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. 1996 Dec;104(Suppl 6):1399–1404. doi: 10.1289/ehp.961041399

Mechanistic considerations in benzene physiological model development.

M A Medinsky 1, E M Kenyon 1, M J Seaton 1, P M Schlosser 1
PMCID: PMC1469768  PMID: 9118926

Abstract

Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in humans are well documented and include aplastic anemia, pancytopenia, and acute myelogenous leukemia. However, the risks of leukemia at low exposure concentrations have not been established. A combination of metabolites (hydroquinone and phenol, for example) may be necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinone to the reactive metabolite benzoquinone. Because benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. In vitro studies of the metabolic oxidation of benzene, phenol, and hydroquinone are consistent with the mechanism of competitive interaction among the metabolites. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus the potential exists for competition among various enzymes for phenol. Zonal localization of phase I and phase II enzymes in various regions of the liver acinus also impacts this competition. Biologically based dosimetry models that incorporate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations relevant for humans.

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Selected References

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  1. Barale R., Marrazzini A., Betti C., Vangelisti V., Loprieno N., Barrai I. Genotoxicity of two metabolites of benzene: phenol and hydroquinone show strong synergistic effects in vivo. Mutat Res. 1990 May;244(1):15–20. doi: 10.1016/0165-7992(90)90101-o. [DOI] [PubMed] [Google Scholar]
  2. Chapman D. E., Namkung M. J., Juchau M. R. Benzene and benzene metabolites as embryotoxic agents: effects on cultured rat embryos. Toxicol Appl Pharmacol. 1994 Sep;128(1):129–137. doi: 10.1006/taap.1994.1190. [DOI] [PubMed] [Google Scholar]
  3. Choy W. N., MacGregor J. T., Shelby M. D., Maronpot R. R. Induction of micronuclei by benzene in B6C3F1 mice: retrospective analysis of peripheral blood smears from the NTP carcinogenesis bioassay. Mutat Res. 1985 May-Jun;143(1-2):55–59. doi: 10.1016/0165-7992(85)90105-8. [DOI] [PubMed] [Google Scholar]
  4. Ciranni R., Barale R., Ghelardini G., Loprieno N. Benzene and the genotoxicity of its metabolites. II. The effect of the route of administration on the micronuclei and bone marrow depression in mouse bone marrow cells. Mutat Res. 1988 Sep-Oct;209(1-2):23–28. doi: 10.1016/0165-7992(88)90105-4. [DOI] [PubMed] [Google Scholar]
  5. Ciranni R., Barale R., Marrazzini A., Loprieno N. Benzene and the genotoxicity of its metabolites. I. Transplacental activity in mouse fetuses and in their dams. Mutat Res. 1988 May;208(1):61–67. doi: 10.1016/0165-7992(88)90022-x. [DOI] [PubMed] [Google Scholar]
  6. Eastmond D. A., Smith M. T., Irons R. D. An interaction of benzene metabolites reproduces the myelotoxicity observed with benzene exposure. Toxicol Appl Pharmacol. 1987 Oct;91(1):85–95. doi: 10.1016/0041-008x(87)90196-7. [DOI] [PubMed] [Google Scholar]
  7. Erexson G. L., Wilmer J. L., Kligerman A. D. Sister chromatid exchange induction in human lymphocytes exposed to benzene and its metabolites in vitro. Cancer Res. 1985 Jun;45(6):2471–2477. [PubMed] [Google Scholar]
  8. Gad-El-Karim M. M., Harper B. L., Legator M. S. Modifications in the myeloclastogenic effect of benzene in mice with toluene, phenobarbital, 3-methylcholanthrene, Aroclor 1254 and SKF-525A. Mutat Res. 1984 Mar;135(3):225–243. doi: 10.1016/0165-1218(84)90126-5. [DOI] [PubMed] [Google Scholar]
  9. Gebhardt R. Metabolic zonation of the liver: regulation and implications for liver function. Pharmacol Ther. 1992;53(3):275–354. doi: 10.1016/0163-7258(92)90055-5. [DOI] [PubMed] [Google Scholar]
  10. Goldstein B. D. Benzene toxicity: a critical evaluation: hematotoxicity in humans. J Toxicol Environ Health Suppl. 1977;2:69–105. [PubMed] [Google Scholar]
  11. Irons R. D., Stillman W. S., Colagiovanni D. B., Henry V. A. Synergistic action of the benzene metabolite hydroquinone on myelopoietic stimulating activity of granulocyte/macrophage colony-stimulating factor in vitro. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3691–3695. doi: 10.1073/pnas.89.9.3691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kenyon E. M., Seeley M. E., Janszen D., Medinsky M. A. Dose-, route-, and sex-dependent urinary excretion of phenol metabolites in B6C3F1 mice. J Toxicol Environ Health. 1995 Feb;44(2):219–233. doi: 10.1080/15287399509531956. [DOI] [PubMed] [Google Scholar]
  13. Kolachana P., Subrahmanyam V. V., Meyer K. B., Zhang L., Smith M. T. Benzene and its phenolic metabolites produce oxidative DNA damage in HL60 cells in vitro and in the bone marrow in vivo. Cancer Res. 1993 Mar 1;53(5):1023–1026. [PubMed] [Google Scholar]
  14. Koop D. R., Laethem C. L., Schnier G. G. Identification of ethanol-inducible P450 isozyme 3a (P450IIE1) as a benzene and phenol hydroxylase. Toxicol Appl Pharmacol. 1989 Apr;98(2):278–288. doi: 10.1016/0041-008x(89)90233-0. [DOI] [PubMed] [Google Scholar]
  15. Luke C. A., Tice R. R., Drew R. T. The effect of exposure regimen and duration on benzene-induced bone-marrow damage in mice. I. Sex comparison in DBA/2 mice. Mutat Res. 1988 Aug;203(4):251–271. doi: 10.1016/0165-1161(88)90017-9. [DOI] [PubMed] [Google Scholar]
  16. McDonald T. A., Waidyanatha S., Rappaport S. M. Measurement of adducts of benzoquinone with hemoglobin and albumin. Carcinogenesis. 1993 Sep;14(9):1927–1932. doi: 10.1093/carcin/14.9.1927. [DOI] [PubMed] [Google Scholar]
  17. McDonald T. A., Waidyanatha S., Rappaport S. M. Production of benzoquinone adducts with hemoglobin and bone-marrow proteins following administration of [13C6]benzene to rats. Carcinogenesis. 1993 Sep;14(9):1921–1925. doi: 10.1093/carcin/14.9.1921. [DOI] [PubMed] [Google Scholar]
  18. McDonald T. A., Yeowell-O'Connell K., Rappaport S. M. Comparison of protein adducts of benzene oxide and benzoquinone in the blood and bone marrow of rats and mice exposed to [14C/13C6]benzene. Cancer Res. 1994 Sep 15;54(18):4907–4914. [PubMed] [Google Scholar]
  19. Medinsky M. A., Sabourin P. J., Lucier G., Birnbaum L. S., Henderson R. F. A physiological model for simulation of benzene metabolism by rats and mice. Toxicol Appl Pharmacol. 1989 Jun 15;99(2):193–206. doi: 10.1016/0041-008x(89)90002-1. [DOI] [PubMed] [Google Scholar]
  20. Medinsky M. A. The application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling to understanding the mechanism of action of hazardous substances. Toxicol Lett. 1995 Sep;79(1-3):185–191. doi: 10.1016/0378-4274(95)03369-v. [DOI] [PubMed] [Google Scholar]
  21. Morris M. E., Pang K. S. Competition between two enzymes for substrate removal in liver: modulating effects due to substrate recruitment of hepatocyte activity. J Pharmacokinet Biopharm. 1987 Oct;15(5):473–496. doi: 10.1007/BF01061758. [DOI] [PubMed] [Google Scholar]
  22. Pang K. S., Gillette J. R. Kinetics of metabolite formation and elimination in the perfused rat liver preparation: differences between the elimination of preformed acetaminophen and acetaminophen formed from phenacetin. J Pharmacol Exp Ther. 1978 Oct;207(1):178–194. [PubMed] [Google Scholar]
  23. Pang K. S., Terrell J. A. Retrograde perfusion to probe the heterogeneous distribution of hepatic drug metabolizing enzymes in rats. J Pharmacol Exp Ther. 1981 Feb;216(2):339–346. [PubMed] [Google Scholar]
  24. Rickert D. E., Baker T. S., Bus J. S., Barrow C. S., Irons R. D. Benzene disposition in the rat after exposure by inhalation. Toxicol Appl Pharmacol. 1979 Jul;49(3):417–423. doi: 10.1016/0041-008x(79)90441-1. [DOI] [PubMed] [Google Scholar]
  25. Rinsky R. A., Smith A. B., Hornung R., Filloon T. G., Young R. J., Okun A. H., Landrigan P. J. Benzene and leukemia. An epidemiologic risk assessment. N Engl J Med. 1987 Apr 23;316(17):1044–1050. doi: 10.1056/NEJM198704233161702. [DOI] [PubMed] [Google Scholar]
  26. Runion H. E., Scott L. M. Benzene exposure in the United States 1978-1983: an overview. Am J Ind Med. 1985;7(5-6):385–393. doi: 10.1002/ajim.4700070505. [DOI] [PubMed] [Google Scholar]
  27. Sabourin P. J., Bechtold W. E., Griffith W. C., Birnbaum L. S., Lucier G., Henderson R. F. Effect of exposure concentration, exposure rate, and route of administration on metabolism of benzene by F344 rats and B6C3F1 mice. Toxicol Appl Pharmacol. 1989 Jul;99(3):421–444. doi: 10.1016/0041-008x(89)90151-8. [DOI] [PubMed] [Google Scholar]
  28. Sabourin P. J., Chen B. T., Lucier G., Birnbaum L. S., Fisher E., Henderson R. F. Effect of dose on the absorption and excretion of [14C]benzene administered orally or by inhalation in rats and mice. Toxicol Appl Pharmacol. 1987 Feb;87(2):325–336. doi: 10.1016/0041-008x(87)90294-8. [DOI] [PubMed] [Google Scholar]
  29. Schlosser P. M., Bond J. A., Medinsky M. A. Benzene and phenol metabolism by mouse and rat liver microsomes. Carcinogenesis. 1993 Dec;14(12):2477–2486. doi: 10.1093/carcin/14.12.2477. [DOI] [PubMed] [Google Scholar]
  30. Seaton M. J., Schlosser P. M., Bond J. A., Medinsky M. A. Benzene metabolism by human liver microsomes in relation to cytochrome P450 2E1 activity. Carcinogenesis. 1994 Sep;15(9):1799–1806. doi: 10.1093/carcin/15.9.1799. [DOI] [PubMed] [Google Scholar]
  31. Seaton M. J., Schlosser P., Medinsky M. A. In vitro conjugation of benzene metabolites by human liver: potential influence of interindividual variability on benzene toxicity. Carcinogenesis. 1995 Jul;16(7):1519–1527. doi: 10.1093/carcin/16.7.1519. [DOI] [PubMed] [Google Scholar]
  32. Smith M. T., Yager J. W., Steinmetz K. L., Eastmond D. A. Peroxidase-dependent metabolism of benzene's phenolic metabolites and its potential role in benzene toxicity and carcinogenicity. Environ Health Perspect. 1989 Jul;82:23–29. doi: 10.1289/ehp.898223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Snyder R., Kalf G. F. A perspective on benzene leukemogenesis. Crit Rev Toxicol. 1994;24(3):177–209. doi: 10.3109/10408449409021605. [DOI] [PubMed] [Google Scholar]
  34. Tsutsumi M., Lasker J. M., Shimizu M., Rosman A. S., Lieber C. S. The intralobular distribution of ethanol-inducible P450IIE1 in rat and human liver. Hepatology. 1989 Oct;10(4):437–446. doi: 10.1002/hep.1840100407. [DOI] [PubMed] [Google Scholar]

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