GIDA KATKI MADDELERİ VE GENETİK ETKİLERİ

Öz

Gıda katkı maddeleri, gıdanın güvenliğini, tazeliğini, lezzetini, dokusunu veya görünümünü korumak veya geliştirmek amacıyla kullanılan maddelerdir. İşlenmiş gıda tüketimi arttıkça, gıda katkı maddelerinin tüketimi de artmıştır. Çalışmalar, yüksek dozlarda ve uzun süre maruz kalmanın canlı organizmalarda toksik, genotoksik, mutajenik etkilere ve üreme, gelişimsel, immünotoksisite gibi bozukluklara neden olabileceğini göstermektedir. Gıda katkı maddelerinin genotoksik etkilerine ilişkin bazı tartışmalar devam etmektedir. Önerilen dozlarda kullanımlarının genellikle güvenli olduğu kabul edilirken, bazı gıda katkı maddelerinin önerilen günlük alım miktarını aşabileceğine dair kanıtlar bulunmaktadır. Ayrıca, gıda katkı maddelerinin vücutta birikmesi olasılığına dikkat çekilmekte ve bu birikimin genetik materyal üzerinde toksik etkilere ve olumsuz sağlık sonuçlarına yol açabileceği vurgulanmaktadır. Bu derleme, özellikle yaygın kullanılan bazı gıda katkı maddelerinin genotoksik etkilerini araştıran güncel çalışmaların bir özetini sunmaktadır.

Anahtar Kelimeler

• gıda katkı maddeleri
• genotoksisite
• gıda güvenliği

Teşekkür

Ece ÇELİK ATALAY'a 100/2000 özel burs programı kapsamında burs sağlayan Yükseköğretim Kurulu'na (YÖK) teşekkür ederiz. Ece ÇELİK ATALAY ayrıca BİDEB/2211-A doktora burs programı kapsamında Türkiye Bilimsel ve Teknolojik Araştırma Kurumu (TÜBİTAK) tarafından sağlanan mali desteğe teşekkür eder.

FOOD ADDITIVES AND GENETIC INFLUENCES

Öz

Food additives are substances used to preserve or improve the safety, freshness, flavor, texture or appearance of food. As the consumption of processed food has increased, so has the consumption of food additives. Studies show that high doses and prolonged exposure can cause toxic, genotoxic, mutagenic effects and disorders such as reproductive, developmental and immunotoxicity in living organisms. The debate on the genotoxic effects of food additives continues. While their use at recommended doses is generally considered safe, there is evidence that some food additives may exceed the recommended daily intake. Furthermore, the possibility of accumulation of food additives in the body has been highlighted, which may lead to toxic effects on genetic material and adverse health outcomes. This review provides a summary of recent studies investigating the genotoxic effects of some common food additives.

Anahtar Kelimeler

• food additives
• genotoxicity
• food safety

Kaynakça

1. Abo-EL-Sooud, K., Hashem, M. M., Badr, Y. A., Eleiwa, M. M., Gab-Allaha, A. Q., Abd-Elhakim, Y. M., Bahy-EL-Dien, A. (2018). Assessment of hepato-renal damage and genotoxicity induced by long-term exposure to five permitted food additives in rats. Environmental Science and Pollution Research, 25: 26341-26350, doi:10.1007/s11356-018-2665-z.
2. Abu-Elfotuh, K., Abdel-Sattar, S. A., Abbas, A. N., Mahran, Y. F., Alshanwani, A. R., Hamdan, A. M. E., Atwa, A. M., . . . El-Din, M. N. (2022). The protective effect of thymoquinone or/and thymol against monosodium glutamate-induced attention-deficit/hyperactivity disorder (ADHD)-like behavior in rats: Modulation of Nrf2/HO-1, TLR4/NF-κB/NLRP3/caspase-1 and Wnt/β-Catenin signaling pathways in rat model. Biomedicine and Pharmacotherapy, 155: 113799, doi:10.1016/j.biopha.2022.113799.
3. Ahmad, S. Y., Friel, J., Mackay, D. (2020). The Effects of Non-Nutritive Artificial Sweeteners, Aspartame and Sucralose, on the Gut Microbiome in Healthy Adults: Secondary Outcomes of a Randomized Double-Blinded Crossover Clinical Trial. Nutrients, 12(11): 3408, doi:10.3390/nu12113408.
4. Akhal’tseva, L., Yurchenko, V., Yurtseva, N., Konyashkina, M. (2022). Evaluation of the genotoxicity of the food dye tartrazine in a micronucleus test in vivo. Hygiene and Sanitation. 2022; 101 (7): 798–801. Hygiene and Sanitation, 10: 0016-9900, doi:10.47470/0016-9900-2022-101-7-798-801.
5. Algarni, A. A. (2021). In vitro effects of Sunset Yellow on Chromosomal Damage and Sister Chromatid Exchanges in Human Peripheral Lymphocytes. Annual Research & Review in Biology, 36(12): 88-94, doi:10.9734/arrb/2021/ v36i1230466.
6. Ali, M. Y., Hassan, G. M., Hassan, A. M. S., Mohamed, Z. A., Ramadan, M. F. (2020). In vivo genotoxicity assessment of sunset yellow and sodium benzoate in female rats. Drug and Chemical Toxicology, 43(5): 504-513, doi:10.1080/ 01480545.2018.1510416.
7. Anonymous (2023). Türk gıda kodeksi. Gıda katkı maddeleri yönetmeliği (2023). Tarım ve Orman Bakanlığı. 13 Ekim 2023 tarih ve 32338 sayılı. Resmi Gazete, Ankara.
8. Anonymous. (2009a). Scientific Opinion on the re‐evaluation Tartrazine (E 102). EFSA Journal, 7(11): 1331, doi:10.2903/j.efsa.2009.1331.

9. Anonymous. (2009b). Scientific Opinion on the re‐evaluation of Azorubine/Carmoisine (E 122) as a food additive. EFSA Journal, 7(11): 1332, doi:10.2903/j.efsa.2015.4072.
10. Anonymous. (2010). Scientific Opinion on the re‐evaluation of Brilliant Blue FCF (E 133) as a food additive. EFSA Journal, 8(11): 1853, doi:10.2903/j.efsa.2010.1853.
11. Anonymous. (2013). Scientific Opinion on the re‐evaluation of aspartame (E 951) as a food additive. EFSA Journal, 11(12): 3496, doi:10.2903/j.efsa.2013.3496.
12. Anonymous. (2014). Scientific Opinion on the re-evaluation of propionic acid (E 280), sodium propionate (E 281), calcium propionate (E 282) and potassium propionate (E 283) as food additives. EFSA Journal, 12(7): 3779, doi:10.2903/j.efsa.2014.3779.
13. Anonymous. (2016a). Scientific Opinion on the re‐evaluation of benzoic acid (E 210), sodium benzoate (E 211), potassium benzoate (E 212) and calcium benzoate (E 213) as food additives. EFSA Journal, 14(3): 4433, doi:10.2903/ j.efsa.2016.4433.
14. Anonymous. (2016b). Re‐evaluation of titanium dioxide (E 171) as a food additive. EFSA Journal, 14(9): e04545, doi:10.2903/j.efsa.2016.4545.
15. Anonymous. (2017). Re‐evaluation of glutamic acid (E 620), sodium glutamate (E 621), potassium glutamate (E 622), calcium glutamate (E 623), ammonium glutamate (E 624) and magnesium glutamate (E 625) as food additives. EFSA Journal, 15(7): e04910, doi:10.2903/ j.efsa.2017.4910.
16. Anonymous. (2020). Screening for Fetal Chromosomal Abnormalities: ACOG Practice Bulletin, Number 226. Obstetrics and Gynecology, 136(4): e48-e69, doi:10.1097/ aog.0000000000004084.
17. Avuloglu-Yilmaz, E., Yuzbasioglu, D., Unal, F. (2020). In vitro genotoxicity assessment of monopotassium glutamate and magnesium diglutamate. Toxicology in Vitro, 65: 104780, doi:10.1016/j.tiv.2020.104780.
18. Bajpayee, M., Kumar, A., Dhawan, A. (2019). The comet assay: assessment of in vitro and in vivo DNA damage. Genotoxicity Assessment: Methods and Protocols: 237-257, doi:10.1007/978-1-4939-9646-9_12.
19. Banerjee, A., Mukherjee, S., Maji, B. K. (2021). Worldwide flavor enhancer monosodium glutamate combined with high lipid diet provokes metabolic alterations and systemic anomalies: An overview. Toxicology Reports, 8: 938-961, doi:10.1016/j.toxrep.2021.04.009.
20. Bellani, L., Muccifora, S., Barbieri, F., Tassi, E., Ruffini Castiglione, M., Giorgetti, L. (2020). Genotoxicity of the food additive E171, titanium dioxide, in the plants Lens culinaris L. and Allium cepa L. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 849: 503142, doi:10.1016/j.mrgentox.2020.503142.
21. Bischoff, N. S., Proquin, H., Jetten, M. J., Schrooders, Y., Jonkhout, M. C., Briedé, J. J., van Breda, S. G., Jenne, D. G. J., Medina-Reyes, E. I., Delgado-Buenrostro, N. L., Chirino, Y. I., van Loveren, H., Delgado-Buenrostro, N. L. (2022). The effects of the food additive Titanium dioxide (E171) on tumor formation and gene expression in the colon of a transgenic mouse model for colorectal cancer. Nanomaterials, 12(8): 1256, doi:10.3390/nano12081256.
22. Borghoff, S. J., Cohen, S. S., Jiang, X., Lea, I. A., Klaren, W. D., Chappell, G. A., Britt, J. K., . . . Wikoff, D. S. (2022). Updated systematic assessment of human, animal and mechanistic evidence demonstrates lack of human carcinogenicity with consumption of aspartame. Food and Chemical Toxicology: 113549, doi:10.1016/j.fct.2022.113549.
23. Bridge-Comer, P. E., Vickers, M. H., Morton-Jones, J., Spada, A., Rong, J., Reynolds, C. M. (2022). Maternal intake of fructose or artificial sweetener during pregnancy and lactation has persistent effects on metabolic and reproductive health of dams post-weaning. Journal of Developmental Origins of Health and Disease, 13(5): 642-649, doi:10.1017/s2040174422000022.
24. Canedo, A., de Jesus, L. W. O., Bailão, E. F. L. C., Rocha, T. L. (2021). Micronucleus test and nuclear abnormality assay in zebrafish (Danio rerio): Past, present, and future trends. Environmental Pollution, 290: 118019, doi:10.1016/j.envpol.2021.118019.
25. Chakraborty, S. P. (2019). Patho-physiological and toxicological aspects of monosodium glutamate. Toxicology Mechanisms and Methods, 29(6): 389-396, doi:10.1080/15376516.2018.1528649.
26. Chappell, G. A., Heintz, M. M., Borghoff, S. J., Doepker, C. L., Wikoff, D. S. (2021). Lack of potential carcinogenicity for steviol glycosides - Systematic evaluation and integration of mechanistic data into the totality of evidence. Food and Chemical Toxicology, 150: 112045, doi:10.1016/j.fct.2021.112045.
27. Chatterjee, T., Ghosh, S. K., Paik, S., Chakravarty, A., Basak, A. K. (2021). Benzoic acid treated Drosophila melanogaster: the genetic disruption of larval brain stem cells and non-neural cells during metamorphosis. Toxicology and Environmental Health Sciences, 13: 215-223, doi:10.1007/s13530-021-00082-w.
28. Chazelas, E., Pierre, F., Druesne-Pecollo, N., Esseddik, Y., Szabo de Edelenyi, F., Agaesse, C., De Sa, A., . . . Touvier, M. (2022). Nitrites and nitrates from food additives and natural sources and cancer risk: results from the NutriNet-Santé cohort. International Journal of Epidemiology, 51(4): 1106-1119, doi:10.1093/ije/dyac046.
29. Chen, Z., Shi, J., Zhang, Y., Han, S., Zhang, J., Jia, G. (2022). DNA Oxidative Damage as a Sensitive Genetic Endpoint to Detect the Genotoxicity Induced by Titanium Dioxide Nanoparticles. Nanomaterials, 12(15): 2616, doi:10.3390/ nano12152616.
30. Cordelli, E., Bignami, M., Pacchierotti, F. (2021). Comet assay: a versatile but complex tool in genotoxicity testing. Toxicology Research (Camb), 10(1): 68-78, doi:10.1093/toxres/tfaa093.
31. Czarnecka, K., Pilarz, A., Rogut, A., Maj, P., Szymańska, J., Olejnik, Ł., Szymański, P. (2021). Aspartame-True or False? Narrative Review of Safety Analysis of General Use in Products. Nutrients, 13(6), doi:10.3390/nu13061957.
32. Çadirci, K., Özdemir Tozlu, Ö., Türkez, H., Mardinoğlu, A. (2020). The in vitro cytotoxic, genotoxic, and oxidative damage potentials of the oral artificial sweetener aspartame on cultured human blood cells. Turkish Journal of Medical Sciences, 50(2): 448-454, doi:10.3906/sag-2001-113.
33. de Moura e Dias, M., Dos Reis, S. A., da Conceição, L. L., Sediyama, C. M. N. d. O., Pereira, S. S., de Oliveira, L. L., Gouveia Peluzio, M. d. C., . . . Milagro, F. I. (2021). Diet-induced obesity in animal models: points to consider and influence on metabolic markers. Diabetology & Metabolic Syndrome, 13(32): 1-14, doi:10.1186/ s13098-021-00647-2.
34. Debras, C., Chazelas, E., Srour, B., Druesne-Pecollo, N., Esseddik, Y., Szabo de Edelenyi, F., Agaësse, C., . . . Touvier, M. (2022). Artificial sweeteners and cancer risk: Results from the NutriNet-Santé population-based cohort study. PLoS Medicine, 19(3): e1003950, doi:10.1371/journal.pmed.1003950.
35. Dorier, M., Béal, D., Marie-Desvergne, C., Dubosson, M., Barreau, F., Houdeau, E., Herlin-Boime, N., . . . Carriere, M. (2017). Continuous in vitro exposure of intestinal epithelial cells to E171 food additive causes oxidative stress, inducing oxidation of DNA bases but no endoplasmic reticulum stress. Nanotoxicology, 11(6): 751-761, doi:10.1080/17435390.2017.1349203.
36. Dos Santos, J. R., de Sousa Soares, L., Soares, B. M., de Gomes Farias, M., de Oliveira, V. A., de Sousa, N. A. B., Negreiros, H. A., . . . de Castro, E. S. J. M. (2022). Cytotoxic and mutagenic effects of the food additive tartrazine on eukaryotic cells. BMC Pharmacology and Toxicology, 23(1): 95, doi:10.1186/s40360-022-00638-7.
37. Du, X., Gao, S., Hong, L., Zheng, X., Zhou, Q., Wu, J. (2019). Genotoxicity evaluation of titanium dioxide nanoparticles using the mouse lymphoma assay and the Ames test. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 838: 22-27, doi:10.1016/j.mrgentox.2018.11.015.
38. Dusinska, M., Mariussen, E., Rundén-Pran, E., Hudecova, A. M., Elje, E., Kazimirova, A., El Yamani, N., Dommershausen, N., Tharmann, J., Fieblinger, D., Herzberg, F., Luch, A., Fieblinger, D. (2019). In vitro approaches for assessing the genotoxicity of nanomaterials. Nanotoxicity: Methods and Protocols, 1894: 83-122, doi:10.1007/978-1-4939-8916-4_6.
39. El-Alfy, N. Z., Alqosaibi, A. I., Mahmoud, M. F., Emam, A. A. (2020). Role of propolis against monosodium glutamate genotoxicity by chromosomal aberration, micronucleus test and comet assay in males. Der Pharmacia Lettre, 12: 13-22.
40. El-Desoky, G. E., Wabaidur, S. M., AlOthman, Z. A., & Habila, M. A. (2020). Regulatory Role of Nano-Curcumin against Tartrazine-Induced Oxidative Stress, Apoptosis-Related Genes Expression, and Genotoxicity in Rats. Molecules, 25(24), doi:10.3390/molecules25245801.
41. El-Hefny, I. M., Al Senosy, N. K., Hozayen, W. G., Ahmed, A. E., Diab, A. Basal, W. T. (2020). Evaluation of the Cytotoxicity and Apoptotic Induction in Human Liver Cell Lines Exposed to Three Food Additives. Recent Patents on Food, Nutrition & Agriculture, 11(3): 193-201, doi:10.2174/2212798411666200217124630.
42. Fadoju, O., Ogunsuyi, O., Akanni, O., Alabi, O., Alimba, C., Adaramoye, O., Cambier, S., Eswara, S., Gutleb, A. C., Bakare, A. (2019). Evaluation of cytogenotoxicity and oxidative stress parameters in male Swiss mice co-exposed to titanium dioxide and zinc oxide nanoparticles. Environmental Toxicology and Pharmacology, 70: 103204, doi:10.1016/j.etap.2019.103204.
43. Ferreira, P. M. P., Sousa, I. J. O., Machado, K. N., da Silva Neto, L. A., de Freitas, M. M., Dos Santos, I. L., do Nascimento Rodrigues, D. C., de Sousa, R, W. R., dos Reis, A.C., Do Nascimento, M. L.L.B., de Meneszes, A-A. P. M., do Nascimento, A.M., de Oliveira Ferreira, J.R., Peron, A.P., de Castro, E. S. J. M. (2022). Antimitotic and toxicogenetic action of Stevia urticifolia aerial parts on proliferating vegetal and mammalian cells: in vitro and in vivo traditional and replacement methods. Journal of Toxicology and Environmental Health, Part A, 85(18): 750-766, doi:10.1080/15287394.2022.2081640.
44. Floriano, J. M., da Rosa, E., do Amaral, Q. D. F., Zuravski, L., Chaves, P. E. E., Machado, M. M., de Oliveira, L. F. S. (2018). Is tartrazine really safe? In silico and ex vivo toxicological studies in human leukocytes: a question of dose. Toxicology Research (Camb), 7(6): 1128-1134, doi:10.1039/ c8tx00034d.
45. Franzke, B., Schwingshackl, L., Wagner, K.-H. (2020). Chromosomal damage measured by the cytokinesis block micronucleus cytome assay in diabetes and obesity-A systematic review and meta-analysis. Mutation Research/Reviews in Mutation Research, 786: 108343, doi:10.1016/ j.mrrev.2020.108343.
46. García-García, R. Searle, S. S. (2016). Preservatives: Food Use. In B. Caballero, P. M. Finglas, F. Toldrá (eds.), Encyclopedia of Food and Health. Academic Press, Oxford, pp. 505-509.
47. Gičević, A., Hindija, L., Karačić, A. (2020). Toxicity of azo dyes in pharmaceutical industry. Paper presented at the CMBEBIH 2019: Proceedings of the International Conference on Medical and Biological Engineering, 16 ̶̶ 18 May 2019, Banja Luka, Bosnia and Herzegovina, 581-587 p.
48. Güzel Bayülken, D., Ayaz Tüylü, B., Sinan, H., Sivas, H. (2019). Investigation of genotoxic effects of paraben in cultured human lymphocytes. Drug and Chemical Toxicology, 42(4): 349-356, doi:10.1080/01480545.2017.1414834.
49. Haighton, L., Roberts, A., Walters, B., Lynch, B. (2019). Systematic review and evaluation of aspartame carcinogenicity bioassays using quality criteria. Regulatory Toxicology and Pharmacology 103: 332-344, doi:10.1016/j.yrtph.2018.01.009.
50. Hamza, R. Z., Al-Eisa, R. A., Mehana, A. E., El-Shenawy, N. S. (2019). Effect of l-carnitine on aspartame-induced oxidative stress, histopathological changes, and genotoxicity in liver of male rats. Journal of Basic and Clinical Physiology and Pharmacology, 30(2): 219-232, doi:10.1515/jbcpp-2018-0064.
51. Hargan, A. A., Daghestani, M. H., Harrath, A. H. (2021). Alterations in APC, BECN1, and TP53 gene expression levels in colon cancer cells caused by monosodium glutamate. Brazilian Journal of Biology, 83: e246970, doi:10.1590/1519-6984.246970.
52. Haverić, A., Haverić, S., Hadžić, M., Lojo-Kadrić, N., Ibrulj, S. (2018). Genotoxicity and cytotoxicity analysis of curcumin and sunset yellow in human lymphocyte culture. Cellular and Molecular Biology, 64(3): 87-91, doi:10.14715/cmb/2018.64.3.14.
53. Hobbs, C. A., Swartz, C., Maronpot, R., Davis, J., Recio, L., Hayashi, S.-m. (2012). Evaluation of the genotoxicity of the food additive, gum ghatti. Food and chemical toxicology, 50(3-4): 854-860, doi:10.1016/j.fct.2011.11.021. Honma, M. (2015). Evaluation of the in vivo genotoxicity of Allura Red AC (Food Red No. 40). Food and Chemical Toxicology, 84: 270-275, doi:10.1016/j.fct.2015.09.007.
54. Hozayen, W., AlSenosy, N., Basal, W., Ahmed, A., Diab, A. (2020). Evaluation of genotoxicity of three food preservatives in drosophila melanogaster using smart and comet assays. Journal of Microbiology, Biotechnology and Food Sciences, 10(1): 38-41, doi:10.15414/jmbfs.2020.10.1.38-41.
55. Jain, S. (2023). Application of Inorganic Anion Sensitive Indicator Electrodes for the Analysis of Food Additives and Preservatives in Food Products. Research Review International Journal of Multidisciplinary, 8(5): 22-35, doi:10.31305/ rrijm.2023.v08.n05.004.
56. Jarmakiewicz-Czaja, S., Piątek, D., Filip, R. (2022). The impact of selected food additives on the gastrointestinal tract in the example of nonspecific inflammatory bowel diseases. Archives of Medical Science, 18(5): 1286-1296, doi:10.5114/ aoms/125001.
57. Javanmardi, F., Rahmani, J., Ghiasi, F., Hashemi Gahruie, H., Mousavi Khaneghah, A. (2019). The Association between the Preservative Agents in Foods and the Risk of Breast Cancer. Nutrition and Cancer, 71(8): 1229-1240, doi:10.1080/ 01635581.2019.1608266.
58. Jiang, N., Naz, S., Ma, Y., Ullah, Q., Khan, M. Z., Wang, J., Lu, X., Luosang, D-Z., Tabassum, S., Chatha, A.M.M., Chatha, A. M. M. (2023). An Overview of Comet Assay Application for Detecting DNA Damage in Aquatic Animals. Agriculture, 13(3): 623, doi:10.3390/ agriculture13030623.
59. Kaya, S. I., Cetinkaya, A., Ozkan, S. A. (2021). Latest advances on the nanomaterials-based electrochemical analysis of azo toxic dyes Sunset Yellow and Tartrazine in food samples. Food and Chemical Toxicology, 156: 112524, doi:10.1016/ j.fct.2021.112524.
60. Kayode, O. T., Rotimi, D. E., Kayode, A. A. A., Olaolu, T. D., Adeyemi, O. S. (2020). Monosodium Glutamate (MSG)-Induced Male Reproductive Dysfunction: A Mini Review. Toxics, 8(1), doi:10.3390/toxics8010007.
61. Khan, I. S., Ali, M. N., Hamid, R. Ganie, S. A. (2020). Genotoxic effect of two commonly used food dyes metanil yellow and carmoisine using Allium cepa L. as indicator. Toxicology Reports, 7: 370-375, doi:10.1016/j.toxrep.2020.02.009.
62. Khayyat, L. I., Essawy, A. E., Sorour, J. M., Soffar, A. (2018). Sunset Yellow and Allura Red modulate Bcl2 and COX2 expression levels and confer oxidative stress-mediated renal and hepatic toxicity in male rats. PeerJ, 6: e5689, doi:10.7717/peerj.5689.
63. Khezerlou, A., Akhlaghi, A. P., Alizadeh, A. M., Dehghan, P., Maleki, P. (2022). Alarming impact of the excessive use of tert-butylhydroquinone in food products: A narrative review. Toxicology Reports, 9: 1066-1075, doi:10.1016/ j.toxrep.2022.04.027.
64. Kirkland, D., Aardema, M. J., Battersby, R. V., Beevers, C., Burnett, K., Burzlaff, A., Czich, A., Donner, E. M., Fowler, P., Johnston, H. J., Krug, H.F., Pfuhler, S, Stankowski, L. F., Jr. (2022). A weight of evidence review of the genotoxicity of titanium dioxide (TiO(2)). Regulatory Toxicology and Pharmacology, 136: 105263, doi:10.1016/ j.yrtph.2022.105263.
65. Kizhedath, A., Wilkinson, S., Glassey, J. (2019). Assessment of hepatotoxicity and dermal toxicity of butyl paraben and methyl paraben using HepG2 and HDFn in vitro models. Toxicology in Vitro, 55: 108-115, doi:10.1016/j.tiv.2018.12.007.
66. Ko, J., Jang, S., Kwon, W., Kim, S. Y., Jang, S., Kim, E., Ji, Y. R., Park, S., Kim, M-I., Choi, S-K., Cho, D-H., Lee, H-S., Lim, Su-Geun, Ryoo, Z. Y. (2022). Protective Effect of GIP against Monosodium Glutamate-Induced Ferroptosis in Mouse Hippocampal HT-22 Cells through the MAPK Signaling Pathway. Antioxidants (Basel), 11(2): 189, doi:10.3390/antiox11020189.
67. Koç, K., Pandir, D. (2018). All aspect of toxic effect of brilliant blue and sunset yellow in Allium cepa roots. Cytotechnology, 70(1): 449-463, doi:10.1007/s10616-017-0161-9.
68. Kramer, N. I., Hoffmans, Y., Wu, S., Thiel, A., Thatcher, N., Allen, T. E., Levorato, S., Traussnig, H., Schulte, S., Boobis, A., Rietjens, I. M. C. M. (2019). Characterizing the coverage of critical effects relevant in the safety evaluation of food additives by AOPs. Archives of Toxicology, 93: 2115-2125, doi:10.1007/s00204-019-02501-x.
69. Kraemer, M., Fernandes, A. C., Chaddad, M. C. C., Uggioni, P. L., Rodrigues, V. M., Bernardo, G. L., Proença, R. (2022). Food additives in childhood: a review on consumption and health consequences. Revista de Saúde Pública, 56: 32, doi:10.11606/s1518-8787.2022056004060.
70. Kumar, N., Singh, A., Sharma, D. K. Kishore, K. (2019). Toxicity of Food Additives. In Food Safety and Human Health. Academic Press, pp. 67-98.
71. Kurt, D., Yalçin, E., Çavuşoğlu, K. (2023). GC-MS and HPLC supported phytochemical analysis of watercress and the protective role against paraben toxicity. Environmental Science and Pollution Research, 30(3): 6033-6046, doi:10.1007/s11356-022-22380-7.
72. Laudisi, F., Stolfi, C., Monteleone, G. (2019). Impact of food additives on gut homeostasis. Nutrients, 11(10): 2334, doi:10.3390/nu11102334.
73. Le Thanh-Blicharz, J., Lewandowicz, J. (2023). The Role of Food Additives. In In Chemical and Functional Properties of Food Components.4 ed., CRC Press, pp. 401-418.
74. Lea, I. A., Chappell, G. A., Wikoff, D. S. (2021). Overall lack of genotoxic activity among five common low- and no-calorie sweeteners: A contemporary review of the collective evidence. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 868-869: 503389, doi:10.1016/j.mrgentox.2021.503389.
75. Maddah, A., Danesh, H., Ghasemi, P., Ziamajidi, N., Salehzadeh, M., Abbasalipourkabir, R. (2023). The Effect of Titanium Dioxide (TiO2) Nanoparticles on Oxidative Stress Status in the HCT116 Human Colon Cancer Cell Line. BioNanoScience, 13: 600-608, doi:10.1007/s12668-023-01103-3.
76. Magnuson, B. A., Roberts, A., Nestmann, E. R. (2017). Critical review of the current literature on the safety of sucralose. Food and Chemical Toxicology, 106: 324-355, doi:10.1016/ j.fct.2017.05.047.
77. Mahmoud, E. F., Mahmoud, M. F., Hegazy, E. (2020). Chitosan Nanoparticles Suppress The Oxidative Stress in Submandibular Salivary Glands and Prevent The Genotoxicity of Monosodium Glutamate in Albino Rats: Histological, Immunohistochemical and Chromosomal Aberrations Analysis Study. Egyptian Dental Journal, 64(4-October (Oral Medicine, X-Ray, Oral Biology & Oral Pathology)): 3485-3498, doi:10.21608/ EDJ.2020.91761.
78. Martins, F. C., Oliveira, M. M., Gaivão, I., R, A. V., Peixoto, F. (2023). The administration of methyl and butyl parabens interferes with the enzymatic antioxidant system and induces genotoxicity in rat testis: possible relation to male infertility. Drug and Chemical Toxicology, 8: 1-8, doi:10.1080/01480545.2023.2176512.
79. Masithoh, R. E., Rondonuwu, F., Setyabudi, F. M. C. S., Cho, B.-K. (2020). Development of calibration model for determination of sweeteners additives in Indonesia rice flour-based food by FT-NIR spectroscopy. IOP Conference Series: Earth and Environmental Science, 542, doi:10.1088/1755-1315/542/1/012017.
80. Mateo Fernández, M., González Jiménez, M. J., Celestino, M. D. R., Font, R., Alonso Moraga, Á., & Merinas Amo, T. (2022). Toxicological and Nutraceutical Screening Assays of Some Artificial Sweeteners. Processes, 10(2): 410, doi:10.3390/ pr10020410.
81. Meng, F., Jiao, X. F., Chen, F., Zhang, X. Y., Duan, Z. Q., Ding, Z. M., Wu, D., Wang, Y-S., Zhang, S-X, Miao, Y-L., Huo, L. J. (2020a). Isobutylparaben Negatively Affects Porcine Oocyte Maturation Through Increasing Oxidative Stress and Cytoskeletal Abnormalities. Environmental Molecular Mutagenesis, 61(4): 433-444, doi:10.1002/em.22356.
82. Meng, X., Xia, C., Ye, Q., Nie, X. (2020b). tert-Butyl-p-benzoquinone induces autophagy by inhibiting the Akt/mTOR signaling pathway in RAW 264.7 cells. Food and Function, 11(5): 4193-4201, doi:10.1039/d0fo00281j. Miller, M. (1985). Danger!: Additives at Work; a Report on Food Additives; Their Use and Control. London: London Food Commission.
83. Mpountoukas, P., Pantazaki, A., Kostareli, E., Christodoulou, P., Kareli, D., Poliliou, S., Mourelatos, C., Lambropoulou, V, Lialiaris, T. (2010). Cytogenetic evaluation and DNA interaction studies of the food colorants amaranth, erythrosine and tartrazine. Food and Chemical Toxicology, 48(10): 2934-2944, doi:10.1016/j.fct.2010.07.030.
84. Nasri, A., Pohjanvirta, R. (2021). In vitro estrogenic, cytotoxic, and genotoxic profiles of the xenoestrogens 8-prenylnaringenine, genistein and tartrazine. Environmental Science and Pollution Research, 28(22): 27988-27997, doi:10.1007/ s11356-021-12629-y.
85. Neto, H. A. P., Ausina, P., Gomez, L. S., Leandro, J. G. B., Zancan, P., Sola-Penna, M. (2017). Effects of Food Additives on Immune Cells As Contributors to Body Weight Gain and Immune-Mediated Metabolic Dysregulation. Frontiers in Immunology, 8: 1478, doi:10.3389/ fimmu.2017.01478.
86. Nixon, E. J., Sakthivel, R., ALOthman, Z. A., Ganesh, P. S., Chung, R.-J. (2023). Lanthanum nickelate spheres embedded acid functionalized carbon nanofiber composite: An efficient electrocatalyst for electrochemical detection of food additive vanillin. Food Chemistry, 409: 135324, doi:10.1016/j.foodchem.2022.135324.
87. Oladele, J. O., Oladele, O. T., Ademiluyi, A. O., Oyeleke, O. M., Awosanya, O. O., Oyewole, O. I. (2020). Chaya (Jatropha tanjorensis) leafs protect against sodium benzoate mediated renal dysfunction and hepatic damage in rats. Clinical Phytoscience, 6(1): 1-8, doi:10.1186/s40816-020-00160-5.
88. Otabe, A., Ohta, F., Takumi, A., Lynch, B. (2019). Mutagenicity and genotoxicity studies of aspartame. Regulatory Toxicology and Pharmacology 103: 345-351, doi:10.1016/j.yrtph.2018.01.023.
89. Ousji, O., Sleno, L. (2020). Identification of In Vitro Metabolites of Synthetic Phenolic Antioxidants BHT, BHA, and TBHQ by LC-HRMS/MS. International Journal of Molecular Sciences, 21(24): 9525, doi:10.3390/ijms21249525.
90. Pandey, H., Kumar, S. (2021). Butylated hydroxytoluene and Butylated hydroxyanisole induced cyto-genotoxicity in root cells of Allium cepa L. Heliyon, 7(5): e07055, doi:10.1016/j.heliyon.2021.e07055.
91. Pasqualli, T., PE, E. C., da Veiga Pereira, L., Adílio Serpa, É., de Oliveira, L. F. S., Machado, M. M. (2020a). Sucralose causes non-selective CD4 and CD8 lymphotoxicity via probable regulation of the MAPK8/APTX/EID1 genes: An in vitro/in silico study. Clinical and Experimental Pharmacology and Physiology, 47(10): 1751-1757, doi:10.1111/1440-1681.13362.
92. Pasqualli, T., Chaves, P. E. E., Pereira, C., Serpa É, A., Oliveira, L. F. S., Machado, M. M. (2020b). Steviol, the active principle of the stevia sweetener, causes a reduction of the cells of the immunological system even consumed in low concentrations. Immunopharmacology and Immunotoxicology, 42(5): 504-508, doi:10.1080/ 08923973.2020.1811309.
93. Pavanello, S., Moretto, A., La Vecchia, C., Alicandro, G. (2023). Non-sugar sweeteners and cancer: Toxicological and epidemiological evidence. Regulatory Toxicology and Pharmacology 139: 105369, doi:10.1016/j.yrtph.2023.105369.
94. Pepino, M. Y. (2015). Metabolic effects of non-nutritive sweeteners. Physiology & behavior, 152: 450-455, doi:10.1016/j.physbeh.2015.06.024.
95. Phipps, K. R., Bali, V., Kukadia, D., Patel, C., Muchhara, J. (2023). Safety assessment of a solid lipid curcumin particle preparation: In vitro and in vivo genotoxicity studies. Journal of Applied Toxicology, 43(6): 929-939, doi:10.1002/jat.4434.
96. Pongsavee, M. (2015). Effect of sodium benzoate preservative on micronucleus induction, chromosome break, and Ala40Thr superoxide dismutase gene mutation in lymphocytes. BioMed Research International, 2015, doi:10.1155/ 2015/103512.
97. Proquin, H., Rodríguez-Ibarra, C., Moonen, C. G., Urrutia Ortega, I. M., Briedé, J. J., de Kok, T. M., van Loveren, H., Chirino, Y. I. (2017). Titanium dioxide food additive (E171) induces ROS formation and genotoxicity: contribution of micro and nano-sized fractions. Mutagenesis, 32(1): 139-149, doi:10.1093/mutage/gew051.
98. Proquin, H., Jetten, M. J., Jonkhout, M. C. M., Garduño-Balderas, L. G., Briedé, J. J., de Kok, T. M., Chirino, Y. I., van Loveren, H. (2018). Gene expression profiling in colon of mice exposed to food additive titanium dioxide (E171). Food and Chemical Toxicology, 111: 153-165, doi:10.1016/ j.fct.2017.11.011.
99. Redza-Dutordoir, M., Averill-Bates, D. A. (2016). Activation of apoptosis signalling pathways by reactive oxygen species. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1863(12): 2977-2992, doi:10.1016/j.bbamcr.2016.09.012.
100. Rencüzoǧullari, E., İla, H. B., Kayraldiz, A., Topaktaş, M. (2001). Chromosome aberrations and sister chromatid exchanges in cultured human lymphocytes treated with sodium metabisulfite, a food preservative. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 490(2): 107-112, doi:10.1016/s1383-5718(00)00142-x.
101. Rinninella, E., Cintoni, M., Raoul, P., Mora, V., Gasbarrini, A., Mele, M. C. (2021). Impact of Food Additive Titanium Dioxide on Gut Microbiota Composition, Microbiota-Associated Functions, and Gut Barrier: A Systematic Review of In Vivo Animal Studies. International Journal of Environmental Research and Public Health, 18(4): 2008, doi:10.3390/ijerph18042008.
102. Rogers, M. D. (2016). Monosodium glutamate is not likely to be genotoxic. Food and Chemical Toxicology, 94: 260-261, doi:10.1016/ j.fct.2016.05.001.
103. Rolo, D., Assunção, R., Ventura, C., Alvito, P., Gonçalves, L., Martins, C., Bettencourt, A., Jordan, P., Vital, N., Pereira, J., Pinto, F., Matos, P., Silva, M.J., Louro, H. (2022). Adverse Outcome Pathways Associated with the Ingestion of Titanium Dioxide Nanoparticles-A Systematic Review. Nanomaterials (Basel), 12(19): 3275, doi:10.3390/nano12193275.
104. Salazar Mercado, S. A., Quintero Caleño, J. D., Rojas Suárez, J. P. (2020). Cytogenotoxic effect of propanil using the Lens culinaris Med and Allium cepa L test. Chemosphere, 249: 126193, doi:10.1016/j.chemosphere.2020.126193.
105. Sambu, S., Hemaram, U., Murugan, R., Alsofi, A. A. (2022). Toxicological and Teratogenic Effect of Various Food Additives: An Updated Review. BioMed Research International, 2022: 6829409, doi:10.1155/2022/6829409.
106. Schiffman, S. S., Scholl, E. H., Furey, T. S., Nagle, H. T. (2023). Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays. Journal of Toxicology and Environmental Health, Part B, 26(6): 307-341, doi:10.1080/10937404.2023.2213903.
107. Shi, J., Han, S., Zhang, J., Liu, Y., Chen, Z., Jia, G. (2022). Advances in genotoxicity of titanium dioxide nanoparticles in vivo and in vitro. NanoImpact, 25: 100377, doi:10.1016/ j.impact.2021.100377.
108. Stevenson, J., Sonuga-Barke, E., McCann, D., Grimshaw, K., Parker, K. M., Rose-Zerilli, M. J., Holloway, J. W., Warner, J. O. (2010). The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children's ADHD symptoms. American Journal of Psychiatry, 167(9): 1108-1115, doi:10.1176/ appi.ajp.2010.09101529.
109. Tagorti, G., Yalçın, B., Güneş, M., Burgazlı, A. Y., Kaya, B. (2023). Comparative evaluation of natural and artificial sweeteners from DNA damage, oxidative stress, apoptosis, to development using Drosophila melanogaster. Drug and Chemical Toxicology: 1-12, doi:10.1080/01480545.2023.2228522.
110. Takumi, A., Kawamata, Y., Sakai, R., Narita, T. (2019). In vitro and in vivo genotoxicity studies on monosodium L-glutamate monohydrate. Regulatory Toxicology and Pharmacology 107: 104399, doi:10.1016/j.yrtph.2019.05.024.
111. Tomé, D. (2018). The roles of dietary glutamate in the intestine. Annals of Nutrition and Metabolism, 73(5): 15-20, doi:10.1159/000494777.
112. Tsatsakis, A., Docea, A. O., Constantin, C., Calina, D., Zlatian, O., Nikolouzakis, T. K., Stivaktakis, P. D., Kalogeraki, A., Liesivuori, J., Tzanakakis, G., Neagu, M. (2019). Genotoxic, cytotoxic, and cytopathological effects in rats exposed for 18 months to a mixture of 13 chemicals in doses below NOAEL levels. Toxicology Letters, 316: 154-170, doi:10.1016/j.toxlet.2019.09.004.
113. Turna Demir, F., Demir, E. (2023). Genotoxicity mechanism of food preservative propionic acid in the in vivo Drosophila model: gut damage, oxidative stress, cellular immune response and DNA damage. Toxicology Mechanisms and Methods, 33(4): 327-336, doi:10.1080/ 15376516.2022.2137871.
114. Valluzzi, R. L., Fierro, V., Arasi, S., Mennini, M., Pecora, V., Fiocchi, A. (2019). Allergy to food additives. Current Opinion in Allergy and Clinical Immunology, 19(3): 256-262, doi:10.1097/ ACI.0000000000000528.
115. Vega-Cabanillas, R., Sisniegas, M., Zavala, F. (2021). Tartrazine induces genotoxicity in lympocytes of BALB/c Mus musculus. Revista Peruana de Medicina Experimental y Salud Pública, 38(4): 587-594, doi:10.17843/rpmesp.2021.384.9356.
116. Veltman, C. H., Pennings, J. L., van de Water, B., Luijten, M. (2023). An Adverse Outcome Pathway Network for Chemically Induced Oxidative Stress Leading to (Non) genotoxic Carcinogenesis. Chemical Research in Toxicology, 36(6): 805-817, doi:10.1021/acs.chemrestox. 2c00396.
117. Walbolt, J., Koh, Y. (2020). Non-nutritive sweeteners and their associations with obesity and type 2 diabetes. Journal of Obesity & Metabolic Syndrome, 29(2): 114, doi:10.7570/jomes19079.
118. Walczak-Nowicka Ł, J., Herbet, M. (2022). Sodium Benzoate-Harmfulness and Potential Use in Therapies for Disorders Related to the Nervous System: A Review. Nutrients, 14(7), doi:10.3390/nu14071497.
119. Wang, Q.-P., Browman, D., Herzog, H., Neely, G. G. (2018). Non-nutritive sweeteners possess a bacteriostatic effect and alter gut microbiota in mice. PloS one, 13(7): e0199080, doi:10.1371/journal.pone.0199080.
120. Wu, L., Zhang, C., Long, Y., Chen, Q., Zhang, W., Liu, G. (2022). Food additives: From functions to analytical methods. Critical reviews in food science and nutrition, 62(30): 8497-8517, doi:10.1080/ 10408398.2021.1929823. Yılmaz, Ş. G., Uçar, A., Yılmaz, S. (2022). Do steviol glycosides affect the oxidative and genotoxicity parameters in BALB/c mice? Drug and Chemical Toxicology, 45(1): 464-469, doi:10.1080/01480545.2020.1716000.
121. Zanfirescu, A., Ungurianu, A., Tsatsakis, A. M., Nițulescu, G. M., Kouretas, D., Veskoukis, A., Tsoukalas, D., Engin, A. B., Aschner, M., Margină, D. (2019). A review of the alleged health hazards of monosodium glutamate. Comprehensive Reviews in Food Science and Food Safety, 18(4): 1111-1134, doi:10.1111/1541-4337.12448.
122. Zeiger, E. (2019). The test that changed the world: The Ames test and the regulation of chemicals. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 841: 43-48, doi:10.1016/j.mrgentox.2019.05.007.