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3-Kloropropandiol, 2-Kloropropandiol, Esterleri ve Glisidil Yağ Asidi Esterinin Toksik Etkileri

3-kloropropandiol (3-MCPD), 2-kloropropandiol (2-MCPD), bunların esterleri ve glisidil yağ asidi esterleri (GE) gıdaveya gıda işlem kaynaklı bulaşanlar sınıfında yer almaktadır. İlk olarak, asitle hidrolize olmuş bitkisel proteinlerde(soya sosu ve sebze proteinleri) tespit edilmiştir. Daha sonraki yıllarda farklı gıdalarda da 3-MCPD ve esterlerininvarlığının tespit edilmesiyle bu bileşiklerin güvenliğine yönelik ilgi artmaya başlamıştır. Günümüzde 3-MCPD, 2-MCPD, bunların yağ asidi esterleri ve GE’nin en yüksek düzeyde palm yağı olmak üzere hemen hemen tüm bitkiselyağlarda, margarinlerde, pasta ve kekler gibi birçok işlenmiş gıdada bulunduğu bilinmektedir. Bu bileşikler aynızamanda bebek mamalarının içeriğinde de yer almaktadır. Bu derlemede tüm bu kullanımlar göz önüne alınarak 3-MCPD, 2-MCPD ve GE’nin toksik etkileri üzerine yapılan çalışmalardan bahsedilmiştir.

Toxic Effects of 3-Chloropropanediol, 2-Chloropropanediol, their Esters and Glycidyl Fatty Acid Ester

3-chloropropanediol (3-MCPD), 2-chloropropanediol (2-MCPD), their esters and glycidyl fatty acid esters (GE) are important food contaminates originating mainly during food processing. These materials were firstly identified in acidhydrolyzed plant proteins such as soybean and other vegetable proteins. Then, the detection of 3-MCPD and its esters in different foods raised interest in the safety profile of these compounds. Nowadays, 3-MCPD, 2-MCPD and their fatty acid esters and GE are known to be present in almost all vegetable oils, mostly in palm oil, margarines and processed foods, especially pastries and cakes. It is also found in baby foods. In this review, studies on the toxic effects of 3-MCPD, 2-MCPD and GE are reviewed.

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[1] Gökırmaklı, Ç, Bayram, M. (2018). Gıda için gelecek öngörüleri: Yıl 2050. Akademik Gıda, 16(3), 351-360.
[2] EFSA Journal, (2016). Chemicals in Food. Overview of selected data collection. https://www.efsa.europa.eu/sites/default/files/corpo rate_publications/files/161215chemicalsinfoodrepor t.pdf (Erişim tarihi: Aralık 2018)
[3] Seefelder, W., Varga, N., Studer, A., Williamson, G., Scanlan, F.P., Stadler, R.H. (2008). Esters of 3- chloro-1,2-propanediol (3-MCPD) in vegetable oils: significance in the formation of 3-MCPD. Food Additives and Contaminants, 25, 391-400.
[4] Abraham, K., Appel, K., Berger-Preiss, E., Apel, E., Gerlin, S., Mielke, H., Creutzenberg, O., Lampen, A. (2013). Relative oral bioavailability of 3-MCPD from 3-MCPD fatty acid esters in rats. Archives of Toxicology, 87, 649-59.
[5] Cho, W.S., Han, B.S., Lee, H., Kim, C., Nam, K.T., Park, K., Choi, M., Kim, S.J., Kim, S.H., Jeong, J., Jang, D.D. (2008). Subchronic toxicity study of 3- monochloropropane-1,2-diol administered by drinking water to B6C3F1 mice. Food and Chemical Toxicology, 46, 1666-73.
[6] Cho, W.S., Han, B.S., Nam, K.T., Park, K., Choi, M., Kim, S.H., Jeong, J., Jang, D.D. (2008). Carcinogenicity study of 3-monochloropropane-1,2- diol in Sprague-Dawley rats. Food Chem Toxicol, 46, 3172-77.
[7] Federal Institute for Risk Assessment, (2007). BfR opinion 047/2007. Infant formula and follow-up formula may contain harmful 3-MCPD fatty acid esters. http://www.bfr.bund.de/cm/349/infant_formula_and _follow_up_formula_may_contain_harmful_3_mcp d_fatty_acid_esters.pdf.
[8] EFSA Journal, (2016). Scientific Opinion: Risk for human health related to the presence of 3- and 2- monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food. EFSA Panel on Contaminants in Food Chain (CONTAM). EFSA Journal, 14(5), 4426, 159 p.
[9] Türk Gıda Kodeksi, Bulaşanlar Yönetmeliği, (2011). http://www.resmigazete.gov.tr/eskiler/2011/12/2011 1229M3-8.htm.
[10] National Toxicology Program (NTP), (2007). National Toxicology Program, Toxicology and carcinogenesis studies of glycidol (CAS No. 556- 52-5) in genetically modified haploinsufficient p16Ink4a/p19Arf mice (gavage study). Technical Report Series No. 13. National Institutes of Health Publication No. 08-5962. Research Triangle Park, NC.
[11] Appel, K., Abraham, K., Berger-Preiss, E., Hansen, T., Apel, E., Schuchardt, S., Vogt, C., Bakhiya, N., Creutzenberg, O., Lampen, A. (2013). Relative oral bioavailability of glycidol from glycidyl fatty acid esters in rats. Archives of Toxicology, 87, 1649- 1659.
[12] Lee, B.Q., Khor, S.M. (2015). 3-Chloropropane-1,2- diol (3-MCPD) in soy sauce: A review on the formation, reduction, and detection of this potential carcinogen. The Comprehensive Reviews in Food Science App, 14(1), 48-66.
[13] Velisek, J., Davidek, J., Kubelka, V., Janicek, G., Svobodova, Z., Simicova, Z.(1980). New chlorinecontaining organic compounds in protein hydrolysates. Journal of Agricultural and Food Chemistry, 28(6), 1142-1154.
[14] Baer, I., de la Calle, B., Taylor, P. (2010). 3-MCPD in food other than soy sauce or hydrolysed vegetable protein (HVP). Anal Bioanal Chem, 396(1), 443-456.
[15] Crews, C., Brereton, P., Davies, A. (2001). The effects of domestic cooking on the levels of 3- monochloropropanediol in foods. Food Additives & Contaminants, 18(4), 271-280.
[16] Edwards, N., Jones, A.R., Waites, G.M.H. (1975). The entry of α-chlorohydrin into body fluids of male rats and its effect upon incorporation of glycerol into lipids. Journal of Reproduction and Fertility, 43, 225-232.
[17] Barocelli, E., Corradi, A., Mutti, A., Petronini, P.G. (2011). Comparison between 3-MCPD and its palmitic esters in a 90-day toxicological study. EFSA Supporting Publications, 8(9), 1-131. http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2 011.EN-187/pdf.
[18] Li, J., Wang, S., Wang, M., Shi, W., Du, X., Sun, C. (2013). The toxicity of 3-chloropropane-1,2- dipalmitate in Wistar rats and a metabonomics analysis of rat urine by ultra-performance liquid chromatography-mass spectrometry. ChemicoBiological Interactions, 206, 337-345.
[19] Onami, S., Cho, Y., Toyoda, T., Mizuta, Y., Yoshida, M., Nishikawa, A., Ogawa, K. (2014). A 13-week repeated dose study of three 3- monochloropropane-1,2-diol fatty acid esters in F344 rats. Archives of Toxicology, 88, 871–80.
[20] Jones, A.R. (1983). Antifertility actions of alphachlorohydrin in the male. Australian Journal of Biological Sciences, 36, 333-350.
[21] Stevenson, D., Jones, A. (1984). The action of (R)- and (S)-α-chlorohydrin and their metabolites on the metabolism of boar sperm. International Journal of Andrology, 7, 79-86.
[22] WHO, (2002). 3-Chloro-1, 2-Propandiol, WHO Food Add. Ser. 48 Geneva, Switzerland. p. 401- 432.
[23] El Ramy, R., Ould Elhkim, M., Lezmi, S., Poul, J.M. (2007). Evaluation of the genotoxic potential of 3- monochloropropane-1,2-diol (3-MCPD) and its metabolites, glycidol and beta-chlorolactic acid, using the single cell gel/comet assay. Food and Chemical Toxicology, 45(1), 41-48.
[24] Robjohns, S., Marshall, R., Fellows, M., Kowalczyk, G. (2003). In vivo genotoxicity studies with 3- monochloropropan-1,2-diol. Mutagenesis, 18(5), 401-404.
[25] Scientific Committee on Food (SCF), (2001). Opinion on 3-monochloropropane-1,2-diol (3- MCPD), updating the SCF opinion of 1994 adopted on 30 May 2001. http://ec.europa.eu.
[26] Zeiger, E., Erson, B., Haworth, S., Lawlor, T., Mortelmans, K. (1988). Salmonella mutagenicity tests: IV. Results from the testing of 300 chemicals. Environmental and Molecular Mutagenesis, 11(12), 1-157.
[27] Jeong, J., Han, B.S., Cho, W.S., Ha, C.S., Lee, B.S., Kim, Y.B., Son, W.C., Kim, C.Y. (2010). Carcinogenicity study of 3-monochloropropane-1, 2-diol (3-MCPD) administered by drinking water to B6C3F1 mice showed no carcinogenic potential. Archives of Toxicology, 84, 719-729.
[28] Sunahara, G., Perrin, I., Marchesini, M. (1993). Carcinogenicity study on 3-monochloropropane1,2-diol (3-MCPD) administered in drinking water to Fischer 344 rats. Report No RE-SR 93003, Nestec Ltd, Research & Development, Switzerland.
[29] Lynch, B.S., Bryant, D.W., Hook, G.J., Earle, N.R., Ian, C.M. (1998). Carcinogenicity of monochloro1,2-propanediol (α-chlorohydrin, 3-MCPD). International Journal of Toxicology, 17, 47-76.
[30] Liu, M., Gao, B.Y., Qin, F., Wu, F.F, Shi, H.M., Luo, W., Ma, A.N., Jiang, Y.R., Xu, X.B., Yu, L.L. (2012). Acute oral toxicity of 3-MCPD mono- and dipalmitic esters in Swiss mice and their cytotoxicity in NRK-52E rat kidney cells. Food and Chemical Toxicology, 50(10), 3785-3791.
[31] Lee, J.K., Byun, J.A., Park, S.H., Kim, H.S., Park, J.H., Eom, J.H., Oh, H.Y. (2004). Evaluation of the potential immunotoxicity of 3-monochloro-1, 2- propanediol in Balb/c mice: I. Effect on antibody forming cell, mitogen-stimulated lymphocyte proliferation, splenic subset, and natural killer cell activity. Toxicology, 204, 1-11.
[32] Sun, J., Bai, S., Bai, W., Zou, F., Zhang, L., Su, Z., Zhang, Q., Ou, S., Huang, Y. (2013). Toxic mechanisms of 3-monochloropropane-1,2-diol on progesterone production in R2C rat Leydig cells. Journal of Agricultural and Food Chemistry, 61, 9955-9960.
[33] Buhrke, T., Frenzel, F., Kuhlmann, J. (2015). 2‑Chloro‑1,3‑propanediol (2‑MCPD) and its fatty acid esters: cytotoxicity, metabolism, and transport by human intestinal Caco-2 cells. Archives of Toxicology, 89, 2243-2251.
[34] Ozcagli, E., Alpertunga, B., Fenga, C., Berktas, M., Tsitsimpikou, C., Wilks, M.F., Tsatsakis, Α.M. (2016). Effects of 3-monochloropropane-1,2-diol (3-MCPD) and its metabolites on DNA damage and repair under in vitro conditions. Food and Chemical Toxicology, 89, 1-7.
[35] Peng, X., Gan, J., Wang, Q., Shi, Z., Xia, X. (2016). 3-Monochloro-1,2-propanediol (3-MCPD) induces apoptosis via mitochondrial oxidative phosphorylation system impairment and the caspase cascade pathway. Toxicology, 372, 1-11.
[36] Kuhlmann, J. (2011). Determination of bound 2,3- epoxy-1-propanol (glycidol) and bound monochloropropanediol (MCPD) in refined oils. European Journal of Lipid Science and Technology, 113, 335-344.
[37] Marchesini, M., Huggett, A. (1992). The acute toxicity of 2-chloropropan 1,2 diol (up and down test) Unpublished report No. FS-RN920011 submitted to WHO by Nestec Ltd, Research & Development, Switzerland.
[38] Jones, A.R., Fakhouri, G. (1979). Epoxides as obligatory intermediates in the metabolism of ahalohydrins. Xenobiotica, 9, 595-599.
[39] Perrin, I., Marchesini, M., Sunahara, G. (1994). Repeated dose oral toxicity 28 day gavage in Sprague Dawley rats of 2 chloropropan-1,3 diol (2- MCPD). Unpublished report No. RE-SR94026 submitted to EFSA by Nestec Ltd, Research & Development, Switzerland.
[40] Schilter, B., Scholz, G., Seefelder, W. (2011). Fatty acid esters of chloropropanols and related compounds in food: toxicological aspects. European Journal of Lipid Science and Technology, 113, 309-313.
[41] Frei, H., Würgler, F.E. (1997). The vicinal chloroalcohols 1,3-dichloro-2-propanol (DC2P), 3- chloro-1,2-propanediol (3-CPD) and 2-chloro-1,3- propanediol (2-CPD) are not genotoxic in vivo in the wing spot test of Drosophila melanogaster. Mutation Research, 394, 59-68.
[42] National Institue of Standarts and Technology (NIST) Chemistry WebBook, SRD 69, (2017). http://webbook.nist.gov/cgi/inchi/InChI%3D1S/C3H 6O2/c4-1-3-2-5-3/h3-4H%2C1-2H2,(Erişim tarihi: Aralık 2018).
[43] Habermeyer, M., Guth, S., Eisenbrand, G. (2011). Identification of gaps in knowledge concerning toxicology of 3-MCPD and glycidol esters. European Journal of Lipid Science and Technology, 113, 314-318.
[44] Cheng, W., Liu, G., Wang, L., Liu, Z. (2017). Glycidyl fatty acid esters in refined edible oils: a review on formation, occurrence, analysis, and elimination methods. Comprehensive Reviews in Food Science and Food Safety, 16.2, 263-281.
[45] Hamlet, C.G., Asuncion, L., Velisek, J., Dolezal, M., Zelinkova, Z., Crews, C. (2011). Formation and occurrence of esters of 3-chloro-1,2-propanediol (3-CPD) in foods: what we know and what we assume. European Journal of Lipid Science and Technology, 113, 279-303.
[46] Food Safety Commission of JAPAN (FSCJ) (2015). Considerations on Glycidol and Its Fatty Acid Esters in Foods. Executive summary, 3(2), 67-69.
[47] Cooper, E.R.A., Jones, A.R., Jackson, H. (1974). Effects of a-chlorohydrin related compounds on the reproductive organs and fertility of the male rat. Journal of Reproduction and Fertility, 38, 379-386.
[48] Brown-Woodman, P.D.C., White, I.G., Ridley, D.D. (1979). The antifertility activity and toxicity of achlorohydrin derivatives in male rats. Contraception, 19, 517-529.
[49] NTP, (1990). Toxicology and carcinogenesis studies of glycidol (CAS No. 556-52-5) in F344/N rats and B6C3F1 mice (gavage studies). Technical Report Series No. 374. National Institutes of Health Publication No. 90-2829. Research Triangle Park, NC.
[50] Kawashima, M., Watanabe, Y., Nakajima, K., Murayama, H., Nagahara, R., Jin, M., Yoshida, T., Shibutani, M. (2017). Late effect of developmental exposure to glycidol on hippocampal neurogenesis in mice: Loss of parvalbumin-expressing interneurons. Experimental and Toxicologic Pathology, 69(7), 517-526.
[51] Akane, H., Saito, F., Shiraki, A., Imatanaka, N., Akahori, Y., Itahashi, M., Wang, L., Shibutani, M. (2014). Gene expression profile of brain regions reflecting aberrations in nervous system development targeting the process of neurite extension of rat offspring exposed developmentally to glycidol. Journal of Applied Toxicology, 34(12), 1389-1399.
[52] Akane, H., Shiraki, A., Imatanaka, N., Akahori, Y., Itahashi, M., Abe, H., Shibutani, M. (2014). Glycidol induces axonopathy and aberrations of hippocampal neurogenesis affecting late-stage differentiation by exposure to rats in a framework of 28-day toxicity study. Toxicology Letters, 224(3), 424-432.
[53] Akane, H., Shiraki, A., Imatanaka, N., Akahori, Y., Itahashi, M., Ohishi, T., Mitsumori, K., Shibutani, M. (2013). Glycidol induces axonopathy by adult-stage exposure and aberration of hippocampal neurogenesis affecting late-stage differentiation by developmental exposure in rats. Toxicological Sciences, 134(1), 140-54.
[54] Marks, T.A., Gerling, F.S., Staples, R.E. (1982). Teratogenic evaluation of epichlorohydrin in the mouse and rat and glycidol in the mouse. Journal of Toxicology and Environmental Health, 9(1), 87- 96.
[55] Slott, V.L., Hales, B.F. (1985). Teratogenicity and embryo lethality of acrolein and structurally related compounds in rats. Teratology, 32, 65-72.
[56] Bakhiya, N., Abraham, K., Gürtler, R., Appel, K.E., Lampen, A. (2011). Toxicological assessment of 3- chloropropane-1,2-diol and glycidol fatty acid esters in food. Molecular Nutrition & Food Research, 55, 509-521.
[57] Guo, T.L., Mc Cay, J.A., Brown, R.D., Musgrove, D.L., Butterworth, L., Munson, A.E., Germolec, D.R., White, K.L. (2000). Glycidol modulation of the immune responses in female B6C3F1 mice. Drug and Chemical Toxicology, 23(3), 433-457.
[58] Irwin, R.D., Eustis, S.L., Stefanski, S., Haseman, J.K. (1996). Carcinogenicity of glycidol in F344 rats and B6C3F1 mice. Journal of Applied Toxicology, 16(3), 201-209
[59] Lijinsky, W., Kovatch, R.M. (1992). A study of the carcinogenicity of glycidol in Syrian hamsters. Toxicol Ind Health, 8(5), 267-271.
[60] Senyildiz, M., Alpertunga, B., Ozden, S. (2017). DNA methylation analysis in rat kidney epithelial cells exposed to 3-MCPD and glycidol. Drug and Chemical Toxicology, 40(4), 432-439.
[61] Aasa, J., Vare, D., Motwani, H.V., Jenssen, D., Törnqvist, M. (2016). Quantification of the mutagenic potency and repair of glycidol-induced DNA lesions. Mutat Res Genet Toxicol Environ Mutagen, 805, 38-45.
[62] Ikeda, N., Fujii, K., Sarada, M., Saito, H., Kawabata, M., Naruse, K., Yuki, K., Nakagiri, H., Honda, H., Tamaki, Y., Nishiyama, N., Kasamatsu, T. (2012). Genotoxicity studies of glycidol fatty acid ester (glycidol linoleate) and glycidol. Food Chem Toxicol, 50(11), 3927-3933.
[63] Aasa, J., Abramsson-Zetterberg, L., Carlsson, H., Törnqvist, M. (2017). The genotoxic potency of glycidol established from micronucleus frequency and hemoglobin adduct levels in mice. Food and Chemical Toxicology, 100, 168-174.
[64] IARC, (2000). Some Industrial Chemicals. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 77, International Agency for Research on Cancer, Lyon, France, pp. 1-529.