Prediction of the comparative intensity of pneumoconiotic changes caused by chronic inhalation exposure to dusts of different cytotoxicity by means of a mathematical model.

Abstract

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.

Pock Model Simulations of Pulmonary Quartz Dust Retention Data in Extended Inhalation Exposures of Rats

“…The authors observed experimental silicosis but did not report an induction of lung tumors. A similarly close relationship may also exist for the studies by Privalova et al (1987) and Katsnelson et al (1994). Both studies probably used the same quartzite specimen, and the exposure concentrations were almost the same.…”

“…Animal husbandry and analytical procedures of determining compartmental retention data may be other causes for discrepancies. Katsnelson et al (1994) quoted a methodical change in quartzite mass analysis and different particle sizes of the inhaled quartzite dust as partial causes for the observed differences between the two quartzite studies. Besides these systematic deviations, the actual data are scarce and show considerable scatter.…”

“…Bellmann et al (1991) used a quartz aerosol (Dörentrup DQ12; Muhle et al, 1991) in a chronic inhalation study for 24 mo and determined pulmonary lung burdens and lung-associated lymph node loads in male and female Fischer 344 rats. Katsnelson et al (1994) exposed white female rats in a subchronic inhalation study for 20 wk to milled quartzite and measured the recovery from pulmonary deposits and lymph node loads 70 days after cessation of exposure.…”

Some inferences from in vivo experiments with metal and metal oxide nanoparticles: the pulmonary phagocytosis response, subchronic systemic toxicity and genotoxicity, regulatory proposals, searching for bioprotectors (a self-overview)

“…They are hardly always living with chronic inflammation of the respiratory system. Meantime, it is long ago that we [96][97][98][99][100] found fairly strong reasons for considering the NL recruitment response to be an important mechanism of partial compensation for the damage caused by cytotoxic micrometric particles to AMs, the main effector of the pulmonary clearance. A mathematical multi-compartmental model of pulmonary region clearance which comprised just this compensatory mechanism simulated very well the pulmonary retention of dusts of varying degrees of cytotoxicity (quartzite rock, titanium dioxide, standard quartz DQ12) under long-term inhalation exposure as well as a decrease in this retention under the effect of such potent protectors of the macrophage against particle cytotoxicity as glutamate.…”

“…It was found that this recruitment is controlled by the mass of macrophage breakdown products (MBP) and especially by their lipid fraction. [96][97][98][99][100] Therefore, the more cytotoxic for AMs are particles deposited in the lungs (or the higher the dose of MBPs obtained by aseptic freezingthawing or ultrasonic destruction of non-activated peritoneal macrophages and then instilled intratracheally), the higher is a count ratio of NLs to AMs in the BALF. Therefore this ratio (NL/AM) can be used as an indirect but highly informative comparative in vivo index for the cytotoxic action of any low-soluble particle, and it was demonstrated that ranking of dusts by this index was well correlated with the ranking of their cytotoxicity based on the Trypan blue exclusion test for cell viability in vitro.…”