Ultrafine particles are a component of air pollution, derived from primary combustion sources, and so we have undertaken a programme of study on the mechanisms of lung injury caused by ultrafine particles. Ultrafine particles made of low-solubility, low-toxicity materials are more inflammogenic in the rat lung than fine respirable, particles made from the same material. Ultrafine particles can cause inflammation via processes independent of the release of transition metals, as shown by the fact that soluble products from ultrafine carbon black have no ability to cause inflammation. The property that drives the greater inflammogenicity of ultrafines is unknown but very likely relates to particle surface area and involves oxidative stress. Increases in intracellular Ca(++) may underlie the cellular effects of ultrafines, although the mechanism whereby ultrafines have this effect is not understood. However, increased influx of Ca(++) into macrophages occurs via the membrane Ca(++) channels following contact with ultrafine particles, and involves oxidative stress. Increased Ca(++) in macrophages exposed to ultrafines can lead to the transcription of key pro-inflammatory genes such as TNFalpha. Ultrafine particles can also impair the ability of macrophages to phagocytose and clear other particles, and this may be pro-inflammogenic.
In 1997, the IARC (International Agency for Research on Cancer) reevaluated its quartz classification from a class 2 carcinogen, to that of a class 1, stating sufficient evidence for carcinogenicity in both humans and experimental animals. However, tumor development did not occur across all occupational settings. It is probable that this is due to the considerable differences in toxicity between workplace quartz in comparison to quartz used in experimental studies. We therefore hypothesized that workplace quartz samples differ in toxicity from standard experimental quartz samples at equal mass. To test this hypothesis we compared 2 workplace quartz samples (RH1 and OM) with standard experimental quartz (DQ12) in several assays commonly used in particle toxicology. The sizes of the quartz samples were as closely matched as possible. The endpoints of this study were inflammation in the rat lung following intratracheal instillation (1000 microg or 250 microg for 3 or 14 days), release of soluble iron, cytotoxicity to cells in culture, and surface reactivity as assessed by hemolysis and ESR. The workplace samples did not cause inflammation at any dose or time point. DQ12 quartz caused marked inflammatory responses, as measured by an increased number of neutrophils in the lungs of instilled animals for both time points and doses. Protein in the bronchoalveolar lavage also increased in animals exposed to DQ12 but not the workplace samples. In vitro, DQ12 had the greatest hemolytic activity but only RH1 released substantial amounts of soluble iron. The increased inflammogenicity of DQ12 was not wholly explained by a greater surface area, by diameter, or by releasable iron. The hemolytic activity of DQ12, while not being informative in terms of understanding the mechanism of carcinogenicity, was the best in vitro predictor for in vivo activity. Therefore the surface reactivity of DQ12 appears to drive its inflammogenicity.
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