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In vitro determinants of asbestos fiber toxicity: effect on the relative toxicity of Libby amphibole in primary human airway epithelial cells.

ABSTRACT: BACKGROUND: An abnormally high incidence of lung disease has been observed in the residents of Libby, Montana, which has been attributed to occupational and environmental exposure to fibrous amphiboles originating from a nearby contaminated vermiculite mine. The composition of Libby amphibole (LA) is complex and minimal toxicity data are available. In this study, we conduct a comparative particle toxicity analysis of LA compared with standard reference asbestiform amphibole samples. METHODS: Primary human airway epithelial cells (HAEC) were exposed to two different LA samples as well as standard amphibole reference samples. Analysis of the samples included a complete particle size distribution analysis, calculation of surface area by electron microscopy and by gas adsorption and quantification of surface-conjugated iron and hydroxyl radical production by the fibers. Interleukin-8 mRNA levels were quantified by qRT-PCR to measure relative pro-inflammatory response induced in HAEC in response to amphibole fiber exposure. The relative contribution of key physicochemical determinants on the observed pro-inflammatory response were also evaluated. RESULTS: The RTI amosite reference sample contained the longest fibers and demonstrated the greatest potency at increasing IL-8 transcript levels when evaluated on an equal mass basis. The two LA samples and the UICC amosite reference sample consisted of similar particle numbers per milligram as well as similar particle size distributions and induced comparable levels of IL-8 mRNA. A strong correlation was observed between the elongated particle (aspect ratio ?3:1) dose metrics of length and external surface area. Expression of the IL-8 data with respect to either of these metrics eliminated the differential response between the RTI amosite sample and the other samples that was observed when HAEC were exposed on an equal mass basis. CONCLUSIONS: On an equal mass basis, LA is as potent as the UICC amosite reference sample at inducing a pro-inflammatory response in HAEC but is less potent than the RTI amosite sample. The results of this study show that the particle length and particle surface area are highly correlated metrics that contribute significantly to the toxicological potential of these amphibole samples with respect to the inflammogenic response induced in airway epithelial cells.

SUBMITTER: Duncan KE

PROVIDER: S-EPMC3892100 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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In vitro determinants of asbestos fiber toxicity: effect on the relative toxicity of Libby amphibole in primary human airway epithelial cells.

Duncan Kelly E KE Cook Philip M PM Gavett Stephen H SH Dailey Lisa A LA Mahoney Ron K RK Ghio Andrew J AJ Roggli Victor L VL Devlin Robert B RB

Particle and fibre toxicology 20140108

<h4>Background</h4>An abnormally high incidence of lung disease has been observed in the residents of Libby, Montana, which has been attributed to occupational and environmental exposure to fibrous amphiboles originating from a nearby contaminated vermiculite mine. The composition of Libby amphibole (LA) is complex and minimal toxicity data are available. In this study, we conduct a comparative particle toxicity analysis of LA compared with standard reference asbestiform amphibole samples.<h4>Me ...[more]

PMID: 24401117

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Project description:Describe respiratory health and quality of life in persons exposed to Libby amphibole asbestos (LAA) contaminated vermiculite. Cross-sectional descriptive. Asbestos-related disease clinic in Libby, Montana USA. 329 individuals exposed to LAA; mostly men, married, between 50 and 69 years; two-thirds lived in the surrounding county; one-third lived elsewhere in the state and USA. Chest radiograph (CXR), pulmonary function data and the St George Respiratory Questionnaire (SGRQ). Exposure categories included vermiculite workers=7.6%; family/household contact of vermiculite worker=32%; and environmental exposure only=60%. Of the participants, 55% had only pleural abnormalities; 5.4% had only interstitial abnormalities; nearly 21% had both abnormalities and 18% had no lung abnormality on chest x-ray. Mean forced vital capacity (FVC) 95.3% (SD=18.7); forced expiratory volume (FEV(1)) mean 87% (SD=20.2); ratio of FEV1(1)/FVC 95.5% (SD=12.0); and diffusing capacity (DLCO) of 83% (SD=21.7) of the percent predicted. The mean total SGRQ (38.5; SD=22.1) indicated a lower quality of life than healthy persons and persons with other chronic conditions. SGRQ subscale means were Symptoms 52.1 (SD=24.9), activity 49.4 (SD=26.9) and impacts 27.5 (SD=21.9). Participants with normal CXR differed significantly from those with both interstitial and pleural abnormalities on total, activity and impacts scores. For activity alone, subjects with normal CXR differed significantly from those with pleural disease; no differences were found for those with interstitial disease. Significant findings were found for smoking history across all pulmonary measures, and for exposure status, radiographic findings, age and gender for select pulmonary parameters. Subjects with any smoking history had significantly worse average total and subscale scores on the SGRQ. Of 329 persons exposed to LAA, the majority (182) had pleural abnormalities identified on CXR. SGRQ scores for persons with abnormalities (pleural, interstitial or both) (269) differed significantly from those with a normal CXR.

Project description: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.Rats were exposed to air, LA (0.5, 3.5, or 25.0 mg/m(3) targets), or AM (3.5 mg/m(3) 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/m(3)), or AM (3.3 mg/m(3)) 6 h/day, 5 days/week for 13 weeks, and assessed 1 day, 1, 3, and 18 months post-exposure. Fibers were relatively short; for 10 mg/m(3) LA, mean length of all structures was 3.7 μm and 1% were longer than 20 μm.Ten days exposure to 25.0 mg/m(3) 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/m(3) 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/m(3)) 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.Inhalation of relatively 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.

Dataset Information

In vitro determinants of asbestos fiber toxicity: effect on the relative toxicity of Libby amphibole in primary human airway epithelial cells.

Publications

In vitro determinants of asbestos fiber toxicity: effect on the relative toxicity of Libby amphibole in primary human airway epithelial cells.

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