Models for mesothelioma incidence following exposure to fibers in terms of timing and duration of exposure and the biopersistence of the fibers

Our plain-English summary of Models for mesothelioma incidence following exposure to fibers in terms of timing and duration of exposure and the biopersistence of the fibers, by G. Berry (Inhalation Toxicology, 1999).

The study

• Author: G. Berry
• Journal: Inhalation Toxicology
• Published: 1999;11(2):111-30
• Cited by: 60 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The health effects of inhaled fibers are related to the intensity and duration of exposure and occur many years after the exposure. In particular, the incidence of mesothelioma after exposure to asbestos is proportional to the intensity of exposure (fibers per milliliter of air) and the duration of exposure, and to the time that has elapsed since the exposure. The incidence increases with time since exposure to a power of between 3 and 4. The disease process resulting from exposure to fibers in the air is presumably related to the dose of fibers in the lungs, which depends on the exposure level and duration, and also on the size characteristics of the fibers influencing their inhalation and retention in the lungs. Models incorporating these characteristics have been found to be satisfactory in explaining the incidence of mesothelioma over time after exposure to asbestos. Most of the epidemiological modeling has been for occupational exposure to one of the amphibole asbestos types (crocidolite or amosite), for which heavy exposure produces a high incidence of mesothelioma. Occupational exposure to chrysotile asbestos has resulted in a much lower incidence of mesothelioma. Crocidolite asbestos is much more biopersistent than chrysotile asbestos in the sense that after retention in the lungs it is eliminated only slowly (half-time of several years). If fibers are eliminated then the dose in the lungs declines following exposure, and this may influence the disease process. This concept is more important for synthetic mineral fibers, such as glass wool, which are used as a substitute for asbestos. These fibers are much less biopersistent than asbestos, with half-times of weeks or even days. Biopersistence is related to the dissolution of fibers. This is a physical-chemical process that may be expected to proceed at about the same rate in rats and humans. The predicted effect of biopersistence of fibers has been explored using the basic mesothelioma incidence model generalized to include a term representing exponential elimination over time. The influence of solubility of fibers on the mesothelioma rate is 17 times higher in humans than in rats. This is because rats are aging and developing cancer at a much quicker rate than humans, and hence the influence of dissolution is less. Thus, the predicted mesothelioma incidence in humans is highly dependent on the rate of elimination across the range covering asbestos and the more durable synthetic fibers, but in rats a similar dependence occurs at a 17 times higher rate of elimination corresponding to the less durable synthetic fibers. The possible carcinogenic effects of fibers are often determined from animal experiments, but these results suggest that the extrapolation from rats to humans is highly dependent on the biopersistence of fibers, in the situation where the elimination is through dissolution of fibers at a rate independent of species and the speed of the cancer process is species dependent. This implies that relatively soluble fibers that do not produce disease in rat experiments are even less likely to produce disease in humans.

In plain English

This single-author article was a mathematical modeling study combined with a review of published evidence. It explored a model of mesothelioma incidence after fiber exposure that adds a term for fibers being gradually eliminated from the lungs, for example by dissolving. The author briefly reviewed an earlier use of the model for former workers at the Wittenoom crocidolite mine in Western Australia, where the data could not distinguish it from simpler models. In new calculations, the author compared hypothetical men exposed from age 20 to 60 with rats given a single fiber injection at 6 weeks of age, across a range of elimination rates. The model was set so that a durable fiber reached a 50% cumulative incidence at age 75 in men and at 110 weeks after injection in rats. The author noted that a lifetime incidence this high is much higher than has been observed in humans. In the model, the effect of fiber elimination on mesothelioma was 17 times greater in humans than in rats. The author concluded that relatively soluble fibers that do not produce disease in rat experiments are even less likely to produce disease in humans. The author called the model a simplification.

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: Mathematical modeling study of mesothelioma incidence, including a fiber elimination term, combined with a review of earlier epidemiological, lung-burden and animal studies
• Who was studied: Mostly model populations. Men's deaths from other causes were taken from the 1994 Australian male life table, and rats' natural deaths from standard Wistar rats. The article also briefly reviewed the author's earlier analysis of 6501 men who worked in crocidolite production at Wittenoom, Western Australia, between 1943 and 1966.
• Exposure: Hypothetical fiber exposure with elimination rates ranging from very durable to rapidly eliminated (up to 1.5 per year for men and 25 per year for rats). Men were exposed continuously from age 20 to 60. Rats received a single intense exposure by injection at 6 weeks. The background discussion covers crocidolite, amosite and chrysotile asbestos and synthetic mineral fibers (glass wool, rock wool, slag wool, refractory ceramic fiber).
• Main results:
  • The model was calibrated so that a durable fiber (elimination rate 0.01 per year) gave a cumulative mesothelioma incidence of 50% at age 75 in men and at 110 weeks after injection in rats.
  • In the model, the influence of fiber solubility on the mesothelioma rate was 17 times higher in humans than in rats, relative to a highly durable fiber and for the timing of exposure considered.
  • For men, the highest elimination rate shown (1.5 per year) gave a modeled cumulative mesothelioma incidence of 2.5 in a million. In rats, the same incidence did not occur until the elimination rate was as high as 26 per year.
  • In the model, elimination rate had its most marked influence in rats above about 0.35 per year (a half-time of 2 years or less). In men, the same influence occurred above about 0.02 per year (a half-time of 35 years or less).
  • The author repeated an earlier calculation using lung-burden data from women exposed to crocidolite while making military gas masks in 1940 to 1945. With the elimination model, the ratio of exposure levels between these women and people without occupational exposure was estimated as 50,000, and the elimination rate as 0.13 per year.
  • Reviewed from the author's earlier (1991) Wittenoom analysis: predicted mesotheliomas among former workers between 1987 and 2020 ranged from 654 with the simplest model, to 573 with a 5-year lag, to 383 with a 5-year lag plus an elimination rate of 0.068 per year. The author described this range as uncertainty about which model is most appropriate.
• The authors' conclusion: The author concluded that the drop in tumor rate with faster fiber dissolution appears much greater in humans than in animals. Relatively soluble fibers that do not produce disease in rat experiments are, in the author's view, even less likely to produce disease in humans. The author suggested this difference may explain why chrysotile gives mesothelioma incidences similar to the amphiboles in rats, while amphiboles give much higher rates after occupational exposure in humans.
• Limitations the authors state:
  • The author stated that the model is a simplification of a more complex process.
  • The results concern only how cumulative incidence relates to elimination rate. They cannot give absolute human mesothelioma incidence from rat studies, because there is no known way to convert dose between species.
  • The model's 50% lifetime mesothelioma incidence is much higher than has been observed in humans.
  • It is not established that mesothelioma risk depends only on the amount of fiber remaining in the lung. Elimination appears faster for long fibers and may follow two exponential phases rather than one.
  • In the Wittenoom data, the elimination model did not fit better than the simplest model, and the data were insufficient to validate it.

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Wittenoom, Western Australia

All asbestos mines

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: Mesothelioma, biopersistence, Occupational Exposure, Amphibole Asbestos, Crocidolite, Amosite, Chrysotile, Mineral Fiber.

Related studies

• Biopersistence of rock wool in lungs after short-term inhalation in rats — Y. Kudo, Y. Aizawa (2008)
• Comparison of Calidria chrysotile asbestos to pure tremolite: inhalation biopersistence and histopathology following short-term exposure — D.M. Bernstein, J. Chevalier, et al. (2003)
• Comparison of Calidria chrysotile asbestos to pure tremolite: final results of the inhalation biopersistence and histopathology examination following short-term exposure — D.M. Bernstein, J. Chevalier, et al. (2005)
• The biopersistence of brazilian chrysotile asbestos following inhalation — D.M. Bernstein, R. Rogers, et al. (2004)
• Evaluation of the deposition, translocation and pathological response of brake dust with and without added chrysotile in comparison to crocidolite asbestos following short-term inhalation: interim results — D.M. Bernstein, R. Rogers, et al. (2014)
• Biopersistences of man-made vitreous fibers and crocidolite fibers in rat lungs following short-term exposures — R.P. Musselman, W.C. Miiller, et al. (1994)

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