Integrating Concentration-Dependent Toxicity Data and Toxicokinetics To Inform Hepatotoxicity Response Pathways

Daniel P. Russo, Lauren M. Aleksunes, Katy Goyak, Hua Qian, Hao Zhu

Research output: Contribution to journalArticlepeer-review

Abstract

Failure of animal models to predict hepatotoxicity in humans has created a push to develop biological pathway-based alternatives, such as those that use in vitro assays. Public screening programs (e.g., ToxCast/Tox21 programs) have tested thousands of chemicals using in vitro high-throughput screening (HTS) assays. Developing pathway-based models for simple biological pathways, such as endocrine disruption, has proven successful, but development remains a challenge for complex toxicities like hepatotoxicity, due to the many biological events involved. To this goal, we aimed to develop a computational strategy for developing pathway-based models for complex toxicities. Using a database of 2171 chemicals with human hepatotoxicity classifications, we identified 157 out of 1600+ ToxCast/Tox21 HTS assays to be associated with human hepatotoxicity. Then, a computational framework was used to group these assays by biological target or mechanisms into 52 key event (KE) models of hepatotoxicity. KE model output is a KE score summarizing chemical potency against a hepatotoxicity-relevant biological target or mechanism. Grouping hepatotoxic chemicals based on the chemical structure revealed chemical classes with high KE scores plausibly informing their hepatotoxicity mechanisms. Using KE scores and supervised learning to predict in vivo hepatotoxicity, including toxicokinetic information, improved the predictive performance. This new approach can be a universal computational toxicology strategy for various chemical toxicity evaluations.

Original languageEnglish (US)
Pages (from-to)12291-12301
Number of pages11
JournalEnvironmental Science and Technology
Volume57
Issue number33
DOIs
StatePublished - Aug 22 2023

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Environmental Chemistry

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