HESI Insights - November 2021

HESI hosted a think-tank style virtual workshop on PROTACs and Molecular Glues Safety on 14-15 October 2021 with experts from industry, academia, and government to discuss challenges associated with safety assessment for these protein degraders. Over the two days, 150+ attendees heard case studies and discussed potential differences between assessment of these molecules and traditional pharmaceuticals to support critical patient populations safely and efficiently. Anticipated follow up includes a perspective piece in a scientific journal on the challenges discussed and a potential new HESI scientific committee.

If interested in being a part of this committee, please email Connie Mitchell (cmitchell@hesiglobal.org).

The HESI EnviroTox Database version 2.0.0 is now available. This update to the database includes the additions outlined below.

New data entries were obtained from the USEPA’s ECOTOX database (from January 2017 – December 2020) and includes the addition of:

• 251 unique chemicals (CAS)
• 5,029 new effects records

Additional curation was performed on EnviroTox Database version 1.3.0 to remove duplicate records. Version 2.0.0 contains:

• 80,912 effects records
• 4,267 unique chemicals (CAS)
• 1,641 unique species

Please contact Dr. Michelle Embry (membry@hesiglobal.org) if you have any questions or encounter any problems using the website or database tools.

Two papers that resulted from the Fall 2020 NICETAM, USEPA, and HESI workshop on “Opportunities and Challenges in Using the Kinetically Derived Maximum Dose Concept to Refine Risk Assessment” are now available in Regulatory Toxicology and Pharmacology.

• Opportunities and challenges related to saturation of toxicokinetic processes: implications for risk assessment (Tan et al., 2021)
• Incorporating human exposure information in a weight of evidence approach to inform design of repeated dose animal studies (Lowe et al., 2021)

These two papers call for a weight of evidence approach that uses available data from shorter-term in vivo and in vitro studies and human exposure to inform study design for repeat dose animal studies. Consideration of instances where systemic exposures depart from proportionality to external doses and the importance of integration of TK information in study design and interpretation are highlighted with representative case studies presented in both papers.

A webinar on this committee work will be presented on 8 December 2021 by Dr. Michelle Embry for the Society of Toxicology (SOT)’s Biological Modeling Specialty Section. Information on how to register will be posted here once available.

A virtual outreach session on the RISK21 Framework was held in October 2021 over four separate days for regulators and scientists involved in chemicals and pesticide risk assessment in Colombia. The course was organized by the Colombia Environmental Health Department of the Ministry of Health and Social Protection and was attended by nearly 40 participants from the organizations in the above.

The course was opened by Dr. Jairo Hernandez (Deputy Director of Environmental Health at the Colombia Ministry of Health and Social Protection) and was conducted in Spanish by Dr. Eliana Munarriz (University of Buenos Aires and HESI Board of Trustees) with support from Ms. Lady Jhoana Dominguez Majin (Universidad Nacional de Colombia and Colombia Ministry of Health and Social Protection) and Drs. Ariana Rossen (National Water Institute, Argentina), Michelle Embry (HESI), and Sandrine Deglin (HESI). Presentations on the principles of the RISK21 approach were interspersed with hands-on group case studies related to key concepts, with a Colombia-specific example discussed in-depth on the last day.

A follow-up session on cumulative risk is being planned for mid-November. Recordings of the course are available at the following YouTube links:

• Day 1:  https://youtu.be/0-rRmkp05OI
• Day 2 (partial recording): https://youtu.be/-wQp1QLudVE
• Day 3: https://youtu.be/PTWEAckUxpQ
• Day 4:  https://youtu.be/-qeFojvbRfM

Please contact Dr. Michelle Embry (membry@hesiglobal.org) if you have any questions about the HESI RISK21 Committee or this course.

The HESI Emerging Systems Toxicology for the Assessment of Risk (eSTAR) Committee held its annual meeting virtually on 28-29 October 2021. Attended by 75+ committee members over two days, the committee reviewed the existing portfolio of projects, including transcriptomic- and miRNA-based biomarkers across four active working groups. Two additional proposals on error-corrected sequencing and cell painting were considered and will be discussed further as potential projects for the committee.

To get involved or to find out more about the ongoing or potential new projects, please contact Connie Mitchell (cmitchell@hesiglobal.org).

The HESI Cardiac Safety Committee is excited to announce that applications are now being accepted for the committee’s new Early Career Seminar Award Series. This award offers an opportunity for postdocs and early career scientists to share their research, learn from, and network with experts in the toxicology and safety pharmacology fields from academia, regulatory agencies, and pharmaceutical companies. Selected candidates will receive a $500 USD award and will be invited to present their research on a public webinar with Cardiac Safety Committee members and other invited guests. Webinar dates will be scheduled with the awardees in Q1 2022.

The deadline to apply is 1 December 2021. Click here to learn more and click here to download the application form.

Leveraging key insights from the 2019 co-sponsored FDA workshop on the “Safety Assessment of Engineered T Cell Therapies,” the Immuno-Safety Technical Committee (ITC) has recently published a manuscript that provides an overview of the current important nonclinical safety assessment considerations for the development of these therapeutic modalities (cytokine release syndrome, neurotoxicity, on-target/off-tumor toxicities, off-target effects, gene editing or vector integration-associated genomic injury.) The manuscript also discusses approaches used for hazard identification of risk assessment and provides a regulatory perspective on such aspects.

The paper is now available online here.

The HESI Developmental and Reproductive Toxicology (DART) Committee’s QSAR Modeling of Rodent Placental Transfer project is looking to collect data on maternal-fetal exposure along with physiochemical descriptors on a variety of small molecules to improve a predictive model for fetal drug exposure in the rat. Integrating exposure data with other alternative assays that predict teratogenicity may broaden our understanding of the effects observed in embryo-fetal development (EFD) studies and strengthen our interpretations by bridging in vitro and in vivo outcomes. If you have maternal-fetal exposure data that you can contribute or you are interested in participating in the study, please fill out this brief survey to confirm your interest and to learn more about the project. An MTA has been drafted to ensure the protection of the identity of compounds contributed to this exercise.

For more information, please contact Dr. Shermaine Mitchell-Ryan (smitchell-ryan@hesiglobal.org).

Congratulations to Dr. Syril Pettit, HESI Executive Director, on beginning her two-year term as an appointed member of the American Public Health Association (APHA) Science Board in November 2021! The Science Board is chosen by the APHA Executive Board to include members with a broad knowledge of public health and to secure a balanced representation of the various disciplines involved in public health. The Science Board supports the mission of APHA by ensuring that policy or strategic recommendations developed by APHA are evidence-based.

HESI staff were involved in planning two sessions at the upcoming virtual SETAC North America 42^nd Annual Meeting taking place on 14-18 November 2021, outlined below.

• Bioinformatics to Inform Cross Species Extrapolations in Regulatory Toxicology: What Tools are Available? (co-chaired by Carlie LaLone, USEPA, Geoff Hodges, Unilever, Nil Basu, McGill University, and Michelle Embry, HESI)
• New Approach Methodologies (NAMs) to Evaluate Endocrine Pathways: Test Development Through Regulation (co-chaired by Scott Lynn, USEPA, Jeff Wolf, EPL, and Michelle Embry, HESI)

This year, the HESI Environmental Epidemiology Committee has been hosting a series of webinars illustrating the critical role that epidemiology can play in the field of quantitative risk assessment.

In our next webinar, which will be held on 17 November 2021 from 1:00PM – 2:00PM EST, Dr. George Maldonado (University of Minnesota School of Public Health) will share his thoughts on how to approach the critical question of causality in environmental epidemiology. His presentation, titled “Causal Reasoning in Epidemiology: Philosophy and Logic,” will be followed by a Q&A session. You can read the presentation abstract and learn more about our speaker here. To register for this webinar, please click here.

You can also watch the recordings of previous webinars online:

• The Contributions of Environmental Epidemiologic Research to Causal Attribution and Risk Assessment by Prof. Harvey Checkoway (University of California, San Diego). The presentation recording is available here.
• API/CLI/HESI joint webinar on ongoing efforts to increase the impact of epidemiology in the field of risk assessment and decision making by Drs. Omobola Mudasiru (American Petroleum Institute), Dana Sargent (Bayer CropScience), and Sandrine Deglin (HESI). The presentation recording is available here.
• A Case for Good Epidemiology Practice Guidelines for Regulatory Risk Assessment byDr. Julie Goodman (Gradient). The presentation is available here.
• Understanding the Replication Crisis and its Implications in Environmental Epidemiology by Dr. Scott Bartell (University of California, Irvine). The presentation recording is available here.

To learn more about the Environmental Epidemiology Committee or the webinar series, or to suggest speakers, please contact Dr. Sandrine Deglin (sdeglin@hesiglobal.org).

The University of Paris-Saclay, University of Paris, and HESI are proud to announce a jointly-hosted online workshop on “Environmental, Genetic, and Social Determinants of Individual Susceptibility to Disease” on 13 December 2021. This exciting webinar will feature leading researchers who bring their cross-disciplinary approaches and perspectives to the many challenges at the intersection of biological, environmental, and societal influences on health outcome. The interactive format will allow for discussion across the speakers and for participants to submit questions. We hope you will join us.

Registration is free – register here. 

Martin van den Berg, PhD, ERT
HESI Chair