Risk Analysis Implications of Dose-Response Thresholds for NLRP3 Inflammasome-Mediated Diseases: Respirable Crystalline Silica and Lung Cancer as an Example

Our plain-English summary of Risk Analysis Implications of Dose-Response Thresholds for NLRP3 Inflammasome-Mediated Diseases: Respirable Crystalline Silica and Lung Cancer as an Example, by L.A.T. Cox (Dose-response, 2019).

The study

• Author: L.A.T. Cox
• Journal: Dose-response
• Published: 2019;17(2):1559325819836900
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Chronic inflammation mediates an extraordinarily wide range of diseases. Recent progress in understanding intracellular inflammasome assembly, priming, activation, cytokine signaling, and interactions with mitochondrial reactive oxygen species, lysosome disruption, cell death, and prion-like polymerization and spread of inflammasomes among cells, has potentially profound implications for dose-response modeling. This article discusses mechanisms of exposure concentration and duration thresholds for NOD-like receptor protein 3 (NLRP3)-mediated inflammatory responses and develops a simple biomathematical model of the onset of exposure-related tissue-level chronic inflammation and resulting disease risks, focusing on respirable crystalline silica (RCS) and lung cancer risk as an example. An inflammation-mediated 2-stage clonal expansion model of RCS-induced lung cancer is proposed that explains why relatively low estimated concentrations of RCS (eg, <1 mg/m3) do not increase lung cancer risk and why even high occupational concentrations increase risk only modestly (typically relative risk <2). The model of chronic inflammation implies a dose-response threshold for excess cancer risk, in contrast to traditional linear-no-threshold assumptions. If this implication is correct, then concentrations of crystalline silica (or amphibole asbestos fibers, or other environmental challenges that act via the NLRP3 inflammasome) below the threshold do not cause chronic inflammation and resulting elevated risks of inflammation-mediated diseases.

In plain English

This article was a theoretical modeling paper, not a study of patients or workers. The author reviewed laboratory research on the NLRP3 inflammasome, a cell structure that triggers inflammation. The author then built a mathematical model linking inhaled respirable crystalline silica (RCS) to lung inflammation and lung cancer risk, using published parameter values. In the model, for DQ12 quartz dust, inhaled concentrations below about 0.13 mg/m3 never reached the level set for acute inflammation. Higher concentrations usually reached it within about 3 to 6 months. For a dust one-eighth as inflammatory as DQ12, the implied threshold was just over 1 mg/m3. The author assumed that chronic inflammation raised the growth rate of premalignant cells by 20%. Under that assumption, modeled relative risks of lung cancer death ranged from 1.00 without inflammation to 1.6 if it began at age 30. The author concluded that the model implies thresholds for lung cancer from agents such as RCS or asbestos. The author also stated that the model was simplified, not thoroughly validated, and yet to be tested on other data sets, including asbestos-induced lung cancer and perhaps mesothelioma.

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 (mathematical) modeling article with a narrative review of NLRP3 inflammasome biology; no new data were collected
• Who was studied: No people or animals were studied. The model used published parameter values, including a human lung silica model from Tran et al and lung cancer rates for nonsmokers from McCarthy et al. Its outputs were compared with published epidemiological data.
• Exposure: Respirable crystalline silica (DQ12 quartz dust assumed), at modeled inhaled concentrations from 0.08 to 0.18 mg/m3. Asbestos was discussed only as another agent the author believes acts through the same mechanism.
• Main results:
  • In the silica lung-burden model, inhaled concentrations below about 0.13 mg/m3 did not reach the threshold for acute inflammation.
  • In the model, most concentrations high enough to reach the acute inflammation threshold did so within about 3 to 6 months.
  • For a quartz dust with one-eighth the inflammatory potency of DQ12, the author estimated a threshold for acute inflammation of just over 1 mg/m3.
  • A standard lung cancer model in which risk rises smoothly with exposure overpredicted the relative risks observed in published studies at high exposures.
  • The author assumed that chronic inflammation raises the premalignant cell growth rate g by 20% (0.075 to 0.09).
  • Under that assumption, modeled relative risks of lung cancer mortality for exposed workers ranged from 1.00 if inflammation was avoided to 1.6 if it began at age 30.
• The authors' conclusion: The author concluded that thresholds for NLRP3-mediated inflammation inside cells ultimately imply dose-response thresholds for lung cancer caused by agents such as RCS or asbestos.
• Limitations the authors state:
  • The modeling was deliberately simplified and ignored short-term changes and random variation, including variation between individuals.
  • The proposed model has not been thoroughly validated. The author said it appears to explain some aggregate epidemiological data fairly well and its component models have been validated on other data sets. The combined model has not yet been applied to diverse data sets, including asbestos-induced lung cancer and perhaps mesothelioma.
  • The combined model has yet to be applied to and validated on diverse data sets beyond RCS.
  • The threshold for chronic inflammation in humans could not be derived from the rat acute-inflammation data used.

Topics

Medical terms in this study, explained in our Lexicon: Dose-response relationship, Crystalline, Lung Cancer, Chronic Inflammation, Cytokine, Reactive Oxygen Species (ROS), Inflammation, Relative Risk.

Related studies

• Dose-response modeling of NLRP3 inflammasome-mediated diseases: asbestos, lung cancer, and malignant mesothelioma as examples — L.A. Cox (2019)
• Assessing occupational erionite and respirable crystalline silica exposure among outdoor workers in Wyoming, South Dakota, and Montana — C. Beaucham, B. King, et al. (2018)
• PKC/ROS-Mediated NLRP3 Inflammasome Activation Is Attenuated by Leishmania Zinc-Metalloprotease during Infection — M.T. Shio, J.G. Christian, et al. (2015)
• Dose-response associations of silica with nonmalignant respiratory disease and lung cancer mortality in the diatomaceous earth industry — H. Checkoway, N.J. Heyer, et al. (1997)
• Re: "Dose-response associations of silica with nonmalignant respiratory disease and lung cancer mortality in the diatomaceous earth industry" — G.W. Gibbs (1998)
• Re: "Dose-response associations of silica with nonmalignant respiratory disease and lung cancer mortality in the diatomaceous earth industry" — M.J. Mirliss (1998)

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