PREDICTION OF FURAN PHARMACOKINETICS FROM HEPATOCYTE STUDIES - COMPARISON OF BIOACTIVATION AND HEPATIC DOSIMETRY IN RATS, MICE, AND HUMANS

Furan is a volatile solvent and chemical intermediate that is hepatoto xic and hepatocarcinogenic in rats and mice but is not mutagenic or DN A-reactive. Furan hepatotoxicity requires cytochrome P450 2E1 bioactiv ation to cis-2-butene-1,4-dial, We have previously shown that furan bi otransformation kinetics determined with freshly isolated rat hepatocy tes in vitro accurately predict furan pharmacokinetics in vivo [Kedder is et al. (1993) Toxicol. Appl. Pharmacol. 123, 274], suggesting that furan biotransformation kinetics determined with freshly isolated mous e or human hepatocytes can be used to develop species-specific pharmac okinetic models. Hepatocytes from male B6C3F1 mice or human accident v ictims (n = 3) were incubated with furan vapors to determine the kinet ic parameters for furan bioactivation and compared to our previous dat a for rat hepatocytes. Isolated hepatocytes from all three species rap idly metabolized furan (V-max of 48 nmol/hr/10(6) mouse hepatocytes, 1 9-44 nmol/hr/10(6) human hepatocytes, and 18 nmol/hr/10(6) rat hepatoc ytes) with high affinity (K-M ranging from 0.4 to 3.3 mu M). The hepat ocyte kinetic data and physiological parameters from the literature we re used to develop dosimetry models for furan in mice and people. The hepatocyte V-max values were extrapolated to whole animals assuming 12 8 x 10(6) hepatocytes/g rodent liver and 137 x 10(6) hepatocytes/g hum an liver. Simulations of inhalation exposure to 10 ppm furan for 4 hr indicated that the absorbed dose (mg/kg), and consequently the liver d ose of cis-2-butene-1,4-dial, was approximately 3- and 10-fold less in humans than in rats or mice, respectively. These results indicate tha t the target organ concentration, rather than the exposure concentrati on, is most appropriate for interspecies comparison of dose. The initi al rates of furan oxidation in rat, mouse, and human liver were approx imately 13-, 24-, and 37-fold greater than the respective rates of blo od flow delivery of furan to the liver after 4-hr exposures to less th an or equal to 300 ppm. One important consequence of blood flow limita tion of furan bioactivation is that the amount of toxic metabolite for med in the liver will be unaffected by increases in V-max due to the i nduction of cytochrome P450 2E1. Therefore, the interindividual variat ions observed in cytochrome P450 2E1 activity among human populations would not be expected to have a significant effect on the extent of fu ran bioactivation in people. These considerations may be important for human cancer risk assessments of other rapidly metabolized rodent car cinogens. (C) 1996 Academic Press, Inc.