Polychlorotrifluoroethylene (PCTFE) Oligomer Pharmacokinetics in Fischer 344 Rats: Development of a Physiologically Based Model

The hydraulic fluid oil polychiorotrifluoroethylene (PCTFE)is hepato- and nephrotoxic in the rat. Male Fischer 344 ratswere exposed to PCTFE either for a single 6-hr exposure (0.5or 0.25 mg/liter) or daily 5 days/week, 6 hr/day, for 13 weeks(0.5, 0.25, or 0.01 mg/liter). Blood, tissue, and urinary PCTFEconcentrations measured postexposure were used to develop aphysiologically based pharmacokinetic (PB-PK) model. The PCTFEhydraulic fluid used was a mixture of trimeric and tetramericoligomers with minor amounts of other chain lengths. The PB-PKmodel was designed to describe the behavior, not of individualoligomers, but of total mass for the trimer and tetramer ineach tissue. Partition coefficients were estimated using themodel to optimize tissue/blood concentration ratios measuredat the end of the 13-week exposure. First-order metabolic rateconstants for both trimeric (2.0 ^hr–1) and tetrameric(1.0 ^hr–1) portions were estimated by optimization againsturinary fluoride data assuming release of 0.77 mole fluorideper mole trimer and 0.844 mole fluoride per mole tetramer metabolized.To obtain accurate simulation of pharmacokinetic data it wasnecessary to hypothesize two fat compartments with diffusion-limitedexchange of PCTFE oligomer with the blood. Relative concentrationsof trimer and tetramer in venous blood, liver, and fat aftera single 6-hr exposure were proportional to inhaled concentrations.Tetramer accumulated preferentially with multiple exposure.Components of PCTFE were metabolized to carboxylic acids withrelease of fluoride. Due to their persistence tetrameric oligomersappear to be more important than trimeric oligomers as causativeagents of PCTFE hepato and nephrotoxicity in the rat.