Quartz exposure of the rat lung leads to a linear dose response in inflammation but not in oxidative DNA damage and mutagenicity

Exposure to quartz and high concentrations of other poorly soluble particle s can lead to the development of lung tumors in the rat. The mechanisms inv olved in particle-induced carcinogenesis seem to include inflammation-assoc iated production of reactive oxygen species (ROS) and DNA damage. ROS induc e 8-oxoguanine (8-oxoGua) and a panel of other oxidation products in DNA. I n proliferating cells such DNA lesions can lead to various types of mutatio ns, which might be critical for cancer-related genes with respect to tumor formation. Quartz is known to mediate the induction of 8-oxoGua in the nucl ear DNA of lung cells when applied to the lung of rats. We have investigate d the time- and dose-dependent biologic effects of quartz and, as a control , corundum, on cell proliferation and various pulmonary inflammation and to xicity markers in rat bronchoalveolar lavage fluid (BALF); on the induction of 8-oxoGua in the DNA of rat lung cells; and on the cellular levels of p5 3 wild-type and p53 mutant (mut) protein. Rats were exposed by intratrachea l instillation to various amounts of quartz (0.3, 1.5, or 7.5 mg/rat) or co rundum (0.3, 1.5, or 7.5 mg/rat) and measured at Days 7, 21, and 90 after e xposure. Corundum had no adverse effects except a slight elevation of 8-oxo Gua at a dose of 7.5 mg/rat. However, significant changes in the BALF were detected at all quartz doses. 8-oxoGua was significantly increased only at 1.5 and 7.5 mg quartz/rat. The amount of cells with detectable p53 wild-typ e protein levels was increased at 1.5 and 7.5 mg quartz/rat at 7 and 21 d. Elevated amounts of cells with enhanced p53 mut protein levels were measure d at all time points after instillation of 7.5 mg quartz/rat.