Biological mechanisms of non-linear dose-response for respirable mineral fibers

Our plain-English summary of Biological mechanisms of non-linear dose-response for respirable mineral fibers, by L.A.T. Cox (Toxicology and Applied Pharmacology, 2018).

The study

• Author: L.A.T. Cox
• Journal: Toxicology and Applied Pharmacology
• Published: 2018;361:137-144
• Type of article: Review
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Sufficiently high and prolonged inhalation exposures to some respirable elongated mineral particles (REMPs), notably including amphibole asbestos fibers, can increase risk of inflammation-mediated diseases including malignant mesothelioma, pleural diseases, fibrosis, and lung cancer. Chronic inflammation involves ongoing activation of the NLRP3 inflammasome, which enables immune cells to produce potent proinflammatory cytokines IL-1β and IL-18. Reactive oxygen species (ROS) (in particular, mitochondrial ROS) contribute to NRLP3 activation via a well-elucidated mechanism involving oxidation of reduced thioredoxin and association of thioredoxin-interacting protein with NLRP3. Lysosomal destabilization, efflux of cytosolic potassium ions and influx of calcium ions, signals from damaged mitochondria, both translational and post-translational controls, and prion-like polymerization have increasingly clear roles in regulating NLRP3 activation. As the molecular biology of inflammation-mediated responses to REMP exposure becomes clearer, a practical question looms: What do these mechanisms imply for the shape of the dose-response function relating exposure concentrations and durations for EMPs to risk of pathological responses? Dose-response thresholds or threshold-like nonlinearities can arise from (a) Cooperativity in assembly of supramolecular signaling complexes; (b) Positive feedback loops and bistability in regulatory networks; (c) Overwhelming of defensive barriers maintaining homeostasis; and (d) Damage thresholds, as in lysosome destabilization-induced activation of NLRP3. Each of these mechanisms holds for NLRP3 activation in response to stimuli such as REMP exposures. It is therefore timely to consider the implications of these advances in biological understanding for human health risk assessment with dose-response thresholds.

Copyright © 2018. Published by Elsevier Inc.

In plain English

This paper was a theoretical analysis by a single author. It drew on previously published laboratory and modeling research and did not collect new data from people or animals. The author examined how the biology of the NLRP3 inflammasome, a cell structure that drives inflammation after inhaling mineral particles such as crystalline silica, elongated mineral particles and asbestos fibers, might shape the relationship between exposure and disease risk. The paper described five general mechanisms that could create exposure thresholds and listed six positive feedback loops involving reactive oxygen species and the inflammasome. The author proposed that, within a cell, inflammasome responses do not occur below certain exposure concentrations, nor when exposures are too brief. The author also proposed that longer, stiffer fibers with iron on their surface may speed lysosome rupture. The author concluded that detailed models can be expected to show threshold-like responses, and that it is timely to consider what this means for health protection. The author stated that thresholds for the spread of inflammation through tissue remain speculative and that much more biochemical detail is needed. The paper gave no exposure threshold values.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Theoretical review and analysis of published biological research and mathematical concepts (no new data collected)
• Who was studied: No people or animals were studied. The paper discusses cell types described in other published work, including monocytes, macrophages, dendritic cells and human mesothelial cells.
• Exposure: Inhaled mineral particles in general: respirable crystalline silica, elongated mineral particles (EMPs) and asbestos fibers, notably amphibole asbestos. No specific doses were analyzed.
• Main results:
  • The author summarized five general mechanisms that can create exposure-response thresholds: receptor-mediated signal transduction, a critical mass or concentration needed to trigger an event, cooperativity in oligomerization, bistability in networks with positive feedback loops, and percolation thresholds in the spread of inflammation through tissue.
  • The author listed six positive feedback loops involving reactive oxygen species (ROS) and NLRP3 inflammasome activation (Table 1).
  • The author's proposed answer to whether a concentration threshold exists was yes: within a cell, NLRP3-mediated responses do not occur unless exposure concentrations are high enough.
  • The author's proposed answer to whether a duration threshold exists was yes: if exposures are too brief, the assembly steps needed for inflammasome activation are not completed.
  • The author proposed that the dose-response relationship is probably switch-like (close to all-or-nothing), while noting that damage and disease from activated loops may progress over decades.
  • The author proposed that greater fiber length, stiffness and availability of iron on the fiber surface can shorten the time to lysosome rupture and the 'Signal 2' that activates the inflammasome.
  • The author cited an earlier study (Thompson et al., 2014), not this paper, as finding that crocidolite asbestos fibers activated inflammasomes in human mesothelial cells. The author took this to show that one of the listed feedback loops is relevant to crocidolite.
• The authors' conclusion: The author concluded that detailed models can be expected to show threshold-like responses to exposure concentrations and durations, and that it is timely to consider what exposure thresholds for inflammation-mediated diseases mean for public and occupational health protection and risk analysis.
• Limitations the authors state:
  • The author stated that percolation thresholds for the spread of inflammation through tissue are currently speculative, only a conjecture.
  • The author stated that the feedback loops described are abstract and do not specify which cell populations are involved or how strongly.
  • The author stated that much more biochemical detail is needed, including on the time course of disease initiation and progression after chronic inflammation begins.
  • The author stated that a fuller picture of the inflammatory network would be far more complex than the few feedback loops shown and would include negative feedback loops.

Topics

Medical terms in this study, explained in our Lexicon: Dose-response relationship, Mineral Fiber, Amphibole Asbestos, Inflammation, Malignant Mesothelioma, Fibrosis, Lung Cancer, Chronic Inflammation.

Related studies

• Respirable stone particles differ in their ability to induce cytotoxicity and pro-inflammatory responses in cell models of the human airways — V.S. Grytting, M. Refsnes, et al. (2021)
• Dose-response modeling of NLRP3 inflammasome-mediated diseases: asbestos, lung cancer, and malignant mesothelioma as examples — L.A. Cox (2019)
• Morphological and chemical mechanisms of elongated mineral particle toxicities — A.E. Aust, P.M. Cook, et al. (2011)
• Separation and characterization of respirable amphibole fibers from Libby, Montana — J.S. Webber, D.J. Blake, et al. (2008)
• The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases — M. Sayan, B.T. Mossman (2016)
• Inflammasome inhibition under physiological and pharmacological conditions — E.A. Caseley, J.A. Poulter, et al. (2020)

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