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TIN

The following study shows that the greatest concentration of tin in the body is in the thymus gland.  Since the thymus is a key immune system gland, my suspicion is that tin may somehow be involved in autoimmune diseases such as thyroid diseases.

J Anal Toxicol 1986 Jan-Feb;10(1):6-9

Tin concentration in the thymus glands of rats and mice and its relation to the involution of the gland.

Sherman LR, Masters J, Peterson R, Levine S

Tin is an ubiquitous element and thus enters mammals through the food chain. It has never been found to be dysfunctional in either plants or animal tissue and has been regarded as an innocuous background material. Of the many organs and glands that have been analyzed for tin, only the thymus gland exhibits an above average value for tin. A complete study on the tin content in the thymus gland has never been published and this work is an attempt to investigate this subject. Three types of rodents were used in this study; inbred Lewis rats, inbred A/KI mice (a breast cancer prone mouse) and outbred COBS mice (a cancer resistant mouse). The tin analysis of the muscle, spleen, and thymus indicated constant values for the muscle and spleen tissue, but an increase in the thymic tin concentration (ppm) with age. Besides normal aging studies, the animals were administered the disodium salt of dexamethasone-21-phosphate (dexa), which causes rapid loss of lymphocytes from the spleen and thymus but has no effect upon the muscle. Tin concentration in the muscles remained constant, showed a loss from the spleen and an increase in the thymus gland. The increase indicates that the tin was probably located in the medulla of the thymus, which may be the active biochemical site for tin in rodents. When compared to the COBS mice, the A/KI mice showed a non-statistical difference in tin content in the muscle and spleen and statistically significant lower tin content in the thymus gland.

The following study suggests that tin toxicity can result in psychiatric abnormalities such as psychosis.

 

G Ital Med Lav Ergon 2000 Jan-Mar;22(1):52-61; discussion 62-3

[Occupational poisoning with psychiatric manifestations].

[Article in Italian]

Candura SM, Butera R, Gandini C, Locatelli C, Tagliani M, Fasola D, Manzo L

Dipartimento di Medicina Preventiva, Universita degli Studi di Pavia.

Numerous occupational intoxications (acute, chronic and their sequelae) may affect the central nervous system and result in a wide variety of neuropsychiatric effects, ranging from subtle behavioural disturbances to overt psychosis. Chemicals causing such manifestations include many metals and organometals (Hg, Mn, Pb, Al, Sn), pesticides (organophosphates), compounds utilised in the industrial setting as solvents or intermediates (carbon disulfide, hydrocarbons and their halogenated derivatives), and combustion products (carbon monoxide). Some types of toxic insults may not be reflected in any clinical manifestation. However, this type of damage may render the brain more vulnerable to additional insult or accelerate physiological loss of neurones with ageing. Thus, occupational exposures to chemicals (Al, Pb, organic solvents) might be involved in the causation of neurodegenerative diseases--such as Alzheimer's disease--which are usually labelled as "idiopathic". A careful occupational anamnesis is crucial to diagnose work-related psychiatric manifestations and--consequently--to interrupt the toxic exposure, to start therapy, and to promote insurance compensation.

 

Sangyo Eiseigaku Zasshi 1997 Jan;39(1):1-20

t

[Biological activity of tin and immunity].

[Article in Japanese]

Arakawa Y

Department of Hygiene and Preventive Medicine, Faculty of Health Sciences, University of Shizuoka, Japan.

Tin generates a wide variety of biological activities deriving from its chemical character. In this article, the biological activities of tin compounds are reviewed with a focus on the connection with immunity. The table of contents is as follows: Introduction, 1. Inorganic Tin and Immunity, 2. Organic Tin and Immunity, 2.1. Immunotoxicity, 2.1.1. Immunosuppression, 2.1.2. Thymus atrophy, 2.1.3. Changes in the membrane surface antigens of T cells, 2.2. Antitumor activity, 2.3. Anti-inflammatory action, 2.4. Tolerance manifestation of thymus atrophy, 3. Cellular and Biochemical Aspects of the Activity Manifestation, 3.1. Intracellular distribution of organotins 3.2. Effects on structure and function of Golgi apparatus and endoplasmic reticulum, 3.3. Effects on physical properties of phospholipid membrane, 3.4. Suppressive effects on cell proliferation system, 3.5. Consideration, Conclusion. To sum up this article, tin compounds (especially organotin compounds) act mainly on cellular immune systems and the mechanism appears to be due to their hydrophobicity-dependent intracellular distribution and their action on the phospholipid metabolism including the inhibition of intracellular phospholipid transport between organelles through an impairment of the structure and functions of the Golgi apparatus and the endoplasmic reticulum (ER), and the consequent inhibition of the membrane-mediated signal transduction system leading to DNA synthesis via phospholipid turnover and Ca2+ mobilization.

The following study suggests that a tin deficiency might be involved in dental problems.

 

Int Dent J 1994 Feb;44(1 Suppl 1):107-18

The effect of stannous fluoride on dentinal hypersensitivity.

Thrash WJ, Dodds MW, Jones DL

Department of Community Dentistry, University of Texas Health Science Center at San Antonio 78284-7917.

Many agents have shown varying degrees of effectiveness on pain resulting from exposed dentine. One which has shown some promising results is stannous fluoride (SnF2). The purpose of the following paper is twofold: to review and summarise the clinical literature pertaining to the relative effectiveness of solutions or gels containing SnF2 in controlling pain associated with dentinal hypersensitivity; and to statistically re-evaluate these studies in combination, in order to develop recommendations for the optimal use of SnF2 for hypersensitivity. Seven blinded clinical studies were identified and reviewed. Five of these compared 0.4 per cent SnF2 gel solution to an identical placebo. One compared a 0.4 per cent SnF2 gel solution and a 0.717 per cent F solution to an aqueous placebo. The final study compared a 0.717 per cent F solution to an aqueous placebo. Statistical power analysis and a combined meta-analysis were used to ensure adequate internal consistency and to contribute to an overall consensus of the efficacy across time. It was concluded that the 0.717 per cent F solution provides a virtually immediate and definable effect, which seems to continue for several months. This effect was present in all subjects used in the study. This solution was applied directly to the sensitive area for one minute and allowed to remain for 3-5 minutes. An additional one minute application was applied if needed. The effect of the 0.4 per cent SnF2 gel appears to be more gradual, perhaps involving a different mechanism of action. This solution requires approximately two to four weeks of continuous treatment to be effective. It was concluded that an effective strategy involving the use of stannous fluoride gel includes the application of the 0.717 per cent F solution in the office, effectively providing immediate relief. The patient would then use the 0.4 per cent SnF2 gel at home in order to achieve the long-term effect. In order to control episodic pain while the gel is developing its effect, a small amount of the 0.717 per cent F solution could be given to the patient for occasional symptomatic application.

 

J Toxicol Sci 1990 Dec;15 Suppl 4:125-51

The neurotoxicology and pathology of organomercury, organolead, and organotin.

Chang LW

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock 72205.

The toxicities of many metals, such as mercury and lead, are known to man since the dawn of civilization. Organic compounds of some heavy metals are known to have a particular toxic impact on the central nervous system. Organomercury, particularly alkyl-mercuric compounds (e.g. methylmercury), has a selective effect on the granule cells of the cerebellum, the nerve cells of the calcarine cortex, and the sensory neurons in the dorsal root ganglia. The well known Minamata Bay disease is the result of a massive epidemic episode of human exposure to alkylmercury contaminated food sources. Mental retardation and other developmental defects are also known to be a consequence of exposure to this toxic metal. Organic lead compounds have been employed as gasoline additives and in other industrial purposes. Unlike its inorganic counterpart, organolead compounds have a more prominent impact on the central nervous system. Pathological changes of the brain stem neurons have been described. Organotin compounds have been used in plastic industries and as agricultural chemicals. Both trimethyl and triethyl tin compounds are found to be extremely neurotoxic. Despite the similarity of their chemical structures, trimethyl and triethyl tins have a diversely different toxic property and effects. While triethyl tin is myelinotoxic, producing edematous and vacuolar changes in the central myelin, trimethyl tin is neurotoxic, producing prominent toxic changes in the neurons of the limbic system (hippocampus, entorhinal cortex, etc.). The factors which determine the specificity and selectivity of the neurotoxic impacts by various organometals are still unknown. In view that most of the organometals are still widely employed by many countries for industrial and for agricultural purposes, caution must be made for their proper handling and disposure to avoid undesirable exposures to workers and environmental contamination of water sources and food-chain for the common public. Since organometals are difficult to eliminate from the central nervous system, injuries usually lead to permanent neurological deficits, such tragedies are frequently long lasting and create not only a medical problem, but also a social economical problem for the society.

 

Thymus 1990 Jun;15(4):223-31

Tin and the thymus gland: a review.

Cardarelli N

Engineering and Science Technology Division, University of Akron, OH 44325.

Experimental studies over the last decade have suggested an association between thymus immune and homeostatic function and exogenous tin. It has been hypothesized that the thymus gland synthesizes and secretes one or more tin bearing factors that enhance immune defenses against malignancy and retard the gradual loss of immune capacity with senescence. This review conciliates data from several divergent areas of research in order to explore the rationale for the above concepts.

 

Thymus 1988-89;12(2):131-4

Tin in the thymus gland of dogs.

Sherman LR, Cardarelli NF

Department of Chemistry, University of Akron, OH 44325-0001.

The thymus glands from four mixed breed dogs were analyzed to determine the water content, chloroform extractable fraction and residue. The thymi samples were assayed for tin and compared to the tin in the spleen and muscle tissue. The tin content in the thymus gland (29.4 ppm) was higher than the muscle (14.9 ppm) or spleen (12.8 ppm). The tin content in the lipid portion of the thymus was approximately four times greater than the non-chloroform extractable fraction (primarily protein).

 

Int J Rad Appl Instrum B 1992 Apr;19(3):297-301

m-[125I]iodoaniline: a useful reagent for radiolabeling biotin.

Khawli LA, Kassis AI

Department of Radiology (Nuclear Medicine), Harvard Medical School, Shields Warren Radiation Laboratory, Boston, MA 02115.

Biotinyl-m-[125I]iodoanilide (BIA) was synthesized by coupling biotin to m-[125I]iodoaniline via a mixed anhydride reaction. m-[125I]Iodoaniline was produced from the tin precursor, which was prepared using a palladium catalyzed reaction of hexabutylditin with m-bromoaniline. The radioiodinated BIA derivative is characterized by a stable amide and/or intact ureido group on the biotin molecule; it may thus be a useful carrier for targeting radionuclides to avidin-conjugated antibodies previously localized on tumors.

 

Pharmacology 1996 Mar;52(3):178-86

Effects of a series of metalloporphyrins on adrenal, testicular and thyroid function in rats.

Drummond GS, Smith TJ, Kappas A

Rockefeller University Hospital, New York 10021, USA.

We have extended our earlier studies [Pharmacology 1986;34:9-16] on the effects of certain synthetic heme analogues and cobalt chloride (CoCl2) on endocrine functions mediated by the hypothalamic-pituitary axis to examine specifically the ability of Sn-protoporphyrin (SnPP) and Sn-mesoporphyrin (SnMP) to perturb adrenal, testicular and thyroid function since there is interest in the use of Sn(tin)-porphyrins in the treatment of hyperbilirubinemia of the newborn. SnPP and SnMP when administered to adult male rats did not alter serum corticosterone, testosterone, thyroxine or triiodothyronine levels when compared to control animals. In addition, administration of exogenous adrenocorticotrophic hormone produced an increase in serum corticosterone levels that was comparable in placebo-treated and SnPP- and SnMP-treated animals. These studies involved doses of both compounds substantially greater than those used clinically. The results clearly indicate that SnMP, presently the compound of choice for use in newborns, and SnPP do not in the doses studied impair adrenal, testicular and thyroid function in vivo.

 

Food Chem Toxicol 1990 Mar;28(3):179-96

Chronic toxicity and carcinogenicity of bis(tri-n-butyltin)oxide (TBTO) in the rat.

Wester PW, Krajnc EI, van Leeuwen FX, Loeber JG, van der Heijden CA, Vaessen HA, Helleman PW

National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.

In a 106-wk toxicity and carcinogenicity study, groups of 60 male and 60 female weanling Wistar rats were fed 0, 0.5, or 50 mg bis(tri-n-butyltin)oxide (TBTO)/kg diet. In males, feed consumption was increased in all treated groups and increased water consumption occurred at 5 and 50 mg/kg. During the second year, body weight decreased in the 50-mg/kg males, while the females in that group showed no weight gain. Excess mortality was confined to the 50-mg/kg group towards the end of the study. Haematological changes, comprising anaemia, lymphocytopenia and thrombocytosis were noted mainly at the high-dose level. Also, signs of decreased kidney function and increased plasma enzyme activities (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) were noted. No effects on serum hormone concentrations (thyrotropin, follicle stimulating hormone, luteinizing hormone or insulin) were observed, except for a decrease in the free thyroxin:thyroxin ratio in both sexes at the high-dose level. Higher serum IgM and IgA levels were present at 50 mg/kg, while, in females, IgG was decreased. At 50 mg/kg, the ovaries, adrenals, spleen (females), heart (males), pituitary, liver and kidneys were increased in weight, but the thyroid weight was decreased in females. The total tin concentrations in liver and kidneys showed a dose relationship and, in general, the concentrations were similar after 1 and 2 yr. Non-neoplastic histological alterations after 1 yr consisted of a decrease in the cell height of the thyroid follicles in all dose groups, with a reduced number of psammoma bodies at 50 mg/kg, a decrease in splenic iron content at 5 (females only) and 50 mg/kg, and a slight bile-duct activation. After 2 yr, only the thyroid changes were still present. In addition, at 2 yr, vacuolation and pigmentation of the proximal tubular epithelium and nephrosis were enhanced at 50 mg/kg. The incidence of benign tumours of the pituitary was significantly elevated and enhanced at 0.5 and 50 mg/kg. At 50 mg/kg increases in pheochromocytomas in the adrenal medulla and in parathyroid adenomas (males) were noted, while adrenal cortical tumours were decreased (males). There was a low, non-dose-related incidence of pancreatic carcinoma. Other tumour rates were in line with control data. It is concluded that lifetime feeding of 50 mg TBTO/kg diet induces toxicity in various organ systems. An increase in some common tumours was found at the high dose, probably due to hormonal or immunological changes.

 

Radiology 1977 Aug;124(2):445-50

The effect of tin on the tissue distribution of 99mTc-sodium pertechnetate.

Ancri D, Lonchampt MF, Basset JY

When tin complex is administered prior to the injection of 99mTc-sodium pertechnetate, the distribution of the tracer is altered such that: (a) the concentration at foci of cerebral pathology is drastically reduced; (b) the concentration in the stomach (mucus cells), thyroid and salivary glands, and choroid plexus is greatly increased; and (c) there is a shift of the tracer from the plasma to the red blood cells. Bone studies utilizing a tin complex should be done after other organs have been evaluated.

 

:Arch Toxicol 1981 Jul;47(4):263-8

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Distribution of tin in the rat and disturbances in the metabolism of zinc and copper due to repeated exposure to SnCl2.

Chmielnicka J, Szymanska JA, Sniec J

The effect of stannous chloride on tissue concentrations of zinc and copper was studied in female rats. The animals were subjected to repeated exposure to seven doses given every other day 2 mg Sn/kg, subcutaneously. About 60% of tin 113Sn was retained in the body. Of this amount, about 95% accumulated in the skin and hair. In the remaining organs the tin concentrations corresponded to 2.57 to 0.0001% of the retained dose. In comparison with the control group a 3-fold increase of the content of zinc was found in the liver while a decrease were revealed in the spleen, heart, brain, lungs, and especially in muscle. A statistically significant decrease of the copper content was found in the blood and brain.

The following study indicates a connection between tin and lithium.

 

Org Lett 2000 Jun 1;2(11):1561-4

Synthesis and reactivity of conformationally locked alpha-aminoorganostannanes and alpha-aminoorganolithiums. Discovery Of a surprising configurational requirement for transmetalation.

Chambournier G, Gawley RE

Department of Chemistry, University of Miami, P.O. Box 249118, Coral Gables, Florida 33124, USA.

[Medline record in process]

2-Tributylstannyl-N-methylpiperidines that are conformationally locked by a 4-tert-butyl substituent were evaluated in transmetalations (Sn-Li exchange) and reactions with electrophiles. When the tin is equatorial, transmetalation occurs smoothly as does reaction with carbonyl electrophiles. Alkyl halides seem to undergo single electron transfer reactions, affording nonselective alkylation products, along with products of radical disproportionation. In a surprise, an axially oriented tin failed to transmetalate, suggesting that a synclinal relationship between the nitrogen lone pair and the carbon-tin bond is a requirement for transmetalation.

 

J Immunol 1989 Dec 15;143(12):3981-7

Immune stimulatory properties of metalloporphyrins.

Novogrodsky A, Suthanthiran M, Stenzel KH

Rogosin Institute, Cornell University Medical College, New York 10021.

A possible approach to the immunotherapy of tumors is to stimulate either specific or nonspecific immune responses in vivo. We recently found that provision of a mitogenic signal to PBMC, by incubation with the oxidizing mitogens, enhanced the effect of IL-2 in generating cytolytic activity. We therefore searched for a mitogen that might safely be administered to patients. The present study is an investigation of the mitogenic properties of iron and tin (Sn)-protoporphyrin and their capacity to induce cytotoxicity in human PBMC. These agents have been administered to humans with little toxicity. Both iron- (hemin) and Sn-protoporphyrin induce mitogenicity in peripheral T cells. This effect is markedly enhanced by low concentrations of IL-2. Hemin and Sn-protoporphyrin, in combination with IL-2, increase IL-2R on PBMC. Hemin alone, and to a greater extent in combination with IL-2, induces cytotoxicity for NK-sensitive and NK-resistant cell lines. Sn-protoporphyrin, a more potent mitogen than hemin, fails to induce cytotoxicity, and has a marked inhibitory effect on cytotoxicity induced by IL-2. Hemin and Sn-protoporphyrin stimulate TNF-alpha and IFN-gamma production by PBMC. IL-2 is synergistic with the metalloporphyrins in eliciting this effect. Metalloporphyrin-induced mitogenesis has a stringent requirement for macrophages. Scavengers of oxygen-free radicals and inhibitors of peroxidase inhibit mitogenicity induced by hemin but not that induced by Sn-protoporphyrin. Hence, an oxidative event may mediate the mitogenic effect of hemin. Our results indicate that hemin is an immunostimulatory agent in vitro and the data warrant further evaluation of its in vivo immunostimulatory and antitumor effect.

 

Aust J Exp Biol Med Sci 1984 Apr;62 ( Pt 2):199-208

Organotin implications in anticarcinogenesis. Background and thymus involvement.

Cardarelli NF, Quitter BM, Allen A, Dobbins E, Libby EP, Hager P, Sherman LR

A comprehensive study of the scientific literature regarding tin content in normal and pathogenic human tissue has disclosed that various organotin materials retard both the onset and growth of cancer in laboratory animals, and decreased tissue tin in humans may be associated with tumour development. Initial studies by the authors have shown that the thymus gland of the mouse possesses a relatively high concentration of tin and is also the major site of accumulation for 14C-labelled tri-n-butyltin fluoride (TBTF). When mammary cancer-prone mice with transplanted tumours were orally dosed continuously with this agent in their drinking water, the tumour growth rate was significantly reduced. Both mouse mammary tumours and human lung tumours show low tin content compared to normal body tissue.

The following study seems to suggest that tin (in combination with vinyl) can facilitate the synthesis of estradiol.  Since there is some evidence that food from tin cans might be a facilitator of hyperthyroidism, at least in cats, there might be some connection between tin from cans, and an increase in estradiol (which seems to increase cadmium uptake). Also there is mention of selenium-estradiol compounds, which I'd like to investigate further.

 

Steroids 1996 Jun;61(6):384-9

Synthesis and estrogen receptor binding of (17 alpha, 20E)- and (17 alpha, 20Z)-21-phenylthio- and 21-phenylseleno-19-norpregna-1,3,5(10),20-tetraene-3,17 beta-diols.

Napolitano E, Fiaschi R, Herman LW, Hanson RN

Department of Pharmaceutical Sciences, Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston, Massachusetts 02115, USA.

Previous studies from our laboratory using 17 alpha-E- and 17 alpha-Z-halovinyl estradiols demonstrated a marked enhancement of receptor binding by the Z-isomers. This suggested tolerance at the 17 alpha-position was not previously observed by investigations using 16 alpha and 17 alpha-substituted estradiols. Because of the synthetic access provided by vinyl tin chemistry, we prepared the 17 alpha-E and Z-phenylthiovinyl and phenylselenovinyl estradiols and compared their binding characteristics to those of the previously reported 16 alpha/17 alpha-phenylseleno and methylseleno estradiols. The results, in addition to demonstrating a facile preparation of the target compounds, indicated that significant receptor affinity was retained by these compounds (relative binding affinity = 24.5-117). The highest affinity was demonstrated by the 17 alpha-Z-phenylthiovinyl estradiol 5a, which, by molecular modeling, exhibited a significantly different molecular conformation from the corresponding 17 alpha-E-phenylthiovinyl isomer or the 17 alpha-phenyl-thioethynyl analog. The current series possessed better binding characteristics than the phenylseleno and methylseleno estradiols but somewhat poorer binding than the 17 alpha-E/Z-halovinyl series. The observations suggest that some steric limitations exist in a portion of the 17 alpha-region, and that the region is better accessed by compounds possessing Z-vinyl stereochemistry.

 

J Steroid Biochem Mol Biol 1993 Nov;46(5):613-22

Synthesis, receptor binding and biodistribution of the gem-21-chloro-21-iodovinylestradiol derivatives.

Ali H, Rousseau J, van Lier JE

MRC Group in the Radiation Sciences, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.

Radioiodinated 11 beta-methoxy-(17 alpha,20E)iodovinylestradiol (11 beta-OMe-IVE2) shows high estrogen receptor (ER)-mediated uterus uptake and good potential as an ER-imaging agent. In order to examine the tolerance of the ER for modification about the iodovinyl substituent, we prepared the (17 alpha,20Z-chloro)21-chloro-21-iodovinylestradiol (4a) and several derivatives featuring 11 beta-methoxy (4b), 11 beta-ethoxy (4c) or 7 alpha-methyl (4d) substituents. All gem-dihalogen derivatives 4a-d were prepared from the 17 alpha-chloroethynyl precursors. The intermediate chlorostannylvinyl derivatives were obtained using tri-n-butyltin hydride and palladium acetate catalyst. Compounds 4a and 4b were labeled with 125I via their corresponding tin intermediates and their tissue distribution was studied in immature female rats. Addition of a 21-Cl to the 17 alpha-ethynylestradiols reduced ER binding affinity, except for the 11 beta-substituted analogs which showed a pronounced increase. Surprisingly, addition of a 21-Cl to the (17 alpha,20E)IVE2 resulted in increased ER binding affinities and augmented ER-mediated uterus uptake, which may result from the pronounced increase in the dipole moment of the molecule. Thus, further modifications at the C-21 position of IVE2 are well tolerated by the ER. However, addition of the 21-Cl also resulted in increased radioiodine uptake by the thyroid, much slower blood clearance and lower uterus to blood/nontarget ratios, suggesting increased in vivo instability of the C--I bond of the gem-chlorine-iodine atoms which may reflect the increase in steric and electronic interference.