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Mar 18, 2020
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Quantitative Systems Toxicology (DILIsym) Modeling of the Acetaminophen Cellular Pathways for Liver Toxicity Supports that Acetaminophen is Not a Carcinogenic Hazard in Humans

Introduction

BACKGROUND: Acetaminophen has a long history of safe use at therapeutic doses, but can cause liver injury at very high doses. The California Office of Environment Health Hazard Assessment (OEHHA) recently called for a scientific review of the carcinogenicity hazard potential of acetaminophen. This Quantitative Systems Toxicology work supported this review as part of a broader scientific weight-of-evidence assessment of the carcinogenicity hazard potential of acetaminophen.

METHODS: DILIsym was applied to model acetaminophen drug exposure, metabolism and mechanisms of cell death. The model was qualified using experimental data and then used to simulate exposure to acetaminophen at therapeutic, supratherapeutic, and overdose conditions across representative populations with the goal of determining whether it is a carcinogenic hazard.

RESULTS: The model results provided the following important insights: a) acetaminophen effects are binary, with therapeutic doses showing no adverse effects, and
high doses causing a burst of oxidative stress as a consequence of mitochondrial dysfunction, which results in cell death and precludes any lasting carcinogenic effects on DNA and b) simulated patients with representative variability in baseline Glutathione (GSH) levels across the population at therapeutic doses of
acetaminophen are at minimal risk of production of oxidative stress in the liver and have excess buffer capacity.

CONCLUSION: Taken together, the simulation results demonstrate that the acetaminophen toxicity and mechanism of cell death at doses above the therapeutic range preclude it from being a carcinogenicity hazard at any dose level. The information from this study was submitted to OEHHA to support their evaluation.

By Kyunghee Yang, Yeshitila Gebremichael, Brett A. Howell, Gary Eichenbaum

Canceled:  ASCPT Annual Meeting March 18-21, 2020 in Houston, Texas

 

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