Genotoxicity of chemical compounds is primarily associated with the interaction with DNA, formation of mutations, damage to chromosomes and initiating carcinogenesis processes. Currently, many compounds found in the environment are considered to be genotoxic agents, among them chromium: trivalent (III) and hexavalent (VI). The genotoxicity of hexavalent (VI) chromium has been proven in numerous epidemiological, in vitro and in vivo studies. The main source of Cr (VI) is environmental pollution associated with its use in various industries. On the other hand, the role of chromium (III) as a microelement is widely discussed. Due to its beneficial properties, associated with maintaining adequate blood glucose levels and supporting weight loss, it is widely used in the form of dietary supplements, often in doses exceeding the daily requirement. However, the safety of chromium compounds is disputable. Data about the mechanism of genotoxic effects are still incomplete.

The aim of this review is to present the current knowledge about the induction of genotoxicity from two forms of chromium: trivalent (III) and hexavalent (VI).

State of knowledge:
Chromium (VI) is a carcinogen with proven mutagenic and genotoxic effects, but this issue is still being investigated by scientists. In recent years, numerous studies have also been conducted on the genotoxic effect of chromium (III).

Due to the still unexplained mechanism of the genotoxic action and incomplete knowledge about the transformation of chromium in the body, further research is needed, especially due to the growing popularity of Cr (III) compounds and their consumption in the form of dietary supplements and doubts as to the safety of its use, as well as environmental exposure to Cr (VI).

The review was prepared under the project the ‘Regional Initiative of Excellence’ programme for 2019–2022 (Project No. 016/RID/2018/19), financed by the Ministry of Science and Higher Education in Warsaw, Poland, The review was also supported by the Medical University in Wrocław, Poland (Grant No. ST-D150.18.004).
Sawicka E, Jurkowska K, Piwowar A. Chromium (III) and chromium (VI) as important players in the induction of genotoxicity – current view. Ann Agric Environ Med. 2021; 28(1): 1–10. doi: 10.26444/aaem/118228
Jena GB, Kaul CL, Ramarao P. Genotoxicity testing, a regulatory requirement for drug discovery and development: impact of ich guidelines. Indian J Pharmacol. 2002; 34: 86–99.
Phillips DH1, Arlt VM. Genotoxicity: damage to DNA and its consequences. EXS. 2009; 99: 87–110.
Mohamed S, Sabita U, Rajendra SV, Raman D. Genotoxicity: Mechanisms, Testing Guidelines and Methods. Glob J Pharmaceu Sci. 2017; 1(5). doi: 10.19080/GJPPS.2017.02.555575.
Hamilton EM, Young SD, Bailey EH, Watts MJ. Chromium speciation in foodstuffs: A review. Food Chem. 2018; 250(1): 105–112. doi: 10.1016/j.foodchem.2018.01.016.
Jurkowska K, Sawicka E, Piwowar A. Chrom – pierwiastek już dobrze znany czy wciąż nieznany – dwa oblicza działania. Farm Pol. 2019; 75(4): 208–218.
O’Flaherty EJ, Kerger BD, Hays SM, Paustenbach DJ. A physiologically based model for the ingestion of chromium(III) and chromium(VI) by humans. Toxicol Sci. 2001; 60(2): 196–213.
Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2007; 283(2–3): 65–87. doi: 10.1016/j.tox.2011.03.001.
Surgiewicz J. Chrom i jego związki – metoda oznaczania. Podstawy i Metody Oceny Środowiska Pracy. 2009; 1(59): 113–118.
Lewicki S, Zdanowski R, Krzyżowska M, Lewicka A, Dębski B, Niemcewicz M, et al. The role of Chromium III in the organism and its possible use in diabetes and obesity treatment. Ann Agric Environ Med. 2014; 21(2): 331–335. doi: 10.5604/1232-1966.1108599.
Piotrowska A, Pilch W, Tota Ł, Nowak G. Biological significance of chromium III for the human organism. Med Pr. 2018; 69(2): 211–23. DOI: 10.13075/mp.5893.00625.
Mishra S, Bharagava RN. Toxic and genotoxic effects of hexavalent chromium in environment and its bioremediation strategies. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2016; 34(1): 1–32. doi: 0.1080/10590501.2015.1096883.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (2012): Chromium(VI) Compounds. In: Arsenic, metals, fibres, and dusts. IARC Monogrophs on the Evaluation of Carcinogenic Risks to Humans; 100(Pt C). International Agency for Research on Cancer (IARC), Lyon pp 147−167.
Skowroń J, Konieczko K. Związki chromu(VI) – w przeliczeniu na Cr(VI) Dokumentacja proponowanych dopuszczalnych wielkości narażenia zawodowego. Podstawy i Metody Oceny Środowiska Pracy 2016; 2(88): 15‒112 DOI: 10.5604/1231868X.1205475.
Fang Z, Zhao M, Zhen H, Chen L, Shi P, Huang Z. Genotoxicity of tri- and hexavalent chromium compounds in vivo and their modes of action on DNA damage in vitro. PLoS One. 2014; 9(8): e103194. doi: 10.1371/journal.pone.0103194.
Levina A, Lay PA. Chemical properties and toxicity of chromium(III) nutritional supplements. Chem Res Toxicol. 2008; 21(3): 563–71. doi: 10.1021/tx700385t.
Sobański L, Sprzęczka-Niedolaz M, Łebek G. Rola chromu w życiu człowieka. Bromat Chem Toksykol. 2007; 2: 113–119.
Hernandez F, Bemrah N, Séby F, Noël L, Guérin T. Cr(VI) and Cr(III) in milk, dairy and cereal products and dietary exposure assessment. 2019; 1: 1–7. doi: 10.1080/19393210.2019.1598506.
Vincent JB. New Evidence against Chromium as an Essential Trace Element. J Nutr. 2017; 147(12): 2212–2219. doi: 10.3945/jn.117.255901.
Sugden K, Stearns D. The role of chromium(V) in the mechanism of chromate-induced oxidative DNA damage and cancer. J Environ Pathol Toxicol Oncol. 2000; 19: 215–230.
Kantor ED, Rehm CD, Du M, White E, Giovannucci, EL. Trends in Dietary Supplement Use Among US Adults From 1999–2012. JAMA. 2016; 316(14): 1464–1474. doi: 10.1001/jama.2016.14403.
Lukaski HC, Siders WA, Penland JG. Chromium picolinate supplementation in women: effects on body weight, composition, and iron status. Nutrition. 2007; 23(3): 187–95. doi: 10.1016/j.nut.2006.12.001.
Lewicki S, Zdanowski R, Krzyżowska M, Lewicka A, Dębski B, Niemcewicz M, et al. The role of Chromium III in the organism and its possible use in diabetes and obesity treatment. Ann Agric Environ Med. 2014; 21(2): 331–5. doi: 10.5604/1232-1966.1108599.
Sahin K, Onderci M, Tuzcu M, Ustundag B, Cikim G, Ozercan IH, et al. Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat. Metabolism. 2007; 5(9): 1233–1240. DOI: 10.1016/j.metabol.2007.04.021.
Clodfelder BJ, Gullick BM, Lukaski HC, Neggers Y, Vincent JB. Oral administration of the biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+increases insulin sensitivity and improves blood plasma variables in healthy and type 2 diabetic rats. J Biol Inorg Chem. 2005; 10(2): 119–30. DOI: 10.1007/s00775-004-0618-0.
Otag A, Hazar M, Otag I, Gürkan A, Okan I. Responses of trace elements to aerobic maximal exercise in elite sportsmen. Glob J Health Sci. 2014; 6(3): 90–96. doi: 10.5539/gjhs.v6n3p90.
Racek J, Sindberg CD, Moesgaard S, Mainz J, Fabry J, Müller L, et al. Effect of chromium-enriched yeast on fasting plasma glucose, glycated haemoglobin and serum lipid levels in patients with type 2 diabetes mellitus treated with insulin. Biol Trace Elem Res. 201; 155(1): 1–4. doi: 10.1007/s12011-013-9758-9.
Yin RV, Phung OJ. Effect of chromium supplementation on glycated hemoglobin and fasting plasma glucose in patients with diabetes mellitus. Nutr J. 2015; 14: 14. doi: 10.1186/1475-2891-14-14.
Ghosh D, Bhattacharyaa B, Mukherjee B, Manna B, Sinha M, Chowdhury J, et al. Role of chromium supplementation in Indians with type 2 diabetes mellitus. J Nutr Biochem. 2002; 13(11): 690–697.
Kleefstra N, Houweling ST, Jansman FG, Groenier KH, Gans RO, Meyboom-de Jong B, et al. Chromium treatment has no effect in patients with poorly controlled, insulin-treated type 2 diabetes in an obese Western population: a randomized, double-blind, placebo-controlled trial. Diabetes Care. 2006; 29(3): 521–525.
Chaudhary S, Van Horn JD. Breakdown kinetics of the tri-chromium(III) oxo acetate cluster ([Cr3O(OAc)6]+) with some ligands of biological interest. J Inorg Biochem. 2007; 101(2): 329–335. DOI: 10.1016/j.jinorgbio.2006.10.006.
Vincent JB. Quest for the molecular mechanism of chromium action and its relationship to diabetes. Nutr Rev. 2000; 58(3 Pt 1): 67–72. DOI: 10.1111/j.1753-4887.2000.tb01841.x.
Pechova A, Pavlata L. Chromium as an essential nutrient: A review. Vet Med (Praha). 2007; 52(1): 1–18.
Hamilton EM, Young SD, Bailey EH, Watts MJ. Chromium speciation in foodstuffs: A review. Food Chem. 2018; 250(1): 105–12.
Eastmond DA, Macgregor JT, Slesinski RS. Trivalent chromium: assessing the genotoxic risk of an essential trace element and widely used human and animal nutritional supplement. Crit Rev Toxicol. 2008; 38(3): 173–90. doi: 10.1080/10408440701845401.
Wierzejska R. Dietary supplements – panacea to contemporary health problems, or the triumph of advertisement? Med Rodz. 2017; 20(2): 136–142.
Song R, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, et al. Effect of Long-Term Estrogen Deprivation on Apoptotic Responses on Breast Cancer to 17β-Estradiol. J Natl Cancer Inst. 2001; 93(22): 1714–1723.
Jafari F, Jafari S, Etesamnia P. Genotoxicity, Bioactivity and Clinical Properties of Calcium Silicate Based Sealers: A Literature Review. Iran Endod J. 2017; 12(4): 407–413. doi: 10.22037/iej.v12i4.17623.
Vyšín L, Pachnerová Brabcová K, Štěpán V, Moretto-Capelle P, Bugler B, Legube G, et al. Proton-induced direct and indirect damage of plasmid DNA. Radiat Environ Biophys. 2015; 54(3): 343–352. DOI: 10.1007/s00411-015-0605-6.
Chatterjee N, Walker GC. Mechanisms of DNA damage, repair and mutagenesis. Environ Mol Mutagen. 2017; 58(5): 235–263. doi: 10.1002/em.22087.
Evans MD, Dizdaroglu M, Cooke MS. Oxidative DNA damage and disease: induction, repair and significance. Mutat Res. 2004; 567(1): 1–61. DOI: 10.1016/j.mrrev.2003.11.001.
Lan J, Gou N, Gao C, He M, Gu AZ. Comparative and mechanistic genotoxicity assessment of nanomaterials via a quantitative toxicogenomics approach across multiple species. Environ Sci Technol. 2014; 48(21): 12937–12945. doi: 10.1021/es503065q.
Eki T. Yeast-based genotoxicity tests for assessing DNA alterations and DNA stress responses: a 40-year overview. Appl Microbiol Biotechnol. 2018; 102(6): 2493–2507. DOI: 10.1007/s00253-018-8783-1.
Czubaszek M, Szostek M, Wójcik E, Andraszek K. Test kometowy jako metoda identyfikacji niestabilności chromosomów. Postepy Hig Med Dosw. 2014; 68: 695–700.
Kamath GH, Rao KS. Genotoxicity guidelines recommended by International Conference of Harmonization (ICH). Methods Mol Biol. 2013; 1044: 431–58. doi: 10.1007/978-1-62703-529-3_24.
Holton NW, Ebenstein Y, Gassman NR. Broad spectrum detection of DNA damage by Repair Assisted Damage Detection (RADD). DNA Repair (Amst). 2018; 66–67: 42–49. doi: 10.1016/j.dnarep.2018.04.007.
Sobol Z, Schiestl RH. Intracellular and extracellular factors influencing Cr(VI) and Cr(III) genotoxicity. Environ Mol Mutagen. 2012; 53(2): 94–100. doi: 10.1002/em.20679.
Zhang Q, Song Y, Amor K, Huang WE, Porcelli D, Thompson I. Monitoring Cr toxicity and remediation processes – combining a whole-cell bioreporter and Cr isotope techniques. Water Res. 2019; 153: 295–303. doi: 10.1016/j.watres.2019.01.009.
Jiang B, Zhu D, Song Y, Zhang D, Liu Z, Zhang X, et al. Use of a whole-cell bioreporter, Acinetobacter baylyi, to estimate the genotoxicity and bioavailability of chromium(VI)-contaminated soils. Biotechnol Lett. 2015; 37(2): 343–8. doi: 10.1007/s10529-014-1674-3.
Zhang Q, Amor K, Galer SJG, Thompson I, Porcelli D. Using stable isotope fractionation factors to identify Cr(VI) reduction pathways: Metal-mineral-microbe interactions. Water Res. 2019; 151: 98–109. doi: 10.1016/j.watres.2018.11.088.
Headlam HA, Lay PA. Spectroscopic characterization of genotoxic chromium (V) peptide complexes: Oxidation of Chromium (III) triglycine, tetraglycine and pentaglycine complexes. J Inorg Biochem. 2016; 162: 227–237. doi: 10.1016/j.jinorgbio.2016.06.015.
Stearns DM, Silveira SM, Wolf KK, Luke AM. Chromium (III) tris(picolinate) is mutagenic at the hypoxanthine (guanine) phosphoribosyltransferase gene in Chinese hamster ovary cells. Mutat Res. 2002; 513(1–2): 135–142.
Król E, Krejpcio Z. Poglądy na temat roli chromu (III) w zapobieganiu i leczeniu cukrzycy. Diabet Prakt. 2008; 9: 168–175.
Stout MD, Nyska A, Collins BJ, Witt KL, Kissling GE, Malarkey DE, et al. Chronic toxicity and carcinogenicity studies of chromium picolinate monohydrate administered in feed to F344/N rats and B6C3F1 mice for 2 years. Food Chem Toxicol. 2009; 47(4): 729–33. doi: 10.1016/j.fct.2009.01.006.
Wang L, Wise JTF, Zhang Z, Shi X. Progress and prospects of reactive oxygen species in metal carcinogenesis. Curr Pharmacol Rep. 2016; 2(4): 178–186. doi: 10.1007/s40495-016-0061-2.
Bock M, Schmidt A, Bruckner T, Diepgen TL. Occupational skin disease in the construction industry. Br J Dermatol. 2003; 149(6): 1165–71.
Wakeman TP, Yang A, Dalal NS, Boohaker RJ, Zeng Q, Ding Q, et al. DNA mismatch repair protein Mlh1 is required for tetravalent chromium intermediate-induced DNA damage. Oncotarget. 2017; 8(48): 83975–83985. doi: 10.18632/oncotarget.20150.
Trzeciak A, Kowalik J, Małecka-Panas E, Drzewoski J, Wojewódzka M, Iwaneńko T, et al. Genotoxicity of chromium in human gastric mucosa cells and peripheral blood lymphocytes evaluated by the single cell gel electrophoresis (comet assay). Med Sci Monit. 2000; 6(1): 24–9.
Zhitkovich A. Chromium in drinking water: sources, metabolism, and cancer risks. Chem Res Toxicol. 2011; 24(10): 1617–29. doi: 10.1021/tx200251t.
Chaudhary S, Pinkston J, Rabile MM, Van Horn JD. Unusual reactivity in a commercial chromium supplement compared to baseline DNA cleavage with synthetic chromium complexes. J Inorg Biochem. 2005; 99(3): 787–94. DOI: 10.1016/j.jinorgbio.2004.12.009.
Nguyen A, Mulyani I, Levina A, Lay PA. Reactivity of chromium(III) nutritional supplements in biological media: an X-ray absorption spectroscopic study. Inorg Chem. 2008; 47(10): 4299–309. doi: 10.1021/ic7024389.
Kumar D, Gangwar SP. Role of antioxidants in detoxification of Cr(VI) toxicity in laboratory rats. J Environ Sci Eng. 2012; 54(3): 441–446.
Rembacz KP, Sawicka E, Długosz A. Role of estradiol in chromium-induced oxidative stress. Acta Pol Pharm. 2012; 69(6): 1372–1379.
Wang Y, Su H, Gu Y, Song X, Zhao J. Carcinogenicity of chromium and chemoprevention: a brief update. Onco Targets Ther. 2017; 10: 4065–4079. doi: 10.2147/OTT.S139262.
Henkler F, Brinkmann J, Luch A. The Role of Oxidative Stress in Carcinogenesis Induced by Metals and Xenobiotics. Cancers (Basel). 2010; 2(2): 376–396. doi: 10.3390/cancers2020376.
Jannetto PJ, Antholine WE, Myers CR. Cytochrome b(5) plays a key role in human microsomal chromium (VI) reduction. Toxicology. 2001; 159(3): 119–133.
Gaddameedi RR, Burgula S, Sairam M, Singh SS. Role of insulin in Cr(VI)-mediated genotoxicity in Neurospora crassa. Lett Appl Microbiol. 2011; 53(1): 14–21. doi: 10.1111/j.1472-765X.2011.03058.x.
O’Brien TJ, Jiang G, Chun G, Mandel HG, Westphal CS, Kahen K, et al. Incision of trivalent chromium [Cr(III)]-induced DNA damage by Bacillus caldotenax UvrABC endonuclease. Mutat Res. 2006; 610(1–2): 85–92. DOI: 10.1016/j.mrgentox.2006.06.015.
Morse JL, Luczak MW, Zhitkovich A. Chromium(VI) causes interstrand DNA cross-linking in vitro but shows no hypersensitivity in cross-link repair-deficient human cells. Chem Res Toxicol. 2013; 26(10): 1591–8. doi: 10.1021/tx400293s.
Ding M, Shi X. Molecular mechanisms of Cr(VI)-induced carcinogenesis. Mol Cell Biochem. 2002; 234–235(1–2): 293–300.
Figgitt M, Newson R, Leslie IJ, Fisher J, Ingham E, Case CP. The genotoxicity of physiological concentrations of chromium (Cr(III) and Cr(VI)) and cobalt (Co(II)): an in vitro study. Mutat Res. 2010; 688(1–2):53–61. doi: 10.1016/j.mrfmmm.2010.03.008.
El-Yamani N, Zúñiga L, Stoyanova E, Creus A, Marcos R. Chromium-induced genotoxicity and interference in human lymphoblastoid cell (TK6) repair processes. J Toxicol Environ Health A. 2011; 74(15–16): 1030–9. doi: 10.1080/15287394.2011.582282.
Novotnik B, Ščančar J, Milačič R, Filipič M, Žegura B. Cytotoxic and genotoxic potential of Cr(VI), Cr(III)-nitrate and Cr(III)-EDTA complex in human hepatoma (HepG2) cells. Chemosphere. 2016; 154: 124–131. doi: 10.1016/j.chemosphere.2016.03.118.
NTP toxicology and carcinogenesis studies of chromium picolinate monohydrate (CAS No. 27882-76-4) in F344/N rats and B6C3F1 mice (feed studies). Natl Toxicol Program Tech Rep Ser. 2010; 556: 1–194.
Staniek H, Kostrzewska-Poczekaj M, Arndt M, Szyfter K, Krejpcio Z. Genotoxicity assessment of chromium(III) propionate complex in the rat model using the comet assay. Food Chem Toxicol. 2010; 48(1): 89–92. doi: 10.1016/j.fct.2009.09.020.
Ateeq M, Rehman Ur H, Zareen S, Rehman A, Ullah W, Shah M, et al. Occupational risk assessment of oxidative stress and DNA damage in tannery workers exposed to Chromium in Pakistan. J Entomol Zool Stud. 2016; 4(6): 426–432.
IARC Monographs on the evaluation of carcinogenic risks to humans. Chromium, Nickiel and Welding. Vol. 49. Chromium and chromium compounds. Lyon, p. 49–256.
Chen QY, Murphy A, Sun H, Costa M. Molecular and epigenetic mechanisms of Cr(VI)-induced carcinogenesis. Toxicol Appl Pharmacol. 2019; 377: 114636. doi: 10.1016/j.taap.2019.114636.
Scientific Committee on Occupational Exposure Limits (SCOEL). Recommendation from the risk assessment for hexavalent chromium. 2004; SCOEL/ SUM/86.
Toxicological profile for Chromium. Agency for Toxic Substances and Disease Registry (ATSDR). U.S. Department of Health and Human Services, Public Health Service. Atlanta 2012.
DeLoughery Z, Luczak MW, Zhitkovich A. Monitoring Cr intermediates and reactive oxygen species with fluorescent probes during chromate reduction. Chem Res Toxicol. 2014; 27(5): 843–51. doi: 10.1021/tx500028x.
Macfie A, Hagan E, Zhitkovich A. Mechanism of DNA-protein cross-linking by chromium. Chem Res Toxicol. 2010; 23(2): 341–7. doi: 10.1021/tx9003402.
O’Brien TJ, Mandel HG, Sugden KD, Komarov AM, Patierno SR. Hypoxia impedes the formation of chromium DNA-adducts in a cell-free system. Biochem Pharmacol. 2005; 70(12): 1814–22. DOI: 10.1016/j.bcp.2005.09.016.
Quievryn G, Peterson E, Messer J, Zhitkovich A. Genotoxicity and mutagenicity of chromium(VI)/ascorbate-generated DNA adducts in human and bacterial cells. Biochemistry. 2003; 42(4): 1062–70. DOI: 10.1021/bi0271547.
Qin Q, Xie H, Wise SS, Browning CL, Thompson KN, Holmes AL, et al. Homologous Recombination Repair Signaling in Chemical Carcinogenesis: Prolonged Particulate Hexavallent Chromoium Exposure Suppresses the Rad51 Response in Human Lung Cells. Toxicol Sci. 2014; 142(1): 117–25. doi: 10.1093/toxsci/kfu175.
Cavallo D, Ursini CL, Fresegna AM, Ciervo A, Maiello R, Rondinone B, et al. Direct-oxidative DNA damage and apoptosis induction in different human respiratory cells exposed to low concentrations of sodium chromate. J Appl Toxicol. 2010; 30(3): 218–225. doi: 10.1002/jat.1487.
Xie H, Wise SS, Holmes AL, Xu B, Wakeman TP, Pelsue SC, et al. Carcinogenic lead chomate induces DNA double-strand breaks in human lung cells. Mutat Res. 2005; 586(2): 160–172. doi: 10.1016/j.mrgentox.2005.06.002.
Krawic C, Zhitkovich A. Toxicological Antagonism among Welding Fume Metals: Inactivation of Soluble Cr(VI) by Iron. Chem Res Toxicol. 2018; 31(11): 1172–1184. doi: 10.1021/acs.chemrestox.8b00182.
Deng Y, Wang M, Tian T, et al. The Effect of Hexavalent Chromium on the Incidence and Mortality of Human Cancers: A Meta-Analysis Based on Published Epidemiological Cohort Studies. Front Oncol. 2019; 9: 24. doi: 10.3389/fonc.2019.00024.
McCarroll N, Keshava N, Chen J, Akerman G, Kligerman A, Rinde E. An evaluation of the mode of action framework for mutagenic carcinogens case study II: chromium (VI). Environ Mol Mutagen. 2010; 51(2): 89–111. doi: 10.1002/em.20525.
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