Determining kinetic constants of chlorinated ethane metabolism in the rat from rates of exhalation.

M L Gargas, M E Andersen

Index: Toxicol. Appl. Pharmacol. 99(2) , 344-53, (1989)

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Abstract

The kinetic constants of chemical metabolism are used to develop physiologically based pharmacokinetic (PB-PK) models which predict the time course distribution of volatile chemicals in mammalian systems. Gas uptake techniques have proved useful in determining kinetic constants for a variety of volatile compounds including the following chloroethanes: ethyl chloride, 1,1-dichloroethane, 1,2-dichloroethane, and 1,1,1-trichloroethane. Unfortunately, low vapor pressure materials and those exhibiting increasing blood and tissue solubilities could not be examined by gas uptake methods. An alternative gas phase method was developed in which rats were first exposed by constant concentration inhalation for 6 hr and then placed in 2.5-liter exhaled breath chambers with fresh air flow and chamber effluent was serially analyzed for test chemical. The resulting elimination behavior was extremely sensitive to metabolism, and kinetic constants for chemical metabolism were estimated by simulation with a PB-PK model containing equations that accurately described the experimental conditions. Optimized maximum metabolic rates (Vmax) were determined for 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, and hexachloroethane with resulting values of 7.69, 6.39, 12.9, 9.71, and 1.97 mg/kg/hr, respectively. With several of these test chemicals the PB-PK modeling identified fur adsorption of chemical as significantly contributing to the exhalation chamber concentration time course after whole body exposure.