Review article. Adverse hematological effects of hexavalent chromium: an overview

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Workers of tanneries, welding industries, factories manufacturing chromate containing paints are exposed to hexavalent chromium that increas¬es the risk of developing serious adverse health effects. This review elucidates the mode of action of hexavalent chromium on blood and its adverse effects. Both leukocyte and erythrocyte counts of blood sharply decreased in Swiss mice after two weeks of intraperitoneal treatment with Cr (VI), with the erythrocytes transforming into echinocytes. The hexavalent chromium in the blood is readily reduced to trivalent form and the reductive capacity of erythrocytes is much greater than that of plasma. Excess Cr (VI), not reduced in plasma, may enter erythrocytes and lymphocytes and in rodents it induces microcytic anemia. The toxic effects of chromium (VI) include mitochondrial injury and DNA damage of blood cells that leads to carcinogenicity. Excess Cr (VI) increases cytosolic Ca2+ activity and ATP depletion thereby inducing eryptosis. Se, vitamin C, and quercetin are assumed to have some protective effect against hexavalent chromium induced hematological disorders.

Aaseth J, Alexander J, Norseth T. (1982). Uptake of 51Cr-chromate by human erythrocytes-a role of glutathione. Acta Pharmacol Toxicol 50: 310-315.

Achal V, Kumari D, Pan X. (2011). Bioremediation of chromium contaminated soil by a brown rot fungus Gloeophyllum sepiarium. Res. J. Microbiol. 6: 166-171.

Ackerley DF, Barak Y, Lynch SV, Curtin J. Matin A. (2006). Eff ect of chromate stress on Escherichia coli K-12. J Bacteriol 188(9): 3371-3381.

Adjroud O. (2009). Eff ects of potassium dichromate on haematological parameters in female and male Wistar albino rats. Ass Univ Bull Environ Res 12: 87-99.

Afolaranmi GA, Grant MH( 2013). The eff ect of ascorbic acid on the distribution of soluble Cr and Co ions in the blood and organs of rats. J Appl Toxicol 33(3): 220-6.

Ahsan MM, Shakoori FR , Shakoori AR. (2006). Biochemical and Haematological Abnormalities in Factory Workers Exposed to Hexavalent Chromium in Tanneries of Kasur District. Pakistan J Zool 38(3): 239-253.

Alpoim MC, Geraldes CF, Oliveira CR, Lima MC. (1995). Molecular mechanisms of chromium toxicity: oxidation of hemoglobin. Biochem Soc Trans. 23: 241-242.

Ashan MM, Shakoori FR, Shakoori AR. (2006). Biochemical and Haematological Abnormalities in Factory Workers Exposed to Hexavalent Chromium in Tanneries of Kasur District. Pak J Zool 38(3): 239-253.

ATSDR (Agency for Toxic Substances and Disease Registry) (2008a). Chromium (TP-7) In: Toxicological Profi le. US Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, pp. 610.

ATSDR (Agency for Toxic Substances and Disease Registry) (2008b) Toxicological Profi le for Chromium. Available at: http: // les/tp7.html#bookmark09.

ATSDR (Agency for Toxic Substances and Disease Registry). (2000). Chromium (TP-7) In: Toxicological Profi le.US Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, pp. 461.

Bagchi D, Bagchi M, Stohs SJ. (2001). Chromium (VI)-induced oxidative stress, apoptotic cell death and modulation of p53 tumor suppressor gene. Mol Cell Biochem 222: 149-158.

Beaumont JJ, Sedman RM, Reynolds SD et al. (2008). Cancer mortality in a Chinese population exposed to hexavalent chromium in drinking water. Epidemiol . 19: 12-23. doi:

Beyersmann D, Buttner B. (1989). Chromate eff ects on red cells membranes. Biol Trace Elem Res 21: 263-270.

Bucher JR. (2007). NTP toxicity studies of sodium dichromate dihydrate (CAS No. 7789-12-0) administered in drinking water to male and female F344/N rats and B6C3F1 mice and male BALB/c and am3-C57BL/6 mice. Toxic Rep Ser 72: 1-G4.

Buynder PV. (2010). Evaluation of chromium in blood. A report prepared by ChemRisk Canada, a division of ChemRisk LLP, Guelph, Ontario N1H7L6.

Cervantes C, Campos-Garciıa J, Devars S, Gutierrez-Corona F, Loza-Tavera H, Torres Guzman JC, Moreno-Sanchez R. (2001). Interactions of chromium with microorganisms and plants. FEMS Microbiol Rev 25: 335-347.

Christensen JM, Holst E, Bonde JP, Knudsen L. (1993). Determination of chromium in blood and serum. Evaluation of quality control procedures and estimation of reference values in Danish subjects. Sci Total Environ. 132: 11-25.

Corbett GE, Dodge DG, O’Flaherty E, Liang J, Throop L, Finley BL, Kerger BD. (1998). In vitro reduction kinetics of hexavalent chromium in human blood. Environ Res. 78(1): 7-11.

Costa M, Zhitkovich A, Toniolo P , Taioli E, Popov T, Lukanova A. (1996). Monitoring Human Lymphocytic DNA-Protein Cross-links as Biomarkers of Biologically Active Doses of Chromate. Env Health Perspective 104: 917-919.

Dana Devi K, Rozati R, Saleha Banu B, Jamil K, Grover P. (2001). . In vivo genotoxic eff ect of potassium dichromate in mice leukocytes using comet assay. Food Chem Toxicol 39: 859-865.

Das AP, Singh S. (2011). Occupational health assessment of chromite toxicity among Indian miners. Indian J Occup Environ Med. 15(1): 6-13.

Dayan AD, Payne AJ. (2001). Mechanisms of chromium toxicity, carcinogenicity and allergenicity: review of the literature from 1985 to 2000. Human Experi Toxicol 20: 439-451.

De Flora S, Mulbah S, Cartiglia C, D‘Agostini F, Longobardi M, E Steele V , Izzotti A. (2012). Smoke-induced micro RNA and related proteome alte rations. Modulation by chemopreventive agents. Int J Cancer 131(12): 2763-73.

De Flora, S. (2000). Threshold mechanisms and site specifi city in chromium (VI) carcinogenesis. Carcinogenesis 21(4): 533-541.

Długosz A, Rembacz K P, Pruss A, Durlak M, Lembas- Bogaczyk J. (2012). Infl uence of Chromium on the Natural Antioxidant Barrier. Pol J Env Studies 21 (2): 331-335.

ECB (European Chemicals Bureau ). (2005). European Union Risk Assessment Report. Chromium trioxide, sodium chromate, sodium dichromate, ammonium dichromate and potassium dichromate Risk Assessment. EUR Report No. 201508

Edel J, Sabbioni E. (1985). Pathways of Cr(III) and Cr(VI) in the rat after intratracheal administration. Hum Toxicol 4: 409-416.

EL-Shafei HM. (2012). Monitoring of Urine and Serum Cellular Enzymes in the Chromium Electroplating Workers. J Bioengineer Biomedical Sci 2: 3.

EPA (U.S. Environmental Protection Agency). (1998). Toxicological Review of Trivalent Chromium. CAS No. 16065-83-1. In support of Summary Information on the Integrated Risk Information System (IRIS) Accession No: PB99-137341

Fernandes MAS, Geraldes CFGC, Oliveira CR, Alpoim MC. (2000). Chromateinduced human erythrocytes haemoglobin oxidation and peroxidation: infl uence of vitamin E, vitamin C, salicylate, deferoxamine, and N-ethylmaleimide. Toxicol Lett 114 : 237-243.

Fernandes MAS, Mota IM, Silva MTL, Oliveira CR, Geraldes CFGC, Alpoim MC. (1999). Human erythrocytes are protected against chromate induced peroxidation. Ecotoxicol Environ Safety 43: 38-46.

Gao M, Levy LS, Braithwaite RA, Brown SS. (1993). Monitoring of total chromium in rat fl uids and lymphocytes following intratracheal administration of soluble trivalent or hexavalent chromium compounds. Human Exp Toxicol 12: 377-382

Geller RJ. (2001). Chromium. In: Sullivan JB, Krieger GR, eds. Clinical environmental health and toxic exposures. 2nd ed. Philadelphia: Lipincott Williams & Wilkins, pp. 926-930.

Glaser U, Hochrainer D, Kloppel H, Kuhnen H. (1985). Low level chromium (VI) inhalation eff ects on alveolar macrophages and immune functions in Wistar rats. Arch Toxicol 57: 250-256.

Halasova E, Matakova T, Musak L, Polakova V, Letkova L, Dobrota D, l Vodicka P. (2012). Evaluating chromosomal damage in workers exposed to hexavalent chromium and the modulating role of polymorphisms of DNA repair genes. Int Arch Occup Env Health 85(5): 473-481.

Huang, YL, Chen CY, Sheu JY, Chuang IC, Pan JH, Lin TH. (1999). Lipid Peroxidation In Workers Exposed To Hexavalent Chromium. J Toxicol Environ Health Part A 56( 4): 235-247.

ARC (International Agency for Research on Cancer). (2012). Chromium (VI) compounds) 100: 147-167.

IPCS (International Programme on Chemical Safety). (2006). Inorganic chromium (III) compounds. Draft. Concise International Chemical Assessment Document. World health Organization, Geneva.

Jabari, M, Aqra F, Sahin S , Khatib A. (2009). Monitoring chromium content in tannery wastewater. J Argent Chem Soc. 97(2): 77-87 http: // ar/pdf9702/9702art7.pdf.

Kerger BD, Butler WJ, Paustenbach DJ, Zhang JD, Li SK.(2009). Cancer Mortality in Chinese Populations Surrounding an Alloy Plant with Chromium Smelting Operations. J Toxicol Environ Health Part A 72: 5: 329.

Kerger BD, Paustenbach DJ, Corbett GE , Finley BL ( 1996). Absorption and elimination of trivalent and hexavalent chromium in humans following ingestion of a bolus dose in drinking water. Toxicol Appl Pharmacol 141: 145-158.

Krupa R, Stanczak M, Walter Z. (2002). Chromium Incorporated in RNA and DNA.Verlag der Z Naturforsch C. 57(9-10): 951-3.

Langird S, Nordhagen A. (1980). Small animal inhalation chambers and the signifi cance of dust ingestion from the contaminated coat when exposing rats to zinc chromate. Acta pharmacol et toxicol 46: 43-46.

Lei Y, Zhang Q, Zhuang Z. (1995). Study on DNA-protein crosslinks induced by chromate and nickel compounds in vivo with 125I-postlabelling assay. Mutation Res 329: 197-203.

Lewalter J, Korallus U, Harzdorf C, Weidemann H. (1985). Chromium blood detection in isolated erythrocytes: A new principle of biological monitoring of exposure to hexavalent chromium. Int Arch Occup Environ Health 55: 305‐318.

Lilien DL, Spivak JL , Goldman ID. (1970). Chromate Transport in Human Leukocytes. J Clin Invest 49(8): 1551-7.

Loubières Y, de Lassence A, Bernier M, Vieillard-Baron A, Schmitt JM, Page B, Jardin F(1999). Acute, fatal, oral chromic acid poisoning. J Toxicol - Clinl Toxicol 37(3): 333-6.

Luczak MW, Zhitkovich A. (2013). Role of direct reactivity with metals in chemoprotection by N-acetylcysteine against chromium(VI), cadmium(II), and cobalt(II). Free Radical Biol Med 65: 262-269.

MacKenzie RD, Anwar RA, Byerrum RU, Hoppert CA. (1959). Absorption and distribution of 5lCr in the albino rat. Arch Biochem Biophys 79: 200-205.

Medeiros MG, Rodrigues AS, Batoréu MC, Laires A, Rueff J, Zhitkovic A. (2003). Elevated levels of DNA-protein crosslinks and micronuclei in peripheral lymphocytes of tannery workers exposed to trivalent chromium. Mutagenesis 18(1): 19-24.

Merritt K, Brown SA. (1995). Release of hexavalent chromium from corrosion of stainless steel and cobalt-chromium alloys. J Biomed Mater Res 29(5): 627-633.

Miksche LW, Lewalter J. (1997).Health surveillance and biological eff ect monitoring for chromium-exposed workers. Reg Toxicol Pharm 26: S94-S99.

Minoia C , Cavalleri A. (1988). Chromium in urine, serum and red blood cells in the biological monitoring of workers exposed to diff erent chromium valency states. Sci. Total Environ 71: 323-327.

Mudhoo A, Garg VK, Wang S. (2012). Heavy Metals: Toxicity and Removal by Biosorption. Env Chem Sustain World. 2012: 379-442.

Mythili K, Karthikeyan B. (2011). Bioremediation of Cr (VI) from Tannery effl uent using Bacillus spp and Staphylococcus spp. Int Multidisciplin Res J 1(6): 38-41.

Nath K, Singh D, Shyam S, Sharma YK. (2009). Phytotoxic eff ects of chromium and tannery effl uent on growth and metabolism of Phaseolus mungo Roxb. J Environ Biol 30: 227-234.

Nigam A, Priya S, Bajpai P, Kumar S. (2014). Cytogenomics of hexavalent chromium (Cr 6+) exposed cells: A comprehensive review. Ind J Med Res 139: 349-370.

NIOSH (Comments of the National Institute for Occupational Safety and Health on the Occupational Safety and Health Administration). (2002). Request for Information Occupational Exposure to Hexavalent Chromium (Cr VI). 29 CFR Part 1910, Docket No. H-0054a, U.S. Department of Health and Human Services Public Health Service Centers for Disease Control and Prevention ,National Institute for Occupational Safety and Health.

NTP (National Toxicology Program). (2008). Toxicology and Carcinogenesis Studies of Sodium Dichromate Dihydrate (CAS No. 7789-12-0) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). Natl Toxicol Program Tech Rep Ser 546: 1-192.

OEHHA (Offi ce of Environmental Health Hazard Assessment). (2011). Public Health Goal for Hexavalent Chromium (Cr VI) in Drinking Water. Pesticide and Environmental Toxicology Branch, California Environmental Protection Agency.

OSHA (Occupational Safety & Health Administration). (2006). Occupational exposure to hexavalent chromium. Final rule. Fed Reg 71: 10099-10385

Patlolla AK, Barnes C, Yedjou C, Velma R, Tchounwou PB. (2009). Oxidative Stress, DNA Damage, and Antioxidant Enzyme Activity Induced by Hexavalent Chromium in Sprague-Dawley Rats. Environ Toxicol 24(1): 66-73.

Paustenbach DJ, Finley BL, Mowat FS, Kerger BD. (2003). : Human health risk and exposure assessment of chromium (VI) in tap water. J Toxicol Environ Health 66(14): 1295-339.

Petrilli FL, Rossi GA, Camoirano A, Romano M, Serra D, Bennicelli C, De Flora A, De Flora S. (1986). Metabolic reduction of chromium by alveolar macrophages and its relationships to cigarette smoke. J Clin Invest 77: 1917-1924. http: //

Poznyak T, Puga JM, Kiseleva E, Martinez. (2002). Chromium Toxic Eff ect Monitoring Using Ozonation Method . Int J Toxicol 21(3): 211-217.

Quievryn G, Goulart M, Messer J, Zhitkovich A. (2001). Reduction of Cr(VI) by cysteine: Signifi cance in human lymphocytes and formation of DNA damage in reactions with variable reduction rates. Mol Cell Biochem 222: 107-118.

Ramzan M, Malik MA, Iqbal Z, Arshad N, Khan SY, Arshad M.(2011) Study of hematological indices in tannery workers exposed to chromium in Sheikhupura (Pakistan). Toxicol Ind Health 27(9): 857-64.

Ray R R , Sarkar NK. (2011). A Report on Myelosuppressive and Lymphopenic Eff ects of Hexavalent Chromium in a Murine Model. J Exp Sci 2(8): 33-36

Ray R R , Sarkar NK. (2012). Light and Scanning Electron Microscopic Studies on Chromium-Induced Anemia in a Murine Model. Bulletin Environl Contamin Toxicol 88: 10-14.

Reynolds M, Stoddard L, Bespalov I, Zhitkovich A. (2007). Ascorbate acts as a highly potent inducer of chromate mutagenesis and clastogenesis: linkage to DNA breaks in G2 phase by mismatch repair. Nucleic acids Res 35(2): 465-76.

Richelmi P, Baldi C, Minoia C. (1984). Blood Levels of Hexavalent Chromium in Rats. In vitro and In vivo Experiments. Int J Environ Anal Chem 17: 181-186

Royer DJ, George JN, Terrell DR. (2010). Thrombocytopenia as an adverse effect of complementary and alternative medicines, herbal remedies, nutritional supplements, foods, and beverages. Eur J Haematol 84: 421-429.

Rudrama Devi K, Kumar J, Naik S. (2011). Eff ect of Ascorbic Acid Prophylaxis on the Frequency of Chromosomal Aberrations in the Peripheral Lymphocytes of Tannery Industrial Workers. IJPI’S J Biotechnol Biotherapeutic 2(7): 1-11.

Samitz MH. (1970). Ascorbic acid in the prevention and treatment of toxic effects from chromates. Acta Dermato-Venereolog 50(1): 59-64.

Sayato, Y., Nakamuro, K., Matsui, S., Ando, M., 1980, Metabolic fate of chromium compounds. I. Comparative behavior of chromium in rat administered with Na2-51Cr04 and 51CrCl3 J Pharm Dyn 3: 17-23.

Schaffer AW, Pilger A, Engelhardt C, Zweymueller K, Ruediger HW. (1999). Increased blood cobalt and chromium after total hip replacement. J Toxicol Clin Toxicol 37(7): 839-44.

Sellappa S, Kripa SK, Shibily P, Joseph S , Balachandar V. (2011). Biomonitoring of Genotoxic Eff ects Among Shielded Manual Metal Arc Welders. Asian Pacifi c J Cancer Prevention 12: 1041-44.

Sharma BK, Singhal PC, Chugh KS. (1978). Intravascular haemolysis and acute renal failure following potassium dichromate poisoning. Postgrad Med J 54(632): 414-415.

Singh N, Verma T , Gaur R. (2013). Detoxifi cation of hexavalent chromium by an indigenous facultative anaerobic Bacillus cereus strain isolated from tannery effl uent. Afric J Biotechnol 12(10): 1091-1103.

Soudani N, Ben Amara I, Troudi A, Hakim A, Bouaziz H, Ayadi Makni F, Zeghal KM, Zeghal N. (2011). Oxidative damage induced by chromium (VI) in rat erythrocytes: protective eff ect of selenium. J Physiol Biochem 67(4): 577-588.

Stana L, Trif A, Stana, LG, Petrovici S, Gravila C. (2009). Cumulative potassium dichromate intake eff ect during pregnancy on the erythrocyte membrane fragility in female off spring at sexual maturity. Lucrări Stiinłifi ce medicină veterinară XLII(2): 291-294.

Standeven AM Wetterhahn KE. (1989). Chromium (VI) Toxicity: Uptake, Reduction, and DNA Damage. Int J Toxicol 8: 1275-1283.

Stern A, Dabt PH. (2009). Derivation of Ingestion-Based Soil Remediation Criteria for Cr+6 Based on the NTP Chronic Bioassay Data for Sodium Dichromate Dihydrate. Risk Assessment Subgroup of the NJDEP Chromium Workgroup.

Stern AH. (2010). A quantitative assessment of the carcinogenicity of hexavalent chromium by the oral route and its relevance to human exposure. Environ Res 110: 798-807.

Suzuki Y, Fukuda K. (1990). Reduction of hexavalent chromium by ascorbic acid and glutathione with special reference to the rat lung. Arch Toxicol 64: 169-176.

Tarasub N,Tarasub C, Ayutthaya WDN. (2008). Eff ects of Quercetin on Acute Toxicity of Rat Spleen and Chromosome Aberrations in Bone Marrow Induced by Hexavalent Chromium. Thammasat Med J. 8(3): 306-316.

Terpilowska S, Siwicki R. (2010). The infl uence of chromium on cell-mediated and humoral-mediated immunity in mice. Central European J Immunol 35(1): 10-13.

Thompson, C. M., Haws, L. C., Harris, M. A., Gatto, N. M., and Proctor, D. M.(2011). Application of the U.S. EPA mode of action Framework for purposes of guiding future research: a case study involving the oral carcinogenicity of hexavalent chromium. Toxicol Sci 119: 20-40.

Torra M, Rodamilans M, Corbella, J, Ferrer R, Mazzara R. (1999). Blood chromium determination in assessing reference values in an unexposed Mediterranean population. Biol Trace Element Res 70: 183-189.

U.S. EPA (U.S. Environmental Protection Agency). (1998). Toxicological review of hexavalent chromium. Washington, DC.

Vasant C, Balamurugan K, Rajaram R, Ramasami T. (2001). Apoptosis of lymphocytes in the presence of Cr (V) complexes: Role in Cr (VI)-induced toxicity Biochem Biophys Res Commun 285: 1354-60

Vilcheck SK, O’Brien TJ, Pritchard DE, Ha L, Ceryak S, Fornsaglio JL, Patierno SR. (2002). Fanconi anemia complementation group A cells are hypersensitive to chromium (VI)-induced toxicity. Environ Health Persp 110(5): 773-7.

Wang JY, Wicklund BH, Gustilo RB, Tsukayama DT. (1997). Prosthetic metals impair murine immune response and cytokine release in vivo and in vitro. J Orthop Res 15: 688-99.

Weber H. (1983). Long-term study of the distribution of soluble chromate-51 in the rat after a single intratracheal administration. J Toxicol Environ Health 11: 749-764.

Werfel U, LangenV, Eickhoff I, Schoonbrood J, Vahrenholz C, Brauksiepe A, Popp W, Norpoth K. (1998). Elevated DNA single‐strand breakage frequencies in lymphocytes of welders exposed to chromium and nickel. Carcinogen 19: 413-418.

WHO (World Health Organization). (1996). Chromium in biological monitoring of chemical exposure in the workplace guidelines. World Health Organization. Geneva, Switzerland, pp. 91-111.

Wiegand HJ, Ottenwälder H ,Bolt HM. (1987). Bioavailability and metabolism of hexavalent chromium compounds. Toxicol Environ Chem. 14(4): 263-275.

Wiegand HJ, Ottenwalder H,Bolt HM. (1984). Disposition of intratracheally administered chromium(III) and chromium(VI) in rabbits. Toxicol Lett 22(2): 273-6.

Xiao F, Chen D, Luo L, Zhong X, Xie Y, Zou L, Zeng M, Guan L, Zhong C. (2013). Time-order eff ects of vitamin C on hexavalent chromium-induced mitochondrial damage and DNA-protein crosslinks in cultured rat peripheral blood lymphocytes. Mol Med Rep 8(1): 53-60.

Zhang JD, Li S. (1997). Cancer mortality in a Chinese population exposed to hexavalent chromium in water. J Occup Environ Med. 39: 315-9.

Zhang XH, Zhang X, Wang XC, Jin LF, Yang ZP, Jiang CX, Chen Q, Ren XB, Cao JZ, Wang Q, Zhu YM. (2011). Chronic occupational exposure to hexavalent chromium causes DNA damage in electroplating workers. BMC Pub. Health. 11: 224.

Zhitkovich A, Song Y, Quievryn G, Voitkun V. (2001). Non-oxidative mechanisms are responsible for the induction of mutagenesis by reduction of Cr(VI) with cysteine: role of ternary DNA adducts in Cr(III)-dependent mutagenesis. Biochem 40(2): 549-60.

Zhumabaeva AN, Zarishnyak NV, Bekmukhambetov E. Zh. (2014). Immunotropic Eff ects of Hexavalent Chromium Soluble Compounds on the Thymus and Peripheral Blood Values in a Subacute Experiment. Bulletin Exp Biol Med 156(4): 512-517.

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