Program Overview

Facilitator: Nicollete Mitchell, Bates College, Lewiston, ME.

Sponsored by FUTURE Committee

Preregistration Required

The Society of Toxicology has a commitment to embracing diversity and optimizing inclusion. At the upcoming Virtual SOT Annual Meeting, we will be facilitating a discussion about diversity, equity, and inclusion (DEI) among toxicologists who interface with undergraduates in the classroom, lab, and workplace. The workshop will be facilitated by Nicollette Mitchell, Director of Equity and Inclusion Education at Bates College.

Following a brief introduction about the importance of DEI, participants will be assigned to smaller groups to discuss where they are situated in their institution, the resources of that institution, and their ability to create change (and perhaps what that change might look like) in the DEI space. At the end of those discussions, all participants will come back together to report out about these conversations. Participants will leave having thought about their own positionality within the DEI space and hearing about that of other educators and their institutions.

Speaker: Laura Lindenfeld, Alan Alda Center for Communicating Science, Stony Brook University, Stony Brook, NY.

In this keynote, Dr. Lindenfeld will introduce participants to the Alda Center’s unique approach to science communication. Building on the foundations of improvisational theater, which cultivates a stronger ability to relate and connect, the Alda Center leverages scientific research on science communication to empower scientists to connect with diverse audiences in clear and vivid ways.

Lecturer: Dana C. Dolinoy, University of Michigan, Ann Arbor, MI.

Toxicant exposures early in life adversely affect health outcomes in both animal models and humans, in part because of epigenetic mechanisms. Accumulating studies also indicate that exposures’ effect on the epigenome can be tissue and even cell specific. Yet toxicoepigenetic animal studies are often conducted with single tissues in bulk and/or limited epigenomic targets (e.g., DNA methylation). Additionally, epigenetic epidemiology analysis of toxicants is almost always restricted to biologically available, “surrogate” (e.g., blood) samples. Using a combination of toxicological and epidemiological approaches, the first of two overarching goals of this lecture is to advance the understanding of the effects of representative perinatal exposures on the epigenome and longitudinal health risks. Second, precision modification of the epigenome holds great promise for our ability to modify environmentally induced changes in gene expression, yet is currently out of reach using common techniques (drugs, transgenics, etc.). Until recently, it was widely believed that Piwi Like RNA-Mediated Gene Silencing (PIWIL) gene expression was confined to the germ line of animals and that neither PIWILs nor piRNAs were present or active in somatic tissues. Our research overturns this accepted knowledge by finding widespread PIWIL expression in multiple somatic tissues in mice and humans. Thus, we are using this class of RNA to develop technology to target specific genes and loci for stable, mitotically heritable silencing at predetermined genomic locations. The research expands the repertoire of epigenome editing tools resulting in therapeutics to treat a broad array of environmental and epigenetic diseases, including imprinted gene disorders and cancer.

Speaker: Rick Woychik, NIEHS/NTP, Research Triangle Park, NC.

This important session will provide an informal venue for attendees to have a candid and open discussion with Rick Woychik, PhD, the Director of the National Institute of Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP). The 30-minute session will begin with a brief summary of the leadership values that Dr. Woychik brings to the position, and the remainder of the session will be devoted to a question-and-answer format concerning scientific directions and priorities for NIEHS, including funding priorities and outlooks and training opportunities.

SOT Debater: Syril D. Pettit, HESI, Washington, DC.
EUROTOX Debater: Alan R. Boobis, Imperial College London, United Kingdom.

Each year, the SOT Annual Meeting includes a debate in which leading toxicologists advocate opposing sides of an issue of significant toxicological importance. The debate continues a tradition that originated in the early 1990s. This year, the debaters will address the proposition “individualized toxicity is the future of risk assessment.” As toxicologists, we seek to define safe operating parameters for the use of a substance in a population. The opportunity to use “real-world evidence” and personal data collection devices (human biomonitoring) to gather information on toxicity from individuals and small populations allows us to envision new ways to refine these parameters as they relate to individuals. Is the future of toxicology and risk assessment headed toward a paradigm that must include approaches for patients/individuals at a public health–protection scale? If so, is it possible (or even desirable) to view risk of small groups of individuals based on discrete risk factors? Can adverse outcome assessments for groups be improved by this approach? Can recent developments in machine learning and other computational methods be applied in toxicology as they are being applied in precision medicine? Does surveillance of a patient’s response via personalized adverse effect monitoring provide a means to qualify the exposure-response relationship that can be tailored to each patient? Would better profiling be helpful to avoid lethal errors? Does an integrated exposure reduce the number of assumptions that need to be made when estimating exposure and thus help reduce the uncertainties in exposure science? Can we address the ethical and political aspects of its application? In addition to inclusion as a Featured Session at this meeting, this debate will again take place (with the debaters taking the reverse positions) in Copenhagen, Denmark, during the EUROTOX 2021 congress, September 26–29, 2021.

Lecturer: Deborah Cory-Slechta, University of Rochester Medical Center, Rochester, NY.

Epidemiological evidence links air pollution (AP) to neurodevelopmental disorders (NDDs) and neurodegenerative diseases (NDGDs). Our studies of inhalation exposures of mice to concentrated ambient ultrafine particles (CAPS) provide biological plausibility for these associations and have begun to examine specific AP contaminants that may underlie these effects. Early postnatal (human third-trimester brain equivalent) CAPS inhalation produced persistent male-biased neuropathological and behavioral features of NDDs, while females showed latent neurotoxicity. Gestational CAPS exposures produced similar neuropathology across sexes, but also increased total brain levels of amyloid and tau in the frontal cortex and hippocampus of females, features of NDGDs. Cumulative neurotoxicity was found following early postnatal + subsequent adult CAPS exposures. Postnatal CAPS exposures markedly elevated brain levels of redox active metals, including Fe and Cu, consistent with brain metal dyshomeostasis, a known feature/mechanism of NDGDs, suggesting oxidative stress/ferroptotic cell death mechanisms. Fe nanoparticle inhalation reproduced specific neuropathology of CAPS in both sexes, and in females, increased total tau, and blunted the time-related increase in numbers of nucleus accumbens neurons. With respect to organic AP contaminants, subchronic inhalation of paraquat, an herbicide linked to Parkinson’s disease (PD), produced significant brain uptake and persistent male-specific deficits in motor function, olfactory discrimination, and midbrain dopamine loss, characteristic PD features. AP with its associated contaminants may be a far-reaching risk factor for NDDs and NDGDs, underscoring the urgent need for additional inhalation models of sex-based critical periods of vulnerability and associated mechanisms.

Lecturer: Norbert E. Kaminski, Michigan State University, East Lansing, MI.

The term cannabinoid encompasses a broad family of molecules, including plant (cannabis)–derived, synthetic, and endogenous compounds possessing diverse biological activities. Indeed, cannabis alone possesses over 100 structurally related cannabinoids, most of which have yet to be studied to any extent. The majority of attention during the past 50 years has focused on the primary psychotropic constituent in cannabis, ∆⁹-tetrahydrocannabinol, and very recently cannabidiol, both of which can influence immune function. A focus of the Kaminski laboratory has been on defining the profile of immune activity by cannabinoids and elucidating the molecular mechanisms mediating cannabinoid immune modulation. A significant advancement in the field came with the identification and cloning of two G-protein coupled cannabinoid receptors, CB1 and CB2, and the establishment of their expression on leukocytes. Identification of cannabinoid receptors quickly led to the discovery of endogenous cannabinoid receptor ligands, raising questions concerning their physiological role, including in immune regulation. An important backdrop to cannabinoid research has been the prevalence of cannabis use, with an estimated 37 million adult users in the US and likely increasing with recent trends toward legalization of recreational consumption. Likewise, medical use of cannabis and cannabidiol has also increased significantly, with many questions about the benefits remaining unanswered. Finally, expression of cannabinoid receptors within the immune system, coupled with the absence of CB2 within the CNS, provides a putative drug target for cannabinoid-mediated immune modulation devoid of psychotropic activity. This presentation will discuss the molecular mechanisms by which cannabinoids modulate the immune system, as well as putative health implications and CB2 as a putative therapeutic target for the treatment of inflammatory diseases. Dr. Kaminski was the recipient of the SOT Merit Award in 2020.

Lecturer: Wout Slob, Rijksinstituut voor Volksgezondheid en Milieu (RIVM), Netherlands.

Wout Slob, PhD, studied biology at Vrije Universiteit Amsterdam, with theoretical biology as his main subject. He obtained his PhD in 1987 with work on applying statistics in biological research, including log transformation and power analysis. Dr. Slob worked at RIVM from 1986 to 1995 as a consulting statistician. During that period, he gradually became more interested in toxicology and risk assessment. From 1996, he specialized in methods for risk assessment of substances, including dose-response modeling, exposure modeling, probabilistic risk analysis, and toxicokinetic modeling. As an expert in these quantitative methods, he played an important role in many international committees. Dr. Slob developed a software program for analyzing dose-response data (PROAST). This is used a lot, nationally and internationally, in the context of risk assessment as well as in the context of scientific research in general. From 2000 to 2010, Dr. Slob also was appointed as a professor for quantitative risk assessment at the Institute of Risk Assessment Sciences (IRAS) of Universiteit Utrecht.

Lecturer: Thomas Knudsen, US EPA/NCCT, Research Triangle Park, NC.

Hosted by: Education and Career Development Committee

Preregistration Required

The goal of the In Vitro Toxicology Lecture series is to feature important research using in vitro and alternative techniques to study basic mechanisms and to develop test methods aimed at replacing animal use whenever feasible. Undergraduate students, graduate students, postdoctoral scholars, and recipients of Colgate-Palmolive awards are among the guests at this event. The speaker will make a short presentation which is the basis for a case study discussion in breakout rooms.

Technologies used by toxicologists, and the biological questions we ask, have become increasingly sophisticated with the integration of data science and computational intelligence. Computer models allow us to mine big-data and synthesize important concepts that can be applied to biologically-complex systems. To operationalize complex data for toxicological evaluation, information must be collected, organized, and assimilated into models that bridge different levels of biological organization. By reconstructing biological tissues in silico into simulated “virtual tissues,” we can demonstrate how dynamic changes occur in response to a particular stimuli such as biomolecular lesions introduced from real world data. This has been captured for several examples in embryo development with data from ToxCast or literature, rendering where, when, and how a particular lesion might lead to an adverse outcome facilitating mechanistic hypothesis generation and predictive toxicology. Discussion will focus on how many models are needed, how smart models must be to support decision-making in the animal-free (3Rs) zone, and practical considerations for technology development, application, and training for predictive toxicology. Disclaimer: does not reflect EPA policy.

Lecturer: Rebecca Fry, University of North Carolina at Chapel Hill, Chapel Hill, NC.

The placenta serves as a temporary organ that is critical for a healthy pregnancy as well as proper fetal development. Numerous environmental toxicants can impact the development and proper functioning of the placenta. The placenta, in turn, can transduce these toxicant-induced signals to the fetus. This lecture will discuss how environmental chemicals—including, but not limited to, inorganic arsenic, cadmium, and perflouralkyl substances—impact cellular signaling within the placenta and influence both early and later-in-life health outcomes. Transdisciplinary approaches that include in vitro and in vivo model systems, as well as human population-based studies, have been key to scientific discovery. These approaches have been essential to identify exposure-outcome associations and the biological mechanisms underlying placental toxicity. This research has elucidated the complex mechanisms through which environmental contaminants alter the placenta, and thus drive pregnancy complications, and later-in-life offspring development. Solution-oriented research focused on disease prevention builds upon this knowledge base.

Lecturer: Dame Amanda Fisher, MRC London Institute of Medical Sciences, United Kingdom.

Professor Dame Amanda Fisher has contributed to many areas of biology, including the molecular discovery of HIV and the impact of chromatin and nuclear location for gene expression. Imprinted genes are epigenetically regulated and show parent of origin-specific expression. These genes have important roles in embryonic growth and metabolism, and their deregulation impacts upon postnatal metabolism and behavior, as well as susceptibility to disease. We recently created a series of luciferase reporter mice that enable imprinted gene expression to be sensitively imaged throughout development in vivo and across successive generations of animals. Our experiments have shown that environmental factors encountered in utero can disrupt epigenetic control within developing embryos and permanently alter the expression of imprinted alleles in offspring. For example, transient exposure to chromatin-modifying drugs such as TSA or 5’Azacytidine provoke the misexpression of paternally inherited (and normally silent) Cdkn1c alleles. In utero exposure to a low-protein maternal diet also induces paternal Cdkn1c re-expression, which is not reversed when offspring resume a normal diet. In a second series of experiments, we have shown that in utero exposure to high-fat maternal diet provokes the de-repression of a different (maternally silenced) imprinted gene, Dlk1. Remarkably, our data indicate that the epigenetic impact of this exposure remains visible across three generations of offspring. These results illustrate how luciferase-based reporter mice can be used to uncover exposures that alter the epigenetic landscape, examine how this occurs, and explore specific vulnerabilities of the developing embryo.

Lecturer: Rogene Henderson, Lovelace Respiratory Research Institute, Albuquerque, NM.

The importance of using regulations to keep our air clean is relevant for two major reasons: to protect the health of all species and to protect the health of our planet. This lecture will address some of the challenges associated with working in this field through the lens of a prodigious career in regulatory toxicology. Dr. Henderson will discuss her early education, which included a double major in chemistry and biology as well as a double minor in German and mathematics. She will then discuss her one-year studies in Munich, Germany, on a Fulbright Scholarship and her subsequent return on a fellowship to perform a graduate study in chemistry at the University of Texas in Austin, Texas. She then will speak about her early career, when after earning a PhD in chemistry, Dr. Henderson joined the newly established Lovelace Respiratory Research Institute under Dr. Roger O. McClellan. She will present on her research, funded by the National Institute of Environmental Health Sciences, on the toxicokinetics of inhaled xenobiotics, which led to the development of novel biomarkers in bronchoalveolar lavage fluid and contributed to the modern field of inhalation toxicology. Dr. Henderson also will touch on how from this basic research, she published over 250 scientific communications, including review articles, chapters, and books, and served on numerous Editorial Boards and study sections. Dr. Henderson will then discuss her experiences as a member and later Chair of the US Environmental Protection Agency Clean Air Scientific Advisory Committee, where she pushed for reasonable regulations of air pollutants and additionally contributed to the World Health Organization’s guidelines for air quality. This lecture will include a discussion of some of the challenges Dr. Henderson faced in the leadership roles she held in regulatory agencies. Dr. Henderson is the 2021 recipient of the SOT Merit Award.

Speakers: Michael J. DeVito, US EPA, Research Triangle Park, NC; Martin van den Berg, Universiteit Utrecht, Utrecht, Netherlands; Suzanne E. Fenton, NIEHS/NTP, Research Triangle Park, NC; Rick Woychik, NIEHS/NTP, Research Triangle Park, NC; and Laurie C. Haws, ToxStrategies Inc., Austin, TX.

Linda S. Birnbaum, PhD, DABT, ATS, has been a visionary making lasting contributions to the science of toxicology through both her own research and her advocacy of research. She also has promoted the application of toxicology research to solving significant public health problems, making the relevance of our science obvious. SOT is marking the occasion of her retirement as National Institute of Environmental Health Sciences (NIEHS) Director with a session that pays tribute to her long career in research and public service. Dr. Birnbaum made seminal contributions in research on the toxicity of dioxins, among the most potent small molecule toxicants. Her research into endocrine disrupters increased our understanding of the range of outcomes that can be attributed to these agents and highlighted the significance of early-life exposures in chronic diseases. As a leader of programs at the US Environmental Protection Agency and NIEHS, Dr. Birnbaum set strategic directions that increased the relevance of toxicology research in public health decision-making and increased the stature of the field among the life sciences community. Finally, Dr. Birnbaum has served as a mentor for numerous women in science. Each of these areas of contribution will be discussed during the session.

JSOT Speaker: Yoshito Kumagai, University of Tsukuba, Tsukuba, Japan.
JSOT Speaker: Yoshiro Saito, Tohoku University, Sendai, Japan.
SOT Speaker: Alicia R. Timme-Laragy, University of Massachusetts Amherst, Amherst, MA.
SOT Speaker: Dean P. Jones, Emory University School of Medicine, Atlanta, GA.

SOT and the Japanese Society of Toxicology (JSOT) are delighted to jointly sponsor a Symposium on a topic of mutual interest: oxidative stress in multiple manifestations of toxicity. Each society has selected from among its membership leaders in the field to provide their perspectives on recent advances in this area. The Symposium will highlight advances in research on the role of oxidative stress in adverse outcomes. Oxidative stress occurs when the products of oxidative processes exceed the cell’s capacity to handle them. The resulting imbalance causes damage to macromolecules, leading to cellular damage and eventually to a variety of disease states. The SOT/JSOT Symposium will explore multiple mechanisms and outcomes of oxidative stress.

Chair(s): Marie C. Fortin, Jazz Pharmaceuticals Inc., Philadelphia, PA; and Ilona G. Bebenek, US FDA, Silver Spring, MD.

Speakers: Roy M. Bannister, Gilead Pharmaceuticals Inc., Foster City, CA; Matt Liu, Regeneron Pharmaceuticals Inc., Tarrytown, NY; Cynthia M. Rohde, Pfizer Inc., Pearl River, NY; Arianne L. Motter, US FDA/CDER, Silver Spring, MD; John Dubinion, US FDA/CDER, Silver Spring, MD; and Claudia Wrzesinski, US FDA/OVRR, Silver Spring, MD.

COVID-19 (Coronavirus Disease 2019), the disease caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), is a public health emergency. Initially identified in China in late December 2019, forensic evidence revealed that the virus was in fact circulating in other regions as early as October 2019 and reached the United States at some point in late 2019. Since its emergence, scientists have been at the forefront of many efforts to fight this virus: public health measures to “flatten the curve,” vaccines to help achieve herd immunity, and therapeutic approaches to treat those who have fallen sick. As our understanding of COVID-19 and its health effects has improved, companies and agencies worldwide have worked hand-in-hand to identify therapeutic approaches and fast-track clinical trials and pathways to emergency use and approvals, in order to reduce time to recovery, improve survival, and mitigate long-term health consequences. In this session, the development of three products that are—at the time of writing of this abstract—either approved or authorized for emergency use, VEKLURY^® (remdesivir, direct acting antiviral from Gilead), casirivimab and imdevimab (antibody cocktail from Regeneron), and Pfizer-BioNTech COVID-19 Vaccine, will be discussed. The pharmacology and mode of action, nonclinical development, and regulatory development pathways for these therapeutics will be covered to the extent possible. Perspectives concerning the development of early- and late-stage drug development during this health crisis also will be provided from the US Food and Drug Administration (US FDA).