Technical Report 122

Biomathematical modelling of respirable dust in human lungs

Based the particle burdens in the lung and hilar lymph nodes measured in US coal miners, Kuempel et al, developed biomathematical model of particle clearance and retention (Kuempel et al, 2001a). They found that the particle clearance and retention as observed in the lungs and lymph nodes of coal miners was poorly described by the one-compartment dosimetry model which is applicable to rats, e.g. (Muhle et al, 1990). Kuempel et al developed a 3-compartment model consisting of the deposition of inhaled particles in the alveolar region, competing processes of either clearance from the alveolar region or translocation to the lung interstitial region, and very slow irreversible sequestration of interstitialised material in the lung-associated lymph nodes. Kuempel et al (2001a) also compared the required lung dust burden in rats and humans which would lead to a decline of the alveolar-macrophage-mediated clearance rate. Based on the differences in macrophage volume and number, the minimal (onset of clearance rate decrease) and maximal (levelling off of the clearance rate decrease) coal dust burdens were estimated and these were found to be approximately 33% higher in humans than in rats (Kuempel et al, 2001a). The decrease of the macrophage-mediated lung clearance as observed in rodent studies was shown not to be a major determinant of the lung burdens in the US miners. The half-time of respirable particle retention in coal miners' lungs was shown to be 5 to 15 years, compared to less than 2 years in persons without dusty jobs. The increased retention half-time in coal miners might be consistent with a substantial portion of the dust being sequestered at all lung dust burdens, due to the longer residence time in the alveolar region. Only in the "overloaded” rat, i.e. at significantly slower alveolar-macrophage-mediated clearance rates, does the lung burden reach concentrations as high as those observed in some humans with occupational dust exposure, such as coal miners. Kuempel et al, (2001b) explored the biomathematical model further in a second publication looking at the model's variability and uncertainty which confirmed the earlier findings, i.e. the best-fitting exposure-dose model to the US miners data had substantial interstitialisation/sequestration of particles and no dose-dependent decline in alveolar clearance. Tran and Buchanan (2000) confirmed the model proposed by Kuempel et al, using a data set from UK coal miners. In addition, they observed a different behaviour of the quartz and non-quartz fraction of coal dust, the first showing a higher tendency to remain in the lung and lymph nodes. More recently, the 3-compartment model has been shown to also best predict the exposure to radioactive cobalt or plutonium (Gregoratto et al, 2010a,b). The model structure was recently adopted by the International Commission on Radiological Protection (ICRP) to describe the long-term clearance and retention of inhaled particles in the alveolar-interstitial region of the human respiratory tract and an additional statistical analysis of the model confirmed once more the conclusions made earlier by Kuempel et al (Sweeney et al, 2013).

In conclusion, albeit that the model has only been validated using a limited number of dusts, it provides rather strong indications that the overload concept as being described for rats is of little relevance for humans which have been chronically exposed to high levels of dusts. The relevance of effects which are observed in rats in conditions at which the alveolar-macrophage-mediated lung clearance has been seriously affected might be limited because such conditions do not appear to occur in humans according to the model developed by Kuempel et al, On the other hand, the interstitialisation/sequestration of particles from the alveolar spaces, possibly followed by translocation to the draining lymph nodes appears to be of higher relevance in humans, even at lower level exposures.