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A rat lung model of exposure, dose and response to inhaled silica.

Authors
Tran-CL; Kuempel-ED; Castranova-V
Source
Ann Occup Hyg, Inhaled Particles IX, 2002 Dec; 46(Suppl 1):14-17
NIOSHTIC No.
20022231
Abstract
The objectives of this study were: (i) to construct a physiologically based mathematical model to describe the retention and clearance of respirable crystalline silica (MIN-U-SIL 5), the inflammatory reaction and the development of fibrosis; (ii) to calibrate/validate the model using animal data from inhalation experiments with MIN-U-SIL 5. A physiologically based mathematical model was constructed with the following features: compartments to describe the retention and clearance of silica, critical lung burdens for initiation of inflammation and fibrosis and recruitment of neutrophils and alveolar macrophages. Data were available from two recent NIOSH studies of rats exposed by inhalation to respirable crystalline silica. Data from the first study were used to estimate the model parameters not obtainable from the earlier studies, using a numerical method combining non-linear least squares analysis and integration of differential equations. The second study was used for model validation by comparing the model predictions with the data. Once validated, the model was used to predict the outcome of a 2 yr inhalation experiment with DQ-12 quartz. Finally, the model was extended to describe the dose-response relationships, including oxidant dose, antioxidant reactions, transcription factor switching, cell damage and fibrosis. A good fit of the model to the data was obtained. The critical doses of MIN-U-SIL 5 were calculated for both inflammation and fibrosis. The model was able to simulate the retention and clearance of DQ-12 quartz. The model was also extended to describe the time course of NF - KB initiation, lipid peroxidation and superoxide dismutase expression. This model has provided a means to relate the inhaled silica dose to inflammation and fibrosis.
Keywords
Exposure-levels; Risk-analysis; Risk-factors; Kinetics; Fibrosis; Lung-burden; Mathematical-models; Author Keywords: crystalline silica; dosimetry models; exposure-dose-response model; poorly soluble particles; risk assessment; toxicokinetics
Contact
C. L. Tran, Institute of Occupational Medicine, Edinburgh, UK
CODEN
AOHYA3
Publication Date
20021201
Document Type
Journal Article
Editors
Ogden-T; Donaldson-K; Cherry-N
Funding Amount
30000
Funding Type
Cooperative Agreement
Fiscal Year
2003
NTIS Accession No.
NTIS Price
Identifying No.
Cooperative-Agreement-Number-U60-CCU-017070
ISSN
0003-4878
NIOSH Division
HELD
Priority Area
Research Tools and Approaches: Risk Assessment Methods
Source Name
Annals of Occupational Hygiene, Inhaled Particles IX
State
OH; WV
Performing Organization
Institute of Occupational Medicine, Edinburgh, Scotland
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