Welcome to December Insights. Inside this edition: 2018 Highlights!
December Insights
2018 Highlights
Cardiac Safety

Throughout 2018, the Cardiac Safety Committee advanced its work on mechanistic approaches for cardiovascular safety assessment. This work will advise continued work in 2019 exploring the use of hiPSC-CMs in nonclinical studies to guide early drug discovery efforts in human-relevant models. The Committee convened a successful workshop on mechanism-based assays, where participants heard presentations on the current state of cardiovascular safety liabilities and new technologies to potentially assess these. HESI also cosponsored a CiPA Update Meeting in May 2018 with the Cardiac Safety Research Consortium (CSRC) and the FDA, which marked a turning point in the CiPA process. The ICH S7B/E14 Group developed a Q&A concept paper based on these results and will form an Implementation Working Group to continue discussions around the CiPA guidance.
Translational Biomarkers of Neurotoxicity

The Translational Biomarkers of Neurotoxicity (NeuTox) Committee completed their in vivo pilot study of biomarkers associated with neurotoxicity in rats to increase early identification of neurotoxicity, enabling early intervention and improving outcomes. The results were shared at the Society of Toxicology 2018 Annual Meeting and the Experimental Biology 2018 Meeting, and a publication featuring some of the study results was selected as a highlight article for Experimental Biology and Medicine ! In addition to the in vivo work, a subteam explored in vitro detection of seizures using microelectrode array technology, completing a pilot study with data contributions from more than 12 sites and plans to finalize the analysis and publish results in 2019.
Risk Assessment in the 21 st Century (RISK21)

In 2018, the RISK21 Committee continued outreach and communication to harmonize the method to how the world evaluates chemicals using a risk-based approach. After identifying the need for additional guidance on problem formulation, a subteam was formed to further underscore the principles of RISK21 and the concept of “fit for purpose.” A conceptual-model building tool that will help to further this work is underway and expected to be fully functional in early 2019. The Committee also accelerated uptake and application of the RISK21 framework via active outreach in the form of hands-on case study workshops and training courses, as well as presentations and discussions with multi-stakeholder audiences. Several case studies were prioritized at the February 2018 Scientific Advisory Board/Ad Hoc Advisory (SAB/AHA) team meeting, and work is ongoing to further develop these examples and others.
Animal Alternatives in Environmental Risk Assessment

This year, HESI's Animal Alternatives in Environmental Risk Assessment Committee proudly released the EnviroTox Database and Tools Platform ( www.envirotoxdatabase.org ) at a special reception at the SETAC North America meeting in November 2018. After continued hard work, the database features a curated compilation of ~91,000 aquatic toxicity records, available on a user-friendly filtering interface. While additional publications on this work and its applications are in preparation and case studies are under development, the committee also published a FOCUS article in Environmental Toxicology & Chemistry on alternative approaches for effluent assessment. The publication discusses a suite of strategies that can be used in a weight of evidence approach to reduce reliance on in vivo fish tests as part of a effluent evaluation "toolbox".
Development of Methods for a Tiered Approach to Assess Bioaccumulation of Chemicals

The Committee completed a series of work that led to the acceptance of two new OECD test guidelines (TG319A and TG319B). The guidelines focus on in vitro methods for fish hepatic clearance, and the results of a HESI-led ring trial were published in Toxicological Sciences . The committee also published “Practical Advice for Selecting or Determining Trophic Magnification Factors for Application Under the European Union Water Framework Directive” in Integrated Environmental Assessment and Management . The Committee formed two new subteams, the first on bird biotransformation and second on invertebrate biotransformation. These subteams are scoping the topics, including initial exploration of what is known regarding biotransformation and toxicokinetics in birds and characterizing the role of biotransformation in invertebrate species. A technical workshop is being planned for 2019 to identify key needs regarding research and coordination for fish in vitro metabolism assays, develop partnerships, and devise a strategic science plan with key stakeholders to systematically address uncertainty. A follow-up applications meeting is also being planned.
Developmental and Reproductive Toxicology (DART)

The Developmental and Reproductive Toxicology (DART) Technical Committee continued its record of productivity, publishing the proceedings from its recent workshops (“Rethinking Developmental Toxicity Testing: Evolution or Revolution?” in Birth Defects Research and “Best Practices for Developmental Toxicity Assessment for Classification and Labeling” in Reproductive Toxicology ) and organizing a symposium at this year’s Teratology Society Annual Meeting that provided a sneak preview of its Neonatal Pediatrics project. As some projects sunset, three new project scoping areas were launched: use of microCT for regulatory decision making, juvenile/neurobehavioral endpoints, and puberty. The DART Committee also continued collaborations within HESI (e.g., with the Immunotoxicology Technical Committee on an Immunotherapy and Pregnancy project) and with external organizations (e.g., NC3Rs on a possible CRACK-IT challenge). 2019 will be equally as productive, with a workshop on thyroid hormone assessment already planned for early May.
Emerging Systems Toxicology for the Assessment of Risk

In 2018, the Application of Genomics to Mechanism-Based Risk Assessment Committee started a new chapter as the Emerging Systems Toxicology for the Assessment of Risk Committee (eSTAR). The new name reflects the program’s growing breadth, including network-based analyses, biomarker development, and the measurement of functional changes across levels of biological organization. This year, the committee’s TGx-DDI biomarker entered into the final stages of the FDA’s new Biomarker Qualification Program mandated under the 21st Century Cures Act. Additionally, the committee launched three new projects, including experimental work to improve yield and quality of formalin-fixed paraffin-embedded DNA, an expert review of challenges and opportunities for utilizing miRNA biomarkers, and a project to develop genetic signatures to inform a carcinogenicity risk assessment.

This year, the Immunotoxicology Technical Committee addressed the safety assessment of CD3 Bispecifics by convening a highly successful workshop cosponsored by the FDA Center for Drug Evaluation and Research. The workshop explored target selection and liability, establishing a FIH dose, clinical experience, and translational aspects. Over the course of two days, the workshop convened 120 people in person and over 500 virtual participants globally while over 30 speakers presented their case examples. This different paradigm in the workshop design marked a change from previous events, which will be mirrored in future workshops that address safety assessments of other modalities of immune-oncology.
Genetic Toxicology (GTTC)

In 2018, the Genetic Toxicology Technical Committee (GTTC) focused on investigating a new generation of testing strategies for assessment of genomic damage, new approaches and technologies for mode-of-action determination and interpretation, and recent developments in quantitative interpretation of genetic toxicity dose-response data. To share their findings and further this examination, the Committee held a workshop in conjunction with the European Environmental Mutagenesis and Genomics Society in Potsdam, Germany. The Committee also published four peer-reviewed journal articles throughout 2018 and began developing another five manuscripts.
Cell Therapy – TRAcking, Circulation, & Safety (CT-TRACS)

CT-TRACS reached an important milestone this year: the committee was elevated from an Emerging Issues Subcommittee to a HESI Technical Committee by a unanimous decision of the Board of Trustees in January 2018, joining 11 other long-term HESI Technical Committees. The committee has identified new projects of interest and value to be executed during the 2018−2020 timeframe, continuing the focus on methodologies to access cell fate in vivo and the need for predictive in vitro test methods for assessing the tumorigenicity risk of cell therapy products.

Additionally, three HESI-organized or co-organized international outreach events were held in 2018: the “ Safety Assessment of Cell Therapy Products: Current Advances and Challenges ” workshop (14 February 2018; Inaugural CGT Catapult Seminar Series, London, UK); a dedicated Lunch Seminar at the ISCT 2018 “Global Regulatory Perspectives” Premeeting Workshop (2 May 2018; Montreal, Canada), and a workshop in collaboration with the California Institute for Regenerative Medicine (CIRM) and the International Alliance for Biological Standardization (IABS) (7 June 2018; Los Angeles) as part of the 4th Cell Therapy Conference on Manufacturing and Testing of Pluripotent Stem Cells and cited in the proceedings article of the meeting (published in Biologicals ).
COMPARE Allergen Database

In February 2018, HESI released the second version of the COMprehensive Protein Allergen REsource (COMPARE) database, COMPARE 2018 . The COMPARE process implements a cutting-edge and high-throughput bioinformatic pipeline to identify a meaningful subset of “candidate allergens” among the millions of sequences being deposited each year in public sequence repositories such as NCBI and UniProt. Identified candidate allergens are then subjected to scientific review and curation by an independent panel of experts from the public sector. COMPARE 2018 includes 2,038 curated protein allergen sequences and is freely accessible at www.comparedatabase.org . Throughout the year, the steering team worked on the next annual update process, as well as several improvements to the database itself. We are excited to share that COMPARE will soon have a “new face,” allowing more user-friendly browsing through the database and retrieval of information. Additionally, a new bioinformatics “FASTA tool” is being developed to allow sequence comparisons, as a built-in feature in the database. These new features are expected to be released in early 2019.
Protein Allergens, Toxins, and Bioinformatics (PATB)

The committee (formerly Protein Allergenicity Technical Committee, PATC) has adopted a new designation, the Protein Allergens, Toxins, and Bioinformatics (PATB) Committee, reflecting a broader scope, expertise, interests, and diversity of collaborators in the fields of bioinformatics and protein toxins, while strengthening its core focus in allergenicity. At the same time, the PATB Committee was delighted to welcome a new member in 2018, adding a clinical allergy and immunology specialty to its list of participants. A major highlight of the year was the organization of the public workshop on “ Bioinformatics Approaches to Assess Safety of Novel Proteins in Relation to Food Hypersensitivity " held 17–18 October 2018, in Copenhagen, Denmark, preceding the 2018 EAACI Food Allergy and Anaphylaxis Meeting . Committee members and guest experts provided a rich program, presenting an overview of various new bioinformatics resources and tools (including the COMPARE Allergen Database) being developed to provide relevant science-based bioinformatics data to inform the safety assessment of novel proteins. Additionally, the committee published peer-reviewed articles concluding two committee research projects: a study on in vitro digestibility methods for food proteins ( Clinical and Translational Allergy ) and a project investigating the effect of genetics (seed variety) and/or environment (geographical location) on soybean allergen content ( Frontiers in Plant Science ).

As an effort to continue its work to examine gut microbial-host dynamics and understand how the gut microbiome affects human health, drug efficacy, and xenobiotic toxicity, the Subcommittee on the Microbiome convened a workshop in June 2018 to discuss research needs in various topic areas. Workshop participants heard from speakers and examined key research needs in biotransformation, biomarker toxicity and disease, biomarkers of adverse effects, human susceptibility, and animal models. As a follow-up to the discussions that took place during the workshop, proceedings are in progress, which will outline and provide prioritized research for the committee, and a publication is anticipated in early 2019.
Environmental Epidemiology for Application in Risk Assessment

In its inaugural year, the Environmental Epidemiology for Application in Risk Assessment steering team launched an effort to maximize the utility of environmental epidemiology in regulatory decision making and risk assessment through a series of focus groups. The preliminary focus groups aimed at increasing the dialogue between epidemiologists and risk assessors/decision makers, and focus groups at EPA headquarters in DC and NIEHS in North Carolina developed and implemented meeting content of focused discussion questions and case studies. For 2019, additional meetings are planned for San Francisco, California; Houston, Texas; and Atlanta, Georgia.
PBPK Models

In May 2018, the EPA and HESI signed a Memorandum of Understanding (MOU) that outlines HESI and EPA’s joint commitments to contributing to a multisector and multidisciplinary HESI working group on PBPK modeling. The MOU details a number of topical areas and approaches that the HESI working group is anticipated to undertake to improve our collective understanding of PBPK models, model documentation, and their consistent application for risk assessment purposes. The Committee continues its work on the PBPK template and framework development. It is anticipated that the template manuscript will be submitted for publication in 1Q2019 and a meeting on the framework project will be held in March 2019.

In February 2018, HESI launched the UVCB Committee to address the challenges associated with the risk assessment of substances of Unknown or Variable Composition, Complex Reaction Products and Biological Materials (UVCB), and more specifically, to develop a cross-sectorial approach for UVCB identification, characterization, and ecological risk assessment. Committee goals, objectives, and initial progress were presented at the SETAC Europe Meeting in Rome in May 2018 and at the SETAC North America Meeting in Sacramento in November 2018. The Committee’s first workshop, held 10–11 December 2018 in Washington, DC, aimed at exploring approaches for UVCB identification and characterization. Twenty-five people attended the meeting and worked toward the ultimate goal of developing a fit-for-purpose risk assessment framework for UVCBs.

This year, HESI's THRIVE program was honored to be recognized as a featured contributor in the inaugural Biden Cancer Summit in Washington, DC. THRIVE was selected from a pool of national applicants as a leader in developing new innovative programs and partnerships that will double the rate of progress against cancer and improve cancer patient experience. THRIVE's innovative programs focus on unintended treatment-related effects that can adversely impact health and quality of life during and following cancer treatment. THRIVE's seed grants catalyze translational research on when and how adverse effects occur and how to avoid or lessen them. In THRIVE's first year, grantees progressed areas such as neuropathic pain associated with breast cancer therapy, adverse effects from immunotherapy, and cardiac dysfunction associated with chemotherapies used to treat childhood cancers.
Happy Holidays From HESI!

Happy Holidays and Happy New Year! Thank you to everyone who helped make 2018 successful for HESI. We wish you all a happy holiday season and a healthy and joyful New Year.
From the Executive Director
How many almost 30-year-olds can say they have achieved all that HESI has in its past 29 years… and in this year alone? As Director, I am very proud of the impactful science HESI’s programs continue to produce. As evidenced here, our science is implemented around the world to improve decisions, enhance human health and safety, and preserve the environment. We could not achieve this scientific quality and scope without the support and intellect of hundreds of international collaborators. Thank you to all who have lent their time and expertise to HESI to help us achieve our mission of a safer, more sustainable world. I wish you all good health in the New Year. 
Syril D. Pettit
HESI Executive Director
Health and Environmental Sciences Institute (HESI)
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