DOSE-DEPENDENT METABOLISM OF 2,2-DICHLORO-1,1,1-TRIFLUOROETHANE - A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL IN THE MALE FISCHER-344 RAT

2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) is used industrially as a refrigerant, as a foam blowing agent, and as a solvent. It is also b eing considered as a replacement for halons and chlorinated fluorocarb ons which have been banned by the Montreal Protocol because they deple te atmospheric ozone. Male Fischer 344 rats were exposed to 1.0, 0.1, and 0.01% HCFC-123 by inhalation. Parent compound was measured in bloo d, fat, and exhaled breath and trifluoroacetic acid (TFA) was measured in blood and urine, A physiologically based pharmacokinetic (PBPK) mo del was developed which included a gut compartment and a variable size fat compartment in addition to the standard flow-limited compartments . Compartment volumes and flows were chosen from the literature, parti tion coefficients were measured in the laboratory, and metabolic param eters were optimized from experimental data using model simulations. L aboratory experiments showed that the TFA blood concentration during t he 1.0% exposure was more than 50% less than the TFA blood concentrati on during the 0.1% exposure. After cessation of the 4-hr exposure, TFA blood concentrations from the 1.0% exposure rebounded and peaked betw een 12 and 26 hr after the exposure at about the same concentration as the 0.1% peak. This rebound phenomenon suggested that it was not kill ing of the metabolic enzymes but substrate inhibition that made the TF A blood concentrations lower than expected. Substrate inhibition by ha lothane, a structural analog of HCFC-123, has been described in the li terature. Only by including a term for substrate inhibition in the PBP K model could pharmacokinetic data for TFA in blood be simulated adequ ately. This combination of laboratory experimentation and PBPK modelin g can be applied to relate the levels of parent and metabolite to toxi c effects with some hope of elucidating the toxic species. This work i s the first step toward developing models that can be used to predict the toxicokinetics of HCFC-123 in humans throughout various potential use scenarios. (C) 1994 Academic Press, Inc.