THE POSSIBLE ROLE OF TRACE ELEMENTS IN THYROID HYPERTROPHIC AND ADENOMATOUS TRANSFORMATION

Vladimir Zaichick  

Radionuclide Diagnostics Department, Medical Radiological Research Centre, Obninsk, 249036, Russia.

ABSTRACT 

Background: Thyroid benign nodules (TBNs) are the most common diseases of this endocrine gland and are common worldwide. Among TBNs the colloid goiter (CG) and thyroid adenoma (TA) are very frequentdiseases. Evaluation of variant of TBNs is clinically important for subsequent therapeutic interventions, as well as for a clearer understanding the etiology of these disorders. The aim of this exploratory study was to examine differences in the content offifty trace elements (TE) in CG and TA tissues. 

Methods: Thyroid tissue levels of TE have prospectively evaluated in 46 patients with CG and 19 patients with TA. Measurements have performed using a combination of non-destructive and destructive methods: instrumental neutron activation analysis with high resolution spectrometry of long-lived radionuclides (INAA-LLR) and inductively coupled plasma mass spectrometry (ICPMS), respectively. Tissue samples were divided into two portions. One was used for morphological study while the other was intended for TE analysis. 

Results: It was observed that in both CG and TA tissues the contents of Ag, Al, Cr, Hg, Mn, Th, and Zn increased, whereas the levels of Au, Be, Cs, Pb, Rb, Sb, Sc, Th, Yb, and Zr were unchanged in comparison with normal thyroid tissue. No differences were found between the TE contents of CG and TA.

Conclusions: From results obtained, it was possible to conclude that the common characteristics of CG and TA tissue samples were of a high level of Ag, Al, Cr, Hg, Mn, Th, and Zn in comparison with normal thyroid and, therefore, these TE could be involved in etiology and pathogenesis of thyroid disorders such as CG and TA.

Keywords: Inductively coupled plasma mass spectrometry, neutron activation analysis, thyroid nodules, trace elements.

 

INTRODUCTION

 

Thyroid benign nodules (TBNs) are universally encountered and frequently detected by palpation during a physical examination, or incidentally, during clinical imaging procedures. TBNs include non-neoplastic lesions, for example, colloid goiter (CG) and neoplastic lesion such as thyroid adenoma (TA)1-3. Evaluation of the variant of TBNs is clinically important for subsequent therapeutic interventions, which is why finding specific characteristics of CG and TA is necessary for the differential diagnosis of these thyroid disorders. For over 20th century, there was the dominant opinion that TBNs is the simple consequence of iodine deficiency. However, it was found that TBNs is a frequent disease even in those countries and regions where the population is never exposed to iodine shortage4. Moreover, it was shown that iodine excess has severe consequences on human health and associated with the presence of TBNs5-8. It was also demonstrated that besides the iodine deficiency and excess many other dietary, environmental, and occupational factors are associated with the TBNsincidence9-11. Among these factors a disturbance of evolutionary stable input of many trace elements (TE) in human body after industrial revolution plays a significant role in etiology of TBNs12. 

Besides iodine, many other TE has also essential physiological functions13. Essential or toxic (goitrogenic, mutagenic, carcinogenic) properties of TE depend on tissue-specific need or tolerance, respectively13. Excessive accumulation or an imbalance of the TE may disturb the cell functions and may result in cellular degeneration, death, benign or malignant transformation13-15. In our previous studies the complex of in vivo and in vitro nuclear analytical and related methods was developed and used for the investigation of iodine and other TE contents in the normal and pathological thyroid16-22. Iodine level in the normal thyroid was investigated in relation to age, gender and some non-thyroidal diseases23,24. After that, variations of many TE content with age in the thyroid of males and females were studied and age- and gender-dependence of some TE was observed25-41. A significant difference between some TE contents in CG and TA in comparison with normal thyroid was demonstrated42-44. To date, the etiology and pathogenesis of CG and TA must be considered as multifactorial. The present study was performed to find out differences in TE contents between the group of CG and TA samples, as well as to clarify the role of some TE in the etiology of thyroid lesions. Having this in mind, the aim of this exploratory study was to examine differences in the content of fifty TE in CG and TA tissues, using a combination of non-destructive instrumental neutron activation analysis with high resolution spectrometry of long-lived radionuclides (INAA-LLR) and destructive inductively coupled plasma mass spectrometry (ICP-MS) method, and to compare the levels of these TEs in the cohort of CG and TA samples.

SUBJECTS AND METHODS

ll patients suffered from CG (n=46, mean age M±SD was 48±12 years, range 30-64) andTA(n=19, mean age M±SD was 41±11 years, range 22-55) were hospitalized in the Head and Neck Department of the Medical Radiological Research Centre. All of them were inhabitants of environmentally sound (non-industrial and unpolluted) region. Thick-needle puncture biopsy of suspicious nodules of the thyroid was performed for every patient, to permit morphological study of thyroid tissue at these sites and to estimate their TE contents. For all patients the diagnosis has been confirmed by clinical and morphological results obtained during studies of biopsy and resected materials (46 euthyroid CG, 4 toxic TA and 15 non-toxic TA). Histological conclusion for all thyroidal lesions was the CG (16 macro-follicular,13 micro-follicular, and 17 macro-micro-follicular) and TA (4 macro-follicular, 4 micro-follicular, 11 macro-micro follicular). All studies were approved by the Ethical Committees of the Medical Radiological Research Centre (MRRC), Obninsk (Reference number 115050610007, year 2017). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments, or with comparable ethical standards Titanium tools were used for biopsy, getting tissue samples from resected materials, and sample preparation to prevent contamination by many alloy metals from stainless steel45. All tissue samples were divided into two portions. One was used for morphological study while the other was intended for TE analysis. After the samples intended for TE analysis were weighed, they were freeze-dried and homogenized46. Using INAA-LLR and ICP-MS, contents of fifty TE including silver (Ag), aluminum (Al),  arsenic (As), gold (Au), boron (B),, beryllium (Be), bismuth (Bi), cadmium (Cd), cerium (Ce), cobalt (Co), chromium (Cr), cesium (Cs), dysprosium (Dy), iron (Fe), erbium (Er), europium (Eu), gallium (Ga), gadolinium (Gd), mercury (Hg), holmium (Ho), iridium (Ir), lanthanum (La), lithium (Li), lutecium (Lu), manganese (Mn), molybdenum (Mo), niobium (Nb), neodymium (Nd), nickel (Ni), lead (Pb), palladium (Pd), praseodymium (Pr), platinum (Pt), rubidium (Rb), antimony (Sb), scandium (Sc), selenium (Se), samarium (Sm), tin (Sn), terbium (Tb), tellurium (Te), thorium (Th), titanium (Ti), thallium (Tl), thulium (Tm), uranium (U), yttrium (Y), ytterbium (Yb), zinc (Zn), and zirconium (Zr) were detected in CG and TA tissue.The pounded samples weighing about 10 mg (for biopsy) and 100 mg (for resected materials) were used for TE measurement by INAA-LLR. The content of Ag, Co, Cr, Fe, Hg, Rb, Sb, Sc, Se, and Zn were determined by INAA-LLR using a vertical channel of the Water-Water-Research nuclear reactor (Branch of Karpov Institute, Obninsk). After non-destructive INAA-LLR investigation the thyroid samples were used for ICP-MS. The samples were decomposed in autoclaves and aliquots of solutions were used to determine the Ag, Al, As, Au, B, Be, Bi, Cd, Ce, Co, Cr, Cs, Dy, Er, Eu, Ga, Gd, Hg, Ho, Ir, La, Li, Lu, Mn, Mo, Nb, Nd, Ni, Pb, Pd, Pr, Pt, Rb, Sb, Se, Sm, Sn, Tb, Te, Th, Ti, Tl, Tm, U, Y, Yb, Zn, and Zr mass fractions by ICP-MS using an ICP-MS Thermo-Fisher “X-7” Spectrometer (Thermo Electron, USA).Information detailing with the NAA-LLR and ICP-MS methods used and other details of the analysis were presented in our earlier publications concerning TE contents in human thyroid29,30,35, prostate47-52, and scalp hair53.To determine contents of the TE by comparison with a known standard, biological synthetic standards (BSS) prepared from phenol-formaldehyde resins were used54. In addition to BSS, aliquots of commercial, chemically pure compounds were also used as standards. Ten sub-samples of certified reference material (CRM) IAEA H-4 (animal muscle) and five sub-samples of CRM of the Institute of Nuclear Chemistry and Technology (INCT, Warszawa, Poland) INCT-SBF-4 Soya Bean Flour, INCT-TL-1 Tea Leaves, and INCT-MPH-2Mixed Polish Herbs were treated and analyzed in the same conditions that thyroid samples to estimate the precision and accuracy of results. A dedicated computer program for INAA-LLR mode optimization was used55. All thyroid samples were prepared in duplicate, and mean values of TE contents were used in final calculation. Mean values of TE contents were used in final calculation for the Ag, Co, Cr, Hg, Rb, Sb, Se, and Zn mass fractions measured by INAA-LLR and ICP-MS methods. Using Microsoft Office Excel software, a summary of the statistics, including, arithmetic mean, standard deviation, standard error of mean, and range (minimal-maximal value), was calculated for TE contents in CG and TA tissue samples. The difference in the results between two groups of samples were evaluated by the parametric Student’s t-test and non-parametric Wilcoxon-Mann-Whitney U-test.

RESULTS

 

Table 1 presents certain statistical parameters (arithmetic mean M, standard deviation SD, standard error of mean, and range) of the Ag, Al, As, Au, B, Be, Bi, Cd, Ce, Co, Cr, Cs, Dy, Er, Eu, Fe, Ga, Gd, Hg, Ho, Ir, La, Li, Lu, Mn, Mo, Nb, Nd, Ni, Pb, Pd, Pr, Pt, Rb, Sb, Sc, Se, Sm, Sn, Tb, Te, Th, Ti, Tl, Tm, U, Y, Yb, Zn, and Zr mass fraction in CG and TA tissue samples.

The ratios of means and the comparison of mean values of Ag, Al, Au, B, Be, Bi, Cd, Ce, Co, Cr, Cs, Er, Fe, Ga, Hg, La, Li, Mn, Mo, Nd, Ni, Pb, Pr, Rb, Sb, Sc, Se, Sm, Sn, Tl, U, Y, Yb, Zn, and Zr mass fractions in CG and TA are presented in Table 2. Table 3 depicts the results of comparison the contents of Ag, Al, Au, B, Be, Bi, Cd, Ce, Co, Cr, Cs, Er, Fe, Ga, Hg, La, Li, Mn, Mo, Nd, Ni, Pb, Pr, Rb, Sb, Sc, Se, Sm, Sn, Tl, U, Y, Yb, Zn, and Zrin CG and TA sample groups with those in normal thyroid(from data analysis of previous publications43,44), as well as comparison the contents of these ChE in CG and TA sample groups.

 

DISCUSSION

 

As was shown before [29,30,35,47-53] good agreement of the 50 TE mass fractions in CRM IAEA H-4, INCT-SBF-4, INCT-TL-1, and INCT-MPH-2 samples determined by both INAA-LLR and ICP-MS methods with the certified data of these CRMs indicates acceptable accuracy of the results obtained in the study 

of CG and TA samples and presented in Table 1 to Table 3. In general, thee differences found for Ag, Al, 

Au, Be, Cr, Cs, Hg, Mn, Pb, Rb, Sb, Sc, Th, Yb, Zn, and Zr contents in CG and TA tissue samples were similar in comparison with normal thyroid tissue (Table 3). In affected tissues contents of Ag, Al, Cr, Hg, Mn, Th, and Zn increased, whereas levels of Au, Be, Cs, Pb, Rb, Sb, Sc, Th, Yb, and Zr did not changed in both groups of samples (Table 3). There was not found any differences between TE contents of CG and TA, when results for these groups were compared with each other (Table 2 and Table 3). Published data on comparison of Ag, Al, As, Au, B, Be, Bi, Cd, Ce, Co, Cr, Cs, Dy, Er, Eu, Fe, Ga, Gd, Hg, Ho, Ir, La, Li, Lu, Mn, Mo, Nb, Nd, Ni, Pb, Pd, Pr, Pt, Rb, Sb, Sc, Se, 

 

Sm, Sn, Tb, Te, Th, Ti, Tl, Tm, U, Y, Yb, Zn, and Zr levels in CG and TA were not found. Thus, from obtained results it was possible to conclude that the common characteristics of CG and TA tissue samples in comparison with normal thyroid were elevated level of Ag, Al, Cr, Hg, Mn, Th, and Zn. Therefore, it is reasonable to conclude that these TE can be involved in etiology and pathogenesis of such thyroid disorders as CG and TA.

Silver 

Ag is a TE with no recognized trace metal value in the human body56. Food is the major intake source of Ag and this metal is authorized as a food additive(E174) in the EU57. Another source of Agis contact with skin and mucosal surfaces because Ag is widely used in different applications (e.g., Jewelry, wound dressings, or eye drops)58. Ag in metal form and inorganic Ag compounds ionize in the presence of water, body fluids or tissue exudates. The silver ion Ag+ is biologically active and readily interacts with proteins, amino acid residues, free anions and receptors on mammalian and eukaryotic cell membranes59. Besides such the adverse effects of chronic exposure to Ag as a permanent bluish-gray discoloration of the skin (argyria) or eyes (argyrosis), exposure to soluble Ag compounds may produce other toxic effects, including liver and kidney damage, irritation of the eyes, skin, respiratory, and intestinal tract, and changes in blood cells60. 

In experimental studies it was shown that Ag nanoparticles may affect thyroid hormone metabolism61.  More detailed knowledge of the Ag toxicity can lead to a better understanding of the impact on human health, including thyroid function.

Aluminum 

Al is the most prevalent metal in the environment. Environmental media may be contaminated with Al from anthropogenic sources and through the weathering of rocks and minerals62. The trace element Al is not described as essential, because there is no biochemical function directly associated with it. Food is the major intake source of Al, followed by drinking water63. The additional sources of human exposure to Al are Al-containing food packaging, foils, cooking utensils and baking trays made of Al, cosmetic products (antiperspirants, sun creams, toothpaste) and drugs (antacid agents)64,65. The toxic effects of Al lead to oxidative stress, immunologic alterations, genotoxicity, and other disorders, including cell membrane perturbation, apoptosis, necrosis and dysplasia. Furthermore, it has been shown in experimental and epidemiological studies that Al can affect thyroid iodide uptake and hormones secretion66,67.

Chromium

The general population can be exposed to low levels of Cr pri­marily through consumption of food and to a lesser degree through inhalation of ambient air and ingestion of drinking water68.Cr-compounds are cytotoxic, genotoxic, and carcinogenic in nature. Some Cr forms, including hexavalent chromium (Cr6+), are toxicants known for their carcinogenic effect in humans. They have been classified as certain or probable carcinogens by the International Agency for Research on Cancer69. The lung cancer risk is prevalent in pigment chromate handlers, ferrochromium production workers, stainless steel welders, and chrome-platers70. Except in Cr-related industries and associated environments, Cr intoxication from environmental exposure is not common. However, it was found, that drinking water supplies in many geographic areas contain chromium in the +3 and +6 oxidation states. Exposure of animals to Cr6+ in drinking water induced tumors in the mouse small intestine71. Many other animal experiments and in vitro studies demonstrate also that Cr can induce oxidative stress and exert cytotoxic effects72. Besides reactive oxygen species (ROS) generation, oxidative stress, and cytotoxic effects of Cr exposure, a variety of other changes like DNA damage, increased formation of DNA adducts and DNA-protein cross-links, DNA strand breaks, chromosomal aberrations and instability, disruption of mitotic cell division, chromosomal aberration, premature cell division, S or G2/M cell cycle phase arrest, and carcinogenesis also occur in humans or experimental test systems70. Recently, in acase-control study on the association of TE exposure and TBNs it has been shown that Cr is a potential influencing factor for the risk of thyroid tumor and goiter73.

Mercury

In the general population, potential sources of Hg exposure include the inhalation of this metal vapor in the air, ingestion of contaminated foods and drinking water, and exposure to dental amalgam through dental care74. Hg is one of the most dangerous environmental pollutants75.The growing use of this metal in diverse areas of industry has resulted in a significant increase of environment contamination and episodes of human intoxication. Many experimental, epidemiologic, and occupational studies of Hg in different chemical states shown significant alterations in thyroid hormones metabolism and thyroid gland parenchyma73,76,77. Moreover, Hg was classified as certain or probable carcinogen by the International Agency for Research on Cancer69. For example, in Hg polluted area thyroid cancer incidence was almost 2 times higher than in adjacent control areas78. 

Manganese

Mnis an essential micronutrient because this TE acts as a co-factor in many enzymatic reactions involved in the metabolisms of lipid, protein, carbohydrate and amino acid, etc.79. The diet, natural and anthropogenic contaminated environment are the main sources of Mn exposure in general populations. It was found in many experimental and epidemiologic studies that excessive environmental Mn exposure may affect the balance of thyroid hormone homeostasis via decreasing serum thyroid hormone levels, including T3 and T479. Furthermore, recently, in a case-control study on the association of TE exposure and TBNs it was shown that Cr is a potential influencing factor for the risk of thyroid tumor and goiter73.

Thorium

Th is a naturally radioactive TE, which effects by its chemical toxicity and radiation on skeleton, nervous and endocrine systems. Environmental contamination by Th, originated mainly from mining activities or spills and contaminated environment is the main source of Th exposure in general populations. The results of many experimental studies indicate that Th administration exerts hazardous effects on the neuroendocrine axis and causes the imbalance of thyroid hormones and structural changes in thyroid gland80,81. Moreover, an epidemiologic and clinicopathologic study found an apparent increased prevalence of both benign and malignant thyroid disease in the group of patients treated with Th-contained compound (Thorotrast)82.

Zinc

Zn, as a trace metal,has structural, catalytic and regulatory roles in normal and pathophysiology. This TE is a constituent of more than 3000 proteins and is a cofactor for over 300 enzymes83. Zn is an essential mediator of cell proliferation and differentiation through the regulation of DNA synthesis and mitosis. Zn also affects DNA repair pathways by regulating multiple intracellular signaling pathways and altering proteins involved in DNA maintenance84. This metal also maintenance the balance of a cellular redox85. Thus, Zn is important cofactors in diverse cellular processes. Concern the thyroid function, Zn is involved in the synthesis of TSH and important for the proper functioning of T3 because T3 nuclear receptors contain Zn ions86, but for all that, there is a strong negative correlation between serum Zn content and thyroid hormone levels87. There are good reasons for such speculations since experimental and epidemiological data support the hypothesis that Zn overload is a risk factor for benign and malignant tumors84,88-90. Food and particularly red meat is a main source of Zn intake for humans91. In other words, by us in glow or high levels of the TE in affected thyroid tissues researchers try to determine the role of either deficiency or excess of all TE in the etiology and pathogenesis of thyroid diseases. In our opinion, abnormal levels of many TE in TBNs could be and a cause, as well as an effect, of thyroid tissue transformation. From the results of such studies, it is not alwayspossible to decide whether the measured decrease or increase in TE level in pathologically altered tissue is the cause of the changes or vice versa.

Limitations

This study has several limitations. Firstly, analytical techniques employed in this study measure only fifty TE (Ag, Al, As, Au, B, Be, Bi, Cd, Ce, Co, Cr, Cs, Dy, Er, Eu, Fe, Ga, Gd, Hg, Ho, Ir, La, Li, Lu, Mn, Mo, Nb, Nd, Ni, Pb, Pd, Pr, Pt, Rb, Sb, Sc, Se, Sm, Sn, Tb, Te, Th, Ti, Tl, Tm, U, Y, Yb, Zn, and Zr) mass fractions. Future studies should be directed toward using other analytical methods which will extend the list of TE investigated in normal thyroid and in pathologically altered tissue. Secondly, the sample size of CG group and, particularly, of TA group was relatively small and prevented investigations of TE contents in these groups using differentials like gender, histological types of CG and TA, nodules functional activity, stage of disease, and dietary habits of patients with CG and TA. Lastly, generalization of our results may be limited to Russian population. Despite these limitations, this study provides evidence on TBNs-specific tissue Ag, Al, Cr, Hg, Mn, Th, and Zn level alteration and shows the necessity to continue TE research of TBNs.

 

 

 

CONCLUSION

 

In this work, TE analysis was performed in CG and TA tissue samples using the INAA-LLR non-destructive analytical method and the ICP-MS destructive analytical method. The combination of these methods has been shown to be a suitable analytical tool for the determination of fifty TE:(Ag, Al, As, Au, B, Be, Bi, Cd, Ce, Co, Cr, Cs, Dy, Er, Eu, Fe, Ga, Gd, Hg, Ho, Ir, La, Li, Lu, Mn, Mo, Nb, Nd, Ni, Pb, Pd, Pr, Pt, Rb, Sb, Sc, Se, Sm, Sn, Tb, Te, Th, Ti, Tl, Tm, U, Y, Yb, Zn, and Zr)content in the tissue samples of human thyroid in norm and pathology, including needle-biopsy specimens. It was observed that in both CG and TA  tissues contents of Ag, Al, Cr, Hg, Mn, Th, and Zn increased, whereas levels of Au, Be, Cs, Pb, Rb, Sb, Sc, Th, Yb, and Zr did not changed in comparison with normal thyroid tissue. It was not found any differences between TE contents of CG and TA.

From the results obtained, it was possible to conclude that the combined characteristics of CG and TA tissue samples were elevated in the level of Ag, Al, Cr, Hg, Mn, Th and Zn in comparison with normal thyroid, and therefore, these TE could be involved in the etiology and pathogenesis of thyroid disorders such as CG and TA.

 

ACKNOWLEDGEMENTS

 

The author is extremely grateful to Profs. Vtyurin BM and Medvedev VS, Medical Radiological Research Center, Obninsk, as well as to Dr. Choporov Yu, former Head of the Forensic Medicine Department of City Hospital, Obninsk, for supplying thyroid samples. The author is also grateful to Dr. Karandaschev V, Dr. Nosenko S, and Moskvina I, Institute of Microelectronics Technology and High Purity Materials, Chernogolovka, Russia, for their help in ICP-AES analysis.

CONFLICT OF INTEREST

 

No conflict of interest associated with this work.

 

REFERENCES

 

  1. Ghartimagar D, Ghosh A, Shrestha MK, Thapa S, Talwar OP. Histopathological spectrum of non-neoplastic and neoplastic lesions of thyroid: A descriptive cross-sectional study. J Nepal Med Assoc 2020; 58(231): 856-861.https://doi.org/10.31729/jnma.5038
  1. Hoang VT, Trinh CT. A review of the pathology, diagnosis and management of colloid goitre. Eur Endocrinol 2020; 16(2): 131-135.https://doi.org/10.17925/EE.2020.16.2.131
  1. Popoveniuc G, Jonklaas J. Thyroid nodules. Med Clin North Am 2012; 96(2): 329-349.https://doi.org/10.1016/j.mcna.2012.02.002
  1. Derwahl M, Studer H. Multinodular goitre: 'much more to it than simply iodine deficiency'. Baillieres Best Pract Res Clin Endocrinol Metab 2000; 14(4): 577-600.https://doi.org/10.1053/beem.2000.0104
  1. Zaichick V. Iodine excess and thyroid cancer. J Trace Elem Exp Med 1998; 11(4): 508-509.
  2. Zaichick V, Iljina T. Dietary iodine supplementation effect on the rat thyroid 131I blastomogenic action. In: Die Bedentung der Mengen- und Spurenelemente. 18. Arbeitstangung. Jena: Friedrich-Schiller-Universitat; 1998:294-306.
  3. Kim S, Kwon YS, Kim JY, Hong KH, Park YK. Association between Iodine Nutrition Status and Thyroid Disease-Related Hormone in Korean Adults: Korean National Health and Nutrition Examination Survey VI (2013-2015).Nutrients 2019; 11(11): 2757.https://doi.org/10.3390/nu11112757
  1. Vargas-Uricoechea ?, Pinzón-Fernández MV, Bastidas-Sánchez BE, et al. Iodine status in the colombian population and the impact of universal salt iodization: a double-edged sword? J Nutr Metab 2019; 2019: 6239243.https://doi.org/10.1155/2019/6239243
  1. Stojsavljevic A, Rovcanin B, Krstic D, et al. Cadmium as main endocrine disruptor in papillary thyroid carcinoma and the significance of Cd/Se ratio for thyroid tissue pathophysiology. J Trace Elem Med Biol 2019; 55: 190-195. https://doi.org/1016/j.jtemb.2019.06.009
  2. Fahim YA, Sharaf NE, Hasani IW, et al. Assessment of thyroid function and oxidative stress state in foundry workers exposed to lead. J Health Pollut 2020; 10(27): 200903.https://doi.org/5696/2156-9614-10.27.200903
  3. Liu M, Song J, Jiang Y, et al. A case-control study on the association of mineral elements exposure and thyroid tumor and goiter. Ecotoxicol Environ Saf 2021; 208: 111615.https://doi.org/1016/j.ecoenv.2020.111615
  4. Zaichick V. Medical elementology as a new scientific discipline. J Radioanal Nucl Chem 2006; 269: 303-309.
  5. Moncayo R, Moncayo H. A post-publication analysis of the idealized upper reference value of 2.5 mI U/L for TSH: Time to support the thyroid axis with magnesium and iron especially in the setting of reproduction medicine. BBA Clin 2017; 7: 115–119.https://doi.org/10.1016/j.bbacli.2017.03.003
  1. Beyersmann D, Hartwig A. Carcinogenic metal compounds: recent insight into molecular and cellular mechanisms. Arch Toxicol 2008; 82(8): 493-512.https://doi.org/10.1007/s00204-008-0313-y
  1. Martinez-Zamudio R, Ha HC. Environmental epigenetics in metal exposure. Epigenetics 2011; 6(7): 820-827.https://doi.org/10.4161/epi.6.7.16250
  2. Zaichik VE, RaibukhinYuS, Melnik AD, Cherkashin VI. Neutron-activation analysis in the study of the behavior of iodine in the organism. Med Radiol (Mosk) 1970; 15(1): 33-36. PMID: 5449249
  3. Zaichik VE, Matveenko EG, Vtiurin BM, Medvedev VS. Intrathyroid iodine in the diagnosis of thyroid cancer. Vopr Onkol 1982; 28(3): 18-24. PMID: 7064415
  4. Zaichick V, Tsyb AF, Vtyurin Trace elements and thyroid cancer. Analyst 1995; 120(3): 817-821.https://doi.org/10.1039/an9952000817 
  5. Zaichick VYe, Choporov Yu Ya. Determination of the natural level of human intra-thyroid iodine by instrumental neutron activation analysis. J Rad Nuc Chem 1996; 207(1):153-161. https://doi.org/10.1007/bf02036535
  6. Zaichick V. In vivo and in vitro application of energy-dispersive XRF in clinical investigations: experience and the future. J Trace ElemExp Med 1998; 11(4): 509-510.
  7. Zaichick V, Zaichick S. Energy-dispersive X-ray fluorescence of iodine in thyroid puncture biopsy specimens. J Trace Mic Tech 1999; 17(2): 219-232.
  8. Zaichick V. Relevance of and potentiality for in vivo intrathyroidal iodine determination. Ann N Y Acad Sci 2000; 904: 630-632.https://doi.org/10.1111/j.1749-6632.2000.tb06530.x
  9. Zaichick V, Zaichick S. Normal human intrathyroidal iodine. Sci Total Environ 1997; 206(1): 39-56.https://doi.org/10.1016/s0048-9697(97)00215-5
  10. Zaichick V. Human intrathyroidal iodine in health and non-thyroidal disease. In: New aspects of trace element research (Eds: M. Abdulla, M. Bost, S. Gamon, P. Arnaud, G. Chazot). London: Smith-Gordon; and Tokyo: Nishimura; 1999:114-119.
  11. Zaichick V, Zaichick S. Age-related changes of some trace element contents in intact thyroid of females investigated by energy dispersive X-ray fluorescent analysis. Trends Geriatr Healthc 2017; 1(1): 31-38.https://doi.org/10.36959/452/579
  12. Zaichick V, Zaichick S. Age-related changes of some trace element contents in intact thyroid of males investigated by energy dispersive X-ray fluorescent analysis. MOJ Gerontol Ger 2017; 1(5): 00028.https://doi.org/10.15406/mojgg.2017.01.00028
  13. Zaichick V, Zaichick S. Age-related changes of Br, Ca, Cl, I, K, Mg, Mn, and Na contents in intact thyroid of females investigated by neutron activation analysis. Curr Updates Aging 2017; 1: 5.1.
  14. Zaichick V, Zaichick S. Age-related changes of Br, Ca, Cl, I, K, Mg, Mn, and Na contents in intact thyroid of males investigated by neutron activation analysis. J Aging Age Relat Dis 2017; 1(1): 1002.
  15. Zaichick V, Zaichick S. Age-related changes of Ag, Co, Cr, Fe, Hg, Rb, Sb, Sc, Se, and Zn contents in intact thyroid of females investigated by neutron activation analysis. J Gerontol Geriatr Med 2017; 3: 015.
  16. Zaichick V, Zaichick S. Age-related changes of Ag, Co, Cr, Fe, Hg, Rb, Sb, Sc, Se, and Zn contents in intact thyroid of males investigated by neutron activation analysis. Curr Trends Biomedical Eng Biosci 2017; 4(4): 555644.https://doi.org/10.19080/CTBEB.2017.04.555644
  17. Zaichick V, Zaichick S. Effect of age on chemical element contents in female thyroid investigated by some nuclear analytical methods. MicroMedicine 2018; 6(1): 47-61.
  18. Zaichick V, Zaichick S. Neutron activation and X-ray fluorescent analysis in study of association between age and chemical element contents in thyroid of males. Op Acc J Bio Eng Bio Sci 2018; 2(4): 202-212.https://doi.org/10.32474/OAJBEB.2018.02.000144
  19. Zaichick V, Zaichick S. Variation with age of chemical element contents in females’ thyroids investigated by neutron activation analysis and inductively coupled plasma atomic emission spectrometry. J Biochem Analyt Stud 2018; 3(1): 1-10.https://doi.org/10.16966/2576-5833.114
  20. Zaichick V, Zaichick S. Association between age and twenty chemical element contents in intact thyroid of males. SM Gerontol Geriatr Res 2018; 2(1): 1014.https://doi.org/10.36876/smggr.101f4
  21. Zaichick V, Zaichick S. Associations between age and 50 trace element contents and relationships in intact thyroid of males. Aging Clin Exp Res 2018; 30(9): 1059–1070.https://doi.org/10.1007/s40520-018-0906-0
  22. Zaichick V, Zaichick S. Possible role of inadequate quantities of intra-thyroidal bromine, rubidium and zinc in the etiology of female subclinical hypothyroidism. EC Gynaecology 2018; 7(3): 107-115.
  23. Zaichick V, Zaichick S. Possible role of inadequate quantities of intra-thyroidal bromine, calcium. IntGyn and Women’s Health 2018; 1(3): IGWHC.MS.ID.000113.https://doi.org/10.32474/IGWHC.2018.01.000113
  24. Zaichick V, Zaichick S. Possible role of inadequate quantities of intra-thyroidal cobalt, rubidium and zinc in the etiology of female subclinical hypothyroidism. Womens Health Sci J 2018; 2(1): 000108.
  25. Zaichick V, Zaichick S. Association between female subclinical hypothyroidism and inadequate quantities of some intra-thyroidal chemical elements investigated by X-ray fluorescence and neutron activation analysis. Gynaecol Perinatol 2018; 2(4): 340-355.
  26. Zaichick V, Zaichick S. Investigation of association between the high risk of female subclinical hypothyroidism and inadequate quantities. Clin Res: Gynecol Obstet 2018; 1(1): 1-18.
  27. Zaichick V, Zaichick S. Investigation of association between the high risk of female subclinical hypothyroidism and inadequate quantities of intra-thyroidal trace elements using neutron activation and inductively coupled plasma mass spectrometry. Acta Scientific Medical Sciences 2018; 2(9): 23-37.
  28. Zaichick V, Zaichick S. Determination of fifty trace element contents in macro and micro follicular colloid nodular goiter. American J Biomed Sci Res 2021; 13(6): 639-650.https://doi.org/10.34297/AJBSR.2021.13.001931 
  29. Zaichick V. Determination of fifty trace element contents in normal and goitrous thyroid using a combination of instrumental neutron activation analysis and inductively coupled plasma mass spectrometry. Metallomics Res 2021; 1(#BRTE320105): 1-19.
  30. Zaichick V. Evaluation of fifty trace element contents in thyroid adenomas using a combination of instrumental neutron activation analysis and inductively coupled plasma mass spectrometry. J Cancer Oncol Res 2021; 2(3): 1-11.
  31. Zaichick V, Zaichick S. Instrumental effect on the contamination of biomedical samples in the course of sampling. The J Anal Chem 1996; 51(12): 1200-1205.
  32. Zaichick V, Zaichick S. A search for losses of chemical elements during freeze-drying of biological materials. J Radioanal Nucl Chem 1997; 218(2): 249-253.https://doi.org/10.1007/BF02039345
  33. Zaichick S., Zaichick V. The effect of age on Ag, Co, Cr, Fe, Hg, Sb, Sc, Se, and Zn contents in intact human prostate investigated by neutron activation analysis. App Radiat Isot 2011; 69(6): 827-833.https://doi.org/10.1016/j.apradiso.2011.02.010 
  34. Zaichick V, Zaichick S. Relations of the neutron activation analysis data to morphometric parameters in pediatric and nonhyperplastic young adult prostate glands. Ad Biomed Sci Eng 2014; 1(1):.26-42.https://doi.org/10.1111/j.2047-2927.2012.00005.x
  35. Zaichick V, Zaichick S. Variations in concentration and histological distribution of Ag, Co, Cr, Fe, Hg, Rb, Sb, Sc, Se, and Zn in nonhyperplastic prostate gland throughout adulthood. Jacobs J Cell Mol Biol 2016; 2(1): 1-16.
  36. Zaichick S, Zaichick V, Nosenko S, Moskvina I. Mass fractions of 52 trace elements and zinc trace element content ratios. Biol Trace Elem Res 2012; 149(2): 171-183. https://doi.org/1007/s12011-012-9427-4 
  37. Zaichick V, Zaichick S. The distribution of 54 trace elements including zinc in pediatric and nonhyperplastic young adult prostate gland tissues. J Clin Lab Inv Upd 2014; 2(1): 1-15.https://doi.org/10.14205/2310-9556.2014.02.01.1
  38. Zaichick V, Zaichick S. Age-related changes in concentration and histological distribution of 54 trace elements in nonhyperplastic prostate of adults. Int Arch Urol Complic 2016; 2(2): 019.https://doi.org/10.23937/2469-5742/1510019
  39. Zaichick S, Zaichick V. The effect of age and gender on 37 chemical element contents in scalp hair of healthy humans. Biol Trace Elem Res 2010; 134(1): 41-54.https://doi.org/10.1007/s12011-009-8456-0 
  40. Zaichick V. Applications of synthetic reference materials in the Medical Radiological Research Centre. Fresenius J Anal Chem 1995; 352: 219-223.https://doi.org/10.1007/BF00322330
  41. Korelo AM, Zaichick V. Software to optimize the multielement INAA of medical and environmental samples. In: Activation Analysis in Environment Protection. Dubna, Russia: Joint Institute for Nuclear Research; 1993:326-332.
  42. Lansdown AB. Critical observations on the neurotoxicity of silver.Crit Rev Toxicol 2007; 37(3): 237-250.https://doi.org/10.1080/10408440601177665
  43. De Vos S, Waegeneers N, Verleysen E, Smeets K, Mast J. Physico-chemical characterisation of the fraction of silver (nano)particles in pristine food additive E174 and in E174-containing confectionery. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2020; 37(11): 1831-1846.https://doi.org/10.1080/19440049.2020.1809719. Epub 2020 Sep 18
  44. Hadrup N, Sharma AK, Loeschner K. Toxicity of silver ions, metallic silver, and silver nanoparticle materials after in vivo dermal and mucosal surface exposure: A review. Regul Toxicol Pharmacol 2018; 98: 257-267.https://doi.org/10.1016/j.yrtph.2018.08.007
  45. Lansdown AB. Silver in health care: antimicrobial effects and safety in use. Curr Probl Dermatol 2006; 33: 17-34.https://doi.org/10.1159/000093928 /
  46. Drake PL, Hazelwood KJ. Exposure-related health effects of silver and silver compounds: a review. Ann Occup Hyg 2005; 49(7): 575-585.https://doi.org/10.1093/annhyg/mei019 
  47. Katarzynska-Banasik D, Grzesiak M, Kowalik K, Sechman A. Administration of silver nanoparticles affects ovarian steroidogenesis and may influence thyroid hormone metabolism in hens (Gallus domesticus). Ecotoxicol Environ Saf 2021; 208: 111427.https://doi.org/10.1016/j.ecoenv.2020.111427
  48. Igbokwe IO, Igwenagu E, Igbokwe NA. Aluminiumtoxicosis: a review of toxic actions and effects. Interdiscip Toxicol 2019; 12(2): 45-70.https://doi.org/10.2478/intox-2019-0007
  49. Krewski D, Yokel RA, Nieboer E, et al. Human health risk assessment for aluminium, aluminium oxide, and aluminium hydroxide. J Toxicol Environ Health B Crit Rev 2007; 10(Suppl 1): 1–269.https://doi.org/10.1080/10937400701597766 
  50. Klotz K, Weistenhöfer W, Neff F, Hartwig A, Van Thriel C, Drexler H. The health effects of aluminum exposure. DtschArztebl Int 2017; 114(39): 653–659.https://doi.org/10.3238/arztebl.2017.0653 
  51. Hashimoto Y, Sekine Y, Otoshi T. Atmospheric aluminum from human activities. Atmospheric Environment. Part B. Urban Atmosphere 1992; 26(3): 295-300.https://doi.org/10.1016/0957-1272(92)90005-D
  52. Orihuela D. Aluminium effects on thyroid gland function: iodide uptake, hormone biosynthesis and secretion. J Inorg Biochem 2011; 105(11): 1464-1468.https://doi.org/10.1016/j.jinorgbio.2011.08.004
  53. Benvenga S, Elia G, Ragusa F, et al. Endocrine disruptors and thyroid autoimmunity. Best Pract Res Clin Endocrinol Metab 2020; 34(1): 101377.https://doi.org/10.1016/j.beem.2020.101377 
  54. Linos A, Petralias A, Christophi CA, Christoforidou E, Kouroutou P, et al. Oral ingestion of hexavalent chromium through drinking water and cancer mortality in an industrial area of Greece. Environ Health 2011; 10:50.
  55. Järup L. Hazards of heavy metal contamination. Br Med Bull2003; 68: 167-182.https://doi.org/1093/bmb/ldg032 
  56. Nigam A, Priya S, Bajpai P, Kumar S. Cytogenomics of hexavalent chromium (Cr 6+) exposed cells: a comprehensive review. Indian J Med Res 2014; 139(3): 349-370. PMID: 24820829
  57. Zhitkovich A. Chromium in drinking water: sources, metabolism, and cancer risks. Chem Res Toxicol 2011; 24(10): 1617-1629. https://doi.org/1021/tx200251t 
  58. Ding SZ, Yang YX, Li XL, et al. Epithelial-mesenchymal transition during oncogenic transformation induced by hexavalent chromium. Toxicol Appl Pharmacol 2013; 269(1): 61-71.https://doi.org/1016/j.taap.2013.03.006 
  59. Liu M, Song J, Jiang Y, et al. A case-control study on the association of mineral elements exposure and thyroid tumor and goiter. Ecotoxicol Environ Saf 2021; 208: 111615.https://doi.org/1016/j.ecoenv.2020.111615 
  60. Kim S-A, Kwon YM, Kim S, Joung H. Assessment of dietary mercury intake and blood mercury levels in the Korean population: Survey 2012–2014. Int J Environ Res Public Health 2016; 13(9):877.
  61. Clarkson TW, Magos L. The toxicology of mercury and its chemical compounds. Crit Rev Toxicol2006; 36: 609-662. https://doi.org/1080/10408440600845619 
  62. Correia MM, Chammas MC, Zavariz JD, et al. Evaluation of the effects of chronic occupational exposure to metallic mercury on the thyroid parenchyma and hormonal function. Int Arch Occup Environ Health 2020; 93(4): 491-502. https://doi.org/1007/s00420-019-01499-0 
  63. Hu O, Han X, Dong G, et al. Association between mercury exposure and thyroid hormones levels: A meta-analysis. Environ Res 2021; 196: 110928.https://doi.org/10.1016/j.envres.2021.110928 
  64. Malandrino P, Russo M, Ronchi A, et al. Increased thyroid cancer incidence in a basaltic volcanic area. Endocrine 2016; 53(2): 471-479.https://doi.org/10.1007/s12020-015-0761-0
  65. Ou C-Y, He Y-H,Sun Y, Yang L, Shi W-X, Li S-J. Effects of sub-acute manganese exposure on thyroid hormone and glutamine (Gln)/glutamate (Glu)-γ- aminobutyric acid (GABA) cycle in serum of rats. Int J Env Res Pub Health 2019; 16(12): 2157.https://doi.org/3390/ijerph16122157
  66. Raskosha OV, Ermakova OV. The peculiarities of separate and combined exposure to low dose-rate gamma-radiation and 232Th nitrate on thyroid gland. Radiats Biol Radioecol 2005; 45(6): 744-750. PMID: 16454345
  67. Abdel-Rahman M, Rezk MM, Moneim AEA, Omar A Ahmed-Farid OA, Essam S. Thorium exerts hazardous effects on some neurotransmitters and thyroid hormones in adult male rats. Naunyn Schmiede bergs Arch Pharmacol 2020; 393(2): 167-176.https://doi.org/10.1007/s00210-019-01718-y 
  68. Rubel LR, Ishak KG. Thorotrast-associated cholangiocarcinoma: an epidemiologic and clinicopatho-logic study. Cancer 1982; 50(7): 1408-1415.
  69. Roohani N, Hurrell R, Kelishadi R, Schulin R. Zinc and its importance for human health: An integrative review. J Res Med Sci 2013; 18: 144–157. PMID: 23914218
  70. To PK, Do MH, Cho J-H, Jung C. Growth modulatory role of zinc in prostate cancer and application to cancer therapeutics. Int J Mol Sci2020; 21(8): 2991. https://doi.org/10.3390/ijms21082991
  71. Barber RG, Grenier ZA, Burkhead JL. Copper toxicity is not just oxidative damage: zinc systems/biomedicines9030316 
  72. Zaichick V., Zaichick S. Wynchank S. Intracellular zinc excess as one of the main factors in the etiology of prostate cancer. J Anal Oncol 2016; 5(3): 124-131.https://doi.org/10.6000/1927-7229.2016.05.03.5
  73. Alam S, Kelleher SL. Cellular mechanisms of zinc dysregulation: a perspective on zinc homeostasis as an etiological factor in the development and progression of breast cancer. Nutrients 2012; 4(8):875-903.https://doi.org/10.3390/nu4080875/
  74. Blazewicz A, Wisniewska P, Skórzynska-Dziduszko K. Selected essential and toxic chemical elements in hypothyroidism-A literature review (2001-2021). Int J Mol Sci 2021; 22(18): 10147.https://doi.org/doi: 10.3390/ijms221810147
  75. Leko MB, Gunjaca I, Pleic N, Zemunik T. Environmental factors affecting thyroid-stimulating hormone and thyroid hormone levels. Int J Mol Sci 2021; 22(12): 6521.https://doi.org/10.3390/ijms22126521
  76. Jouybari L, Kiani F, Akbari A, et al. A meta-analysis of zinc levels in breast cancer. J Trace Elem Med Biol2019; 56: 90-99. https://doi.org/1016/j.jtemb.2019.06.017 
  77. Zaichick V, Tsyb A, Matveenko E, Chernichenko I. Instrumental neutron activation analysis of essential and toxic elements in the child and adolescent diets in the Chernobyl disaster territories of the Kaluga Region. Sci Total Environ 1996; 192:269–274.https://doi.org/10.1016/s0048-9697(96)05321-1