S08-01 Advancing Cardiotoxicity Risk Assessment: Integrative Modeling with New Approach Methodologies

Abstract

The cardiovascular system is vulnerable to pharmaceuticals and environmental chemicals, but risk assessment remains challenging due to data gaps and reliance on animal testing. New Approach Methodologies (NAMs) – comprising in vitro, in chemico, and in silico techniques – provide efficient, human-relevant strategies to enhance hazard and risk assessment.

We developed an integrative modeling workflow using physiologically based pharmacokinetic (PBPK) models to translate bioactive concentrations from over 300 high-throughput screening (HTS) assays targeting cardiovascular-relevant endpoints into human daily equivalent administered doses (EADs) for more than 800 substances. These chemicals span categories such as personal care products, flame retardants, herbicides, pesticides, pharmaceuticals, and industrial byproducts.

Human-relevant risk predictions were generated by comparing in vitro-derived EADs with human exposure estimates and in vivo points of departure (PODs) from toxicological studies. Additionally, geospatial analysis was applied to evaluate combined risks for various populations across different U.S. regions.

Our approach integrates HTS data, animal study-derived PODs, human exposure estimates, geospatial exposure data, and PBPK modeling to identify chemicals with potential cardiovascular toxicity at relevant exposure levels. Key targets of concern included endothelial cell signaling, nuclear hormone receptors, and other critical cardiovascular pathways.

This workflow advances human health risk assessment from molecular mechanisms to population-level insights. It identifies communities disproportionately affected by chemical exposures, enhancing predictive capabilities for regulatory decision-making and prioritizing chemicals for further testing.