Program Overview

There is an urgent need to take what we have learned in our new data-driven era of medicine and use it to create a new system of precision medicine, delivering the best, safest, cost-effective preventative or therapeutic intervention at the right time, for the right patients. Dr. Butte’s lab at the University of California San Francisco builds and applies tools that convert trillions of points of molecular, clinical, and epidemiological data—measured by researchers and clinicians over the past decade and now commonly termed “big data”—into diagnostics, therapeutics, and new insights into disease. Dr. Butte, a computer scientist and pediatrician, will highlight his center’s recent work on integrating electronic health records data across the entire University of California and how analytics on this “real-world data” can lead to new evidence for drug efficacy, new savings from better medication choices, and new methods to teach intelligence—real and artificial—to more precisely practice medicine.

Chair(s):

Students and postdoctoral scholars who would like to attend this event should register for $10 (nonrefundable) with their Annual Meeting registration. Lunch service is available for guests with tickets who arrive before 12:15 pm. After lunch, the speaker makes a short presentation, which is the basis for a case study discussion at each table.

2022 Lecture Abstract

A scientific and technological revolution is underway, and new approach methodologies are helping us push the frontiers of our understanding of drug safety. Anthracyclines are widely used chemotherapeutic agents used in the treatment of cancers such as leukemia and breast cancer; however, their clinical utility is limited due to their known adverse effects on cardiovascular function. Although the mechanism underlying their cardiotoxicity remains elusive, there’s been great interest in developing formulas that would mitigate this toxicity, one of which has been shown to demonstrate clinical benefit (O’Brien, 2003). Until now, it has been difficult to compare the relative cardiotoxicity of different drugs or formulations using standard nonclinical or clinical models. Animals are usually not sensitive enough, and it is challenging to study in patient populations due to existing disease and other confounding factors.

Human-induced pluripotent stems cells–derived cardiomyoctyes (hiPSC-derived cardiomyocytes) present many of the characteristics of healthy human cardiac muscle cells, including gene and protein expression and rhythmic beating. Using these cells, we were able to characterize the relative cardiotoxicity of free versus nano-lipo-encapsulated drugs (CPX-351) by using a variety of biomarkers representative of cellular function (beating), cellular bioenergetics (mitochondrial respiration), and cellular health (ATP, LDH) as well as clinical markers such as cardiac troponin. These biomarkers provided insight into the mechanisms of toxicity, allowing us to be able discriminate between formulations in a way that is clinically relevant and is capable of recapitulating the relative cumulative toxicity of anthracyclines without the need for in vivo experiments.

Panelists:

A construction worker on a hog farm walks into the bathroom. He later is found unresponsive on the ground. Was it drugs? I mean, it’s probably drugs. But wait, could it be something else? The coworker who found him smelled something funny coming from a hole in the bathroom floor. A graduate student, punished to work long hours sequencing DNA by gel, collapses. Is it from sheer exhaustion or a toxic inhalational exposure? And someone please call OSHA; another worker from that same hog farm collapses and his skin appears gray. He was working on experimenting with which bait hogs liked to eat to assist others trying to control the wild pig population. Come watch the panelists get stumped trying to determine the possible culprit compound for these patient presentations. There also will be lively discussion regarding the diagnosis and management of these exposures.

Chair(s):

This year, the debaters will address the proposition: Is there a role for artificial intelligence (AI) and machine learning (ML) in risk decisions? The debaters will discuss the principles and limitations of these tools for decision-making. Specific questions to be addressed include: Can recent developments in AI and ML be applied in toxicology as they are being applied in precision medicine and other fields? Are current algorithms inherent to AI and ML sufficiently refined for the design of safer products? Are these applications sufficiently robust to identify toxic “signatures,” providing information for safety and risk assessment? Are they sufficiently reliable to predict toxicity and can they account for genetic and other toxicodynamic variability? Are they able to predict risk associated with exposures to mixtures? Can they predict the potential toxicity of new compounds or relate chemical structure or activity to risk? How can we tell if the results of AI and ML are accurate and defensible? 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 Maastricht, Netherlands, during the XVIth International Congress of Toxicology, September 18–22, 2022.

Respiratory toxicity of particles and fibers is a global issue that has been associated with progress of civilization and continues to harm human health. This Symposium provides the latest scientific findings about cellular and molecular mechanisms for the toxic effects of fine/ultrafine particles, wood/biomass smoke PM, and asbestos fibers as a session jointly organized by SOT and the Japanese Society of Toxicology (JSOT). Impact of inhalation exposure to those particles and fibers causes various kinds of events not only inside but also outside respiratory system, which includes intracellular and intercellular machineries related to cell death and inflammation and extends to the immune as well as the neuronal system. The Symposium will contribute to more understanding of the diseases caused by those toxicities.

Panelists:

Attendees also will have an opportunity to interact with the editorial team of Toxicological Sciences in a discussion session. While this session is primarily geared toward manuscript authors, peer reviewers and readers of Toxicological Sciences also will benefit from participating.

The 60-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.

Research of the past decades provides a basis for understanding how DNA oxidation, alkylation, and instability, balanced by DNA damage tolerance and repair, drive mutagenesis. Nevertheless, our ability to predict individual susceptibility to chemical mutagens or the etiology of individual cancers remains limited in part because there exists a mismatch between our low-resolution understanding of the dynamic process of DNA damage formation and removal on a genome-wide level versus our sophisticated single-base genome-wide picture of mutational landscapes of human cancers. Very recently, several strategies have emerged for base-resolution genome-wide mapping of DNA damage, including chemical probe– and ligation-based strategies. We have mapped DNA damage in mammalian cells and gained new insight on how damage profiles are governed by chemical sources and cellular repair proficiency, and, finally, related chemical exposures with in vitro mutation signatures. This research involves applying a combination of strategies for evaluating damage regions in the human genome based on DNA damage–tailored chemical probes and bioanalysis methods, including single nucleotide mapping of damage in whole genomes, and in vitro strategies to determine the impact of enzymatic deficiencies on mutation signatures. Elucidation of DNA damage and repair from chemical exposure to DNA alkylating drugs, diet-derived reactive nitrogen species, and reactive oxygen species will be presented. Chemical structure and sequence-specific chemical probe–based strategies for tracking DNA damage overcomes previous limitations to understanding the distribution of DNA damage formation and repair and its genome-wide impact on the accumulation of mutations. Furthermore, it provides information concerning the relationship between DNA repair enzyme function and mutation signatures that could lead to new approaches for quantifying risk on the basis of early biomarkers and characterization of causative factors of individual cancers.

During preimplantation development, human embryos are composed of pluripotent embryonic cells, which eventually form the fetus, and extra-embryonic cells, which contribute to the placenta and yolk sac. The central question we address is: What are the molecular mechanisms that regulate these early cell fate choices in human embryos? We are using CRISPR/Cas9-mediated genome editing, TRIM-Away protein depletion, dominant negative mutations, and small molecules to dissect the function of genes during human embryogenesis. These methods have enabled us to uncover that the first lineage specification event in human embryos is the initiation of a placental program. Our work has also uncovered a high frequency of unintended on-target mutations following genome editing in human primary cells. By integrating signaling insights from human blastocysts, we have defined human embryonic stem cell culture conditions that more closely recapitulate the embryonic niche. The molecular basis of these early cell lineage decisions is of fundamental importance and has wide-reaching clinical implications for infertility, miscarriages, developmental disorders, and therapeutic applications of stem cells.

These satellite meetings have provided an informal setting in which interested stakeholders could receive high-level updates on cutting-edge approaches in toxicology, all within a single session. The meetings have featured a number of invited presentations, followed by an opportunity for participants to ask questions, make announcements, or offer comment on germane topics. In their early years, the satellite meetings put considerable emphasis on large-scale, government-led, high-throughput testing programs in the United States—namely, Tox21 and ToxCast. In more recent years, as the field has evolved, the session has broadened to include updates on a spectrum of related projects in the US and outside the US, highlighting additional technologies (e.g., microphysiological systems, artificial intelligence, and other new approach methodologies) and additional programs (e.g., EU Tox-Risk). The speakers are among the main drivers of their respective efforts.

Presentation mode: R=Remote, IP=In Person, TBD=To Be Determined

The proposed program is as follows (speakers and topics are subject to change):

12:30 PM
Box lunch (for preregistered, in-person participants)

1:00 PM
Welcome
Martin Stephens (Johns Hopkins University) [R]

1:10 PM
Invited speakers (10-minute presentations, each followed by five minutes of discussion)

• 1:10 PM: NCATS Screening Effort in the Tox21 Program—Menghang Xia (NIH/NCATS) [TBD]
• 1:25 PM: Modeling Tox21 Data for Toxicity Prediction and Mechanism Deconvolution—Ruili Huang (NIH/NCATS) [TBD]
• 1:40 PM: NICEATM Update: Advances in Predictive Toxicology—Helena Hogberg (NIEHS/NICEATM) [IP]
• 1:55 PM: Advancing Alternative Methodologies at the US FDA—Suzanne Fitzpatrick (US FDA) [R]
• 2:10 PM: Progress on 21st-Century Toxicology and Chemical Risk Assessment at US EPA—Alison Harrill (US EPA) [TBD]
• 2:25 PM: Progress on Implementing Section 4(h) of TSCA at US EPA—Tala Henry (US EPA) [IP]
• 2:40 PM: NAM-Based Approaches for Next-Generation Risk Assessment: From EU-ToxRisk to the RISK-HUNT3R Project—Bob van de Water (Universiteit Leiden) [R]
• 2:55 PM: Update: Japanese Projects Regarding a New Approach Method (NAM) for Systematic Toxicology—Seiichi Ishida (Sojo University and National Institute of Health Sciences Japan) [R]
• 3:10 PM: Animal-Free Safety Assessment Collaboration: Cosmetics Safety Assessment Training Program—Catherine Willett (Humane Society International) [IP]
• 3:25 PM: In Vitro Studies’ Critical Appraisal Tool Development by EBTC—Katya Tsaioun (Johns Hopkins University) [IP]
• 3:40 PM: Update on CAAT Activities Advancing 21st-Century Toxicology—Thomas Hartung (Johns Hopkins University) [IP]

4:00 PM
Open microphone for Q&A and discussion

4:30 PM
Adjourn