ICCVAM Biennial Report 2020-2021

Mounting evidence supports the contribution of environmental chemicals to cardiovascular disease burden. NIEHS scientists evaluated chemicals in the Tox21 chemical library for cardiotoxicity potential by focusing on HTS assays whose targets are associated with adverse events related to cardiovascular failure modes (Krishna et al. 2021). The objective of the evaluation was to develop new hypotheses around environmental chemicals of potential interest for adverse cardiovascular outcomes using Tox21 and ToxCast HTS data. Bioactivity signatures relevant to cardiotoxicity were identified for 40 targets measured in 314 assays and used to prioritize 1,138 Tox21 chemicals. The approach identified drugs with known cardiotoxic effects in a variety of use classes including estrogenic modulators, anti-arrhythmic drugs, and antipsychotic drugs like chlorpromazine. Several classes of environmental chemicals such as organotins, bisphenol-like chemicals, pesticides, and quaternary ammonium compounds demonstrated strong bioactivity against cardiovascular targets. Screening outcomes were added to existing data from literature studies using cultured heart cells, animals, or human epidemiological approaches to prioritize these chemicals for further testing.

A number of chemicals identified in the initial Tox21 screen were found to inhibit potassium channels important to cardiac rhythm regulation (Krishna et al. 2022). A set of molecular descriptors was applied to characterize these chemicals. Machine learning approaches were then applied to build robust statistical models that can predict the probability of any new chemical to cause cardiotoxicity via this mechanism.