title: Mutagenesis by man-made mineral fibres in the lung of rats.
abstract: The potential of two asbestos substitute mineral fibres--rock (stone) wool RW1 and glass wool MMVF10--to induce gene mutations, DNA strand breaks, inflammation and oxidative stress has been studied in rats. Male homozygous lamda-lacI transgenic F344 rats were intratracheally instilled with single doses of 1 and 2 mg/animal of fibres or with multiple doses of 2 mg/animal administered weekly on four consecutive weeks (8 mg in total). Exposure to RW1 fibres for 16 weeks significantly increased mutant frequency (MF) in the lung in a dose-dependent manner, while MMVF10 fibres did not exhibit any increase of MF at any dose. RW1 fibres gave a significant increase of MF at a dose of 1 mg. Four weeks after instillation, neither the single nor the multiple doses significantly increased MF for both fibre types. To investigate mechanisms for induction of mutations, other genotoxicity markers and parameters of inflammatory and oxidative damage were determined in relation to MF. A weak correlation of mutagenicity data with other genotoxicity parameters studied was observed. DNA strand breaks as measured by comet assay were increased in alveolar macrophages and lung epithelial cells of RW1 and MMVF10 treated rats. RWl fibres caused more extensive lung inflammation as measured by release of neutrophils into broncho-alveolar lavage fluid than MMVF10 fibres. The effects were observed 16 weeks post-exposure, indicating a persistence of the pathogenic process during the exposure period. Only minor differences in the extent of inflammatory processes were observed between the doses of 2 mg and 4 x 2 mg, suggesting that any threshold for inflammation lies below the dose of 2 mg. With the exception of the highest dose of MMVF10 fibres after 16 weeks of exposure, no significant increase of oxidative damage as measured by levels of malondialdehyde in lung tissue was observed. MMVF10 fibres caused weaker inflammation in the lung of rats and did not exhibit any mutagenic effect. We conclude that a weak but chronic inflammation (more likely than acute inflammation or direct oxidative damage) in the lung tissue of fibre treated rats characterized by moderate influx of inflammatory cells into BAL is probably responsible for the observed mutagenic effect of RW1 fibres.
authors.affiliation: GSF-National Research Centerfor Environment and Health, Institute of Toxicology, Ingolstaedter Landstrasse 1, D-85764 Neuherberg, Germany. jtopinka@biomed.cas.cz
authors.forename: J b
authors.initials: Jb
authors.lastname: Topinka
authors.forename: P
authors.initials: P
authors.lastname: Loli
authors.forename: M
authors.initials: M
authors.lastname: Dusinská
authors.forename: M
authors.initials: M
authors.lastname: Hurbánková
authors.forename: Z
authors.initials: Z
authors.lastname: Kováciková
authors.forename: K
authors.initials: K
authors.lastname: Volkovová
authors.forename: A
authors.initials: A
authors.lastname: Kazimírová
authors.forename: M
authors.initials: M
authors.lastname: Barancoková
authors.forename: E
authors.initials: E
authors.lastname: Tatrai
authors.forename: T
authors.initials: T
authors.lastname: Wolff
authors.forename: D
authors.initials: D
authors.lastname: Oesterle
authors.forename: S A
authors.initials: SA
authors.lastname: Kyrtopoulos
authors.forename: P
authors.initials: P
authors.lastname: Georgiadis
mesh_terms: D000818:Animals; D001194:Asbestos / Q000494:pharmacology / Q000633:toxicity; D015415:Biomarkers; D018893:Bronchoalveolar Lavage; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D019016:Mineral Fibers / Q000009:adverse effects*; D016296:Mutagenesis / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007375:Interleukin-1; D019016:Mineral Fibers; D014409:Tumor Necrosis Factor-alpha; D001194:Asbestos; D008315:Malondialdehyde