Kinetics of deposition and clearance of inhaled mineral dusts during chronic exposure

Our plain-English summary of Kinetics of deposition and clearance of inhaled mineral dusts during chronic exposure, by J.H. Vincent, A.M. Johnston, A.D. Jones, et al (British Journal of Industrial Medicine, 1985).

The study

• Authors: J.H. Vincent, A.M. Johnston, A.D. Jones, R.E. Bolton, J. Addison
• Journal: British Journal of Industrial Medicine
• Published: 1985;42(10):707-15
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

New inhalation studies have been carried out with rats exposed to UICC (Union International Contre le Cancer) amosite asbestos, with the main aim of further elucidating the factors the influence the accumulation of dust in the lung during prolonged chronic exposure. The results show that, for exposure times beyond a few weeks, the lung burden rises linearly and does not level off as predicted by simple models based on ideas taken from the 1966 report of the Task Group on Lung Dynamics. Furthermore, the lung burden is found to scale directly in proportion to the exposure concentration in a way that seems to contradict the overload hypothesis stated earlier. Nevertheless, the general pattern exhibited by our results for asbestos is markedly similar to that found elsewhere for rats inhaling diesel fume, leading to the suggestion that it is general (and not specific to fibrous dust); and the hypothesis that, whereas overload of clearance can take place at high lung burdens after exposure has ceased, it is cancelled by the sustained stimulus to clearance mechanisms provided by the continuous challenge of chronic exposure. The linearity of the increase in lung burden is explained in terms of a kinetic model involving sequestration of some inhaled material to parts of the lung where it is difficult to clear. The particular sequestration model favoured is one where, the longer a particle remains in the lung without being cleared, the more likely it will be sequestrated (and therefore less likely cleared). It is believed that such ideas may eventually be useful in forming exposure-dose relations for epidemiology.

In plain English

This was an animal experiment. The authors exposed male Wistar rats to UICC amosite asbestos at target respirable concentrations of 1 or 10 mg/m3, seven hours a day, five days a week, for up to one year. Groups of 12 were killed in fours 3, 10 or 38 days after exposure ended, and dust in the lungs and mediastinal and hilar lymph nodes was measured. Adjusted for concentration, results at both levels fell on a single relationship. Beyond 40 days of exposure, lung burden rose linearly (correlation coefficient 0.92) instead of levelling off as a simple model predicted. The authors also tested an overload model. In it, once lung burden passes 1 mg, the medium clearance compartment fails and all deep-lung dust passes to the slow one. This model fitted the 10 mg/m3 data better than the simple model. However, it predicted a divergence between the two levels that the data did not show. A 'sequestration' model, in which some dust moves to a hard-to-clear compartment, fitted well. The authors concluded that lung burden scaled with exposure level. They cautioned against assuming the same linear rise in people.

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: Animal inhalation experiment (rats), comparing measured lung burdens against mathematical lung-clearance models
• Who was studied: Outbred male SPF Wistar rats of the AF/HAN strain, all older than eight months, at the Institute of Occupational Medicine, Edinburgh. They were exposed in groups of 12, with up to 48 per chamber at a time, and killed in subgroups of four at 3, 10 and 38 days after exposure ended.
• Exposure: Airborne UICC amosite asbestos at target respirable dust concentrations of 1 mg/m3 and 10 mg/m3, for seven hours a day on five days a week, for durations of up to one year
• Main results:
  • When lung burdens were adjusted for exposure concentration, the results for the 1 mg/m3 and 10 mg/m3 groups fell on a single relationship. The authors took this to suggest that clearance did not depend on the size of the lung burden.
  • The measured lung burdens agreed with the simple kinetic model during the early weeks of exposure. Later they were much larger than the model predicted, with no levelling off.
  • For exposure times longer than 40 days, with all post-exposure times combined, lung burden rose in a strongly linear way with exposure time. The correlation coefficient was 0.92 (printed '0-92').
  • The authors tested an 'overload' model. In it, once deep lung burden reached an assumed threshold of 1 mg, the medium clearance compartment failed completely and all deep-lung material moved into the slow clearance compartment. For 10 mg/m3, this model agreed better than the simple model. For 1 mg/m3, it simply followed the simple model. The divergence it predicted between the two exposure levels was not seen in the experimental data.
  • The authors also tested a 'sequestration' model. In it, material moves from the usual deep-lung compartments into a compartment that does not clear, using a transfer time constant of 80 days chosen empirically. This model agreed well with the experimental data.
• The authors' conclusion: The authors concluded that, during chronic exposure, lung burden of UICC amosite in rats rose substantially faster than the simple kinetic model predicted. It kept increasing linearly and scaled in proportion to the respirable dust exposure level. They favoured a sequestration model and suggested that clearance overload does not account for the chronic-exposure results.
• Limitations the authors state:
  • Interpreting experiments on living animals with kinetic models is limited by biological variability. This is especially so in long studies, where ageing or the onset of disease could change the response.
  • The results come from short-lived rats. They should not be taken to mean that lung burdens in people under chronic exposure keep rising linearly.
  • New experiments are needed to test whether the favoured sequestration model is valid.
  • The work did not set out to answer questions about the underlying biology, such as the mechanisms of overload and sequestration or the role of macrophages.
  • Further studies across species and dust types are needed. Until then, general conclusions should remain tentative.

Topics

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

Medical terms in this study, explained in our Lexicon: Deposition, UICC, Amosite, Epidemiology.

Related studies

• An overload hypothesis for pulmonary clearance of UICC amosite fibres inhaled by rats — R.E. Bolton, J.H. Vincent, et al. (1983)
• Accumulation of mixed mineral dusts in the lungs of rats during chronic inhalation exposure — C.H. McMillan, A.D. Jones, et al. (1989)
• Deposition pattern and clearance pathways of inhaled chrysotile asbestos — A.R. Brody, L.H. Hill (1981)
• Studies on the deposition of inhaled fibrous material in the respiratory tract of the rat and its subsequent clearance using radioactive tracer techniques. 1. UICC crocidolite asbestos — J.C. Evans, R.J. Evans, et al. (1973)
• 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)
• Kinetics of the bronchoalveolar leucocyte response in rats during exposure to equal airborne mass concentrations of quartz, chrysotile asbestos, or titanium dioxide — K. Donaldson, R.E. Bolton, et al. (1988)

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