Hepatotoxicity of silver nanoparticles: Benchmark concentration modeling of an in vitro transcriptomics study in human iPSC-derived hepatocytes

Regul Toxicol Pharmacol. 2024 Aug:151:105653. doi: 10.1016/j.yrtph.2024.105653. Epub 2024 May 31.

Abstract

Despite two decades of research on silver nanoparticle (AgNP) toxicity, a safe threshold for exposure has not yet been established, albeit being critically needed for risk assessment and regulatory decision-making. Traditionally, a point-of-departure (PoD) value is derived from dose response of apical endpoints in animal studies using either the no-observed-adverse-effect level (NOAEL) approach, or benchmark dose (BMD) modeling. To develop new approach methodologies (NAMs) to inform human risk assessment of AgNPs, we conducted a concentration response modeling of the transcriptomic changes in hepatocytes derived from human induced pluripotent stem cells (iPSCs) after being exposed to a wide range concentration (0.01-25 μg/ml) of AgNPs for 24 h. A plausible transcriptomic PoD of 0.21 μg/ml was derived for a pathway related to the mode-of-action (MOA) of AgNPs, and a more conservative PoD of 0.10 μg/ml for a gene ontology (GO) term not apparently associated with the MOA of AgNPs. A reference dose (RfD) could be calculated from either of the PoDs as a safe threshold for AgNP exposure. The current study illustrates the usefulness of in vitro transcriptomic concentration response study using human cells as a NAM for toxicity study of chemicals that lack adequate toxicity data to inform human risk assessment.

Keywords: Benchmark dose modeling; Concentration response; Hepatocyte; Induced pluripotent stem cell; New approach methodology; Silver nanoparticle.

MeSH terms

  • Benchmarking
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / genetics
  • Dose-Response Relationship, Drug*
  • Gene Expression Profiling / methods
  • Hepatocytes* / drug effects
  • Hepatocytes* / metabolism
  • Humans
  • Induced Pluripotent Stem Cells* / drug effects
  • Metal Nanoparticles* / toxicity
  • No-Observed-Adverse-Effect Level
  • Risk Assessment
  • Silver* / toxicity
  • Transcriptome* / drug effects

Substances

  • Silver