Pharmacokinetic modeling of the lung burden from repeated inhalation of nickel aerosols.

The saturable nature of the clearance of soluble nickel compounds from the lung was studied by repeated exposures of rats to respirable submicron-size nickel aerosols. Using Michaelis-Menten type kinetics for removal of nickel lung burdens and a constant rate of deposition, the lung nickel burdens were simulated by computer. The computer simulation was used to design a repeated exposure regimen to test further the hypothesis of saturable clearance. Male Sprague-Dawley rats were exposed for 2 h/day to nickel chloride aerosols at either 90 or 400 micrograms Ni/m3 for up to 14 days. During the 22 h between exposures and up to 3 days post-exposure rats were kept in clean air. The particle size of the aerosol ranged from 0.7 to 0.9 micron mass median aerodynamic diameter with a geometric standard deviation of 1.2-1.4. A steady-state nickel lung burden was observed at 90 micrograms/m3, as predicted from computer modeling, while lung burdens continued to increase with repeated exposure to 400 micrograms Ni/m3. The best fit for the experimental data was obtained with a maximum clearance velocity (Vmax) of 34.6 ng Ni/g X h and a Michaelis-Menten constant for transport (Kt) of 1380 ng Ni/g. The percentage of submicron nickel chloride aerosols retained in the lung was 6.9%. These data support the hypothesis of a saturable clearance mechanism for soluble nickel and provide physiological constants useful for estimating human health risks from nickel inhalation.

Duke Scholars

Author Robert L. Wolpert Statistical Science