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This was originally scheduled to be a session during the ASCCT 14th Annual Meeting in October 2025.  However, due to the October-November 2025 US Federal Government shutdown, as FDA employees and researchers, none of the presenters were allowed to give the session as planned.  We are thrilled they will now present their work in full as a webinar open to everyone!

9:30am - 12:00pm ET / 14:30 - 17:00 UTC

FEATURING
Yitong Liu, PhD, DABT: Senior Research Pharmacologist, US FDA
Michael Santillo, PhD: Senior Research Chemist, US FDA
Xiugong Gao, PhD: Research Biologist, US FDA
Kirsten Eckstrum, PhD: Research Biologist, US FDA
Piper Hunt, PhD: Research Biologist, US FDA

ABSTRACTS

Overview of Cannabis Toxicity and Human Use (Y. Liu): The use of cannabis-derived products has grown substantially in recent years, driven by an increased public interest in both recreational and health applications. In addition to well-known cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), a wide array of emerging compounds, including delta-8 THC and cannabigerol (CBG), are now widely available in consumer products. Although often marketed as natural or wellness-enhancing, accumulating evidence suggests that some of these substances may pose risks to human health. Documented adverse effects include the psychoactive and intoxicating effects of THC, as well as hepatotoxicity associated with CBD in both clinical and preclinical studies. The rapid expansion of the market has also led to the proliferation of lesser-known products, such as delta-8 THC, further complicating the evaluation of safety and potential human health impacts. This presentation will begin with an overview of the definitions and major classes of cannabinoids found in cannabis, including major cannabinoids (THC and CBD) and over 100 minor cannabinoids (e.g., THC-type, CBD-type, and CBG-type cannabinoids). It will then review the adverse health effects of cannabis and selected cannabinoids, highlighting key mechanisms of toxicity, including hepatotoxicity and reproductive and developmental toxicity. The presentation will conclude with a discussion of the consumer use of cannabis products, such as edibles, tinctures, capsules, and topicals.

In vitro and in silico biological target screening of cannabinoids (M. Santillo): Although there has been increasing interest in cannabis derived consumer products, many cannabinoids have unknown effects on human health. Using new approach methods, screening cannabinoids for binding to biological targets (receptors, ion channels, transporters, and enzymes) can serve as an initial step to identify potential human health effects of these compounds. Here, an overview will be presented on over a dozen cannabinoids, their interactions with safety-related targets, and potential health effects. Using in vitro enzyme inhibition and competitive ligand binding assays, important relationships were observed between target binding potency and cannabinoid structure due to carboxylic acid groups, alkyl chain lengths, and ring substructures. These structural features may cause differences in human health effects. Some examples of potent targets for cannabinoids include receptors (cannabinoid, adrenergic, serotonin) and transporters (norepinephrine, serotonin, dopamine). Among these targets, cannabinoids can bind in the high nanomolar range, which may translate to effects in the cardiovascular and nervous systems. Despite target binding being observed in vitro, cannabinoids aggregated into colloids depending on their molecular structure and concentration. Colloidal aggregation is a form of assay interference that may cause false positives in target binding assays, and more thorough work is needed to confirm this phenomenon in the future. In addition to in vitro assays, in silico screening by quantitative structure-activity relationship (QSAR) models identified additional targets for future exploration (e.g., retinoic acid receptors). Overall, in silico and in vitro biological target screening can help identify potential health effects of cannabinoids and prioritize future testing.

Transcriptomic point-of-departure derivation for hemp extract and four major cannabinoids using a human iPSC-derived hepatotoxicity model (X. Gao): The rapid rise of cannabis-derived consumer products in the United States and worldwide has sparked increasing safety concerns. While cannabidiol (CBD) has been linked to hepatotoxicity in clinical and preclinical studies, the safety profiles of other non-intoxicating cannabinoids remain largely uncharacterized. To protect public health, it is essential to establish safe exposure thresholds for these compounds. New approach methodologies (NAMs), particularly those leveraging bioinformatic analyses of high-throughput transcriptomic data, are emerging as powerful tools in chemical risk assessment and regulatory decision-making. Among these, transcriptomic points of departure (tPODs) derived from benchmark concentration (BMC) modeling of gene expression data offer a pragmatic and efficient approach for quantitative risk assessment of data-poor chemicals. In this presentation, we report findings from a concentration-response transcriptomic study of a hemp extract and its four major constituent cannabinoids – CBD, cannabichromene (CBC), cannabigerol (CBG), and cannabinol (CBN) – in hepatocytes derived from human induced pluripotent stem cells (iPSCs). Using BMDExpress software, we performed BMC modeling on microarray data to derive tPODs for each compound. The resulting potency rankings were consistent with in vitro cytotoxicity data, and the tPOD for CBD aligned with a previously published value based on apical endpoints from clinical and animal studies. A brief comparative analysis of toxicity mechanisms across the cannabinoids will also be presented. Overall, our findings highlight the value of transcriptomic BMC analysis as a NAM for human health risk assessment and provide tPOD estimates that may support regulatory decision-making on hemp extract and cannabinoids.

Examining the hepatotoxic potential of cannabidiol, cannabidiol-containing hemp extract, and cannabinol at consumer-relevant exposure concentrations in primary human hepatocytes (K. Eckstrum): Hemp extracts and products containing cannabidiol (CBD) and other phytocannabinoids derived from hemp have recently entered the marketplace. Liver injury has been observed in clinical trials of CBD on some occasions in association with Epidiolex, a drug using CBD to treat Dravet syndrome and Lennox-Gastaut syndrome. However, there is limited information on the hepatotoxicity of other phytocannabinoids purified from hemp and hemp extracts. To address this gap, primary human hepatocytes (PHH) were treated with CBD, cannabinol (CBN), or CBD-matched hemp extract for 24 or 48 hours at consumer relevant concentrations, 10 nM to 25 μM, based on concentrations reported in hemp products. Hepatotoxicity was determined by measuring lactate dehydrogenase, apoptosis, albumin secretion, urea secretion and mitochondrial membrane potential. Cytotoxicity was not significantly altered by CBD, CBN, or hemp extract at any concentration, however, there was a modest but significant loss in hepatocyte function with decreased albumin, urea, and mitochondrial membrane potential when treated with the highest concentration of hemp extract (25 μM). 25 μM of CBD alone only decreased albumin compared to control, suggesting that inclusion of other cannabinoids may contribute to either the toxicity of the extract or the solubility and delivery of the CBD to the cells. This study addresses data gaps in understanding cannabinoid hepatotoxicity in vitro, however, further studies are needed to correlate these consumer relevant exposures to biological effects of cannabinoids in the liver.

Assessment of the effects of cannabidiol in Caenorhabditis elegans (P. Hunt): Multiple genetic pathways and molecular signaling cascades involved in organismal development and neuronal function are well conserved across phyla, supporting the use of small alternative animal models such as C. elegans in toxicity assessment. From nematodes to humans, endocannabinoid signaling plays essential roles in organismal development, and exposure to exogenous cannabinoids can alter endocannabinoid signaling resulting in adverse developmental outcomes. C. elegans can consume cannabidiol (CBD) via emulsions mixed with nutrient media, providing a platform for oral toxicity testing in a small model organism. In adult C. elegans, 25-100µg/mL CBD reduced the expression of an oxidative stress response reporter in a dose-response manner. Adult exposures of 400µg/mL CBD and above induced acute toxicity and reduced progeny production. Effects on juvenile growth were seen at 200µg/mL CBD, consistent with greater CBD toxicity to developing C. elegans. CBD was associated with hypoactivity in juveniles, but in adults CBD counteracted high-fat diet induced hypoactivity. C. elegans development from hatching to egg-laying adult takes about 3 days and is divided into four post-embryonic developmental stages. C. elegans exposed to CBD for 24h post hatching had longer delays to the third and fourth larval stages than did cohorts continuously exposed to CBD, consistent with a withdrawal-like effect. For all C. elegans endpoints in this study, a CBD-rich hemp extract was slightly less toxic than purified CBD at the same CBD exposures. Dosimetry indicated that all observed C. elegans adverse effects occurred at exposures that exceeded recommended CBD dosing for humans.

PRESENTER BIOS

Dr. Yitong Liu is a Senior Research Pharmacologist and Diplomate of the American Board of Toxicology with over 15 years of experience in regulatory science at the FDA's Human Foods Program. She specializes in using New Approach Methods, including quantitative structure-activity relationship (QSAR) modeling, physiologically based pharmacokinetic (PBPK) modeling, and in vitro assays, to evaluate the safety and pharmacokinetic properties of food substances, particularly botanical dietary supplements and phytochemicals. As a regulatory review scientist, Dr. Liu has conducted safety assessments for New Dietary Ingredient (NDI) Notifications, including complex botanical products, and has provided expert input on compliance actions, policy development, and interagency collaborations. Dr. Liu serves as a Subject Matter Expert for toxicology and pharmacokinetics across multiple FDA working groups and external committees, including the FDA’s Cannabis Product Committee and the U.S. Pharmacopeia's Dietary Supplements Admission, Evaluation, and Labeling Committee. She leads the in silico toxicity and ADME team at the Botanical Safety Consortium, an international public-private initiative advancing botanical safety assessment. She has authored 31 peer-reviewed publications and book chapters in leading journals, presented her research at over 40 national and international conferences, and received numerous FDA awards recognizing her outstanding contributions to food safety science and regulatory review.

Dr. Michael F. Santillo is a senior research chemist in the FDA's Human Foods Program with over 15 years of experience specializing in toxicology. His research centers on developing, applying, and combining multiple new approach methods (NAMs) to evaluate the safety of chemicals in foods and dietary supplements. Dr. Santillo employs biological target screening across multiple organ systems, evaluating chemical interactions with enzymes, receptors, ion channels, and transporters using both in silico QSAR models and in vitro biochemical and cell-based assays. He integrates this target screening data with complementary in vitro and in silico data (e.g., metabolism predictions) to improve the accuracy and relevance of NAMs data. In addition to his role as a research scientist, Dr. Santillo has also served as a regulatory reviewer, assessing the safety of dietary ingredients and food contact substances in industry submissions to the FDA. Dr. Santillo co-leads FDA's participation in Tox21, a NAMs research consortium among multiple federal agencies, and has participated in international activities including OECD assay validation review panels, the ONTOX consortium, and others. Dr. Santillo has published 29 articles and book chapters and served on the editorial boards for the Journal of Pharmacological and Toxicological Methods and SLAS Technology. He received his Ph.D. in chemistry from Penn State University, where his research focused on developing microfluidic platforms for cell-based assays.

Dr. Xiugong Gao is a Research Biologist in the Office of Chemistry and Toxicology, Human Foods Program, at the U.S. Food and Drug Administration (FDA). He serves as Principal Investigator for the Toxicogenomics and Stem Cell Research Programs and has more than 20 years of experience applying transcriptomics and human in vitro models to toxicity testing and chemical safety assessment. His research focuses on dose–response transcriptomic modeling to support hazard identification, risk assessment, and regulatory decision-making for food-related chemicals and dietary supplements. Dr. Gao actively contributes to national and international scientific advisory and regulatory initiatives in toxicogenomics and risk assessment. He has served on the U.S. Environmental Protection Agency (EPA) Transcriptomic Assessment Products Panel and participated in cross-sector efforts such as the Health and Environmental Sciences Institute (HESI) Transcriptomic Point of Departure workgroup to advance the regulatory application of transcriptomics. He has held leadership roles within the Society of Toxicology, including President of the Stem Cells Specialty Section, and has co-chaired the SOT–FDA Colloquium on Toxicogenomics. Dr. Gao has authored more than 80 peer-reviewed publications and delivered approximately 80 presentations at national and international scientific conferences. His work has been recognized with multiple honors, including the FDA CFSAN Exceptional Achievement Award and the Best Paper Award at the U.S. Army Science Conference.

Dr. Kirsten Eckstrum is a Research Biologist in the Division of Toxicology (OCT/OLOAS/HFP). Her lab work focuses on evaluation of New Approach Methods (NAMs) that can potentially be utilized to advance food safety evaluations. Kirsten received her PhD from the University of Illinois Urbana-Champaign (UIUC) in 2017, before joining the division. She has published manuscripts on the evaluation of a microphysiological system using compounds of known hepatotoxic potential to assess the sensitivity, specificity, variability, and power of the model. She additionally supported studies on food-related compounds of concern for short term, rapid analysis. Now, she focuses on a tiered approach for the evaluation of potential hepatotoxicity of botanical extracts utilizing both rapid and microphysiological systems.

Dr. Piper R. Hunt is a Research Biologist at the FDA Human Foods Program where she is a leader in the development of novel alternative methods for toxicity assessment. She earned her PhD in Human Genetics and Molecular Biology from the Johns Hopkins University School of Medicine and has over two decades of experience spanning molecular genetics, nutraceutical assessment, toxicology, and alternative model development. Dr. Hunt served as principal investigator and lead author on 13 peer-reviewed publications with more than 1,500 citations, advancing NAMs testing for acute, developmental, and reproductive toxicity, with a particular focus on Caenorhabditis elegans. Her recent work has demonstrated the ability of C. elegans to distinguish reversible from irreversible developmental effects, improving cross-species hazard prediction and strengthening the scientific foundation for NAM adoption in regulatory decision-making. In addition to her research, she provides critical regulatory support for FDA reviews and contributes to national and international expert working groups, including the Botanical Safety Consortium.

Time will be provided during this webinar for audience-led Q&A. Materials and recordings from the webinar will be posted to the ASCCT Webinar Archive.