Skip to main content

Advertisement

Log in

Acute oral toxicity and liver oxidant/antioxidant stress of halogenated benzene, phenol, and diphenyl ether in mice: a comparative and mechanism exploration

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

The lethal doses (LD50s) of fluorinated, chlorinated, brominated, and iodinated benzene, phenol, and diphenyl ether in mice were ascertained respectively under the consistent condition. The acute toxicity of four benzenes orders in fluorobenzene (FB) < iodobenzene < chlorobenzene≈bromobenzene, that of four phenols orders in 4-iodophenol≈4-bromophenol < 4-chlorophenol (4-MCP) < 4-fluorophenol (4-MFP), and that of four diphenyl ethers orders in 4,4′-iododiphenyl ether < 4,4′-difluorodiphenyl ether < 4,4′-dichlorodiphenyl ether≈4,4′-dibromodiphenyl ether. General behavior adverse effects were observed, and poisoned mouse were dissected to observe visceral lesions. FB, 4-MCP, and 4-MFP produced toxic faster than other halogenated benzenes and phenols, as they had lower octanol–water partition coefficients. Pathological changes in liver and liver/kidney weight changes were also observed. Hepatic superoxide dismutase, catalase activities, and malondialdehyde level were tested after a 28-day exposure, which reflects a toxicity order basically consistent with that reflected by the LD50s. By theoretical calculation and building models, the toxicity of benzene, phenol, and diphenyl ether were influenced by different structural properties.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Albinaa ML, Alonsoa V, Linaresa V, Bellésa M, Sirventc JJ, Domingoa JL, Sáncheza DJ (2010) Effects of exposure to BDE-99 on oxidative status of liver and kidney in adult rats. Toxicology 271:51–56

    Article  Google Scholar 

  • Beliaeff B, Burgeot T (2002) Integrated biomarker response: a useful tool for ecological risk assessment. Environ Toxicol Chem 21:1316–1322

    Article  CAS  Google Scholar 

  • Bunnett JF (1957) A new factor affecting reactivity in bimolecular nucleophilic displacement reactions. J Am Chem Soc 79:5969–5974

    Article  CAS  Google Scholar 

  • Bunnett JF, Merritt WD Jr (1957) The nucleophilic reactivity of sodium thiophenoxide with aromatic substrates. J Am Chem Soc 79:5967–5969

    Article  CAS  Google Scholar 

  • Bunnett JF, Garbisch EW Jr, Pruitt KM (1957) The “element effect” as a criterion of mechanism in activated aromatic nucleophilic substitution reactions. J Am Chem Soc 79:385–391

    Article  CAS  Google Scholar 

  • Bustos M, Beraza N, Lasarte J, Baixeras E, Alzuguren P, Bordet T, Prieto J (2003) Protection against liver damage by cardiotrophin-1: a hepatocyte survival factor up-regulated in the regenerating liver in rats. Gastroenterology 125:192–201

    Article  CAS  Google Scholar 

  • Canadian Council on Animal Care (CCAC) Guidelines Committee (2010) CCAC guidelines on: euthanasia of animals used in science Programs. Canadian Council on Animal Care, Ottawa

    Google Scholar 

  • Cao ST, Wang X, Liu HX, Yang GY, Wang ZY (2010) Determination of the toxicities of 16 halogenated benzenes to photobaeterium phosphoeum and 2D- and 3D-QSAR studies. Chinese J Struct Chem 29:1007–1014

    CAS  Google Scholar 

  • Chapman NB, Parker RE (1951) Nucleophilic displacement of fluorine from organic compounds. Part I. Kinetics of the reactions of 1-fluoro-2:4-dinitrobenzene with primary aromatic amines. J Chem Soc:3301–3307.

  • Chaudiére J, Ferrari-lliou R (1999) Intracellular antioxidants: from chemical to biochemical mechanisms. Food Chem Toxicol 37:949–962

    Article  Google Scholar 

  • Dearden JC (1985) Partitioning and lipophilicity in quantitative structure–activity relationships. Environ Health Perspect 61:203–228

    Article  CAS  Google Scholar 

  • Drijvers D, Langenhove HV, Herrygers V (2000) Sonolysis of fluoro-, chloro-, bromo- and iodobenzene: a comparative study. Ultrason Sonochem 7:87–95

    Article  CAS  Google Scholar 

  • Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA, Halliwell B, van der Vliet A (1988) Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391:393–397

    Article  Google Scholar 

  • Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision A.1. Gaussian, Inc., Wallingford CT.

  • Fu X, Ji R, Jorgen D (2009) Acute, subacute toxicity and genotoxic effect of Bio-Quinone Q10 in mice and rats. Regul Toxicol Pharm 53:1–5

    Article  CAS  Google Scholar 

  • Gershon H, Clarke DD, Gershon M (1995) Antifungal activity of halophenols and halonitrophenols. Monatsh Chem 126:1161–1166

    Article  CAS  Google Scholar 

  • Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9:515–540

    Article  CAS  Google Scholar 

  • Katayama S, Irifune M, Kikuchi N, Takarada T, Shimizu Y, Endo C, Takata T, Dohi T, Sato T, Kawahara M (2007) Increased γ-aminobutyric acid levels in mouse brain induce loss of righting reflex, but not immobility, in response to noxious stimulation. Anesth Analg 104:1422–1429

    Article  CAS  Google Scholar 

  • Klassen C (1991) Principles of toxicology. In: Gilman AG, Tall TW, Nies AS, Taylor P (eds) Pharmacological basis of therapeutics. McGraw-Hill, New York, pp 49–61

    Google Scholar 

  • Krupka RM, Deves R (1980) Reaction of the glucose carrier in erythrocytes with halodinitrobenzenes. J Biol Chem 225:2051–2055

    Google Scholar 

  • Lai I, Chai YT, Simmons D, Luthe G, Coleman MC, Spitz D, Haschek WM, Ludewig G, Robertson LW (2010) Acute toxicity of 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) in male Sprague–Dawley rats: effects on hepatic oxidative stress, glutathione and metals status. Environ Int 36:918–923

    Article  CAS  Google Scholar 

  • Li X, Zhang T, Min X, Liu P (2010) Toxicity of aromatic compounds to Tetrahymena estimated by microcalorimetry and QSAR. Aquat Toxicol 98:322–327

    Article  CAS  Google Scholar 

  • Liu JQ, Robins MJ (2007) SNAr displacements with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl) purine nucleosides: synthesis, kinetics, and mechanism. J Am Chem Soc 129:5962–5968

    Article  CAS  Google Scholar 

  • Liu XX, Li JY, Yu JX, Sun SQ, Wang YJ, Liu HX (2012) QSAR of acute toxicity of halogenated phenol to green fluorescent protein by using density functional theory. Bull Environ Contam Toxicol 89:950–954

    Article  CAS  Google Scholar 

  • Lu GH, Wang C, Li YM (2006) QSARs for acute toxicity of halogenated benzenes to bacteria in natural waters. Biomed Environ Sci 19:457–460

    CAS  Google Scholar 

  • Matés JM, Pérez C, Núñez de Castro I (1999) Antioxidant enzymes and human diseases. Clin Biochem 32:595–603

    Article  Google Scholar 

  • Mhin BJ, Lee JE, Choi WY (2002) Understanding the congener-specific toxicity in polychlorinated dibenzo-p-dioxins: chlorination pattern and molecular quadrupole moment. J Am Chem Soc 124:144–148

    Article  CAS  Google Scholar 

  • Michael MK, Wang YG, Hua L, Hu J, Li LL, Lei F, Du LJ (2010) Acute toxicity of berberine and its correlation with the blood concentration in mice. Food Chem Toxicol 48:1105–1110

    Article  Google Scholar 

  • Molinspiration cheminformatics. (2012) http://www.molinspiration.com/cgi-bin/properties.

  • Ouvrard C, Berthelot M, Laurence C (1999) The first basicity scale of fluoro-, chloro-, bromo- and iodo-alkanes: some cross-comparisons with simple alkyl derivatives of other elements. J Chem Soc, Perkin Tran 2:1357–1362

    Article  Google Scholar 

  • Ouyang W, Beckett O, Ma Q, Paik JH, DePinho RA, Li MO (2010) Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol 11:618–627

    Article  CAS  Google Scholar 

  • Öberg TG (2002) Prediction of vapour pressures for halogenated diphenyl ether congeners from molecular descriptors. Environ Sci Pollut Res 9:405–411

    Article  Google Scholar 

  • OECD (2001) Guideline 423: acute oral toxicity–acute toxic class method. Organization for Economic Co-operation and Development, Paris

    Google Scholar 

  • Patneau DK, Mayer ML, Jane DE, Watkins JC (1992) Activation and desensitization of AMPA/kainate receptors by novel derivatives of willardiine. J Neurosci 12:595–606

    CAS  Google Scholar 

  • Peng YF, Liu TB (2009) QSAR study of halogen phenols toxicity to Tetrahymena pyriformis. Chinese J Struct Chem 28:218–222

    Google Scholar 

  • Pero RW, Babiarz-Tracy P, Fondy TP (1977) 3-fluoro-1-hydroxypropan-2-one (fluorohydroxyacetone) and some esters: syntheses and effects in BDFI mice. J Med Chem 20:644–647

    Article  CAS  Google Scholar 

  • Shirasaka T, Murakami K, Ford H Jr, Kelley JA, Yoshioka H, Kojima E, Aoki S, Broder S, Mitsuya H (1990) Lipophilic halogenated congeners of 2′,3′-dideoxypurine nucleosides active against human immunodeficiency virus in vitro. Proc Natl Acad Sci USA 87:9426–9430

    Article  CAS  Google Scholar 

  • Shi JQ, Liu HX, Sun L, Hou HF, Xu Y, Wang ZY (2011) Theoretical study on hydrophilicity and thermodynamic properties of polyfluorinated dibenzofurans. Chemosphere 84:296–304

    Article  CAS  Google Scholar 

  • Song LZ, Zhao XD, Fu J, Wang XL, Sheng YP, Liu XW (2012) DFT investigation of Ni(II) adsorption onto MA-DTPA/PVDF chelating membrane in the presence of coexistent cations and organic acids. J Hazard Mater 199–200:433–439

    Article  Google Scholar 

  • Stegeman JJ, Brouwer M, Di Giulio RT, Forlin L, Fowler BA, Sanders BM, VanVeld PA (1992) Enzyme and protein synthesis as indicator of contaminant exposure and effect. In: Huggett RJ (ed) Biomarkers: biochemical, physiological, and histological markers of anthropogenic stress. SETAC Special Publication Series. Lewis Publisher, Boca raton, pp 235–335

    Google Scholar 

  • Tubaro A, Sosa S, Carbonatto M, Altinier G, Vita F, Melato M, Satake M, Yasumoto T (2003) Oral and intraperitoneal acute toxicity studies of yessotoxin and homoyessotoxins in mice. Toxicon 41:783–792

    Article  CAS  Google Scholar 

  • Tubaro A, Del Favero G, Beltramo D, Ardizzone M, Forino M, De Bortoli M, Pelin M, Poli M, Bignami G, Ciminiello P, Sosa S (2011) Acute oral toxicity in mice of a new palytoxin analog: 42-Hydroxy-palytoxin. Toxicon 57:755–763

    Article  CAS  Google Scholar 

  • U.S. National Library of Medicine (2011) Toxicology Data Network (Toxnet). Available from http://toxnet.nlm.nih.gov/.

  • Valentine JS, Wertz D, Lyons T, Liou L, Goto J, Butler E (1998) The dark side of dioxygen biochemistry. Curr Opin Chem Biol 2:253–262

    Article  CAS  Google Scholar 

  • Volpes R, van den Oord JJ, Desmet VJ (1990) Immunohistochemical study of adhesion molecules in liver inflammation. Hepatology 12:59–65

    Article  CAS  Google Scholar 

  • Wang LS, Han SH (1999) Quantitative structure–activity relationship (QSAR). Chemical Industry Press, Beijing, China

    Google Scholar 

  • Wei T, Zhu WH, Zhang JJ, Xiao HM (2010) DFT study on energetic tetrazolo-[1,5-b]-1,2,4,5-tetrazine and 1,2,4-triazolo-[4,3-b]-1,2,4,5-tetrazine derivatives. J Hazard Mater 179:581–590

    Article  CAS  Google Scholar 

  • Whalley WB (1950) Organic fluoro-compounds. Part II. The preparation of alkyl 2:4-dinitrophenyl ethers from 1-fluoro-2:4-dinitrobenzene. J Chem Soc:2241–2243.

  • Yan XF, Xiao HM, Ju XH, Gong XD (2005) DFT study on the QSAR of nitroaromatic compound toxicity to the fathead minnow. Chinese J Chem 23:947–952

    Article  CAS  Google Scholar 

  • Zeng M, Lin ZF, Yin DQ, Zhang YL, Kong DY (2011) A K ow-based QSAR model for predicting toxicity of halogenated benzenes to all algae regardless of species. Bull Environ Contam Toxicol 86:565–570

    Article  CAS  Google Scholar 

  • Zhang QM, Zhu LS, Wang J, Xie H, Wang JH, Han YN, Yang JH (2012a) Oxidative stress and lipid peroxidation in the earthworm Eisenia fetida induced by low doses of fomesafen. Environ Sci Pollut Res. doi:10.1007/s11356-012-0962-5

    Google Scholar 

  • Zhang XS, Liu F, Chen BY, Li Y, Wang ZY (2012b) Acute and subacute oral toxicity of polychlorinated diphenyl sulfides in mice: determining LD50 and assessing the status of hepatic oxidative stress. Environ Toxicol Chem 31:1485–1493

    Article  CAS  Google Scholar 

  • Zhao YY, Tao FM, Zeng EY (2008) Theoretical study of the quantitative structure–activity relationships for the toxicity of dibenzo-p-dioxins. Chemosphere 73:86–91

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research was financially supported by the National Natural Science Foundation of China (No. 41071319, 20977046, and 20737001), the National Basic Research Program of China (2009CB42160-4), the Fundamental Research Funds for the Central Universities of China (No. 1112021101), and the Major Science and Technology Program for Water Pollution Control and Treatment of China (No. 2012ZX07506-001).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zunyao Wang.

Additional information

Responsible editor: Philippe Garrigues

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(XLS 151 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shi, J., Feng, M., Zhang, X. et al. Acute oral toxicity and liver oxidant/antioxidant stress of halogenated benzene, phenol, and diphenyl ether in mice: a comparative and mechanism exploration. Environ Sci Pollut Res 20, 6138–6149 (2013). https://doi.org/10.1007/s11356-013-1622-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-013-1622-0

Keywords

Navigation