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Lung particle overload: old school -new insights?

Borm P, Cassee FR, Oberdörster G - Part Fibre Toxicol (2015)

View Article: PubMed Central - PubMed

Affiliation: Zuyd Hogeschool, Department of Life Sciences & Health, PO Box 550, 6400, AN, Heerlen, The Netherlands. paul.borm@zuyd.nl.

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The paper had a major impact on our thinking on the retained dose and clearance upon inhalation of respirable dust... At the core of the particle overload hypothesis is the question about the relevancy for humans of both non-neoplastic and neoplastic effects observed specifically in rats exposed chronically to extremely high concentrations of poorly soluble particles of low acute toxicity (PSP)... Morrow proposed that a continuously increasing prolongation of particle lung clearance of PSP occurs when the retained lung burden exceeds a certain threshold; he identified that this effect on particle clearance is due to an impairment of the alveolar macrophage (AM) clearance function and concluded from his analysis of the data that the impaired clearance correlates with the phagocytized volumetric loading of AM... Morrow’s pioneering studies prompted additional research into the fate of particles in the lung under normal and overload conditions; for example, an increasing interstitial access of particles associated with overload ; or, the finding that a decrease in the alveolar inflammatory response despite increasing doses of ultrafine TiO2 – as indicated by the number of inflammatory neutrophils in lung lavage samples – may be explained by a shift of the inflammation from the alveolar space to the interstitium when more than 50% of the lung deposited dose has translocated to the pulmonary interstitium... Morrow also recognized that other metrics be considered in the ongoing discussion about the “overload” phenomenon; in particular he co-authored a paper indicating that severely retarded AM clearance of test particles following sub-chronic inhalation of ultrafine TiO2 in rats occurred at AM phagocytized doses far below the 6% AM threshold volume, but that the phagocytized particle surface area correlated very well with the observed clearance impairment of both the ultrafine and fine TiO2... The workshop participants concluded that “the lung tumors observed in chronic rat inhalation studies with high dose PSPs … are due to a secondary genotoxicity”, which in rats “operates only at high doses and high levels of neutrophils” and for “PSP, pathology in rodents indicates that if there is no inflammation there is no fibrosis, and if there is no fibrosis, there is no cancer”... More important however, was the split in opinions regarding the relevance of the theory to humans, if so how extrapolation should occur... Both the ILSI workshop in 1998 and MAK workshop in 2000 were not conclusive on this topic, since data to support it were missing... Clearly, studies aimed at generating new insights regarding the fate of phagocytized particles in AM of rodents and primates are required to advance our thinking about the 25-year old phenomenon of lung particle overload... After reading both invited reviews, some conclusions and questions can be summarized as:Before lung particle overload was brought to the attention of the scientific community by the late professor Morrow, Davies had concluded from studying dust accumulation and retention in the lungs of coal miners that an observed greatly enhanced rate of accumulation “must be associated with an increased likelihood of a particle being retained in the lungs after it has been deposited upon the surface of an alveolus”... The originally proposed mechanism for such impaired clearance in terms of volumetric loading of AM still seems to hold for larger particles; however, the particle surface area dose-metric is a valid alternative, especially when nanoparticles are involved, knowing that surface properties and chemistry can make a significant difference in terms of particle-cell interaction which is not associated with simply the volume of the particle in question... The dissolution rate of the phagocytized particles inside a phagolysosome is an important determinant of the particulate state; regardless as to whether the volume or surface area is considered as dose-metric... Also, significant differences between rodents and primates regarding interstitial particle sequestration and associated retention kinetics need to be considered... We believe this enables the arguments to be separated from the political arena, allowing a renewed objective debate... This procedure goes back to the roots and mission of the founding of our open-access journal, dedicated to general aspects of particle and fibre toxicology.

No MeSH data available.


SEM picture of Alveolar Macrophages in lung lavage of a rat 24 hrs after instillation of 10.3 μm polystyrene spheres: AM in foreground with 1 phagocytized sphere showing no clearance; normal functional AM with ruffled surface in background [2].
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Fig1: SEM picture of Alveolar Macrophages in lung lavage of a rat 24 hrs after instillation of 10.3 μm polystyrene spheres: AM in foreground with 1 phagocytized sphere showing no clearance; normal functional AM with ruffled surface in background [2].

Mentions: Morrow [1] proposed the lung particle overload hypothesis based on a careful analysis of many publications on effects and disposition of particles delivered to the lungs of rodents. At the core of the particle overload hypothesis is the question about the relevancy for humans of both non-neoplastic and neoplastic effects observed specifically in rats exposed chronically to extremely high concentrations of poorly soluble particles of low acute toxicity (PSP). Morrow proposed that a continuously increasing prolongation of particle lung clearance of PSP occurs when the retained lung burden exceeds a certain threshold; he identified that this effect on particle clearance is due to an impairment of the alveolar macrophage (AM) clearance function and concluded from his analysis of the data that the impaired clearance correlates with the phagocytized volumetric loading of AM. More specifically, he suggested that the impairment starts when the average composite phagocytized volume exceeds 6% of the normal AM volume, and that complete cessation of clearance occurs when this phagocytized volume reaches 60% of the normal AM volume. Morrow proposed to test this hypothesis by administering tracer doses (below overload) of radioactively-labelled either 3 μm or 10 μm polystyrene spheres to rats, the volume of one 10 μm sphere (600 μm3) being equivalent to ~60% of a rat’s AM volume. The clearance of both particle sizes via in vivo counting of chest radioactivity over 6 months in a collimated detector system confirmed that the 10 μm particles were not cleared, whereas the 3 μm particles cleared with a rat specific normal retention T½ of 80 days [2]. Indeed, examination of lung lavage samples showed that AM had readily phagocytized the large spheres so that one sphere completely filled one AM (Figure 1).Figure 1


Lung particle overload: old school -new insights?

Borm P, Cassee FR, Oberdörster G - Part Fibre Toxicol (2015)

SEM picture of Alveolar Macrophages in lung lavage of a rat 24 hrs after instillation of 10.3 μm polystyrene spheres: AM in foreground with 1 phagocytized sphere showing no clearance; normal functional AM with ruffled surface in background [2].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4419487&req=5

Fig1: SEM picture of Alveolar Macrophages in lung lavage of a rat 24 hrs after instillation of 10.3 μm polystyrene spheres: AM in foreground with 1 phagocytized sphere showing no clearance; normal functional AM with ruffled surface in background [2].
Mentions: Morrow [1] proposed the lung particle overload hypothesis based on a careful analysis of many publications on effects and disposition of particles delivered to the lungs of rodents. At the core of the particle overload hypothesis is the question about the relevancy for humans of both non-neoplastic and neoplastic effects observed specifically in rats exposed chronically to extremely high concentrations of poorly soluble particles of low acute toxicity (PSP). Morrow proposed that a continuously increasing prolongation of particle lung clearance of PSP occurs when the retained lung burden exceeds a certain threshold; he identified that this effect on particle clearance is due to an impairment of the alveolar macrophage (AM) clearance function and concluded from his analysis of the data that the impaired clearance correlates with the phagocytized volumetric loading of AM. More specifically, he suggested that the impairment starts when the average composite phagocytized volume exceeds 6% of the normal AM volume, and that complete cessation of clearance occurs when this phagocytized volume reaches 60% of the normal AM volume. Morrow proposed to test this hypothesis by administering tracer doses (below overload) of radioactively-labelled either 3 μm or 10 μm polystyrene spheres to rats, the volume of one 10 μm sphere (600 μm3) being equivalent to ~60% of a rat’s AM volume. The clearance of both particle sizes via in vivo counting of chest radioactivity over 6 months in a collimated detector system confirmed that the 10 μm particles were not cleared, whereas the 3 μm particles cleared with a rat specific normal retention T½ of 80 days [2]. Indeed, examination of lung lavage samples showed that AM had readily phagocytized the large spheres so that one sphere completely filled one AM (Figure 1).Figure 1

View Article: PubMed Central - PubMed

Affiliation: Zuyd Hogeschool, Department of Life Sciences & Health, PO Box 550, 6400, AN, Heerlen, The Netherlands. paul.borm@zuyd.nl.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

The paper had a major impact on our thinking on the retained dose and clearance upon inhalation of respirable dust... At the core of the particle overload hypothesis is the question about the relevancy for humans of both non-neoplastic and neoplastic effects observed specifically in rats exposed chronically to extremely high concentrations of poorly soluble particles of low acute toxicity (PSP)... Morrow proposed that a continuously increasing prolongation of particle lung clearance of PSP occurs when the retained lung burden exceeds a certain threshold; he identified that this effect on particle clearance is due to an impairment of the alveolar macrophage (AM) clearance function and concluded from his analysis of the data that the impaired clearance correlates with the phagocytized volumetric loading of AM... Morrow’s pioneering studies prompted additional research into the fate of particles in the lung under normal and overload conditions; for example, an increasing interstitial access of particles associated with overload ; or, the finding that a decrease in the alveolar inflammatory response despite increasing doses of ultrafine TiO2 – as indicated by the number of inflammatory neutrophils in lung lavage samples – may be explained by a shift of the inflammation from the alveolar space to the interstitium when more than 50% of the lung deposited dose has translocated to the pulmonary interstitium... Morrow also recognized that other metrics be considered in the ongoing discussion about the “overload” phenomenon; in particular he co-authored a paper indicating that severely retarded AM clearance of test particles following sub-chronic inhalation of ultrafine TiO2 in rats occurred at AM phagocytized doses far below the 6% AM threshold volume, but that the phagocytized particle surface area correlated very well with the observed clearance impairment of both the ultrafine and fine TiO2... The workshop participants concluded that “the lung tumors observed in chronic rat inhalation studies with high dose PSPs … are due to a secondary genotoxicity”, which in rats “operates only at high doses and high levels of neutrophils” and for “PSP, pathology in rodents indicates that if there is no inflammation there is no fibrosis, and if there is no fibrosis, there is no cancer”... More important however, was the split in opinions regarding the relevance of the theory to humans, if so how extrapolation should occur... Both the ILSI workshop in 1998 and MAK workshop in 2000 were not conclusive on this topic, since data to support it were missing... Clearly, studies aimed at generating new insights regarding the fate of phagocytized particles in AM of rodents and primates are required to advance our thinking about the 25-year old phenomenon of lung particle overload... After reading both invited reviews, some conclusions and questions can be summarized as:Before lung particle overload was brought to the attention of the scientific community by the late professor Morrow, Davies had concluded from studying dust accumulation and retention in the lungs of coal miners that an observed greatly enhanced rate of accumulation “must be associated with an increased likelihood of a particle being retained in the lungs after it has been deposited upon the surface of an alveolus”... The originally proposed mechanism for such impaired clearance in terms of volumetric loading of AM still seems to hold for larger particles; however, the particle surface area dose-metric is a valid alternative, especially when nanoparticles are involved, knowing that surface properties and chemistry can make a significant difference in terms of particle-cell interaction which is not associated with simply the volume of the particle in question... The dissolution rate of the phagocytized particles inside a phagolysosome is an important determinant of the particulate state; regardless as to whether the volume or surface area is considered as dose-metric... Also, significant differences between rodents and primates regarding interstitial particle sequestration and associated retention kinetics need to be considered... We believe this enables the arguments to be separated from the political arena, allowing a renewed objective debate... This procedure goes back to the roots and mission of the founding of our open-access journal, dedicated to general aspects of particle and fibre toxicology.

No MeSH data available.