Dose-response modeling of NLRP3 inflammasome-mediated diseases: asbestos, lung cancer, and malignant mesothelioma as examples

Our plain-English summary of Dose-response modeling of NLRP3 inflammasome-mediated diseases: asbestos, lung cancer, and malignant mesothelioma as examples, by L.A. Cox (Critical Reviews in Toxicology, 2019).

The study

• Author: L.A. Cox
• Journal: Critical Reviews in Toxicology
• Published: 2019;49(7):614-635
• Type of article: Review
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Can a single fiber of amphibole asbestos increase the risk of lung cancer or malignant mesothelioma (MM)? Traditional linear no-threshold (LNT) risk assessment assumptions imply that the answer is yes: there is no safe exposure level. This paper draws on recent scientific progress in inflammation biology, especially elucidation of the activation thresholds for NLRP3 inflammasomes and resulting chronic inflammation, to model dose-response relationships for malignant mesothelioma and lung cancer risks caused by asbestos exposures. The modeling integrates a physiologically based pharmacokinetics (PBPK) front end with inflammation-driven two-stage clonal expansion (I-TSCE) models of carcinogenesis to describe how exposure leads to chronic inflammation, which in turn promotes carcinogenesis. Together, the combined PBPK and I-TSCE modeling predict that there are practical thresholds for exposure concentration below which asbestos exposure does not cause chronic inflammation in less than a lifetime, and therefore does not increase chronic inflammation-dependent cancer risks. Quantitative examples using model parameter estimates drawn from the literature suggest that practical thresholds may be within about a factor of 2 of some past exposure levels for some workers. The I-TSCE modeling framework explains previous puzzling aspects of asbestos epidemiology, such as why age at first exposure is a better predictor of lifetime MM risk than exposure duration. It may be a valuable tool for risk analysts when LNT assumptions are not justified due to inflammation response thresholds mediating dose-response relationships.

In plain English

This review studied no patients or workers. The author combined three mathematical models, largely from earlier work, to explore how amphibole asbestos fibers might cause lung cancer and malignant mesothelioma through chronic inflammation. The model assumed identical fibers and used relative air concentrations, with 1 possibly representing fairly heavy industrial exposure. Chronic inflammation began only once tissue fibers reached a threshold, roughly estimated at hundreds of thousands to millions of long, thin fibers per gram of dry tissue. Predicted mesothelioma risk by age 90 was about 100 times greater if chronic inflammation began at age 10 rather than 60. For lung cancer the difference was about a factor of 2. An illustrative scenario supposed that at least 3 months at relative concentration 3 is needed to trigger chronic inflammation. On that basis, concentration 0.4 delayed it to at least 132 years in the mesothelium and 137 years in the lung. The author concluded that practical thresholds may lie within about a factor of 2 of some past exposure levels. The author noted the model ignores individual differences and cannot yet be linked to real fiber counts.

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: Article labeled a review that presents a theoretical computer model. It links a model of fiber movement in the body, an inflammation model and a two-stage cancer model. No new human or animal data were collected.
• Who was studied: No real population. The model was run on simplified hypothetical exposure scenarios, using parameter values taken from the published literature.
• Exposure: Hypothetical inhalation of identical amphibole asbestos fibers, expressed as relative air concentrations. The author suggested a relative concentration of 1 might be thought of as the exposure of an industrially exposed worker with fairly heavy exposure. No actual fiber concentration was assigned to this value.
• Main results:
  • In the model, chronic inflammation began when fibers in tissue reached a threshold number. The author roughly estimated this threshold at hundreds of thousands to millions of long (over 5 micrometer), thin fibers per gram dry weight of tissue.
  • Predicted lifetime risk of malignant mesothelioma by age 90 was approximately 100 times greater when chronic inflammation started at age 10 (top curve) than at age 60 (bottom curve).
  • For lung cancer, the predicted risk ratio between onset of chronic inflammation at age 10 and at age 60 was only about a factor of 2.
  • Clearance of fibers from the body was predicted to be fully saturated at a relative exposure concentration of about 3.
  • Halving the relative exposure concentration from 0.8 to 0.4 reduced the relative fiber deposition rate by more than 4-fold: from 0.25 to 0.06 in the mesothelium and from 0.34 to 0.08 in the lung.
  • The illustrative base scenario supposed that at least 3 months at a relative concentration of 3 is needed to trigger chronic inflammation and increased mesothelioma risk. Under that assumption, reducing the concentration to 1 increased the time to chronic inflammation in the mesothelium to about 173 months, close to 15 years.
  • In the same scenario, reducing the relative concentration from 3 to 0.4 increased the time to chronic inflammation in the mesothelium to at least 132 years. This is a lower bound resting on the assumed minimum of 3 months at a relative concentration of 3.
  • The corresponding figure for the lung, calculated under the same lower-bound assumption, was 137 years. The author suggested such an exposure level might be regarded as virtually safe, in the sense that inflammation-driven increases in mesothelioma and lung cancer risk would not be triggered within a realistic lifetime.
• The authors' conclusion: The author concluded that practical exposure thresholds might be within about a factor of 2 of some past exposure levels for many workers, if they have not already been reached. Below such thresholds, exposures would not cause detectably increased lifetime risk.
• Limitations the authors state:
  • The model did not account for differences between individuals in how fibers move through the body or how tissues respond.
  • The model assumed all fibers were identical and used relative rather than actual concentrations. Differences in fiber length, shape, stiffness and chemistry were not considered.
  • The model's inflammation threshold could not be linked to actual fiber counts in real workplaces.
  • Competing causes of death, other risk factors and co-exposures were ignored in the risk calculations.
  • No validated human dose-response model for this inflammation pathway at realistic exposure levels was available.
  • The quantitative results came only from illustrative scenarios.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

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

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