Nonlinear dose-time-response functions and health-protective exposure limits for inflammation-mediated diseases

Our plain-English summary of Nonlinear dose-time-response functions and health-protective exposure limits for inflammation-mediated diseases, by L.A. Cox (Environmental Research, 2020).

The study

• Author: L.A. Cox
• Journal: Environmental Research
• Published: 2020;182:109026
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Why have occupational safety regulations in the United States not been more successful in protecting worker health from mesothelioma risks, while apparently succeeding relatively well in reducing silicosis risks? This paper briefly discusses biological bases for thresholds and nonlinearities in exposure-response functions for respirable crystalline silica (RCS) and asbestos, based on modeling a chronic inflammation mode of action (mediated by activation of the NLRP3 inflammasome, for both RCS and asbestos). It applies previously published physiologically based pharmacokinetic (PBPK) models to perform computational experiments illuminating how different time courses of exposure with the same time-weighted average (TWA) concentration affect internal doses in target tissues (lung for RCS and mesothelium for asbestos). Key conclusions are that (i) For RCS, but not asbestos, limiting average (TWA) exposure concentrations also tightly constrains internal doses and ability to trigger chronic inflammation and resulting increases in disease risks (ii) For asbestos, excursions (i.e., spikes in concentrations); and especially the times between them are crucial drivers of internal doses and time until chronic inflammation; and hence (iii) These dynamic aspects of exposure, which are not addressed by current occupational safety regulations, should be constrained to better protect worker health. Adjusting permissible average exposure concentration limits (PELs) and daily excursion limits (ELs) is predicted to have little impact on reducing mesothelioma risks, but increasing the number of days between successive excursions is predicted to be relatively effective in reducing worker risks, even if it has little or no impact on TWA average concentrations.

Copyright © 2019 Elsevier Inc. All rights reserved.

In plain English

This was a computer-modeling study, not a study of real workers. The author used two previously published models, one for respirable crystalline silica and one for amphibole asbestos fibers treated as identical, idealized fibers. The models simulated how the timing of exposure affects internal doses: silica in lung immune cells and fibers lodged in the mesothelium. For silica, packing the same weekly dose into shorter, higher bursts raised peak internal levels less than 1.5-fold. For asbestos, the same total exposure given as brief, high concentrations produced accumulation rates an order of magnitude greater; under steady exposure, doubling relative concentration from 1 to 2 raised the predicted rate about 13-fold. In four simulated runs, randomly varying exposures tended to accumulate fibers faster over 90 days than steady exposure at the same mean. The author concluded that for asbestos, limiting average exposure does very little to limit predicted risk, and that time between excursions deserves more emphasis. The author noted that the models ignore differences between individuals and that the asbestos results rest on a single model of idealized fibers.

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: Computer simulation (modeling) study that applied previously published PBPK models for silica and asbestos; no human or animal subjects were studied
• Who was studied: No real people; hypothetical simulated workers exposed over consecutive time intervals such as work weeks
• Exposure: Modeled amphibole asbestos fibers (assumed all of the same length, width and stiffness, in relative concentration units) and respirable crystalline silica (constant concentrations from 0.08 to 0.18 mg/m3). Exposures were either uniform or concentrated into shorter, higher bursts with the same total amount per interval.
• Main results:
  • Silica model, constant exposure: with the model's parameter values, the minimum air concentration needed to eventually cause inflammation was about 0.13 mg/m3.
  • Silica model, constant exposure: most exposure levels that led to inflammation did so within about 3 to 6 months.
  • Asbestos model, constant exposure: doubling relative exposure concentration from 1 to 2 increased the predicted rate of fiber accumulation in the mesothelium about 13-fold.
  • Asbestos model: no exposure concentration avoided eventually exceeding any given threshold fiber load. In a worked example, if baseline exposure triggered chronic inflammation in at least 4 years, a relative concentration of 0.2 would take at least 110 years.
  • Silica model, time-varying exposure with the same weekly dose: peak internal silica in alveolar macrophages was less than 1.5 times higher for 5 times the concentration over 1 day (curve 5) than for uniform exposure over 5 days (curve 1).
  • Asbestos model, time-varying exposure with the same weekly dose: fiber accumulation rates in the mesothelium were an order of magnitude greater for brief, high concentrations than for longer, lower ones.
  • Asbestos model, illustrative example: if a relative concentration of 1 for 5 days a week led to chronic inflammation in 120 years, twice that concentration for 2.5 days a week would lead to it in only 25 years.
  • Asbestos model, additional simulations not shown in the article: doubling concentration while doubling the time between exposure starts (1 week to 2 weeks) gave about half the predicted accumulation rate compared with doubling concentration while halving weekly exposure duration.
  • Asbestos model: in 4 simulated realizations of randomized exposure with the same mean concentration (1) as a steady exposure, fibers tended to accumulate in the mesothelium faster over 90 days.
  • Additional simulations not shown in the article indicated the finding that closely spaced spikes are disproportionately hazardous held when model parameters were varied by a factor of 2 in either direction.
• The authors' conclusion: The author concluded that for asbestos, unlike silica, limiting average (TWA) exposure does very little to limit predicted risk, and that excursions and the times between them dominate predicted risk. The author suggested that, if the model results hold in practice, controlling the time between excursions deserves more emphasis.
• Limitations the authors state:
  • The asbestos conclusions rest on a single PBPK model of hypothetical, idealized, identical fibers, while real fibers vary widely in shape, length, stiffness and chemistry.
  • The models are not meant to be accurate for any individual worker and do not model differences between individuals.
  • Only one simple mode of action was modeled; tumor growth and the latency period before tumors appear were ignored.
  • Variability and uncertainty in data and model parameters were not addressed.

Topics

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

Medical terms in this study, explained in our Lexicon: Inflammation, Mesothelioma, Silicosis, Crystalline, Chronic Inflammation, Time-Weighted Average (TWA), Mesothelium, Excursion Limit.

Related studies

• Dose-response modeling of NLRP3 inflammasome-mediated diseases: asbestos, lung cancer, and malignant mesothelioma as examples — L.A. Cox (2019)
• The Potential Protective Effects of Polyphenols in Asbestos-Mediated Inflammation and Carcinogenesis of Mesothelium — M. Benvenuto, R. Mattera, et al. (2016)
• 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)
• Risk Analysis Implications of Dose-Response Thresholds for NLRP3 Inflammasome-Mediated Diseases: Respirable Crystalline Silica and Lung Cancer as an Example — L.A.T. Cox (2019)

Browse more research in Environmental Research, or return to medical research.