Physiologically Based Pharmacokinetics of Uptake by Inhalation of a Series of 1,1,1-Trihaloethanes: Correlation with Various Physicochemical Parameters

Abstract

The uptake via inhalation of a series of 1,1,1-trihaloethanes was studied using a closed recirculated atmosphere exposure chamber. Rats were exposed to an initial concentration of 1,1,1-trihaloethane and the rate of disappearance of chamber concentration was monitored over a period of 3 h. The in vivo metabolic rate constants for the uptake of the 1,1,1-trihaloethanes were determined using a physiologically based pharmacokinetic computer model. The uptakes for 1,1,1-trihaloethane, 1,1 -dichloro-1 -fluoroethane, 1 -chloro-1,1 -difluoro-ethane, and 1,1,1 -trilluoro-ethane were described by single first-order processes with first-order rate constants, k_ic, of 3.78 ± 0.02, 3.15 ± 0.11, 2.59 ± 0.02, and 1.17 ± 0.01 h⁻¹ kg⁻¹, respectively. The pharmacokinetic behavior of the four 1,1,1-trihaloethanes correlated well with the physicochemical characteristics; αmol (molar polarizability), calculated log P (clog P, an estimate of the octanol: water partition coefficient), and δH_act (enthalpy of activation). A decrease in the rate of uptake of 1,1,1-trihaloethane correlated with increase in fluorine content. The derivation of partition coefficients for the main tissue compartments comprising the body and their use in physiologically based pharmacokinetic models are, however, empirical and convenient. Therefore the use of αmol and clog P in predictive toxicology is limited. Total liver glutathione was significantly depleted by 4000 ppm 1,1,1 -trihaloethane, by 8000 ppm 1,1-dichloro-1-fluoroethane, and by 10,000 ppm of both 1-chloro-1,1-difluoro-ethane and 1,1,1 -trifluoroethane. No change in liver glutathione disulfide concentration was detected with any of the chemicals. Lung glutathione status was not altered after exposure to any of the four 1,1,1-trihaloethanes. No changes were detected in the activities of glutamate dehydrogenase, sorbitol dehydrogenase, or lactate dehydrogenase in the serum of exposed rats, indicating a lack of any tissue damage under the exposure conditions. The data presented indicate that compounds in this series are poorly metabolized and have a low level of toxicity.