Mind the Gaps: Prioritizing Activities to Meet Regulatory Needs for Acute Systemic Lethality

October 30-31, 2019
Porter Neuroscience Research Center
National Institutes of Health
Bethesda, Maryland, USA

Workshop Presentations

Kristie Sullivan, M.P.H., PCRM

Acute Systemic Toxicity Testing: Past, Present, and Future
Amy Clippinger, Ph.D., PETA International Science Consortium Ltd.

Regulatory Needs: Can Existing Data Be Used to Derive Acute Lethality Estimates Without Animal Tests?
Warren Casey, Ph.D., NICEATM

Case Study Presentation and Discussion: Calculating the Toxicity of Plant Protection Products
Raja Settivari, Ph.D., Corteva Agriscience

Group Discussion: Evaluating Mixtures for Acute Lethality
Raja Settivari, Ph.D., Corteva Agriscience

Demonstration: Structure-based Approaches to Predicting Acute Toxicity: The Collaborative Acute Toxicity Modeling System (CATMoS)
Kamel Mansouri, Ph.D., Integrated Laboratory Systems, Inc. (ILS - contractor supporting NICEATM)

Case Study Presentation and Discussion: Integration of In Vitro and In Silico Tools for Acute Toxicity Prediction
Kyle Glover, Ph.D., U.S. Army

Group Discussion: Leveraging AI to Identify Acutely Toxic Substances
Kamel Mansouri, Ph.D., ILS

Group Discussion: Information Gaps and How to Adddress Them in a Systematic Fashion
Dan Wilson, Ph.D., Dow Chemical

Group Discussion: Where Can We Predict Acute Lethality with Mechanistic In Vitro Models?
Dan Wilson, Ph.D., Dow Chemical

Group Discussion: How Should ADME Be Considered
Sanjeeva Wijeyesakere, Ph.D., FMC

Group Discussion: What Does the AOP Framework Contribute?
Steve Edwards, Ph.D., RTI International

Group Discussion: How Would You Supplement Existing Model Predictions/Methods with Information Specific to Particular Classes of Chemicals?
Warren Casey, Ph.D., NICEATM

Group Discussion: Regulatory Applicability: How Do We Prioritize our Next Activities?
Kristie Sullivan, M.P.H., PCRM

Group Discussion: Operationalizing Findings and Recommendations
David Allen, Ph.D., ILS

Acute systemic toxicity tests are the most commonly performed type of safety test worldwide. Participants in this workshop considered approaches available to assess acute lethality associated with chemicals and chemical mixtures, with the purpose of designing comprehensive strategies to predict toxicity while avoiding animal tests. The specific areas for discussion included:

  • Defining how to calculate the LD50 of a chemical mixture/formulated product
  • Identifying gaps where model (or assay) development or optimization is needed
  • Understanding regulatory needs for model (or assay) outputs
  • Pinpointing the types of mechanistic information that would be useful
  • Establishing the feasibility of using artificial intelligence in model development

Group discussions focused on issues specific to particular classes of chemicals, mechanisms of acute toxicity, prioritization of activities, and recommending next steps. Follow-up actions include an analysis of variability in the in vivo test to establish confidence in toxicity predictions, a comprehensive assessment of an additivity equation for predicting mixtures toxicity, and exploring the addition of biological and mechanistic information to complement in silico predictions.

The workshop was organized by NICEATM and the Physicians Committee for Responsible Medicine (PCRM).