Technical Report 122

Dose metrics

A substantial number of experimental observations have led to the general concept of dust overloading of the lungs (e.g. Klosterkötter and Bueman, 1961, Ferin 1972, 1977, Green et al 1983, Lee et al, 1985). The essence of this experimental finding is bipartite: (a) long-term exposure to relatively high dust concentrations leads to excessive pulmonary dust burdens whereby the pulmonary clearance of persistently retained particles by alveolar macrophages becomes progressively reduced until it essentially ceases: at this time, lung dust burdens increase linearly at a build-up rate approximating the rate of dust deposition; (b) as excessive lung burdens develop, a number of alterations appear in both the disposition of retained particles and their pattern of induced responses and toxic actions within the lungs.

In this context of a more qualitative description, a quantitative definition of the overload condition was still missing; it was not clear whether such an overload theory could be generally applied to all persistent dust and for other species besides rat. In his paper of 1988 (Morrow 1988) Morrow for the first time provided a mechanistic hypothesis and proposed that overload condition was caused and perpetuated by a loss in mobility of alveolar macrophages (AM). He considered the build-up and clearance kinetic of the alveolar region. Assuming first order clearance kinetics, a chronic exposure to certain concentration of a poorly soluble dust would achieve a steady-state condition after a time period corresponding to about five times the retention half time. In this simple model, deposition rate was the factor for build-up of lung burden and retention half time was the factor influencing the clearance. This type of curve had been demonstrated earlier during chronic studies (Leach 1970 and Stöber et al, 1967). It describes what is to be expected during chronic inhalation exposure.

Another aspect of Morrow´s hypothesis was to evaluate factors affecting the mobility of the AM to translocate from the lungs. By reviewing several seemingly isolated highly germane experiments, he considered directed migration by chemotactic factors as the least contentious. The actions of several chemo-attractants, activators and modulators (e.g. macrophage migratory inhibition factor, fibronectin and colony stimulation factors) were mainly examined in vitro. How much they contribute to the cessation of AM mobility is not clear. Scanning electron microscopic examination indicated that volumetric loading-related changes of AM´s cytoskeletal system likely contributed to inability of AM to spreading and locomotion (also Section 4).

Mainly, the following three dose metrics have been used trying to identify and describe the relationship between particle exposure and lung overload conditions.