Assessment of the biochemical pathways for acetaminophen toxicity: Implications for its carcinogenic hazard potential

Hartmut Jaeschke, F. Jay Murray, Andrew D. Monnot, David Jacobson-Kram, Samuel M. Cohen, Jerry F. Hardisty, Evren Atillasoy, Anne Hermanowski-Vosatka, Edwin Kuffner, Daniele Wikoff, Grace A. Chappell, Suren B. Bandara, Milind Deore, Suresh Kumar Pitchaiyan, Gary Eichenbaum

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (≤4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death – thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities.

Original languageEnglish (US)
Article number104859
JournalRegulatory Toxicology and Pharmacology
StatePublished - Mar 2021


  • Acetaminophen
  • Carcinogenicity
  • Genotoxicity
  • Mechanisms
  • Metabolism
  • Mutagenicity
  • Paracetamol
  • Toxicity

ASJC Scopus subject areas

  • Toxicology


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