Respiratory tract burdens of Cobalt from inhalation of soluble aerosols: Simulation by a two-compartment model
Cobalt (Co) is a toxic and carcinogenic metal emitted into the atmosphere by the combustion of fossil fuels and by industrial processes. To estimate the human lung and body burdens resulting from inhalation of cobalt aerosols, Sprague-Dawley rats were exposed to CoCI2, aerosol concentrations for 2 h in a head only apparatus either as a single exposure or daily as a repeated exposure for 7 d. Co aerosols (0.80-0.93 MMAD, Δg 1.32-1.41) were deposited in the nasopharyngeal region (NP) and lung with measured efficiencies of 2.3% and 5.4% Kinetics of NP Co removal were first-order, with estimated clearance rate of 0.4 h-1 or a t1/2 of 1.8 h. Lung deposition efficiencies were greater by about 20% when corrected for removal occurring during deposition. Lung Co removal decreased over time, consistent with a two-compartment model. A new method of computer modeling is presented solving for the parameters of the model that can be used with organs aside from the lung. A single set of parameters could be used to simulate the entire nearly 10-fold concentration range of exposure, from 284 to 1372 μg Co/m3 for single exposures. We assumed that all of the deposited Co entered one compartment (compartment 1) and was eliminated from a second (Compartment 2). Compartment 1 is tentatively assigned to the lung epithelium cells and compartment 2 to the endothelial cells. The elimination rate from compartment 2 was 0.788 h-1. Intercompartmental transitions were 0.056 h-1 (k12 and 0.023 h-1 (k21), derived from characteristic relaxation times of 4.0 h and 56.8 h for single exposures. With repeated daily Co aerosol exposures, the terminal clearance slowed. The entire set of repeated exposures could be simulated by intercompartmental transitions of 0.0243 h-1(k12) and 0.0203 h-1 (k21) and an elimination rate from the lung to the blood of 0.08 h-1 (C1). Since both the acute and repeated exposure clearance rates are faster than those for insoluble particles removed by mucociliary clearance, Co removal from the lung is due to removal of the Co ion. Since the rate of elimination from compartment 2 is greater than from compartment 1, chronic exposures will result in prolonged concentrations in the cells of compartment 2, but greater concentrations for shorter times in compartment 1. These results should guide toxicity experiments to seek cell type selective effects of Co in the lung cells corresponding to compartments 1 and 2. Our results also offer insight into a more physiological redefinition of maximum tolerated dose for use in chronic cancer bioassays. The fidelity of the model in describing a nearly 70-fold concentration range of aerosol exposures suggests that extrapolation to human exposures at the lower ambient levels is reasonable. Because of the multicompartmental distribution of Co, simple linear extrapolation is inappropriate. Other chemicals deposited in the lung may follow such multicompartmental distributions, also raising questions of the advisability of using linear extrapolations in risk analysis. © 1989 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
Menzel, DB; Wolpert, RL; Francovitch, RJ; Shoaf, CR; Boger, JR; Tayyeb, MI
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