title: Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite.
abstract: In former mine workers and residents of Libby, Montana, exposure to amphibole-contaminated vermiculite has been associated with increased incidences of asbestosis and mesothelioma. In this study, long-term effects of Libby amphibole (LA) exposure were investigated relative to the well-characterized amosite asbestos in a rat model. Rat-respirable fractions of LA and amosite (aerodynamic diameter≤2.5 μm) were prepared by water elutriation. Male F344 rats were exposed to a single dose of either saline, amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal (IT) instillation. One year after exposure, asbestos-exposed rats displayed chronic pulmonary inflammation and fibrosis. Two years postexposure, lung inflammation and fibrosis progressed in a time- and dose-dependent manner in LA-exposed rats, although the severity of inflammation and fibrosis was smaller in magnitude than in animals exposed to amosite. In contrast, gene expression of the fibrosis markers Col 1A2 and Col 3A1 was significantly greater in LA-exposed compared to amosite-exposed rats. There was no apparent evidence of preneoplastic changes in any of the asbestos-exposed groups. However, all asbestos-exposed rats demonstrated a significant increase in the expression of epidermal growth factor receptor (EGFR) 2 yr after instillation. In addition, only LA-exposed rats showed significant elevation in mesothelin (Msln) and Wilms' tumor gene (WT1) expression, suggesting possible induction of tumor pathways. These results demonstrate that a single IT exposure to LA is sufficient to induce significant fibrogenic, but not carcinogenic, effects up to 2 yr after exposure that differ both in quality and magnitude from those elicited by amosite administration at the same mass dose in F344 rats. Data showed that LA was on a mass basis less potent than amosite.
authors.affiliation: Curriculum in Toxicology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Cyphert
authors.forename: D J
authors.initials: DJ
authors.lastname: Padilla-Carlin
authors.forename: M C
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: J H
authors.initials: JH
authors.lastname: Shannahan
authors.forename: A
authors.initials: A
authors.lastname: Nyska
authors.forename: U P
authors.initials: UP
authors.lastname: Kodavanti
authors.forename: S H
authors.initials: SH
authors.lastname: Gavett
mesh_terms: D000818:Animals; D017639:Asbestos, Amosite / Q000633:toxicity*; D017636:Asbestos, Amphibole / Q000633:toxicity*; D015415:Biomarkers; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D016162:Genes, Wilms Tumor / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D000090204:Mesothelin; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D017636:Asbestos, Amphibole; D015415:Biomarkers; D058851:GPI-Linked Proteins; C000715529:Msln protein, rat; D017639:Asbestos, Amosite; C483803:Egfr protein, rat; D066246:ErbB Receptors; D000090204:Mesothelin