Rats were exposed to quartz dust (about 90 mg/m3) for five hours a day, five times a week either throughout the 48 weeks of the experiment or for a total of 40 weeks plus eight weeks of "rest."Cytological study of bronchoalveolar lavage showed that at a certain level of silicotic changes in the lungs, a pronounced breakdown in pulmonary dust clearance by macrophages could be observed. There was, however, a concomitant compensatory increase in the contribution to pulmonary phagocytosis by the neutrophil leukocytes (NL). As a result, pulmonary dust kinetics could be mathematically described using a constant clearance rate both throughout the 48 weeks of exposure and during the eight weeks after the end of the 40 week exposure. It is shown in a separate experiment that enhanced recruitment of NL into the airways may be due not only to an attractant effect of the products of macrophage breakdown (PMB) themselves but also to the release of an NL attractant factor by viable macrophages activated under influence of the PMB.

Optical microscopy (OM), semi-contact atomic force microscopy (sc-AFM), and transmission electron microscopy (TEM) were applied to examine cells in the broncho-alveolar lavage fluid (BALF) obtained from rats 24 hours after instillation of different metallic particles suspended in deionised water or of water without any particles. In a comparative experiment with iron oxide Fe 3 O 4 (magnetite) particles having a mean diameter of 10 nm, 50 nm or 1 μm, it was demonstrated that, given equal mass doses, nanoparticles (NPs) induce much more intensive recruitment of phagocytes with a much more significant shift toward neutrophil leukocytes (NL) count in the BALF cell population than micrometric particles do, this shift being an indirect but informative index of particle cytotoxicity for alveolar macrophages (AM). Judging by NL/AM ratio, this cytotoxicity diminishes in the sequence: 10 nm > 50 nm> 1 μm, while judging by OM counts of visible aggregated particles within AMs and NLs and by sc-AFM count of micro-invaginations on the surfaces of these cells, their avidity for particles decreases in the same succession. The same dependence of cell recruitment and of phagocytic activity on NP cytotoxicity was found when the NP diameters were quite similar (ca. 3.5-4.0 nm) but the cytotoxicity of one metal (in our experiment, nanosilver) was higher than that of another (nanogold). TEM pictures of AMs from rats administered the 10 nm magnetite testify to the ability of AMs to actively engulf single NPs and their small aggregates which then form larger conglomerates within fused phagosomes. Some of these large phagosomes lost their membrane, and so freed NPs came into close contact with the nuclear membrane and with mitochondrial membranes and cristae causing their marked damage.

A multicompartmental model for the kinetics of dust retention in the pulmonary region of the lung and in the tracheobronchial lymph nodes has been developed. The model reflects the following ideas concerning the basic features ofthis process: (1) penetration into the pulmonary interstitium and translocation to the lymph nodes are possible for nonphagocytised particles only; (2) these processes depend on the degree of damage to macrophages by dust and on the extent of compensatory enhancement in the recruitment of neutrophils taking part in the clearance of the pulmonary region free surface; (3) a certain proportion of initially penetrating particles is continuously returned to this surface together with recruited pulmonary macrophages. The model ensures a satisfactory approximation to experimental data on the retention ofquartz in the lung and lymph nodes during long term inhalation exposure, and simulation of the kinetic effects associated with both the damage to and the protection of the macrophagal clearance mechanism.Various mathematical models for the kinetics of deposition and retention of dust in the lung are usually proposed as a basis for predicting "the accumulation of lung burden during prolonged chronic exposure relevant to the exposure of workers to mineral dusts in a wide range of industries"' and, thus, as an instrument for "exposure assessment for occupational epidemiology".23Another Modelling the kinetics of the deposition and retention of particles in the "deep lung" (meaning the region that was called "pulmonary" by the ICRP Task Group on Lung Dynamics4 and many other authors) Vincent et al considered two mutually independent compartments of "medium" and "slow" clearance; the third compartment (of "fast" clearance) corresponded to the tracheobronchial region. The model, however, does not account for the physiological mechanisms that determine the differences in the rate of clearance of the compartments, and its structure is not claimed to describe actual relations between them.Most investigators (for example5) identify the rapidly removed part of dust deposited in the pulmonary region as that which is removed directly from the free surface ofthe acinus towards the mucociliary escalator, and the slowly removed part as that which has already penetrated into the "fixed tissues" (into the lung interstitium). Thus in both the route of deposition and the route of elimination, real compartments of dust in the "deep lung" are connected in series rather than in parallel as in the model.'One ofthe variants ofthis model assumes a sudden and complete failure of the medium clearance compartment and, therefore, transfer of all material into the slow clearance compartment. In another variant of the same model, both compartments have parallel exits not only to the mucociliary escalator but also to some intralung kinetic trap that has no exit at all. Like the basic model,' both of these variants ensure a

A multicompartmental mathematical model has been used to simulate variations in the cytotoxicity of dusts in the kinetics of the retention, in the pulmonary region and tracheobronchial lymph nodes, of practically insoluble quartzite and titanium dioxide dust particles deposited on the free surfaces of the acini from alveolar air. Experiments with these dusts were conducted on rats exposed to virtually the same dust concentrations in the air for an experimental period of 20 weeks and a period of 10 weeks after exposure. Satisfactory approximation to the experimental data on the retention of these dusts is obtained by using the model parameters that depend either on damage to lung macrophages by phagocytosed particles or on the response of the host organism to this damage by enhanced recruitment of neutrophilic leucocytes; all the other variables of the model being unchanged. The values of the "action integral" computed from this model and multiplied by the index of comparative cytotoxicity of particles in vitro satisfactorily approximate to quantitative differences in the intensity of pneumoconioses caused by the dusts under study by the end of the experimental period. On the whole, the results of the mathematical model agree with the hypothesis that the cytotoxicity of particles plays a key part in both the process of retention of dust in the lung parenchyma and lung associated lymph nodes, and the pathological process caused by the retained dust. Thus given the factors and conditions on which the deposition of practically insoluble dusts in the pulmonary region depends, it is necessary to take into account the multiplicative nature of these two effects of cytotoxicity when predicting the comparative risk of pneumoconiosis. (Occup Environ Med 1994;51:173-180) The breakdown of lung macrophages as a result of ingesting poorly soluble dust particles is a key link in the pathogenesis of pneumoconioses. This link determines both the effectiveness of lung clearance (and thus the kinetics of retention of dust in the lung parenchyma and lung associated lymph nodes) and the intensity of pathological changes in these organs caused by long term dust retention. Most of the researchers in this field share this view, with subtle differences. It still remains, however, a hypothesis that has not been treated quantitatively. The dual effect of cytotoxicity of dust is not disputed, but the statement that it has a key role still remains a speculative one.

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