Lung Particle Overload: Implications for Occupational Exposures to Particles

Chronic pulmonary inflammation, pulmonary fibrosis, and even lung tumors developed in a number of chronic inhalation studies in rats with highly insoluble nonfibrous particles of low cytotoxicity. Concerns were expressed that these responses are due to excessive particulate lung burdens, and the term "particle overload" was coined to characterize these conditions. The hallmark of the particle-overloaded lung is an impairment of alveolar macrophage (AM)-mediated lung clearance which has been demonstrated in all species tested so far and which eventually leads to accumulation of excessive lung burdens. Experimental evidence suggests that the volume of the particles phagocytized by AM: is most critical for causing their impaired clearance function, and that the condition of lung overload is reached once the retained lung particle burden reaches a level equivalent to a volume of approximately 1 μl/g of lung. Cytotoxic particles also cause impaired AM clearance function, yet at a much lower lung burden which does not qualify as particle overload. Significant species differences exist with respect to the induction of adverse chronic effects in response to lung overload; i.e., mice and hamsters are less prone to developing chronic inflammation and pulmonary fibrosis, and lung tumors have been observed only in rat studies. Lung tumors or fibrosis in the rats were seen only at lung burdens having caused impaired particle clearance, and a threshold dose for the adverse chronic effects can be postulated which is defined by a lung particle burden not causing impairment of clearance. Thus, the lung tumors observed in chronic rat studies at very high particulate exposure concentrations may not be relevant for human extrapolation to low-exposure concentrations. Evidence in humans suggests that particle-overloaded lungs, e.g., in coal workers, respond with fibrosis, but no increased incidence of lung tumors has been found in this group. However, it cannot be excluded that other types of chronically inhaled particles may have a carcinogenic potential in the human lung if accumulating to very high lung burdens. More research is needed for a detailed understanding of the basic mechanism leading to nonfibrous particle-induced tumorigenesis in the lungs of different species. Altered particle accumulation and retention kinetics and chronic inflammation in the overloaded lung indicate that the maximum tolerated dose (MTD) has been exceeded. No specific guidelines for inhalation studies defining the MTD have been established; general guidelines are not necessarily applicable for chronic inhalation studies. One suggestion is to define the MTD in chronic particle inhalation studies as a maximum functionally tolerated dose (MFTD) based on a functional parameter of lung particle clearance. However, other endpoints based on an evaluation of alveolar inflammation and lung histology should be included as well. For the estimation of the MTD or MFTD a range-finding study of sufficient length, preferably 3 months, would be required. It is important to realize, however, that with increasing chronicity of exposure and increasing age of the animals, a shift in the dose-response relationship may occur. One important conclusion from our understanding of lung particle overload is that occupational exposure limits should be set to prevent impaired AM-mediated lung clearance which will-avert the accumulation of high pulmonary dust burdens; conceivably, this will also prevent the subsequent induction of adverse chronic effects including inflammation, fibrosis, and tumors since these particle-induced tumors are likely secondary to continued inflammation, tissue damage, and cell proliferation. Extrapolation from rat studies of such exposure limits predicts that present occupational standards for highly insoluble particles of low cytotoxicity may not prevent lung overload in humans and should be reevaluated.