Comparative metabolism of carbon tetrachloride in rats, mice, and hamstersusing gas uptake and PBPK modeling

No study has comprehensively compared the rate of metabolism of carbon tetr achloride (CCl4) across species. Therefore, the in vivo metabolism of CCl4 was evaluated using groups of male animals (F344 rats, B6C3F(1) mice, and S yrian hamsters) exposed to 40-1800 ppm CCl4 in a closed, recirculating gas- uptake system. For each species, an optimal fit of the family of uptake cur ves was obtained by adjusting Michaelis-Menten metabolic constants K-m (aff inity) and Vmax (capacity) using a physiologically based pharmacokinetic (P BPK) model. The results show that the mouse has a slightly higher capacity and lower affinity for metabolizing CCl4 compared to the rat, while the ham ster has a higher capacity and lower affinity than either rat or mouse. A c omparison of the V-max to K-m ratio, normalized for milligrams of liver pro tein (L/h/mg) across species, indicates that hamsters metabolize more CCl4 than either rats or mice, and should be more susceptible to CCl4-induced he patotoxicity. These species comparisons were evaluated against toxicokineti c studies conducted in animals exposed by nose-only inhalation to 20 ppm C- 14-labeled CCl4 for 4 h. The toxicokinetic study results are consistent wit h the in vivo rates of metabolism, with rats eliminating less radioactivity associated with metabolism ((CO2)-C-14 and urine/feces) and more radioacti vity associated with the parent compound (radioactivity trapped on charcoal ) compared to either hamsters or mice. The in vivo metabolic constants dete rmined here, together with in vitro constants determined using rat, mouse, hamster, and human liver microsomes, were used to estimate human in vivo me tabolic rates of 1.49 mg/h/kg body weight and 0.25 mg/L for V-max and K-m, respectively. Normalizing the rate of metabolism (V-max/K-m) by milligrams liver protein, the rate of metabolism of CCl4 differs across species, with hamster > mouse > rat > human.