Animal studies to investigate the deposition and clearance of inhaled mineral dusts. Final report on CEC Contract 7248/33/026

The influence of various factors (including electrical charge, exposure concentration, duration of exposure, and particle toxicity) on the deposition and clearance of inhaled mineral dusts was investigated in experiments with rats exposed to dust for 7 hours per day, 5 days per week.The mineral dust aerosols were generated using commercially available dust dispensers. The levels of electrostatic charge on particles in aerosols generated by four types of dispenser were determined for each of three types of dust – quartz, mica and coalmine dust. Three of the dispensers produced particle charges typical (in both magnitude and bipolar distribution) of those measured in previous studies for workplace aerosols. One of these dispensers – the Wright dust feed -was used for the main programme of inhalation studies. The fourth dispenser -the Fluidised Bed – produced unusually high levels of charge (for all three dusts) with predominance of negative charge (for quartz and mica).The effect of charge produced by mechanical generation of the aerosol (by the Wright dust feed) on the deposition of dust in the lung was tested with one group of rats exposed to the charged dust and a control group exposed to a neutralised aerosol. Lung burdens of rats from the test and control groups showed no significant difference for aerosols of quartz, titanium dioxide and mica. This null result contrasts with a substantial effect (up to 100% increase in lung burden) found in similar studies conducted previously with asbestos fibres.It was concluded that electrostatic forces are not normally a significant factor in the lung deposition of most types of mechanically-dispersed mineral dust with the exception of fibrous dusts. However, it was calculated that the unusually high levels of charge produced by the fluidised bed could increase deposition in the lung.The main programme of experiments was directed at elucidating the accumulation of lung burden during chronic (i.e., repeated) exposure. For this, rats were exposed to a toxic dust (quartz, Eurostandard A9950) and a relatively non-toxic dust (titanium dioxide) at target concentrations of, respectively, 0.1, 1.0, 10, 30, and 1.0, 10, 30, and 90 mg/m3 of respirable dust for periods of up to 16 weeks. During these exposures, groups of 12 rats were removed at intervals of exposure time (T) and killed in subgroups at post-exposure times (AT) up to 38 days. The dusts for these experiments were chosen so as to provide particle toxicities which span the range in which coal dust is intermediate. The results showed that lung burdens scaled with respect to exposure concentration, lung burdens increased progressively with exposure time, lung burdens decreased with time post-exposure,and transfer to lymph nodes appeared to commence when the lung burden reached a threshold level which was higher (1800 ��g) for the non-toxic dust than for the toxic dust (900 /��g). This accumulation of lung burden was modelled mathematically by incorporating a sequestration compartment into a conventional model with two clearance compartments. Under this model, lung burden rises (eventually linearly) with exposure time, unlike the prediction from earlier models (e.g., TGLD, 1971) where the lung burden was expected to eventually reach a plateau with deposition and clearance approaching equilibrium. A description of transfer to the lymph nodes was also included in this new model, with the rate of transfer being taken as proportional to the amount by which the lung burden exceeds the threshold level for the onset of transfer.The performance of the new model was tested with further experiments over extended exposure periods (titanium dioxide at 10 mg/m3 for up to 22 months) and extended times post-exposure (up to 255 days for titanium dioxide at 50 mg/m3).These lung burden results supported the general form of the model. However,they also revealed a clear dependence of post-exposure clearance on lung burden (i.e., post-exposure clearance was slower for the group exposed at the higher concentration).This contrasts with the lung burdens scaling with exposure concentration during ongoing exposure. Lymph node burden results from the titanium dioxide exposure at 50 mg/m3 agreed well with the predictions from the model, lymph node results from the 10 mg/m3 exposure agreed less well in magnitude but followed the predicted trend. Some results (for lymph nodes only) were also obtained for quartz (at 10 mg/m3) with extended post-exposure times and these also followed the prediction in trend but not magnitude.The effect of mixed dust exposure on the clearance kinetics was examined in an experiment in which one group of rats was exposed to titanium dioxide at 20 mg/m3 plus quartz at 10 mg/m3, and a second group exposed at concentrations of 30 and 1 mg/m3, respectively. The titanium dioxide (at both 20 and 30 mg/m3) and the quartz (at 10 mg/m3) accumulated at the same rate as when inhaled singly. Post-exposure clearance of the non-toxic dust was impaired by the presence of quartz, and the onset of transfer (of the non-toxic dust) to the lymph nodes occurred at a lower lung burden.Two experiments were conducted in which rats were exposed to coalmine dusts that had been collected by dry filtration of dust from the air in two coalmines, one mining anthracite coal and the other mining a low rank coal. These groups of rats were exposed for periods of 16 and 32 weeks at concentrations of 50 mg/m3, and lung and lymph node burdens analysed for subgroups of six rats at post-exposure times of 3, 66, 129 and 255 days. Lung burdens of dust (and all the components) increased approximately linearly with exposure time – as expected from the sequestration model. The accumulation rates were similar for the two types of coalmine dust (e.g., approximately 5 ��g of coal in the lung per mg/m3 of exposure concentration of coal and per day of exposure). Nevertheless, there were significant differences in retention between the two types of coalmine dust. Retention post-exposure appeared to be greater for the anthracite dust; for this dust there was significantly faster transfer to the lymph nodes and an indication -not statistically substantiated – of slower lung clearance than for the low rank dust, except for the quartz component. For the quartz component, the retention (post-exposure) was significantly greater for the low rank coalmine dust. Examination of the lung and lymph node burden results in conjunction with those from the parallel studies of the cellular response in the rat lung (Donaldson et al, 1988), produced evidence that inflammation is associated with an impairment of clearance and the stimulation of increased lymph node transport. For example, clearance during exposure appeared to be less for the high concentrations of titanium dioxide (90 and 30 mg/m3) than for the low concentrations (10 and 1 mg/m3). This was associated with an increase in the inflammatory response late in the exposure periods for the higher concentrations. Clearance during exposure was negligible for quartz which provoked a high level of inflammatory response. The detection of these differences between the clearance of these two types of dust suggests that the new kinetic model of clearance can be further developed to take account of the nature of the particles.Finally, it is proposed that the form of the new model – describing the effects of chronic exposure – will provide a more effective means of intrepreting human exposure histories for the purposes of epidemiology, risk assessment and health management. “”