Citation:

Green, M., A. Kluever, C. Chen, S. Dobreniecki, W. Halpern, B. Hannas, A. Hoberman, M. McNerney, S. Mitchell-Ryan, T. Shafer, S. Van Cruchten, AND T. White. HESI workshop summary: Interpretation of developmental and reproductive toxicity endpoints and the impact on data interpretation of adverse events. Birth Defects Research. John Wiley & Sons, Inc., Hoboken, NJ, 116(2):e2311, (2024). https://doi.org/10.1002/bdr2.2311

Impact/Purpose:

Developmental and reproductive toxicology (DART) is a highly specialized subfield of toxicology. Experts with fluency in interpretation of DART data rely on years of graduate, postgraduate, and applied professional experience to elucidate and discern adverse effects of substance exposure in developing organisms, including embryos, fetuses, infants, and children. Hence, it is essential to perform a careful analysis (e.g., rigorous WoE methodology, data quality evaluation, relevant weighting of endpoint data) to identify adverse DART endpoints because this may impact regulatory decision-making. The workshop featured presentations and discussions with DART experts. Attendees also engaged in breakout group discussions, guided by DART experts, to assess endpoint adversity in case studies. The case studies involved reviewing complex datasets, including NAMs data for developmental neurotoxicity, and provided hands-on experience with immediate feedback from subject matter experts. The workshop concluded with a brainstorming session to discuss lessons learned, including areas of consensus, divergence, and recommendations.

Description:

The Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (HESI-DART) group held a hybrid in-person and virtual workshop in Washington, DC, in 2022. The workshop was entitled, "Interpretation of DART in Regulatory Contexts and Frameworks." There were 154 participants (37 in person and 117 virtual) across 9 countries. The purpose of the workshop was to capture key consensus approaches used to assess DART risks associated with chemical product exposure when a nonclinical finding is identified. The decision-making process for determining whether a DART endpoint is considered adverse is critical because the outcome may have downstream implications (e.g., increased animal usage, modifications to reproductive classification and pregnancy labeling, impact on enrollment in clinical trials and value chains). The workshop included a series of webinar modules to train and engage in discussions with federal and international regulators, clinicians, academic investigators, nongovernmental organizations, contract research organization scientists, and private sector scientists on the best practices and principles of interpreting DART and new approach methodologies in the context of regulatory requirements and processes. Despite the differences in regulatory frameworks between the chemical and pharmaceutical sectors, the same foundational principles for data interpretation should be applied. The discussions led to the categorization of principles, which offer guidance for the systematic interpretation of data. Step 1 entails identifying any hazard by closely analyzing the data at the study endpoint level, while Step 2 involves assessing risk using weight of evidence. These guiding principles were derived from the collective outcomes of the workshop deliberations.

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