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Subclinical effects of groundwater contaminants

III. Effects of repeated oral exposure to combinations of benzene and toluene on immunologic responses in mice

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Abstract

Toxicity of environmental pollutants may be expressed as combined effects of a chemicals. Benzene, a proven hematotoxic agent, frequently occurs with toluene in cocontaminated groundwater. Groups of CD-1 male mice were exposed continuously for 4 weeks to benzene (166 mg/l), toluene (80 and 325 mg/l), and combinations of benzene (166 mg/l) + toluene (80 mg/l or 325 mg/l) in drinking water. Benzene-induced anemia was alleviated by simultaneous toluene treatment. Leukopenia and lymphopenia were observed in the case of benzene only and benzene + toluene (80 mg/l)-treated mice. The cytopenia, however, was less severe in the benzene + toluene (325 mg/l)-treated group. Immunotoxicity induced by benzene treatment alone was characterized by involution of thymic mass and suppressions of both B- and T-cell mitogeneses, mixed lymphocyte culture response to alloantigens, the tumor lytic ability of cytotoxic T-lymphocytes as determined by51Cr-release assay, and antibody production response to T-dependent antigen (sheep red blood cells). IL-2 secretion by Con A-stimulated mouse T-cells was decreased in the benzene-treated group. Toluene (325 mg/l) completely inhibited these adverse effects when it was coadministered with benzene, while the low dose of toluene (80 mg/l) did not protect against benzene-induced depressions of immune functions. Toluene administered alone at levels up to 325 mg/l showed no obvious immunotoxic effects. Results of this study demonstrated that toluene, in sufficient amounts, has an antagonistic effect on benzene immunotoxicity.

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References

  • Aksoy M (1985) Benzene as a leukemogenic and carcinogenic agent. Am J Ind Med 8: 9–20

    PubMed  Google Scholar 

  • Andrews LS, Lee EW, Witmer CM, Kocsis JJ, Snyder R (1977) Effects of toluene on metabolism, disposition, and hematopoietic toxicity of [3H]-benzene. Biochem Pharmacol 26: 293–300

    PubMed  Google Scholar 

  • Aoyama K (1986) Effects of benzene inhalation on lymphocyte subpopulations and immune response in mice. Toxicol Appl Pharmacol 85: 92–101

    PubMed  Google Scholar 

  • Aranyi C, O'Shea WJ, Sherwood RL, Graham JA, Miller FJ (1985) Effects of toluene inhalation on pulmonary host defenses of mice. Toxicol Lett 25: 103–110

    PubMed  Google Scholar 

  • Aranyi C, O'Shea WJ, Graham JA, Miller FJ (1986) The effects of inhalation of organic chemical air contaminants on murine lung host defenses. Fundam Appl Toxicol 6: 718–720

    Google Scholar 

  • Bakke OM, Scheline RR (1970) Hydroxylation of aromatic hydrocarbons in the rat. Toxicol Appl Pharmacol 16: 691–700

    PubMed  Google Scholar 

  • Brief RS, Lynch J, Bernath T, Scala RA (1980) Benzene in the wort place. Am Ind Hyg Assoc J 41: 616–623

    PubMed  Google Scholar 

  • Cronkite EP, Bullis JE, Inoue T, Drew RT (1984) Benzene inhalation produces leukemia in mice. Toxicol Appl Pharmacol 75: 358–361

    PubMed  Google Scholar 

  • Cunningham AJ, Szenberg A (1968) Further improvements in the plaque technique for detecting single antibody producing cells. Immunology 14: 599–601

    PubMed  Google Scholar 

  • Dean BJ (1985) Recent findings on the genetic toxicology of benzene, toluene, xylenes and phenols. Mutat Res 154: 153–181

    PubMed  Google Scholar 

  • Eastmond DA, Smith MT, Irons RD (1987) An interaction of benzene metabolites reproduces the myelotoxicity observed with benzene exposure. Toxicol Appl Pharmacol 91: 85–95

    PubMed  Google Scholar 

  • Ereson GL, Wilmer JL, Kligerman AW (1985) Sister chromatid exchange induction in human lymphocytes exposed to benzene and its metabolitesin vitro. Cancer Res 45: 2471–2477

    PubMed  Google Scholar 

  • Exon JH, Talcott PA, Koller LD (1983) Effect of lead, polychlorinated biphenyls, and cyclophosphamide on rat natural killer cells, interleukin 2, and antibody synthesis. Fundam Appl Toxicol 5: 158–164

    Google Scholar 

  • Farrar JJ, Benjamin WR, Hilfiker ML, Howard M, Farrar WL, Fuller-Farrar J (1982) The biochemistry, biology, and role of interleukin 2 in the induction of cytotoxic T cell and antibody-forming B cell responses. Immunol Rev 63: 129–166

    PubMed  Google Scholar 

  • Fishbein L (1985) An overview of environmental and toxicological aspects of aromatic hydrocarbons II. Toluene. Sci Total Environ 42: 267–288

    Google Scholar 

  • Gad-El-Karim MM, Harper BL, Legator MS (1984) Modifications in the myeloclastogenic effect of benzene in mice with toluene, phenobarbital, 3-methylcholanthrene, aroclor 1254 and SKF-525A. Mutat Res 135: 225–243

    PubMed  Google Scholar 

  • Gad-El-Karim MM, Sadagopa Ramanujam VM, Legator MS (1986) Correlation between the induction of micronuclei in bone marrow by benzene exposure and the excretion of metabolites in urine of CD-1 mice. Toxicol Appl Pharmacol 85: 464–477

    PubMed  Google Scholar 

  • Gaido KW, Wierda D (1985) Modulation of stromal cell function in DBA/2J and B6L3F1 mice exposed to benzene or phenol. Toxicol Appl Pharmacol 81: 469–475

    PubMed  Google Scholar 

  • Gamett HM, Cronkite EP, Drew RT (1983) Effect ofin vivo exposure to benzene on the characteristics of bone marrow adherent cells. Leukemia Res 7: 803–810

    Google Scholar 

  • Gillis S, Ferm MM, Winny O, Smith KA (1978) T cell growth factor. Parameters of production and a quantitative microassay for activity. J Immunol 120: 2027–2032

    PubMed  Google Scholar 

  • Gilmour SK, Kalf GF, Snyder R (1986) Comparison of the metabolism of benzene and its metabolite phenol in rat liver microsomes. Adv Exp Med Biol 197: 223–235

    PubMed  Google Scholar 

  • Goldstein BD (1983) Clinical hematoxicity of benzene. Adv Mod Environ Toxicol 4: 51–61

    Google Scholar 

  • Grabstein K (1980) Cell-mediated cytolytic responses, In: Mishell BB, Shiigi SM (eds) Selected methods in cellular immunology. W. H. Freeman and Company, San Francisco, pp 124–137

    Google Scholar 

  • Green JD, Leong BKJ, Siendy L (1978) Inhaled benzene fetotoxicity in rats. Toxicol Appl Pharmacol 46: 9–18

    PubMed  Google Scholar 

  • Harigaya K, Miller ME, Cronkite EP, Drew RT (1981) The detection ofin vivo hematotoxicity of benzene byin vitro liquid bone marrow cultures. Toxicol Appl Pharmacol 60: 346–353

    PubMed  Google Scholar 

  • Hayden JW, Peterson RJ, Bruckner JV (1977) Toxicology of toluene (methylbenzene): review of current literature. Clin Toxicol 114: 549–559

    Google Scholar 

  • Hsieh GC, Sharma RP, Parker RDR (1988) Subclinical effects of groundwater contaminants. I. Alternation of humoral and cellular immunity by benzene in CD-1 mice. Arch Environ Contam Toxicol 17: 151–158

    PubMed  Google Scholar 

  • Hsieh GC, Sharma RP, Parker RDR (1989) Immunotoxicologic evaluation of toluene exposure via drinking water in mice. Environ Res 49: 93–103

    PubMed  Google Scholar 

  • Ikeda M, Ohtsuji H (1972)In vivo suppression of benzene and styrene oxidation by co-administered toluene in rats and effects of phenobarbital. Xenobiotica 2: 101–106

    PubMed  Google Scholar 

  • Irons RD (1985) Quinones as toxic metabolites of benzene. J Toxicol Environ Health 16: 673–678

    PubMed  Google Scholar 

  • Irons RD, Dent JG, Baker TS, Rickert DE (1980) Benzene is metabolized and covalently bound in bone marrow in situ. Chem Biol Interact 30: 241–245

    PubMed  Google Scholar 

  • Irons RD, Neptun DA, Pfeifer RW (1981) Inhibition of lymphocyte transformation and microtubule assembly by quinone metabolites of benzene: evidence for a common mechanism. J Reticuloendothel Soc 30: 359–372

    PubMed  Google Scholar 

  • Irons RD, Pfeifer RW, Aune TM, Pierce CW (1984) Soluble immune response suppressor inhibits microtubule functionin vivo and microtubule assemblyin vitro. J Immunol 133: 2032–2036

    PubMed  Google Scholar 

  • Kuna RA, Kapp RW Jr (1981) The embryotoxic/teratogenic potential of benzene vapor in rats. Toxicol Appl Pharmacol 57: 1–7

    PubMed  Google Scholar 

  • Lewtas J (1985) Development of a comparative potency method for cancer risk assessment of complex mixtures using short-termin vivo andin vitro bioassays, Toxicol Ind Health 1: 193–203

    PubMed  Google Scholar 

  • Li GL, Yin SN, Watanabe T, Nakatsuka H, Kasahara M, Abe H, Ikeda M (1986) Benzene-specific increase in leukocyte alkaline phosphatase activity in rats exposed to vapors of various organic solvents. J Toxicol Environ Health 19: 581–589

    PubMed  Google Scholar 

  • Maltoni C, Conti B, Cotti G, Belpoggi F (1985) Experimental studies on benzene carcinogenicity at the Bologna Institute of Oncology: current results and ongoing research. Am J Ind Med 7: 415–446

    PubMed  Google Scholar 

  • Pathiratne A, Puyear RL, Brammer JD (1986a) A comparative study of the effects of benzene, toluene, and xylenes on theirin vitro metabolism and drug-metabolizing enzymes in rat liver. Toxicol Appl Pharmacol 82: 272–280

    PubMed  Google Scholar 

  • Pathiratne A, Puyear RL, Brammer JD (1986b) Activation of14Ctoluene to covalently binding metabolites by rat liver microsomes. Drug Metab Dispos 14: 386–391

    PubMed  Google Scholar 

  • Pfeifer RW, Irons RD (1981) Inhibition of lectin stimulated agglutination and mitosis by hydroquinone: reactivity with intracellular sulfhydryl groups. Exp Mol Pathol 35: 189–198

    PubMed  Google Scholar 

  • Pfeifer RW, Irons RD (1982) Effect of benzene metabolites on phytohemagglutinin-stimulated lymphopoiesis in rat bone marrow. J Reticuloendothel Soc 31: 155–170

    PubMed  Google Scholar 

  • Pfeifer RW, Irons RD (1983) Alteration of lymphocyte function by quinones through sulfhydryl-dependent disruption of microtubule assembly. Int J Immunopharmacol 5: 463–470

    PubMed  Google Scholar 

  • Post GB, Snyder R, Kalf GF (1985) Inhibition of RNA synthesis and interleukin-2 production in lymphocytesin vitro by benzene and its metabolites, hydroquinone andp-benzoquinone. Toxicol Lett 29: 161–168

    PubMed  Google Scholar 

  • Pyykko K (1980) Effects of methylbenzenes on microsomal enzymes in rat liver, kidney and lung. Biochem Biophys Acta 633: 1–9

    PubMed  Google Scholar 

  • Pyykko K (1983) Time-course of effects of toluene on microsomal enzymes in rat liver, kidney and lung during and after inhalation exposure. Chem Biol Interact 44: 299–310

    PubMed  Google Scholar 

  • Rinsky RA, Smith AB, Hornung R, Filloon TG, Young RJ, Okun AH, Landrigan PJ (1987) Benzene and leukemia, an epidemiologic risk assessment. New Engl J Med 316: 1044–1050

    PubMed  Google Scholar 

  • Rosenthal GJ, Snyder CA (1985) Modulation of the immune response toListeria monocytogenes by benzene inhalation. Toxicol Appl Pharmacol 80: 502–510

    PubMed  Google Scholar 

  • Rosenthal GJ, Snyder CA (1987) Inhaled benzene reduces aspects of cell-mediated tumor surveillance in mice. Toxicol Appl Pharmacol 88: 35–43

    PubMed  Google Scholar 

  • Rozen MG, Snyder CA (1985) Protracted exposure of C57BL/6 mice to 300 ppm benzene depresses B- and T-lymphocyte numbers and mitogen responses. Evidence for thymic and bone marrow proliferation in response to the exposures. Toxicology 37: 13–26

    PubMed  Google Scholar 

  • Rozen MG, Snyder CA, Albert RE (1984) Depression in B- and T-lymphocyte mitogen-induced blastogenesis in mice exposed to low concentrations of benzene. Toxicol Lett 20: 343–349

    PubMed  Google Scholar 

  • Sato A, Nakajima T (1979) Dose-dependent metabolic interaction between benzene and toluenein vivo andin vitro. Toxicol Appl Pharmacocl 48: 249–250

    Google Scholar 

  • Sawahata T, Rickert DE, Greenlee WF (1985) Metabolism of benzene and its metabolites in bone marrow. In: Irons RD (ed) Toxicology of the blood and bone marrow. Raven Press, New York, pp 141–148

    Google Scholar 

  • Sharma RP, Gehring PJ (1979) Immunologic effects of vinyl chloride in mice. Ann NY Acad Sci 320: 551–563

    PubMed  Google Scholar 

  • Sipes IG, Gandolfi AJ (1986) Biotransformation of toxicants. In: Klaassen CD, Amdur MO, Doull J (eds) Casarett and Doull's Toxicology: the basic science of poisons, 3rd edn. Macmillan, New York, pp 64–98

    Google Scholar 

  • Snyder CA, Goldstein BD, Sellakumar AR, Bromberg I, Laskin S, Albert RE (1980) The inhalation toxicology of benzene: incidence of hematopoietic neoplasms and hematoxicity in AKR/J and C57BL/6J mice. Toxicol Appl Pharmacol 54: 323–331

    PubMed  Google Scholar 

  • Snyder R, Longacre SL, Sammett D, Witmer CM, Kocsis JJ (1983) Relationship between the toxicity and metabolism of benzene. Adv Mod Environ Toxicol 4: 23–36

    Google Scholar 

  • Suleiman SA (1987) Petroleum hydrocarbon toxicityin vitro: effect of n-alkanes, benzene and toluene on pulmonary alveoelar macrophages and lysosomal enzymes of the lung. Arch Toxicol 59: 402–407

    PubMed  Google Scholar 

  • Tice RR, Vogt TF, Costa DL (1982) Cytogenetic effects of inhaled benzene in murine bone marrow. Environ Sci Res 25: 257–275

    Google Scholar 

  • Toftgard R, Nilsen OG, Gustafsson J (1982) Dose dependent induction of rat liver microsomal cytochrome p-450 and microsomal enzymatic activities after inhalation of toluene and dichloromethane. Acta Pharmacol Toxicol 51: 108–114

    Google Scholar 

  • Tunek A, Olofsson T, Berlin M (1981) Toxic effects of benzene and benzene metabolites on granulopoietic stem cells and bone marrow cellularity in mice. Toxicol Appl Pharmacol 59: 149–156

    PubMed  Google Scholar 

  • Tunek A, Hogstedt D, Olofsson T (1982) Mechanism of benzene toxicity. Effects of benzene and benzene metabolites on bone marrow cellularity number of granulopoietic stem cells and frequency of micronuclei in mice. Chem Biol Interact 39: 129–138

    PubMed  Google Scholar 

  • US Environmental Protection Agency (1980a) Ambient water quality criteria for benzene. 440/5-80-018. US Government Printing Office, Washington DC

    Google Scholar 

  • US Environmental Protection Agency (1980b) Ambient water quality criteria for toluene. EPA 440/5-80-075. US Government Printing Office, Washington DC

    Google Scholar 

  • US Environmental Protection Agency (1986a) Quality criteria for water. EPA 440/5-86-001. US Government Printing Office, Washington DC

    Google Scholar 

  • US Environmental Protection Agency (1986b) Test methods for evaluating solid waste. Volume 1B: Laboratory Manual, Physical/Chemical Methods. 3rd Edition. SW-846. US Government Printing Office, Washington DC, pp 5030-1–5030-21

    Google Scholar 

  • US National Academy of Sciences (1982) Alkylbenzene. Washington DC

  • US Office of Technology Assessment (1984) Protecting the national groundwater from contamination, Vol I (OTA-O-233) US Govt Printing Office, Washington DC

    Google Scholar 

  • Ungvary, G, Tatrai, E (1985) On the embryotoxic effects of benzene and its alkyl derivatives in mice, rats and rabbits. Arch Toxicol Suppl 8: 425–430

    PubMed  Google Scholar 

  • Van Doorn R, Bos RD, Brounds RME, Leijedekkers CM, Henderson PI (1980) Effect of toluene and xylene on liver glutathione and their urinary excretion as mercapturic acids in the rat. Arch Toxicol 43: 293–304

    PubMed  Google Scholar 

  • Watson J (1979) Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J Exp Med 150: 1510–1519

    PubMed  Google Scholar 

  • Wierda D, Irons RD (1982) Hydroquinone and catechol reduce the frequency of progenitor B-lymphocytes in mouse spleen and bone marrow. Immunopharmacology 4: 41–54

    PubMed  Google Scholar 

  • Wierda D, Irons RD, Greenlee WF (1981) Immunotoxicity in C57BL/6 mice exposed to benzene and aroclor 1254. Toxicol Appl Pharmacol 60: 410–417

    Google Scholar 

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  1. Gin C. Hsieh

    Present address: Department of Pharmacology and Toxicology, University of Texas College of Pharmacy, 78712, Austin, TX, USA

Authors and Affiliations

  1. Center for Environmental Toxicology Department of Biology Dairy and Veterinary Sciences, Utah State University, 84322, Logan, UT, USA

    Gin C. Hsieh & Robert D. R. Parker

  2. Center for Environmental Toxicology Department of Animal, Dairy and Veterinary Sciences, Utah State University, 84322, Logan, UT, USA

    Raghubir P. Sharma & Brian J. Hughes

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  1. Gin C. Hsieh
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  2. Robert D. R. Parker
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  3. Raghubir P. Sharma
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  4. Brian J. Hughes
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Hsieh, G.C., Parker, R.D.R., Sharma, R.P. et al. Subclinical effects of groundwater contaminants. Arch Toxicol 64, 320–328 (1990). https://doi.org/10.1007/BF01972993

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