Advertisement

Mechanistic Studies of Benzene Toxicity — Implications for Risk Assessment

  • Martyn T. Smith
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)

Abstract

Benzene has been an established human carcinogen for some time now. Its use in the scientific laboratory, its disposal and use in the workplace is therefore tightly regulated in developed nations. It continues to be used, however, as a solvent in developing countries resulting in extremely high exposures. Further, with the introduction of unleaded gasoline in many countries, environmental and occupational exposure to benzene has increased. Most unleaded gasoline contains approximately 1% benzene, but some varieties contain 5% or more. The annual production of benzene in the US exceeds 1.2 billion gallons, accounting for 30% of worldwide production. Approximately 165,000 metric tons are released annually into the air in the US. Benzene is therefore a ubiquitous environmental pollutant. Smoking is another source of benzene exposure. A one pack/day smoker takes in 1800 μg benzene each day, while non-smokers are exposed to 180 – 1300 μg per day (1).

Keywords

HL60 Cell Sister Chromatid Exchange Mouse Bone Marrow Accelerator Mass Spectrometry Protein Adduct 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Wallace LA. The exposure of the general population to benzene. Princeton, New Jersey: Princeton Scientific Publishing, 1989. (Mehlman MA, ed. Advances in Modern Environmental Toxicology Volume XVI — Benzene: Occupational and Environmental Hazards — Scientific Update;.Google Scholar
  2. 2.
    IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 1987: Suppl. 6: 91-95.Google Scholar
  3. 3.
    Yin SN, Li GL, Tain FD, et al. Leukaemia in benzene workers: A retrospective cohort study. Br J Ind Med 1987;44 (2): 124–128.Google Scholar
  4. 4.
    Huff JE, Haseman JK, DeMarini DM, et al. Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice. Environ. Health Perspect. 1989;82: 125–163.Google Scholar
  5. 5.
    Snyder R, Kalf GF. A perspective on benzene leukemogenesis. Crit Rev Toxicol 1994;24: 177–209.PubMedCrossRefGoogle Scholar
  6. 6.
    Koop DR, Laethem CL, Schnier GC. Identification of ethanol-inducible P450 isozyme 3a (P450IIEl) as a benzene and phenol hydroxylase. Toxicol Appl Pharmocol 1989;98: 278–288.CrossRefGoogle Scholar
  7. 7.
    Witz G, Maniara W, Mylavarapu V, Goldstein B. Comparative metabolism of benzene and trans, trans-muconaldehyde to trans, trans-muconic acid in DBA/2N and C57BL/6 Mice. Biochem Pharmacol 1990;40: 1275–1280.PubMedCrossRefGoogle Scholar
  8. 8.
    Witz G, Gad S, Tice R, Oshiro Y, Piper C, Goldstein B. Genetic toxicity of the benzene metabolite trans, trans-muconaldehyde in mammalian and bacterial cells. Mutat Res 1990;240: 295–306.PubMedCrossRefGoogle Scholar
  9. 9.
    Goldstein BD, Witz G, Javid J, Amoruso MA, Rossman T. Muconaldehyde, a potential toxic intermediate of benzene metabolism. Adv Exp Med 1982; 136A: 331–339.Google Scholar
  10. 10.
    Smith MT, Yager JW, Steinmetz KM, Eastmond DA. Peroxidase-dependent metabolism of benzene’s phenolic metabolites and its potential role in benzene toxicity and carcinogenicity. Environ Health Perspect 1989; 82: 23–29.PubMedCrossRefGoogle Scholar
  11. 11.
    Eastmond DA, Smith MT, Ruzo LO, Ross D. Metabolic activation of phenol by human myeloperoxidase and horseradish peroxidase. Mol Pharmacol 1986; 30: 674–679.PubMedGoogle Scholar
  12. 12.
    Subrahmanyam VV, O’Brien PJ. Phenol oxidation product(s), formed by a peroxidase reaction, that bind to DNA. Xenobiotica 1985; 15(10): 873–885.PubMedCrossRefGoogle Scholar
  13. 13.
    Subrahmanyam VV, Ross D, Eastmond DA, Smith MT. Potential role of free radicals in benzene-induced myelotoxicity and leukemia. Free Rad Biol Med 1991; 11: 495–515.PubMedCrossRefGoogle Scholar
  14. 14.
    Schattenberg DG, Stillman WS, Gruntmeir JJ, Helm KM, Irons RD, Ross D. Peroxidase activity in murine and human hematopoietic progenitor cells: Potential relevance to benzene-induced toxicity. Mol Pharmacol 1994; 46: 346–351.PubMedGoogle Scholar
  15. 15.
    Schlosser MJ, Shurina RD, Kalf GF. Prostaglandin H synthase catalyzed oxidation of hydroquinone to a sulfhydryl-binding and DNA-damaging metabolite. Chem Res Toxicol 1990;3(4): 333–339.PubMedCrossRefGoogle Scholar
  16. 16.
    Eastmond DA, Smith MT, Irons RD. An interaction of benzene metabolites reproduces the myelotoxicity observed with benzene exposure. Toxicol Appl Pharmacol 1987; 91: 85–95.PubMedCrossRefGoogle Scholar
  17. 17.
    Subrahmanyam VV, Kolachana P, Smith MT. Metabolism of hydroquinone by human myeloperoxidase: Mechanisms of stimulation by other phenolic compounds. Arch Biochem Biophys 1991; 286: 76–84.PubMedCrossRefGoogle Scholar
  18. 18.
    Guy R, Dimitriadis E, Hu P, Cooper K, Snyder R. Interactive inhibition of erythroid 59 Fe utilization by benzene metabolites in female mice. Chem.-Biol. Interact. 1990;74: 55–62.PubMedCrossRefGoogle Scholar
  19. 19.
    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;244: 15–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Marrazzini A, Chelotti L, Barrai I, Loprieno N, Barale R. In vivo genotoxic interactions among three phenolic benzene metabolites. Mutat Res 1994; 341: 29–46.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen H, Eastmond D. Syngergistic increase in chromosomal breakage within the euchromatin induced by an interaction of the benzene metabolites phenol and hydroquinone in mice. Carcinogenesis 1995;in press.Google Scholar
  22. 22.
    Chen H, Eastmond D. Inhibition of human topoisomerase II by benzene metabolites (Abstract). The Toxicologist 1995: 15(1): 221.Google Scholar
  23. 23.
    Subrahmanyam V, Doane-Setzer P, Steinmetz K, Ross D, Smith M. Phenol-induced stimulation of hydroquinone bioactivation in mouse bone marrow in vivo: Possible implications in benzene myelotoxicity. Toxicology 1990;62: 107–116.PubMedCrossRefGoogle Scholar
  24. 24.
    Kolachana P, Subrahmanyam VV, Meyer KB, Zhang L, Smith MT. Benzene and its phenolic metabolites produce oxidative DNA damage in HL60 cells in vitro and in the bone marrow in vivo. Cancer Res 1993; 53: 1023–1026.PubMedGoogle Scholar
  25. 25.
    Zhang L, Smith M, Bandy B, Tamaki S, AJ D. Role of quinones, active oxygen species and metals in the genotoxicity of 1,2,4-benzenetriol, a metabolite of benzene. London: Richelieu Press, 1995. (Nohl H, Esterbauer H, Rice-Evans C, eds. Free radicals in the Environment, and Toxicology Google Scholar
  26. 26.
    Sasiadek M. Nonrandom distribution of breakpoints in the karyotypes of workers occupationally exposed to benzene. Environ Health Perspect 1992; 97: 255–257.PubMedCrossRefGoogle Scholar
  27. 27.
    Forni A, Pacifico E, Limonta A. Chromosome studies in workers exposed to benzene or toluene or both. Arch Environ Health 1971;22: 373–378.PubMedCrossRefGoogle Scholar
  28. 28.
    Dean BJ. Recent findings on the genetic toxicology of benzene, toluene, xylenes and phenols. Mutat Res 1985;154: 153–181.PubMedCrossRefGoogle Scholar
  29. 29.
    Erexson GL, Wilmer JL, Kligerman AD. Sister chromatid exchange induction in human lymphocytes exposed to benzene and its metabolites in vitro. Cancer Res;45: 2471-2477.Google Scholar
  30. 30.
    Morimoto K, Wolff S, Koizumi A. Induction of sister-chromatid exchanges in human lymphocytes by microsomal activation of benzene metabolites. Mutat Res 1983; 119: 355–360.PubMedCrossRefGoogle Scholar
  31. 31.
    Yager JW, Eastmond DA, Robertson ML, Paradisin WM, Smith MT. Characterization of micronuclei induced in human lymphocytes by benzene metabolites. Cancer Res 1990; 50: 393–399.PubMedGoogle Scholar
  32. 32.
    Glatt H, Padykula R, Berchtold GA, et al. Multiple activation pathways of benzene leading to products with varying genotoxic characteristics. Environ Health Perspect 1989;82: 81–89.PubMedCrossRefGoogle Scholar
  33. 33.
    Pongracz K, Kaur S, Burlingame A, Bodell W. Detection of (3’-hydroxy)-3, N4-benzetheno-2’-deoxy-cytidine-3’-phosphate by 32P-postlabeling of DNA reacted with p-benzoquinone. Carcinogenesis 1990;11(No. 9): 1469–1472.PubMedCrossRefGoogle Scholar
  34. 34.
    Levay G, Bodell WJ. Potentiation of DNA adduct formation in HL-60 cells by combinations of benzene metabolites. Proc Natl Acad Sci 1992;89: 7105–7109.PubMedCrossRefGoogle Scholar
  35. 35.
    Jowa L, Kalf GF, Witz G, Snyder R. DNA or nucleoside adducts with hydroquinone (HQ) and benzoquinone (BQ). Toxicologist 1985;5(1): 146.Google Scholar
  36. 36.
    Yin W, Li G, Yin S. DNA adduct formation in rodents exposed to benzene. Toxicologist 1992; 12: 250.Google Scholar
  37. 37.
    Levay G, Pathak D, Bodell W. Detection of benzene-DNA adducts in the white blood cells of mice treated with benzene. 86th annual meeting American Association for Cancer Research. Toronto, Canada, 1995: 111, abstract 658.Google Scholar
  38. 38.
    Creek M, Vogel J, Turtletaub K. Extremely low dose benzene pharmacokinetics and macromolecular binding in B6C3F1 male mice. Abstract 1703. The Toxicologist 1994;14(l): 430.Google Scholar
  39. 39.
    Rothman N, Li G-L, Dosemeci M, et al. Hematoxicity among Chinese workers heavily exposed to benzene. American Journal of Industustrial Medicine 1995 (in press).Google Scholar
  40. 40.
    Langlois R, Nisbet B, Bigbee W, Ridinger D, Jensen R. An improved cytometric assay for somatic mutations at the glycophorin-A locus in humans. Cytometry 1990; 11: 513–521.PubMedCrossRefGoogle Scholar
  41. 41.
    Smith MT, Rothman N, Holland NT, et al. Biomarkers of genetic damage in humans exposed to benzene. EMS Abstracts 1994;23(Suppl 23): 63.Google Scholar
  42. 42.
    Rothman N, Haas R, Hayes R, et al. Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans. Proceedings of the National Academy of Science USA 1995 (in press).Google Scholar
  43. 43.
    Renz JF, Kalf GF. Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: Inhibition of conversion of Pre-IL-1 a to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity. Blood 1991;78: 938–944.PubMedGoogle Scholar
  44. 44.
    Irons RD, Stillman WS, Colagiovanni DB, Henry VA. Synergistic action of the benzene metabolite hydroquinone on myelopoietic stimulating activity of granulocyte/macrophage colony-stimulating factor in vitro. Proc Natl Acad Sci 1992;89: 3691–3695.PubMedCrossRefGoogle Scholar
  45. 45.
    McDonald T, Yeowell-O’Connell K, Rappaport S. 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 Research 1994;54: 4907–4914.PubMedGoogle Scholar
  46. 46.
    Tice RR, Costa DL, Drew RT. Cytogenetic effects of inhaled benzene in murine bone marrow: Induction of sister chromatid exchanges, chromosomal aberrations, and cellular proliferation inhibition in DBA/2 mice. Proc Natl Acad Sci 1980;77: 2148–2152.PubMedCrossRefGoogle Scholar
  47. 47.
    Eastmond DA, Rupa DS, Hasegawa LS. Detection of hyperdiploidy and chromosome breakage in interhpase lymphocytes following exposure to the benzene metabolite hydroquinone using multicolor fluorescence in situ hybridization with DNA probes. Mutat Res 1994; 322: 9–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Martyn T. Smith
    • 1
  1. 1.Division of Environmental Health Sciences School of Public HealthUniversity of CaliforniaBerkeleyUSA

Personalised recommendations