Carcinogenesis, Vol. 20, No. 8, 1511-1520,
August 1999
© 1999 Oxford University Press
Carcinogenesis |
Use of a mathematical model of rodent in vitro benzene metabolism to predict human in vitro metabolism data
1 Chemical Industry Institute of Toxicology, 6 Davis Drive, PO Box 12137, Research Triangle Park, NC 27709-2137 and
2 Biomathematics Program, North Carolina State University, Raleigh, NC, USA
Benzene, a ubiquitous environmental pollutant, is known to cause leukemia and aplastic anemia in humans and hematotoxicity and myelotoxicity in rodents. Toxicity is thought to be exerted through oxidative metabolites formed in the liver, primarily via pathways mediated by cytochrome P450 2E1 (CYP2E1). Phenol, hydroquinone and trans-trans-muconaldehyde have all been hypothesized to be involved in benzene-induced toxicity. Recent reports indicate that benzene oxide is produced in vitro and in vivo and may be sufficiently stable to reach the bone marrow. Our goal was to improve existing mathematical models of microsomal benzene metabolism by including time course data for benzene oxide, by obtaining better parameter estimates and by determining if enzymes other than CYP2E1 are involved. Microsomes from male B6C3F1 mice and F344 rats were incubated with [14C]benzene (14 µM), [14C]phenol (303 µM) and [14C]hydroquinone (8 µM). Benzene and phenol were also incubated with mouse microsomes in the presence of trans-dichloroethylene, a CYP2E1 inhibitor, and benzene was incubated with trichloropropene oxide, an epoxide hydrolase inhibitor. These experiments did not indicate significant contributions of enzymes other than CYP2E1. Mathematical model parameters were fitted to rodent data and the model was validated by predicting human data. Model simulations predicted the qualitative behavior of three human time course data sets and explained up to 81% of the total variation in data from incubations of benzene for 16 min with microsomes from nine human individuals. While model predictions did deviate systematically from the data for benzene oxide and trihydroxybenzene, overall model performance in predicting the human data was good. The model should be useful in quantifying human risk due to benzene exposure and explicitly accounts for interindividual variation in CYP2E1 activity.
Abbreviations: AML, acute myelogenous leukemia; BHT, hydroxytoluene; CYP, cytochrome P450; DCE, trans-dichloroethylene; LSS, liquid scintillation spectrometry; TBAS, tetrabutylammonium hydrogen sulfate; TCPO, trichloropropene oxide; TWA-PEL, time-weighted average permissible exposure level
3 To whom correspondence should be addressed Email: schlosser{at}ciit.org
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