Evidence of a no-effect level in silica-induced rat lung mutagenicity but not in fibrogenicity.
Exposure to silica can lead to fibrosis and the development of lung tumors in the rat. Based on these animal studies and on epidemiological data, silica has been classified as a human carcinogen. The initial mechanisms have not been finally clarified, but particle-induced tumor formation is at least closely associated with inflammation, the production of reactive oxygen species (ROS) and DNA damage. We investigated the dose-dependent effects of silica on the formation of the major DNA oxidation product 8-oxoguanine (8-oxo-Gua) in rat lung cells, on p53 (p53) and p53 mutant protein (p53 mut) synthesis, as well as on the amount of the surfactant phospholipids phosphatidylinositol (PI) and phosphatidylglycerol (PG) in the bronchoalveolar lavage fluids (BALF) as indicators of fibrotic processes in the lung. Rats were exposed by intratracheal instillation to various amounts of DQ12 quartz (0.15, 0.3, 0.6, 1.2, 2.4 mg/animal) and lungs were investigated after 21 and 90 days. PG decreased and PI increased quartz dose dependently. 8-oxoGua was significantly increased only after 1.2 and 2.4 mg quartz/animal. Cells expressing p53 protein were increased at 1.2 and 2.4 mg, p53 mutant protein only at 2.4 mg/animal. This indicates a no-effect level for mutagenicity at a low, but still fibrogenic quartz exposure.
Seiler
F
F
Institute of Hygiene and Occupational Medicine, University of Essen Medical School, Germany.
Rehn
B
B
Rehn
S
S
Bruch
J
J
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D019044:Image Cytometry; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D009154:Mutation; D019055:No-Observed-Adverse-Effect Level; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011663:Pulmonary Surfactants / Q000032:analysis; D011791:Quartz / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D009153:Mutagens; D011663:Pulmonary Surfactants; D016159:Tumor Suppressor Protein p53; D011791:Quartz; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA