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Persistent Effects of Libby Amphibole and Amosite Asbestos Following Subchronic Inhalation in Rats
Gavett, S., C. Parkinson, G. Willson, C. Wood, A. Jarabek, K. Roberts, U. Kodavanti, AND D. Dodd. Persistent Effects of Libby Amphibole and Amosite Asbestos Following Subchronic Inhalation in Rats. Particle and Fibre Toxicology. BioMed Central Ltd, London, Uk, 13(1):17, (2016).
This paper addresses Sustainable Healthy Communities research on technical support for policy, guidance, and targeted research for contaminated site management (SHC 126.96.36.199). We find that inhalation exposure of rats to Libby amphibole (LA) asbestos produces persistent inflammatory and fibrotic responses in the lung. Mechanistic studies show that inflammation and activation of growth factor pathways may persist and contribute to lung tumorigenesis long after initial LA exposure. The results further inform risk assessment efforts by EPA on the Libby, Montana Superfund site.
Background: Human exposure to Libby amphibole (LA) asbestos increases risk of lung cancer, mesothelioma, and non-malignant respiratory disease. This study evaluated potency and time course effects of LA and positive control amosite (AM) asbestos fibers in male F344 rats following nose-only inhalation exposure. Methods: Rats were exposed to air, LA (0.5, 3.5, or 25.0 mg/m3 targets), or AM (3.5 mg/m3 target) for 10 days and assessed for markers of lung inflammation, injury, and cell proliferation. Short-term results guided concentration levels for a stop-exposure study in which rats were exposed to air, LA (1.0, 3.3, or 10.0 mg/m3), or AM (3.3 mg/m3) 6 hours/day, 5 days/week for 13 weeks, and assessed 1 day, 1 month, 3 months, and 18 months post-exposure. Fibers were relatively short; for 10 mg/m(3)LA, mean length of all structures was 3.7 um and 1% were longer than 20 um. Results: Ten days exposure to 25.0 mg/m3 LA resulted in significantly increased lung inflammation, fibrosis, bronchiolar epithelial cell proliferation and hyperplasia, and inflammatory cytokine gene expression compared to air. Exposure to 3.5 mg/m3 LA resulted in modestly higher markers of acute lung injury and inflammation compared to AM. Following 13 weeks exposure, lung fiber burdens correlated with exposure mass concentrations, declining gradually over 18 months. LA (3.3 and 10.0 mg/m3) and AM produced significantly higher bronchoalveolar lavage markers of inflammation and lung tissue cytokines, Akt, and MAPK/ERK pathway components compared to air control from 1 day to 3 months post-exposure. Histopathology showed alveolar inflammation and interstitial fibrosis in all fiber-exposed groups up to 18 months post-exposure. Positive dose trends for incidence of alveolar epithelial hyperplasia and bronchiolar/alveolar adenoma or carcinoma were observed among LA groups. Conclusions: Inhalation of realitively short LA fibers produced inflammatory, fibrogenic and tumorigenic effects in rats which replicate essential attributes of asbestos-related disease in exposed humans.Fiber burden, inflammation, and activation of growth factor pathways may persist and contribute to lung tumorigenesis long after initial LA exposure. Fiber burden data are being used to develop a dosimetry model for LA fibers, which may provide insights on mode of action for hazard assessment.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL PUBLIC HEALTH DIVISION
CLINICAL RESEARCH BRANCH