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Cox LA, Goodman JE, Engel AM. Chronic inflammation, Adverse Outcome Pathways, and risk assessment: A diagrammatic exposition. Regul Toxicol Pharmacol. 2020;114:104663doi: 10.1016/j.yrtph.2020.104663.
Cox, L. A., Goodman, J. E., & Engel, A. M. (2020). Chronic inflammation, Adverse Outcome Pathways, and risk assessment: A diagrammatic exposition. Regulatory toxicology and pharmacology : RTP, 114104663. https://doi.org/10.1016/j.yrtph.2020.104663
Cox, Louis Anthony, et al. "Chronic inflammation, Adverse Outcome Pathways, and risk assessment: A diagrammatic exposition." Regulatory toxicology and pharmacology : RTP vol. 114 (2020): 104663. doi: https://doi.org/10.1016/j.yrtph.2020.104663
Cox LA, Goodman JE, Engel AM. Chronic inflammation, Adverse Outcome Pathways, and risk assessment: A diagrammatic exposition. Regul Toxicol Pharmacol. 2020 Jul;114:104663. doi: 10.1016/j.yrtph.2020.104663. Epub 2020 Apr 21. PMID: 32330641.
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Regul Toxicol Pharmacol. 2020 Jul;114:104663. doi: 10.1016/j.yrtph.2020.104663. Epub 2020 Apr 21.

Chronic inflammation, Adverse Outcome Pathways, and risk assessment: A diagrammatic exposition.

Regulatory toxicology and pharmacology : RTP

Louis Anthony Cox, Julie E Goodman, Anna M Engel

Affiliations

  1. Cox Associates and University of Colorado, 503 N. Franklin Street, Denver, CO, 80218, USA. Electronic address: [email protected].
  2. Gradient, One Beacon Street, 17th Floor, Boston, MA, 02108, USA. Electronic address: [email protected].
  3. Gradient, One Beacon Street, 17th Floor, Boston, MA, 02108, USA. Electronic address: [email protected].

PMID: 32330641 DOI: 10.1016/j.yrtph.2020.104663

Abstract

Inflammasomes are a family of pro-inflammatory signaling complexes that orchestrate inflammatory responses in many tissues. The NLRP3 inflammasome has been implicated in several diseases associated with chronic inflammation. In this paper, we present an Adverse Outcome Pathway (AOP) for NLRP3-induced chronic inflammatory diseases that demonstrates how NLRP3 can cause a transition from acute to chronic inflammation, and ultimately the onset of disease. We present a simple graphical description of the main features of internal dose time courses that are important when pharmacodynamics are governed by an activation threshold. Similar considerations hold for other AOPs that are rate-limited by processes with activation thresholds. The risk analysis implications of AOPs with threshold or threshold-like pharmacodynamic responses include the need to consider how cumulative dose per unit time is distributed over time and the possibility that safe, or virtually safe, exposure concentrations can be defined for such processes.

Copyright © 2020 Elsevier Inc. All rights reserved.

Keywords: Acute inflammation; Adverse outcome pathway; Chronic inflammation; Inflammasome; Mode of action; Risk analysis; Threshold

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors had complete contro

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