Gıda ve Çevreden Alınan Bor Bileşiklerinin Toksikolojik Değerlendirmesi

Bor, endüstri ve tarımda yaygın olarak kullanılan ve çevrede doğal olarak bulunan bir bileşik olduğundan birçokaraştırmacı tarafından ilgi odağı olmuştur. Bu makalede, içme suyu, gıdalar ve farklı kaynaklardan kaynaklanan bormaruziyetinin insan ve hayvanlar üzerindeki etkileri ve çeşitli gıdaların bor miktarları verilmiştir. Bor bileşenlerineinsanlar ve hayvanlar oral, solunum ve temas yoluyla maruz kalmaktadır. Maruziyet sınırları bu bileşenlerin etkileriüzerinde oldukça önemlidir. Önerilen miktarlarda vücuda alınan borun çeşitli metabolik, beslenme, hormonal vefizyolojik süreçlere etkisi değerlendirildiğinde, insanlarda temel bir besin ögesi olmasa da diyet açısından önemliolduğu ve hücresel fonksiyonlarda olumlu etkileri olduğu kanıtlanmıştır. Hem hayvan hem de insanlar için bor alımı

Toxicological Evaluation of Boron Compounds Taken from Food and Environment

Since boron is widely used in industry and agriculture and naturally found in environment, it has been the focus of attention by many researchers, recently. In this review, in addition to the effects of boron exposure from different sources on humans and animals, the amounts of boron in various foods and recommended boron intake levels are also summarized. Humans and animals are exposed to boron components through oral consumption, inhalation and skin contact. Exposure limits are very important on the effects of these ingredients. Even though boron is not essential for humans, it is important for diet and cellular functions. In case of taking recommended amounts to body, it was shown that it had positive effects on metabolic, nutritional, hormonal and physiological functions. It is known that boron intake of >1.0 mg/day may be beneficial for both animals and humans, but it may be inconvenient to take it in excess. As important boron sources, sufficient amounts of fruits, vegetables, nuts and legumes should be included in the daily diet. In addition, drinking water is the primary source of boron for adults. There is no clear evidence of the carcinogenicity of boron in animals based on data on developmental and reproductive toxicity. Boron is easily excreted from body and there is lack of data indicating it as carcinogen or mutagen. More studies are needed on the dietary requirements, metabolic functions, therapeutic applications, and important regulatory expressions of boron components.

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[1] Kılıç, A.M., Kılıç, Ö., Andaç, İ., Çelik, A.G. (2009). Boron mining in Turkey, the marketing situation and the economical importance of Boron in the World IV. In International Boron Symposium, Eskişehir, Turkey.
[2] Parks, J.L., Edwards, M. (2005). Boron in the environment. Critical Reviews in Environmental Science and Technology, 35(2), 81-114.
[3] Howe, P.D. (1998). A review of boron effects in the environment. Biological Trace Element Research, 66(1-3), 153-166.
[4] Bolaños, L., Lukaszewski, K., Bonilla, I., Blevins, D. (2004). Why boron? Plant Physiology and Biochemistry, 42(11), 907-912.
[5] Nielsen, F.H. (1997). Boron in human and animal nutrition. Plant and Soil, 193(1-2), 199-208.
[6] Başoğlu, A., Sevinc, M., Guzelbektas, H., Civelek, T. (2000). Effect of borax on serum lipid profile in dogs. Online Journal of Veterinary Research, 4, 153-156.
[7] Kabu, M., Civelek, T. (2012). Effects of propylene glycol, methionine and sodium borate on metabolic profile in dairy cattle during periparturient period. Revue De Medecine Veterinaire, 163(8), 419-430.
[8] Hunt, C.D. (2012). Dietary boron: progress in establishing essential roles in human physiology. Journal of Trace Elements in Medicine and Biology, 26(2-3), 157-160.
[9] EFSA (Panel on Food Additives and Nutrient Sources added to Food (ANS)). (2013). Scientific Opinion on the re‐evaluation of boric acid (E 284) and sodium tetraborate (borax) (E 285) as food additives. EFSA Journal, 11(10), 3407.
[10] UKEVM (U.K. Expert Group on Vitamins and Minerals). 2002. Preliminary Risk Assessment— Boron, London, UK: Food Standards Agency.
[11] Moore, J.A., Expert Scientific Committee. (1997). An assessment of boric acid and borax using the IEHR evaluative process for assessing human developmental and reproductive toxicity of agents. Reproductive Toxicology, 11(1), 123-160.
[12] Culver, B.D., Shen, P.T., Taylor, T.H., Feldstein, A.L., Anton-Culver, H., Strong, P.L. (1993). Absorption of boron by sodium borate and boric acid production workers. Report to US Borax, August, 11.
[13] Culver, B.D., Hubbard, S.A. (1996). Inorganic boron health effects in humans: An aid to risk assessment and clinical judgment. The Journal of Trace Elements in Experimental Medicine: The Official Publication of the International Society for Trace Element Research in Humans, 9(4), 175- 184.
[14] Rainey, C.J., Nyquist, L.A., Christensen, R.E., Strong, P.L., Culver, B.D., Coughlin, J.R. (1999). Daily boron intake from the American diet. Journal of the American Dietetic Association, 99(3), 335- 340.
[15] Samman, S., Foster, M., Hunter, D. (2011). The role of boron in human nutrition and metabolism. Boron Science: New Technologies and Applications, 73, 73-82.
[16] WHO (World Health Organization). (1998). International Programme on Chemical Safety. Environmental Health Criteria 204. Boron. 1-10.
[17] EU. (1995). Technical guidance document. European Commission: Risk Assessment of New and Existing Substances.
[18] Goldbach, H.E., Wimmer, M.A. (2007). Boron in plants and animals: is there a role beyond cell‐wall structure? Journal of Plant Nutrition and Soil Science, 170(1), 39-48.
[19] Nielsen, F.H. (2000). The emergence of boron as nutritionally important throughout the life cycle. Nutrition, 16(7-8), 512-514.
[20] Penland, J.G. (1998). The importance of boron nutrition for brain and psychological function. Biological Trace Element Research, 66(1-3), 299- 317.
[21] Bai, Y., Hunt, C.D. (1996). Dietary boron enhances efficacy of cholecalciferol in broiler chicks. Journal of Trace Elements in Experimental Medicine, 9(3), 117-132.
[22] Fort, D.J., Stover, E.L., Strong, P.L., Murray, F.J., Keen, C.L. (1999). Chronic feeding of a low boron diet adversely affects reproduction and development in Xenopus laevis. The Journal of Nutrition, 129(11), 2055-2060.
[23] Hegsted, M., Keenan, M.J., Siver, F., Wozniak, P. (1991). Effect of boron on vitamin D deficient rats. Biological Trace Element Research, 28(3), 243- 255.
[24] Young, E.G., Smith, R.P., MacIntosh, O.C. (1949). Boric acid as a poison: Report of six accidental deaths in infants. Canadian Medical Association Journal, 61(5), 447-450.
[25] Kent, N.L., McCance, R.A. (1941). The absorption and excretion of minor elements by man: Silver, gold, lithium, boron and vanadium. Biochemical Journal, 35(7), 837-844.
[26] Weir Jr, R.J., Fisher, R.S. (1972). Toxicologic studies on borax and boric acid. Toxicology and Applied Pharmacology, 23(3), 351-364.
[27] Goldbloom, R.B., Goldbloom, A. (1953). Boric acid poisoning: report of four cases and a review of 109 cases from the world literature. The Journal of Pediatrics, 43(6), 631-643.
[28] Nielsen, F.H. (2008). Is boron nutritionally relevant? Nutrition Reviews, 66(4), 183-191.
[29] Benderdour, M., Bui-Van, T., Dicko, A., Belleville, F. (1998). In vivo and in vitro effects of boron and boronated compounds. Journal of Trace Elements in Medicine and Biology, 12(1), 2-7.
[30] Cui, Y., Winton, M.I., Zhang, Z.F., Rainey, C., Marshall, J., De Kernion, J.B., Eckhert, C.D. (2004). Dietary boron intake and prostate cancer risk. Oncology Reports, 11(4), 887-892.
[31] Mahabir, S., Spitz, M.R., Barrera, S.L., Dong, Y.Q., Eastham, C., Forman, M.R. (2008). Dietary boron and hormone replacement therapy as risk factors for lung cancer in women. American Journal of Epidemiology, 167(9), 1070-1080.
[32] Korkmaz, M., Uzgören, E., Bakırdere, S., Aydın, F., Ataman, O.Y. (2007). Effects of dietary boron on cervical cytopathology and on micronucleus frequency in exfoliated buccal cells. Environmental Toxicology: An International Journal, 22(1), 17-25.
[33] Penland, J.G. (1994). Dietary boron, brain function, and cognitive performance. Environmental Health Perspectives, 102(suppl 7), 65-72.
[34] Devirian, T.A., Volpe, S.L. (2003). The physiological effects of dietary boron. Critical Reviews in Food Science and Nutrition, 43(2), 219- 231.
[35] Nielsen, F.H. (2009). Micronutrients in parenteral nutrition: boron, silicon, and fluoride. Gastroenterology, 137(5), S55-S60.
[36] Eckhert, C., Barranco, W., Kim, D. (2007). Boron and prostate cancer a model for understanding boron biology. Advances in Plant and Animal Boron Nutrition, 291-297.
[37] Duydu, Y., Aydın, S., Undeger, U., Yavuz Ataman, O., Aydos, K., Düker, Y., Maximilian Bolt, H. (2016). Is boric acid toxic to reproduction in humans? Assessment of the animal reproductive toxicity data and epidemiological study results. Current Drug Delivery, 13(3), 324-329.
[38] Bolt, H.M., Başaran, N., Duydu, Y. (2020). Effects of boron compounds on human reproduction. Archives of Toxicology, 94, 714-724.
[39] Blevins, D.G., Lukaszewski, K.M. (1994). Proposed physiologic functions of boron in plants pertinent to animal and human metabolism. Environmental Health Perspectives, 102(suppl 7), 31-33.
[40] Appel, P.W., Na-Oy, L. (2012). The borax method of gold extraction for small-scale miners. Journal of Health and Pollution, 2(3), 5-10.
[41] MacGillivray, P.C., Fraser, M.S. (1953). Boric acid poisoning in infancy arising from the treatment of napkin rash. Archives of Disease in Childhood, 28(142), 484.
[42] Linden, C.H., Hall, A.H., Kulig, K.W., Rumack, B.H. (1986). Acute ingestions of boric acid. Journal of Toxicology: Clinical Toxicology, 24(4), 269-279.
[43] Restuccio, A., Mortensen, M.E., Kelley, M.T. (1992). Fatal ingestion of boric acid in an adult. The American Journal of Emergency Medicine, 10(6), 545-547.
[44] Hubbard, S.A. (1998). Comparative toxicology of borates. Biological Trace Element Research, 66(1- 3), 343-357.
[45] Price, C.J., Strong, P.L., Murray, F.J., Goldberg, M.M. (1997). Blood boron concentrations in pregnant rats fed boric acid throughout gestation. Reproductive Toxicology, 11(6), 833-842.
[46] Scialli, A.R., Bonde, J.P., Brüske-Hohlfeld, I., Culver,B.D., Li, Y., Sullivan, F.M. (2010). An overview of male reproductive studies of boron with an emphasis on studies of highly exposed Chinese workers. Reproductive Toxicology, 29(1), 10-24.
[47] Culver, B.D., Shen, P.T., Taylor, T.H., LeeFeldstein, A., Anton-Culver, H., Strong, P.L. (1994). The relationship of blood-and urine-boron to boron exposure in borax-workers and usefulness of urineboron as an exposure marker. Environmental Health Perspectives, 102(suppl 7), 133-137.
[48] Price, C.J., Strong, P.L., Marr, M.C., Myers, C.B., Murray, F.J. (1996). Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation. Fundamental and Applied Toxicology, 32(2), 179-193.
[49] Draize, J.H., Kelley, E.A. (1959). The urinary excretion of boric acid preparations following oral administration and topical applications to intact and damaged skin of rabbits. Toxicology and Applied Pharmacology, 1(3), 267-276.
[50] Heindel, J.J., Price, C.J., Field, E.A., Marr, M.C., Myers, C.B., Morrissey, R.E., Schwetz, B.A. (1992). Developmental toxicity of boric acid in mice and rats. Fundamental and Applied Toxicology, 18(2), 266-277.
[51] Price, C.J., Marr, M.C., Myers, C.B., Seely, J.C., Heindel, J.J., Schwetz,B.A. (1996). The developmental toxicity of boric acid in rabbits. Fundamental and Applied Toxicology, 34(2), 176- 187.
[52] Murray, F.J., Schlekat, C.E. (2004). Comparison of risk assessments of boron: alternate approaches to chemical-specific adjustment factors. Human and Ecological Risk Assessment, 10(1), 57-68.
[53] Ku, W.W., Chapin, R.E., Wine, R.N., Gladen, B.C. (1993). Testicular toxicity of boric acid (BA): relationship of dose to lesion development and recovery in the F344 rat. Reproductive Toxicology, 7(4), 305-319.
[54] Ku, W.W., Shih, L.M., Chapin, R.E. (1993). The effects of boric acid (BA) on testicular cells in culture. Reproductive Toxicology, 7(4), 321-331.
[55] Krishnan, B.B., Selvaraju, S., Gowda, N.K.S., Subramanya, K.B., Pal, D., Archana, S., Bhatta, R. (2019). Dietary boron supplementation enhances sperm quality and immunity through influencing the associated biochemical parameters and modulating the genes expression at testicular tissue. Journal of Trace Elements in Medicine and Biology, 55, 6-14.
[56] Sabuncuoğlu, B., Kocatürk, P., Yaman, O., Kavaş, G., Tekelioğlu, M. (2006). Effects of subacute boric acid administration on rat kidney tissue. Clinical Toxicology, 44(3), 249-253.
[57] Sander, J.E., Dufour, L., Wyatt, R.D., Bush, P.B., Page, R.K. (1991). Acute toxicity of boric acid and boron tissue residues after chronic exposure in broiler chickens. Avian Diseases, 745-749.
[58] Dani, H.M., Saini, H.S., Allag, I.S, Sareen, K. (1971). Effect of boron toxicity on protein and nucleic acid contents of rat tissues. Research Bulletin of the Panjab University, 22(1-2), 229-235.
[59] Ball, R.W., Harrass, M.C., Culver, B.D. (2001). Boron. Patty's Toxicology, 885-934.
[60] Turkez, H., Geyikoglu, F., Tatar, A., Keles, M.S., Kaplan, İ. (2012). The effects of some boron compounds against heavy metal toxicity in human blood. Experimental and Toxicologic Pathology, 64(1-2), 93-101.
[61] Weinthal, E., Parag, Y., Vengosh, A., Muti, A., Kloppmann, W. (2005). The EU drinking water directive: the boron standard and scientific uncertainty. European Environment, 15(1), 1-12.
[62] EPA, U. (2008). Drinking water health advisory for boron. Health and Ecological Criteria Division. US Environmental Protection Agency, Washington, DC.
[63] EPA, U. (2008). Health effects support document for boron. Health and Ecological Criteria Division. US Environmental Protection Agency, Washington, DC.
[64] EFSA (European Food Safety Authority). (2004). Opinion of the Scientific Panel on Dietetic Products, Nutrition, and Allergies (NDA) on the tolerable upper intake level for boron (sodium borate and boric acid). EFSA Journal, 80, 1-22.
[65] EFSA (European Food Safety Authority). (2005). Opinion of the Scientific Panel on Contaminants in Food Chain on a request of the Commission related to concentration limits for boron and fluoride in natural mineral waters. EFSA Journal, 237, 1-8.
[66] Başaran, N., Duydu, Y., Bolt, H.M. (2012). Reproductive toxicity in boron exposed workers in Bandirma, Turkey. Journal of Trace Elements in Medicine and Biology, 26(2-3), 165-167.
[67] Xing, X., Wu, G., Wei, F., Liu, P., Wei, H., Wang, C. Elashoff, D. (2008). Biomarkers of environmental and workplace boron exposure. Journal of Occupational and Environmental Hygiene, 5(3), 141-147.
[68] Kelly, G.S. (1997). Boron: a review of its nutritional interactions and therapeutic uses. Alternative Medicine Review, 2(1), 48-56.
[69] Şaylı, B.S. (2003). Low frequency of infertility among workers in a borate processing facility. Biological Trace Element Research, 93(1-3), 19-29.
[70] Imbus, H.R., Cholak, J., Miller, L.H., Sterling, T. (1963). Boron, cadmium, chromium, and nickel in blood and urine: A survey of American working men. Archives of Environmental Health: An International Journal, 6(2), 286-295.
[71] Garabrant, D.H., Bernstein, L., Peters, J.M., Smith, T.J., Wright, W.E. (1985). Respiratory effects of borax dust. Occupational and Environmental Medicine, 42(12), 831-837.
[72] Wegman, D. H., Eisen, E.A., Hu, X., Woskie, S.R., Smith, R.G., Garabrant, D.H. (1994). Acute and chronic respiratory effects of sodium borate particulate exposures. Environmental Health Perspectives, 102(suppl 7), 119-128.
[73] Hu, X., Wegman, D. H., Eisen, E.A., Woskie, S.R., Smith, R.G. (1992). Dose related acute irritant symptom responses to occupational exposure to sodium borate dusts. Occupational and Environmental Medicine, 49(10), 706-713.
[74] Block, C. (2003). Human and Environmental Risk Assessment on ingredients of household cleaning products. Jornadas-Comite Espanol De La Detergencia, 33, 39-44.
[75] Şaylı, B.S. (2001). Assessment of fertility and ınfertility in boron exposed Turkish subpopulations. Biological Trace Element Research, 81, 255-267.
[76] Şaylı, B.S. (1998). An assessment of fertility in boron-exposed Turkish subpopulations: 2. Evidence that boron has no effect on human reproduction. Biological Trace Element Research, 66(1-3), 409-422.
[77] Şaylı, B.S. (1998). The sex ratio of offspring of people exposed to boron. Reproductive Toxicology, 12(6), 673-674.
[78] Whorton, D., Haas, J., Trent, L. (1994). Reproductive effects of inorganic borates on male employees: birth rate assessment. Environmental Health Perspectives, 102(suppl 7), 129-132.
[79] Whorton, M.D., Haas, J.L., Trent, L., Wong, O. (1994). Reproductive effects of sodium borates on male employees: birth rate assessment. Occupational and Environmental Medicine, 51(11), 761-767.
[80] Liu, P., Wei, H., Guoping, W., Fusheng, W. (2006). Effects of occupational exposure to boron on the sperm quality of males. Chinese Journal of Industrial Hygiene and Occupational Diseases, 24(3), 167-169.
[81] Duydu, Y., Başaran, N., Bolt, H.M. (2012). Exposure assessment of boron in Bandırma boric acid production plant. Journal of Trace Elements in Medicine and Biology, 26(2-3), 161-164.
[82] Duydu, Y., Başaran, N., Aydın, S., Üstündağ, A., Yalçın, C.Ö., Anlar, H.G. Ickstadt, K. (2018a). Evaluation of FSH, LH, testosterone levels and semen parameters in male boron workers under extreme exposure conditions. Archives of Toxicology, 92(10), 3051-3059.
[83] Duydu, Y., Başaran, N., Üstündağ, A., Aydın, S., Yalçın, C Ö., Anlar, H.G., Ickstadt, K. (2018b). Birth weights of newborns and pregnancy outcomes of environmentally boron-exposed females in Turkey. Archives of Toxicology, 92(8), 2475-2485.
[84] Duydu, Y., Başaran, N., Yalçın, C.Ö., Üstündağ, A., Aydın, S., Anlar, H.G., Ickstadt, K. (2019). Boronexposed male workers in Turkey: no change in sperm Y: X chromosome ratio and in offspring’s sex ratio. Archives of Toxicology, 93(3), 743-751.
[85] Korkmaz, M., Yenigün, M., Bakırdere, S., Ataman, O.Y., Keskin, S., Müezzinoğlu, T., Lekili, M. (2011). Effects of chronic boron exposure on semen profile. Biological Trace Element Research, 143(2), 738-750.
[86] Robbins, W.A., Xun, L., Jia, J., Kennedy, N., Elashoff, D. A., Ping, L. (2010). Chronic boron exposure and human semen parameters. Reproductive Toxicology, 29(2), 184-190.
[87] Turkez, H., Geyikoğlu, F., Tatar, A. (2013). Borax counteracts genotoxicity of aluminum in rat liver. Toxicology and Industrial Health, 29(9), 775-779.
[88] Nielsen, F.H., Meacham, S.L. (2011). Growing evidence for human health benefits of boron. Journal of Evidence-Based Complementary & Alternative Medicine, 16(3), 169-180.
[89] Hunt, C.D., Shuler, T.R., Mullen, L.M. (1991). Concentration of boron and other elements in human foods and personal-care products. Journal of The American Dietetic Association, 91(5), 558- 568.
[90] Anderson, D.L., Cunningham, W.C., Lindstrom, T.R. (1994). Concentrations and intakes of H, B, S, K, Na, Cl, and NaCl in foods. Journal of Food Composition and Analysis, 7(1-2), 59-82.
[91] Hunt, C.D., Meacham, S.L. (2001). Aluminum, boron, calcium, copper, iron, magnesium, manganese, molybdenum, phosphorus, potassium, sodium, and zinc: concentrations in common western foods and estimated daily intakes by infants; toddlers; and male and female adolescents, adults, and seniors in the United States. Journal of The American Dietetic Association, 101(9), 1058-1060.
[92] Rainey, C., Nyquist, L. (1998). Multicountry estimation of dietary boron intake. Biological Trace Element Research, 66(1-3), 79-86.
[93] Nielsen, F.H., Penland, J.G. (1999). Boron supplementation of peri‐menopausal women affects boron metabolism and indices associated with macromineral metabolism, hormonal status and immune function. The Journal of Trace Elements in Experimental Medicine: The Official Publication of the International Society for Trace Element Research in Humans, 12(3), 251-261.
[94] Penland, J.G. (1995). Quantitative analysis of EEG effects following experimental marginal magnesium and boron deprivation. Magnesium Research, 8(4), 341-358.
[95] Nielsen, F.H. (1996). Evidence for the nutritional essentiality of boron. The Journal of Trace Elements in Experimental Medicine, 9, 215-229.
[96] Nielsen, F.H., Gallagher, S.K., Johnson, L.K., Nielsen, E.J. (1992). Boron enhances and mimics some effects of estrogen therapy in postmenopausal women. The Journal of Trace Elements in Experimental Medicine, 5, 237-246.
[97] Velioğlu, S., Saylı, B.S., Altunsoy, S. (1999). Bor madeni havzalarında üretilen bazı gıdalarda bor miktarlarının belirlenmesi üzerine bir araştırma. Gıda, 24(1), 13-19.
[98] Şimşek, A., Velioğlu, Y.S., Coşkun, A.L., Saylı, bor.S. (2003). Boron concentrations in selected foods from borate‐producing regions in Turkey. Journal of the Science of Food and Agriculture, 83(6), 586-592.
[99] Pizzorno, L. (2015). Nothing boring about boron. Integrative Medicine: A Clinician's Journal, 14(4), 35-48.
[100]Kim, M.H., Bae, Y.J., Lee, Y.S., Choi, M.K. (2008). Estimation of boron intake and its relation with bone mineral density in free-living Korean female subjects. Biological Trace Element Research, 125(3), 213-222.
[101]Boyacıoğlu, O., Orenay-Boyacıoğlu, S., Yıldırım, H., Korkmaz, M. (2018). Boron intake, osteocalcin polymorphism and serum level in postmenopausal osteoporosis. Journal of Trace Elements in Medicine and Biology, 48, 52-56.
[102]Khaliq, H., Juming, Z., Ke-Mei, P. (2018). The physiological role of boron on health. Biological Trace Element Research, 186(1), 31-51.
[103]Militaru, C., Donoiu, I., Craciun, A., Scorei, I.D., Bulearca, A.M., Scorei, R.I. (2013). Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition, 29(1), 178-183.
[104]Reyes-Izquierdo, T., Nemzer, B., Gonzalez, A.E., Zhou, Q., Argumedo, R., Shu, C., Pietrzkowski, Z. B. (2012). Short-term intake of calcium fructoborate improves WOMAC and McGill scores and beneficially modulates biomarkers associated with knee osteoarthritis: a pilot clinical double-blinded placebo-controlled study. American Journal of Biomedical Sciences, 4(2), 111-122.
[105]Scorei, R., Mitrut, P., Petrisor, I., Scorei, I. (2011). A double-blind, placebo-controlled pilot study to evaluate the effect of calcium fructoborate on systemic inflammation and dyslipidemia markers for middle-aged people with primary osteoarthritis. Biological Trace Element Research, 144(1-3), 253- 263.