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

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.
Competing Interests: 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 control over the design, conduct, interpretation, and composition of this manuscript. The contents of this manuscript are solely the responsibility of the authors and do not necessarily reflect the views or policies of their employers. J. Goodman and A. Engel received support from the George Washington University (GWU) for developing this manuscript. Dr. Goodman has served as an expert in multiple litigation matters involving asbestos-containing products. None of the underlying research or analysis for this paper was performed during the context of those engagements or was sponsored by any of the defendants. Dr. Cox's work on the risk modeling approach reported here was supported by his employer, Cox Associates LLC, which has received research funding in 2018–2020 from the following sources: (1) a research contract from the National Stone, Sand, and Gravel Association to develop and apply risk models and machine learning methods and causal analytics to risk assessment for mineral dusts and fibers; (2) a research project with the GWU Regulatory Studies Center to investigate and explain the role of the NLRP3 inflammasome in risk analysis.
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