Development of a dosimetric model for assessing the health risks associated with inhaling coalmine dusts. Final report on CEC research contract 7280/07/015

The Institute of Occupational Medicine has contributed to the development of mathematical models of deposition and clearance of fibres and other inhaled particles over many years. The earliest of these studies (Middleton et al, 1977, 1979) addressed differences in deposition and clearance of different varieties of asbestos fibres inhaled by rats during a six week period of exposure . This was followed by an assessment of the effect of lung burden on the clearance of fibres (Bolton et al, 1983). Subsequent studies developed models to describe the deposition, clearance and sequestration of mineral dusts and fibres during chronic exposure, using data from animal studies of rats exposed for up to one year using both fibres and mineral dusts (Vincent et al, 1985, 1987; Jones et al, 1988; Jones et al, 1989). These latter studies were concurrent with complementary studies to examine the inflammatory response provoked by such dusts (Donaldson et al, 1988) which described the changing state of the population of the phagocytic cells that provide the principal mechanism of clearance.The purpose of a mathematical model of the deposition, retention and clearance of particles or fibres has been to provide a systematic and quantitative description of the processes which determined the likelihood that an inhaled particle or fibre is either retained or cleared. Previous models have generally been developed by using experimental lung burden data to obtain best fit values of transfer rate coefficients for the transport of particles from the lung (Vincent et al, 1985; Stflber et al, 1989). More recently, attempts have been made to develop models to incorporate a description of the actual biological mechanisms and where the values of transport coefficients are constrained to be consistent with information regarding the relative number of different type of cells and the number in lavaged cells (Katsnelson et al, 1992). In this report, the realism of the model is taken another stage further by basing it on the kinetics of the inflammatory response (i.e. of the population of phagocytic cells, chemotactic factors, etc…)Consequently, a mathematical model describing the retention and clearance of particles has been developed and tested on two types of particles, quartz and titanium dioxide, TiO2 (the former being cytotoxic (Allison et al, 1966) and the latter ‘inert’ (Ferin and Oberdorster, 1985)). The current model has described the process of deposition of particles in the alveolar region, and their subsequent retention and clearance, in terms of the mechanisms of cell biology, specifically that of phagocytosis by alveolar macrophages (AM) and neutrophils (also known as golymorphonuclear or PMN cells). To model phagocytosis by AMs, the AM population is subdivided into different load-classes and estimated parameters of the kinetics are assigned to the transfer of macrophages between load-classes.For TiO2, the model predicts the sequestration of AMs in the alveolar space. This is the consequence of the loss of macrophage mobility when excessive amounts of particles are phagocytosed. This is most pronounced when, at very high lung burden, the clearance of TiO2 particles from the lung by AMs becomes impaired to the extent that the particle clearance at post exposure decreases with increasing lung burden. This is known as the ‘overload phenomenon’.For quartz, the model describes the necrosis of macrophages caused by the ingestion of quartz particles and the subsequent release of these particles.onto the alveolar surface. Since any macrophages which attempt to phagocytose these quartz particles are likely to be damaged, these particles will not be successfully removed from the alveoli; instead their continuing presence on the epithelium will increase their likelihood of being interstitialised. As macrophages die, inflammatory cytokines are released into the alveolar space resulting in a recruitment of further AMs and PMNs. When macrophage necrosis is continuing, recruitment is also ongoing, leading to ‘chronic inflammation’. This inflammatory recruitment is described in a functional form and is included in the model.The final part of the model describes the fate of particles which have escaped phagocytosis by the alveolar phagocytes. These particles may be cleared from the alveolar surface to the tracheobronchial region or they may cross the epithelium into the interstitium. Once in the interstitium as free particles they may be cleared to the lymph nodes, or phagocytosed by interstitial macrophages (IM)- Phagocytosed particles may either be sequestrated in the interstitium or eventually removed to the lymph nodes.The model was used to simulate the retention and clearance of quartz and TiQ, at different concentrations. The simulations of the AM and PMN response to the deposition of quartz or TiO2 as well as the time course of the lung burden and lymph node burden of these dusts under different exposure levels have compared well with the data from experimental studies carried out at the IOM; also, the model has successfully simulated the breakdown of the clearance mechanism under high exposure level to TiQj, the “”overload phenomenon”” (Morrow, 1988, 1992). Finally, the possibility of extending the model to the mathematical modelling of fibres, the scaling of animal to human data and a framework for the mathematical modelling of lung injury and diseases are also discussed. “”