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Mapping Interindividual Variability of Toxicodynamics Using High-Throughput Transcriptomics and Primary Human

Marije Niemeijer1, Witold Więcek2, Shuai Fu2

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Environmental Health Perspectives
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This summary is machine-generated.

Understanding human toxicodynamic variability is crucial for chemical safety. This study reveals significant interindividual differences in cellular stress responses, informing better risk assessment and safety factors for diverse populations.

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Area of Science:

  • Toxicology and pharmacology
  • Genomics and transcriptomics
  • Population health and risk assessment

Background:

  • Interindividual variability in toxicodynamic responses impacts chemical risk assessment.
  • Cellular stress response pathways are early indicators of chemical-induced toxicity.
  • Understanding this variability is key to establishing population-wide safety factors.

Purpose of the Study:

  • To map variability in cellular stress response activation across a large panel of primary human hepatocytes (PHHs).
  • To quantify toxicodynamic interindividual variability for deriving safety uncertainty factors.
  • To assess the influence of PHH panel size on variability estimation.

Main Methods:

  • High-throughput transcriptomics on over 8,000 samples from 50 PHH donors.
  • Exposure to four toxicological stimuli: tunicamycin (UPR), diethyl maleate (OSR), cisplatin (DDR), and TNFα (NF-κB).
  • Population mixed-effect modeling to analyze benchmark concentrations (BMCs) and gene expression variability.

Main Results:

  • Significant interindividual variability in BMCs for UPR (864-fold), OSR (13-fold), DDR (13-fold), and NF-κB (259-fold).
  • Small PHH panel sizes led to underestimation of variance and inaccurate population variability estimates.
  • Estimated toxicodynamic variability factors ranged from 1.6 to 6.3.

Conclusions:

  • High-throughput transcriptomics and population modeling enhance understanding of interindividual variability in stress pathway activation.
  • This approach improves confidence in in vitro-based predictions of adverse responses, particularly hepatotoxicity.
  • The findings contribute to more accurate risk assessment for diverse human populations.