, MA.

Dosimetry Modeling to Aid In Vitro to In Vivo Extrapolation (IVIVE) of Inhaled Nanomaterials for Risk Assessment Applications. Annie Jarabek, US EPA, Research Triangle Park, NC.

Advances in Developing Adverse Outcome Pathways to Assess Inhalation Toxicity of Nanomaterials. Sybille Brule, Louvain Centre for Toxicology and Applied Pharmacology, Brussels, Belgium.

Highlights and Conclusions from the Session. Justin Teeguarden, Pacific Northwest National Laboratory, Richland, WA.

Chemical Grouping for 21st-Century Toxicology, Risk Assessment, and Decision Making

S  Symposium

Chairperson(s):

Jane Ellen Simmons, US EPA, Research Triangle Park, NC; and Mark Nelms, Oak Ridge Institute for Science and Education, Oak Ridge, TN.

Primary Endorser:

Mixtures Specialty Section

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section


“Grouping” is a generic term describing placing chemicals in groups based on characteristics or factors that the assembled chemicals have in common to enable consideration of more than one chemical at the same time. Developing chemical groups is necessary for a variety of useful purposes, including something as seemingly simple, but as critically important, as safe chemical storage. Key uses of grouping in toxicology, risk assessment, and decision making include identification of co-occurring chemicals in the environment, the body, or the exposome; creating and prioritizing groups for chemical mixtures toxicology and mixtures risk assessment; and identifying chemicals that are toxicologically similar (i.e., that share the same adverse outcome pathway (AOP) or have AOPs that start with different molecular initiating events (MIEs), but converge later in the pathway) or are toxicologically independent. Another important use is developing groups that facilitate the filling of data gaps by techniques such as read-across, trend analysis, extrapolation, interpolation, and QSAR; this use of grouping results in reduced experiment effort, saving time, resources, and experimental animals. Grouping also benefits green chemistry and enables the use of molecular design for reducing unwanted toxicity. Traditionally, groups have been based on exposure alone or toxicity alone. Strategies laid out in Toxicology Testing in the 21st Century: A Vision and a Strategy (National Research Council [NRC] 2007) and Exposure Science in the 21st Century: A Vision and a Strategy (NRC, 2012) and corresponding advances in exposure science, high-throughput toxicology, ’omics sciences, and computational technologies have resulted in a wide array of next generation methods and tools. The purpose of this session is to highlight how these advances are being translated and used in next-generation grouping approaches. In this session, experts from industry, academia, and government will present state-of-the-art insights into new methods currently being developed and employed that have current or future application to chemical groups. The importance of accurate grouping in decision making will be illustrated in the brief introduction. The first full presentation will showcase a novel, fully-integrated text mining-based tool capable of automatically analyzing relevant literature and classifying a given chemical according to its carcinogenic mode of action based on a structured taxonomy. The second talk will focus on using a mechanistic understanding of the interaction between a chemical and the MIE within an AOP, coupled with 2D chemical structure information, to group chemicals and how inclusion of chemical bioactivity profiles may then be used to refine the initial groupings. The third presentation will present the application of the concept of connectivity mapping in a predictive toxicology paradigm, where gene-expression profiles and pattern-matching software are used to find connections between chemicals, adverse events, and genes to group chemicals with similar mechanisms of action. The fourth talk will illustrate how chemical categories associated with specific MIEs can be utilized to guide higher level QSAR methods, such as comparative molecular field analysis, that enable quantitative predictions to be made regarding chemical binding affinity and/or downstream bioactivity without needing to fully elucidate the shape of the binding pocket of the biological target. The final presentation of the session will explore the influence of grouping decisions and misclassification errors that might occur on risk prediction when using the relative potency factors method to assess mixtures risk, focusing on variability introduced if the same (or different) dose-response curve shape is assumed for all chemicals in the group when the shapes truly differ (or are the same) or when independence is assumed for convergent AOPs and the resulting uncertainty of the estimated mixture response. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.


Why Do We Need 21st-Century Grouping Methods? Jane Ellen Simmons, US EPA, Research Triangle Park, NC.

CRAB 2.0: A Text Mining-Based Approach for Grouping Chemicals According to Carcinogenic Modes of Action. Imran Ali, Karolinska Institutet, Stockholm, Sweden.

Adverse Outcome Pathway Networks: Use of 2D Chemical Structure and Bioactivity Profile to Generate Chemical Categories. Mark Nelms, Oak Ridge Institute for Science and Education, Oak Ridge, TN.

Use of Connectivity Mapping (CMap) as a Tool to Group Chemicals Based on Mode of Action. K. De Abrew, Proctor and Gamble Company, Cincinnati, OH.

Using Chemical Categories to Inform Quantitative Risk Assessment. Timothy Allen, University of Cambridge, Cambridge, United Kingdom.

Estimating the Impact of Grouping Misclassification on Risk Prediction When Using the Relative Potency Factors Method to Assess Mixtures Risk. Jeffery Swartout, US EPA, Cincinnati, OH.

Decoding Oxidative Stress from Inflammation: Implications for Exposure, Toxicity, and Disease

S  Symposium

Chairperson(s):

Maria Kadiiska, NIEHS, Research Triangle Park, NC; and Thomas van’t Erve, NIEHS, Research Triangle Park, NC.

Primary Endorser:

Mechanisms Specialty Section

Other Endorser(s):

Neurotoxicology Specialty Section
Reproductive and Developmental Toxicology Specialty Section


Free radical damage, inflammation, and/or oxidative stress have been implicated in numerous toxicity and disease mechanisms. Most of the time, inflammation and oxidative stress are perceived as one and the same. However, current research is proving this perception to be inaccurate and oversimplified. Despite sharing many similarities, the two mechanisms have complex and unique upstream and downstream targets. Failing to distinguish between the two mechanisms is detrimental to accurate data interpretation in experimental animal models of toxicity and human conditions. The translation of this important distinction into in vivo and human research has been limited, as has the translation into quantitative aspects of the role of oxidative stress in human disease. However, decoding oxidative stress from inflammation and identifying each mechanism’s unique targets are of great consequence because they may ultimately lead to the design and implementation of corresponding appropriate treatment strategies. This symposium/workshop will: 1) discuss the mechanistic distribution between oxidative stress and inflammation in vivo and in human conditions; 2) define the correct and incorrect interpretation of oxidative stress and inflammation; and 3) outline the progress obtained so far and future directions for this emerging complex field. The chair will present a brief overview on biomarker research and why distinguishing between oxidative stress and inflammation is required for correct biomarker interpretation. The first speaker will discuss redox-signaling implying a fundamental role for NF-κB p50 in the regulation of chronic neuroinflammation by free radicals. Understanding this complex regulatory node is vital in determining how microglia can become a chronic source of inflammation and reactive oxygen species. The contribution of either pathway is vital in understanding progressive neuron and central nervous system damage. The second speaker will show a new approach to quantify the contribution of oxidative stress and inflammation using the lipid peroxidation marker F2-isoprostane in conjunction with prostaglandins. In addition, he will discuss the misinterpretation of mechanism in past literature. Using a meta-analysis, he will present the potential discrepancy between oxidative stress and inflammation in reproductive health, central nervous system diseases, and others. The third speaker will present new findings on the importance of the distinction between inflammation and oxidative stress in an epidemiologic study on birth outcomes. This work is the first large-scale application of the new F2-isoprostane/prostaglandin ratio approach. Correct distinction between the two mechanisms is crucial to accurately identifying future interventions, minimizing the risk for pregnancy complications and compromised infant health. From a more translational perspective, the fourth speaker will discuss the relation between used markers of inflammation and oxidative stress to redox-related diseases. He will show the reasons why antioxidants acting by scavenging ROS might not prevent their detrimental effects and also may interfere with essential signaling roles in clusters of human diseases. Since inflammation, free radical damage, and oxidative stress are not “diseases,” distinguishing among them in vivo and in human disorders could lead to better interceptive strategies and correct interpretation of the results in former and future studies. While inflammation and oxidative stress are discussed separately in many publications, lectures, and past SOT presentations, the complex cross-talk and importance to distinguish between the two mechanisms is rarely investigated. This session will offer specific approaches to measure, calculate, distinguish, and correctly identify the differences between the effects of oxidative stress and inflammation. The session will propose a classification of exposures, toxicities, and diseases decoded by distinguishing oxidative stress from inflammation.


Biomarkers of Oxidative Stress. Maria Kadiiska, NIEHS, Research Triangle Park, NC.

Role for NF-κB p50 in the Regulation of Chronic Neuroinflammation by Free Radicals. Michelle Block, Indiana University School of Medicine, Indianapolis, IN.

Overcoming Bias in F2-Isoprostane Oxidative Stress Measurement: Quantifying the Contribution of Inflammation. Thomas van’t Erve, NIEHS, Research Triangle Park, NC.

Inflammation Differentiated from Oxidative Stress in Reproductive Epidemiology: Understanding the Environmental Impact on Birth Outcomes. Kelly Ferguson, NIEHS, Research Triangle Park, NC.

Emerging Indications of Biomarkers for Use in Humans within a Cluster of Redox-Related Diseases: Relevance of Biomarkers of Oxidative Stress, Inflammation, Antioxidants, and Redox Signaling. Harald Schmidt, Maastricht University, Maastricht, Netherlands.

Estrogen Receptor Signaling as a Mechanism of Developmental Toxicity

S  Symposium

Chairperson(s):

Daniel Gorelick, University of Alabama at Birmingham, Birmingham, AL; and Tamara Tal, US EPA, Research Triangle Park, NC.

Primary Endorser:

Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):

Molecular and Systems Biology Specialty Section


Estrogens are steroid hormones that influence the development and function of nearly every major organ system in the body—from the gonads to the central nervous system. Xenobiotic agents that mimic estrogens or influence estrogen production or metabolism can exert profound effects on organismal development. Aberrant estrogen receptor signaling is classically associated with reproductive toxicity. However, in the last decade, it has become apparent that abnormal estrogen receptor signaling during development can cause widespread changes in cardiovascular, immune, and metabolic functions. With the development of new molecular tools, improved understanding of developmental biology, and the use of new model organisms, tremendous advances have been made in understanding how estrogen receptors regulate development at the molecular, cellular, and physiological levels. This session will explore cutting-edge research in developmental toxicology, revealing the mechanisms by which estrogen receptors influence organismal development. Using an adverse outcome pathway framework, the speakers will explore estrogen receptor-mediated toxicity from the molecular initiating event (receptor activation) through adverse outcomes, such as organ malformation and dysfunction, thus linking early signaling events to organismal toxicity. The first speaker will discuss new in vitro and in silico screening approaches to predict and model estrogen receptor toxicity and how these approaches are being used for hazard assessment and testing prioritization and are leading compound development under the new Toxic Substances Control Act guidelines. To evaluate high-throughput estrogen receptor toxicity predictions, novel in vivo models are required. The second speaker will present on a novel zebrafish model being used to explore why some embryonic tissues are more sensitive to estrogen exposure than others. The third presentation will outline the similarities and differences by which estrogens and related sex hormones influence gonad development at the molecular and cellular levels and how these mechanisms can be hijacked by exposure to xenoestrogens during critical periods of development. The final two speakers will focus on adverse outcomes and discuss how estrogen receptors influence developmental toxicity in a sexually dimorphic manner with a focus on energy homeostasis and social, sexual, or anxiety-like behaviors in offspring of exposed mothers. These five speakers, using diverse approaches and model systems, will demonstrate how understanding the detailed mechanisms by which estrogen receptors influence developmental toxicology will improve the ability to identify potentially deleterious xenoestrogens and pharmaceutical estrogens with less side effects on patients and their offspring.


Introduction. Daniel Gorelick, University of Alabama at Birmingham, Birmingham, AL.

Large-Scale Screening of Chemicals for Estrogen Receptor Activity: What Have We Learned? Richard Judson, US EPA, Research Triangle Park, NC.

Using Zebrafish In Vivo and In Vitro Models to Evaluate Estrogenic Endocrine Disruptors. Maria Bondesson, Indiana University, Bloomington, IN.

Estrogen Actions in Zebrafish Gonads: A Delicate Balance. Camerron Crowder, University of Alabama at Birmingham, Birmingham, AL.

Maternal Exposures to Estrogenic Endocrine-Disrupting Compounds Cause Sex-Dependent Effects on Energy Homeostasis. Troy Roepke, Rutgers, The State University of New Jersey, New Brunswick, NJ.

Sexually Dimorphic Effects of Estrogenic Environmental Endocrine Disruptors on the Developing Brain. Andrea Gore, University of Texas, Austin, TX.

High-Throughput Transcript Profiling and Functional Assessment: From Screening to Systems Biology Strategies for Personal Chemical Safety Predictions

S  Symposium

Chairperson(s):

Chris Corton, US EPA, Durham, NC; and Bob van de Water, Universiteit Leiden, Leiden, Netherlands.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Molecular and Systems Biology Specialty Section


High-throughput screening (HTS) assays are an important component of chemical safety evaluation programs carried out by a number of organizations. However, it is recognized that the assays do not sufficiently cover all potentially important pathways. In the last few years, adaptation of gene expression profiling to high-throughput formats has been increasingly considered an attractive alternative to individual assays due to lower costs and the ability to essentially measure all pathways simultaneously. While microarrays have been used extensively in more focused lower-throughput studies and comprise the bulk of large publicly-available databases, technologies that can measure the targeted expression of the entire genome are emerging as attractive alternatives. Novel computational approaches are increasingly being used to move the field from using transcript profiles as hypothesis-generation tools to accurately predicting effects. Functional genomics strategies that identify gene-chemical interactions in gene-knockdown screens have proven valuable to validate predictions from transcript profiling and to determine species-specific effects. These integrated high-throughput genomics approaches will allow identification of relevant key events that are quantifiable in high-throughput (HT) transcriptomic settings and predict cell and biological changes, as well as human-translational, implications. This session highlights major advances in the field of using transcript profiling and functional genomics in a number of areas important in risk assessment. The first presentation will highlight recent results of a large-scale HT screen of 1,000 chemicals in a human cell line, allowing dose-response modeling of biological pathways on a massive scale. The second and third presentations will describe novel computational approaches which utilize both private and publically available databases to make predictions of molecular targets of chemicals and perturbations in gene networks that lead to toxicity. The last two talks will discuss exciting work which identifies genetic modifiers of responses to chemicals, allowing assessment of individual susceptibility to chemical injury. This session will be of wide interest, including to scientists interested in the application of gene expression profiling and in vitro assays to regulatory decision making.


Introduction. Chris Corton, US EPA, Durham, NC.

High-Throughput Transcriptomics: From Screening to Pathways. Imran Shah, US EPA, Durham, NC.

Identification of Potential Chemical Carcinogens in Compendia of Gene Expression Profiles. Chris Corton, US EPA, Durham, NC.

Reducing Noise and Boosting Biological Signal Detection in Large Transcriptomic Datasets James Stevens, Lilly Research Laboratories, Indianapolis, IN.

High-Throughput Identification of Genotype-Specific Vulnerabilities to Drug Treatment. Chris Mader, Broad Institute of MIT and Harvard, Cambridge, MA.

Functional Genomics of Cellular Stress Pathways: Towards a Personalized Chemical Safety Assessment. Bob van de Water, Universiteit Leiden, Leiden, Netherlands.

Revising Biology: Using Genomic and Epigenomic Editing to Gain Novel Insight into the Molecular Mechanisms of Toxic Exposure Effects and Susceptibility

S  Symposium

Chairperson(s):

Shaun McCullough, US EPA, Chapel Hill, NC; and Marie Fortin, Rutgers, The State University of New Jersey, Piscataway, NJ.

Primary Endorser:

Molecular and Systems Biology Specialty Section

Other Endorser(s):

Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section


The genome and epigenome work hand-in-hand as central regulators of cell fate and function and, thus ,serve as key mediators of susceptibility and toxic exposure effects. The use of traditional molecular methods has established a foundation with respect to the molecular mechanisms underlying the adverse effects of many toxic exposures; however, their efficacy in defining causative relationships between gene products, genetic polymorphisms, and epigenetic modification states with toxic exposure effects and susceptibility has been limited. The recent development of practical applications for clustered, regularly interspaced, short palindromic repeat (CRISPR), and Piwi-interacting RNA (piRNA) technology holds the potential to overcome these obstructions by permitting the selective revision of both the genome and epigenome in both toxicology research and clinical applications. CRISPR-mediated gene editing allows for the selective introduction or correction of mutations, deletion of target DNA, or introduction of fluorescent markers/biosensors or epitope tags to endogenous target genes or other loci. Further, piRNAs and deactivated CRISPR-associated protein 9 (dCas9) fusions with enzymes that add or remove epigenetic modifications can be targeted to alter both DNA methylation and histone modifications at specific loci to directly link changes in epigenetic modification states to exposure outcomes and susceptibility. The application of these technologies will open the door to the next generation of precision therapeutics and revolutionize the field of toxicology by providing novel opportunities to understand and modulate exposure-related disease and susceptibility at the genetic and epigenetic level. The goal of this session is to examine the range of applications of genome and epigenome engineering from their use in molecular and mechanistic toxicology studies to their potential as therapeutic strategies and to review the inherent safety considerations that their use entails. To achieve this, the session will bring experts together to discuss the development of these technologies and their current use in toxicity studies covering cultured human cells, mouse models, and human clinical trials. The session will answer questions such as: How do CRISPR-Cas9-mediated genomic/epigenomic engineering and piRNAs work, and what are the benefits and challenges facing their integration into the field of toxicology? Can CRISPR-Cas9 genomic editing be used to explore the role of key toxicity-associated pathways, such as NF-kB and NRF2, in the response to oxidative stress? How can the targeted modification of epigenetic states with dCas9 and piRNAs be used to provide causative relationships between specific epigenetic loci and disease/exposure outcomes? What is the current state of CRISPR-based therapies, and how does the toxicity and efficacy testing of these next-generation pharmaceuticals differ from that used for traditional therapeutic agents? The session will create a better understanding for the benefits, challenges, and applications of genome- and epigenome-engineering approaches in toxicology studies and will provide perspective on the unique considerations required during the development and testing of these technologies as next-generation therapeutic agents.


CRISPR and piRNAs: Fundamental Mechanisms and Key Applications of the Next Generation of Molecular Technologies in the Field of Toxicology. Shaun McCullough, US EPA, Chapel Hill, NC.

Use of CRISPR/Cas9 to Elucidate the Role of Nrf2 in the Response of T Cells to Electrophilic and Oxidative Stress. Cheryl Rockwell, Michigan State University, East Lansing, MI.

Applications of CRISPR/Cas9-Based Epigenetic Editing Technologies in Modeling and Treating Human Disease. Isaac Hilton, Duke University, Durham, NC.

Development of piRNAs for Target-Specific DNA Methylation. Dana Dolinoy, University of Michigan, Ann Arbor, MI.

Leading the Edge: Toxicity and Safety Testing with CRISPR/CAS-Based Therapeutics. Monika Chabicovsky, MC Toxicology Consulting GmbH, Vienna, Austria.

Marijuana Safety: Issues Facing the Regulatory, Medical, and Academic Environments

RI  Regional Interest

Chairperson(s):

George Corcoran, Wayne State University, Detroit, MI; and Sol Bobst, ToxSci Advisors, Houston, TX.

Primary Endorser:

Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):

Clinical and Translational Toxicology Specialty Section
Ethical, Legal, Forensics, and Societal Issues Specialty Section


The presentations in this session will build upon a recent series of SOT Annual Meeting Roundtable and Workshop Sessions that broadly examined the legal applications and boundaries of toxicology and law. The 2016 Workshop Session “Cannabis in the Courtroom” explored topic areas for scientific testimony and briefly touched on the public health and safety impacts of legalized marijuana products. This session expands upon topics raised during the 2016 session which relate to the lack of federal oversight of the cannabis industry. With the growing acceptance of marijuana use and its legalization in some form (medical, recreational) by 28 states and the District of Columbia, including new medical marijuana legislation passed in Texas in 2017, marijuana has become a booming business that essentially is unregulated at the federal level because of the conflict imposed through listing of marijuana as a Schedule I drug by the Drug Enforcement Administration (DEA). Texas has just passed medical marijuana laws in limited cases, opening up a new market for entrepreneurs in the state. Currently, the US government has relinquished authority to the states with respect to the growing, distributing, and selling of marijuana where it is legal to do so under state laws. This session will explore the impact of the current absence of federal oversight on public health and safety by presenting a number of scenarios and outcomes stemming from the widespread and legal uses of cannabis in more than half of the states and the stark differences in individual state regulations. Topics will include: 1) safety concerns for edible marijuana products; 2) regulatory status of marijuana and its implications for academic research; 3) policy implications for federal authorities in light of public perceptions of marijuana’s benefits and risks; and 4) patient safety concerns with use of non-approved drug products and access to such products. The session will include a discussion from the legal perspective on the problems encountered with the “hands-off" approach currently taken by the federal government and will conclude with a panel discussion.


Marijuana and Public Safety Concerns: States in Charge. Laura Plunkett, Integrative Biostrategies LLC, Houston, TX.

Model Systems and Regulations for Cannabinoid Research in Academia. Barbara Kaplan, Mississippi State University, Starkville, MS.

Ensuring the Safety of “Edibles” in West Virginia: Lessons Learned for New Medical Marijuana Legislation in Texas. Erik Janus, Compassion West Virginia, Huntington, WV.

RMPC Colorado Marijuana Human Exposures by Age: 2014–2016. Chris Hoyte, Rocky Mountain Poison Control Center, Denver, CO.


Tuesday, March 13

8:00 AM to 10:45 AM

Clinical and Translational Toxicology: From Theory to Therapy

S  Symposium

Chairperson(s):

Horst Thiermann, Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany; and Sally Bradberry, National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit, Birmingham, United Kingdom.

Primary Endorser:

Clinical and Translational Toxicology Specialty Section


Advancing the prevention and treatment of human toxicity is achieved only as a result of enthusiastic collaboration between scientists and clinicians from a wide range of disciplines. Together, they negotiate the painstaking, sometimes-tortuous path of translational toxicology—from bench to bedside, from theory to therapy. A better appreciation of the opportunities available to each discipline, as well as an improved understanding of the challenges and limitations each face, can enhance future collaboration and facilitate progress. This symposium will provide insight into the contemporary challenges and research opportunities encountered by toxicological experts from a wide range of disciplines, representing the laboratory, drug industry, and emergency room, as well as licensing and administration authorities, to inspire fruitful collaboration.


Introduction: The Translational Nature of Clinical Toxicology. John-Michael Sauer, Critical Path Institute, Tucson, AZ.

Restoration of Nerve Agent-Induced Paralysis of Human Respiratory Muscles In Vivo: How to Translate Results from In Vitro to the Clinic? Horst Thiermann, Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.

Glutamate Dehydrogenase in Diagnosis of Liver Injury: A Biomarker Journey from Enabling Clinical Trials to Improving Medical Care. Jiri Aubrecht, Pfizer, Inc., Groton, CT.

From Bedside to Bench—What Only Our Patients Can Teach Us. Sally Bradberry, National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit, Birmingham, United Kingdom.

Importance of Translation from In Vitro Testing to Approved Products and Treatments. Donna Mendrick, US FDA, Silver Spring, MD.

Summary of Clinical and Translational Toxicology: From Theory to Therapy. John-Michael Sauer, Critical Path Institute, Tucson, AZ.

Mitochondria Biogenesis and Dysfunction in Cellular Senescence in Cardiopulmonary System

S  Symposium

Chairperson(s):

Irfan Rahman, University of Rochester, Rochester, NY; and James Wagner, Michigan State University, East Lansing, MI.

Primary Endorser:

Inhalation and Respiratory Specialty Section

Other Endorser(s):

Cardiovascular Toxicology Specialty Section
Mechanisms Specialty Section


Emerging evidence sheds light on new mitochondrial functions that are not related to cellular energy production, which involve mitophagy (removal of damaged mitochondria from a cell prior to cell death) and mitochondrial protein quality control. Mitochondrial function is associated with fission, fusion, and mitophagy in health and disease. Mitochondrial proteins, such as Pink1, Parkin, and Drp1, along with sub-organellar signaling by oxidant stress and redox changes, are involved in mitochondrial dysfunction. This is associated with inflammation and cellular senescence via DNA damage and alterations in telomeric shelterin complex (a complex which protects telomeres from DNA damage). Toxicological perspectives on mitochondria or mitochondria toxicology (MitoTox) research include a multidisciplinary approach in different target organs in the pathogenesis of cardiopulmonary and vascular diseases. The goal of this session is to highlight the recent advances of mitochondria research in toxicology, particularly in mitochondria biogenesis, dysfunctional mitophagy, redox changes, cell signaling, and DNA damage/repair or rejuvenation of the damaged mitochondria upon toxic chemical or environmental insults in epithelial cells, fibroblasts, and myocytes in cellular senescence (premature aging) of the cardiopulmonary system. The information in the session will share the change in paradigm of involvement of mitochondrial stress signaling that would improve the gap in understanding the mechanisms of mitochondrial dysfunction in cellular senescence in the cardiopulmonary system.


Mitochondria-Nuclear Signaling and Mitophagy by Toxicants in DNA Damage and Lung Cellular Senescence. Irfan Rahman, University of Rochester, Rochester, NY.

Impairment of Mitochondrial Function by Particulate Matter and Nanometals in Cardiovascular and Pulmonary Diseases. John Hollander, West Virginia University School of Medicine, Morgantown, WV.

Cardiovascular Mitochondrial Dynamics and Dysfunction by Exposure to Ultrafine or Nano Particulate Matter. Christopher Wingard, Bellarmine University, Louisville, KY.

Mitochondrial DNA Damage and Dysfunction in Vascular Disease by Environmental Toxicants. Jessica Fetterman, Boston University School of Medicine, Boston, MA.

Redox Regulation of Mitochondrial Dysfunction and Cellular Senescence in Atherosclerosis. Reto Asmis, University of Texas Health Science Center at San Antonio, San Antonio, TX.

Advancing the Adverse Outcome Pathway Framework: An International Horizon-Scanning Approach

W  Workshop

Chairperson(s):

Rory Conolly, US EPA, Research Triangle Park, NC; and Markus Hecker, University of Saskatchewan, Saskatoon, SK, Canada.

Primary Endorser:

Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):

Biological Modeling Specialty Section
Risk Assessment Specialty Section


In 2007, the US National Research Council laid out a vision and strategy for toxicity testing in the 21st century, which aspired to transform current testing approaches by making greater use of recent scientific advances in cell-based and computational methods. The adverse outcome pathway (AOP) framework, which emerged to address this vision, has since gained international traction as a systematic approach for capturing existing knowledge to transparently link mechanistic data to apical toxicity endpoints as a means to inform research and risk assessment. While the framework has evolved significantly since its introduction in 2010, it was recognized that a survey of the broader scientific community would be useful in identifying challenges and in guiding future initiatives. To that end, a horizon-scanning exercise was conducted to solicit questions from the global scientific and regulatory communities, including the SOT community, concerning the perceived challenges and/or limitations that must be addressed to realize the full potential of the AOP framework in research and regulatory decision making. Questions submitted from all sectors and from across the globe were used to identify key themes that, if addressed, would significantly advance development and application of the AOP framework. Following this exercise, a Society of Environmental Toxicology and Chemistry (SETAC) Pellston™ Workshop, comprised of international participants representing industry, government, academia, and non-governmental organizations (NGOs), was held in Cornwall, Ontario, Canada, in April 2017 to begin exploring these themes and answering associated key questions. This session will serve as a podium to present the outcomes of the horizon-scanning exercise and of the Pellston™ Workshop and to foster discussion with attendees in order to continue advancing the AOP framework. Specifically, presentations will cover topics such as the development and application of AOP networks, quantitative AOPs and associated modeling approaches, and the status of and future needs for application of the framework in regulatory decision making. Furthermore, talks will explore a roadmap to enhance awareness of, involvement in, and acceptance of the AOP framework by regulatory agencies, scientists, and other stakeholder groups. Presentations will review frequently asked questions identified during the horizon scanning and address common misunderstandings pertaining to the AOP framework. Finally, the audience will be asked to participate in a panel discussion following the presentations to build upon ideas and outcomes derived from the PellstonTM Workshop.


Introduction. Rory Conolly, US EPA, Research Triangle Park, NC.

Adverse Outcome Pathways: Moving from a Scientific Concept to a Globally-Accepted Framework. Carlie LaLone, US EPA, Duluth, MN.

Adverse Outcome Pathway Networks: Development, Analytics, and Applications. Marie Fortin, Alcami, Edison, NJ.

How to Build and Apply Quantitative Models from Adverse Outcome Pathways. Edward Perkins, US Army Engineer Research and Development Center, Vicksburg, MS.

Using Adverse Outcome Pathways to Inform Decision Making for Chemical Innovation, Regulation, and Stewardship. Michelle Embry, ILSI Health and Environmental Sciences Institute (HESI), Washington, DC.

Making the AOP Framework Sustainable: Stakeholder Identification, Communication, and Engagement. Maurice Whelan, European Commission Joint Research Centre, Ispra, Italy.

Computational Predictions for Dermal Penetration of Chemicals: Should More Complexity Be Considered in Addition to Simple Passive Diffusion?

W  Workshop

Chairperson(s):

Marina Evans, US EPA, Research Triangle Park, NC; and Ronald Baynes, North Carolina State University, Raleigh, NC.

Primary Endorser:

Dermal Toxicology Specialty Section

Other Endorser(s):

Comparative and Veterinary Specialty Section


Risk assessment for thousands of chemicals, due to their potential exposure as environmental contaminants, is a daunting task. Because it is not feasible to obtain experimental data for this many chemicals, computational predictions have become part of the strategy for risk due to dermal penetration. An integrative modeling framework will become essential in this computational prediction strategy. While dermal exposure is a common mode of exposure, computational modeling for dermal penetration remains a challenging research area. This session will explore current approaches used to predict dermal penetration for chemicals with a wide spectrum of physical properties and applications. Some pharmaceutical products include dermal application of pesticides/insecticides. Consumer products include the additional challenge of consisting of mixtures and diverse combinations of vehicles with active ingredients. The physiology of the skin will be included into the computational predictions, including hydration, swelling, and additional components, such as nails or hair follicles. The impact of all these components will be discussed for inclusion in future dermal penetration predictions.


Computational Prediction of Dermal Diffusivity for Large Number of Chemicals: Challenges and Applications. Marina Evans, US EPA, Research Triangle Park, NC.

Skin Absorption of Metal Worker Fluids and Complexities Inherent in Additional Components. Ronald Baynes, North Carolina State University, Raleigh, NC.

Impact of Natural Compounds on Dermal Absorption for Consumer Products and Their Computational Prediction. James Riviere, North Carolina State University, Raleigh, NC.

The Skin Is a Non-Homogenous Physiological Organ—What Should We Consider for Computational Predictions? Gerald Kasting, University of Cincinnati, Cincinnati, OH.

In Silico-In Vitro Extrapolation for Dermal Exposure. Jessica Spires, Simulations Plus, Lancaster, CA.

Defining Domains of Applicability for Zebrafish within Toxicology: A Retrospective and Prospective Workshop

W  Workshop

Chairperson(s):

Jennifer Freeman, Purdue University, West Lafayette, IN; and David Volz, University of California Riverside, Riverside, CA.

Primary Endorser:

Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Molecular and Systems Biology Specialty Section


Over the past 20 years, adoption and integration of the application of zebrafish as a toxicological model system has magnified in most areas of toxicology-based research. As a well-recognized biomedical research model, zebrafish presents numerous strengths that have been leveraged in many toxicity studies. Rapid ex vivo development of a small, near-transparent singular embryo permits ease for assessing chemical perturbations at all stages of early development, as well as use in high-throughput chemical screens and automated phenotyping. In addition, a complete genome sequence, array of tools for manipulating gene function, and availability of several thousand mutant and transgenic lines provides, similarly to mouse models, readily available resources for comprehensive mechanistic studies of toxicity. Furthermore, maturation at three months of age and a shorter lifespan allow for multi- and transgenerational studies and efficient identification and evaluation of developmental origins of health and disease. As researchers continue to expand the use of the zebrafish in toxicology, limitations of this animal model also are being identified. In this session, the first presentation will highlight what has been learned from more than two decades of using zebrafish in toxicity research, which has spanned developmental mechanistic studies to current applications in high-throughput screening of chemicals and chemical mixtures. The second talk will discuss zebrafish as a comparative model to rodent neurobehavioral testing, including analysis of larval behavior outcomes with long-term neurobehavioral dysfunction in adults. The third speaker will focus on the advantages and challenges of using zebrafish to define mechanisms of immediate (larval), later in life (adult), and transgenerational consequences of a developmental toxicant exposure linking single-cell transcriptomic, epigenomic, and phenotypic outcomes. The fourth presentation will highlight the strengths and constraints for using transgenic zebrafish in drug development and therapeutics for epilepsy. The final speaker will address the benefits of using zebrafish as a replacement for mammalian toxicity testing and the importance of accounting for toxicokinetic processes and dosimetry. Overall, the session will bring together several leading research laboratories that have extensive experience with the zebrafish model in various toxicological disciplines to provide a reflection of the knowledge that has been gained over the past 20 years relative to the strengths and constraints of the model system in toxicological experiments. In addition, this session will explore a comparison of zebrafish to other animal models, best practices, current questions, and future research needs.


Introduction. Jennifer Freeman, Purdue University, West Lafayette, IN.

Utilizing the Power of High-Throughput Zebrafish Screening to Identify Hazardous Chemicals and to Help Design Safer Chemicals. Robert Tanguay, Oregon State University, Corvallis, OR.

Comparison of Larval and Adult Neurobehavioral Assays in Zebrafish after Toxicant Exposure during Early Development. Edward Levin, Duke University, Durham, NC.

Molecular Mechanisms for Persistence of the Effects of Developmental Toxicants: Using Zebrafish to Explore the Barker Hypothesis on the Fetal Basis of Adult Disease/Dysfunction and Their Potential for Transgenerational Inheritance. Michael Carvan, University of Wisconsin Milwaukee, Milwaukee, WI.

Exploring the Role of Toxicokinetics in the Response of Zebrafish Embryos and Larvae to Chemical Exposure. Kristin Schirmer, Eawag, Duebendorf, Switzerland.

Strengths and Constraints for Using Zebrafish for Epilepsy Drug Development. Kristine Willett, University of Mississippi, University, MS.

Get the Lead Out: The Persistent Problem of Lead Exposure from Soil, Dust, and Water

W  Workshop

Chairperson(s):

Michael Hughes, US EPA, Research Triangle Park, NC; and Karen Bradham, US EPA, Research Triangle Park, NC.

Primary Endorser:

Metals Specialty Section

Other Endorser(s):

Occupational and Public Health Specialty Section


The heavy metal lead, a known neurotoxicant, has been used for centuries in a variety of industries and household and consumer products. The choice to use lead is a reflection of its physical/chemical properties, including softness, ductility, poor conductibility, and resistance to corrosion. While a natural component of the Earth’s crust, high concentrations of lead in the environment, particularly soil, have resulted from human activity and its resistance to natural degradation. From the decades-long use of lead as a fuel additive, soils in urban areas with high traffic volume have been found to have highly elevated levels of lead. In residences that pre-date 1978, when lead-based paint was banned in the United States, dust from deteriorating paint contains elevated levels of lead. The soils on and near several industrial smelting sites, such as in East Chicago, IN, also have high levels of lead. Finally, lead is found in drinking water in homes that have water pipes containing lead, with leaching a complex function of pH, alkalinity, and source water characteristics. It is well-noted that homes typically located in older urban centers have drinking water with a high risk of elevated lead levels, particularly if the water is corrosive. Elevated blood levels have been found in people, particularly children, who were exposed to soils, dust, and water containing high levels of lead. The main public health issue with lead is that it is neurotoxic, especially to children. Elevated levels of lead in children can result in behavioral disorders and impairment of intelligence and learning. There is no known biological requirement for lead, although it is absorbed fairly well following ingestion or inhalation. Lead accumulates in bone, as it has similar properties as calcium, taking its place in this organ. Lead in bone can be a long-term source of internal exposure, as it can be released from bone into the systemic circulation and distributed to other organs. This session will bring together experts on lead with regard to its exposure, neurotoxicological effects, and the use of models to predict blood lead levels in individuals exposed to lead in soil, dusts, and water. The first presenter will discuss the positive association between lead in soil or bioaccessible (an in vitro method simulating the gastrointestinal tract) lead and blood lead levels in children in an urban area. This presentation will show the feasibility of using in vitro methods to improve child lead risk assessments in the place of total soil lead content. The second presentation will share how soil lead levels and children’s blood levels have changed pre- and 10 years post-Hurricane Katrina in New Orleans, Louisiana. It was observed that with decreased soil lead levels after hurricane, the blood lead levels in the children also decreased. The third presentation will focus on the potential mechanisms of lead that result in adverse health outcomes following maternal lead exposure with the potential development of neurotoxicity in the offspring. This includes studies from both human and laboratory animal maternal exposures. The fourth presentation will evaluate the impact of varying regional screening levels on blood lead predictions in the Integrated Exposure Uptake Biokinetic (IEUBK) model to aid in reducing uncertainty in human health risk assessments. The final presentation will describe the application of the US Environmental Protection Agency’s (EPA) SHEDS-Multimedia and IEUBK models to determine the level of lead in drinking water that should result in children’s blood lead levels that are less than specified values. The analysis reveals the importance of the soil and dust ingestion exposure pathway. The session will share information on the association between exposure to lead in soils, dusts, and water to blood lead levels, neurotoxic mechanisms of lead exposure, and modeling efforts to predict children’s blood lead levels following exposure. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.


Bioaccessibility of Lead in Urban Residential Philadelphia Soils. Karen Bradham, US EPA, Research Triangle Park, NC.

The Astonishingly Holistic Role of Soil in Lead Exposure of Children. Howard Mielke, Tulane University School of Medicine, New Orleans, LA.

Lead-Induced Neurotoxicities: From Maternal Exposure to Neurodegenerative Alzheimer’s Disease. Wei Zheng, Purdue University, West Lafayette, IN.

Evaluating the Impact of Alternate Assumptions on Soil Remedial Levels Using EPA’s Integrated Exposure Uptake Biokinetic (IEUBK) Model. Barbara Beck, Gradient, Cambridge, MA.

Probabilistic Modeling of Childhood Multimedia Lead Exposures: Examining the Soil Ingestion Pathway. Rogelio Tornero-Velez, US EPA, Research Triangle Park, NC.

Nanotoxicology: State of the Science and the Path Forward

W  Workshop

Chairperson(s):

Treye Thomas, US Consumer Product Safety Commission, Rockville, MD; and Aaron Erdely, NIOSH, Morgantown, WV.

Primary Endorser:

Nanotoxicology Specialty Section


The US National Nanotechnology Initiative (NNI) was established in 2001 to support the responsible development of the emerging science of nanotechnology and bring together stakeholders from the federal government, industry, and academia. The goal was to thoroughly address the potential health and safety implications of nanomaterials. Stakeholders emphasized the complexity of nanotoxicology, the importance of understanding the novel physicochemical properties of nanomaterials, and how traditional toxicity testing strategies should be modified to address these unique properties. The toxicology community has responded to this call-to-action through the emergence of nanotoxicology as a subspecialty, including the 2008 launch of the SOT Nanotoxicology Specialty Section. Over the past 10 years, thousands of peer-reviewed studies have been published in journals, including those developed specifically for nanotoxicology, in addition to numerous meetings and symposia. Currently, the nanotoxicology community is at a critical juncture where stakeholders have begun to pose serious questions regarding the achievements of this new science. Concerns include the presentation and robustness of the data in published studies and whether standardized and validated methods were used. General questions surround whether available data meet critical data gaps, whether nanotoxicology should continue to exist as a subdiscipline of toxicology, and whether funding should be consolidated. The toxicology community should work in tandem with other disciplines that play a critical role in understanding the relative risks associated with nanomaterials. This session will bring together researchers and scientists from the federal government, industry, and academia to provide an overview of the lessons learned and the support provided to industry for commercializing nano-enabled products. The session will present carbon nanotube toxicity as a case study of the efforts to understand whether toxicity of engineered nanomaterial exposures is adequately understood. Other topics include the state of the science in terms of human health effects, the role of the NNI in assuring responsible development of nanotechnology, and the future directions of industries for incorporating nanotechnology. Lastly, the path forward for nanotoxicology, highlighting knowledge gaps and emerging research needs, will be presented, followed by an open discussion with the panel of speakers.


Introduction. Treye Thomas, US Consumer Product Safety Commission, Rockville, MD.

State of the Science: Nanotoxicology of Carbon Nanotubes (CNTs). Vincent Castranova, West Virginia University, Morgantown, WV.

State of the Science: Human Health Effects of Engineered Nanomaterials. Mary Schubauer-Berigan, NIOSH, Cincinnati, OH.

Ensuring Responsible Development of Nanotechnology. Lisa Friedersdorf, National Nanotechnology Coordination Office (NNCO), Arlington, VA.

An Industry Perspective on the Federal Role in Nanotoxicology. Shaun Clancy, Evonik, Parsippany, NJ.

Nanotoxicology and the Path Forward. Alison Elder, University of Rochester, Rochester, NY.


11:00 AM to 12:20 PM

Alternative Toxicology Approaches to Evaluate Next-Generation Nicotine Products

R  Roundtable

Chairperson(s):

John Fowle III, Science to Inform LLC, Pittsboro, NC; and Erin Hill, Institute for In Vitro Sciences, Gaithersburg, MD.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Inhalation and Respiratory Specialty Section
Risk Assessment Specialty Section


The development and uptake of novel nicotine products, including e-cigarettes, has grown rapidly around the world in the last decade, creating a need to evaluate the potential health risks associated with the use of these products. The US Food and Drug Administration Center for Tobacco Products and the European Union Tobacco Products Directive have made recommendations and issued guidance documents outlining the criteria for assessing the risks of these novel products. As part of these proposed frameworks, significant nonclinical testing is required. A wide variety of stakeholders are concerned about the large number of animals that potentially could be used for testing. This roundtable will explore the opportunities and challenges in utilizing in vitro and other alternative toxicology testing methods for the assessment of e-cigarettes. The panel members, representing a wide range of viewpoints, including academia, industry, and government, will discuss: 1) how global regulations are impacting research; 2) what innovations are necessary to make the science ready for regulatory decision making; 3) how to foster collaboration to ensure standardization of approaches; 4) what lessons can be taken from other industries and agencies adopting alternative approaches; 5) what role industry and other stakeholders can play; and 6) how progress can be accelerated.


Alternative Toxicology Approaches to Evaluate Next-Generation Nicotine Products. John Fowle III, Science to Inform, LLC, Pittsboro, NC.

A Roadmap to Establishing New Approaches for Toxicity Testing: Improving Human Relevance and Reducing Animal Use. Warren Casey, NIEHS, Research Triangle Park, NC.

E-Cigarettes: The Lesser Evil or the Public Health Opportunity of the 21st Century? Thomas Hartung, Johns Hopkins Center for Alternatives to Animal Testing , Baltimore, MD.

Successful Collaborations between Industry and Regulators. Erin Hill, Institute for In Vitro Sciences, Gaithersburg, MD.

Alternative Toxicology Approaches for the Evaluation of Next-Generation Nicotine Products: Manufacturer’s Perspective. Christopher Proctor, British American Tobacco, London, United Kingdom.

Arsenic, a Gift and Malice: From Discovery to Detrimental Effects, a Historical Perspective

HH  Historical Highlights

Chairperson(s):

Brinda Mahadevan, Abbott Laboratories, Mumbai, India; and Madhu Soni, Soni & Associates, Inc., Vero Beach, FL.

Primary Endorser:

Metals Specialty Section

Other Endorser(s):

Association of Scientists of Indian Origin Special Interest Group
Food Safety Specialty Section


From natural/industrial toxin to chemical warfare, murder to crime fiction, healer to poison, arsenic remains a powerful force in modern life. Arsenic toxicity is a global health problem affecting millions of people. Apart from the limit on levels of arsenic (10 parts per billion (ppb)) in drinking water established by the US Environmental Protection Agency, the US Food and Drug Administration (FDA) has been measuring total arsenic concentration in foods through its Total Diet Study and has come up with limit levels. In order to better understand the toxicity of arsenic, one needs to consider arsenic speciation, which includes inorganic arsenic (As III, As V, and total), as well as organic arsenic (dimethylarsenic acid and monomethylarsenic acid). The US FDA found that inorganic arsenic exposure in infants and pregnant women can result in a child’s decreased performance on certain developmental tests that measure learning based in epidemiological evidence about arsenic, including dietary exposure. More recently, the US FDA has proposed an “action level” of 10 ppb for inorganic arsenic in apple juice. The objectives of this symposium are to provide: 1) historical and scientific understanding of arsenic from toxicology and therapeutic perspective; 2) safety policies; 3) recent updates on mechanism of arsenic toxicity and carcinogenesis; and 4) the thought process on arsenic exposure through food.


Introduction to Millennial Use of Arsenic and Toxicological Effects. Madhu Soni, Soni & Associates, Inc., Vero Beach, FL.

A Historical Perspective on the Dichotomy of Arsenic as a Poison and Medicinal Agent. Michael Hughes, US EPA, Research Triangle Park, NC.

Arsenic Carcinogenesis. Samuel Cohen, University of Nebraska Medical Center, Omaha, NE.

The Daunting Task of Looking for Arsenic in Foods: An FDA Perspective. Suzanne Fitzpatrick, US FDA, College Park, MD.

In It to Win It: How to Negotiate During the Interview Process

EC  Education-Career Development

Chairperson(s):

Karilyn Sant, University of Massachusetts, Amherst, MA; and Cynthia Browning, Brown University, Providence, RI.

Primary Endorser:

Postdoctoral Assembly

Other Endorser(s):

Career Resource and Development Committee
Graduate Student Leadership Committee


After years of professional training, early-career toxicologists are eager to start interviewing to finally secure their dream job. While nailing the interview is important, navigating the delicate process of negotiations is critical to successfully sealing the deal. However, negotiations are often kept private, giving trainees little knowledge of negotiation logistics and etiquette. Further, negotiating procedure and tactics can vary widely between academia, industry, and government. This session is designed to provide trainees with tips and strategies that will help them successfully navigate the negotiation process. Speakers, representing successful toxicologists from academia, industry, and government, will: 1) provide an overview of the negotiation process; 2) give advice on specific items that are included in recruitment packages; and 3) present practical examples of negotiating skills and techniques. The presentations will be interactive and will engage the audience through live polling technology, role playing, and mock negotiations. These discussions will be highly relevant to all student and postdoctoral attendees, as well as senior toxicologists considering a transition across the professional sectors. This career development session will stimulate an active discussion about how negotiations proceed and provide trainees with strategies, tips, and the confidence to navigate this daunting process and secure their dream job.


Strategies for Negotiating Both Salary Compensation and Start-Up Package to Assure Productivity and Success in Your First Academic Job at a Research-Intensive Institution. John Richburg, University of Texas, Austin, TX.

Getting to Yes: Academic Negotiations at a Primarily Undergraduate Institution. Larissa Williams, Bates College, Lewiston, ME.

The Art of Interviewing and Negotiating for Your First Post-Training Job in the Pharmaceutical Industry. Joseph Cichocki, Alnylam Pharmaceuticals, Cambridge, MA.

There’s Usually No Harm in Asking. Marie Fortin, Alcami Corporation, Wilmington, NC.

Negotiating with the Federal Government: What’s Actually on the Table? Tamara Tal, US EPA, Research Triangle Park, NC.


1:30 PM to 4:15 PM

Application of Data from New Approaches in Regulatory and Product Safety Decisions

S  Symposium

Chairperson(s):

Russell Thomas, US EPA, Research Triangle Park, NC; and Mike Rasenberg, European Chemicals Agency (ECHA), Helsinki, Finland.

Primary Endorser:

Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Risk Assessment Specialty Section


Following more than 10 years of evolution in applied toxicology from the release of the seminal National Research Council report Toxicity Testing in the 21st Century: A Vision and a Strategy and the progress-to-date highlighted in the 2017 report, Using 21st Century Science to Improve Risk-Related Evaluations, there is now broad recognition of the problem to be targeted with innovations in applied toxicology: Hazard and exposure assessments are needed for thousands of chemicals, and the data gaps present cannot be filled using solely traditional methods in toxicology and exposure science due to time and resources. High-throughput predictions for bioactivity and exposure are beginning to inform both regulatory and product safety decisions, including prioritization, screening-level assessments for emerging contaminants, read-across, and product development and safety assessment decisions. Critical to the use of high-throughput and alternative methods for decisions informed by toxicology is definition of the qualitative and quantitative uncertainty of these methods to ensure conservative protection of human and ecological health. The purpose of this symposium is to provide details on successful first implementations using high-throughput toxicology tools in specific types of decisions and how the associated uncertainty with these tools was understood and accounted for within the decision. Importantly, the lessons learned from these early applications of high-throughput methods to regulatory and product safety decisions will provide the context for modification of high-throughput tools and data interpretation to meet the ongoing challenges of more rapid and efficient safety assessments.


Application to Prioritization for Health Canada’s CMP. Tara Barton-MacLaren, Health Canada, Toronto, ON, Canada.

GenRA: From Research and Implementation to Practical Application. Grace Patlewicz, US EPA, Research Triangle Park, NC.

Utilizing Novel Data Streams to Characterize Emerging Contaminants in the Superfund Program. Alicia Frame, US EPA, Arlington, VA.

Utilization of High-Throughput Data for Product Safety Assessment. Reza Rasoulpour, Dow AgroSciences, Indianapolis, IN.

Application to Risk Assessment: Can Bioactivity Predictions Be Used as a Conservative Point-of-Departure? Katie Paul Friedman, US EPA, Research Triangle Park, NC.

Effectively Leveraging Cellular Functional Genomics Strategies for Elucidating Chemical Mechanisms of Action

S  Symposium

Chairperson(s):

Audrey Bone, US EPA, Research Triangle Park, NC; and Federica Piccioni, Broad Institute of MIT and Harvard, Cambridge, MA.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Mechanisms Specialty Section
Molecular and Systems Biology Specialty Section


High-throughput toxicity testing has become increasingly important in the field of toxicology, as evidenced by the advent of programs such as Tox21 and ToxCast. However, these programs cover a fairly limited amount of biological space and are constrained by current knowledge of biological pathways of toxicity. In order to comprehensively assess the potential for chemical hazard without the bias of only investigating known pathways, more wide-ranging screening techniques are needed. In recent years, new technologies have been developed that broadly can be referred to as functional genomics (or proteomics), which are capable of globally determining genes/gene products that are critically involved in chemical interactions. Techniques include, but are not limited, to: 1) yeast knockout collection with haploinsufficiency profiling/homozygous deletion profiling (HIP/HOP) technology and the like, which uses chemical tolerance or intolerance to identify toxicity targets; 2) CRISPR-Cas9 knockout screening in human cells, which functions similarly to the HIP/HOP screen; 3) proteomics methods that identify specific chemical-protein interactions in the context of the entire cellular milieu; and 4) transcriptomics methods which use the technologies of next-generation sequencing (NGS) to study the cellular state of healthy, chemically perturbed, and/or diseased tissue. These techniques cover more comprehensive biological space that may provide data leading to discovery of new biological targets and pathways of toxicity. In addition, since these techniques provide some measure of cell health as a result of gene manipulation linked to chemical insult, the role of each gene in either chemical tolerance or intolerance can be functionally ascertained. The purpose of this session is to provide an overview of the cell-based techniques that are currently in use or being developed to demonstrate powerful new ways of determining mechanisms of toxicity for environmental and other chemicals. One of the co-chairs will provide an introductory overview of functional genomics and describe how these technologies could be applied in 21st-century toxicology. The first speaker will describe the use of a large panel of diverse cell types, including cell lines, iPSC and primary cells, with critical gene targets modified using CRISPR-Cas9 technology to identify critical chemical targets. Validation of results using both CRISPRi (inactivation) and CRISPRa (activation) of targets identified also will be demonstrated and use of these approaches in understanding off-target effects of drugs. The second speaker will discuss the use of CRISPR technology to identify genes following arsenic exposure that promote the endoplasmic reticulum stress response and apoptosis in human cells. Experimental data presented will include novel validated gene hits, in particular, those of the polycomb repressive complex and microRNAs. The third speaker will continue the discussion of the use of CRISPR technology in human cells for functional genomics by presenting work done in human erythroleukemic K562 cells exposed to arsenic trioxide or acetaldehyde. The speaker will present data that demonstrates not only the utility of this approach to identify novel toxicity pathways, as he will show in the case of arsenic trioxide, but also the capability to assign potential roles to uncharacterized proteins based on known toxicity pathways, as he will show in the case of acetaldehyde and DNA repair. The fourth speaker will compare use of gain of function and loss of function genomic screens using lentivirus to deliver an open reading frame library into human cells to characterize mechanisms of action of drugs in cancer cell lines and compare this approach to CRISP-Cas9 methods. The final speaker will discuss an unbiased chemical proteomics platform that identifies chemical-protein interactions in intact cells by a variety of techniques such as target identification by ligand stabilization. Applications of the methods will be provided, such as identification of the target of a brominated flame retardant. The material in this session will demonstrate how functional genomics techniques have the potential to address a major gap in current toxicological paradigms. Determining chemical mechanisms of toxicity are currently limited by incomplete knowledge of biology. Functional genomics techniques provide an opportunity to develop high-throughput toxicity testing with the advantage of covering a more complete biological space and a functional measure of toxicity. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US Environmental Protection Agency.


Filling in the Gaps: The Role Functional Genomics Can Play in 21st-Century Toxicology. Audrey Bone, US EPA, Research Triangle Park, NC.

The Use of CRISPR-Cas9 Technology for Validation and De-Validation of Targets from Functional Genomics Lorenz Mayr, AstraZeneca, Cambridge, United Kingdom.

CRISPR Genetic Screens on Cellular Stress Response to Proteo-Toxicants. Quan Lu, Harvard T.H. Chan School of Public Health, Boston, MA.

Genome-Wide CRISPR-Cas9 Screens in Human Cell Lines Provide Novel Mechanistic Insights into Toxic Responses to Arsenic and Acetaldehyde Amin Sobh, University of California Berkeley, Berkeley, CA.

Pooled Genome-Wide Screens as a Powerful Tool for Studying Drug Mechanism of Action in Cancer. Federica Piccioni, Broad Institute of MIT and Harvard, Cambridge, MA.

Development of a Hybrid Chemical Proteomics Platform for Proteome-Wide Identification of Protein Targets of Environmental Chemicals. Hui Peng, University of Toronto, Toronto, ON, Canada.

Stressors from Within: Neuroendocrine Regulation of Air Pollution-Induced Pulmonary and Systemic Health Effects

S ITS  Symposium/Innovations in Toxicological Sciences Session

Chairperson(s):

Urmila Kodavanti, US EPA, Durham, NC; and Samantha Snow, US EPA, Durham, NC.

Primary Endorser:

Inhalation and Respiratory Specialty Section

Other Endorser(s):

Women in Toxicology Special Interest Group


Air pollution research has traditionally focused on exploring the mechanisms linking acute and chronic exposure to lung injury/inflammation and, ultimately, the development and exacerbation of airway diseases. More recently, evidence has emerged linking air pollution to adverse cardiovascular health effects, neurological diseases, systemic inflammation, diabetes, obesity, steatohepatitis, and poor reproductive and developmental outcomes. A novel paradigm has been proposed involving the role of central nervous system activation to explain pulmonary and extra-pulmonary effects of inhaled pollutants. The new evidence in general brings forth a compelling common mechanism involving sympathetic-adrenomedullary and hypothalamus-pituitary-adrenal axes-mediated systemic homeostatic stress responses that can explain the widespread multi-organ metabolic and immune effects of air pollution. The role of these neuroendocrine axes in mediating systemic effects of pollutants has been overlooked in the past. This mechanism emphasizes the importance of considering a systems biology approach for inhaled pollutants and other stressors and proposes a common mechanistic pathway for chemical and non-chemical stressors. The unifying hypothesis involving the neuroendocrine axes will be presented and supported by each speaker to specifically explore: 1) the basic understanding of how acute physical and psychological stresses (good stress) through neuroendocrine activation mediate immune cell egress and extravasation and other homeostatic changes and, in the long term, contribute to chronic inflammatory diseases (bad stress); 2) epidemiological evidence linking environmental stressors, specifically air pollutants, to the neuroendocrine pathway leading to exacerbation of inflammatory conditions of asthma and chronic obstructive pulmonary disease (COPD), which will include looking at the interactive effects of psychological and environmental stressors during development and susceptibility to chronic respiratory diseases; 3) how irritant pollutants likely activate neuroendocrine stress response through nociception by stimulation of sensory nerves, including vagal C-fibers, and integrate sensory signals to the brain to stimulate stress-responsive centers including hypothalamus, which is involved in a flight-or-fight response upon physical stress encounter; 4) experimental studies examining how exposure to inhaled pollutants through neuroendocrine stress response pathways activate adrenergic and steroidal mechanisms and alter systemic metabolic homeostasis to affect liver, muscle, and adipose tissue lipid and glucose metabolism and influence lung injury/inflammation; and 5) the development of a glucocorticoid receptor adverse outcome pathway to integrate the new mechanistic information on environmental sensory irritants and metabolic and immune dysfunction through neuroendocrine stress axes activation and tissue-specific activation of stress hormone receptors. The goal of this session is to synthesize and discuss these emerging findings in order to build a consensus that neuroendocrine stress axes play a major role in air pollutant and environmental health effects and disease susceptibility. The topics covered also will highlight areas where redirection of research efforts might better address the most critical knowledge gaps in the understanding of air pollutant-induced modulation of neuroendocrine pathways and disease susceptibility and improve health risk assessment.


Neuroendocrine-Immune Effects of Stress in Health and Disease. Firdaus Dhabhar, University of Miami Miller School of Medicine, Miami, FL.

Role of Social and Physical Stressors in Programming of Chronic Lung Diseases and Therapeutic Interventions. Rosalind Wright, Icahn School of Medicine at Mount Sinai, New York, NY.

Autonomic Regulation of Systemic Health Effects of Air Pollution: The Role of Sensory Stimulation. Thomas Taylor-Clark, University of South Florida, Tampa, FL.

Air Pollution and Neuroendocrine Stress-Mediated Systemic Metabolic and Inflammatory Response. Urmila Kodavanti, US EPA, Durham, NC.

Adverse Outcome Pathway Network of Adrenergic and Glucocorticoid Signaling Links Inhaled Pollutants with Multiple Adverse Outcomes. Stephen Edwards, US EPA, Durham, NC.

Big Data in Toxicology: How to Achieve Transparency and Reproducibility

W  Workshop

Chairperson(s):

Agnes Karmaus, ILS, Research Triangle Park, NC; and Lyle Burgoon, US Army Engineer Research and Development Center, Research Triangle Park, NC.

Primary Endorser:

Ethical, Legal, Forensics, and Societal Issues Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Regulatory and Safety Evaluation Specialty Section


You have performed your experiment or analysis, generated or used toxicological big data, want to publish it, and need it to be transparent and reproducible. What do you do? This is one of the challenges faced when using or generating toxicological big data (high-throughput screening, high-content assays, or ’omics technologies). Data analyses have become more complex, with increasing scrutiny being placed on the computational methods to ensure analyses are clearly communicated (transparency) and easily reproduced. Supplementary data files may be insufficient to adequately relay the necessary detail or metadata, nor meet the data quality needs and minimum information criteria required for risk assessors to utilize such data/analyses. This session seeks to address these challenges facing toxicologists highlighting platforms for data sharing, how to cite alternative data sources, and the minimum information required for reproducibility and transparency that will help lead toward regulatory acceptance of big data. Furthermore, in order for complex models to be broadly utilized and reproducible, and clear methodologies, as well as developing fit-for-purpose models that address specific needs, are required. This session will encompass various viewpoints—from the research perspective to that of regulators and industry—providing suggestions and resources for establishing reliable and useful models, as well as promoting transparent communication regarding the use of big data and computational approaches in the toxicological sciences. An aim of the sesson is to promote awareness regarding the dissemination and use of big data in toxicology, and it will conclude with a panel discussion including all speakers.


Introduction. Agnes Karmaus, ILS, Research Triangle Park, NC.

Challenges Facing Publication and Transparency for Big Data in Toxicology. Lyle Burgoon, US Army Engineer Research and Development Center, Research Triangle Park, NC.

Big Data in Toxicology: Remodeling the Publishing Landscape. Gary W. Miller, Emory University, Atlanta, GA.

Resources and Alternative Publication Streams for Big Data. Antony Williams, US EPA, Research Triangle Park, NC.

Utility of Big Data: Developing Reliable Fit-for-Purpose Data Models. Matthew Martin, Pfizer, Inc., Groton, CT.

Establishing Confidence in Prediction Models. Lars Carlsson, AstraZeneca, Mölndal, Sweden.

Mitochondria: Critical Targets in Pharmaceutical and Environmental Toxicity

W  Workshop

Chairperson(s):

Bob van de Water, Universiteit Leiden, Leiden, Netherlands; and Yvonne Will, Pfizer, Inc., Groton, CT.

Primary Endorser:

Drug Discovery Toxicology Specialty Section

Other Endorser(s):

Molecular and Systems Biology Specialty Section


Mitochondria are essential for cellular metabolism, and mitochondrial damage is a key event in adverse outcome pathways. Toxic insults causing mitochondrial dysfunction can lead to cellular necrosis due to loss of adenosine triphosphate production, to apoptosis through cytochrome-C leakage, and to many other adverse events, including reactive oxygen species production. Speakers from academia and industry will discuss several aspects of mitochondrial toxicity in the context of pharmaceutical and environmental toxicity. The goal is to present current insights into the central role of mitochondria in distinct toxicity pathways and state-of-the-art approaches to investigating mitochondrial toxicity. The latest technologies, including transcriptomics, proteomics, and metabolomics, as well as fluorescent protein reporters in combination with high-resolution microscopy, provide time-resolved mechanistic insight into cause and consequences of chemical-induced mitochondrial injury. The session will start with cutting edge work that centers on the mechanisms by which mitochondrial quality is maintained and how damaged mitochondria are removed from the cell. This will be followed by new findings obtained through metabolomic characterization of isolated human mitochondria and definition of the mitochondrial exposome. The next presentation will feature exciting work showing how off-target adverse drug effects on mitochondrial energetics cause muscle dysfunction. The following presenter will discuss innovative approaches to unraveling mitochondrial toxicity pathways as developed in the EU-ToxRisk project. The final presenter will address how changes in mitochondrial biogenesis serve as a cellular adaptive mechanism counteracting drug-induced liver toxicity. This session will be of general interest to scientists interested in cellular and tissue-level mechanisms of toxicity. In addition, attendees with an interest in state-of-the-art approaches to unraveling pathways of toxicity in a time- and concentration-resolved manner will benefit from the session. Finally, this session will be of interest to regulatory scientists incorporating information from in vitro assays in the decision-making process.


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

New Insights in Mitochondrial Quality Control and Mitophagy. Åsa Gustafsson, University of California San Diego, San Diego, CA.

The Mitochondrial Exposome Douglas Walker, Emory University, Atlanta, GA.

Drug-Induced Myopathy through Adverse Effects on Mitochondrial Energetics. Frans Russel, RIMLS, Amsterdam, Netherlands.

EU-ToxRisk: Advances in High-Content Microscopy Analysis for Mitochondrial Toxicity. Erik Danen, Universiteit Leiden, Leiden, Netherlands.

Increased Mitochondrial Biogenesis as a Cellular Adaptive Mechanism Counteracting Drug-Induced Liver Toxicity. Paul Carmichael, Unilever, Sharnbrook, United Kingdom.

Safety Evaluation of Plant-Based Color Additives Used In Foods

W  Workshop

Chairperson(s):

Yu (Janet) Zang, US FDA, College Park, MD; and Maria Bastaki, International Association of Color Manufacturers (IACM), Washington, DC.

Primary Endorser:

Food Safety Specialty Section

Other Endorser(s):

Mixtures Specialty Section
Regulatory and Safety Evaluation Specialty Section


Color plays a significant role in food choice by influencing consumer preference, taste perception, and acceptability. With an increasing number of consumers looking for foods with “clean labels,” the market demand for “natural” colors has recently been rising significantly. There have been a growing number of food manufacturers turning away from synthetic colors and towards extracts from plant sources, primarily because of the increasing public interest in “natural” products. Currently, global regulatory agencies do not have a harmonized viewpoint as to the definition of color additives from botanical sources and their use requirements. In the United States, any unapproved color additive from a natural source is subject to premarket safety review by the US Food and Drug Administration (US FDA) with the same safety standard as for synthetic color additives. For plant-based color additives, considerations include chemical identity and composition, manufacturing process, source plant material, heat, pH, light stability, and pesticide and toxic element contamination. In the European Union, a decision tree is used to help determine when an ingredient can be considered a coloring food versus a coloring additive, with the latter being subject to scientific safety assessment. Failure to be aware of the regulatory review requirements can lead to compliance and labeling challenges and possibly charges of adulteration and misbranding upon importation of finished food items. Dialogues and collaborations among stakeholders, including color manufacturers, industrial end users, researchers, and regulatory scientists, are needed. They should work together to harmonize and optimize the safety evaluation of plant-based color additives. This workshop brings together food color experts from these stakeholder groups to share their experiences and perspectives on this topic. Following an introduction that will summarize the use pattern of food colors, speakers will discuss wide-ranging topics related to the safety evaluation of plant-based color additives used in foods, including: (1) the differences between synthetic and natural color with regard to manufacturing and practical applications; (2) segments along the supply chain and manufacturing process impacting the safe use of these colors; (3) issues with product quality related to adulteration and contamination that compromise the safety; (4) United States Pharmacopeia (USP)’s experiences in establishing identity and specification standards for plant extracts; (5) the US FDA review process and special considerations; and (6) highlights of the most recent developments by global regulatory authorities. Examples of data packages sent to the US FDA, European Food Safety Authority (EFSA), and the Joint Food and Agricultural Organization of the United States (FAO)/World Health Organzation (WHO) Expert Committee on Food Additives to support safety will be presented.


The Safe Use of Plant-Based Color Additives: An Introduction. Maria Bastaki, International Association of Color Manufacturers (IACM), Washington, DC.

Safety Considerations in Using Natural Color Additives: Industry’s Perspectives. George Pugh Jr., The Coca-Cola Company, Atlanta, GA.

Coloring and Co-Existing Ingredients in Plants Used to Dye Foods. Stephen Talcott, Texas A&M University, College Station, TX.

Establishing Standards for Natural Extracts: Experiences from USP. Hellen Oketch-Rabah, United States Pharmacopeia (USP), Rockville, MD.

Assessing the Safety of Plant-Based Food Colors in a Regulatory Setting. Yu (Janet) Zang, US FDA, College Park, MD.

Global Regulations for Plant-Based Food Colors. Sue Ann McAvoy, Sensient Colors LLC, St. Louis, MO.

Communicating Science: Unconventional Oil and Gas Operations as a Case Study

RI  Regional Interest

Chairperson(s):

David Steup, Shell Oil Company (Retired), Houston, TX; and Erica Bruce, Baylor University, Waco, TX.

Primary Endorser:

Lone Star Regional Chapter

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section


Ten years ago, there was a rapid increase in oil and natural gas development activities (OGD) in various unconventional resource basins around the country. The increase was the result of an innovative use of existing technologies (horizontal drilling and hydraulic fracturing). The transformation also led to a rapid increase in the build out of the infrastructure required to deliver the product to the markets (i.e., pipelines, compressor stations) and facilities for processing the product (i.e., natural gas process facilities, liquefaction facilities). While the increase was a boon to the economy, it also generated scrutiny from policymakers, researchers, and advocates who commonly cited health concerns. As the decade mark of the nationwide ramp up in industry operations and activities approaches, some of the same challenges still exist. One of the aspects of addressing health concerns might be to align risk perceptions with the actual risks related to OGD and infrastructure development activities. Texas has a rich history of OGD going back to the early 20th century and is home to some of the largest shale basins (the Permian Basin, Eagle Ford Shale, and Barnett Shale) in the United States. Industry activities are a critical part of the Texas economy, and despite the challenges, Texas has managed to maintain these activities while addressing the growing environmental and health concerns. Toxicological principles and toxicologists are at the core of developing the information required to address the concerns and to bridge the risk divide. In this session, various stakeholders will share their experiences on how they have worked to address the divide between perceived risk versus actual risk as they develop regulations, formulate policies, and conduct and report research findings. Speakers are drawn from local stakeholder groups (i.e., industry, regulators, academia, and non-governmental organizations) to provide a variety of perspectives. The session will feature a risk communication specialist, who will provide some insight into overcoming the challenges. The goal of the session is to stimulate discussion on the role of toxicologists in risk and science communication, the challenges and solutions to effective communication on controversial public health issues, and the difficulty related with developing policy decisions on a polarizing issue. While OGD provides a case study, the issues faced by the oil and natural gas industry can be transposed across settings where public health concerns are elevated from public opinion.


Introduction. Erica Bruce, Baylor University, Waco, TX.

Industry Perspective on the Challenges Related to Communicating Risks for Unconventional Oil and Gas Operations. Uni Blake, American Petroleum Institute, Washington, DC.

Unconventional Natural Gas and Oil Drilling and Public Health in the Marcellus Shale. Trevor Penning, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Perspectives from the Texas Commission on Environmental Quality (TCEQ) Related to Risk Communication and Unconventional Oil and Gas Operations in Texas. Tiffany Bredfelt, Texas Commission on Environmental Quality, Austin, TX.

Perspectives from a Risk Communication Expert: Focus on Unconventional Oil and Gas Operations. Vincent Covello, Center for Risk Communication, New York, NY.

Communication of Scientific Findings and Risk Perception Associated with Unconventional Oil and Natural Gas Development Elena Craft, Environmental Defense Fund, Austin, TX.

Radiation Toxicity: Historical Perspective on Epidemiological and Experimental Evidence Informing Standards

HH  Historical Highlights

Chairperson(s):

Roger O. McClellan, Toxicology and Risk Analysis, Albuquerque, NM; and Philip Wexler, National Library of Medicine, Bethesda, MD.

Primary Endorser:

Specialty Section Collaboration and Communication Group

Other Endorser(s):

Carcinogenesis Specialty Section
Regulatory and Safety Evaluation Specialty Section


The literature on the health effects of external radiation exposures and internally-deposited radionuclides, most of which was developed post-World War II, is extraordinarily voluminous and robust. This literature includes information on the sources of radiation and radionuclides, environmental and occupational exposures, substantial epidemiological findings, and complementary findings from controlled exposures of molecules, cells, tissues, and populations of multiple species of laboratory animals. The substantial scientific literature has been used to inform the settings of radiation exposure standards for workers and the general population. The radiation protection scheme takes account of radiation quality and dose protraction. The presentations in this session will briefly review the history of key discoveries in the radiation field and the development of radiation protection standards, as well as the historical development of knowledge on radiation effects discovered using both epidemiological and experimental approaches. Mutations and cancer, which have traditionally been primary endpoints in radiation protection standards, will be highlighted. Various models describing radiation dose-response relationships, including the use of the linear no-threshold model, will be covered. Uncertainties and controversies in the knowledge base will be discussed, including the extent to which the setting of radiation protection standards has subsequently influenced the standard setting for chemical exposures. Further, in light of the thousands of nuclear weapons stockpiled around the world, this session also will put into perspective the human and environmental consequences of ionizing radiation that could ensue from their potential use.


Key Historical Events in the Discovery of Radiation Phenomena and Sources of Radiation Exposure. Philip Wexler, National Library of Medicine, Bethesda, MD.

History of Radiation Protection Standards. John Poston Sr., Texas A&M University, College Station, TX.

Key Epidemiological Findings on Health Effects of External Exposure and Internally-Deposited Radionuclides, with an Emphasis on Cancer as an Endpoint. David Hoel, The Medical University of South Carolina, Charleston, SC.

Role of Studies with Internally-Deposited Radionuclides in Laboratory Animals to Inform Radiation Protection Standards. Roger McClellan, Toxicology and Risk Analysis, Albuquerque, NM.

Role of Molecular and Cellular Data in Radiation Risk Assessment Antone Brooks, Washington State University (Retired), Pullman, WA.

Early Efforts to Develop Quantitative Exposure-Cancer Response Models for Chemically-Induced Cancer. Kenny Crump, Louisiana Tech University, Ruston, LA.


4:30 PM to 5:50 PM

Perfecting Your “Elevator Speech”

EC  Education-Career Development

Chairperson(s):

Joseph Cichocki, Alnylam Pharmaceuticals, Cambridge, MA; and Kathryn Page, The Clorox Company, Pleasanton, CA.

Primary Endorser:

Career Resource and Development Committee

Other Endorser(s):

Education Committee
Postdoctoral Assembly


Effectively communicating science to the general public and to experts in the field is a skill that must be mastered in order to build your career. For most individuals, and especially most trainees, orally presenting a seminar or formalized science speech is much easier than giving a brief, two-to-three minute talk about one’s science and its impact on the general public. This “elevator speech,” however, is often the most important talk one will ever give, as you often have to communicate your science in a brief, succinct, and clear fashion in order to convey your message to lay individuals and experts alike. Further, during job interviews, you will not have one hour to talk to every interviewer individually, but, rather, will have to quickly summarize your work in a couple of minutes. This session will provide tips and tricks to deliver your “elevator speech,” which will be useful for your interactions not only at the SOT Annual Meeting and ToxExpo, but also in your daily professional (and maybe personal) life. Following a brief introduction, a panel of experts and early-career scientists will provide examples and advice on how to quickly summarize a scientific project into a brief two-to-three minute speech. Following the short panel discussion, a 35-minute “hands-on” session will follow in which the session chairs will facilitate attendees as they perform their two- to three-minute “elevator speeches” in small groups. Five minutes will be allocated to wrap-up the session following the hands-on activity.


Introduction. Joseph Cichocki, Alnylam Pharmaceuticals, College Station, TX.

Body Language and First Impressions Marie Fortin, Alcami Corporation, Piscataway, NJ.

Perfecting Your Pitch: Key Features of an Elevator Speech to Help You Reach the Top Floor. Shaun McCullough, US EPA, Chapel Hill, NC.

What NOT to Do... Ruth Roberts, ApconiX, Alderley Edge, United Kingdom.

Panel Discussion/Q&A. Kathryn Page, The Clorox Company, Pleasanton, CA.

Hands-On Activity. Joseph Cichocki, Alnylam Pharmaceuticals, Cambridge, MA.


Wednesday, March 14

8:00 AM to 10:45 AM

Cardiovascular Adverse Effects Are Still Causing Late Attrition of Novel Therapeutics: Developing Solutions to Detect and Avoid Cardiovascular Toxicity in the Clinic

W  Workshop

Chairperson(s):

John Kremer, Covance, Madison, WI; and Mark Holbrook, VAST Pharma Solutions, Harrogate, United Kingdom.

Primary Endorser:

Cardiovascular Toxicology Specialty Section

Other Endorser(s):

Drug Discovery Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section


Cardiovascular (CV) liabilities continue to be a leading cause of drug attrition in late-stage clinical trials and post-market approval. Aspects of the current paradigm have adequately characterized (e.g., benefit vs. risk) compounds for hERG blockade and QT interval prolongation, but a method to detect arrhythmogenesis directly, rather than using surrogates, still needs to be defined. Even so, the rate of attrition due to CV liabilities has remained intractably high, primarily due to non-QTc-related liabilities (e.g., blood pressure, contractility). This session will start by highlighting several high-profile drug withdrawals due to unexpected CV liability to establish the problem statement. Specific examples will include Terfenidine (QT prolongation, Torsades de Pointes); Vioxx/COX-2 inhibitors (myocardial infarction, stroke); and Torcetrapib (increased cardiac events, hypertension). The individual speakers will address this problem by describing new scientific and strategic approaches to detect and characterize potential liabilities, culminating in a panel discussion with the audience. Specifically, the first presentation will describe the use of human-induced pluripotent stem cell-derived cardiomyocytes to profile safety and potential mechanisms for drug-induced arrhythmia or structural cardiotoxicity. The second and third presentations will focus on the use of rodent and large animal models, respectively, in safety (normal healthy animals) or efficacy (disease models) studies, including key considerations, such as study design, model selection and characterization, and translatability to clinical endpoints. The fourth presenter will add to the discussion of translation from preclinical (in vitro, ex vivo, in silico, and in vivo) to clinical and the importance of statistical power to delineate a positive vs. negative signal for a better integrated CV risk assessment. The final presenter will build on this discussion of statistical sensitivity by presenting a retrospective analysis of power for CV data reported in recent investigational new drug (IND) submissions and a regulatory viewpoint on the use of alternative in vivo models. The session will end with a brief summary of strategies to improve CV safety assessment to enhance patient safety and reduce the risk of compound failure and will be followed by a panel discussion to outline how researchers across multiple disciplines and organizations can share approaches and data to improve the testing paradigm. The goal of the session is to provide a data-driven, comprehensive discussion on how to revise CV safety assessments to improve patient safety and reduce the rate of late-stage compound failures.


Introduction. John Kremer, Covance, Madison, WI.

Use of hiPSC-Derived Cardiomyocytes for Cardiac Safety Evaluation. Liang Guo, Frederick National Laboratory for Cancer Research, Frederick, MD.

Incorporation of Cardiovascular Assessment in Early Efficacy or Safety Studies in Rodents. Richard Macia, Covance, Madison, WI.

Clinically-Relevant Large Animal Models of Heart Failure: Model Selection, Limitations, and Optimization. Kim Hoagland, Thousand Oaks, CA.

Translation from Nonclinical to Clinical Cardiovascular Safety: What Constitutes a Safety Risk? Mark Holbrook, VAST Pharma Solutions, Harrogate, United Kingdom.

A Regulatory Discussion of Cardiovascular Safety Pharmacology Studies. Donald Jensen, US FDA, Washington, DC.

Environmental Chemical-Microbiome Interactions in Disease Susceptibility

W  Workshop

Chairperson(s):

Mitzi Nagarkatti, University of South Carolina, Columbia, SC; and Gary Perdew, Pennsylvania State University, University Park, PA.

Primary Endorser:

Comparative and Veterinary Specialty Section

Other Endorser(s):

Biotechnology Specialty Section
Toxicologic and Exploratory Pathology Specialty Section


The human body harbors trillions of microbes, and there exists a symbiotic association between humans and microbes. Such an interaction plays a critical role in maintaining homeostasis. Because the microbial ecosystem is found throughout the body, it is constantly exposed to environmental chemicals. Thus, there is constant crosstalk between the environmental chemicals and microbiota, leading to altered bioavailability of chemicals and/or microbial dysbiosis that could trigger disease process. To that end, it is critical to get a better understanding of the mechanisms of these complex interactions between environmental chemicals and microbiota. Such studies may help in understanding why certain individuals are more susceptible to certain diseases when compared to others. This session will explore recent findings that provide conclusive answers, demonstrating that certain environmental insults cause microbial dysbiosis and consequently trigger various diseases. This session will start with introduction to the field, followed by a presentation of data on how bacterially-generated and exogenous chemicals alter the bacterial composition and metabolism within the gut, leading to altered host homeostasis by activating the Ah receptor (AhR). The session will provide evidence that inhalation of Staphylococcal enterotoxin-B (SEB) triggers acute lung injury (ALI) in mice that can be effectively blocked by resveratrol, an AhR ligand. Interestingly, SEB triggered dysbiosis in the lung and gut microbiota, thereby suggesting gut-lung axis. Moreover, resveratrol treatment reversed the dysbiosis, thereby suggesting that AhR activation may prevent SEB-induced inflammation through alterations in the microbiome. Presenters will provide evidence that specific microbial genotoxic activities originating from various microbial strains, such as Escherichia coli, Atopobium parvulum, and Campylobacter jejuni, promote development of colorectal cancer (CRC). Also, it will be demonstrated that CRC development could be modulated using genetic and pharmacological intervention aimed at the microbiota. These studies represent the first step toward validating the microbiota as a potential therapeutic target for prevention/treatment of CRC. Presenters will discuss obesogenic chemicals and describe how they interact with gut microbiota and promote adiposity in animals. Talks will focus on obesogenic activity of tributyltin. Together, the presentations will be organized in such a way that they will transition from introducing the topic on how crosstalk between environmental chemicals and microbiota plays a critical role in health and disease to addressing, in the second talk, more specific questions, such as the gut-lung axis in regulating the inflammatory disease. The third and fourth presenters will focus on specific disorders, such as cancer and obesity, with the third talk also highlighting how altering the microbiota would serve as a therapeutic tool to prevent/treat colon cancer. Together, this workshop will provide an exciting opportunity for all participants to gain new knowledge of the complexity of the interactions between the environmental chemicals to which people are constantly exposed and the microbiota, as well as novel insights into how they regulate the pathogenesis of a variety of clinical disorders.


Modulation of the AhR within the Gastrointestinal Tract Mediates Both Protective and Adverse Outcomes. Gary Perdew, Pennsylvania State University, University Park, PA.

Staphylococcus Enterotoxin B (SEB) Triggers Acute Lung Injury (ALI) through Dysbiosis in Gut-Lung Axis and AhR Ligands Protect the Lungs through Reversal of Microbiome. Mitzi Nagarkatti, University of South Carolina, Columbia, SC.

Tributyltin Exposure Alters Post-Embryonic Growth, Adiposity, and Intestinal Microbiota Assembly in Zebrafish. John Rawls, Duke University School of Medicine, Durham, NC.

Cancer: Mining the Microbiota for Answers Christian Jobin, University of Florida, Gainesville, FL.

Matching Analytical Methods to Markets: Balancing Regulatory Expectations and Technical Challenges

W IAT  Workshop/Innovations in Applied Toxicology Session

Chairperson(s):

Barbara Henry, W.L. Gore & Associates Inc., Elkton, MD; and Sherry Parker, WuXi AppTec Inc., St. Paul, MN.

Primary Endorser:

Medical Device and Combination Product Specialty Section


Today, regulators, supply chain partners, and customers want to know what is in the products they buy that might harm them. From a risk assessment perspective, the absence of clear consensus and regulatory guidance for chemical characterization of medical devices, drug-device combination products, and their components delays commercialization of life-benefiting technology, leads to increased animal testing as a clearly-defined path to market, and is expensive. This session will seek to open the dialogue on the challenges and potential paths forward for manufacturers of medical devices, device-drug combination products, and manufacturers of components to those industries. The first presenter will briefly compare several extractables and leachables (E&L) approaches, including ISO 10993 and those by the United States Pharmacopeia, Product Quality Research Institute, the US Food and Drug Administration (US FDA), the Extractables Work Group of the BioPhorum Operations Group, and the Bio-Process Systems Alliance. Once the stage is set, the next presenter will focus on ISO 10993 -1, -17, and -18 acknowledging the importance of chemical characterization of medical devices, as well as the current lack of sufficient detail to plan extraction, analysis, and interpretation for risk assessment. Proposed revisions to the standards and guidance will be discussed. Remember the expression “garbage in, garbage out”? In order to have high-quality risk assessments, the data must be high quality. The next topic will be the essential collaboration between the chemist and toxicologist in the design, execution, and interpretation of E&L studies. Knowing what the product is made with, manufacturing steps, potential contaminants, residuals, and impurities helps the toxicologist identify potential chemicals of concern, which the chemist will then need to find and quantify using appropriate solvents, extraction conditions, and analytical techniques. How low should you go (limit of detection) to support the risk assessment for the intended use of the product? When to be aggressive in extractions and when to use “kinder and gentler” extractions simulating clinical-use conditions of products will be addressed. This topic will end with risk assessment approaches, including handling of unknown chemicals and use of the Threshold of Toxicological Concern (TTC) for a permanently-implanted medical device and a drug-device combination product. Now, that the opening presentations have shared a collaborative plan of attack for E&L, does it matter which lab does the analysis? Inter-laboratory variability related to compound identification and quantitation, including equipment sensitivity and the available chemical library, will be discussed by the next presenter. Disparity in the number of reported compounds among four test laboratories for the same test articles, despite the same extraction solvents, conditions, and analytical techniques, will be shared. Considerable quantitative and qualitative differences potentially impacting the risk assessment will be discussed. The final presentation will provide light at the end of this complex and complicated tunnel by sharing US FDA expectations of E&L studies for medical devices and combination products. The presentation will include LODs, LOQs, sensitivity, extraction methods, and the interpretation of qualitative, semi-quantitative, and quantitative data, as well as issues frequently encountered. To close out the session, the panel will answer audience questions regarding lab selection, unknowns, use of the TTC, Cramer Classes, and in silico approaches. This session will feature information and provocative discussions that will be transferable to other E&L applications and should be of interest to contract labs and manufacturers of parts intended for use in medical devices, pharmaceutical processing, or single-use systems, as well as regulators.


Introduction. Barbary Henry, W.L. Gore & Associates Inc., Elkton, MD.

Which Guidance to Follow for Which Market? Barbara Henry, W.L. Gore & Associates Inc., Elkton, MD.

Extractables and Leachables Testing for Medical Devices—What About ISO 10993 Series? JAlbrecht Poth, Dr. Knoell Consult GmbH, Mannheim, Germany.

Designing Chemical-Characterization Studies for Medical Devices and Combination Products with the Risk Assessment in Mind: Current Approaches and Challenges. Sandi Schaible, WuXi AppTec Inc., St. Paul, MN.

Variation in Chemical-Characterization Results from Four Test Laboratories. Monica Posgai, Johnson & Johnson, Cincinnati, OH.

An Overview of Regulatory Considerations for Chemical Characterization of Medical Devices and Combination Products. Ji Guo, US FDA Center for Devices and Radiological Health, Silver Spring, MD.

Q&A—Seed Questions and Audience Participation Sherry Parker, WuXi AppTec Inc., St. Paul, MN.

Mechanisms of Ocular Sulfur Mustard Toxicity and Potential Therapies

W  Workshop

Chairperson(s):

Vasilis Vasiliou, Yale School of Public Health, New Haven, CT; and Marion Gordon, Rutgers, The State University of New Jersey, Piscataway, NJ.

Primary Endorser:

Ocular Toxicology Specialty Section

Other Endorser(s):

Women in Toxicology Special Interest Group


Sulfur mustard is a chemical weapon used in World War I and the Iran-Iraq War of the 1980s. The US government still lists it as a potential warfare and terrorist agent. While exposures are often not lethal, long-term or recurrent damage to the eyes, skin, and lungs can occur. Sulfur mustard is presently a concern because it has been reported that ISIS has produced and used sulfur mustard against its adversaries. In an ISIS conflict with Syrians on August 21, 2015, unsuspecting victims developed blisters, and sulfur mustard residue was confirmed on pieces of artillery shells. Individuals do not usually feel exposure to sulfur mustard exposure until a few hours after it has occurred. This results in confusion and panic, making mustard an ideal terrorist agent. To date, there are no US Food and Drug Administration-approved therapies to treat sulfur mustard exposure of any organ, partly due to the fact that the mechanisms of toxicity of mustards are not yet well-understood. Because of government restrictions on the use of sulfur mustard, academics often use nitrogen mustard for preliminary exposures experiments and subsequently confirm their results with sulfur mustard exposures performed by companies or the Department of Defense, who are authorized to use the agent. The goal of this session is to highlight: 1) research resulting in new information on molecular pathways activated by mustard exposure; 2) new developments in how ocular exposures are performed to attain the most reliable and reproducible injury; and 3) research efforts using the newer molecular pathway information to identify potential therapies for ocular sulfur mustard exposure. Speakers will include an industry representative providing a new method of ocular mustard exposure, as well as researchers from academic, federal, and private institutions who are using the recently-identified mechanisms of mustard toxicity to identify potential ocular therapies.


Introduction. Vasilis Vasiliou, Yale School of Public Health, New Haven, CT.

CounterACT: Countermeasures against Chemical Threats—Ocular Exposures. Houmam Araj, NIH National Eye Institute (NEI), Bethesda, MD.

Acute and Chronic Pathologies in the Corneal Endothelium Following Ocular Sulfur Mustard Exposure: A New Model of Corneal Injury Progression Patrick McNutt, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD.

Ocular Injuries by Vesicating Agents: Models and Development of Medical Countermeasures. Neera Tewari-Singh, University of Colorado, Aurora, CO.

Engineered FGF-1s as Therapeutics for Ocular Vesicant Injury. David Eveleth, Trefoil Therapeutics LLC, San Diego, CA.

Reaching Hazard Conclusions for Endocrine-Disrupting Chemicals: Adapting Systematic Review Methods

W  Workshop

Chairperson(s):

Johanna Rochester, The Endocrine Disruptor Exchange (TEDX), Grand Junction, CO; and Vickie Walker, NIEHS, Research Triangle Park, NC.

Primary Endorser:

Reproductive and Developmental Toxicology Specialty Section

Other Endorser(s):

Neurotoxicology Specialty Section
Risk Assessment Specialty Section


Reviews of environmental chemicals, such as endocrine-disrupting chemicals (EDCs), are essential for identifying hazards to the health of humans and wildlife, yet they often lead to inconclusive results that can stall the regulatory process. Attempts to review this literature to arrive at hazard conclusions are often unstandardized, including weight of evidence reports or narrative reviews that lack transparency and reproducibility. To address this, systematic review methods have been developed to evaluate environmental health questions. These methods include the Office of Health and Translation (OHAT) Approach for Systematic Review, the University of California San Francisco (UCSF) Navigation Guide, and the systematic review and integrated assessment (SYRINA) of EDCs. Systematic review methodology increases the objectivity and transparency in an evaluation by using a pre-defined, multistep process to identify, critically assess, and synthesize evidence. They also contain specific methods to address study quality, among other factors. When appropriate, systematic reviews employ meta-analytical techniques that can help in the interpretation of apparently conflicting results and provide a clearer picture summarizing the overall body of evidence. These methodologies are adapted from the medical field, which has developed, used, and empirically tested systematic review methods to evaluate medical research and reach evidence-based clinical decisions about patient care and interventions. Recognition of the value of systematic review methods has increased among the environmental health community over the last five years. In fact, the US National Academy of Sciences (NAS) recently convened a panel to evaluate how systematic review procedures can be used as part of an overall strategy to evaluate potential “low-dose” endocrine-mediated effects for environmental chemicals. The NAS panel, consisting of experts from academia, non-government organizations, government, and industry, developed systematic reviews of two EDCs to illustrate the utility of systematic reviews in decision making. The resulting report will use the systematic reviews to conclude if the data support a likely causal association, evaluate the nature and relevance of dose-response relationships, and discuss how human and animal data streams can be integrated. This session will outline systematic review approaches in environmental health from government, academic, and industry perspectives. It will begin with an overview of systematic review methods in environmental health, including the SYRINA systematic review framework developed specifically for EDCs, which provides a method to identify chemicals as EDCs and assesses the strength of the association between exposure and adverse outcome. The next talk will present a case study using the UCSF Navigation Guide approach to investigate the neurotoxic effects of polybrominated diphenyl ethers (PBDEs), as an example of non-reproductive health effects associated with EDCs. The last two speakers are members of the NAS committee and will provide an overview of the timely, cutting-edge evidence and insight from the NAS panel’s report of systematic review use in low-dose environmental toxicology, including its role in regulatory toxicity practices. The NAS strategy and recommendations for evaluating low-dose adverse effects that act through endocrine-mediated pathway will be outlined. The NAS report developed case studies that examined low-dose adverse effects of two EDCs: PDBEs and phthalates. These case studies will be used to illustrate how systematic review methods can be used to evaluate human and animal evidence of adverse effects of EDCs, considerations for health effects evidence and dose-response concordance in integrating the human and animal evidence, and how a published systematic review can be critically evaluated and used when the focus is appropriate for the research question under consideration. They also will discuss the committee’s recommendations for moving forward in integrating systematic review methods for evidence-based decision and policymaking.


Introduction: Systematic Review and Environmental Health. Johanna Rochester, The Endocrine Disruption Exchange (TEDX), Grand Junction, CO.

SYRINA: Developing a Method for the Systematic Review of EDC Studies. Laura Vandenberg, University of Massachusetts Amherst, Amherst, MA.

PDBEs and Neurodevelopment: A Systematic Review Using the Navigation Guide. Juleen Lam, University of California San Francisco, San Francisco, CA.

NAS Case Study on Developmental Reproductive Effects. Andrew Rooney, NIEHS, Research Triangle Park, NC.

Phthalate Male Reproductive Toxicity: Comparison of Hazard Conclusions and Dose Responses from the NAS Systematic Review and Traditional Toxicity Testing Studies. Kamin Johnson, The Dow Chemical Company, Midland, MI.

Reducing the Uncertainty of Read-Across Predictions by New Approach Methodologies: Application in Regulatory Human Risk Assessments

W  Workshop

Chairperson(s):

Ivan Rusyn, Texas A&M University, College Station, TX; and Nicole Kleinstreuer, NTP NICEATM, Durham, NC.

Primary Endorser:

Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Risk Assessment Specialty Section


A paradigm shift is ongoing in human risk assessment, away from the traditional in vivo animal studies towards new approach methodologies (NAM). NAM include in vitro, ex vivo, or ’omic technologies, as well as in silico and toxicokinetic modeling. Currently, hazard assessment and derivation of point of departure values are based on the apical toxicity findings in animal studies. These apical endpoints seldom provide detailed mechanistic information to inform extrapolation of these findings to humans. NAM have the potential to provide a deeper understanding of key and intermediate steps leading to a certain apical finding, a concept known as adverse outcome pathways (AOP). However, the integration of NAM data into risk assessments is challenging, in particular for complex endpoints, such as repeated dose or reproductive toxicity. This session will provide an in-depth overview of the use of NAM in regulatory and investigative toxicology, starting with a regulatory perspective, followed by industry examples, and then broadening the scope to cover the most up-to-date developments from the EU-ToxRisk and US academic and government research programs. A focus will be on read-across case studies, by which the use of NAM and mechanistic data is demonstrated. Learnings from the proof-of-concept read-across approaches and case examples will help to develop new mechanism-based chemical safety testing strategies. This session will include a discussion on the limitations and advances of such approaches and the path forward to substantiate and support a paradigm shift in regulatory risk assessment practices.


Use of Read-Across under the REACH Regulation. Mike Rasenberg, European Chemicals Agency (ECHA), Helsinki, Finland.

How Can Read-Across Be Substantiated with Additional Biological Data? Learnings from Industry Submissions. Hennicke Kamp, Ludwigshafen am Rhein, Germany.

EU-ToxRisk Case Studies: New Approach Methodologies in Read-Across. Sylvia Esccher, Fraunhofer ITEM, Hanover, Germany.

Categorization of UVCBs Using Chemical-Biological Read-Across. Ivan Rusyn, Texas A&M University, College Station, TX.

Current and Future Opportunities for US Regulatory Application of Read-Across. Nicole Kleinstreuer, NTP NICEATM, Durham, NC.


11:00 AM to 12:20 PM

Is a Common Mechanism of Action Essential to Conduct a Cumulative Risk Assessment or Just Nice to Have?

R  Roundtable

Chairperson(s):

Suzanne Fitzpatrick, US FDA, College Park, MD; and Elaine Faustman, University of Washington, Seattle, WA.

Primary Endorser:

Mixtures Specialty Section

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section


Current risk assessments of chemicals for regulatory purposes do not generally take into account the “real-life” exposure to multiple substances, but rely instead on the assessment of individual substances in individual commodities. Humans, however, are routinely exposed simultaneously to numerous chemicals via multiples routes of exposure. These mixtures can be variable, constantly changing, and essentially undefinable. One major question is whether a common mechanism of action is a critical element for conducting a cumulative risk assessment. The complex toxicology of chemical mixtures and the diversity of the routes of exposure may call for the development of both mechanism-based and non-mechanism-based quantitative frameworks for risk assessment to estimate the impact on health, thereby increasing the efficiency and effectiveness of these evaluations. Consideration of the new testing concepts, such as in vitro models, the exposome, adverse outcome pathways, and computational models, and how this may help inform our discussion on chemical mixtures will be included in the roundtable talks. This roundtable will conclude with a debate on the different approaches to assess the potential health impacts of exposure to chemical mixtures.


Why the Confusion on Mixture Risk Assessment? Elaine Faustman, University of Washington, Seattle, WA.

The US EPA Approach to Evaluating Mixtures. Evisabel Raig, US EPA, Washington, DC.

Risk of Mixtures Should Be Assessed on a Case-by-Case Basis Depending on the Available Data. A. Wallace Hayes, Harvard T.H. Chan School of Public Health, Boston, MA.

The EuroMix Project: Defining International Strategies for Mixtures Risk Assessment. Alan Boobis, Imperial College London, London, United Kingdom.

Panel Debate: State of the Science, or What to Advise Scientists on How to Conduct a Mixtures Risk Assessment. Suzanne Fitzpatrick, US FDA, College Park, MD.

Unlocking the 'Omics Archive: Enabling Toxicogenomic/Proteomic Investigation from Archival Samples

R  Roundtable

Chairperson(s):

Deidre Dalmas, GlaxoSmithKline, King of Prussia, PA; and Susan Hester, US EPA, Research Triangle Park, NC.

Primary Endorser:

Clinical and Translational Toxicology Specialty Section

Other Endorser(s):

Molecular and Systems Biology Specialty Section
Toxicologic and Exploratory Pathology Specialty Section


Formalin fixation and paraffin embedding (FFPE) is a cross-industry gold standard for preparing nonclinical and clinical samples for histopathological assessment which preserves tissue architecture and enables storage of tissue in archival banks. These archival banks are an untapped resource and vast repository of tissue from regulatory toxicology studies, novel animal bioassays, clinical trials, or epidemiologic studies with corresponding detailed pathological assessments. Although these FFPE archives hold keys to various unknown mechanisms and/or disease processes, direct use of archival samples for transcriptomic or proteomic profiling has been relatively limited. Formalin fixation degrades RNA and results in cross-linking and fragmentation, which is thought to significantly impair transcriptomic/proteomic analyses. Because of the roadblocks, there is a need to develop novel methods that can reliably access gene and protein information from FFPE tissue-enabling retrospective investigations from pathologically-anchored samples, which would otherwise be very costly and require additional patient or animal samples to retest in order to obtain this information from prospectively-collected frozen tissue. The goal of this session is to highlight recently-developed novel approaches to reliably access quantitative gene and protein information from FFPE tissue and convey how these approaches can be used to interrogate mechanisms of toxicity and aid in biomarker development/analysis from both nonclinical and clinical samples. The session will first showcase novel methods to overcome limitations of using FFPE tissue archived for four and a half years, enabling access to robust transcriptomic and proteomic information from nonclinical regulatory toxicology studies, and how these approaches have been utilized to support regulatory filings. The session will then highlight and compare gene expression profiles derived from archived FFPE tissue preserved in formalin for eight, 19, and 26 years, using novel methods developed for DNA microarray analysis, as well as exosome enrichment approaches utilizing nucleic acid samples and whole-transcriptome sequencing (RNA-Seq) library preparation methodologies. Despite individual efforts across the industry, methods to enable RNA-Seq evaluation from limiting quantities and quality RNA was, until recently, still not possible. Because the issue is too complex to be solved by individual organizations working in isolation and with limited resources, the ILSI Health Environmental and Sciences Institute (HESI) Genomics Committee FFPE Working Group has been developing methods to “demodify” FFPE RNA, enabling subsequent, more robust RNA-Seq analysis. Novel methods developed to improve RNA yield and sequencing results from limiting quantities and quality RNA FFPE samples will be highlighted, followed by a comparison across frozen and FFPE samples fixed under varying alcohol and/or formalin conditions. Lastly, development and utilization of novel methods to enable global proteomic and phosphoproteomic analysis of case matched frozen and FFPE clinically-derived samples using mass spec-based technologies will be emphasized. Utilization of the novel methods described, now enable retrospective generation of quantitative gene and protein information from phenotypically-anchored archival nonclinical and clinical FFPE tissue to interrogate mechanisms of toxicity, aid in biomarker development, enable creation of a critical translational bridge between emerging in vitro and in vivo data, and evaluation of chemically-induced adverse health effects established in prior toxicologic and epidemiologic studies, as well as enabling data gaps to be closed in adverse outcome pathways (AOPs).


Introduction. Raegan O’Lone, ILSI Health and Environmental Sciences Institute (HESI), Washington, DC.

Understanding Benefits and Limitations of Formalin-Fixed Paraffin-Embedded (FFPE) Tissue Enables Retrospective Nonclinical Genomic and Proteomic Investigations. Deidre Dalmas, GlaxoSmithKline, King of Prussia, PA.

Finding Salvation in Degradation—Using Degraded Formalin-Fixed Paraffin-Embedded (FFPE) Samples for RNA Sequencing. Christopher Mason, Weill Cornell Medical College, New York, NY.

Demodification Methods for Improving Quality of RNA from Formalin-Fixed Paraffin-Embedded (FFPE) Samples (ILSI HESI Genomics Committee). Susan Hester, US EPA, Research Triangle Park, NC.

Global Proteomic and Phosphoproteomic LC-MS Analysis of Case Matched Frozen and Formalin-Fixed Paraffin-Embedded (FFPE) Tissues. Daniel Chelsky, Caprion Biosciences, San Francisco, CA.

Good Cell and In Vitro Method Practices against the "Reproducibility Crisis"

IS  Informational

Chairperson(s):

David Pamies, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; and Sandra Coecke, European Commission Joint Research Centre, Ispra, Italy.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section

Other Endorser(s):

Stem Cells Specialty Section


There is a strong belief that in vitro methods are fast becoming the key tool for a new way of doing toxicology. However, their potential will not be fully realized if they are not developed and applied in a way in which scientific integrity and quality are assured—the data they produce will not be trusted by decision makers. A revealing paper (Nature 2016, 533:452–454) showed that 70% of researchers have tried and failed to reproduce another scientist’s experiment, and more than half of the researchers failed to reproduce their own experiments. These dramatic data call for incentives for better practice. With the development of new high-throughput technologies, stem cells, and new culture technologies (organo-typical cell cultures, organ-on-a-chip technologies), new challenges are presented for reproducibility of such advanced test systems. This session will summarize the challenges of working with in vitro cell and tissue-based culture methods and will describe the different initiatives that have taken place in recent years to give guidance on good cell and good in vitro method practices as measures against the reproducibility crisis in science. The session also will elaborate on the use of human-induced pluripotent stem cell-based systems for regulatory purposes and how to validate the new generation of high-throughput in vitro methods and microphysiological systems.


21st-Century Cell Culture for 21st-Century Toxicology. David Pamies, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Development of an OECD Guidance Document on Good In Vitro Method Practices (GIVIMP). Sandra Coecke, European Commission Joint Research Centre, Ispra, Italy.

Good Cell Culture Practice in the Development of Human Pluripotent Stem Cell-Based Systems. Glyn Stacey, Institute of Biomedical Science, London, United Kingdom.

Validation of In Vitro Cell-Based Assays for the Tox21 Program. Menghang Xia, NIH, Bethesda, MD.

Systematic Characterization of Microphysiological Systems (MPS). Murat Cirit, Massachusetts Institute of Technology Genomics Facilities Core, Rock Point, VA.

Career Opportunities in Regulatory Toxicology

EC  Education-Career Development

Chairperson(s):

William Farland, Colorado State University and William H. Farland Consulting LLC, Rockport, ME; and Angela Lynch, ToxPlus Consulting and Roosevelt University College of Pharmacy, Haymarket, VA.

Primary Endorser:

Education Committee

Other Endorser(s):

Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section


This session will serve as an introduction to current issues and opportunities in regulatory toxicology for graduate students and early-career scientists, as well as to motivate them to seek training experiences that will increase their knowledge of the approaches to and challenges of bringing modern-day toxicology into a risk or safety assessment process. The SOT Graduate Education Subcommittee, via its Awareness of Regulatory Toxicology (ART) Working Group, has assembled experts in regulatory toxicology to discuss opportunities available for toxicology trainees and others interested in pursuing careers in regulatory toxicology. Resources developed by ART for trainees interested in these careers also will be presented to attendees. Regulatory bodies within the United States and other countries use scientific data from various sources to assess the safety of chemicals and drug candidates in order to inform regulatory policy and determine approvals for use. In turn, industry uses scientific data to meet regulatory requirements and to achieve product stewardship and sustainability goals. Training in and application of modern, laboratory-based science must be married to the legislative and regulatory processes in order to inform decisions that are understandable and benefit the public. Many toxicology and postdoctoral training programs do not cover regulatory toxicology or regulatory processes to a significant degree. In addition, scientists who engage in the regulatory process through advisory boards or public comment on specific issues may not be fully aware of the regulatory process and/or impacts of regulatory decisions. Although toxicologists often gain experience while on the job, accessing training or internships in regulatory toxicology early in a scientist’s career benefits trainees by increasing knowledge of how scientific data can be used in the public domain, as well as by increasing awareness of available job opportunities. In addition, knowledge of the regulatory use of toxicology information also benefits toxicologists considering service in an advisory capacity to government or industry.


Introduction. Angela Lynch, ToxPlus Consulting and Roosevelt University College of Pharmacy, Haymarket, VA.

Training in Regulatory Toxicology: Understanding Opportunities and Present-Day Challenges. James Klaunig, Indiana University, Bloomington, IN.

The Role of Regulatory Toxicology in Drug Development. Tao Wang, Achaogen, San Francisco, CA.

Generating Toxicology Data to Meet the Needs of Regulatory Agencies. Allison Greminger, ExxonMobil Biomedical Sciences Inc., New York, NY.

Evolving Approaches in Regulatory Toxicology: Integrating Pathway-Based Screening and Testing to Support Modern Chemical Safety Assessments and Harmonize International Approaches. David Dix, US EPA, Washington, DC.

Panel Discussion/Q&A. William Farland, Colorado State University and William H. Farland Consulting, LLC, Rockport, ME.

1:30 PM to 4:15 PM

Atherosclerosis as a Model to Understand the Combined Effects of Environmental Chemical and Non-Chemical Stressors

S  Symposium

Chairperson(s):

Danielle Carlin, NIEHS, Research Triangle Park, NC; and Michelle Olive, NHLBI, Bethesda, MD.

Primary Endorser:

Mixtures Specialty Section

Other Endorser(s):

Cardiovascular Toxicology Specialty Section
Molecular and Systems Biology Specialty Section


Atherosclerosis can lead to cardiac infarction and stroke and is a foremost candidate for identifying health effects associated with chemical and non-chemical stressors since much is known about the morbidity and mortality of this multifactorial disease. However, the evaluation of cumulative human health effects from multiple environmental exposures (i.e., chemical and non-chemical) represents a special research challenge due to the inherent complexity of the topic and requires careful examination of the potential interaction of these exposures. For example, further exploration is required of the biological mechanisms/pathways by which exposure to both environmental chemicals (e.g., air pollution, polycyclic aromatic hydrocarbons, metals, polychlorinated biphenyls, pesticides, and endocrine-disrupting chemicals) and non-chemical stressors (e.g., psychosocial, lifestyle, quality-of-life, poor nutrition, and physical stressors) over time leads to health effects and the roles the stressors may play in the development of diseases known to be associated with them (e.g., cancer, cardiac, metabolic, neurological, etc.). For the purposes of this session, combined exposures pertain to any set of environmental chemicals and non-chemical stressors that may contribute jointly to adverse human health outcomes, irrespective of whether people are exposed to the chemical(s)/non-chemical stressors at the same/different times or through similar/distinct sources or routes. Some of the other areas requiring further research on this complex topic include a better understanding of both the composition of real-world exposure to chemical and non-chemical stressors; the potential biological interactions between chemical and non-chemical stressors; and the development and validation of predictive models of combined exposure toxicity to characterize the hazard associated with these combined exposures. This session will bring together experts to discuss the state-of-the-science pertaining to underlying complex biological mechanisms/pathways associated with, when combined, chemical and non-chemical stressors in relation to atherosclerosis. Specifically, presentations will include a general overview of the etiology of atherosclerosis from chemical and non-chemical stressors, the biological mechanisms being evaluated by the extramural community, atherogenic mechanisms of environmentally-relevant chemicals, how diet and physical activity may modify atherosclerotic events, and how conceptual models can be created to evaluate complex causal pathways in this disease. In addition, this symposium also may be able to be used as a model for other diseases known to be associated with both chemical and non-chemical stressors and the roles these stressors may play in cumulative risk.


General Overview of the Public Health Burden of Atherosclerosis. Wayne Cascio, US EPA, Research Triangle Park, NC.

Non-Chemical Stressors in Atherosclerosis Research: The Extramural Portfolio Supported by the National Heart, Lung, and Blood Institute. Michelle Olive, NHLBI, Bethesda, MD.

Atherogenic Mechanisms of Superfund Chemicals. Sanjay Srivastava, University of Louisville, Louisville, KY.

Diet and Physical Activity as Modifiers of Pollutant-Induced Inflammatory Diseases: Implications in Atherosclerosis. Bernhard Hennig, University of Kentucky, Lexington, KY.

Using Conceptual Models to Evaluate the Complex Causal Pathways Involved in Cumulative Risk Assessment of Cardiovascular Disease. Charles Menzie, Exponent, Alexandria, VA.

Mechanisms of Autophagic Function and Dysfunction in Neurotoxicity and Neurodegeneration

S  Symposium

Chairperson(s):

Johnny Wise, Purdue University, West Lafayette, IN; and Aaron Bowman, Vanderbilt University Medical Center, Nashville, TN.

Primary Endorser:

Neurotoxicology Specialty Section

Other Endorser(s):

Graduate Student Leadership Committee
Metals Specialty Section


This session will be composed of graduate and postdoctoral trainees presenting primary research focused on autophagic pathways that go awry in neurodegenerative diseases and how relevant environmental toxicants affect these pathways. Autophagy is a tightly regulated catabolic process that enables a cell to conduct bulk degradation of protein aggregates or dysfunctional organelles in a specific or nonspecific manner. Autophagic pathways have been observed to be impaired under a variety of neurotoxic and neurodegenerative disease conditions. Further, environmental toxicants, such as neurotoxic metals, that are associated with altered risk or modification of neurodegenerative disease pathogenesis may interact with genetic risk factors of these diseases by disrupting autophagy. Investigation of these pathways is likely to provide key insight into early cellular events of these diseases, as disruptions to autophagic pathways occur prior to neurodegeneration or behavioral phenotypes. The session will begin with brief introductions regarding the structure of this trainee-led session and the trainees speaking, as well as a brief primer on autophagy and its potential role in neurodegenerative disease. In each talk, the trainee speakers will relate how autophagic dysfunction in their models contributes to disease pathogenesis and how their chemical(s) of interest exacerbate or ameliorate dysfunction. The first trainee speaker will discuss the role of autophagy in the toxicity of arsenic in cortical astrocytes. This speaker will present her findings on how AMPK and mTOR signaling regulate ATG5-dependent autophagy and apoptosis in astrocytes. The second trainee speaker will discuss the effects of manganese (Mn) exposure on autophagy-lysosome pathway in primary astrocytes, the mechanism(s) underlying Mn-induced autophagic dysregulation, and the functional relation between compromised autophagy and mitochondrial dysfunction. The third trainee speaker will continue the discussion about Mn in Huntington’s disease (HD), focusing on the contribution of excess manganese to neurons in HD and how the drug KB-R7943 can normalize Mn uptake. The fourth trainee speaker will change the topic to Parkinson’s disease (PD) and will delve into how optineurin, a protein previously not considered in PD, contributes to pathogenesis through autophagic dysfunction. This speaker will emphasize the role of autophagic dysfunction on early mechanisms of PD and how they contribute to disease progression. The fifth trainee speaker will discuss the contribution of endosulfan to PD pathogenesis, as well as the relationship between autophagy and apoptosis in PD. The final trainee speaker will discuss the effects of low-dose chemical exposures on autophagic mechanisms in PD and further examine how these effects are altered even after chemical exposure is removed. Given that autophagy dysfunction is increasingly recognized as a common, early event in sporadic neurodegenerative diseases, it is imperative to understand how environmental chemicals disrupt normal autophagy pathways to gain a better understanding of disease pathogenesis, progression, and possible therapeutic intervention. Finally, the session will highlight the research program of six trainee SOT members via a forum centered on the cutting-edge techniques of today’s toxicology trainees.


Introduction. Aaron Bowman, Vanderbilt University Medical Center, Nashville, TN.

Potential for Autophagy as a Primary Mechanism of Environmentally-Induced Neurodegeneration. Jason Cannon, Purdue University, West Lafayette, IN.

Autophagy: Friend or Foe in Arsenic-Induced Toxicity? Carla Garza-Lombo, University of Nebraska Lincoln, Lincoln, NE.

Role of Autophagy in Manganese-Induced Neurotoxicity. Ziyan Zhang, Albert Einstein College of Medicine, Bronx, NY.

Manganese Modifies the AKT/mTOR Pathway and Autophagy: Implications for Huntington’s Disease Pathology. Miles Bryan, Vanderbilt University Medical Center, Nashville, TN.

Optineurin Is a Critical Player in Parkinson’s Disease Pathogenesis. Johnny Wise, Purdue University, West Lafayette, IN.

Environmental Neurotoxic Pesticide Endosulfan Induces Autophagy Preceding Apoptotic Cell Death in Dopaminergic Neuronal Cells: Relevance to Etiopathogenesis of Parkinson’s Disease. Adithiya Charli, Iowa State University, Ames, IA.

Dopaminergic Cell Recovery and Resilience In Vitro: The Role of Autophagy. Georgina Harris, Johns Hopkins Center for Alternatives to Animal Testing, Baltimore, MD.

The Role of the Epigenome in the Etiology of Metal-Induced Disease

S  Symposium

Chairperson(s):

Rebecca Fry, University of North Carolina at Chapel Hill, Chapel Hill, NC; and Miroslav Styblo, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Primary Endorser:

Metals Specialty Section

Other Endorser(s):

Mechanisms Specialty Section
Reproductive and Developmental Toxicology Specialty Section


Toxic metals, such as arsenic, cadmium, lead, and mercury, represent a major public health threat for populations worldwide. Exposures to these metals can be through various sources, including, but not limited to, contaminated food and water. In terms of associated health effects, chronic exposure to toxic metals has been linked to cancers of numerous organs, including the lung, liver, and bladder. Toxic metals also are associated with non-cancer endpoints, such as adverse neurodevelopmental outcomes and cardiometabolic disease, including diabetes mellitus and cardiovascular disease in adults. Of particular concern are prenatal and early-life exposures to toxic metals that are associated with increased risk of low birth weight, preterm birth, susceptibility to infection, and later-life cancers. Among the many proposed cellular mechanisms that underlie toxic metals-associated disease are epigenetic modifications, including DNA methylation, histone modifications, and micro-RNA (miRNA) dysregulation. This symposium will highlight the complex role of the epigenome in the etiology of toxic metals-induced disease. The session speakers will present results from epigenomic studies spanning in vitro cell culture models, rodent models, and human populations exposed to toxic metals. The diseases of focus will include diabetes, developmental effects in children, and metabolic disorders related to exposures to arsenic, cadmium, lead, and mercury. The presentations will highlight the role of toxic metals as epigenetic modifiers of DNA methylation and miRNA expression and mediators of a panoply of diseases. The use of epigenetic data for risk assessment and disease risk prediction also will be discussed.


Prenatal Arsenic Exposure and the Epigenome: Informing Disease Mechanisms and the Risk Assessment Process. Rebecca Fry, University of North Carolina at Chapel Hill, Chapel Hill, NC.

The Role of microRNAs in the Etiology of Diabetes Associated with Chronic Exposure to Arsenic. Praveen Sethupathy, Cornell University, Ithaca, NY.

Epigenomic Effects of Cadmium on the Placenta Influence Newborn and Early-Childhood Growth. Carmen Marsit, Emory University, Atlanta, GA.

Mitochondria Direct Arsenic-Induced Epigenetic Regulation of Stem Cell Fate. Aaron Barchowsky, University of Pittsburgh, Pittsburgh, PA.

Epigenome-Wide Association Studies of Prenatal Metal Exposures in a Longitudinal Pre-Birth Cohort. Andrea Baccarelli, Columbia University, New York, NY.

Microbiota as a Target or Mediator of Adverse Effects: Implications for Toxicology

W  Workshop

Chairperson(s):

Bennard van Ravenzwaay, BASF, Ludwigshafen am Rhein, Germany; and Shana Sturla, ETH Zürich, Zürich, Switzerland.

Primary Endorser:

Molecular and Systems Biology Specialty Section

Other Endorser(s):

Carcinogenesis Specialty Section
Reproductive and Developmental Toxicology Specialty Section


The microbiome has emerged as a key regulator of development and disease. A disruption in host-associated microbial communities is correlated with obesity, immune, and cardiovascular diseases and, increasingly, with adverse developmental outcomes. Current research is starting to unravel microbiome-host interactions that may explain these effects by examining microbiota as a target or mediator of chemical toxicity. One mechanism by which microbiota may modify toxicity is via chemical-dependent changes in the production of small molecules that disrupt normal biological processes in the host. Humans share 99.9% of their genome, yet the vastly larger microbiota-genomic space is much less conserved and, therefore, may partially explain inter-individual susceptibility to chemical exposures. Due to high inter- and intraspecies variability within microbiota and its responsiveness to external factors, it is essential to determine the effects of chemical exposures on gut microbiota composition, function, community organization, and resulting host-microbiota interactions. There also is a need to identify molecules produced by gut microbiota and their effects on the host, as well as understanding how xenobiotic compounds are biotransformed by resident microbiota. This mechanistically-focused session highlights emerging interactions between gut microbes and the host that contribute to altering exposure and susceptibility to drugs and chemicals. The first talk will provide an overview of the metabolic capacity of the gut microbiome and, using a combination of metagenomics, metabolomics, synthetic biology, and cutting-edge experimental host-microbiota model systems, reveal the metabolic characterization of individual microbial species and their roles in human biology and disease. The second talk will focus on understanding the toxicological impact of chemical transformations of food carcinogens and how these reactions are mediated by microbial communities. The third presenter will describe an innovative zebrafish model to test whether host-associated microbiota modify the developmental neurotoxicity of environmental chemicals. The fourth presenter will discuss microbiota in the context of cancer therapeutics. The fifth talk will provide a framework for the assessment of risks associated with microbiome changes via the investigation of the microbiome’s functionality, defined as the production of metabolites absorbed by the host. Hazard identification and risk assessment do not currently consider host-microbiota interactions that are disrupted by xenobiotic exposure. This session will bring together academic, government, and industry scientists who are using novel experimental systems to determine the composition and organization of gut microbiota. Relevant to the field of toxicology, the effects of chemical exposures on host-microbiome interactions and the mechanisms by which microbiota perform biotransformations of drugs and environmental chemicals will be discussed in this session.


Introduction. Bennard van Ravenzwaay, BASF, Ludwigshafen am Rhein, Germany

Metabolic Capability of the Gut Microbiome. Michael Fischbach, University of California San Francisco, CA.

Gut Microbial Transformations of Carcinogens and Their Toxicological Relevance. Shana Sturla, ETH Zürich, Zürich, Switzerland.

Environmental Chemicals Disrupt the Microbiota-Gut-Brain Axis during Zebrafish Development. Tamara Tal, US EPA, Research Triangle Park, NC.

Discovering and Controlling the Gut Microbiome’s Impact on Xenobiotic Metabolism. Matthew Redinbo, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Influence of the Microbiome on Plasma Metabolite Patterns: Can Microbiome Changes Be Detected by Metabolomics? Christina Behr, BASF and Wageningen University & Research, Ludwigshafen am Rhein, Germany

Toxicology and Public Health Solutions for Environmental Emergency-Related Contamination Events

RI  Regional Interest

Chairperson(s):

Ivan Rusyn, Texas A&M University, College Station, TX; and Michael Honeycutt, Texas Commission on Environmental Quality (TCEQ), Austin, TX.

Primary Endorser:

Specialty Section Collaboration and Communication Group

Other Endorser(s):

Mixtures Specialty Section
Regulatory and Safety Evaluation Specialty Section


Climate change and shifts in domestic economic activity markedly increase risks from catastrophic chemical contamination events resulting from weather-related or anthropogenic emergencies. These events are especially acute in the coastal areas, and Texas represents a region where many past and recent events demonstrated an acute need to characterize and manage both existing and environmental emergency-created hazardous waste sites through the development of the tools that can be used by first responders, the impacted communities, and the government bodies involved in site management and cleanup. The complexities of hazardous chemical exposures, potential adverse health impacts, and the need to rapidly and comprehensively evaluate the potential hazards of exposures to complex mixtures during emergency events create unique challenges in toxicology and public health. This session will bring together a diverse set of governmental, academic, and industry stakeholders to highlight solutions and research strategies that are available today for disaster research and response. Approaches that span from computational tools to novel in vitro models to population-based human studies of exposure and adverse health effects will be highlighted to present a range of options that are either already available and have been implemented or are on the short-term horizon. Design and implementation of comprehensive solutions for complex exposure- and hazard-related challenges is a goal for environmental health that aims to protect the communities and infrastructure that are vulnerable to major weather-related events.


Unique Challenges in Environmental Emergency Preparedness and Response in the Coastal Areas. Michael Honeycutt, Texas Commission on Environmental Quality (TCEQ), Austin, TX.

Deep Water Horizon Oil Spill—Lessons Learned in Applying Novel Assessment Methodologies in Emergency Response. Richard Judson, US EPA, Research Triangle Park, NC.

Designing Effective Rapid Toxicological Research in Response to Environmental Public Health Disasters. Scott Masten, NIEHS, Research Triangle Park, NC.

Rapid Estimation of Hazard and Risk Using Computational Tools. Jessica Wignall, ICF International Inc., Fairfax, VA.

Novel Approaches to Rapid and Informative Exposure Analysis from Environmental Samples and Mixtures. Erin Baker, Pacific Northwest National Laboratory, Pasco, WA.

Population-Based Studies before, during, and after Emergencies—Building Resilience in Coastal Communities. Jennifer Horney, Texas A&M University, College Station, TX.


4:30 PM to 5:50 PM

The Kinetically-Derived Maximum Dose (KMD), a New Dimension to the Maximum Tolerated Dose (MTD)

R  Roundtable

Chairperson(s):

Jeanne Domoradzki, The Dow Chemical Company, Midland, MI; and Alan Boobis, Imperial College London, London, United Kingdom.

Primary Endorser:

Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):

Risk Assessment Specialty Section


Evaluations of chemicals tested under dose-selection protocols using a maximum tolerated dose (MTD) design (e.g., decreased body weight and/or histological injury) are increasingly revealing that interpretation is confounded by the onset of non-dose-proportionate systemic dose (i.e., nonlinear toxicokinetics). This is due to saturated absorption, distribution, and metabolism and/or clearance mechanisms of parent chemical and/or metabolites. Recent toxicity testing guidance from the Organisation for Economic Co-operation and Development (OECD) and US Environmental Protection Agency (US EPA) and other evaluations from the National Academy of Sciences (NAS) and ILSI Health and Environmental Sciences Institute (HESI) have clearly indicated that toxicity observed only under nonlinear toxicokinetic conditions often has limited, if any, quantitative relevance to risks to human health if the onset of dose-non-proportionality is well separated from real-world human exposures. Detection of nonlinear toxicokinetics has been improved by analytical techniques/approaches that have made assessment of systemic/internal dose in test animals substantially more sensitive, lower cost, and higher throughput. In addition, determination of whether the onset of toxicokinetic nonlinearity is well separated from human exposure is increasingly possible given rapid improvements in modeling and/or analytical biomonitoring analyses supporting human environmental-exposure assessments. Saturation of any biological process should be evaluated for its relevance to dose-response relationships relative to human exposure. Systemic dose non-proportionality should not be treated any differently from toxicity findings due to excessive stress indicated by the conventional MTD approach. Use of evidence of dose non-proportionality for selection of an acceptable top dose for animal toxicity testing has been termed the kinetically-derived maximum dose (KMD). Despite the convergence of these indisputable advances, however, current toxicity test protocols and interpretation of existing toxicity test findings continue to be largely dominated by long-ingrained concepts of conventional MTD thinking. Current toxicity test dose selection often is conducted oblivious to a prior evaluation of toxicity at internal non-dose-dependent metrics, and conversely, extensive, costly, and animal-intensive post hoc mode-of-action analyses are frequently implemented to address high-dose specific toxicity findings that could (should) otherwise be ruled out as quantitatively non-human relevant on systemic dose alone. Thus, effective implementation of the fundamental toxicology principle of “the dose makes poison” must include an ever-expanding commitment to consideration of animal and human internal dose evaluations as a key part of chemical risk assessment. The rapid expansion of analytical technologies, exposure assessments, and reducing the use of animals demands nothing less.The objective of this session is to catalyze understanding and discussion surrounding the use of systemic dose kinetics in selection of improved human-relevant doses in animal toxicity testing and/or retroactive interpretation of high-dose specific toxicity findings in evidence-based human risk assessments. The presentations will address: 1) a review of background and biological mechanisms accounting for non-linear responses in toxicity studies; 2) the KMD, conceptualization and mechanisms for experimental identification; 3) application of KMD principles to post hoc interpretation of high-dose specific toxicity studies; and 4) regulatory perspectives on use of findings at non-dose-proportional doses in human risk assessment. The roundtable discussion between speakers and the audience will address the implications of KMD-based assessments for the practice of toxicology and risk assessment, such as: 1) the KMD as a replacement for the MTD; 2) research and policy constraints in the use KMD; 3) adequacy of existing regulatory toxicity testing guidance and protocol design (e.g., toxicokinetics to support KMD evaluations); 4) offering an alternative to conducting conventional high-dose specific mode-of-action investigations; 5) assisting design and interpretation of adverse outcome pathway (AOP)/mode-of-action studies; and 6) informing life-stage-specific differences in toxicity.


Introduction. Jeanne Domoradzki, The Dow Chemical Company, Midland, MI.

The Mechanistic Basis of Non-Proportionate Systemic Doses in Toxicology Studies and Implications for Chemical Risk Assessment. Alan Boobis, Imperial College London, London, United Kingdom.

Use of KMD in Regulatory-Mandated Toxicity Testing of Non-Pharmaceuticals: From Concept to Application. Shakil Saghir, Smithers Avanza, Gaithersburg, MD.

Kinetically-Derived Maximum Dose: A Key Initiating Event Impacting Need for Mode-of-Action Investigations of High-Dose Specific Toxicity. James Bus, Exponent, Midland, MI.

Regulatory Perspectives on the Use of Toxicokinetic Data in Human Risk Assessment. Anna Lowit, US EPA, Washington, DC.

The US Tox21 Collaboration: A Decade of Experience and a New Vision for the Future

IS  Informational

Chairperson(s):

Bette Meek, University of Ottawa, Ottawa, ON, Canada; and Kevin Crofton, US EPA, Research Triangle Park, NC.

Primary Endorser:

Carcinogenesis Specialty Section

Other Endorser(s):

In Vitro and Alternative Methods Specialty Section
Molecular and Systems Biology Specialty Section


In 2007, Tox21 was launched as a multi-agency collaborative effort among the National Institutes of Health (NIH)’s National Institute of Environmental Health Sciences (NIEHS, National Toxicology Program (NTP), and the National Center for Advancing Translational Sciences (NCATS); the US Environmental Protection Agency (US EPA)’s National Center for Computational Toxicology (NCCT); and the US Food and Drug Administration (US FDA). The objective of this partnership was to shift the assessment of chemical hazards from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, in vitro assays, with the ultimate aim of improving human and environmental risk assessments. In this regard, the collaborative was highly successful in that thousands of chemicals have been screened in hundreds of bioassays. These data have been publicly released for consideration and use in a range of contexts, including regulatory decisions. However, complex challenges remain. The intent of this symposium is to review the 2017 strategic plan for Tox21 and gain feedback from the diverse stakeholders at SOT. The new strategic plan promotes: 1) addressing key limitations in in vitro assays; 2) continued development and use of alternative test systems that predict human toxicity; 3) management and curation of large chemical libraries; 4) curation of legacy in vivo toxicity studies; 5) performance-based validation of high-throughput in vitro, in silico, stem cell and microphysiological systems, and other emerging technologies; and 6) development and use of in vitro methods for characterizing pharmacokinetics. Each of the speakers will summarize lessons learned and outline their agency's approaches aimed at solving complex challenges. The strategy embraces transparency and technological change, aims to protect human health environment, with an ultimate goal of fostering broader acceptance of alternative data streams in regulatory decisions.


A New Tox21 Strategic Plan and the Integration of EPA Science. Russell Thomas, US EPA, Research Triangle Park, NC.

Evolution of Tox21 High-Throughput Screening: Accomplishments and New Strategic Directions. Anton Simeonov, NCATS, Rockville, MD.

The Future of Tox21: Changing the NTP Landscape. Richard Paules, NIEHS, Research Triangle Park, NC.

Determining the Predicative Ability of In Vitro Microphysiological Systems to Answer Critical Regulatory Questions. Suzanne Fitzpatrick, US FDA, College Park, MD.

Validation for 21st-Century Science. Warren Casey, NTP NICEATM, Research Triangle Park, NC.

Research-Based Approaches to Improve Teaching Effectiveness in Toxicology Classrooms

EC  Education-Career Development

Chairperson(s):

Barbara Kaplan, Mississippi State University, Mississippi State, MS; and Larissa Williams, Bates College, Lewiston, ME.

Primary Endorser:

Education Committee

Other Endorser(s):

Career Resource and Development Committee
Postdoctoral Assembly


Teaching students effectively at all levels in science requires continuous learning on the part of the instructor. Not only is content knowledge increasing, so are the tools to teach it. At the heart of pedagogy, though, is research about how students learn to maximize educational outcomes and retention. While lecturing has been the predominant method of instruction since the founding of universities, there is evidence to suggest that this is not the most effective way to teach. Through national initiatives such as the National Science Foundation’s Vision and Change in Undergraduate Biology Education, research-based teaching methods are having a growing impact in higher education. This session will bring together educators to talk about best practices in student-centered teaching that are applicable to all educational levels. The topics to be discussed include: 1) an introduction to designing course methods, assignments, and assessments to optimize students’ opportunities to learn; 2) lessons learned from a flipped classroom; 3) the use of problem formulation and experimental design in the context of a graduate immunotoxicology classroom; 4) how community-engaged learning and research can improve comprehension, recruitment, and retention; and 5) case studies from industry to teach about risk communication. This session will conclude with time for questions, giving audience members an opportunity to further explore these and other related topics. This session will be of interest to current educators and those interested in teaching, such as graduate students and postdocs.


Introduction. Larissa Williams, Bates College, Lewiston, ME.

Scientific Teaching: Using the Rigor of Science to Facilitate Learning in the Classroom. Edwin Barea-Rodriguez, University of Texas at San Antonio, San Antonio, TX.

Lessons Learned from a Flipped Classroom. Larissa Williams, Bates College, Lewiston, ME.

Graduate Toxicology Presented in the Context of Problem Formulation and Experimental Design. Barbara Kaplan, Mississippi State University, Mississipi State, MS.

Taking the Student Out of the Classroom with Community-Engaged Learning and Research. Christian Curran, Northern Kentucky University, Highland Heights, KY.

Effective Communication of Toxicology Principles Is Critical to the Industry Toxicologist. Steven Hermansky, ConAgra Foodservice, Omaha, NE.


Thursday, March 15

8:30 AM to 11:15 AM

In Vitro Test Methods to Model Local Respiratory Effects after Exposure to Pulmonary Toxicants: Not Just Smoke and Mirrors

S  Symposium

Chairperson(s):

Holger Behrsing, Institute for In Vitro Sciences, Gaithersburg, MD; and Mark Higuchi, US EPA, Research Triangle Park, NC.

Primary Endorser:

In Vitro and Alternative Methods Specialty Section


The lungs are exposed to a wide range of toxicants, including environmental, pharmaceutical, and occupational. Evaluating this assortment of toxicants has necessitated the development of physiologically-relevant in vitro models. These in vitro models have proven to be sensitive, robust, reproducible, and capable of providing a diverse outcome of responses. These responses focus on inflammation characterized by cytokine secretion, mucus production, goblet cell hyperplasia, and increased ciliary beat frequency. This session will explore recent findings in in vitro toxicology that link a variety of pulmonary toxicants with their common inflammatory outcomes. The first speaker will focus on in vitro pulmonary models and their incorporation into a testing scheme. In the second presentation, a comparison of cell lines to 3D air-liquid interface (ALI) will be detailed. The third speaker will discuss in vivo-in vitro comparisons, as well as 3D ALI. The fourth speaker will demonstrate dosimetry modeling of in vitro e-cigarette exposure. Speaker five will reveal the factors that must be taken into account for proper in vitro exposure modeling. Further comparisons between different in vitro exposure systems will be explained by speaker six. Finally, the last speaker will lay out the requirements to achieve in vitro testing regulations and the role each sector must play in achieving regulation. These speakers, who come from a mix of government and industry backgrounds, demonstrate how a range of pulmonary exposures can be evaluated using in vitro methods for detecting local respiratory effects and the steps necessary to establish regulations for these testing methods.


Introduction. Holger Behrsing, Institute for In Vitro Sciences, Gaithersburg, MD.

Modern In Vitro Test Systems Provide Human-Relevant Toxicity Data to Support Product Development and Regulatory Decision Making. Holger Behrsing, Institute for In Vitro Sciences, Gaithersburg, MD.

In Vivo-In Vitro Comparison of Acute Respiratory Tract Toxicity Using Different 2D and 3D Models and a Successful Example Using Physico-Chemical Characteristics of the Test Substance. Robert Lansiedel, BASF, Ludwigshafen am Rhein, Germany.

The Challenge of Integrating Non-Animal Alternative Approaches to Assess the Risk to Human Health from Inhaled Materials. Jon Hotchkiss, The Dow Chemical Company, Midland, MI.

In Vitro/Ex Vivo Exposure System Dosimetry: Successes and Challenges. Mike Oldham, Altria Client Services, Richmond, VA.

Operating Procedures to Improve Efficiencies of In Vitro Exposure Systems at the Air-Liquid Interface. Mark Higuchi, US EPA, Research Triangle Park, NC.

Understanding Air-Liquid Interface Cell Exposure Systems: A Comprehensive Assessment of Various Systems under Identical Conditions Jose Zavala, US EPA, Research Triangle Park, NC.

Novel Non-Animal Respiratory Test Methods Show Great Promise, So How Do We Get Them into Routine Use: Points to Consider for Industrial and Regulatory Acceptance. Hans Raabe, Institute for In Vitro Sciences, Gaithersburg, MD.

Deliberations in Regulatory and Safety Assessment of Food Substances in Early Life

W  Workshop

Chairperson(s):

Wallace Hayes, Harvard University, Cambridge, MA, and Michigan State University, East Lansing, MI; and Brinda Mahadevan, Abbott Laboratories, Mumbai, India.

Primary Endorser:

Regulatory and Safety Evaluation Specialty Section

Other Endorser(s):

Food Safety Specialty Section
Women in Toxicology Special Interest Group


Neonates and younger children have a greater degree of vulnerability from consuming food than older children and adults. Much of this vulnerability is due to higher consumption per kilogram body weight. In comparison to adult dietary patterns, neonates and younger children’s food behavior is largely atypical. It also is important to remember that neonates and younger children are in a rapidly developing phase of their life cycle when most organs are still developing and differentiating, leaving them in a potentially vulnerable state regarding ingredients and foods consumed. For the most part, regulatory guidelines for foods and food ingredients are in place; however, in the case of neonates and very young children, deliberation regarding the need for additional information to ensure the safety of food ingredients in early life is an area of ongoing discussion. The current paradigm for safety characterization of an ingredient for use in infant formula is, for the most part, limited to chemical characterization, anticipated exposure levels, and data from nonclinical and clinical studies. Additionally, acceptable daily intakes (ADIs) currently do not apply to infants less than 12 weeks of age. The scientific community is pondering the need for a paradigm shift in the regulation of ingredients added to infant formula consumed in early stages of life. The objectives of this workshop are to address: 1) the need to derive a holistic understanding of exposure to ingredients in food during early stages of life and its associated toxicities with special emphasis on neonatal biology; 2) if there are key elements needed beyond the currently required toxicological studies to enable decision making on the adequacies or inadequacies of existing ADIs in early stages of life; 3) what the age-specific factors are that need to be considered in developing kinetic models for early stages of life and how normal inter-individual and other sources of variability should be included in modeling predictions, and 4) if there are any differences and similarities in the safety assessment strategies that are in place for the safety of ingredients in early stages of life and how these uncertainties impact regulatory decision making.


Does Infant Exposure Matter in Safety Assessment? Wallace Hayes, Harvard University, Cambridge, MA, and Michigan State University, East Lansing, MI.

Applying Concepts of Life Stage for Safety Assessment and Understanding the Needs for Children. Elaine Faustman, University of Washington, Seattle, WA.

Integrated Safety Assessments of Food Additives in Early Life. Anne Constable, Nestlé Research Centre, Lausanne, Switzerland.

Threshold of Toxicological Concern (TTC) Versus Other Methods in Risk Assessment of Food Constituents. Dieter Schrenk, Technische Universität Kaiserslautern, Kaiserslautern, Germany.

Regulatory Toxicology Challenges in Life-Stage-Specific Safety Assessments April Neal-Kluever, US FDA, Washington, DC.

Nonclinical to Clinical Translation of Antibody-Drug Conjugates

W  Workshop

Chairperson(s):

Subramanya (Subbu) Karanth, Medimmune, Gaithersburg, MD; and Amy Sharma, Amgen, Seven Oaks, CA.

Primary Endorser:

Biotechnology Specialty Section

Other Endorser(s):

Clinical and Translational Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section


Antibody drug conjugates (ADCs) are a rapidly growing class of targeted anticancer therapeutics that now account for a significant fraction of pharmaceutical pipelines. Despite initial clinical success and marketing approvals of Kadcyla and Adcetris, clinical development continues to be impeded by safety issues. Of the greater than 50 ADCs evaluated in early clinical trials, approximately 20 have been discontinued due to lack of efficacy and/or intolerable toxicity. Significant efforts to overcome these hurdles are currently underway, including engineering efforts to develop next-generation molecules with different mechanisms of action and superior conjugation stability. In addition to technology advances, there also is a significant need to develop translational strategies to optimize the therapeutic window and decrease the rate of attrition for novel ADCs. The purpose of this session is to bring together experts to discuss recent progress and challenges in the design and development of ADCs. The session will explore strategies for preclinical safety assessment that can be used to improve therapeutic indices of next-generation ADCs.


Introduction and Overview. Subramanya (Subbu) Karanth, Medimmune, Gaithersburg, MD.

Translational Value of Nonclinical Safety Studies. Nicola Stagg, Genentech Inc., San Francisco, CA.

Safety Perspectives Including Class Effects and Off-Target Toxicity.Haley Neff-LaFord, Seattle Genetics, Bothell, WA.

A Regulatory Update on Nonclinical Expectations to Support the Safety of ADCs. Whitney Helms, US FDA, Silver Spring, MD.

Translational Strategies to Maximize Therapeutic Index of ADCs Mary Jane Hinrichs, Medimmune, Gaithersburg, MD.

A Search for Biomarkers of Neurotoxicity: A Practical Approach

W  Workshop

Chairperson(s):

David Herr, US EPA, Research Triangle Park, NC; and Michael Aschner, Albert Einstein College of Medicine, Bronx, NY.

Primary Endorser:

Neurotoxicology Specialty Section

Other Endorser(s):

Clinical and Translational Toxicology Specialty Section
Regulatory and Safety Evaluation Specialty Section


Human exposures to drugs, chemicals, and chemical mixtures often are associated with symptoms suggestive of nervous system involvement (headache, fatigue, cognitive changes, etc.), yet broadly applicable screening methods to assess the neurotoxic condition in animal models are lacking. Thus, there is a need for more sensitive and specific biomarkers that can help diagnose and predict neurotoxicity that are relevant across animal models and translatable to the clinic. Fluid-based biomarkers, such as those found in serum, plasma, urine, and cerebrospinal fluid, have great potential due to the relative ease of sampling, but at present, data on their expression and translation are lacking or inconsistent. In order to identify such novel fluidic biomarkers associated with the development and expression of neurotoxicity and to evaluate their relative sensitivity with established phenotypic anchors of neurotoxicity, a pilot study was designed under the auspices of the ILSI Health and Environmental Sciences Institute (HESI) Technical Committee on Translational Biomarkers of Neurotoxicity—members include representatives from academia, industry, and government. Trimethyltin (TMT) was selected as a prototypic compound since relevant data are available on dose response, time course, and site of action. Neuropathology was confirmed by traditional histopathological assessments, behavioral changes, and alterations in neurochemical and neuroinflammatory biomarkers in brain areas targeted by a single dose of TMT (7.0 mg/kg body weight) at two, six, 10, and 14 days. Using state-of-the-art assessment techniques, the researchers identified specific biological chemicals or patterns of biological chemicals in serum, plasma, or cerebral spinal fluid that are associated with nerve cell damage/degeneration caused by TMT. Such changes include alterations in the status of the metabolome and the expression of microRNAs, as well as levels of interleukins and other related circulating antigen factors. Histopathological assessments of TMT effects in select non-brain tissues enabled improved interpretation of the brain specificity of these changes. Correlation of high-throughput endpoints with markers of neurotoxicity, especially glial fibrillary acid protein, neuropathological loss of neurons, and oxidative damage to neurons as presented here provide a guideline by which to establish fluidic biomarkers of neurotoxicity. The data from this pilot study also will help design follow-on studies utilizing other known neurotoxicants to determine the generalizability of the findings in an effort to develop and validate a set of biochemical markers of neurotoxicity that will be accessible clinically. Such clinical biomarkers should prove valuable to research ranging from preclinical studies to clinical trials and assist with the monitoring of the severity of and recovery from brain injury.


Introduction. David Herr, US EPA, Reseach Triangle Park, NC.

Overview of the Biomarker Initiative to Identify Biological Fluid-Based Indicators of Neurotoxicity. Merle Paule, NCTR, Jefferson, AR.

Glial Fibrillary Acidic Protein (GFAP) and Related Astroglial Proteins as Biomarkers of NeurotoxicityJames O’Callaghan, NIOSH, Morgantown, WV.

Changes in the Metabolome May Serve as Peripheral Biomarkers of CNS Toxicity. David Herr, US EPA, Research Triangle Park, NC.

Neurotoxicant Effects on Non-Brain Tissues: Understanding Biomarker Specificity. Ingrid Pardo, Pfizer Inc., Groton, CT.

Biochemical and Molecular Endpoints as Biomarkers of Neurotoxicity and Their Correlation with Neuropathological Damage Syed Imam, NCTR, Jefferson, AR.

Workshop Discussion. Abby Li, Exponent, Oakland, CA; and Allison Harrill, NIEHS, Research Triangle Park, NC.

The NIEHS Nanotechnology Health Implications Research (NHIR) Consortium

IS  Informational

Chairperson(s):

Srikanth Nadadur, NIEHS, Research Triangle Park, NC; and Robert Tanguay, Oregon State University, Corvallis, OR.

Primary Endorser:

Nanotoxicology Specialty Section


The widespread use of engineered nanomaterials (ENMs) in consumer products is a concern for potential unintended exposure to ENMs and the impact on health. The overarching goal of the National Institute of Environmental Health Sciences (NIEHS) Nano Environmental Health and Safety (Nano EHS) program is to gain fundamental understanding of the molecular and pathological pathways implicated in potential adverse health effects of ENMs. In the absence of an identified pathology associated with ENMs, the NIEHS took a proactive approach aimed at developing an ENMs-biological interactions knowledge base, based on physicochemical properties of ENMs. This comprehensive knowledge base is hoped to guide and develop in silico approaches for human health risk characterization and potential intervention or remedial measures, as well the design of benign nanomaterials. The NIEHS recognized the need to promote collaborative team science efforts to address the multidisciplinary nature of assessing ENMs on environmental health and safety. Towards this goal, based on the past two decades of promoted research through the Nano GO Consortium and NIEHS Centers for Nanotechnology Health Implications Research (NCNHIR) and the research outcomes from these efforts, the NIEHS Nanomaterials Health Implications Research (NHIR) Consortium was established in 2016. This consortium will expand the library of ENMs and physico-chemical properties focusing on specific materials with high production and use in consumer products, as well as recently emerging 2D and 3D ENMs containing new transitional metals and whose toxicology is unknown at the nanoscale. The comprehensive toxicological profile for these ENMs surveyed using a wide range of systems reflecting more physiologically relevant models will benefit the future goals of this program (i.e., to promote computational modeling efforts to predict association between ENM physicochemical properties and potential health effects).


Introduction. Srikanth Nadadur, NIEHS, Research Triangle Park, NC.

Engineered Nanomaterial Synthesis, Characterization, and Method Development Center for Nano-Safety Research. Philip Demokritou, Harvard T.H. Chan School of Public Health, Boston, MA.

Key Events in Modulation of Lung Infection Susceptibility by Engineered NanomaterialsBrian Thrall, Pacific Northwest National Laboratory, Richland, WA.

Analytical Assessment of Protein Conformational Change Induced by Interaction with Nanomaterials. Wenwan Zhong, University of California Riverside, Riverside, CA.

Multidimensional In Vivo Assessments of Engineered Nanomaterials and Biological Interactions. Robert Tanguay, Oregon State University, Corvallis, OR.

Biological Response Profiles of Selected Engineered Nanomaterials after Perinatal Exposure. Peter Thorne, University of Iowa, Iowa City, IA.

Toxicological Profiling of Engineered Nanomaterials in the Mononuclear Phagocyte System in the Liver and the Immune System. Tian Xia, University of California Los Angeles, Los Angeles, CA.

Toxicity of Metallic Engineered Nanomaterials to Corneal Epithelial Cells. Soohyun Kim, University of California Davis, Davis, CA.

Impact of Early-Life Exposure to Engineered Nanomaterials. Timothy Fennell, RTI International, Research Triangle Park, NC.