Contributions from two HESI committees were mentioned in the latest Joint Research Center status report of the EU Reference Laboratory for alternatives to animal testing. In a section titled ‘Development of safety assessment workflows’, the report recognized the ecotoxicity database EnviroTox (www.envirotoxdatabase.org) along with the development of a standardized workflow for the derivation of Predicted No Effect Concentration values for aquatic systems. The Next Generation Ecological Risk Assessment Committee recently gave an overview on the database and tools and the webinar recording is available to the public here. The Genetic Toxicology Technical Committee is also recognized in a section titled ‘Classification and Labeling’ for agreeing to re-visit existing data regarding a substance’s molecular interaction with germ cell DNA and providing their opinion on what positive endpoints in somatic tissues and/or level of exposure in gonads would allow classification and labelling as germ cell mutagen without germ cell testing. This will aid the UN Subcommittee on the Globally Harmonized System of Classification and Labelling of Chemicals clarify the classification criteria for germ cell mutagenicity. These are just two examples of HESI’s commitment to collaborate to help resolve the global health and environmental challenge of animal use in research.
Click to read the full JRC Status Report
Click to learn more about the HESI EnviroTox Database
Click to learn more about the HESI Genetic Toxicology Technical Committee (GTTC)
Deadline extended to April 15th
HESI’s Genetic Toxicology Technical Committee Historical Control Distribution (HCD) Working Group is querying laboratories about their experiences with compiling, maintaining and using historical control data and distributions for genetic toxicology assay acceptance and evaluation. The compiled data will be used to determine where consensus approaches exist and, where possible, make recommendations on compiling, maintaining and monitoring historical control data and distributions.
The survey is available on the HESI GTTC website here.
Completed surveys are requested by April 15, 2022.
For questions or more information, please contact Connie Chen.
This short piece published in Nature Reviews Drug Discovery is a call for collective action to advance the safety assessment of Targeted Protein Degraders (TPDs). The publication was born out of the HESI PROTACs and Molecular Glues Safety Workshop held October 14-15, 2021.
Targeted protein degraders (TPDs) are emerging classes of therapeutics that have the potential to address difficult drug targets in new ways. In 2021, experts convened to discuss challenges in TPD safety evaluation, and supported supplementing individual efforts to address these challenges with collective development of novel decision frameworks, tools and a shared evidence base.
• Develop novel decision frameworks that integrate in silico, in vitro and in vivo data to inform the clinical risk profile.
• Advance accepted methods to characterize the unique pharmacokinetics of heterobifunctional protein degrader therapeutics.
• Build a shared evidence base for translational safety species selection
Link to full article: Targeted protein degraders: a call for collective action to advance safety assessment. Jones LH, Mitchell CA, Loberg L, Pavkovic M, Rao M, Roberts R, Stamp K, Volak L, Wittwer MB, Pettit S. Nature Review Drug Discovery. 23 March 2022.
For more information on HESI’s Targeted Protein Degrader Safety Committee visit the committee webpage HERE.
Cardiac safety remains a serious issue during drug development. The mission of HESI’s Cardiac Safety Committee is to improve public health by reducing unanticipated cardiovascular-related adverse effects from drugs or chemicals, and to develop innovative approaches to support early detection and prediction as well as improved understanding of cardiovascular toxicology and pathobiology. This publication in Toxicological Sciences by the committees’ Pro-Arrhythmia Working Group shows that nonclinical models used to predict cardiac safety during drug development do not absolutely replicate the clinical conditions; however, best practices can be used to improve the nonclinical assay quality and achieve the highest predictive power.
The QT interval is the section on the electrocardiogram (ECG) that represents the time it takes for the electrical system to fire an impulse through the ventricles and then recharge. It is translated to the time it takes for the heart muscle to contract and then recover. Evaluating whether a new medication prolongs the QT interval, which is a risk factor for ventricular arrhythmia, is critical for safe drug development and is evaluated using both in vivo and in vitro models during nonclinical drug development. The relevance of the QT interval as a sole indicator of risk is questionable because many studies confirm that QT prolongation alone does not necessarily precede the development of arrhythmias. Since drug safety scientists must act in a cautious manner, the development of a drug is likely to be discontinued if there are nonclinical indicators of QT prolongation, no matter how extensive the validation studies.
A 3-phased project was conducted by the HESI Pro-Arrhythmia Working Group starting with a detailed literature review and followed by a collaborative HESI-FDA database of 150 new drug candidates to evaluate how predictive nonclinical studies are to clinical outcomes. Phase three included a closer examination of several drugs from the database to identify possible reasons for the lack of predictivity from nonclinical to clinical outcomes. Results from the literature review and database show that nonclinical models do not absolutely replicate the clinical conditions they are used to predict; however, best practices can be used to improve the nonclinical assay quality and achieve the highest predictive power. (1) Assays must cover a broad and appropriate range of drug concentrations or doses to include, if not exceed, estimated clinical exposures, (2) standardized study conditions should be met, and (3) additional drug information, such as plasma protein binding properties, should be used to complement data analysis and interpretation. Application of the recommended best practices outlined in the article should enhance the overall quality of data and improve the interpretation and translation of nonclinical to clinical data. Although gaps exist in the translation of nonclinical assays to the clinic, we hope the content of this article allows researchers and clinicians to have increased confidence in those preclinical tests and encourages them to develop novel assay platforms and improve current methodologies. By understanding how predictive the preclinical studies are to the clinical outcomes, we can then take a closer look at why some drugs are not predicted preclinically and how to improve on that.
Click to read the full article:
The Challenges of Predicting Drug-Induced QTc Prolongation in Humans. Jean-Pierre Valentin, Peter Hoffmann, Catherine Ortemann-Renon, John Koerner, Jennifer Pierson, Gary Gintant, James Willard, Christine Garnett, Matthew Skinner, Hugo M Vargas, Todd Wisialowski, Michael K Pugsley. Toxicological Sciences. 11 February 2022
Click to learn more about the HESI Cardiac Safety Committee
Click to learn more about the Health and Environmental Sciences Institute (HESI)
Webinar Recording Available!
The EnviroTox database contains 80,912 aquatic toxicity effects records representing 1,641 species and 4,267 unique chemical identifiers and was specifically developed to provide a curated dataset to explore the concept of the ecological threshold of toxicological concern (ecoTTC). These data are associated with physical chemistry data and curated taxonomic information, including a process that assigns acute and chronic effects, and that identifies PNECs based on the available data. Several mode of action schemes are also included to facilitate development of a best approach for grouping compounds. This database has been made freely available via a web-based query system that integrates the various tools. This interface allows users to explore and upload data, derive threshold values based on specific criteria, and explore the use and application of ecoTTCs.
This presentation provides an overview of the EnviroTox database and tools, with a demonstration on how this valuable resource can be used. Please visit www.envirotoxdatabase.org to give it a try!
2022 Society Of Toxicology Meeting
Connie Mitchell (HESI) and Dr. Vanessa Cheng (formerly University of California Riverside) presented a poster in person on behalf of the eSTAR Carcinogenomics Working Group at the Society Of Toxicology Meeting on 30 March 2022.
ITC, DART, GTTC & CT-TRACS
Save the Date! The following are internal meetings:
April 26-27, 2022 – HESI ITC Spring Business Meeting
May 4-5, 2022 – HESI DART Spring Business Meeting (Virtual)
May 16-17, 2022 – GTTC Annual Meeting (Hybrid)
May 19-20, 2022 – HESI CT-TRACS Spring Business Meeting
21 April 2022 @9:00am ET
Please join us for an upcoming webinar, organized by the HESI Next Generation Ecological Risk Assessment Committee.
Speaker: Dr. Dave Kuo, Kuo Research & Consulting
Talk Title: Bioaccumulation and Biotransformation in Birds: Data Gaps, Challenges, Opportunities, and Future Strategies
Abstract: Birds constitute a diverse and large group of species with many critical ecological roles. A substantial literature review of bioaccumulation and biotransformation of organic chemicals in birds was undertaken to support scoping and prioritization of future research. The objectives were to characterize available bioaccumulation, toxicokinetic, and biotransformation data, identify knowledge gaps, determine how existing data can be used, and explore the strategy and steps forward. This talk will discuss major data gaps and challenges identified through the review, and outline the research needs and directions that best support further characterization and understanding of the biological fate of organic chemicals in birds. The webinar will close with a series of forward-looking strategies for this big challenge.
2 May 2022
This committee workshop will aid in the selection of compounds for prospective studies, review of the Ames assay protocol, as well as inform what additional in vitro or in vivo follow-up strategies are needed.
12 May 2022@10am ET
The HESI Cardiac Safety Committee is please to announce the last webinar in their Early Career Seminar Award Series. This competitive award is given to postdoctoral or early career scientists who have compelling research related to cardiovascular safety and risk assessment, and the webinar series offers an opportunity for awardees to share their research, learn from, and network with experts at HESI. The webinar will feature the work of Dr. Shagun Krishna, NTP-NIEHS, and is scheduled for 12 May 2022 at 10:00 am ET.
Registration is free, contact for details: HESI Cardiac Safety firstname.lastname@example.org
25 May 2022
May 25, 2022
The Cell Therapy – TRAcking, Circulation & Safety (CT-TRACS) Committee will present on their pilot project “New approaches for identification of potential off-target mutations associated with CRISPR genome editing in cell therapies” at the Advanced Therapies 2022 Congress, London, UK.
May 30th-June 3rd, 2022
HESI is among 30+ international organizations and companies supporting a series of annual Microphysiological systems (MPS) World Summits to present the latest scientific achievements, discuss the advances and challenges, and enable communication between young and newly interested scientists and pioneers of the MPS field.
HESI’s mission aligns with the proposed goal of the MPS World Summit of planning a series of global conferences on microphysiological systems towards bringing all stakeholders together from across sectors and career stages to promote the development and application of this technology, to facilitate its expanded scientific and regulatory use.
Please see the 2022 Summit event page for more details (https://mpsworldsummit.com/session/hybrid-conference/).
The Summit will be a hybrid event, held May 30th-June 3rd, 2022. For questions about the initiative, feel free to reach out to HESI’s contact point: Lucilia Mouriès (email@example.com).
8-9 June 2022, Hybrid Event
SaveTheDate! Don’t miss the 2022 HESI Annual meeting on June 8-9, 2022. Online and In Person meeting options available!
Meeting Sessions include:
Hard to believe, but the day has finally come that HESI staff are all back together in the office!!! What a great thing to hear voices, laughter, and discussion up and down the hallway after so long. I am proud of how well our team has stayed in touch with each other – and with all of you – during this difficult period. We’ve done well despite it all, but there is no substitute for being in person. On that note, I am thrilled that we will have an in person (hybrid) Annual Meeting and Board meeting this year if all stays well. I do hope to see many of you there! Be well and give back.
Syril D. Pettit, DrPH, MEM
HESI Executive Director