From brou@istar.ca Thu Apr 20 09:13:15 2000 Date: Wed, 19 Apr 2000 01:26:26 -0800 To: All participants of the "International Workshop on Endocrine Disruptors and Pharmaceutically Active Chemicals in Drinking Water": AWWA Research Foundation The University of Iowa Center for Health Effects of Environmental Contamination Water Environment Research Foundation Water Reuse Foundation April 17, 2000 Re: Conference: April 19-21, 2000 in Chicago, Illinois. Dear participants, We just received notification that a workshop is scheduled for this week concerning "Endocrine Disruptors and Pharmaceutically Active Chemicals in Drinking Water". While we realize that this mail might not reach you in time to affect discussion subjects, we hope that perhaps this letter could be distributed among all participants. Our concern has to do with addition of fluorides into the public water supply, a measure which has been undertaken for over 50 years and presumed to be of benefit in caries reduction. As we have conducted extensive research into the effects of fluoride on the endocrine system, we would like to inform you of some of the most important findings and hereby hope that this will lead to re-assessment of the toxicity of fluoride. We will briefly address 5 major concerns: 1) G Proteins 2) Thyroid Cancer 3) Anti-thyroid Effects/Brief History 4) Fluorosilicic Acid 5) Fluoride and Zinc Deficiency 1) G PROTEINS In 1994 the Nobel Prize in Physiology or Medicine was given to Alfred G. Gilman and Martin Rodbell for the discovery of G (guanine nucleotide-binding) proteins and their role in cellular signal transduction. The G protein design explains how such extracellular "first messengers" as hormones generate intracellular "second messengers", such as cyclic adenosine monophosphate (cAMP). In thyroid pathology all thyroid hormone synthesis, thyroid growth, etc. is mediated by thyrotropin, the thyroid-stimulating-hormone (TSH), through G protein activation. TSH is considered the "natural" general G protein activator in thyroid pathology (Laugwitz et al, 1996). Normally, the binding of TSH to its receptor activates G protein, which stimulates the effector systems and then quickly becomes inactive. The end result of this signal-transduction process in the thyroid gland is stimulation of thyroid hormone synthesis and thyroid growth. Without TSH, G proteins are _inactive_.(Utiger, 1995; Totsuka et al,1982). Due to its extensive use in laboratory experiments over the last two decades, specifically to bypass normal receptor-dependent mechanisms, fluorides have also become known as the "universal" G protein activator. Of particular importance here is the fact that aluminum fluoride compounds form greatly potentiate fluoride toxicity, thereby greatly reducing here-to-known toxicity threshold levels. Such compounds can form in food, drinking water and in the organism. Mere micromolar amounts of aluminum are required to greatly potentiate fluoride toxicity. One of the two current models explaining the molecular mechanism of fluoride effects on bone is centered around the formation of fluoroaluminate (AlF4-) in the system (Susa 1999). Of course aluminum is also used in water treatment. The great toxic potential and pharmacological effects of fluoroaluminate has been reviewed in great detail (Strunecka & Patocka, 1999) . In laboratory experiments TSH and fluoride are directly additive (Delemer B,1991; de Menidoza & Farias, 1978; Orgiazzi et al, 1976). The TSH regulation of thyroid hormone synthesis is achieved through G Protein activation of cAMP. There are more than 2000 references on MEDLINE clearly documenting fluoride's abilities to activate cAMP (see links below). Incidentally, cAMP levels have been chosen to be an indicator in blood chemistry relating to different states of chronic fluorosis (Guan, 1991). [Fluoride can also mimick the action of thyrotropin-releasing-hormone (TRH) which acts as neuromodulator and/or neurotransmitter in the central nervous system (CNS) (Martin et al. 1986; Raspe et al, 1986; Gautwig et al, 1983)] 2) Thyroid Cancer Patients with constitutively active adenylyl cyclase have hyperactive tumors. It has been established that mere cAMP elevation is enough to stimulate thyroid growth as well as thyroid cancer growth (Shaver et al, 1993; Orgiazzi et al, 1976; Ledent et al, 1991; Zielke et al, 1999). Such tumours are found elevated in fluoridated areas, and can be clearly seen in the actual data of the NTP carcinogenenis study on sodium fluoride. A study by Studer et al (1992), aimed at dissecting the cellular mechanisms that underly the growth of actively expanding human goiter nodules, inspected thirty-two nodules from different patients, all removed because of steady recent growth. The study found that ALL goiter nodules contained areas where the epithelial cells were morphologically grossly altered and heavily loaded with p21ras. Actively replicating cells were scattered in tiny foci all over the nodules. Regionally heterogeneous p21ras content in morphologically identical cells suggests growth occurring in "bursts and waves." According to May (1951) all blood in the system passes through the thyroid 16 times in 24 hours, approximately 4 to 5 times more than the kidney. It is therefore very likely that either passing fluoride compounds may be responsible for the "waves" of p21ras activation, or a concentrated compound. (The nature of the fluoride compound accumulating in the thyroid gland has never been investigated. AlF4- has been used to activate ras mutants and p21ras in the laboratory (Coleman et al, 1994; Kleuss et al, 1994; Xu et al, 1997). Fluorides act directly like TSH in stimulating the growth of cold nodules. 3) Anti-thyroid Effects/Brief History Fluorides were used in Germany, Austria, Argentina and Switzerland for over 30 years extensively as medication to treat hyperthyroidism. In 1932 Wilhelm May first reported on his findings using sodium fluoride in the treatment of hyperthyroidism. May had been largely inspired by the work of Goldemberg who was based in Buenos Aires and had published extensively between 1919 and 1930 on his findings of applying fluorides as anti-thyroid medication. Goldemberg firmly believed that the occurrence of goiter and cretinism was NOT due to iodine deficiency, but to excessive fluoride intake from air, food and water. Investigating areas then commonly referred to as "goiterous waters" ('Kropfwaesser') and reviewing the work by Repin, Gautier, Clausmann, McCarrison, Parhou and Goldstein, Pighini, Cristiani, Cahages, Houssay, Tappeiner, Schulz, Brandt and Pisotti, Goldemberg became convinced of a fluorine-iodine antagonism and thus began using fluorides in the successful treatment of hyperthyroidism. As a result of Goldemberg's findings, May likewise began with fluoride therapy in preliminary trials involving 39 patients in Germany, publishing the results in 1932. By 1935 he had observed the antagonism successfully in 800 more patients. Like Goldemberg, von Mundy, and Todd, May found that the fluoride-iodine antagonism was most easily observable through fluoride's action on glycolysis in the liver. [Glucose is required to convert thyroxine (T4) to the biologically active triiodothyronine (T3). This occurs mainly in the liver, if glucose is adequate]. According to Dresel and Goldner glycolysis in the liver was to be seen as the FIRST sign of thyroid hormone activity. Abelin had shown that priority in the treatment of hyperthyroidism had to be given to improving the disturbed liver function. It is now well known that the thyroid gland only produces 20% of active T3 and that remaining synthesis occurs in peripheral tissue, mainly the liver. Later Stuber and Land reported their findings that glycolysis was inhibited directly correlating with increasing fluoride levels in the blood (May 1937). Of course it is now well established that fluoride inhibit enolase in a direct dose-responsive relationship. (Berry et al, 1988; US PHS, 1991) Other studies revealed that impaired glucose tolerance was demonstrated in 10 of 25 (40%) patients with endemic fluorosis (Trivedi et al, 1993) It is adenosine triphosphate (ATP) which regulates T4 uptake into the liver. Bobek and Kahl showed clear impaired hormone transport in mice at 1ppm (1975). Because it was known that fluorides accumulated in the system, and eventually would cause the opposite condition - hypothyroidism, May was driven to find alternative compounds after it became known that all organic fluoride compounds maintained not only their character as an anti-thyroid, but could greatly enhance such activity. (Schoeller and Gehrke, 1929; May 1937). In 1937 Dr. Georg Litzka reported on the use of 3-fluorotyrosine in the treatment of hyperthyroidism. When tyrosine was bound to fluorine, the action of fluorine were not only sustained, but greatly magnified and a mere 0.1mg/day F- had therapeutic effects on humans (May, 1937). For May, 3-fluorotyrosine became the treatment of choice in hyperthyroidism. The product was released on the open market as "Pardinon". Within 6 to 8 weeks patients became symptom-free, and employment-ready. Between Jan.1, 1935 and October 1936, May further cured 501 patients successfully with fluorotyrosine. Other open market medications followed, including the Knoll produced 3-fluor(o)-4-hydroxyphenylacetic acid which became known under the tradename "Capacin". Similar data of fluorides effects in liver can now be easily obtained investigating tolylfluanid (pesticide), Prozac, phenothiazine, halothane and other fluorinated anesthetics, 5-fluororacil, or many other fluorinated medications. Also in 1932, Gorlitzer von Mundy, being aware that fluorides also get absorbed through the skin, began fluoride treatments of hyperthyroid patients in Austria by prescribing 20 minute baths containing 30ccm (0.03l) HF per 200 liters of water. He reported on his successful treatment spanning over 30 years and involving over 600 patients at a 1962 international symposium on fluoride toxicity (Gordonoff, 1964). In 1958 Galetti published data on applying sodium fluoride in the treatment of hyperthyroidism. Applying doses ranging from 0.9 to 4.5 F- to patients, in all cases but 1 fluoride showed reduced plasma bound iodine. In ALL cases but 1 the Basic Metabolic Rate (BMR) decreased. This was achieved sometimes within 20 days. 6 of 15 patients were completely healed. One patient was clinically cured by 2.72 mg F-/day over a period of four month period. 4) Fluorosilicic Acid In over 90 percent of fluoridated water supplies fluorosilicic acid is used, a toxic hazardous waste product which has never been safety-tested for human consumption. This product contains also radionuclides, as has been acknowledged by the EPA. As fluorides mimick TSH in the system it also has the ability to enhance endocytosis, the amount of material taken up in a cell. Fluorides abilities to enhance uptake of virues, mycotoxins, etc. are well documented in the literature (available upon request). Enhanced lead uptake has been demonstrated in areas where such fluoridating agents are used (Masters and Coplan, 1999). As lead and silica are further anti-thyroid agents, a multiple assault on the endocrine system can be expected, to be observable in the group most susceptible to thyroid dysfunction - the black population. This is indeed the case (Masters and Coplan, 1999; Butler et al, 1985). In addition there are several sensitive mechanisms observed in the drinking water between silica, fluoride and aluminum and the occurrence of Alzheimer's Disease, a disease closely related to thyroid pathology - a matter of G proteins (Hershey et al, 1983; Jacqmin-Gadda et al, 1996; Strunecka and Parocka, 1999). 5) Fluoride and Zinc Deficiency The role of zinc deficiency in thyroid dysfunction has not, as of yet, received as much attention as selenium and iodine. Although exact mechanisms have not clearly been identified, it has been recognized that zinc plays an essential role in thyroid hormone metabolism (Ganapathy and Volpe, 1999; Nishi et al, 1980; Bremner & Fell, 1977; Dolev et al, 1988; Buchinger et al, 1988). In the clinical laboratory, the main interest of zinc determination in red blood cells now concerns thyroid pathology (Vitoux et al, 1999). Zinc concentration in erythrocytes has become an important marker of peripheral tissue response to thyroid hormones, indicating duration of pre-existing thyroid disorder (Tiran 1993). Recent studies in rats found that single and combined deficiencies of selenium, zinc, and iodine have distinct effects on thyroid metabolism and structure (Ruz et al, 1999). Ozata et al (1999) found that iodine and zinc - but not selenium and copper - deficiency exists in a male Turkish population with endemic goiter. Zinc plays a vital role in biochemical function as it is the essential component of the active site of a multitude of enzymes. Thirty years ago, only three enzymes that required zinc for their activities were identified; today more than 300 such enzymes have been classified (Prasad, 1996) The discovery of zinc "finger proteins" within the past two decades has further led to vastly improved understanding of how cells replicate and divide. Zinc is required for each step of cell cycle in microorganisms and is essential for DNA synthesis (Prasad, 1989). Considering that nuclear receptors for the steroid/thyroid superfamily are all zinc finger proteins, it is not surprising that zinc deficiency impairs the metabolism of thyroid hormones, androgens, and growth hormones. Suboptimal zinc status can seriously impair human health, performance, reproductive functions, and mental and physical development (Roth and Kirchgessner, 1999). Zinc deficiency affects testicular functions adversely in man and animals. Zinc is essential for spermatogenesis. (Prasad, 1989) Not only are low levels of zinc are associated with advanced gastrointestinal cancer (Jia, 1991) - as is selenium -, and lung cancer (Piccinini et al, 1996), but a study testing zinc and copper levels in erythrocytes, plasma, and whole blood in 35 various cancer patients - comparing to 24 normal individuals - found a decrease in zinc in all three blood constituents of all cancer patients (Aldor et al, 1982). Zinc depletion follows experimental fluorosis in mice (Kanwar and Singh,1981). In the liver a significant fall in the levels of zinc is registered. Effects are directly dose-dependent, just as is the case with fluoride-induced iodine deficiency. In rats fed spring water enriched with NaF resulting in 0.8, 1.1 or 2.2 ppm F¯ during 180 days, zinc ions were depleted in most tissues (Boeckhhaebisch & Oliveira, 1997). Other work has also shown that a fluoride intake in rodents comparable to the total intake by man in fluoridated areas leads to zinc deficiency in the testis, liver and kidneys (Krasowska, 1992, 1996). Li et al (1995) showed that excessive fluoride intake since early childhood reduced mental work capacity and that the effect on zinc metabolism was a mechanism of influence by excessive fluoride intake, echoing earlier reports by Shen et al (1992). Hlynczak et al (1980) also found significant alterations in workers exposed to fluorine compounds. Recent research also indicates that zinc finger proteins are essential for GTP hydrolysis (Vitale et al, 1998). Of course it has long been kown that fluorides inhibit hydrolysis. (1000 studies on MEDLINE) Dugad et al (1988;1989) showed how anions of three fluorinated agents tested form complexes with carbonic anhydrases I and II ( a zinc containing enzyme, also used as marker for pre-existing thyroid condition) that have 2:1 inhibitor/enzyme stoichiometry, meaning the stoichiometry of the interaction of this inhibitor with both enzymes is 2 mol of inhibitor bound per mole of enzyme. Zinc deficiency causes "black teeth" in rats (Teraki and Ishiyama, 1990). Zinc and fluoride were water quality variables associated with mottling in a study investigating the prevalence of dental mottling in school-aged lifetime residents of 16 Texas communities (Butler et al, 1985). Platelets from zinc-deficient rats take up significantly less external calcium. Low zinc status in rats impairs calcium uptake and aggregation of platelets stimulated by fluoride. (Emery & O'Dell, 1991; 1993) CLOSING COMMENTS: As you are embarking to discuss the role of endocrine disruptors in the drinking water we urge you to consider the overwhelming and irrefutable evidence that fluoride compounds are perhaps the most potent endocrine disruptor of all. Over 170 symptoms of fluoride poisoning have been compared to ones found in thyroid disorders and found to be identical (Schuld, 1999). The three stages of chronic skeletal fluorosis co-incide with the three stages found in thyroid disorders. Are we forever to evaluate health effects of fluoride on data which was established in the 1930's when the field of endocrinology was yet to be properly established? It is stated that because dental fluorosis does not compromise oral health or tooth function, an increase in dental fluorosis does not represent a public health concern. You will find that once the toxicity of fluoride is properly investigated based on CURRENT scientific knowledge it can only be seen as an endocrine disruptor of the worst kind possible, as it directly mimicks the function of TSH and TRH, with consequences for every cell in the human body. As it is TSH which regulates iodine, zinc and selenium, how much longer are we going to continue to allow a non-essential element to interfere with absolutely essential ones? As thyroid cancer patients, who now number over 500,000 in the US and increase by over 16,000 cases every year, are required to keep their TSH levels suppressed as not to facilitate recurrence, what does the addition of a TSH analogue in the public water supply mean for them? How much longer can you and we afford to allow the dental profession to be the authority on a proven anti-thyroid medication? Please act. 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