חוות דעת ייצוגית Declan Waugh

14th January 2014 This information is submitted on behalf of the people of Israel to Tel Aviv District Court upon
the request of the lawyer Dan Ashkenazi and the lawyer Dikla Baranes, the representatives of the petitioner (Jacob Gurman). This document addresses some of the critical toxicological and human health risks associated with artificial fluoridation of public water. As you are aware the challenges faced by the State and the citizens of your country to the soaring rise in the burden of chronic disease are unprecedented. The number of patients presenting with chronic diseases including arthritis, heart disease, respiratory problem, cancer, mental health conditions such as depression and dementia as well as metabolic diseases such as obesity, diabetes have risen dramatically in recent years. While this has occurred for various reasons, it is clear however that public health authorities in certain countries where artificial fluoridation is practiced continue to live in a state of denial as to the increasing evidence of the role of fluoride exposure to chronic disease burdens; particularly where these disease burdens are significantly above the norm and where there is an established documented role in the contribution of fluoride in the pathogenesis of these diseases. It is evident that national authorities either lack the capacity or are unwilling to examine the published scientific facts that clearly demonstrate how artificial fluoridation of their populations is a serious threat to public health. This document aims to identify the key issues and major risk factors associated with artificial fluoridation that ultimately may significantly reduce the risk of chronic illness from exposure to highly soluble inorganic fluorides. When examining the published scientific evidence a number of facts are beyond dispute. This letter and supporting documentation aims to set the record straight about a number of indisputable facts, the foremost of which is that the fluoride ion is a proinflammatory agent and that exposure to fluoride increases free radical production and oxidative stress in humans. Inflammation forms the basis of many physiological and pathological processes. Chronic and low grade inflammation forms the basis of many human diseases ranging from type 2 diabetes and depression to heart disease, many forms of cancer, as well as many neurological diseases. Atherosclerosis provides an example of a chronic disease that involves inflammatory mechanisms and fluoride has been demonstrated to have a causal role in atherosclerosis. Fluoride is recognized as a low dose endocrine disrupting substance that can alter the normal endocrine function at dietary intake concentrations significantly below the typical dietary intake levels present in fluoridated communities. It is also acknowledged that fluoride disrupts cellular calcium and magnesium homeostatis and is a potent enzymatic and metabolic inhibitor. Research has demonstrated that fluoride is a risk factor in cardiovascular disease, as well as other major diseases including inflammatory respiratory disease and metabolic diseases such as diabetes and obesity. Fluoride is also now recognised as a neurotoxin that may contribute to reduced IQ and neurodegenerative disorders such as Alzheimers. Recent research has also documented that fluoride inhibits the immune system increasing susceptible to biochemical injury from other toxins. Fluoride is also a bioaccumulative toxin, once ingested it accumulates in the body over time, therefore as people live longer the level of environmental contamination in the human body increases. People with higher levels have a greater risk of chronic health problems.
It is an irrefutable fact that in countries that implement artificial fluoridation policies that infants and adults are chronically exposed to fluoride at levels that are detrimental to their health and general wellbeing. The failure of the State to so far recognise this fact is deeply worrying especially when chronic overexposure of infants was identified by a scientific committee of the European Food Safety Authority in 2006. The report also addresses the chronic overexposure of the adult population to fluorides discussing in particular the recent published study by Chan et al., (2013) on dietary fluoride exposure of the UK population which found that a significant percentage of the adult population were chronically exposed to fluoride at levels that were detrimental to their health and general wellbeing from the consumption of tea, without exposure to fluoridated water or foodstuffs. Importantly, their findings on fluoride concentrations in tea are in agreement with all published data reported by researchers globally. I have included in the appendix a detailed report, which while only addressing specific scientific areas of concern, nevertheless incorporates the published scientific evidence from peer reviewed publications to demonstrate how artificial fluoridation is contributing to chronic overexposure of the population, particularly infants, who represent the most sensitive subgroup. The report documents the published scientific studies which demonstrate how fluoride exposure is contributing to chronic disease. The following twenty one points summarises some of the key facts. Each of these statements are irrefutable facts and scientific references are provided in the appendix. Indisputable facts: 1. In countries that practice artificial fluoridation of public water bottle fed infants are chronically overexposed to fluoride at levels that are detrimental to their health and wellbeing. Chronic overexposure to fluoride also exists in the adult population in both fluoridated and non-fluoridated countries from consumption of tea. The exposure increases when tea is constituted with fluoridated water. Fluoride is a pro-inflammatory agent which increases the inflammatory response in humans. Chronic and low grade inflammation forms the basis of many human diseases ranging from type 2 diabetes and depression to heart disease, endocrine disorders, metabolic diseases, respiratory and musculoskeletal disease, many forms of cancer, and neurological diseases such as dementia. Increasing proinflammatory status is a recognised causal factor in developing hyperglycemia and insulin resistance. Maternal hyperglycemia has a causal relationship with increasing fetal growth and pregnancy complications including cesarean section, in addition to contributing to increased childhood obesity. Fluoride inhibits normal carbohydrate metabolism, resulting in an accumulation of fatty acids and an increased risk of obesity and diabetes. The RoI has the highest prevalence of childhood obesity in the EU and 24% of adults are classified as obese. The top six countries for obesity among OECD member nations are all countries with artificial fluoridation programmes.
2.
3.
4.
5.
Fluoride alters normal endocrine function. Altered endocrine function is associated with increased cholesterol concentrations, increased incidence of depression, diminished response to standard psychiatric treatment, cognitive dysfunction, and, in pregnant women, decreased IQ of their offspring. For individuals with iodine deficiency a total dietary intake of 0.7 3.6mg per day is known to adversely affect thyroid function, up to 50% of European population are deficient in iodine. The European Food Safety Authority has established that total daily dietary fluoride intakes, excluding medicine and toothpaste, for individuals living in countries with artificial fluoridation may exceed 6.5mg per day. Consequently it can be stated with absolute certainty that artificial fluoridation of public water is contributing to disruption of healthy endocrine function and diseases associated with exposures to endocrine disrupting. Fluoride increases the production of free radicals and oxidative stress. Free radical and oxidative stress are causal factors in cancer. According to the World Health organisation (2013) the Republic of Ireland (RoI) has the highest incidence of cancer in Western Europe almost twice that of the mean incidence of entire European Region. In addition, according to the National Cancer Registry of Ireland the risk of developing cancers including leukaemia, bladder, prostate, oesophagus, cervix pancreas and brain/central nervous system cancers was significantly higher in RoI than in NI, which is nonfluoridated. Fluoride increases the production of calcitonin at dietary intake levels less than those reported for individuals living in fluoridated communities. Increased calcitonin levels are associated with coronary artery disease, inflammatory lung disease, major depressive disorders, and migraine and play a pivotal role in the pathogenesis of prostate cancer. Elevated calcitonin is also associated with thyroid cancer, lung, ovarian, pancreatic and breast cancer. The prevalence of depressive disorders, heart disease and cancer in the RoI are significantly above the European region and amongst the highest reported internationally. The European Medicines Agencys Committee for Medicinal Products for Human Use (2012) determined that calcitronin increases cancer risk and have advised that calcitronin medications no longer be prescribed by medical physicians. Free radicals and oxidative stress are causal factors in neurological disease including depressive anxiety disorders. It is an established medical fact that oxidative damage in the brain causes nervous system impairment contributing to schizophrenia, depression, anxiety disorders and high anxiety levels. Ireland has the highest prevalence of depressive disorders in Europe. In addition, anxiety disorders are also the most common class of psychiatric disorders in the US, the country with the longest period of artificial fluoridation, affecting approximately 28.8% of the US population. In stark contrast the European Study of the Epidemiology of Mental Disorders (2004) reported a prevalence rate for anxiety disorders among six European countries of 6.8%.
6.
7.
8.
9.
Fluoride has also been demonstrated to directly stimulate activation of G proteins. G proteins have been implicated in the pathophysiology several diseases including, inflammation, neurological diseases, cardiovascular diseases, cancer, and endocrine disorders. Fluoride is documented to cause coronary vasospasms by stimulating G-proteins to release EDRF (endothelium-derived relaxing factor).Vasospasms are known to be a major risk factor in ischemia and strokes. The Republic of Ireland has the second highest mortality rate from ischaemic heart disease in the Western Europe and premature deaths for individuals below 65 yrs of age from ischaemic heart disease are above the EU15 and EU27. Free radicals play causal role in pathogenesis of atherosclerosis leading to vascular diseases. Oxidative stress plays a causal role in neurodegenerative diseases such as Parkinsons disease (PD), Alzheimers disease (AD) and Multiple Sclerosis (MS). Fluoride alters Calcium and Magnesium homeostasis with wide ranging implications for public health including increased risk of osteoporosis, thyroid disorders, obesity, hypertension and colon cancer. According to the National Cancer Registry Ireland the incidence of colon cancer in the RoI is higher than the European average for both males and females. In 2010, according to the Institute of Public Health (IPH), more than 950,000 (62.2%) adults aged 45+ years in RoI have hypertension and more than 67,000 (3.7%) adults aged 1844 years in RoI have clinically diagnosed hypertension. By 2020 the IPH reported that the number of adults aged 45+ years with hypertension is expected to rise by 28% to more than 1,220,000. The differences in prevalence rates in the Island of Ireland are remarkable, with more than 75% of adults aged 65 years or over in the RoI clinically diagnosed with hypertension compared to 48% in non-fluoridated Northern Ireland. Similar regional differences have been reported for prevalence rates of osteoporosis, with prevalence rates in the RoI twice that reported for the UK. In addition, the estimated prevalence of overweight in adults in the RoI is 37%, with 24% documented as obese. Fluoride is a cholinesterase inhibitor. There is a recognised causal relationship between cholinesterase inhibitors and pulmonary disorders including pneumonia, persistent cough, bronchitis, and asthma. Within Europe the RoI also has the highest prevalence of adult and childhood asthma. Death rates from diseases of the respiratory system in Ireland are almost double the EU average and the RoI also has the highest hospitalization of 0-14 yrs. olds for asthma among European counties. The countries with the highest burdens of pulmonary respiratory disease globally, at levels significantly above the global averages, are all countries with advanced artificial fluoridation programmes. Fluoride inhibits carbohydrate metabolism through inhibition of key enzymes contributing to increased rates of obesity. As a proinflammatory agent fluoride contributes to hyperglycemia and insulin resistance. There is an established association between diminished insulin resistance and hyperglycemia in pregnancy and childhood obesity. The highest rates of adult obesity among OECD countries are reported in countries with artificial fluoridation, including
10.
11.
12.
13.
the U.S.A, New Zealand, Australia and the RoI. Among European countries the RoI has the highest prevalence of overweight and obese children in the European region, while the prevalence of overweight in adults is 37%, with a further 24% meeting current body mass index (BMI) criteria for obesity. 14. Fluoride inhibits enolase. In addition to its innate glycolytic function enolase plays an important role in several biological and pathophysiological processes including autoimmune disorders, cardiovascular health, inflammatory respiratory disease, cancer, Alzheimer's disease, rheumatoid arthritis, inflammatory bowel disease and general disease prevention. Fluoride impairs glucose tolerance and causes decreased insulin expression and increased insulin resistance. Glucose intolerance is a gateway to developing type 2 diabetes. Incidence rates for diabetes in the RoI are significantly above those for Northern Ireland or the European region. Increased insulin resistance and impaired gyycemic control are established risk factors in depressive disorders. The RoI has one of the highest incidence rates for depressive disorders in the world. Fluoride inhibits Lipase. Among individuals with conditions that can contribute to a lipase deficiency, there is the potential for problems to develop, such as prostate disorders, high cholesterol, an increased risk for diabetes, and difficulty losing weight, decreased lipase activity is a primary risk factor in obesity. Inhibition of lipase also results in an accumulation of higher fatty acids which contribute to cardiovascular disease. Individuals with cystic fibrosis, Crohns disease, and celiac disease are a particular high risk group for deficiencies in lipase. Their risk is confounded by exposure to artificially fluoridated water. The RoI one of the highest incidences rates for cystic fibrosis, Crohns and celiacs disease in the world. Fluoride inhibits cellular production of lactate. Lactate plays a crucial role in protecting the central nervous systems including neurobiology. The RoI has one of the highest incidence rates for neurological disorders in the world. Fluoride inhibits arginase. It has been established that arginase inhibitors increase the risk of inflammatory diseases and cancers in humans. The RoI one of the highest incidences rates for inflammatory diseases and cancer in the world. Fluoride inhibits folate contributing to increased homocysteine levels. Folate is important for the functioning of the central nervous system at all ages of development. Folate deficiency induces neurotoxicity due to accumulation of homocysteine. Fluoride is an enzyme inhibitor that contributes to hyperhomocysteinemia, or the accumulation of HCY, in humans. Homocysteine is implicated in many pathological conditions including cardiovascular diseases, neural tube defects, and is now recognised as a risk factor in Alzheimers disease (AD) and dementia. There is also growing evidence that homocysteine plays a role in
15.
16.
17.
18.
19.
20.
21.
alcoholism, depression and anorexia nervosa. Homocysteine metabolism has been documented as a risk factor of Downs syndrome (DS). Research has demonstrated a positive relationship between homocysteine levels and increased hostile behaviour in schizophrenia. Homocysteine may also be an important factor in Parkinsons disease. Furthermore, it has been found that a high plasma concentration of homocysteine may contribute to epilepsy. The RoI has one of the highest incidence rates for neural tube defects, Downs syndrome, cardiovascular disease, depression, schizophrenia, epilepsy and alcoholism in the world. 22. Fluoride has been found to adversely affect collagen and contribute to inflammatory skin diseases such as atopic eczema and psoriasis. The RoI has one of the highest prevalences of skin diseases internationally significantly above European prevalence rates. Skin conditions are the fourth most common reason for GP visits in Ireland and the prevalence of skin diseases such as skin cancer, leg ulcers and atopic eczema has increased steadily in recent decades. Today, between 25% and 33% of the Irish population suffer from a dermatological condition at any one time.Elevated prevalences of skin diseases significantly above the global average are also prominent in other countries with artificial fluoridation Fluoride exposure increases the risk of epilepsy through reducing melatonin and increased homocysteine levels. Epilepsy is the second most commonly seen neurological condition in primary care worldwide; the adult prevalence rates of epilepsy in the RoI are almost twice the European prevalence rates and are also significantly higher than the prevalence rates reported for Northern Ireland, Scotland, England and Wales. Fluoride as an inflammatory agent contributes to inflammatory bowel disease (IBD). The incidence rates for IBD in the RoI are twice that of non-fluoridated Northern Ireland and the highest incidences of this disease internationally are to be found in countries with artificial fluoridation programmes.
23.
24.
These are not insignificant findings in any sense of the word. Any one should in a normal society demand an immediate end to artificial fluoridation in the interest of public safety. The scientific evidence is overwhelming, artificial fluoridation is contributing to chronic illness and is directly impacting on the physical, emotional and psychological wellbeing of consumers. A simply measure can be taken almost immediately to protect public health that will reduce the burden of chronic disease, that is ending artificial fluoridation of public water supplies. In this context, it is important to note the Public health approaches in most developed countries worldwide, particularly in Europe has been to either avoid or move away from artificial fluoridation of public water supplies on grounds of insufficient evidence to demonstrate its safety and the long term public health consequences. The evidence in this report not only supports their understanding but demonstrates the long term impact of such a policy in contributing to chronic diseases and ill health.
For your records I also include in attachments, my latest study on the contribution of fluoride to chronic inflammatory respiratory diseases in children and adults which also includes information on Israel. These findings were presented in October 2013 at an international fluoride conference in the Middle East attended by some of the worlds leading experts in fluoride toxicity to which I was invited to participate as a keynote speaker. This study documents how fluoride exposure has significantly contributed to inflammatory respiratory diseases and examines the evidence from over 30 countries internationally. My research paper was submitted to a leading scientific journal for peer review and publication in December 2013.
Sincerely yours,
Declan Waugh BSc. CEnv. MCIWEM. MIEMA. MCIWM Environmental Scientist and Risk Management Consultant EnviroManagement Services 11 Riverview Bandon, Co. Cork Ireland.
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease
Report for The Government of Ireland The European Commission and World Health Organisation
Prepared By
Declan Waugh BSc. CEnv. MCIWEM. MIEMA. MCIWM EnviroManagement Services, Bandon, Co. Cork, Republic of Ireland.
January 2014
Contents
1. 2. 3. 4. Abstract ......................................................................................................................... 1 Fluoride and Infant Exposure ........................................................................................ 2 Fluoride Exposure of Adults ......................................................................................... 4 Fluoride, Endocrine Disorders, Health effects and Pathophysiological Mechanism .... 6 Fluoride exposure increases Calcitonin levels in Humans ............................. 8 5. Fluoride, Impaired Glucose Tolerance, Diabetes and Obesity. ..................................... 9 6. Fluoride Inhibition of Enolase, Health effects and Pathophysiological Mechanisms . 14 7. Fluoride inhibition of Lactate, Health effects and Pathophysiological Mechanisms .. 15 8. Fluoride, Folate, Health effects and Pathophysiological Mechanisms ........................ 15 9. Fluoride inhibition of Lipase, Health effects and Pathophysiological Mechanisms ... 16 10. Fluoride inhibits Calcium Homeostasis....................................................................... 17 11. Fluoride inhibits Magnesium Homeostasis ................................................................. 18 12. Fluoride inhibition of Manganese metallenzyme arginase .......................................... 19 13. Fluoride inhibition of Cholinesterase and Pulmonary disease .................................... 20 14. Fluoride, Increased production of Free radicals, Oxidative stress and Cancer............ 22 Figure 1. Comparison of Cancer incidence for RoI and European Region ... 28 Figure 2. Global incidence of Cancer ............................................................ 28 15. Fluoride, Increased production of Free Radicals, Oxidative Stress and Neurodegenerative Disorders ...................................................................................... 29 16. Fluoride, Inhibition of Homocysteine, Health effects and Pathophysiological Mechanisms ................................................................................................................. 31 Folate deficiency increases Homocysteine levels......................................... 31 Fluoride inhibition of S-adenosylhomocysteine hydrolase .......................... 32 Health effects of Hyperhomocysteinemia ..................................................... 32 17. Fluoride, Free Radicals and Vascular Disease. ........................................................... 33 18. Fluoride, Inflammation and Disease............................................................................ 36 Musculoskeletal Pain ...................................................................................... 36 Inflammatory Bowel Diseases ........................................................................ 37 Skin Disorders ................................................................................................ 39 19. Fluoride and Epilepsy .................................................................................................. 42 20. Conclusion ................................................................................................................... 43 References ............................................................................................................................... 44
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014
1. Abstract
It is evident that pro inflammatory inducers such as highly soluble inorganic fluoride, from artificial fluoridation of water, are recent and manmade. The recent increase in chronic inflammatory diseases coincides with the period of commencement of fluoridation worldwide. The fact, that most chronic diseases have also risen to prominence during this time (albeit along with an aging population) and importantly, that the highest burdens of inflammatory and other associated diseases are typically to be found in artificially fluoridated countries such as the USA, Australia, Republic of Ireland, New Zealand and Canada would clearly suggest a causal role for artificial fluoridation in contributing to chronic disease burdens. Where exposure to proinflammatory agents persists, the response over time may become chronic. This is evident in the accumulation of fluoride in humans living in fluoridated regions which have been found to be significantly higher than those of non-fluoridated communities. Because fluoride is a bioaccumulative toxin continued exposure results in significant accumulation of this toxin in human tissues over the individuals lifetime. In addition, the impact of chronic overexposure of infants to fluoride is resulting in unprecedented epidemics of metabolic and neurological disorders with catastrophic healthcare, societal and economic consequences. The economic costs alone are staggering and the implications for future generations are enormous. This report examines the scientific facts demonstrating chronic overexposure of fluoride in infants as well as adults, and the biological mechanisms of how fluoride is contributing to disease. This report provides the relevant current published scientific information from peer reviewed scientific journals, from which it is evident that the preponderance of scientific data clearly demonstrates that increasing fluoride exposure of the population through artificial fluoridation is contributing to a wide range of chronic diseases that are prevalent in certain countries today. It is clearly evident that increased fluoride exposure has a direct inhibitory effect on energy metabolism in human cells and that the inhibitory effect of fluoride on enolase, folate, lactic acid, lipase, arginase, cholinesterase, calcium and magnesium homeostasis, in addition to inhibition of homocysteine metabolism, combined with fluorides contribution to increased production of free radicals and oxidative stress, as well as fluoride exposure contributing to elevated calcitonin is having far reaching consequences for human health, ultimately contributing to a wide range of chronic diseases that are known to have particularly high prevalences in countries with artificial fluoridation programmes. The evidence is now irrefutable, artificial fluoridation is contributing to low level chronic poisoning of the population and poses a real and immediate threat to life, public health and safety. Immediate action must be taken by public health authorities to end this policy. Additional factors associated with artificial fluoridation, including how the chemical intoxication of individuals without their informed consent is a violation of medical ethics; the noncompliance with legislation on the use of chemicals that require detailed toxicological and epidemiological evidence demonstrating their safety for human or the environment, and the life cycle of artificial fluoridation which results in the contamination of the entire food chain with highly soluble inorganic fluorides are not addressed in this report.
1|Page
2. Fluoride and Infant Exposure

It is generally accepted that infants under 12 months are the highest risk group for developing dental fluorosis due to consumption of formula milk feed reconstituted with fluoridated water in the first year of life. Dental fluorosis is the most obvious visible toxic effect of fluoride. It is further known that the condition overwhelmingly applies to infants who are fed formula milk prepared with fluoridated water. This view is supported by UK Medical Research Council (2002) when they reported that individuals most likely to have supra-optimal fluoride intakes are formula-fed infants in fluoridated areas [1]. It is important to acknowledge that for infants up to 6 months of age there are no established Safe Dietary Upper Tolerable Intake Levels for Fluoride exposure. Nevertheless, the U.S Institute of Medicine have reported that the adequate intake of fluoride for infants aged 0-6 months of age is 0.01mg/kg/day [2]. Recent risk assessments conducted internationally have concluded that babies fed formula milk prepared with fluoridated water will exceed the established upper tolerable safe level for fluoride exposure for healthy adults [3,4,5]. According to the European Food Safety Authority (2006), the fluoride intake for babies fed formula milk constituted with fluoridated tap water (0.8mg/l) would be approximately 0.16mg fluoride/kg body weight/day compared to 0.00030.0016mg/kg/day for breast fed babies [5]. This represents an alarming 100-533 fold increased exposure to fluoride compared to breast fed infants. When compared to the adequate intake level reported by the U.S Institute of Medicine it represents a 16 fold exceedance (1600%). Importantly, the EFSA also reported that additional dietary sources of fluoride, in particular, fluoride exposure from prescribed medications can also be a major contributor to infant dietary fluoride intake. While the EFSA noted that this may contribute in some circumstances up to 75% of the total dietary exposure for infants. This presents yet another public health risk especially in fluoridated communities as no product information is available to consumers or medical physicians providing the fluoride contend of medications. Logically, for infants already overexposed to fluoride from fluoridated formula milk, their exposure further increases when other sources of fluoride such as medications are included. It should also be noted that the EFSA reported that severe clinical gastrointestinal symptoms were observed in children administered a single dose of 1mg/kg body weight [5]. While these observations did not include infants, Bubenik (2002) reported that low melatonin may be associated with ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic [6]. This latter finding has an obvious importance considering the high prevalence of infantile colic during the first few months of life in certain countries and especially when one considers that the U.S NRC reported how fluoride can reduce melatonin in humans [7]. Given the obvious sensitivity of new born infants to toxins, such a prolonged chronically high exposure to highly soluble inorganic fluorides, from the consuming fluoridated formula milk, can clearly be expected to compromise their digestive, immune and endocrine systems. Interestingly, the Canadian Paediatric Society recommend that no fluoride should be given before teeth have erupted and no fluoride supplement should be given to an
2|Page
infant before six months of age [8]. Furthermore, they recommend that fluoride concentrations should be stated on any foods or drinks containing fluoride [8]. For older children up to eight years of age the EFSA proposed a Tolerable Upper Intake Level of 0.1 mg/kg [5]. For children older than eight years and adults the EFSA recommended a UL of 0.12 mg fluoride/kg body weight [5]. It is clearly evident that these UL are significantly exceeded for infants where fluoridated water is used to prepare formula milk. From a public health point of view these facts are crucially important. It is in this context, the World Health Authority drinking water guidelines specify that the Tolerable Daily Intake (TDI) from all sources including drinking water should not be exceeded [9]. The WHO recommend that "if the potential exposure from drinking water in an incident is greater than the Tolerable Daily Intake or exposure is likely to be extended beyond a few days, then this would require consideration in conjunction with health authorities. In such circumstances, it may be possible to target action to avoid exposure at the specific group concerned, such as supplying bottled water for bottle fed infants." Alternatively, the WHO recommended that "such steps can be used on a household basis to reduce exposure and allow the continued use of the supply without interruption." [9]Furthermore, the WHO observed that specific subpopulations, in particular bottle fed infants, are at greater risk from a substance than the rest of the population due to high exposure. The WHO also noted that some genetic subpopulations may show greater sensitivity to particular toxicity. Based on our previous discussion this would include, for example, individuals with cystic fibrosis, Crohns disease or celiac disease [9]. More recently the European Food Safety Authority commissioned a study identifying health outcomes upon which Dietary Reference Values for fluoride could be established [10]. This review only reported on fluoride intake levels below the tolerable upper intake (1.5 mg/day for children aged 1-3 years, 7 mg/day for adolescents and adults 15 years), and only included forms of fluoride that are naturally present in foods, or approved by the EC for use in foods (potassium fluoride; sodium fluoride) or food supplements (calcium fluoride; potassium fluoride; sodium fluoride; sodium monofluorophosphate). The review did not include fluoride intake from artificially fluoridated water using hexafluorosilicic acid. The review concluded that few studies existed which met the scientific standards for inclusion criteria and the majority were assessed as being at high risk of bias. Of critical importance however the report highlighted that there was a lack of high quality evidence upon which DRVs may potentially be based for fluoride; consequently the authors were unable to provide recommendations for establishing safe dietary intake reference values for fluoride. This in itself is an astonishing finding and one which clearly supports the observations of the US NRC scientific committee when they recommended in excess of sixty epidemiology, toxicology, clinical medicine and environmental exposure assessments that need to be undertaken in order to fill knowledge gaps in the toxicological assessment and long term health effects of fluoride ingestion. Based on these findings it is apparent that Public Health Authorities in fluoridated countries are negligent in protecting the most vulnerable in society at their most sensitive period of development, from chronic overexposure to fluoride.
3|Page
3. Fluoride Exposure of Adults

The total dietary exposure of an individual is the sum of exposure from all food and other sources consumed in a day. Because of the wide variability of exposures to fluoride it is impossible to control the total dietary intake of fluoride for any individual. Nevertheless the risk factors for increased exposures to fluoride increase significantly when public water supplies are fluoridated and dietary exposures cannot be controlled to protect the health and welfare of citizens when such a policy is enacted. This view is supported the European Food Safety Authority (2006) who reported that while the intake of fluoride from water can be estimated with some certainty an estimation of fluoride intake from other sources is prone to the influence of a wide variety in individual habits[5]. Alarmingly, the EFSA reported up to 50 fold variations in fluoride content of human bone depending on fluoride intake. Importantly, the NRC reported that the dietary intake of fluoride by adults in the UK is expected to be high, due largely to the consumption of popular beverages such as tea [11]. The NRC committee specifically noted that the fluoride content of commercial instant teas can be substantial and that consumption of tea can result in individual dietary exposure of up to 9mg of fluoride a day [11]. Importantly, the U.S National Academy of Science (NAS) recommends a Dietary Reference Intakes (DRI) of 4mg per day for healthy adults [12]. Ireland has the highest consumption of tea in the world surpassing the UK in the consumption of tea, consuming on average 20% more tea than the average UK tea drinker. Consequentially the potential fluoride dietary intake for a significant subgroup of the adult population in Ireland is greater for many individuals compared to the risk for consumers in the UK. A further and significant risk factor for the population of Ireland is that less than 10% of the UK population compared to (7580%) of the Irish population are provided with artificially fluoridated water. Boiling fluoridated tap water increases the concentrations of fluoride in water and food. Where public water is used for preparation of food products significant increases in fluoride content have been noted [5.13,14]. A current study by Chan et al., (2013) examined the dietary fluoride exposure of the UK population from tea consumption. The study determined the fluoride concentrations in a selection of 38 commercial teas sold in the UK market, including the leading commercial supermarket brands which are also sold in the Irish market. The study determined that many of the teas contained elevated concentrations of fluoride up to 8.85 mg/L [15]. These measurements were made on tea infusions prepared with deionised water. Importantly, their findings on fluoride concentrations in tea are in agreement with published data reported by researchers globally [5,16-51]. While the authors concluded that detrimental health effects could occur when an adult consumes 1 L of tea daily, especially when prepared using a UK supermarket economy brands, it should be noted that the concentration of fluoride in tea beverages is further increased by using boiled fluoridated water to prepare the product. The increased exposure was acknowledged by the European Food Safety Authority who reported that if fluoridated water were drunk and used for the preparation of food and tea (1-2 L of water/day; 500 mL of tea (2 cups) with a fluoride concentration of 5 mg/L) 3.5 to 4.0 mg fluoride would be added to the daily dietary intake of an individual compared to consumers living in non-fluoridated areas [5]. The EFSA reported that even more extreme scenarios are possible and not completely unrealistic.
4|Page
This is reflected in the ROI where many adults consume 6-8 cups of tea daily made using boiled fluoridated water. Based on the measured concentrations of fluoride in tea, the total daily dietary fluoride intake for many individuals will be multiples of the recommended DRI as recommend by the NAS and will significantly exceed the tolerable upper intake level of 7mg fluoride per day as recommended by the EFSA. More importantly, fluoride exposures will vastly exceed the levels that have been reported to alter thyroid function in both healthy and iodine deficiency populations. These findings are of interest not just for endocrine disorders, which is discussed later, but also cancer risk. Shafique et al., (2012) in a large cohort prospective study of Scottish males reported that tea may be a potentially modifiable and highly prevalent risk factor for prostate cancer in men [52]. The association of fluoride exposure and increased calcitonin is well established [11]. Calcitonin is an amino acid polypeptide hormone secreted by the parafollicular cells of the thyroid gland. Increased calcitonin is known to play a pivotal role in the pathogenesis of prostate cancer [53, 54,55]. Vandenberg et al. (2012) reported that water fluoridation chemicals were as endocrine disrupting chemicals (EDCs) at low dose levels [56]. According to the European Environment Agency (2012) there is evidence linking foetal exposure to EDCs with prostate cancer [57]. Furthermore, Woodward and Pedoe (1999) in a nationwide large scale random population study of men and women aged 40-59 years found increased coronary risk factors, coronary risk and mortality for tea drinkers compared to coffee drinkers [58]. Critically, these observations support the findings of Gutowska et al., (2010) who reported that fluoride may be atherogenic, promoting the formation of fatty deposits in arteries [59] and of Kanbay et al. (2012) when they reported that increased calcitonin levels are associated with greater severity of coronary artery disease [60]. It is not possible for individuals to estimate their risk of exposure or control their dietary intake of fluoride when they are not provided with any information on the fluoride levels of foodstuffs or medications purchased. This concern was addressed by the WHO over twenty years ago when they recommended that the fluoride content should be printed on products, especially for countries with large artificial water uoridation programmes due to increased fluoride exposures of their populations [51]. Based on these indisputable scientific facts, it is obvious that artificial fluoridation cannot in any way be regarded as safe. It is a scientific fact that artificial fluoridation is contributing to chronic fluoride overexposure and detrimental health effects among the wider population. The known health effects will be discussed in the following sections.
5|Page
4. Fluoride, Endocrine Disorders, Health effects and Pathophysiological Mechanism

Hypothyroidism affects 510% of the general population with increased prevalence in older
individuals and females. Hyperthyroidism is less common, affecting 1% of the general population [61]. It is generally accepted that the thyroid gland is one of the most sensitive organs because of its histopathological and functional responses to excessive amounts of fluoride [62-65]. Fluoride is known to interfere with thyroid gland function and thereby can adversely affect growth and cause degenerative changes in the central nervous system and impairment of brain function in humans and animals [66-68]. In a review published over 30 years ago, McLaren discussed the accumulation of F in the thyroid and its possible relationship to morphological and functional changes [69]. It is estimated that 2 billion individuals globally have an insufficient iodine intake [70]. In Europe it is estimated that 47.8% of school-aged children and 46.1% of the general population are deficient in iodine [71] and it has been reported that up to 50% of pregnant women in the UK and Ireland may be significantly iodine deficient [72]. Secondly, in fluoridated countries regardless of iodine status, a large percentage of the adult population are exposed to fluoride at levels that are harmful to their general health. Iodine deficiency produces a thyroid hormone pattern consistent with subclinical hypothyroidism (ScH) [73]. According to the NRC (2006) ScH can cause bone demineralization, is associated with increased cholesterol concentrations, increased incidence of depression, diminished response to standard psychiatric treatment, cognitive dysfunction, and, in pregnant women, decreased IQ of their offspring [11]. In regards to thyroid function and general health, it is important to recognize that thyroid hormone concentrations are correlated with adverse effects in organ systems other than the nervous system in the adult, including the cardiovascular system and control of serum lipids [74,75,76] pulmonary system [77,78,79] and kidney. Total cholesterol, low density lipoproteins (LDL), nonhigh density lipoproteins (non-HDL), and triglycerides increase linearly with increasing TSH, and HDL decreases consistently with increasing TSH across normal reference ranges without evidence of any threshold effect [80]. Within the reference ranges for TSH, there is a linear positive association between TSH and both systolic and diastolic blood pressure [80]. Intimal medial thickness (IMT), a measure of atherosclerosis and predictive of coronary vascular disease and stroke, is inversely related to free T4 after controlling for lipids, clinical factors, and thyroid autoantibodies [81]. Not surprisingly, alterations in thyroid homeostasis have been found to increase the risk of cardiovascular disease [82-84]. Rodondi et al., (2006) in a meta-analysis of 14 epidemiologic studies found an overall increase in risk of coronary heart disease (CHD) of over 65% in those with subclinical hypothyroidism (elevation in TSH with normal T4) [85].Therefore, epidemiologic as well as mechanistic and therapeutic evidence substantiates the concern that thyroid disrupting chemicals may adversely affect cardiovascular risk in humans by reducing serum T4.
6|Page
A recent scientific review by Vandenberg et al. (2012) examining low dose exposures to endocrine-disrupting chemicals (EDCs) lists water fluoridation additives added to prevent dental caries as EDCs with reported low dose effects in animals or humans [56]. The report documents that EDCs inhibit insulin secretion, inhibit parathyroid hormone secretion and reduce thyroid hormone output [56]. Importantly, the U.S National Academies reported that in humans effects on thyroid function were associated with fluoride exposures of 0.05-0.13 mg/kg/day when iodine intake was adequate and 0.01-0.03 mg/kg/day when iodine intake was inadequate [11]. This exposure equates to a total dietary fluoride intake of between 0.7 - 3.5mg per day at which thyroid function may be impaired. It is an established fact, as noted by the European Food Safety Authority, that the levels of dietary exposure ranging between 0.7 and 3.5mg/day are greatly exceeded in fluoridated communities [8].
US National Research Council Review of Fluoride in Drinking Water, 2006 Fluoride Total Fluoride exposure Intake mg/day mg/kg/day Altered thyroid function when iodine intake adequate 0.05-0.1 3.5-9.1 Altered thyroid function when iodine intake inadequate 0.01-0.03 0.7-3.5 NAS (National Academy of Science) (2004). Dietary reference intakes (DRI)* The NAS, recommended dietary reference intake (DRI) of 4 mg fluoride a day for adults Chan et al (2013) Human exposure assessment of fluoride from tea* Fluoride concentrations in black tea infusions prepared with deionised water ranged up to 8.85 mg/L Dietary fluoride intake when 5 cups of tea consumed per day 0.15 Up to 11mg made with deionised water Dietary fluoride intake when 5 cups of tea consumed per day 0.17 Up to 12mg made with fluoridated water European Food Safety Authority, 2006** Total Dietary intake from all sources when not using 0.5-1.2 fluoridated water, no fluoridated salt, fluoridated supplements and no fluoride containing dentifrice Total dietary intake without fluoride from toothpaste taken >6mg into account but including intake from drinking fluoridated water and using it for preparation of food and tea (1-2L of water/day; 500ml of tea with a fluoride concentration of 5mg/l) Using the current data from Chan et al. (2013) the total >13mg dietary intake from drinking fluoridated water and using it for preparation of food and tea (1-2L of water/day; 5 cups of tea per day with a fluoride concentration of 8.85mg/l) and excluding fluoride from toothpaste or other sources such as medications. Note:
*NAS (National Academy of Science) (2004). Dietary reference intakes (DRI): Recommended intakes for individuals. Food and Nutrition Board, Institute of Medicine, National Academies. **Laura Chan , Aradhana Mehra, Sohel Saikat, Paul Lynch. Human exposure assessment of fluoride from tea (Camellia sinensis L.): A UK based issue. Food Research International 51 (2013) 564 570 *** European Food Safety Authority, Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of Fluoride, EFSA Journal 2005 192, 1-54
7|Page
Fluoride exposure increases Calcitonin levels in Humans Calcitonin is an amino acid polypeptide hormone secreted by the parafollicular cells of the thyroid gland. The US National Research Council reported that elevated Calcitonin has been noted at fluoride intakes as low as 3.8 mg/day in humans (approximately 0.06 mg/kg/day) and was found routinely at intakes of at least 9 mg/day (approximately 0.15 mg/kg/day) [11]. The NRC reported that intakes of 9mg per day or higher are expected in countries where there is a high consumption of tea [11]. As noted previously, the European Food Safety Authority, has established that dietary fluoride intake levels of greater than 6.5mg per day are expected in fluoridated communities [5]. The importance of these findings are self-evident, especially when research has demonstrated that increased calcitonin levels are associated with greater severity of coronary artery disease [60], inflammatory lung disease, lung cancer, breast cancer and thyroid cancer [86]. In addition, Shah et al. (1994), Sabbisetti et al. (2005) and Sha et al. (2008) reported that elevated calcitonin plays a pivotal role in the pathogenesis of prostate cancer [53,54,55] elevated serum levels of calcitonin have also been identified in many other cancers including thyroid, lung and breast, leukemia, ovarian and pancreatic cancers [86,352-357]. Research has also established that elevated calcitonin is associated with major depressive disorders [87] as well as having a causative role in neurological disorders such as migraine [88, 89]. The European Medicines Agencys Committee for Medicinal Products for Human Use (2012) determined that elevated levels of the hormone calcitonin increases cancer risk and have advised that calcitonin medications no longer be prescribed by medical physicians [366]. In summary, based on our previous discussion it is clear that: Individual dietary intake of fluoride can vary significantly depending on consumption of fluoridated water, tea and other foodstuffs as well as use of medications. The fluoride exposure that may affect thyroid function in healthy individuals is greatly exceeded for many individuals living in fluoridated communities. The margin of risk for effects on thyroid function is increased up to 5 fold in individuals with iodine deficiency. Up to 48% of the European population have been reported to be deficient in iodine. Consequently, a very significant percentage of the population living in fluoridated communities will be adversely affected by increased fluoride exposure from artificial fluoridation of water. In countries where there is a high consumption of tea, dietary fluoride intakes for consumers will be substantially higher. The RoI and the UK and the largest consumers of tea per capita internationally, therefore their populations will have substantially greater dietary fluoride intake. The use of fluoridated water in preparing tea beverages can increase the dietary intake of fluoride by up to 13%. Fluoride exposure arising from consumption of fluoridated water increases the production of calcitonin. Elevated calcitonin has been identified as a contributory risk factor in heart disease, inflammatory lung disease, depressive disorders, migraine and cancer.
8|Page
5. Fluoride, Impaired Glucose Tolerance, Diabetes and Obesity.

Pre-diabetes exists when blood glucose is elevated, but not as high as type 2 diabetes. Hyperglycemia is a condition characterized by high blood sugar levels. When this occurs during pregnancy, but not prior to pregnancy, it is called gestational diabetes. Type 1 diabetes is an autoimmune disease that occurs when the pancreas no longer produces any insulin or produces very little insulin. It usually develops in childhood or adolescence and affects up to 10% of people with diabetes. There is no cure. It is treated with lifelong insulin injections and careful attention to diet and physical activity. Type 2 diabetes is a disease that occurs when the pancreas does not produce enough insulin to meet the bodys needs and/or the body is unable to respond properly to the actions of insulin (insulin resistance). Type 2 diabetes usually occurs later in life (although it can occur in younger people) and affects approximately 90% of people with diabetes. There is no cure. In North America and elsewhere, the incidence of diabetes has reached epidemic proportions with further increase continuing [90]. The increases appear to be most profound in countries with artificial fluoridation including Ireland, Australia, New Zealand, Brazil and Mexico. In diabetes, the main cause of microcirculatory damage is the consequence of non-enzymatic glycosylation of proteins, which is the consequence of high extracellular glucose levels [91]. The effect of fluoride on carbohydrate metabolism was noted as far back as the 1930s and 40s when fluoride was identified as a potent inhibitor of enolase [92,93]. Vasudevan et al. (2011) reported that fluoride will inhibit the enzyme, enolase, and consequently the glycolysis [94]. In 1950, Professor Rapp published a report titled The Pharmacologic Effects of Fluorides in which he reported on fluorides effects upon enzymes, cells and calcifying tissues [95]. In the case upon enzymes he noted that there is a selective activity demonstrated in its effects. Since enzymes can be considered to be complexes consisting of proteins, vitamins, and a metallic component, and since the metal portion of each enzyme is not identical with that of another enzyme, it follow that those enzymes which have metallic components capable of being rendered insoluble, or nor-available, will be affected by the presence of fluorides. According to Rapp one of the most important systems of enzymes that are susceptible to fluorides are those involved with phosphate transport. The effect of phosphatases and phosphorylases become important from several points of view. In the first place, phosphate transporting enzymes are important in the absorption of carbohydrates from the small intestine. Rapp noted that when these enzymes are absent or poisoned in any manner, sugar absorption takes place only slowly. Secondly, these enzymes are also important in the utilization of carbohydrates in the body. Indirectly they are also concerned with the metabolism of fats and proteins. In the presence of an adequate amount of fluorides, these enzymes are poisoned and normal sugar metabolism is disturbed. Rapp compared the blood sugar, muscle and liver glycogen, and blood lactic acid concentrations under the influence of fluorides and observed that the results indicate that the effects are very similar to those obtained in diabetes, and suggested that the presence of fluorides seems to interfere with metabolic systems similar to those affected by an insufficiency of insulin. In regard to the effects of fluoride on cellular function, Rapp further noted that all cells are affected by fluoride to a greater or lesser degree. The extent of the effect on the cell seems to be directly related to the cells dependence on carbohydrate metabolism [95].
9|Page
The U.S National Academies (2006) reported that among the major endocrine effects of fluoride exposure is impaired glucose tolerance and noted that the primary mechanism appears to involve inhibition of insulin production. This was a matter of some concern to the scientific committee given the increasing prevalence of diabetes mellitus; accordingly the scientific committee advised that any role of fluoride exposure in the development of impaired glucose metabolism or diabetes is potentially significant. [11]. Rigalli et al. (1990) reported that fluoride had an inhibitory effect on the secretion of insulin [96]. Garcia et al. (2009) demonstrated that fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress [97]. O Barbier et al. (2010) reported that that biologically relevant doses of fluoride can result in impairment of glucose tolerance or increased blood glucose and decreased insulin synthesis [98]. Numerous other studies have demonstrated that impaired glycemic control and insulin restance are risk factors for depressive disorders such as major depression [99-102] Balasubramanyam et al. (2010) reported that fluoride is a risk factor in both the development of obesity and diabetes [103]. A recent scientific review by Vandenberg et al. (2012) examining low dose exposures to endocrine-disrupting chemicals (EDCs) lists water fluoridation additives added to prevent dental caries as EDCs with reported low dose effects in animals or humans [56]. The report documents that EDCs inhibit insulin secretion, parathyroid hormone secretion and reduce thyroid hormone output. A current publication on endocrine disrupting chemicals by the Inter-Organisation Programme for the Sound Management of Chemicals (IOMC) for the WHO and United Nations Environment Programme also lists water fluoridation chemicals as low dose EDCs [104]. The report highlights how obesity, diabetes and metabolic disorders are due to disruption of the energy storageenergy balance endocrine system and thus are potentially sensitive to EDCs. According to the IOMC fat development and weight gain is a good example of complex physiological systems that are influenced by endocrine disruptors. There are a number of endocrine disruptors that have been shown to affect weight gain, insulin sensitivity and glucose tolerance indicating a potentially important role for endocrine disruptors in the development of obesity type 2 diabetes and metabolic syndrome [104]. The elements of the endocrine system that control weight gain and metabolism/energy expenditure include the adipose tissue, pancreas, GI tract, liver, skeletal muscle, bone and brain, and endocrine disruptors could specifically and directly affect each of these tissues by interfering with their various hormone systems [104]. The NRC review (2006) identified how fluoride and fluoride compounds may interfere with each of these tissues [11]. Ropero et al., (2008) and Sargis et al., (2010) noted that because obesity is an endocrine-related disease/dysfunction, it is potentially sensitive to endocrine disrupting chemicals [105, 106]. According to the IOMC current research suggests that exposure to some endocrine disrupting chemicals during pregnancy can lead to altered cholesterol metabolism, weight gain and type 2 diabetes in the offspring later in life [104]. This view is
10 | P a g e
supported by Ong et al., (2000) and McAllister et al., (2009) when they reported that there is evidence that the obesity risk may begin early in life, during pregnancy, and in early childhood and that rapid weight gain, in the first few months of life, is associated with obesity later in life [107,108]. The U.S National Academies (2006) reported that fluoride is a pro-inflammatory agent that increases the inflammatory response to irritants in humans; consequently exposure to fluoride increases the proinflammatory status [11]. In 2012, in a review paper on glycolysis in the control of blood glucose homeostasis, the Chinese Academy of Medical Sciences reported how increasing proinflammatory status produce pro-hyperglycemic factors and bring about hyperglycemia and insulin resistance [109]. Peterson (1954) reported the relationship between maternal glucose metabolism, gestational diabetes (hyperglycemia) and birth weight has been attributed to increased nutrient transfer to the fetus due to diminished insulin sensitivity leading to maternal utilization of free fatty acids for energy [110]. The fetus is thought to respond by increasing insulin secretion, with increased fat storage to prevent fetal hyperglycemia and ultimately increased fetal weight [110]. Hodge and Smith (1965) reported that fluoride inhibits lipase resulting in an accumulation of fatty acids [111]; fatty acids and obesity induce endoplasmic reticulum (ER) stress in liver, which suppresses insulin production and contributes to diabetes [112]. Scholl et al. (2001) also reported that birth weight increased with increasing maternal glucose [113]. In addition, it was reported that maternal complications increased twofold or more with high glucose concentrations and included cesarean section and clinical chorioamnionitis [113]. According to the authors, their findings suggest that higher, but seemingly normal maternal glucose concentration predisposes to or is a marker for placental inflammation and infection [113]. Hiller et al. (2007) also reported that increasing hyperglycemia in pregnancy (gestational diabetes) is associated with an increased risk of childhood obesity [114]. In childhood, insulin resistance associated with hyperinsulinemia is a major risk factor for the development of decreased glucose tolerance in obese children. Chamberlain and Burroughs (1962) reported that low levels of fluoride result in partial blocking of normal carbohydrate metabolism and that lower magnesium levels in the presence of fluoride significantly reduced metabolic pathways of cellulose digestion. This inhibition was further increased when low levels of manganese are combined with low levels of magnesium [115]. The evidence of fluoride ability to contribute to diabetes was also reported by Tokar et al (1992) who documented that decreasing insulin concentration and increasing of the C-peptide levels in blood serum were caused by the fluorine intoxication [116]. Available evidence therefore clearly suggests that the risk of obesity in children and adults increases with increasing exposure to fluoride. Epidemiological data supports this observation. According to a recent OECD report the top five OECD countries with the highest incidence of adult obesity are the United States, Mexico, New Zealand, Chile and Australia [117]. It is an acknowledged fact that artificial fluoridation is practiced in each of these countries. The prevalence of obesity in the U.S is 35% for males and 36% for females, Canada 37% for males and 23% for
11 | P a g e
females, Australia 35.6% for males and 21% for females, New Zealand 25% for males and 26% for females [118]. In Ireland, based on the findings from the 2008-10 National Adult Nutrition Survey (NANS), estimated prevalence of overweight in adults is 37%, with a further 24% meeting current body mass index (BMI) criteria for obesity with 26% for males and 21% for females documented as obese[119]. Alarmingly the report noted that the prevalence of obesity in 18-64 year old adults has increased significantly between 1990 and 2011, from 8% to 26% in men, and from 13% to 21% in women. This would place the RoI in sixth place among the top OECD countries with adult obesity, all of which practice artificial fluoridation. The rates of adult obesity in these six countries are more than twice that of countries in the European region, where obesity rates among adults ranged from 6-13% [117]. Given the documented overexposure of infants to fluoride from consumption of formula milk constituted with artificially fluoridated water research would suggest that the risk of obesity is greater for infants. It is noteworthy therefore that Whelton et al (2007) reported the prevalence of obesity in boys and girls in RoI at 7 and 8% respectively [120]. This compares to 2.6 and 2.7% for the Netherlands, 2.8 and 2.8% for Norway, 3.7 and 1.4% for Sweden 3.6 and 3.7% for Poland, 6 and 5.6 % for Italy, 5.8 and 4.2% for Iceland [121]. Furthermore, L.A. Moreno et al. (2011) reported that Ireland had the highest prevalence rates of overweight and obese infants (27.7%). among preschool children 0-6 yrs of age within the European region [121]. It is acknowledged fact that within the European region Ireland is the only country with a policy of mandatory fluoridation of public water supplies, consequently its children are the most overexposed to fluoride within the European region. It should also be noted that glucose intolerance is often a gateway to developing type 2 diabetes [122]. Type 1 diabetes is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addisons disease (AD), and other autoimmune diseases. Thyroid disorders remain the most frequent autoimmune disorders associated with type 1 diabetes [123]. Barker (2006) reported that the prevalence of autoimmune thyroid disease in the population with type 1 diabetes has the potential to affect growth, weight gain, diabetes control, menstrual regularity, and overall well-being [123]. The Russian Academy of Sciences recently published a review (2012) of scientific literature on the molecular toxicity of fluoride, and noted how fluoride induces endoplasmic reticulum (ER) stress [124]. The endoplasmic reticulum (ER) is a cellular compartment responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. Xu C et al. (2005) reported that accumulating evidence suggests that ER stress plays a role in the pathogenesis of diabetes, contributing to pancreatic -cell loss and insulin resistance [125]. ER stress has also importantly been linked obesity and insulin resistance in type 2 diabetes. Disturbances in the normal functions of the ER lead to cell death if ER dysfunction is severe or prolonged. Important roles for ER-initiated cell death pathways have been recognized for several other diseases, including diabetes, heart disease, hypoxia, ischemia/reperfusion injury and neurodegeneration [125].
12 | P a g e
Researchers Menoyo et al. (2005) and Lin et al. (1976) demonstrated the effect of fluoride on glucose metabolism using in vivo and in vitro experimental models and confirmed that biologically relevant doses of fluoride result in impairment of an oral glucose tolerance test and decreased insulin synthesis [126,127]. It has also been reported by Montalvo et al. (2009) that fluoride exposure regulates insulin gene expression in murine beta pancreatic cells, resulting in reduced insulin secretion [128]. Oberley (1988) reported that oxygen radicals are not only involved in the cause of diabetes; they also appear to play a role in some of the complications seen in longterm treatment of diabetes [129]. Importantly, Trivedi et al. (1993) demonstrated that impaired glucose tolerance was reversed when excess fluoride from the water was eliminated [130]. It seems reasonable to suggest that increasing fluoride exposure, as a result of fluoridation, has resulted in increasing pro-inflammatory status contributing to increasing maternal glucose concentrations, increasing fetal growth and pregnancy complications including cesarean section, while also contributing to increased childhood obesity and the prevalence of depressive disorders. Taken together, these findings are very significant especially considering the dramatic increase in depressive disorders and childhood obesity in fluoridated countries combined with the alarming increase in cesarean section. The role of fluoride in impaired glycemic control and insulin resistance as well as promoting free radical production and oxidative stress clearly must be regarded as significant especially given the total dietary exposure of the Irish population to fluorides from consuming artificially fluoridated water and fluoride contaminated food products combined with their consumption of tea, which is very high in fluoride. This is particularly alarming given the recent published findings on dietary fluoride exposure of the UK population which concluded that a significant percentage were chronically exposed to fluoride at levels that were detrimental to their health and general wellbeing [12]. This conclusion was made based on the measured fluoride levels in over thirty individual tea products all prepared with non fluoridated deionised water. Ireland has the highest consumption of tea per capita in the World, above that of the UK and beverages are prepared in Ireland using fluoridated water, consequently the risk of chronic overexposure to fluoride is much greater for consumers in the RoI. Based on the scientific evidence previously discussed, it is obvious that the exposure of the Irish population to fluorides must be examined in the context of the increased prevalence of diabetes and obesity within the population. Evidence suggests that the populations exposure to fluorides is directly contributing to these chronic diseases. According to the HSE, it is thought that one in 20 people in Ireland have diabetes with half still undiagnosed and Type II diabetes is increasing rapidly due to increasing levels of obesity [131]. According to Diabetes Ireland the prevalence of diabetes in Ireland is 6.1 per cent of the population compared to 3.8% for Northern Ireland and 4.45 % for the UK [132]. Diabetes Ireland reports that there are 200,000 people with diabetes and a further 200,000 who have diabetes but are unaware that they have the condition, in addition they report that a further 250,000 people have impaired glucose tolerance or "pre-diabetes" of which 50% will develop diabetes in the next 5 years if lifestyle changes are not made [133]. Type I (insulin dependent) diabetes is increasing in children, particularly in under-fives while Type 2 (non-insulin dependent) diabetes
13 | P a g e
is increasing across all age groups. In the RoI, the incidence of type 1 diabetes is 16.8 per 100,000, which is above the European average [342]. The largest study undertaken in the RoI to date involving 8,800 people without a prior diagnosis of diabetes, aged 45 to 75 years, chosen randomly to attend for clinical evaluation and a fasting plasma glucose test, reported an alarming 11% have tested positive for Diabetes and PreDiabetes [135]. These findings suggest that diabetes prevalence is much higher than previously reported and considering that the Department of Health has reported that people with diabetes are five times more likely to require hospital admission and the risk of major medical complications for people with diabetes is up to 11 times that for people without diabetes [131] present a dire forecast for public health in Ireland.
6. Fluoride Inhibition of Enolase, Health effects and Pathophysiological Mechanisms

The interference of fluoride in normal carbohydrate metabolism is well established. Warburg and Christain (1941) determined that fluoride inhibits enolase by producing a magnesium fluorophosphate which displaces magnesium from the enzyme surface and forms an inactive complex with the enolase [136]. Utter and Werkman (1942) found that the magnesium ion needed with enolase for converting 2-phosphoglyceric acid to phosphopyruvic acid was precipitated by fluoride as an insoluble fluoromagnesium-phosphor-protein complex [137]. Chamberlain and Burroughs (1962) reported that low levels of fluoride result in partial blocking of normal carbohydrate metabolism and that lower magnesium levels in the presence of fluoride significantly reduce metabolic pathways of cellulose digestion [115]. This inhibition was further increased when low levels of manganese are combined with low levels of magnesium [115]. Enolase is the enzyme responsible for the reversible conversion of D-2phosphoglycerate (2PGA) and phosphoenolpyruvate (PEP) in glycolysis and gluconeogenesis, two metabolic pathways that are often vital for cellular function [138]. In addition to its innate glycolytic function new evidence has been recently presented to suggest that enolase plays an important role in several biological and pathophysiological processes including autoimmune disorders, cardiovascular health, inflammatory respiratory disease, cancer, Alzheimer's disease, rheumatoid arthritis, inflammatory bowel disease and general disease prevention[138,139,140]. Wygrecka et al. (2009) further reported that -enolase plays a central role in regulating cellular inflammatory response and in inflammatory lung disease [140]. Thus, inhibition of enolase by fluoride in addition to fluoride exposure increasing calcitonin levels provides another potential link between exposure to fluoride and inflammatory disease. The interference of fluoride in fat metabolism has also been documented. Johnson and Lardy (1950) found evidence to suggest that fluoride inhibits fatty acid oxidation at some step prior to the formation of B-keto acids and subsequent to the oxidation of the unsaturated fatty acid [141]. Geyer et al. (1950, 1951) in investigating fat metabolism found that the utilization of octanoic acid was reduced by fluoride [142,143]. Hodge and Smith (1965) reported that fluoride inhibits lipase resulting in an accumulation of fatty acids [111].
14 | P a g e
7. Fluoride inhibition of Lactate, Health effects and Pathophysiological Mechanisms

Glycolysis may be defined as the enzymatic conversion of carbohydrate into lactate. Recent evidence, and new lines of investigation, now place lactate as an active metabolite, capable of moving between cells, tissues and organs, where it may be oxidised as a fuel or reconverted to form pyruvate or glucose [144]. There is also mounting evidence in support of lactate utilisation in the brain [145], via the astrocyteneurone lactate shuttle, a system clearly capable of affecting substrate delivery and neurone function [146,147]. Sanchea-Abarca et al. (2001) reported that lactate is an important metabolic substrate for the brain during the postnatal period and also plays a crucial role in the traffic of metabolites between astrocytes and neurons [148]. Imagawa et al. (2006) reported that lactate plays an important role in the central nervous system as a metabolic substrate between neurons and astrocytes [149]. Philp et al. (2005) reported that lactate may act as a metabolic signal to specific tissues, becoming a metabolite pseudo-hormone as well as having a role in wholebody coordination of sympathetic/parasympathetic nerve system control in addition to playing a role in maintaining muscle excitability during intense muscle contraction [144]. It is long known that fluoride inhibits cellular production of lactate [150-153]. Astles et al (1994) reported that fluoride also rapidly inhibited production of lactate in whole blood [154]. In a study on energy metabolism in human erythrocytes Feig et al (1971) reported that lactate production was immediately and drastically curtailed in the presence of fluoride while the rate of glucose utilization was reduced more gradually [155]. The authors concluded that fluoride exerts multiple effects on erythrocyte physiology and metabolism. Fluoride inhibited membrane ATPase 40% at 1 mole/litre and completely at 5 and 10 moles/litre [155]. This finding is particular relevance to fluoridation of drinking water as Guy et al (1976) reported that the concentration of fluoride in blood plasma for residents living in fluoridated communities was 1 mol/litre [156].
8. Fluoride, Folate, Health effects and Pathophysiological Mechanisms

The folic acid cycle is an important metabolic pathway that provides intermediates for the reactions of nucleotide synthesis and cellular methylation [157]. Folate is important for the functioning of the central nervous system at all ages of development. Its metabolism provides a methyl, group, via its metabolite 5methyltetrahydrofolate, which is necessary for the remethylation of the neurotoxic amino acid homocysteine back to methionine, an essential amino acid that plays a key role in the generation of methyl groups required for numerous biochemical reactions. Deficiencies in folate induces homocysteine accumulation [158]. Folate deficiency induces neurotoxicity by multiple routes, including increasing cytosolic calcium and oxidative stress via increasing levels of the neurotoxin homocysteine (HC), and inducing mitochondrial and DNA damage[159].
15 | P a g e
It has been suggested that polymorphisms in genes that encode folate-metabolizing enzymes may act as potential risk factors for Down syndrome (DS), through the alteration of maternal folic acid metabolism, leading to centromeric hypomethylation and chromosomal nondisjunction [160]. Wald et al. (2002 reported that elevated plasma homocysteine concentrations are associated with folate deficiency and have been associated with increased risk of ischaemic heart disease and stroke in adult life[161]. An elevated risk of DS has also been observed in the presence of elevated HHcy concentration [162,163]. Poor folate status has been associated with increased risk of cancer, especially colon cancer, possibly due to abnormal synthesis and methylation of DNA[164]. Furthermore, folate deficiency has been linked to abnormal mental function[165]. The metabolism of Folate is a glucose dependent process which is susceptible to metabolic poisons such as fluorides [166-169]. Furthermore while it is known that folate deficiency induce neurotoxicity by multiple routes, it is less well known that folate deficiencies can also compromise health by altering calcium homeostasis [170]. Fluoride is known to induce or exacerbate calcium deficiency by decreasing calcium absorption in the gastro-intestinal tract, thus increasing the bodys calcium requirements [11]. Logically, therefore the health risks for individuals with low folate intake, and low calcium intake are compounded with increasing fluoride exposure. For example, multiple studies have demonstrated that the risk of developing colorectal cancer is increased when both folate and calcium intake are low [171-174]. It is noteworthy also that Fenech et al. (2005) reported that high calcium intake protects against the genome damaging effects of folate deficiency while low calcium intake exacerbate the effects [175]. Considering that folic acid deficiency is one of the most common vitamin deficiency worldwide [176], it is reasonable to suggest that any possible association between fluoride exposure, fluorides inhibition of glucose metabolism, fluorides role in altering calcium homeostasis and fluorides role in inhibition of S-adenosylhomocysteine hydrolase in combination with lower folate levels increasing homocysteine concentrations while also contributing to calcium deficiencies is significant.
9. Fluoride inhibition of Lipase, Health effects and Pathophysiological Mechanisms

Lipase is an enzyme that the body uses to break down fats like cholesterol and triglycerides from ingested foods so they can be absorbed in the intestines. Lipase is primarily produced in the pancreas but is also in the mouth and stomach. Low lipase levels are to be found in Individuals with cystic fibrosis, Crohn's disease, and celiac disease. Among individuals with conditions that can contribute to a lipase deficiency, there is the potential for problems to develop, such as prostate disorders, high cholesterol, an increased risk for diabetes, and difficulty losing weight [177,178]. Langin et al. (2005) reported that decreased lipase activity is a primary risk factor in obesity [179]. Fluoride has been demonstrated to inhibit liver lipase and pancreas lipase [93,180]. Hodge and Smith (1964) reported fluoride at low concentrations (0.005 M) is known to inhibit lipase resulting in an accumulation of higher fatty acids [111].
16 | P a g e
It is now accepted that an accumulation of fatty acids and obesity induce endoplasmic reticulum (ER) stress in liver, which suppresses insulin production and contributes to diabetes [181]. It is further known that fatty acids inhibit hormone-sensitive lipase (HSL) [182]. HSL is has important physiological functions affecting adipocyte lipolysis, steroidogenesis, spermatogenesis, and perhaps insulin secretion and insulin action [183]. Arner (1996) reported that increases in adipocyte lipolysis is a risk factor in obesity and diabetes [184]. Miller and Auchus (2011) reported that alteration to steroidgenesis can contribute to disorders in reproduction, fertility, hypertension, obesity, and physiological homeostasis [185]. Chi et al (1998) reported that abnormalities of phospholipids contribute to hypertension [186]. Importantly, the Food and Nutrition Board of the U.S National Research Council (1952) reported that minimum level of fluoride that produces certain toxic effects for lipase inhibition was 0.2ppm [187]. More recently Guan et al. (2000) showed that the same concentration of fluoride that caused dental fluorosis affected kidney phospholipids [188]. This strongly indicates that the contribution of fluoride from artificial fluoridation to total dietary exposure is contributing to chronic disease and physiological disorders.
10.Fluoride inhibits Calcium Homeostasis

There is no doubt that fluoride possesses the ability to complex calcium, thereby reducing its ionic concentrations [111]. The reduction in calcium ion concentration of the blood plasma and the body fluids could have a number of unfortunate physiological sequelae: muscle contraction is weakened; nerve conduction is depressed,; blood clotting time may be greatly lengthened; cell membrane permeability may be drastically altered, thereby changing the entire pattern of exchange of metabolites in the cell [111]. Fluoride is known to induce or exacerbate calcium deficiency by decreasing calcium absorption in the gastro-intestinal tract, thus increasing the bodys calcium requirements [11]. Vitamin D3 is one of the primary biological regulators of calcium homeostasis [189], low calcium absorption has been linked to reduced vitamin D status [190,191] and low vitamin D levels are associated with increased risk of asthma and asthma morbidity[192]. The toxic effects of fluoride are more severe and complex in geographical areas with low calcium in drinking water and amongst individuals with dietary calcium deficiency. High risk subpopulation groups include growing children, adolescents, pregnant and lactating mothers, because of the greater demands for calcium [193-196]. It is not surprising therefore, that asthma is the most common chronic disease of childhood [197-200]. Prevalence rates have substantially increased in countries with artificial fluoridation, where the highest burdens of this disease are found globally at prevalence rates significantly above (hundreds of percent) those of other developed countries [201-204]. Asthma has been also reported to affect 3.7 to 8.4 percent of pregnant women [205], making it potentially the most common serious medical
17 | P a g e
problem to complicate pregnancy [206]. As noted previously fluoride exposure at biological relevant concentration has been found to elevate calcitonin in humans [11] and elevated calcitonin is an established risk factor in inflammatory lung disease [86]. It is further acknowledged that fluoride exposure can alter both thyroid and parathyroid function contributing to subclinical hypothyroidism, subclinical hyperthyroidism and secondary hyperparathyroidism [11, 207]. Heaney (2003) reported that low calcium intake is associated with increased risk of osteoporosis, thyroid disorders, obesity, colon cancer and hypertension, [207]. It is estimated that 6.5% of the population in Ireland have osteoporosis [208], compared to 3.2% for the UK [209]. This represents 100% increased prevalence in the RoI. As noted previously estimated prevalence of overweight in adults in the RoI is 37%, with 24% documented as obese [119]. According to the National Cancer Registry Ireland, the incidence of colon cancer in Ireland is higher than the European average for both males and females [210]. In 2010, the Institute of Public Health (IPH) reported that more than 950,000 (62.2%) adults aged 45+ years in RoI have hypertension and more than 67,000 (3.7%) adults aged 18-44 years in RoI have clinically diagnosed hypertension[211]. By 2020 the IPH report that the number of adults aged 45+ years with hypertension is expected to rise to more than 1,220,000 (63.1%)[211]. This represents a 28% increase (an additional 270,000 adults aged 45+ years) in ten years. The differences in prevalence rates in the Island of Ireland are remarkable, with more than 75% of adults aged 65 years or over in the RoI clinically diagnosed with hypertension compared to 48% in non-fluoridated Northern Ireland[211].
11.Fluoride inhibits Magnesium Homeostasis

There is no doubt that fluoride possesses the ability to complex magnesium thereby reducing its ionic concentrations [111]. Magnesium is a required cofactor for over 300 enzyme systems [212]. Fluoride forms magnesium-fluoride complexes that have an inhibitory effect on many enzymes. For example, Utter and Werkman (1942) found that the magnesium ion needed with enolase for converting 2-phosphoglyceric acid to phosphopyruvic acid was precipitated by fluoride as an insoluble fluoromagnesiumphosphor-protein complex [137]. Chamberlain and Burroughs (1962) reported that low levels of fluoride result in partial blocking of normal carbohydrate metabolism and that lower magnesium levels in the presence of fluoride significantly reduce metabolic pathways of cellulose digestion. This inhibition was further increased when low levels of manganese are combined with low levels of magnesium [115]. Among its other effects, ingestion of fluoride increases the requirement for certain nutrients. For example, the metabolic requirement for magnesium is increased by fluoride, sequestering it into the skeleton and thereby making magnesium less biologically available [213]. There has been a gradual decline of dietary magnesium in the developed economies in recent decades, largely due to increased consumption of processed foods which are low in magnesium [214]. Magnesium deficiency is now relatively common in many developed countries such as the USA [215]. There are also interactions between magnesium, calcium and vitamin D [215]. During magnesium depletion, intracellular calcium rises. Since calcium plays an important role in skeletal and smooth muscle contraction, a state of magnesium depletion may
18 | P a g e
result in muscle cramps, hypertension, and coronary and cerebral vasospasms [215]. Fatemi et al. (1991) reported that even mild degrees of magnesium depletion, may result in a significant fall in the serum calcium concentration [216]. Magnesium is also important in vitamin D metabolism and/or action [215]. The magnesium ion has an inhibitory action on smooth muscle contraction [217], on histamine release from mast cells [218] and on acetylcholine release from cholinergic nerve terminals [219]. Neuromuscular hyper-excitability is the initial problem cited in individuals who have or are developing magnesium deficiency [220], generalised seizures may also occur [215]. Magnesium has been shown to relax bronchial smooth muscle in vitro by modulating calcium ion transport at the cellular level; low serum concentrations have been associated with diminished respiratory muscle power [221]. It is also suggested that magnesium may decrease the production of free radicals [223] which are a major contributor to inflammation. The Institute of Medicine (1997) reported that a lower dietary magnesium intake was associated with impaired lung function, bronchial hyper-reactivity, and an increased risk of wheezing [215]. Kazaks et al. (2010) reported that magnesium supplementation has been demonstrated to shows improvement in both objective and subjective measures of lung function with benefits for asthma control and quality of life [224]. A particularly high risk group for magnesium deficiency are individuals who consume excessive alcohol [215]. Excessive alcohol has been shown to cause renal magnesium wasting, which, if a diet is marginal in magnesium content, could place an individual at risk for magnesium depletion [215]. Nearly all chronic alcoholics have symptoms of magnesium depletion [215] and intake of alcohol is associated with new-onset asthma in adults [225]. Overall, there is strong evidence to suggest that magnesium plays a protective role in inflammatory respiratory disease. Therefore, any factor that may alter magnesium homeostasis could lead to increased risk of asthma. Marier (1980) reported that increased dietary intake of fluoride reduces intestinal magnesium resorption, owing to high chemical affinity of both elements and production of MgF+ and MgF2 [226]. The fact that large scale epidemiological studies have demonstrated that the highest burdens of asthma are to be found in countries with fluoridation policies further supports this observation [201-204-]. Clearly, therefore it can be ascertained that increased dietary intake of fluoride plays an inhibiting role in magnesium bioavailability thereby increases the health risks associated with magnesium deficiency. Disorders associated with magnesium deficiency include a number of diseases such as metabolic diseases, cardiovascular and neuromuscular function, hypertension, osteoporosis, diabetes and asthma [215].
12.Fluoride inhibition of Manganese metallenzyme arginase

The fluoride ion inhibits the manganese metallenzyme arginase [227-231]. The enzyme arginase metabolizes L-arginine to L-ornithine and urea. Besides its fundamental role in the hepatic urea cycle, arginase also plays a crucial role in the immune system of man. L-arginine deficiency can cause immunosuppression [232] has been found to increase the proliferation of lymphoma cells in mice [233] and has
19 | P a g e
been linked pathogenetically with bronchial hyperreactivity[232]. Arginase also plays a crucial role in tumour immunobiology [234,235]. Arginase was also shown to participate in the suppression of tumour-infiltrating lymphocytes in patients with prostate carcinoma [236] non-small cell lung carcinoma [237] and multiple myeloma [238]. Human granulocyte arginase plays a crucial role in reducing inflammatory reactions by suppression of T-cell proliferation and cytokine synthesis [239]. Consequently, it is reasonable to suggest that arginase inhibitors will increase the risk of inflammatory diseases and cancer. Arginase inhibitors can also potentially interfere with the urea cycle in the liver causing hyperammonemia and associated clinical problems [231] including an increased risk of seizures [240]. 13. Fluoride inhibition of Cholinesterase and Pulmonary disease One of the most significant findings regarding fluoride is that associated with cholinesterase inhibition. It is an established fact that fluorides inhibit cholinesterases, including acetylcholinesterase (AChE) [11,241,242]. The U.S Army Medical Research Institute of Chemical Defence have documented that fluoridated cholinesterase inhibitors were developed by Germany in World War II for use as chemical weapons and tested, manufactured and stockpiled for use. They further document that the principle mechanism of action of cholinesterase inhibitors is pulmonary toxicity [243]. As noted previously fluoride exposure at biological relevant concentration has been found to elevate calcitonin in humans [11] and elevated calcitonin is an established risk factor in pulmonary toxicity [86]. Hoi and Hoskins (1987) reported that inhibition of AChE results in excessive stimulation of cholinergic synapses, which leads to bronchial constriction, laryngospasm, muscle weakness, convulsion, and ultimately death [244]. Hirshman (1992) reported that cholinesterase inhibitors may provoke bronchospasm by increasing acetylcholine (ACh) at parasympathetic nerve terminals [245]. Helou and Rhalimi (2010) reported that cholinesterase inhibitors are associated with increased risk of pulmonary disorders including pneumonia, persistent cough, bronchitis, and asthma [246]. Bardal et al (2011) reported that increased ACh would be expected to cause bronchial constriction as well as an increase in bronchial secretions, both of which could exacerbate the symptoms of asthma and potentially promote an asthma attack [247]. Hilmas et al. (2006) reported that ACh release causes broncho-constriction and that excess ACh at smooth muscles surrounding airways due to AChE inhibition can produce significant increased airway resistance that is readily characterized on inspiratory and expiratory auscultation of the lungs [248]. It has been recognized that the effector muscles of respiration including diaphragmatic, intercostal, abdominal, and accessory muscles of respiration are very sensitive to the toxic effects of AChE inhibitors [248]. In addition, AChE inhibitors are toxic to accessory muscles of respiration leading to an excess of Ach; excessive stimulation of nicotinic cholinergic synapses and eventual flaccid paralysis. Subsequent expansion of the chest wall to inflate the lungs will not occur and respiration will cease [248]. The same biological
20 | P a g e
effect occurs on humans following lethal ingestion of soluble inorganic fluoride resulting in death by respiratory paralysis [93]. In reporting cholinesterase inhibitors it is important also to note that fluorosilicic /hexafluorosilicic acid, the chemical used predominantly for artificial fluoridation dissociates into free fluoride ions, silicic acid or colloidal silica at near neutral pH, but may form silicofluoride complexes at lower pH conditions typical of those found in many common beverages, such as soft drinks[11]. Logically it is therefore also possible that they may be present in the acidic environment of the stomach. Finney et al. (2006) demonstrated that the dissociation of silicofluorides resulted in the creation of either "colloidal silica" or an "oligomerosilicate": the first is a sheet of silicate, the second a string of silica atoms, like beads[249]. Vetch et al. (2012) reported that colloidal silica is also known to act as an acetylcholinesterase inhibitor [250]. Plloth (2012) reported that the toxicity and biological activity of colloidal silica dispersions relate to their ability to absorb to cellular surfaces which can affect membrane structures and integrity [251]. Toxicity is linked to mechanisms of interactions with outer and inner cell membranes, signalling responses, and vesicle trafficking pathways. Interaction with membranes may induce the release of endosomal substances, reactive oxygen species, cytokines and chemokines and thus induce inflammatory responses [251]. Kaewamatawong et al. (2005, 2006) compared the pulmonary toxicity of ultrafine and fine colloidal silica particles after intratracheal instillation in mice. The smaller particles had a greater ability to induce lung inflammation and tissue damage [252,253]. Electron microscopy showed both particles on the bronchiolar and alveolar wall surface and in the cytoplasm of alveolar epithelial cells, alveolar macrophages and neutrophils [252,253]. In view of the preceding comments, it is important to recognise that despite some of the best ambient air quality in the world, the prevalence of childhood and adult asthma in Ireland is now amongst the highest in the world, far greater than any other European country. This has not always been so, in recent decades the prevalence of asthma has increased fivefold in the RoI [254]. This increase has occurred in parallel with implementation of community artificial water fluoridation programmes. Asthma is now the most common and fastest growing chronic disease in the RoI with one in five children now diagnosed with asthma. According to ISAAC data for the period 19992004, asthma prevalence in children across the European study centers varied from less than 5% to over 25%. The highest prevalences of asthma symptoms in children aged 67 years (>20%) and 1314 years (>25%) were found in Ireland. .For the RoI asthma prevalence rates were more than 300% above some member states [255]. The ISAAC protocol Study (19952007) reported that between 1995 and 2007, the symptoms of severe asthma in children living in RoI increased significantly by 39% [256]. The RoI also has the highest hospitalization of 0-14 yrs. olds for asthma among European counties [257]. In addition currently in the RoI diseases of the respiratory system are the cause of one in five deaths, one third of deaths from respiratory disease are due to pneumonia, which is the leading respiratory killer, with COPD the third largest cause of respiratory deaths [258]. Data from the World Health Organisation shows that death rates from diseases of the respiratory system in Ireland are almost double the EU average [259]. According to ECRHS data, the RoI also has
21 | P a g e
the highest prevalence of adult asthma in Europe, twice the European average [201]. Critically, Balanda and Wilde (2001) in a cross sectorial study on all Ireland mortality data by the Institute of Public Health in Ireland, reported that incidence of mortality from asthma and chronic lower respiratory disease were significantly higher in RoI (fluoridated) compared to non-fluoridated Northern Ireland or the EU 15 countries [260]. Based on the published findings and advances in scientific knowledge on the molecular mechanisms of cytotoxicity of fluoride and its role in the in the pathophysiology of disease, it is clearly evident that the direct inhibitory effect of fluoride on energy metabolism in human cells, its inhibitory action on enolase, folate, lactic acid, lipase, arginase, cholinesterase, and homocysteine and its ability to alter calcium and magnesium homeostasis and elevate calcitonin levels may have far reaching consequences for human health.
14.Fluoride, Increased production of Free radicals, Oxidative stress and Cancer

It is well known that low/moderate concentrations of reactive oxygen species (ROS) affect a great number of physiological functions [261]. However, when ROS concentration exceeds the anti-oxidative capacity of an organism, animal cells enter a state termed oxidative stress, in which the excess ROS induces oxidative damage on cellular components [261,262]. As a result, ROS and oxidative stress has been implicated in a large range of diseases, including cancer, diabetes, male infertility, autoimmune diseases, atherosclerosis, hypertension and cardiovascular disorders, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing [263-265]. There is now a vast amount of published scientific data demonstrating that fluoride causes an increase in free radical production, reactive oxygen species and oxidative stress [11, 98,266-294]. A close association between chronic fluoride toxicity and increased oxidative stress has been reported in humans [295-298]. Oxidative stress is commonly measured in erythrocytes since they are susceptible to oxidative reactions because of the presence of polyunsaturated lipid-rich plasma membrane [299]. Fluoride has been demonstrated, both in vivo and in vitro, to increase lipid peroxidation in human erythrocytes [295]. In erythrocytes of children afflicted with skeletal fluorosis, increases in malondialdehyde (MDA) levels, decreases in glutathione (GSH) levels, increases glutathione peroxidase (GSH-px) activity and decreases in superoxide dismutase (SOD) activity were reported[300]. Fluoride inhibits the activities of SOD and GSH-px causing a heavy accumulation of free radicals and hydrogen peroxide resulting in damage to various cells [301]. Wang et al. reported that fluorosis is associated with an increase in lipid peroxides and a decrease in antioxidants [302]. The effect of fluoride in the induction of oxidant stress is attributable to interaction of
22 | P a g e
fluoride ions with the amide groups of thioretinaco ozonide. Conformational change in the binding of thioretinamide groups to the cobalt of thioretinaco by hydrogen bonding with fluoride would be expected to inhibit the binding of superoxide and other oxygen radicals to the active site of oxidative phosphorylation, resulting in inhibition of ATP synthesis and accumulation of oxygen radical species within cells[303]. Furthermore, Sbarra AJ and Karnovsky ML (1959), Gabler et al. (1979-1986) and Curnutte et al.(1979) demonstrated that superoxide radical production by leukocytes is modulated by -fluoride, providing a means for producing intracellular oxidative stress [304-307]. It has been reported that oxidative stress produced by free radicals is greater if fluoride impairs the production of free radical scavengers [298,308,309]. Melatonin is a free radical scavenger and magnesium is also hypothesised to reduce free radicals in humans. The U.S. National Academies reported that fluoride may inhibit melatonin [11]; fluoride also inhibits magnesium homeostasis [111]. It is now acknowledged that free radicals, ROS and oxidative stress increase the risk of developing a wide range of chronic diseases including cancer. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells [261]. The role of free radicals in cancer development was identified as far back as 1996 in the European Journal of Cancer [310]. This fact has also been confirmed by Verschoor et al. (2013) in the journal Cancer and Metabolism [311] . Furthermore, McCully (2009) reported that oxidative stress is caused by failure of ATP synthesis and accumulation of reactive oxygen radicals, theoretically because of inhibition of thioretinaco ozonide function within mitochondria and endoplasmic reticulum [303]. Depletion of thioretinaco ozonide from cellular membranes is suggested to underlie the carcinogenic effects of fluoride and other electrophilic carcinogens [303]. A study by Xu et al (2013) published in the journal Environmental Toxicology documented that fluoride induced reactive oxygen species cause cytotoxicity (toxic to human cells) in human cells [312]. Fluoride has also been demonstrated to directly stimulate activation of G proteins [123,313,314]. G proteins have been implicated in the pathophysiology several diseases including, cancer, cardiovascular diseases, hypertension, neuropsychiatric disorders such as alcoholism and schizophrenia, inflammation, asthma, diabetes and endocrine disorders [315-323] Over reactive G Proteins are characteristic of some tumours [322]. Activation of G proteins has been identified in adrenal and ovarian tumours [324] and in epidermoid carcinoma (skin cancers) [325]. Verschoor ML. et al (2013) reported in the journal Cancer and Metabolism that increased production of reactive oxygen species increases cancer cell proliferation, the growth of new capillary blood vessels that tumours need to grow, contributing to enhanced tumor progression and the spread of cancer within the human body [311]. The consequences of this according to the study will be more aggressive cancer
23 | P a g e
proliferation particularly in prostate, ovarian, breast, and intestinal cancers [311]. Kensler and Trush (1984) reported that the molecular mechanisms of action of free radicals promote tumour growth [326] while Copeland (1986) reported that free radicals play a key role in chemical carcinogenesis [327]. Dreher and Junod (1996) similarly concluded that a large body of evidence suggests important roles of oxygen free radical in the expansion of tumour clones and the acquisition of malignant properties. In view of these facts, they concluded that oxygen free radicals may be considered as an important class of carcinogens [310]. The U.S NRC also (2006) reported that melatonin is to be found in the cells lining the gut from stomach to colon and its functions are mainly protective, including free radical scavenging [11]. The NRC also suggested that fluoride is likely to inhibit melatonin production contributing to a reduction in the ability of the body to fight cancer [11]. These scientific observations are important when one considers that Sainz et al. (2005) reported how melatonin inhibits the growth of several types of cancer cells and markedly influences the proliferative status of prostate cancer cells [328]. Studies have also demonstrated how reduced Melatonin has been linked to both increased incidence of prostate [328] and breast cancer [329,330,331]. Suzen (2006) reported that men with prostate cancer and women with breast cancer tend to have lower levels of melatonin than those without the disease [332]. Schernhammer et al. (2006) also reported how reduced melatonin is associated with increased cancer risk [333]. Reduced melatonin has also been associated with hypertension [334] and Alzheimer's disease [335]. Konturek et al. (2007) reported in the journal of Physiology and Pharmacology that in the upper portion of gastrointestinal tract, melatonin exhibits a wide spectrum of activities such as circadian entrainment, free radicals scavenging activity, protection of mucosa against various irritants and healing of various GIT lesions such as stomatitis, esophagitis, gastritis and peptic ulcer [336]. Bubenik (2002) suggested that low melatonin may be associated with colorectal cancer, ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic [337]. Hardeland (2112) reported that reduced melatonin is associated with numerous disorders and diseases, including Alzheimers disease, autism, schizophrenia, epilepsy, coronary heart disease, cases of cancer, migraine, various other neurological and stressful conditions, pain, cardiovascular diseases, , endocrine and metabolic disorders, in particular diabetes Type 2 [338]. The NRC (2006) also reported that secondary hyperparathyroidism, for which fluoride exposure is a risk factor, may itself contribute to a number of diseases, including colorectal cancer, osteoporosis, hypertension, arteriosclerosis, degenerative neurological diseases, diabetes mellitus and some forms of muscular dystrophy [11]. As noted previously fluoride inhibits folate metabolism and low folate is known to increase the risk of colon cancer [164]. The cancer risk is increased in individuals with low folate and low calcium [171-174]. The NRC (2006) reported that fluoride is known to induce or exacerbate calcium deficiency by decreasing calcium absorption in the gastro-intestinal tract, thus increasing the bodys calcium requirements [11].
24 | P a g e
One of the most distinguishable cancer facts from worldwide epidemiological data is that countries with artificial fluoridation programmes have significantly higher incidences of prostate cancer. For example, Ferlay et al. (2007) reported that the incidence of prostate cancer in the RoI was the highest of all 30 European countries, with incidence rates 75% above the European Union (EU25) [339]. Elevated incidence of prostate cancer is also documented for Australia, Canada, New Zealand, and the USA [340]. Significantly, the US NRC (2006) further reported that fluoride, at levels below the daily dietary intakes levels experienced in communities provided with artificially fluoridated water, contributed to elevated calcitonin in humans [11]. As noted previously Shah et al. (1994), Sabbisetti et al. (2005) and Sha et al. (2008) reported that elevated calcitonin plays a pivotal role in the pathogenesis of prostate cancer [5355]. Alarmingly, Ferlay et al. (2010) reported that there was a 4-5 fold difference in incidence rates of prostate cancer in the RoI, Australia, Canada, New Zealand, and the USA compared to the global incidence rate [340]. Interestingly, Shafique et al., (2012) reported that tea, which is extremely high in fluoride, may be a potentially modifiable and highly prevalent risk factor for prostate cancer in men [52]. Furthermore, Vandenberg et al. (2012) reported that water fluoridation chemicals are recognised as EDCs at low dose levels [56] and the European Environment Agency (2012) reported that there is evidence linking foetal exposure to EDCs with prostate cancer [57]. It has been documented elsewhere that men with prostate cancer have lower levels of melatonin than those without the disease [337]. The NRC reported that fluoride exposure may inhibit melatonin in humans [11]. Furthermore, Sainz et al. (2005) found that melatonin inhibits the growth of several types of cancer cells and reported that melatonin markedly influences the proliferative status of prostate cancer cells [328]. It has also been documented that insulin like growth factor-I (IGF-I) is increased with increasing fluoride exposure [341-344]. Elevated blood levels of IGF-I have been associated with several cancers, most commonly with prostate cancer. A recent metaanalysis of 12 prospective studies reported a 38% increased risk of developing prostate cancer when comparing the highest to lowest quartile of IGF-I levels [345]., It has also been demonstrated that fluoride inhibits the hydrolysis of acid phosphatase [346,347]. The inhibition of hydrolysis will result in elevated concentrations of the enzyme. It has been reported that prostatic acid phosphatase may have a causal role in prostate cancer [348-351]. Apart from the role of elevated calcitonin in prostate cancer [53-55], the incidence of elevated serum levels of calcitonin has also been identified in many other cancers including thyroid, lung and breast, leukemia, ovarian and pancreatic cancers [86,352-357] Interestingly a 2009 study by the Royal College of Surgeons in Ireland reported that "Thyroid cancer has undergone a seismic epidemiology shift in the last 30 years" reporting that between 1973 and 2002 the incidence of thyroid cancer for both sexes increased 240%. Incidence rates for females increased by 300% in the same period [358]. This dramatic increase coincides with the period of commencement of water fluoridation in the RoI.
25 | P a g e
Furthermore the RoI has the highest incidence rate of ovarian cancer in Western Europe, as well as higher incidence rates of colorectal, lung, non-Hodgkins Lymphoma, anaplastic thyroid cancer and pancreatic cancers compared to the European average [359]. Mortality rates for ovarian cancer in Ireland are the highest in Europe. Irish female colorectal cancer incidence is 15% higher than the EU average and males 11% higher [360]. In 2006, the RoI had the second highest incidence of breast cancer in Europe and according to the European Cancer Observatory figures Ireland has the 4th highest breast cancer mortality rate of 30 European countries [361]. Ireland also has the highest incidence of non-Hodgkins lymphoma (for females) in all 27 EU Member States [362]. The HSE have noted that if the occurrence of non-Hodgkin's lymphoma continues to rise at the current rate, it is estimated that it will be as common as breast or lung cancer by 2025 [363]. Perhaps one of the most disturbing findings as documented by the National Cancer Registry of Ireland was that between 1994 and 2004 incidence rates for chronic lymphoblastic leukaemia (the most common form of leukaemia) were 53.5% higher for males and 53.1% higher for females in the RoI compared to Northern Ireland [364]. Incredibly, the report highlighted that male incidence rates increased in Republic of Ireland by 2.8% per year during 1994-2004 while remaining static in Northern Ireland [364]. Inexplicably since 2004, the National Cancer Registry no longer reports the differences in this disease, instead providing a mean of the combined incidence difference for all types of Leukaemia, which for 2009 was 29.6% higher in the RoI compared to NI. However, based on data for the period 1994-2004 and reported rates of increase in the disease in the RoI, it is assumed that for the period 2013 there was a 78.3% increased prevalence of this disease in the RoI compared to NI. Apart from the established cancer risk from calcitonin it is also important to note that research has demonstrated that the fluoride ion inhibits the enzyme arginase [227231]. The arginase enzyme metabolizes L-arginine, and L-arginine deficiency has been reported to cause immunosuppression [232] and increase the proliferation of lymphoma cells [233]. The current All Ireland Cancer Atlas report provides information on cancer prevalences in the island of Ireland between the RoI and NI; the major differences were not confined however to leukaemia [365].Importantly, the report found: The risk of developing many of the cancers presented was higher in RoI than in NI. The risk of non-melanoma skin cancer, melanoma, leukaemia, bladder, pancreas and brain/central nervous system cancers was significantly higher for both sexes in RoI. For men, the risk of prostate cancer was higher in RoI and, for women, cancer of the oesophagus and cervix. The report also concluded that: there was a marked geographical variation in the risk of some common cancers... the most consistent geographical distribution of cancer risk was seen for three cancers (pancreas, brain/central nervous system and leukaemia) which showed an increasing gradient of risk from northeast to southwest. [365].
26 | P a g e
Furthermore, the report documented that the risk for bladder cancer was up to 14% higher in the ROI, Pancreatic cancer up to 22%, skin cancer up to 18%, prostate cancer 29%, oesophageal cancer up to 8%, brain cancer up to 20% and cancer of the cervix and uterus up to 11% higher in the RoI compared to Northern Ireland [365]. The Institute of Public Healths All-Ireland study by Balanda and Wilde (2001) similarly documented significantly increased mortality from these diseases in the RoI compared to NI [260]. Among the disease with significantly increased mortality in the RoI compared to NI were disease resulting from endocrine disorders, immune disorders, neurological disorders, metabolic disorders, hormone related cancers, musculoskeletal diseases and bone diseases such as arthritis. For example, mortality from diabetes was 470% higher, endocrine and metabolic disorders (350%) rheumatoid arthritis (277%) and diseases of the musculoskeletal system (228%) in the RoI compared to NI [260]. Collectively the differences in cancer prevalences are remarkable and demonstrates that the population in the RoI are exposed to an environmental contaminant that is clearly contributing to increased burdens of disease and cancer that is not present in NI. NI remains non fluoridated. It is of immense importance therefore, to note, that the European Medicines Agencys Committee for Medicinal Products for Human Use (2012) determined that calcitonin medicines are associated with increased risk of cancer [366]. As previously noted, the cancers that are associated with elevated calcitonin have all been reported to be elevated compared to international standards in the RoI. While the European Medicines Agency have advised certain calcitonin medication should no longer be prescribed by medical physicians to reduce the increased risk of developing cancer, the Irish Medicines Board remain silent on the health risks posed from artificial fluoridation chemicals for the treatment of dental caries. Dental caries. Is a transmissible bacterial disease [367,369], in certain countries drinking water is treated with a hexafluorosilicic acid for the treatment of this disease. It is logical therefore that artificial fluoridation chemicals are medicinal products used only for the treatment of a disease. As chemical agents it is established that fluoridation chemicals contribute to increased production of calcitonin in humans through increased exposure to fluoride ions. Consequently, water fluoridation chemicals must therefore be regarded as calcitonin medicines, substances which are documented to increase cancer risk in humans. All these findings provide strong evidence that increased fluoride exposure is a significant contributor to cancer disease burdens in the RoI as well as in other fluoridated countries internationally. Epidemiological evidence supports this hypothesis. It is acknowledged that the incidence of cancer in the Republic of Ireland, as shown in Figure 1, is almost twice the mean incidence rate for the European Region. This data is provided by the WHO [370]
27 | P a g e
Figure 1. Comparison of Cancer incidence for RoI and European Region
To put this information in context, in the last ten years alone, this would correlate to an ADDITIONAL 180,000 people in the Republic of Ireland that have been diagnosed with cancer ABOVE the mean EU Regional cancer incident rate for the same period. Furthermore, data from Globocan 2008 provides comparison of cancer incident rates (top 25 cancers) between Ireland and other fluoridated countries internationally and other geographic regions of the world [340]. For the most fluoridated countries internationally including the RoI, Australia, New Zealand, United States, Canada and Israel, .the incidence of cancers, excluding non-melanoma skin cancers, are significantly above the European and world wide global averages Figure 2. Global incidence of Cancer
28 | P a g e
15. Fluoride, Increased production of Free Radicals, Oxidative Stress and Neurodegenerative Disorders
Oxidative stress has been associated with several diseases which are specific for nervous system impairment including neurodegenerative diseases and neuropsychiatric diseases, such as schizophrenia and major depressive disorder [261,262,371,372,373]. It is now accepted that oxidative stress is a part of the pathology in schizophrenia and major depressive disorders and plays a major role in the development of these diseases [261,262,371,372,364,375]. Yan et al. (2013) reported that oxidative stress is a recognized mode of action of fluoride and that fluoride increases the release of inflammatory cytokines and ROS which may exert neurotoxicity on the central nervous system [375]. Similarly, Bouayed et al.,(2009) reported that oxidative stress in the brain causes nervous system impairment and has been implicated in depression, anxiety disorders and high anxiety levels [373]. Fluoride has also been demonstrated to directly stimulate activation of guanine nucleotide binding proteins (G proteins) [111,313,314]. G proteins have been implicated in the pathophysiology of bipolar affective disorder [376]. Melien (2007) reported that G proteins have been implicated in the pathophysiology several diseases including, neurological diseases, inflammation, cardiovascular diseases, cancer, and endocrine disorders [315]. Bharti and Srivastava (2009) reported that fluoride can increase the generation of ROS and lipid peroxidation (LPO) in brain [377]. Shuhua et al. (2012) demonstrated that fluoride induced oxidative stress activates BV-2 microglia cells in the brain providing a potential oxidative stress mechanism for fluoride-related brain damage [378]. The U.S National Academies (2006) further reported that fluoride increases free radicals in the brain that may result in increased risk of certain neurological diseases such as Alzheimers disease and that fluoride complexes diminish the energy essential for brain function [11]. Exposures to fluorides have also been demonstrated to result in increased amounts of inflammatory cytokines [379]. In humans, exposure to elevated cytokines during pregnancy has been associated with neurodevelopmental damage, such as periventricular leukomalacia, cerebral palsy, and mental retardation [380]. In addition to the direct neurotoxic effects of proinflammatory cytokines growing evidence suggests a causal relationship between foetal exposure to proinflammatory cytokines schizophrenia and psychotic outcome in offspring. Specifically. prenatal exposure to maternal proinflammatory cytokines has been found to alter multiple areas of the brain that have been implicated in neurological diseases and these cytokines have been linked to psychotic outcome in offspring [380]. As previously discussed Mathe et al. (1994) found that elevated calcitonin was a marker trait for major depressive disorders [87] and the NRC reported that fluoride exposure contributes to elevated calcitonin in humans [11].
29 | P a g e
Emerging evidence also suggests that genetic polymorphisms may make certain individuals more susceptible to the negative effects of inflammation and are more vulnerable to multiple diseases and infections [380]. This view is supported by evidence published by Zhang et al. (2011) when it was demonstrated that individuals carrying the specific polymorphisms were significantly more sensitive to fluoride toxicity [381]. Consequently, it is likely that carriers of genetic polymorphisms associated with inflammation could be more vulnerable to the damaging effects of prenatal exposure to fluoride, thus increasing the likelihood of psychotic onset in adulthood. Yamaguti et al.( 2013) reported that the ingestion of fluoride at low concentrations impaired anti-oxidative defence systems and caused oxidative stress in experimental animals [382] Bandyopadhyay et al. (2012) reported that fluoride increases free radical production and at the same time inhibits the antioxidant enzymes SOD, GST and catalase, which probably make the tissue more susceptible to biochemical injury [284]. This suggests that exposure to fluoride also increases the risk of developing disease from exposure to other toxic substances, for example aluminium or lead. Uttara et al (2009), Yun-Zhong et al (2002) and Freidovich (1999) reported that overproduction of free radicals can cause oxidative damage to biomolecules, (lipids, proteins, DNA), eventually leading to many chronic diseases such as atherosclerosis, cancer, diabetics, rheumatoid arthritis, post-ischaemic perfusion injury, myocardial infarction, cardiovascular diseases, chronic inflammation, stroke and septic shock, aging and other degenerative diseases in humans [383,384,385]. Uttara et al (2009) further noted that oxidative stress has been documented to cause neurodegenerative diseases such as Parkinsons disease (PD), Alzheimers disease (AD), Multiple Sclerosis (MS) and amyolotrophic lateral sclerosis (ALS) [383]. The U.S National Academies (2006) stated: Fluoride is likely to cause decreased melatonin production and to have other effects on normal pineal function, which in turn could contribute to a variety of effects in humans. The NRC further documented, that reduction in melatonin in humans can result among other things in early sexual maturity in adolescents, increased physiological effects including anxiety disorders, psychiatric disease and sudden death syndrome [11]. Konturek et al. (2007) reported that in the upper portion of gastrointestinal tract, melatonin exhibits a wide spectrum of activities such as circadian entrainment, free radicals scavenging activity, protection of mucosa against various irritants and healing of various GIT lesions such as stomatitis, esophagitis, gastritis and peptic ulcer [336]. Bubenik (2002) suggested that low melatonin may be associated with colorectal cancer, ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic [6]. These latter findings are of particularly concern for public health in the RoI, where the highest incidence rates for schizophrenia are to be found globally [386] and where Ireland has the highest prevalence of depressive disorders in Europe [387]. In addition, according to the WHO the cancer incidence in Ireland is almost double the mean of the entire European Region [370] and the Institute of Public Health have documented that the incidence of Sudden Infant Death Syndrome in the Republic of Ireland is 300% above that of non-fluoridated Northern Ireland [260].
30 | P a g e
It is also relevant to note in the context of what has been reported previously, that the prevalence of diabetes in the Republic of Ireland is 60% higher than in nonfluoridated Northern Ireland. The prevalence of hypertension is 30% higher in RoI compared to NI. The prevalence of coronary heart disease is 40% higher in RoI compared to NI and the HSE has reported that over 725,000 in the RoI suffer from a neurological condition [388]. Anxiety disorders are also the most common class of psychiatric disorders in the US affecting approximately 28.8% of the US population [389]. In stark contrast the European Study of the Epidemiology of Mental Disorders (2004) reported a 12 month prevalence rate for anxiety disorders for non-institutionalized inhabitants from Belgium, France, Germany, Italy, the Netherlands and Spain aged 18 or older of 6.4% and a lifetime prevalence rate of 13.6%.[390]. This dramatic difference in prevalence of anxiety disorders is startling and clearly suggests that artificial fluoridation is a significant factor in contributing to this disease burden. What is even more remarkable is that the total cost of this disease for the US economy was estimated to be $42.3 billion in 1990 [391].
16. Fluoride, Inhibition of Homocysteine, Health effects and Pathophysiological Mechanisms

Homocysteine is a neurotoxic nonproteinogenic amino acid implicated in many pathological conditions including cardiovascular diseases, neural tube defects, and is no recognised as a risk factor in Alzheimers disease (AD) and dementia [158]. There is also growing evidence that different psychiatric disorders such as alcoholism [392], depression [393,394] and anorexia nervosa [395] are associated with elevated plasma homocysteine levels. Homocysteine metabolism has been documented as a risk factor of Down Syndrome (DS). An elevated risk for DS has been observed with irregular homocysteine metabolism [396]. Research has demonstrated a positive relationship between homocysteine levels and increased hostile behaviour in schizophrenia [397]. Homocysteine may also be an important factor in Parkinsons disease [398,399]. Furthermore, it has been found that a high plasma concentration of homocysteine may contribute to epilepsy [400] and cardiovascular disease [401] including ischaemic heart disease, deep vein thrombosis and stroke [161]. Homocysteine circulates in plasma mostly in its oxidised form bound to proteins and is measured as total homocysteine, (tHcy), the sum of free and protein bound. Homocysteine is metabolised to either cysteine or to methionine. A major part of homocysteine is remethylated to methionine. Folate deficiency increases Homocysteine levels Homocysteine elimination is regulated by two metabolic pathways, namely the transmethylation and the transulfuration pathways. Its elimination via these two metabolic pathways is modulated by folate. Folate provides, via its metabolic end product 5-methyltetrahydrofolate, a methyl group that is used to reconvert homocysteine back to methionine through the transmethylation pathway [158].
31 | P a g e
Homocysteine accumulates in the cell and is exported to the circulation system when homocysteine metabolism is impaired [402-405]. Folate deficiency or inhibition of folate metabolism induces hyperhomocysteinemia or homocysteine accumulation [158]. Fluoride inhibition of S-adenosylhomocysteine hydrolase S-adenosylhomocysteine hydrolase (SAHH) is a ubiquitous enzyme that plays a central role in methylation-based processes by maintaining the intracellular balance between S-adenosylhomocysteine (SAH) and S-adenosylmethionine. S-adenosyl-Lhomocysteine is formed from S-adenosylmethionine during methyl transfer, and is hydrolyzed by SAHH to adenosine and L-homocysteine from which methionine is regenerated from N5-methyltetrahydrofolate. Inactivation of this enzyme may take place by two mechanisms, one of which is fluoride dependent. The mechanism of inactivation is through the formation of acylfluorides that bring about deactivation of enzyme activity by forming stable covalent bonds with nucleophilic groups in the enzymes [406]. Muzard et al (1998) and Liu et al. (1996) also documented the role of fluoride in inhibiting SAHH [407,408] This clearly highlights the importance of increased fluoride exposure in the elimination of HCY through the inhibition of folate metabolism which contributes to increased HCY and by contributing fluoride ions which form acylfluorides deactivating the enzymes required for methylation of homocysteine also resulting in hyperhomocysteinemia or the accumulation of HCY in the body. Health effects of Hyperhomocysteinemia Numerous clinical and epidemiological studies have indicated that Hyperhomocysteinemia (Hhcy) is an independent risk factor for atherothrombotic disease. Hhcy is an independent risk factor for cardiovascular disease, including ischaemic heart disease, stroke, and peripheral vascular disease, cerebrovascular disease, in addition to dementia-type disorders, and osteoporosis-associated fractures [409,410]. It has been reported that up to 40% of patients diagnosed with premature coronary artery disease, peripheral vascular disease, or recurrent venous thrombosis present with Hhcy [411]. A meta- analysis of 27 of these studies, including more than 4000 patients, estimated that a 5 mol/L increase in tHcy was associated with an odds ratio of 1.7 for coronary artery disease, 1.5 for cerebrovascular disease or the same increase in risk as for 0.5 mmol/L increase in cholesterol [412]. Substantial evidence has established a connection between HCY metabolism and cognitive function [158]. Abnormal levels of HCY have been related to multiple cognitive dysfunctions including age-related memory loss, vascular dementia, and Alzheimers disease [413-,415]. Miller, (1999) reported that HCY crossing the blood brain barrier or being released by cells within the brain could act as a potent neurotoxin [416]. Another important findings is that studies have found that elevated concentration of tHcy have been observed in patients with renal disease, the increased levels of tHcy are mainly due to impaired removal of homocysteine from the blood by the kidney [417,418] This is particularly relevant to fluoride, as individuals with impaired renal function are a high risk group for fluoride toxicity due to higher retention of fluoride. Elevated concentrations of homocysteine have also been found in children and adolescents with diabetic complications and in children with arterial hypertension [419].
32 | P a g e
These findings are significant as Ruiz at al.,(2007) reported that physical activity, fitness and body fat are not associated with tHcy levels in children and adolescents [420]. Refsum et al., (1991) measured significantly elevated plasma homocysteine levels in children with acute lymphoblastic leukemia prior to therapy [421]. Elevated homocysteine levels have also been reported as a risk factor related to seizures in children with leukemia [422]. Studies have also demonstrated that homocysteine levels are significantly elevated in autistic children [423,424].
17. Fluoride, Free Radicals and Vascular Disease.

Niki (2011) reported that free radicals have been implicated in the pathogenesis of various diseases including atherosclerosis leading to vascular diseases [425]. Gutowska et al.,(2010) reported that chronic exposure of humans to fluorine compounds in water and food may be atherogenic (promote the formation of fatty deposits in the arteries) via the activation of oxidative stress and increased ROS production [59]. Valko et al. (2006) reported that ROS are linked to the pathogenesis of cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, cancer and ageing [261]. Studies have shown, as previously noted, that deficits in thyroid homeostasis [74,75,85,426,427] and increases in homocysteine are associated with significantly increased cardiovascular risk[76,401] including ischaemic heart disease, deep vein thrombosis and stroke [161]. A meta-analysis of 14 epidemiologic studies (Rodondi et al., 2006) found an overall increase in risk of coronary heart disease (CHD) of over 65% in those with subclinical hypothyroidism (elevation in TSH with normal T4) [85].Wald et al. (2002) conducted a meta-analysis to determine if there is a causal relationship between elevated homocysteine (HCY) levels and inflammatory heart disease, stroke and deep vein thrombosis (DVT). The authors found that there were significant associations between HCY and the diseases [161]. Fluoride inhibits folate metabolism [166-169] and deficiencies in folate induces homocysteine accumulation [158]. It has been reported that fluoride is a risk factor in both the development of obesity and diabetes [103]. It is now known that biologically relevant doses of fluoride results in impairment of glucose tolerance or increased blood glucose and decreased insulin synthesis [98]. Research published in 2010 demonstrated that fluoride also affects the aorta (main artery) and heart in ways that lead to increased heart attacks [428,429] This confirms earlier studies showing that high blood-fluoride levels have an effect on body calcium, leading to calcification of the aorta and other arteries[430,431]. Turla et al. (1985) observed that fluoride inhibits calmodulin [432]. Pogwizd and Bers (2002) reported that loss of calmodulin activity has been linked to congestive heart failure as characterized by a high incidence of Sudden Adult Death Syndrome (SADS) [433]. Considering that the RoI has one of the highest prevalences of adult SADs in the world, this finding is particularly alarming and clearly suggests that fluoride exposure may play a role in the high burden of SADs in this country.
33 | P a g e
Varol et al. (2010a, 2010b) examined the effect of fluoride exposure on cardiovascular system in a clinical setting and observed that elastic properties of ascending aorta were impaired in patients with endemic chronic fluorosis and that chronic fluoride toxicity can cause aortic stiffness in patients as well as ventricular diastolic and global dysfunctions [434,435]. Furthermore Varol et al. (2012) found that fluoride toxicity can cause atherosclerosis at molecular level, as well as aortic stiffness and disturbed ventricular distensibility at clinical level [435]. Research has also demonstrated that fluoride accumulates in aorta vascular walls and that a significant correlation exists between fluoride uptake and coronary calcifiation [436]. Evora and Nobre (1999) reported that the loss of function of adenylate cyclase in the ischaemic myocardium is caused by the action of free radicals [323]. It has also been documented by Takamori et al. (1956) that fluoride damages the heart muscle, especially in subjects deficient in Vitamins A and D [437]. Iwasi et al. (1956) observed that fluoride decreases the energy building glycogen in heart muscles [438] Ma et al. (2012) investigated the effect of exposure to fluoride alone on inflammatory response in rabbit aorta and found that fluoride increased the expression of VCAM-1, P-sel, MCP-1, IL-8, and IL-6 at the RNA and protein levels [439]. All of these individual factors are now known to play a critical role in development of heart disease [440-448]. Fluoride has also been demonstrated to directly stimulate activation of G proteins [124,313,314]. Melien (2007) reported that G proteins have been implicated in the pathophysiology several diseases including, cardiovascular diseases, neurological diseases, inflammation, cancer, and endocrine disorders [315]. Kots et al. (1993) reported that patients with increased Gi-proteins showed a more severe deterioration of their coronary arteries than those with decreased Gi-proteins [449]. Varol (2013) reported that water borne fluoride can contribute to high blood pressure (hypertension) in humans [213]. Hypertension can lead to atherosclerosis and narrowing of the blood vessels making them more likely to block from blood clots or bits of fatty material breaking off from the lining of the blood vessel wall. Damage to the arteries can also create weak places that rupture easily or thin spots that balloon out the artery wall resulting in an aneurism [450]. Most strokes (about 80%) are ischaemic, and most of those are caused by atherosclerosis. It is now established that insulin affects coronary artery calcification [56]. The NRC (2006) reported that fluoride affects insulin sensitivity and glucose tolerance [11]. Fluoride has been documented to cause biphasic responses in human, bovine, and porcine coronary arteries by stimulating G-proteins to release EDRF (endotheliumderived relaxing factor) [323]. Vasospasms have been shown to be a biphasic phenomenon [451] and are known to be a major risk factor in ischemia and strokes [452]. The dysfunction of G-proteins in the endothelium has also been postulated as responsible for the endothelial dysfunction in conditions of endothelial cell regeneration after injury, atherosclerosis, and coronary vasospasms [323]. Kanbay et al. (2012) reported that increased calcitonin levels are associated with greater severity of coronary artery disease (CAD) [60]. The US NRC (2006) reported that daily dietary intake levels of fluoride below 4mg per day have been demonstrated to contribute to elevated calcitonin in individuals [11].
34 | P a g e
The European Food Safety Authority reported that dietary fluoride intakes of > 6.5mg per day can occur among individuals in fluoridated communities [5]. The NRC (2006) reported that dietary intake levels can exceed 9mg per day among tea drinkers [11]. Interestingly, Tokushima (1961) found that children with dental fluorosis have a higher incidence of heart damage than those without fluorosis [453]. Similarly, Wang et al.( 1997) reported an increase in abnormal heart rhythm in patients with dental fluorosis [454]. These findings are of considerable importance considering that the York Review (2000) reported that artificial fluoridation of water is known to significantly contribute to dental fluorosis [455]. It is alarming therefore to note that O Mullane et al. (2003) Browne et al. (2005) and Verkerk et al. (2010) observed that the prevalence of dental fluorosis, representing chronic overexposure of the population to fluoride, has reached endemic proportions in Ireland due primarily to artficial water fluoridation [456-458]. Remarkably the study by O Mullane et al. identified that the prevalence of dental fluorosis in communities with no fluoridated water was as low as 1.5% compared to 37% in fluoridated communities [456]. The significance of these findings is self-evident, especially when one considers, as noted previously in this report, the established role of fluoride in increasing free radical production, ROS, oxidative stress and calcitonin in humans, as well as the role of fluoride in lipase inhibiting which results in an accumulation of higher fatty acids. It is obvious that any role of fluoride exposure in increasing the risk of cardiovascular disease is significant particularly given that the clinical manifestations of atherothrombotic disease, cardiac arrhythmias, myocardial infarction and stroke account for the majority of deaths especially in countries which practice artificial fluoridation. For example, the RoI has the second highest mortality rate from ischaemic heart disease in the Western Europe [117] and premature deaths from ischaemic heart disease for individuals under 65yrs of age in Ireland averaged 25 per 100,000, compared to 18 deaths in the EU15 and 24 in the EU27 [459]. From 2000 to 2004 Ireland had on average 144 deaths from coronary heart disease per 100,000 of the population, which was higher than EU 15 of 92 deaths per 100,000 and higher than the EU 27 of 113 deaths per 100,000 [460].
The only country with a higher incidence of CHD to Ireland in Europe is Finland. The incidence of CHD in Finland can be explained largely by the extremely low calcium levels present in drinking water. Calcium levels in drinking water sourced from springs in Finland have been found to contain less than 6mg/l calcium and from shallow and deep wells less than 20mg/ [461] In Finland, the proportion of drinking water sourced from groundwater is approximately 60% compared to 50% for Sweden and 20% for Norway. Since the early 1960s, epidemiological studies have reported that soft waters (i.e., water low in calcium) are associated with increased morbidity and mortality from cardiovascular disease (CVD) in particular cardiovascular, ischaemic heart and hypertensive heart diseases [462-464]. Elevated natural fluoride concentrations due to bedrock geology are found in the most populated regions of Finland primarily in the south eastern and south western parts of the country [465]. In the areas covered by rapakivi granites, fluoride concentrations in water pumped from wells drilled into bedrock generally vary between 0.5 and 3.0 mg/l [466]. 35 | P a g e
18. Fluoride, Inflammation and Disease

The U.S National Academies (2006) reported that fluoride is a pro-inflammatory agent that increases the inflammatory response to irritants in humans [11]. Chronic and low grade inflammation forms the basis of many human diseases ranging from type 2 diabetes and depression to heart disease, many forms of cancer, and even dementia [467]. Notably, low dose endocrine disrupting agents have also been identified as inducers of inflammation [468,469]. Fluoride is acknowledged as a low dose endocrine disrupting agent [53,11]. As noted previously, the NRC (2006) reported that fluoride can alter the normal endocrine function at dietary intake concentrations significantly below the typical dietary intake levels present in fluoridated communities. Musculoskeletal Pain Inflammation is also a major contributor to chronic musculoskeletal pain [470]. The US NRC (2006) reported that excessive intake of fluoride will manifest itself in musculoskeletal disease with a high morbidity [11].According to the WHO the RoI has the second highest morbidity from musculoskeletal disease [434]and rheumatoid arthritis in the European Region [471] It has been scientifically observed and documented that the early stages of (sub-clinical) fluorosis is usually associated with stiffness, backache and joint pain which may suggest the diagnosis of rheumatism, rheumatoid arthritis, ankylosing spondylitis and osteomalacia.[472-480]. The U.S National Research Council Scientific Committee reported that excessive intake of fluoride will manifest itself in a musculoskeletal disease with associated symptoms such as chronic joint pain, arthritic symptoms, calcification of ligaments and osteosclerosis of cancellous bones. In patients with reduced renal function the potential for fluoride accumulation in the skeleton is increased. People with renal insufficiency will have elevated plasma fluoride concentrations compared to normal healthy persons. [11] The scientific committee found that lifelong exposure to fluoride at 2mg/L fall within or excess the range associated with Stage II and Stage III skeletal fluorosis. [11] The figure of 2mg/L must be examined in the context of total dietary fluoride intakes from consumption of liquid beverages, not just water. In Ireland, the main beverage consumed by adults is tea, which may have fluoride content in the range of > 6mg/L when prepared with fluoridated tap water. The NRC reported that fluoride intakes from consumption of tea can exceed 9mg/day for some individuals [11]. As noted previously Chan et al.(2013) reported that excessive dietary intakes of fluoride from consumption of tea based on measured fluoride concentrations of beverages can be detrimental to the health of consumers [15]. This study was conducted by measuring the fluoride content of tea prepared with deionised water. For consumers in areas with artificial fluoridation of public water the risk of chronic exposure significantly increases as artificial; fluoridation of water increases in the fluoride content of all foods and beverages prepared with public water. While musculoskeletal pain is one of the most easily recognisable symptoms of overexposure to fluoride brought on from excessive quantities of fluoride deposited in the skeleton and soft tissues, it is apparent that in most western countries fluoride exposure is never examined when treating patients for chronic musculoskeletal pain.
36 | P a g e
To my knowledge, no study has ever been undertaken in the RoI or other country with fluoridation policies to determine if individuals with symptoms of chronic musculoskeletal pain have a high dietary exposure or sensitivity to fluoride. This is remarkable especially for the RoI given dietary exposure to fluoride and particularly when musculoskeletal pain involving bones, muscles, ligaments, tendons, and nerves has been reported as the most widely reported condition amongst the wider Irish population [481]. It has been reported that in the RoI approximately 400,000 adults suffer from chronic back pain alone [482]. In addition it has been reported that some 34% of women and 23% of men in the RoI are affected by arthritis [483]. It is estimated that 18% of arthritis patients are less than 55 years old, while 1,000 Irish children are living with juvenile arthritis (JA) and it has been reported that by the year 2030 one quarter of adults aged 18 years and older will have doctor-diagnosed arthritis [483]. Susheela and Bhatnagar (2002) reported how in a study of 10 individuals with clinical manifestations of fluorosis with musculoskeletal pain including chronic joint pain and arthritic symptoms, that a diet with adequate levels of calcium, vitamins C and E, and other antioxidants and access to drinking water with low levels of fluoride resulted in a decrease in urinary and blood fluoride levels and after a period of one year there was complete recovery of muscular weakness, polyuria, polydypsea, pain and rigidity in the joints as well as gastrointestinal complaints.[480] I can testify as an individual who was diagnosed with a chronic inflammatory disease from gross tendonitis arising from calcification of shoulder ligaments, that in the seven years that I suffered this extremely painful and debilitating condition not once did a medical consultant, medical physician or therapist question if my condition was associated with fluoride exposure; even when chronic joint pain and calcification of ligaments is a recognised determinant of early stage skeletal fluorosis [11]. Despite years of physical therapy, cortisone injections and prescribed medications for pain management, I was finally only able to make a complete recovery by reducing my fluoride intake, principally through avoidance of fluoridated water for drinking or food preparation. Through elimination of fluoride from my diet within a period of weeks the pain levels and inflammation subsided dramatically and I have made complete recovery. I would not have known that I suffered from significant calcification of my ligaments without undertaking a MIR scan, an action that ultimately diagnosed my condition. I would also not have started my research into artificial fluoridation without being a victim of prolonged exposure to fluoride, which in my case started from birth as a bottle fed infant residing in a community with artificial fluoridation of public water supplies. As a result of my previous health problems I continue to avoid fluoridated public water supplies for drinking or food preparation. Inflammatory Bowel Diseases Inflammatory Bowel Diseases (IBD) is a broad term that describes conditions with chronic or recurring immune response and inflammation of the gastrointestinal tract. It is acknowledged that environmental factors play an important role in the disease [474].
37 | P a g e
The two most common inflammatory bowel diseases are ulcerative colitis and Crohns disease. IBD is considered to be common in the Western world, and its incidence has sharply increased during the last few decades [485-488]. There are marked variations with higher prevalence rates reported in North America and in countries with Anglo Saxon ethnic derivation. However Shivananda et al. (1996) reported that when Asian people migrate from countries of low incidence of the disease to urban-industrial societies of the West, they become as susceptible to the disease as the population of their host countries, suggesting environmental factors in the aetiology of Crohns disease [489]. The same pattern has been found for inflammatory respiratory disease. For both inflammatory diseases the countries with the highest burdens are predominantly those with artificial fluoridation of public water supplies such as Australia, New Zealand, US, Canada, the RoI and the UK. Within the island of Ireland, there is a significant variation in the incidence of IBD between non-fluoridated NI and the RoI. For example, the reported incidence rates for Crohns disease in RoI are 5.9 per 100,000 population [490], which is more than twice that reported for Northern Ireland [491]. Similar incidence rates as reported for the RoI have been found in the USA, Canada, New Zealand and Australia [492-495], all countries with artificial fluoridation of public water supplies. Hope et al. (2012) reported that the RoI has one of the highest rates of childhood inflammatory bowel disease in the world. Alarmingly, the research reported a 90% increase in cases of childhood IBD in the past decade [496]. In the RoI, it is now estimated that 1 in 180 of the population are affected by the disease [487]. Since commencement of artificial fluoridation in New Zealand, in the past fifty years there has also been a dramatic rise in the incidence of IBD [498-501]. Similarly Australia has one of the worlds highest rates of IBD internationally [502]. In the UK, significant regional variations have been reported with a higher incidence of CD to be found in Newcastle, in the North East of England [503]. Interestingly, Newcastle is one of the few regions of England with artificial fluoridation of public water supplies. Similarly, in Canada, marked variations in incidence have been reported, with incidence rates in fluoridated providences such as Alberta and Nova Scotia twice that of non-fluoridated regions such as British Colombia [503]. ubuku (2005) investigated the gastric effect low fluoride exposure (0.5ppm) and demonstrated that low fluoride levels can damage histological structure in gastric mucosa, due to the formation of hydrofluoric acid (HF) in the stomach [504]. A similar study by Easmann et al (1985) demonstrated that fluoride exposure produced a much greater degree of damage and cell loss (due to the formation of hydrofluoric acid) than that from naturally occurring hydrochloric acid, a strong acid that helps to break down food in the stomach [505]. Adverse effects of topical fluoride preparations on gastrointestinal tract have also been demonstrated in several other studies [506-514]. In examining the effect of fluoride on gastrointestinal tract Susheela AK, et al. (1992) concluded that ingested fluoride damages gastroduodenal mucosa and that gastrointestinal discomfort can be an early warning sign of fluorosis [515]. The NRC (2006) reported that the primary symptoms of GI injury are nausea, vomiting, and abdominal pain [11]. Such symptoms have been reported in case
38 | P a g e
studies [516,517] and in a clinical study involving double blind tests on subjects drinking water artificially fluoridated at 1.0 mg/L [518]. Feltman and Kosel (1961) determined that about 1% of subjects complained of GI symptoms following exposure to 1.2mg/L fluoride [519]. In examining the overall evidence the NRC concluded that one can rule out the influence of poor nutrition (the absence of dietary calcium in the stomach) contributing to the GI upset from fluoride ingestion [11].The NRC noted that early clinical trials on fluoride and osteoporosis involved administration of fluoride as enteric coated tablets along with calcium supplements, which would have reduced the gastric effect of fluoride[11]. Furthermore the NRC observed that it is important to realize that GI effects depend more on the net concentration of the aqueous solution of fluoride in the stomach than on the total fluoride dose in the fluid or solid ingested. The presence of gastric fluids already in the stomach when the fluoride is ingested can affect the concentration of the fluoride to which the gut epithelium is exposed [11]. The effect of fluoride exposure and its potential contribution to gastric distress in infants has never been properly examined. However a study by Scariati PD et al. (1997) in fluoridated USA, compared exclusively breastfed infants, with infants who were exclusively formula-fed and found that bottle fed infants had an 80% increase in their risk of developing diarrhea [520].
Skin Disorders Roholm was the first to document the pre-skeletal phase of chronic fluoride intoxication in patients. Symptoms included gastrointestinal, circulatory and respiratory disorders, neuromuscular pain, neurological and dermatological disorders [521]. Harold (1945), Schwartz (1942) and Tome (1949) reported irritation of the skin and dermatitis in workers exposed to fluorides [522-524]. Other references on the effects of fluorides on skin include Feltman (1956), Kaplan (1952), Klauder et al. (1955), Waldbott (1955,a,b,c) Waldbott (1956 a,b) and Demole & Held (1953) [525533]. In examining the burden of disease among residents in the environs of fluorideemitting aluminium and fertilizer factories in Ontario and British Columbia, Canada; Bolzano, Italy; and Southern Ohio, USA, George Waldbott M.D. noted the same observations as Roholm, including skin disorders among patients exposed to fluorides [534].Exposure to fluorides in an occupational work environment was identified as a cause of acne by Epstein a German clinical physician [535]. In one of the most significant large scale double blind clinical studies undertaken Feltmann and Kosel (1961) in a fourteen year study on prenatal and postnatal exposure to fluorides reported that a percentage of the population reacted adversely to fluoride [519]. These reactions occurring in children of all ages in the study group affected the dermatologic, gastro-intestinal and neurological systems. Eczema, atopic dermatitis and urticaria occurred with the use of fluorides and disappeared upon use of a placebo only to reoccur again when a fluoride tablet was unknowingly given to the patient [519].
39 | P a g e
Maculae degeneration is a relatively common skin disorder more frequently seen in women and children. Waldbott and Celcilioni (1969) reported skin lesions-Chizzola maculae inflammation around the capillary blood vessels-on the skin of individuals exposed to fluoride in the neighbourhood of an aluminium factory in Chizzola Italy [536]. The health Authorities subsequently established that exposure to fluoride was related to the lesions [537]. In 1980, Giovanazzi et al. reported that the prevalence of maculae was significantly higher in children from Chizzola than from a control population of children. For example they reported that more than 65% of students in elementary school in Chizzola presented with maculae while only 13% were positive in the control group. This rose to 90% of children in secondary school compared to 12% in the control group [538]. Waldbott also reported that dermatitis and hives are not uncommon following intake or, or bathing in, fluoridated water [539]. The occurrence of contact dermatitis from the use of fluoridated toothpaste containing 0.1% (1000ppm) fluoride has been confirmed by several investigators`; moreover, controlled patch tests for sodium and stannous fluoride were positive [540,541]. Modely et al. (1987) reported that the dermatologic manifestations of fluoride/fluorine exposure have not been fully examined and recommended that detailed studies be undertaken examining skin disorders correlated with gross pathology, specific histopathology, and plasma levels of fluorine [542]. Williams et al (1999) reported that skin disorders such as atopic eczema exhibit wide variations in prevalence both within and between countries inhabited by similar ethnic groups, suggesting that environmental factors may be critical in determining disease expression [543]. In a study undertaken in Finland Lamberg et al (1997) reported that the significant decrease in the number of other skin disorders post cessation of fluoridation appears to support the view that a segment of the population may have some kind of intolerance to fluoride [544]. Bowcock et al (2004) also reported that exposure to environmental toxins play a role in the development of skin disorders such as psoriasis and concluded that environmental causes of psoriasis may include chemical injury to the body [545].
Skin Diseases in Ireland Skin disease is a serious and common problem in Ireland. Many significant skin disorders are increasing in incidence. Skin conditions are the fourth most common reason for GP visits in Ireland. Each year, 15% of all GP visits are attributed to a skin complaint. The prevalence of skin diseases such as skin cancer, leg ulcers and atopic eczema has increased steadily over the past 20 years. And today, between 25% and 33% of the Irish population suffer from a dermatological condition at any one time [546].
40 | P a g e
Atopic Eczema Studies also show that up to 20% of Irish children have suffered from atopic eczema by the age of four [547]. For the UK it is estimated at 12-15% [548]. Williams et al reported higher prevalences of atopic eczema symptoms in Australia, New Zealand and Northern Europe (Ireland/UK/Scandinavia), and lower prevalences were reported in Eastern and Central Europe and Asia. In comparison to Ireland the prevalence of atopic eczema was 2% in Iran and 1% in Albania [549]. Harrop et al. (2007) reported the 12-month period prevalence of eczema from 25 European centers. The prevalence ranged from 2.2% in Switzerland, Spain (4.2%), Germany (5.1%), Belgium (5.9%), France (8%), Sweden (9%) and Italy (6.6%) [550]. In comparison, Hanifin et al. reported eczematous symptoms in 17.1% of the US population [551]. In New Zealand the prevalence of eczema in children is between 15-20% [552]. Gold and Kemp (2005) reported that atopic diseases such as eczema affect 23% of Australia children aged between 6-7 years of age and 16% of 13-14 year olds [553]. Robertson et al. (2004) reported that the lifetime prevalence of atopic eczema symptoms in 67 year olds in Melbourne (fluoridated) increased significantly from 22.6% in 1993 to 32.3% in 2002 [554] Grize et al. (2006) reported that the lifetime prevalence of atopic eczema symptoms increased in 57 year old children in Switzerland from 11.7% (1992) to 17.4% (2001) [555]. Switzerland has the highest market share of fluoridated salt in the European region and commenced a national salt fluoridation programme in 1983. The market share of fluoridated salt in 1986 was 73%, however during 1992 this fell to 48-55% due to technical problems. These problems were resolved in 1994 after which the market sales of fluoridated salt peaked at 83% and remain at this level [556]. It is noteworthy that the prevalence of atopic eczema was 48% lower when sales of fluoridated salt were significantly decreased. The evidence clearly indicates that the highest burdens of the disease are to be found in countries with artificial fluoridation with prevalences rates more than double those of most non-fluoridated countries. Interestingly, Lerma et al.(2009) reported a high prevalence of clinically diagnosed atopic dermatitis (35.8%) among children in the Canary islands [557]. The Canary islands are volcanic islands and it has been reported that drinking water has elevated fluoride levels ranging from 2.50 and 4.59 mg l [558].
Psoriasis Psoriasis has a worldwide distribution with prevalence varying according to race and geographical location. Prevalence of psoriasis varies in different parts of the world. For most of the data given, the range extends from around 0.5% to close to 2.5% [559]. Psoriasis and atopic dermatitis (AD) are chronic and relapsing inflammatory diseases of the skin associated with various immunologic abnormalities. Approximately 30% of psoriasis patients also have joint involvement, indicative of psoriatic arthritis. The immune system has been strongly implicated in the pathogenesis of psoriasis [560]. It is now hypothesised that psoriasis is an autoimmune disease with defects in self-tolerance [561]. The latter study by Bowcock et al reported that exposure to environmental toxins as well as genetics play a role in the development of psoriasis and AD. The authors noted in particular that
41 | P a g e
environmental causes of psoriasis may include chemical injury [561]. As previously noted Bandyopadhyay et al. (2012) reported that fluoride increases free radical production and at the same time inhibits the antioxidant enzymes SOD, GST and catalase, which probably make the tissue more susceptible to biochemical injury [284]. Prevalence of Psoriasis in Ireland Ireland has one of the highest prevalence of psoriasis in the world with an estimated prevalence of more than twice the global average at 5.5% within the population [562564]. Psoriasis is one of the commonest skin diseases seen in dermatological practice in Ireland [565]. Based on the above figures psoriasis is the most prevalent autoimmune disease in Ireland affecting over 200,000 individuals. In a recent study conducted in Ireland it was reported that the prevalence of psoriasis increases to 15% in patients who misuse alcohol [566]. This latter finding is particularly relevant to Ireland as alcoholic beverages produced in Ireland contain more fluoride than any other similar EU product, due to the fact that fluoridated water supplies are used in the manufacturing process. Warnakulasuriya et al. (2002) reported mean fluoride concentrations of 0.080.71mg/L in beers available in Great Britain; with one Irish beer contained fluoride at 1.12mg/L[567]. The authors of the latter study concluded that beers brewed in locations with high fluoride water levels may contribute significantly to the daily fluoride intake, particularly in alcohol misusing subjects and this may contribute to alcohol-associated bone disease [567]. Drzdz et al. (1980) reported that pre and post natal exposure to 10mg/L of fluoride in drinking water resulted in a decrease of soluble and insoluble collagen in skin and lungs of exposed rats [568]. The decease of collagen was not age-dependent. The NRC scientific committee compared the fluoride bone concentrations in humans and rats on the basis of drinking water concentration and observed that the results suggest that rats require water concentrations 10 to 20 times higher than humans to achieve comparable concentrations [11].
19. Fluoride and Epilepsy

Epilepsy is the most common serious brain disorder world-wide. It is the second most commonly seen neurological condition in primary care, and the most commonly seen among neurologists. This report has already documented how fluoride exposure can increase the risk of epilepsy through reduced melatonin, inhibition of folate, arginase and S-adenosylhomocysteine hydrolase. It is not surprising therefore to find that the prevalence of epilepsy in the RoI is significantly above the European prevalence rates. The prevalence of epilepsy in Ireland for 20-64 years is 10-11 per 1000 and in ages 65 and older 15-16 per 1000. Between 2002 and 2005 the prevalence of treated epilepsy increased by an alarming 7%. National Irish self report data collected through collaboration with the Central Statistics Office (CSO) through their Quarterly National Household Survey (QNHS), a nationwide population-based survey revealed that nationally 10 per 1,000 persons over the age of 18 years self-reported that they had received a diagnosis of epilepsy by a doctor [569]. The UK has an adult prevalence of 6.1 per 1000, Northern Ireland 7.6 per 1000, Wales 7.3 per 1000 and Scotland 7.3 per 1000 [570]. The prevalence of epilepsy in Europe for 20-64 years is 6 per 1000 and in ages 65 and older 7 per 1000 [571].
42 | P a g e
The lower prevalence in Europe is statistically significant. It is not surprising, based on the information presented so far, to observe that the USA, has similar epilepsy prevalence rates to that of the RoI [572]. The USA, like the RoI has advanced artificial community water fluoridation programmes providing artificially fluoridated water to over 60 per cent of the population. The similarities would again strongly indicate that the policy of artificial fluoridation of drinking water is contributing to this neurological condition among the population.
20. Conclusion
It is evident that pro inflammatory inducers such as highly soluble inorganic fluoride, from artificial fluoridation of water, are recent and manmade. The recent increase in chronic inflammatory diseases coincides with the period of commencement of fluoridation worldwide. The fact, that most chronic diseases have also risen to prominence during this time (albeit along with an aging population) and importantly, that the highest burdens of inflammatory and other associated diseases are typically to be found in artificially fluoridated countries such as the USA, Australia, Republic of Ireland, New Zealand and Canada would clearly suggest a causal role for artificial fluoridation in contributing to chronic disease burdens. Where exposure to pro-inflammatory agents persists, the response over time may become chronic. This is evident in the accumulation of fluoride in humans living in fluoridated regions which have been found to be significantly higher than those of non-fluoridated communities. Because fluoride is a bioaccumulative toxin continued exposure results in significant accumulation of this toxin in human tissues over the individuals lifetime. In addition, the impact of chronic overexposure of infants to fluoride is resulting in unprecedented epidemics of metabolic and neurological disorders with catastrophic healthcare, societal and economic consequences. The economic costs alone are staggering and the implications for future generations are enormous. The preponderance of scientific data clearly demonstrates that increasing fluoride exposure of the population through artificial fluoridation is contributing to a wide range of chronic diseases that are prevalent in certain countries today. It is clearly evident that increased fluoride exposure has a direct inhibitory effect on energy metabolism in human cells and that the inhibitory effect of fluoride on enolase, folate, lactic acid, lipase, arginase, cholinesterase, calcium and magnesium homeostasis, in addition to inhibition of homocysteine, combined with fluorides contribution to increased production of free radicals, oxidative stress and elevated calcitonin levels, is having far reaching consequences for human health, ultimately contributing to a wide range of chronic diseases that are known to have particularly high prevalences in countries with artificial fluoridation programmes. The evidence is now irrefutable, artificial fluoridation is contributing to low level chronic poisoning of the population and poses a real and immediate threat to life, public health and safety. Immediate action must be taken by public health authorities to end this policy.
43 | P a g e
References
[1] Medical Research Council working group report: Water fluoridation and health, September 2002 [2] FNB (Food and Nutrition Board) (1997). Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Institute of Medicine National Academy Press, Washington DC. [3] Critical review of any new evidence on the hazard profile, health effects, and human exposure to fluoride and the fluoridating agents of drinking water, a report produced in 2011 by the SCHER (Scientific Committee on Health and Environmental Risks) of the European Commission. [4] Estimated Dietary Fluoride Intake for New Zealanders, Institute of Environmental Science & Research Limited , Christchurch Science Centre, 2009 [5] Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a request from the Commission related to the Tolerable Upper Intake Level of Fluoride, The EFSA Journal (2005) 192, 1-65, published on 7 June 2006. [6] Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci. 2002 Oct;47(10):2336-48. [7] Miller K.E., Colic: Prevalence, Risk Factors, and Potential Sequelae, Am Fam Physician. 2003 May 1;67(9):2005-2006 [8] J Godel; Canadian Paediatric Society, Nutrition and Gastroenterology Committee Paediatr Child Health 2002;7(8):569-72 [9] http://www.who.int/water_sanitation_health/dwq/gdwq3rd_add1.pdf [10] Literature search and review related to specific preparatory work in the establishment of Dietary Reference Values. Preparation of an evidence report identifying health outcomes upon which Dietary Reference Values could potentially be based for magnesium, potassium and fluoride. Department of Nutrition, Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK, May 2012 [11] National Research Council of the National Academies, Fluoride in Drinking Water,2006 [12] NAS (National Academy of Science) (2004). Dietary reference intakes (DRI): Recommended intakes for individuals. Food and Nutrition Board, Institute of Medicine, National Academies. [13] US EPA (1980) Reviews of the environmental effects of pollutants: IX Fluoride, Cincinnati, US Environmental Protection Agency, 441 pp (EPA-600/1-78-050). [14] Jackson, R.D., E.J. Brizendine, S.A. Kelly, et al. 2002. The fluoride content of foods and beverages from negligibly and optimally fluoridated communities. Community Dent. Oral. Epidemiol. 30:382391 [15] Laura Chan et al. Human exposure assessment of fluoride from tea (Camellia sinensis L.) Food Research International 51 (2013) 564570 [16] Cao et al. Safety evaluation on fluoride content in black tea, Food Chemistry 88 (2004) 233236 [17] Cao et al. Fluoride levels in various black tea commodities: Measurement and safety evaluation, Food and Chemical Toxicology 44 (2006) 11311137 [18] Alturfan E et al. Fluoride levels in various black tea, herbal and fruit infusions consumed in Turkey, Food and Chemical Toxicology [19] Malinowska, E., Inkielewicz, I., Czarnowski, W., Szefer, P., Assessment of fluoride concentration and daily intake by human from tea and herbal infusions. Food Chem. Toxicol. 2008. 46, 10551061. [20] Fluoride and aluminum in teas and tea-based beverages, Rev. Sade Pblica vol.38 no.1 So Paulo Feb. 2004 [21] Cury JA. [Fluoride concentration in Brazilian teas and their significance in caries prevention]. Rev Gaucha Odontol 1981;29:136-8.
44 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [22] Chan JT, Koh SH. Fluoride content in caffeinated, decaffeinated and herbal teas. Caries Res 1996;30:88-92. [23] Gulati P, Singh V, Gupta MK, Vaidya V, Dass S, Prakash S. Studies on the leaching of fluoride in tea infusions. Sci Total Environ 1993;138:213-22 [24] Cao, J., Zhao, Y., & Liu,W. (2001). Processing procedures of brick tea and their influenceson fluorine content. Food and Chemical Toxicology, 39, 959962. [25] Malinowska, E., Inkielewiczb, I., Czarnowskib, W., & Szefera, P. (2008). Assessment of fluoride concentration and daily intake by human from tea and herbal infusions. Food and Chemical Toxicology, 46, 10551061. [26] Duckworth, S. C., & Duckworth, R. (1978). The ingestion of fluoride in tea. British Dental Journal, 145, 368370. [27] Shu, W. S., Zhang, Z. Q., Lan, C. Y., & Wong, M. H. (2003). Fluoride and aluminiumconcentrations of tea plants and tea products from Sichan Province, PR China. Chemosphere, 52, 14751482 [28] Fung, K. F., Zhang, Z. Q., Wong, J. W. C., & Wong, M. H. (1999). Fluoride contents in tea and soil from tea plantations and the release of fluoride into tea liquor during infusion. Environmental Pollution, 104, 197205. [29] S. Kalayci, and G. Somer, Factors affecting the extraction of fluoride from tea: Application to three samples. Fluoride, 36: 267-270, 2003. [30] S. Tokalioglu, S. Kartal, and U. Sahin, Determination of fluoride in various samples and some infusions using a fluoride selective electrode. Turk. J. Chem., 28, 204-11, 2004. [31] M. Yuwono, Determination of fluoride in black, green, and herbal teas by ion-selective electrode using a standard addition method. Dent. J., 38(2), 91-95, 2005. [32] M. Amanlou, F. Nabati, H. Azizian and H. Farsam, Assessment of fluoride content and daily intake from different brands of tea bags in Iran, Research in Pharmaceutical Sciences, October 2008; 3(2): 55-59 [33] Amir Hussein Mahvi, Mohammad Ali Zazoli,, Masoud Younecian,a Yahya Esfandiarib, Fluoride content of Iranian black tea and tea liquor, Fluoride 39(4)266268, OctoberDecember 2006 [34] J. R. Smid*, B. J. Kruger, The fluoride content of some teas available in Australia, Australian Dental Journal Volume 30, Issue 1, pages 2528, February 1985 [35] M. B. Rajkovic, and I. D. Novakovic, Determination of fluoride content in drinking water and tea infusions using fluoride selective electrode. J. Agri. Sci., 52(2), 155-168, 2007. [36] T. Karak, and R. M., Trace elements in tea leaves, made tea and tea infusion: A review. Food Research International, 43(9), 2234-2252, 2010. [37] Yi Lu ,Wen-Fei Guo , and Xian-Qiang Yang, Fluoride Content in Tea and Its Relationship with Tea Quality, J. Agric. Food Chem., 2004, 52 (14), pp 44724476 DOI: 10.1021/jf0308354 [38] Tsyr-Horng Shyu, Jiann-Hwa Chen and Yi-Hwar Lee, Determination of Fluoride in Tea Leaves and Tea Infusions by Ion Selective Electrode, Journal of Food and Drug Analysis, Vol. 17, No. 1, 2009, Pages 22-27 [39] W. S. Shu, Z. Q. Zhang, C. Y. Lan, and M. H. Wong, Fluoride and aluminium concentrations of tea plants and tea products from Sichuan Province, PR China. Chemosphere, 52, 1475-1482, 2003. [40] K.O. Moseti, J.K.Wanyoko, T. Kinyanjui, F.N. Wachira, Extractability of Fluoride into Black Tea Liquors, Kenya, International Journal of Environmental Protection May. 2013, Vol. 3 Iss. 5, PP. 14-19 [41] USDA National Fluoride Database of Selected Beverages and Foods, Release 2, Nutrient Data Laboratory Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, 2005 [42] UK Expert Group on Vitamins and Minerals , EVM/01/3/P Review of Fluoride, 2001 [43] International Programme on Chemical Safety (IPCS) (2002). Fluorides. Environmental Health Criteria 227, World Health Organization, Geneva. [44] Smid, J.R. and Kruger, B.J. (1985) The fluoride content of some teas available in Australia. Australian Dental Journal 30, 25-28. 45 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [45] J. Fawell et al. World Health Organisation Fluoride in Drinking Water, 2006 [46] Bergmann, R. 1995 Fluorid in der Ernhrung des Menschen. Biologische Bedeutung fr den wachsenden Organismus. Habilitationsschrift. Virchow-Klinikum der HumboldtUniversitt, Berlin, 133 pp. [47] Dabeka, R.W. and McKenzie, A.D. 1995 Survey of lead, cadmium, fluoride, nickel and cobalt in food composites and estimation of dietary intakes of these elements by Canadians in 19861988. J. Assoc. Off. Anal. Chem. Int., 78, 897909. [48] Dabeka, R.W. and McKenzie, A.D. 1995 Survey of lead, cadmium, fluoride, nickel and cobalt in food composites and estimation of dietary intakes of these elements by Canadians in 19861988. J. Assoc. Off. Anal. Chem. Int., 78, 897909. [49] Kenneth Izuora, Jennifer G. Twombly, Gary M. Whitford, Jennifer Demertzis, Roberto Pacifici, and Michael P. Whyte, Skeletal Fluorosis from Brewed Tea, J Clin Endocrinol Metab, August 2011, 96(8):00000000 [50] Fluorides, Environmental Health Criteria 227, World Health Organization 2002. [51] Fluorides And Oral Health, World Health Organization, Technical Report Series 846, 1994. [52] Shafique K, McLoone P, Qureshi K, Leung H, Hart C, Morrison DS. Tea consumption and the risk of overall and grade specific prostate cancer: a large prospective cohort study of Scottish men. Nutr Cancer. 2012 Aug;64(6):790-7. doi: 10.1080/01635581.2012.690063. Epub 2012 Jun 14. [53] Shah GV, Rayford W, Noble MJ, Austenfeld M, Weigel J, Vamos S, Mebust WK. Calcitonin stimulates growth of human prostate cancer cells through receptor-mediated increase in cyclic adenosine 3',5'-monophosphates and cytoplasmic Ca2+ transients. Endocrinology. 1994 Feb;134(2):596-602. [54] Sabbisetti VS, Chirugupati S, Thomas S, Vaidya KS, Reardon D, Chiriva-Internati M, Iczkowski KA, Shah GV. Calcitonin increases invasiveness of prostate cancer cells: role for cyclic AMP-dependent protein kinase A in calcitonin action. Int J Cancer. 2005 Nov 20;117(4):551-60. [55] Shah GV, Thomas S, Muralidharan A, Liu Y, Hermonat PL, Williams J, Chaudhary J. Calcitonin promotes in vivo metastasis of prostate cancer cells by altering cell signaling, adhesion, and inflammatory pathways. Endocr Relat Cancer. 2008 Dec;15(4):953-64. doi: 10.1677/ERC-08-0136. Epub 2008 Sep 10. [56] Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR, Lee DH, Shioda T, Soto AM, vom Saal FS, Welshons WV, Zoeller RT, Myers JP (2012). Hormones and endocrinedisrupting chemicals: Low dose effects and nonmonotonic dose responses. Endocrine Reviews, June 2012, 33(3):378-455. [57] The impacts of endocrine disrupters on wildlife, people and their environments, European Environment Agency, Technical report No 2/2012 [58] Woodward M, Tunstall-Pedoe H., Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortalityJ Epidemiol Community Health 1999; 53 :481487 [59] Gutowska I, Baranowska-Bosiacka I, Bakiewicz M, Milo B, Siennicka A, Marchlewicz M, Wiszniewska B, Machaliski B, Stachowska E. Fluoride as a pro-inflammatory factor and inhibitor of ATP bioavailability in differentiated human THP1 monocytic cells. Toxicol Lett. 2010 Jul 1;196(2):74-9. doi: 10.1016/j.toxlet.2010.03.1167. Epub 2010 Apr 22. [60] Kanbay M, Wolf M, Selcoki Y, Solak Y, Ikizek M, Uysal S, Segall L, Armutcu F, Eryonucu B, Duranay M, Goldsmith D, Covic A. Association of serum calcitonin with coronary artery disease in individuals with and without chronic kidney disease. Int Urol Nephrol. 2012 Aug;44(4):1169-75. doi: 10.1007/s11255-011-0076-x. Epub 2011 Dec 1. [61] Barker J.M. Type 1 Diabetes-Associated Autoimmunity: Natural History, Genetic Associations, and Screening, The Journal of Clinical Endocrinology & Metabolism April 1, 2006 vol. 91 no. 4 1210-1217 [62] Shashi, A (1988) Biochemical effects of fluoride on thyroid gland during experimental fluorosis. Fluoride 21: 127130. 46 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [63] Susheela, AK, Bhatnagar, M, Vig, K, Mondal, NK (2005) Excess fluoride ingestion and thyroid hormone derangements in children living in Delhi, India. Fluoride 38: 98 108. [64] Monsour, PA, Kruger, BJ (1985) Effect of fluoride on soft tissues in vertebrates. Fluoride 18: 53 61. [65] Bouaziz, H, Soussia, L, Guermazi, F, Zeghal, N (2005) Fluoride-induced thyroid proliferative changes and their reversal in female mice and their pups. Fluoride 38: 185 192. [66] Zhan, XA, Li, JX, Wang, M, Xu, ZR (2006) Effects of fluoride on growth and thyroid function in young pigs. Fluoride 39: 95100. [67] Schuld, A (2005) Is dental fluorosis caused by thyroid hormone disturbances? Fluoride 38: 9194. [68] Trabelsi, M, Guermazi, F, Zeghal, N (2001) Effect of fluoride on thyroid function and cerebellar development in mice. Fluoride 34: 165173. [69] McLaren, JR (1976) Possible effects of fluoride on the thyroid. Fluoride 9: 105116. [70] Zimmermann MB., Iodine Deficiency, Endocrine Reviews June 1, 2009 vol. 30 no. 4 376-408 [71] Iodine Deficiency in Europe, A Continuing Public Health Problem, World Health Organisation, 2007 [72] Lazarus and Smyth, Iodine deficiency in the UK and Ireland, The Lancet, Volume 372, Issue 9642, Page 888, 13 September 2008 [73] Zimmermann MB, Aeberli I, Melse-Boonstra A, Grimci L, Bridson J, Chaouki N, Mbhenyane X, Jooste PL.Iodine treatment in children with subclinical hypothyroidism due to chronic iodine deficiency decreases thyrotropin and C-peptide concentrations and improves the lipid profile. Thyroid. 2009 Oct;19(10):1099-104. doi: 10.1089/thy.2009.0001. [74] Asvold BO, Bjoro T, Nilsen TI, Vatten LJ (2007a). Association between blood pressure and serum thyroid-stimulating hormone concentration within the reference range: a population-based study. Journal of Clinical Endocrinology and Metabolism, 92(3):841-845 [75] Biondi B, Palmieri EA, Klain M, Schlumberger M, Filetti S, Lombardi G (2005). Subclinical hyperthyroidism: clinical features and treatment options. European Journal of Endocrinology, 152(1):1-9. [76] Osman F, Gammage MD, Sheppard MC, Franklyn JA (2002). Clinical review 142: cardiac dysrhythmias and thyroid dysfunction: the hidden menace? Journal of Clinical Endocrinology and Metabolism, 87(3):963-967. [77] Krude H, Schutz B, Biebermann H, von Moers A, Schnabel D, Neitzel H, Tonnies H, Weise D, Lafferty A, Schwarz S, DeFelice M, von Deimling A, van Landeghem F, DiLauro R, Gruters A (2002). Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. The Journal of clinical investigation, 109(4):475-480. [78] Lei J, Nowbar S, Mariash CN, Ingbar DH (2003). Thyroid hormone stimulates Na-KATPase activity and its plasma membrane insertion in rat alveolar epithelial cells. American Journal of Physiology. Lung Cellular and Molecular Physiology, 285(3):L762-772. [79] Mendelson CR, Boggaram V (1991). Hormonal control of the surfactant system in fetal lung. Annual Review of Physiology, 53:415-440. [80] Asvold BO, Vatten LJ, Nilsen TI, Bjoro T (2007b). The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study. European Journal of Endocrinology, 156(2):181-186. [81] Dullaart RP, de Vries R, Roozendaal C, Kobold AC, Sluiter WJ (2007). Carotid artery intima media thickness is inversely related to serum free thyroxine in euthyroid subjects. Clinical Endocrinology, 67(5):668-673. [82] Gerdes AM, Iervasi G,Thyroid Replacement Therapy and Heart Failure, Contemporary Reviews in Cardiovascular Medicine, Circulation. 2010; 122: 385-393 [83] Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid. 2000; 10: 665679. [84] Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, L'Abbate A, Pingitore A. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007; 167: 15261532. 47 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [85] Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC (2006). Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. The American journal of medicine, 119(7):541-551. [86] Becker, K.L., Nash D, Silva O.L., Snider R,H. and Moore C.F. Increased Serum and Urinary Calcitonin Levels in Patients with Pulmonary Disease, Chest 79:2, Feb 1981 [87] Math AA, Agren H, Lindstrm L, Theodorsson E. Increased concentration of calcitonin gene-related peptide in cerebrospinal fluid of depressed patients. A possible trait marker of major depressive disorder. Neurosci Lett. 1994 Dec 5;182(2):138-42. [88] Goadsby, P. J., Edvinsson, L., Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28: 183-187, 1990. [89] Lassen, L. H., Haderslev, P. A., Jacobsen, V. B., Iversen, H. K., Sperling, B., Olesen, J. CGRP may play a causative role in migraine. Cephalalgia 22: 54-61, 2002 [90] Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care 2000;23:1278-83. [91] Chiba YF, Garbin CAS, Sumida DH, Effect of F intake on carbohydrate metabolism, glucose tolerance, and insulin signaling, Fluoride 45(3 Pt 2)236241 July-September 2012 [92] Lohmann, K., O Meyerhof, Biochem. Z. 273 (1934) 60. [93] Borei Hans, The Inhibition of Cellular Oxidation by Fluoride, Arkiv For Kemi, Mineralogi Och Geologi, Utgivet AV, K Svenska Vetenskapsakademien Band 20 A, No 8. 1945 [94] Vasudevan DM., Sreekumari S, Vaidyanathan K, Textbook of Biochemistry for Dental Students, 2nd Edition. ISBN 978-93-5025-488-2 [95] Rapp, G. WM., The Pharmacology of Fluoride, The Bur, Reprint No 53, 1950. [96] Rigalli A, Ballina JC, Roveri E, Puche RC. Inhibitory effect of fluoride on the secretion of Insulin. Calcif Tissue Int 1990;46:333-38. [97] Garca-Montalvo EA, Reyes-Prez H, Del Razo LM. Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress. Toxicology. 2009 Sep 19;263(2-3):75-83. doi: 10.1016/j.tox.2009.06.008. Epub 2009 Jun 21. [98] O. Barbier et al. Molecular mechanisms of fluoride toxicity, Chemico-Biological Interactions 188 (2010) 319333 [99] Tashiro A, Hongo M, Ota R, Utsumi A, Imai T (1997) Hyper-insulin response in a patient with depression. Changes in insulin resistance during recovery from depression. Diabetes Care 20: 19241925. [100] Winokur A, Maislin G, Phillips JL, Amsterdam JD (1988) Insulin resistance after oral glucose tolerance testing in patients with major depression. Am J Psychiatry 145: 325330. [101] Domenici E, Will DR, Tozzi F, Prokopenko I, Miller S, et al. (2010) Plasma Protein Biomarkers for Depression and Schizophrenia by Multi Analyte Profiling of Case-Control Collections. PLoS ONE 5(2): e9166. doi:10.1371/journal.pone.0009166 [102] Okamura F, Tashiro A, Utumi A, Imai T, Suchi T, et al. (2000) Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metabolism 49: 12551260. doi: 10.1053/meta.2000.9515 [103] Muthuswamy Balasubramanyam, Raji Lenin and Finny Monickaraj, Endoplasmic Reticulum Stress In Diabetes: New Insights Of Clinical Relevance, Indian Journal of Clinical Biochemistry, 2010 / 25 (2) 111-118, [104] State of the Science of Endocrine Disrupting Chemicals 2012, An assessment of the state of the science of endocrine disruptors prepared by a group of experts for the United Nations Environment Programme and World Health Organization. [105] Ropero AB, Alonso-Magdalena P, Quesada I, Nadal A (2008). The role of estrogen receptors in the control of energy and glucose homeostasis. Steroids, 73(9-10):874-879. [106] Sargis RM, Johnson DN, Choudhury RA, Brady MJ (2010). Environmental endocrine disruptors promote adipogenesis in the 3T3- L1 cell line through glucocorticoid receptor activation. Obesity (Silver Spring), 18(7):1283-1288. [107] Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB (2000). Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ (Clinical Research Ed.), 320(7240):967-971. 48 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [108] McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M, Benca RM, Biggio J, Boggiano MM, Eisenmann JC, Elobeid M, Fontaine KR, Gluckman P, Hanlon EC, Katzmarzyk P, Pietrobelli A, Redden DT, Ruden DM, Wang C, Waterland RA, Wright SM, Allison DB (2009). Ten putative contributors to the obesity epidemic. Critical Reviews in Food Science and Nutrition, 49(10):868-913. [109] Xin Guo, Honggui Li, Hang Xu, Shihlung Woo, Hui Dong, Fuer Lu, Alex J. Lange, Chao dong Wu, Glycolysis in the control of blood glucose homeostasis, Acta Pharmaceutica Sinica B2012;2(4):358367 [110] Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol 1954;16:33042 [111] Hodge H.C., Smith FA.,Fluorine Chemistry, University of Rochester School of Medicine and Dentistry, Volume 4, Edited by J.H. University of Florida, Academic Press, 1965 [112] Dcio L. Eizirik,Alessandra K. Cardozo and Miriam Cnop, The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus, Endocrine Reviews February 1, 2008 vol. 29 no. 1 4261 [113] Scholl T.O.,Sowers M.F , Chen X and Lenders C., Maternal Glucose Concentration Influences Fetal Growth, Gestation, and Pregnancy Complications, Am. J. Epidemiol. (2001) 154 (6): 514-520. doi: 10.1093/aje/154.6.514 [114] Hillier TA, Pedula KL, Schmidt MM, Mullen JA, Charles MA, Pettitt DJ.Childhood obesity and metabolic imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care. 2007 Sep;30(9):2287-92. Epub 2007 May 22. [115] Chamberlain C.C, Buroughs W., Effect of Fluoride, Magnesium and Manganese Ions on in Vitro Cellulose Digestion by Rumen Microorganisms. J Anim Sci, 1962, 21:428-432. [116] Tokar VI, Zyrianova VV, Shcherbakov SV. Chronic effect of fluorides on the status of the pancreatic insular apparatus of workers. Gig Sanit. 1992 Nov-Dec;(11-12):42-4. [117] OECD Indicators 2011 [118] International Obesity Taskforce, Obesity Worldwide 2008-2010. [119] The cost of overweight and obesity on the island of Ireland, Safefood November 2012, ISBN: 978-1-905767-335 [120] Whelton, H., Harrington, J., Crowley, E., Kelleher, V., Cronin, M., & Perry, I.J. (2007), Prevalance of overweight and obesity on the island of Ireland: results from the North South Survey of Childrens Height, Weright and Body Mass Index, 2002. BMC Public Health, 7, 187. [121] Moreno L., Ahresn W., Pigeot I., Epidemiology of Obesity in Children and Adolescents: Prevalence and Etiology, 2011, Springer Series on Epidemiology and Public Health 2, DOI 10.1007/978-1-4419-6039-9_4, [122] International Diabetes Federation. Web: http://www.idf.org/diabetesatlas/5e/what-isdiabetes [123] Barker J.M. Type 1 Diabetes-Associated Autoimmunity: Natural History, Genetic Associations, and Screening, The Journal of Clinical Endocrinology & Metabolism April 1, 2006 vol. 91 no. 4 1210-1217 [124] Natalia Ivanovna Agalakova and Gennadii Petrovich Gusev, Sechenov Institute of Evolutionary Physiology and Biochemistry Russian Academy of Sciences, Molecular Mechanisms of Cytotoxicity and Apoptosis Induced by Inorganic Fluoride, International Scholarly Research Network ISRN Cell Biology Volume 2012, Article ID 403835, 16 pages doi:10.5402/2012/403835 [125] Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 2005 Oct;115(10):2656-64. [126] Menoyo L., Rigalli A., Puche R.C., Effect of fluoride on the secretion of insulin in the rat, Arzneimittelforschung 55 (2005) 455460. [127] B.J. Lin, M.J. Henderson, B.B. Levine, B.R. Nagy, E.M. Nagy, Effects of iodoacetate and fluoride on islate respiration and insulin biosynthesis, Horm. Metab. Res. 8 (1976) 353 358. 49 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [128] E.A. Garcia-Montalvo, H. Reyes-Perez, L.M. Del Razo, Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress, Toxicology 263 (2009) 7583. [129] Oberley LW. Free radicals and diabetes. Free Radic Biol Med. 1988;5(2):113-24. [130] Trivedi N, Mithal A, Gupta SK, Godbole MM, Godbole for the Fluoride Collaborative Study Group: Reversible impairment of glucose tolerance in patients with endemic fluorosis: Fluoride Collaborative Study Group. Diabetologia 1993;36(9):826-8. [131] Health Status of the population of Ireland, Causes of Illness in Ireland, HSE, 2008 [132] Diabetes UK [133] Diabetes Federation of Ireland [134] Diabetes: The Policy Puzzle, Is Europe Making Progress, The International Diabetes Federation (2012). [135] Vhi Healthcare screening programme (2011) Web: https://www.vhi.ie/personalise/controller/PrItemDisplay?PRYear=2010&prId=23 [136] Warburg, O. & W. Christian, Naturwissenschaften, 29 (1941) 590. [137] Utter, M. F. and C. H. Werkman. 1942. Effect of metal ions on the reactions of phosphpyruvate by Escherichia coll. J. Biol. Chem. 146:289 [138] V. Pancholi, Multifunctional -enolase: its role in diseases, Cellular and Molecular Life Sciences, vol. 58, no. 7, pp. 902920, 2001. [139] ngels Daz-Ramos, Anna Roig-Borrellas, Ana Garca-Melero, and Roser LpezAlemany, -Enolase, a Multifunctional Protein: Its Role on Pathophysiological Situations, Journal of Biomedicine and Biotechnology Volume 2012 (2012), Article ID 156795, 12 pages http://dx.doi.org/10.1155/2012/156795 [140] M. Wygrecka, L. M. Marsh, R. E. Morty et al., Enolase-1 promotes plasminogenmediated recruitment of monocytes to the acutely inflamed lung, Blood, vol. 113, no. 22, pp. 55885598, 2009. [141] Johnsons, R.B., and Lardy, H.A. (1950) J.Biol. Chem. 184, 235-242 [142] Geyer, R.P.,Matthews, L.W., and State, F.J. (1950). J. Biol. Chem, 182, 101-108 [143] Geyer, R.P.,Cunningham, M., and Pendergast, J. (1951). J. Biol. Chem, 188, 185-191 [144] Philp A, Macdonald AL, Watt PW. Lactate--a signal coordinating cell and systemic function. J Exp Biol. 2005 Dec;208(Pt 24):4561-75. [145] Ide, K. and Secher, N. H. (2000). Cerebral blood flow and metabolism during exercise. Prog. Neurobiol. 61,397 -414. [146] Pellerin, L. and Magistretti, P. J. (2003). How to balance the brain energy budget while spending glucose differently. J. Physiol. 546,325 [147] Pellerin, L., Pellegri, G., Bittar, P. G., Charnay, Y., Bouras, C., Martin, J.-L., Stella, N. and Magistretti, P. J. (1998). Evidence supporting the existence of an astrocyte-neuron lactate shuttle. Dev. Neurosci. 20,291 -299. [148] Snchez-Abarca LI, Tabernero A, Medina JM. Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia. 2001 Dec;36(3):321-9. [149] Imagawa T, Yamamoto E, Sawada M, Okamoto M, Uehara M. Expression of lactate dehydrogenase-A and -B messenger ribonucleic acids in chick glycogen body. Poult Sci. 2006 Jul;85(7):1232-8. [150] Meyerhof, O. & K. Lohmann, Biochem. Z. 185 (1927) 113. [151] Lipmann, F., Biochem. Z. 227 (1930) 110. [152] Meyerhof, O., Biochem. Z. 178 (1926) 462. [153] S V Sutton, G R Bender, and R E Marquis, Fluoride inhibition of proton-translocating ATPases of oral bacteria. Infect Immun. 1987 November; 55(11): 25972603.PMCID: PMC259948 [154] Astles R, Williams CP, Sedor F. Stability of plasma lactate in vitro in the presence of antiglycolytic agents. Clin Chem 1994;40:1327-30. [155] Stephen A. Feig, Stephen B. Shohet, and D G. Nathan, Energy Metabolism in Human Erythrocytes, The Journal of Clinical Investigation Volume 50 197, 1731 [156] Guy W, Taves D, & Brey W (1976) Organic fluorocompounds in human plasma: prevalence and characterization. Am Chem Soc Symp Ser, 28: 117134. 50 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [157] Brustolin, R. Giugliani anf T,M, Felix, Genetics of homocysteine metabolism, and associated disorders. Braz J Med Biol Res, January 2010 Volume 43 (1) 1-7 [158] Folic acid and Folates, Vitamins and Hormones, Volume 79, 2008, Ed: Gerald Litwack, ISBN: 978-0-12-374232-2 [159] Tjiattas L, Ortiz DO, Dhivant S, Mitton K, Rogers E, Shea TB. Folate deficiency and homocysteine induce toxicity in cultured dorsal root ganglion neurons via cytosolic calcium accumulation. Aging Cell. 2004 Apr;3(2):71-6. [160] James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, GibsonJB, Yi P, Tafoya DL, Swenson DH, Wilson VL, Gaylor DW(1999) Abnormal folate metabolism and mutation in the methy-lenetetrahydrofolate reductase gene may be maternal risk factorsfor Down syndrome. Am J Clin Nut 70:495501 [161] Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease, evidence of causality from a meta analysis BMJ 2002:325:1201 [162] Brustolin, R. Giugliani anf T,M, Felix, Genetics of homocysteine metabolism, and associated disorders. Braz J Med Biol Res, January 2010 Volume 43 (1) 1-7 [163] J Gueant, G Anello, P Bosco, R Gueant-Rodriguez, A Romano, C Barone, P Gerard, and C Romano, Homocysteine and related genetic polymorphisms in Down's syndrome IQ, J Neurol Neurosurg Psychiatry. 2005 May; 76(5): 706709. [164] Choi SW, Mason JB. Folate AND CARCINOGENESIS. An integrated scheme. J Nutr 2000;130:129-32 [165] Joyal CC, Lalonde r, Vikis-Freibergs V, Botez mi. Are age-related behavioural disorders improved by folate administration? Exp Aging Res 1993; 19:367-76 [166] Mandelbaum-Shavit F, Grossowicz N. Pediococcus cerevisiae mutant with altered transport of folates. J Bacteriol. 1975 Aug;123(2):400-6. [167] Mandelbaum-Shavit F, Grossowicz N. Carrier-mediated transport of folate in a mutant of Pediococcus cerevisiae. J Bacteriol. 1973 May;114(2):485-90. [168] McElwee PG, Scott JM. Folate metabolism in Streptococcus faecalis. Biochem J. 1972 May;127(5):901-5. [169] Aly Nahas, Peter F. Nixon, and Joseph R. Berlino, Uptake and Metabolism of N5Formyltetrahydrofolate by L1210 Leukemia Cells, Cancer Research 32,1416-1421, July 1972 [170] Tjiattas L, Ortiz DO, Dhivant S, Mitton K, Rogers E, Shea TB. Folate deficiency and homocysteine induce toxicity in cultured dorsal root ganglion neurons via cytosolic calcium accumulation. Aging Cell. 2004 Apr;3(2):71-6. [171] Willett,W.C. (2001) Diet and cancer: one view at the start of the millennium. Cancer Epidemiol. Biomarkers Prev., 10, 38. [172] Lamprecht,S.A. and Lipkin,M. (2003) Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat. Rev. Cancer, 3, 601614 [173] Giovannucci,E. (2003) Diet, body weight and colorectal cancer: a summary of epidemiological evidence. J. Womens Health, 12, 173182. [174] Bailey,L.B. (2003) Folate, methyl-related nutrients, alcohol, and the MTHFR 677CT polymorphism affect cancer risk: intake recommendations. J. Nutr., 133(Suppl. 1), 3748S 3753S. [175] Fenech M, Baghurst P, Luderer W, Turner J, Record S, Ceppi M and Bonassi S., Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, -carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genome instabilityresults from a dietary intake and micronucleus index survey in South Australia, Carcinogenesis (May 2005) 26 (5): 991-999. doi: 10.1093/carcin/bgi042 [176] Ronzio Robert A, The Encyclopedia of Nutrition and Good Health, Second Edition, 2003, ISBN 0-8160-4966-1 [177] Hamilton Health Care system: Health Library Lipase. Web http://www.hamiltonhealth.com/ [178] http://www.prostate.net/prostate-health-supplements-a-z/lypase-lipase-healthbenefits/#sthash.hNaWMGTf.dpuf 51 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [179] Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Rydn M, Arner E, Sicard A, Jenkins CM, Viguerie N, van Harmelen V, Gross RW, Holm C, Arner P. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005 Nov;54(11):3190-7. [180] Loevenhart .A.S., Peirce G., The inhibiting effect of sodium fluoride on the action of Lipase. J. Biol. Chem 1907, 2:397-413 [181] Dcio L. Eizirik,Alessandra K. Cardozo and Miriam Cnop, The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus, Endocrine Reviews February 1, 2008 vol. 29 no. 1 4261 [182] Kraemer FB. and Shen-WJ,. Hormone-sensitive lipase control of intracellular tri-(di-) acylglycerol and cholesteryl ester hydrolysis, October 2002 The Journal of Lipid Research, 43, 1585-1594. [183] Kraemer FB. and Shen-WJ,. Hormone-sensitive lipase control of intracellular tri-(di-) acylglycerol and cholesteryl ester hydrolysis, October 2002 The Journal of Lipid Research, 43, 1585-1594. [184] Arner P.1996. Regulation of lipolysis in fat cells. Diabetes Rev. 4: 450463. [185] Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011 Feb;32(1):81-151. doi: 10.1210/er.2010-0013. Epub 2010 Nov 4. [186] Chi Y, Gupta RK. Alterations in heart and kidney membrane phospholipids in hypertension as observed by 31P nuclear magnetic resonance. Lipids. 1998 Oct;33(10):102330. [187] A Survey of the Literature of Dental Caries, Food and Nutrition Board of the National Research Council Publication 225, National Academy of Sciences ,1952 [188] Guan, Z.Z., K.Q. Xiao, X.Y. Zeng, Y.G. Long, Y.H. Cheng, S.F. Jiang, and Y.N. Wang. 2000. Changed cellular membrane lipid composition and lipid peroxidation of kidney in rats with chronic fluorosis. Arch. Toxicol. 74(10):602608. [189] Norman. W.A., From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health, Am J Clin Nutr August 2008 vol. 88 no. 2 491S499S [190] Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature 1987; 325: 62-65. [191] Davies M, Heys SE, Selby PL, et al. Increased catabolism of 25-hydroxyvitamin D in patients with partial gastrectomy and elevated 1,25-dihydroxyvitamin D levels. Implications for metabolic bone disease. J Clin Endocrinol Metab 1997; 82: 209-212 [192] Stephanie Korn, Marisa Hbner, Matthias Jung, Maria Blettner and Roland Buhl, Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency, Respiratory Research 2013, 14:25 [193] Teotia SPS and Teotia M. Fluorosis-India. Technical report on metabolism of fluoride in the newborns, infants and children living in endemic fluorosis areas. Sponsored Project, Department of Environment, Government of India. 1987; p1-56. [194] Teotia SPS Teotia M. Endemic fluoride: Bones and teeth. Ind, J. Environ. Toxicol: 1991; 1:1-16. [195] Teotia M, Teotia SPS, Singh K.P.: Endemic Chronic fluoride toxicity and dietary calcium deficiency interaction syndromes of Bone disease and Deformities in India. Year 2000, Indian j pediatr 1998; 65:371-81. [196] Teotia SPS, Teotia M. Fluoride and calcium interactions: Syndromes of bone disease and deformities(Human studies) In: Frame B, Potts JT Jr (Eds). Clinical Disorders of Bone and Mineral Metabolism. Excerpta medica, Amsterdam 1983; P 520-21 [197] Floyd J. Malveaux, The State of Childhood Asthma: Pediatrics 2009;123;S129 DOI: 10.1542/peds.2008-2233B [198] Williams H, McNicol KN. Prevalence, natural history and relationship of wheezy bronchitis and asthma in children. An epidemiological study. BMJ 1969;iv:321-5. [199] Lee DA, Winslow NR, Speight AN, Hey EN. Prevalence and spectrum of asthma in childhood. BMJ 1983;286: 1256-8. 52 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [200] Speight ANP, Lee DA, Hey EN. Underdiagnosis and undertreatment of asthma in childhood. BMJ 1983;286:1253-6. [201] Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC), Eur Respir J 1998; 12: 315335 [202] Lai C K W, Beasley R, Crane J, Foliaki S, Shah J, Weiland S, the ISAAC Phase Three Study Group, Global variation in the prevalence and severity of asthma symptoms: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC), Thorax 2009;64:476483. doi:10.1136/thx.2008.106609 [203] Burney PGJ, Luczynska C, Chinn S, Jarvis D. The European Community Respiratory Health Survey. Eur Respir J 1994; 7: 954960 [204] European Community Respiratory Health Survey (ECRHS).Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). Eur Respir J 1996; 9: 687695 [205] Kwon HL, Belanger K, Bracken MB. Asthma prevalence among pregnant and childbearing-aged women in the United States: estimates from national health surveys. Ann Epidemiol 2003;13(5):31724. [206] National Asthma Education and Prevention Program. Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment Update 2004 (U.S. Department of Health and Human Services, National Institutes of Health Publication No. 05-3279), which is available at http://www.nhlbi.nih.gov/health/prof/lung/asthma/astpreg.htm [207] Heaney R.P. Long-latency deficiency disease: insights from calcium and vitamin D1,2,3,4. Am J Clin Nutr November 2003 vol. 78 no. 5 912-919 [208] Irish Osteoporosis Society, 2010 [209] Osteoporosis in the UK at... Breaking Point 2010, A report on the current management of postmenopausal women with osteoporosis in the UK [210] The National Cancer Registry Ireland. Web: http://ncri.ie/cancerinfo/emergedissues.shtml [211] Institute of Public Health, Hypertention Briefing. Web: http://www.publichealth.ie/sites/default/files/Hypertension%20Briefing%2015%20May%202 012%20FINAL.pdf [212] Wacker WE, Parisi AF. 1968. Magnesium metabolism. N Engl J Med 45:658663, 712717, 772776. [213] Varol, Water-Borne Fluoride and Primary Hypertension, Guest editorial review Fluoride 46(1)36, January-March 2013 [214] Marier JR. 1986. Magnesium content of the food supply in the modern-day world. Magnesium 5:18. [215] Institute of Medicine. Dietary Reference Intake for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, D.C.: National Academy Press; 1997. [216] Fatemi S, Ryzen E, Flores J, Endres DB, Rude RK. 1991. Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism. J Clin Endocrinol Metab 73:10671072. [217] Spivey W, Skobeloff E, Levin R. Effect of magnesium chloride on rabbit bronchial smooth muscle. Ann Emerg Med 1990; 19:1107-12 [218] Rolla G, Bucca C, Bugiani M, Arossa W, Spinaci S. Reduction of histamine-induced bronchoconstriction by magnesium in asthmatic subjects. Allergy 1987; 42: 186-8 [219] Coetzee EJ, Dommisse J. Anthony J. A randomised controlled trial of intravenous magnesium sulphate versus placebo in th e management of women with sever pre-eclampsia. Br J Obstet Gynaecol 1998; 105:300-3 [220] Rude RK, Singer FR. 1980. Magnesium deficiency and excess. Ann Rev Med 32:245 259. [221] Molloy DW, Dhingra S, Solven F, Wilson A, McCCarthy DS. Hypomagnesemia and respiratory muscle power. Am Rev Respir Dis 1984:129:497-8 53 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [222] Fawcett WJ, Haxby EJ, Male DA.,Magnesium: Physiology and Pharmacology, Br J Anaesth 1999; 83: 302-20 [223] Kazaks AG, Uriu-Adams JY, Albertson TE, Shenoy SF, Stern JS. Effect of oral magnesium supplementation on measures of airway resistance and subjective assessment of asthma control and quality of life in men and women with mild to moderate asthma: a randomized placebo controlled trial. J Asthma. 2010 Feb;47(1):83-92. [224] Sofie Lieberoth, Vibeke Backer, Kirsten Ohm Kyvik, Lars Rauff Skadhauge, Janne Schurmann Tolstrup, Morten Grnbk, Allan Linneberg, Simon Francis Thomse. Intake of alcohol and risk of adult-onset asthma, Respiratory Medicine - February 2012 (Vol. 106, Issue 2, Pages 184-188, DOI: 10.1016/j.rmed.2011.11.004) [225] Marier J R. Observations and implications of the (Mg F) interrelations in bio-systems: a review and comments on magnesium intake and fluoride intake in the modern-day world. Proceedings of the Finnish Dental Society 76. 82-92, 93-102, 1980. [226] Pethe, S., Boucher, J.-L., and Mansuy, D. (2002) Interaction of anions with rat liver arginase: specific inhibitory effects of fluoride, J. Inorg. Biochem. 88, 397-402. [227] Lenti, C. (1945) Inhibition and reactivation of arginase, Bull. Soc Ital. Biol. Sper.29, 636-637. [228] Van Pilsum, J. F., Taylor, D., Zakis, B., and McCormick, P. (1970) Simplified assay for transamidinase activities of rat kidney homogenates, Anal. Biochem. 35, 277- 286. [229] Tormanen, C. D. (2003) Substrate inhibition of rat liver and kidney arginase with fluoride,J. Inorg. Biochem. 93 , 243-246. [230] Cama et al. (2004) Inhibitor Coordination Interactions in the Binuclear Manganese Cluster of Arginase, Biochemistry 2004, 43, 8987-8999 [231] Markus Munder, Arginase: an emerging key player in the mammalian immune system, Br J Pharmacol. 2009 October; 158(3): 638651. [232] Chen PC, Broome JD. Mouse macrophage arginase. Proc Soc Exp Biol Med. 1980;163:354359. [233] Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007;117:11551166 [234] Rodriguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev. 2008;222:180191. [235] Bronte V, Kasic T, Gri G, Gallana K, Borsellino G, Marigo I, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med. 2005a;201:1257 1268. [236] Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004;64:58395849. [237] Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med. 2006b;203:26912702 [239] Munder M, Schneider H, Luckner C, Giese T, Langhans CD, Fuentes JM, Kropf P, Mueller I, Kolb A, Modolell M, Ho AD. Suppression of T-cell functions by human granulocyte arginase. Blood. 2006 Sep 1;108(5):1627-34. Epub 2006 May 18. [240] Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord. 2010 Sep;11(3):171-8. doi: 10.1007/s11154-010-9146-0. [241] Cimasoni G. Inhibition of cholinesterases by fluoride in vitro. Biochem J. 1966 Apr;99(1):133-7. [242] Westendorf, J. The Kinetics of Acetylcholinesterase Inhibition and the Influence of Fluoride and Fluoride Complexes on the Permeability of Erythrocyte Membranes. Ph.D. Thesis. [Engl. Transl.] von Moltke, J., Transl. University of Hamburg: Hamburg, Germany, 1975 [243] Hilmas C., Adler M.,, and Baskin S.I., Pulmonary Toxicity of Cholinesterase inhibitors. Published in Toxicology of Organophosphate and carbamate compounds (ed. R.C. Gupta). New York: Academic Press, pp.389-397, 2006. 54 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [244] Hoi, I.K., and Hoskins, B. (1987). Biological and pharmacological aspects of neurotoxicity from and tolerance to organophosphorus cholinesterase inhibitors. In Handbook of Toxicology (T.J.Haley and W.O. Berndt, Eds.), pp 44-73. Hemisphere, Washington, DC [245] Hirshman CA. Anesthesia for Patients with Reactive Airway Disease. ASA Refresher Course Lectures 1992; 221. [246] Helou R, Rhalimi M. Cholinesterase inhibitors and the risk of pulmonary disorders in hospitalized dementia patients. J Popul Ther Clin Pharmacol. 2010 Fall;17(3):e379-89. Epub 2010 Oct 26. [247] Bardal S K., Waechter J E., Martin D S. Applied Pharmacology, 1st edition, Elsevier, 2011 ISBN-13 9781437703108 [248] Hilmas C., Adler M.,, and Baskin S.I., Pulmonary Toxicity of Cholinesterase inhibitors. Published in Toxicology of Organophosphate and carbamate compounds (ed. R.C. Gupta). New York: Academic Press, pp.389-397, 2006. [249] Finney, et al., "Re-examination of Hexafluorosilicate Hydrolysis by 19F NMR and pH Measurement," Environ. Sci. Technol. 2006, 40, 2572-2577. [250] Vetch D, Letinov H, Tuarov I. Methods of pharmaceutical technology in preparation of pellets for detection of acetylcholinesterase inhibitors, Ceska Slov Farm. 2012 Oct;61(5):234-9. [251] Claudia Fruijtier-Plloth, The toxicological mode of action and the safety of synthetic amorphous silicaA nanostructured material, Toxicology, Volume 294, Issues 23, 11 April 2012, Pages 6179 [252] Kaewamatawong, T., Kawamura, N., Okajima, M., Sawada, M., Morita, T., Shimada, A., 2005. Acute pulmonary toxicity caused by exposure to colloidal silica: particle size dependent pathological changes in mice. Toxicol. Pathol. 33, 743749. [253] Kaewamatawong, T., Shimada, A., Okajima, M., Inoue, H., Morita, T., Inoue, K., Takano, H., 2006. Acute and subacute pulmonary toxicity of low dose of ultrafine colloidal silica particles in mice after intratracheal instillation. Toxicol. Pathol. 34,958965. [254] Masoli et al. Global Burden of Asthma, Development for the Global Initiative for Asthma, Medical Research Institute of New Zealand & University of Southampton [255] Zubair Kabir, Patrick J. Manning, Jean Holohan, Patrick G. Goodman, and Luke Clancy, Prevalence of Symptoms of Severe Asthma and Allergies in Irish School Children: An ISAAC Protocol Study, 19952007, Int J Environ Res Public Health. 2011 August; 8(8): 31923201. Published online 2011 August 2. doi: 10.3390/ijerph8083192 [256] ISAAC [web site]. International Study of Asthma and Allergies in childhood (http://isaac.auckland.ac.nz) [257] Severe Asthma in Ireland and Europe, Asthma Society of Ireland, 2007 [258] Brennan N.,McCormack S., O Connor T., Inhale Report, 2nd Edition, Irish Thoracic Sosiety, 2008 [259] World Health Organisation (2007), European Health for all Database www.euro.who.int/hfadb [260] Balanda K, Wilde J. Institute of Public Health in Ireland, Inequalities in Mortality, A report on All Ireland Mortality Data 1989-1998. 2001 [261] Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell B. 2007;39:4484. [262] Delattre J, Beaudeux JL, Bonnefont-Rousselot D. Radicaux libres et stress oxydant. Aspects biologiques et pathologiques. ditions Mdicales internationales. 2005:1492. [263] Aitken RJ, Roman SD. Antioxidant systems and oxidative stress in the testes. Oxidative Medicine and Cellular Longevity. 2008;1:1524. [264] Sharma A, Chinoy NJ: Role of free radicals in fluoride-induced toxicity in liver and kidney of mice and its reversal. Fluoride 31: S26, 1998 [265] Shivarajashankara YM, et al. (2001), Oxidative stress in children with skeletal fluorosis. Fluoride 34:103-07. [266] Hui Xu, Chun-hong Wang et al. (2003), Lipid peroxidation and fluorosis. Fluoride 36: 165 170. 55 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [267] Ruiz-Payan A. (2006). Chronic effects of fluoride on growth, blood chemistry and thyroid hormones in adolescents residing in three communities in Northern Mexico. ETD Collection for University of Texas, El Paso.Paper AAI3214004. [268] Shanthakumari D, et al. (2006), Antioxidant defense systems in red blood cell lysates of men with dental fluorosis living in Tamil Nadu, India. Fluoride 39:231-39. [269] Gavriliuk LA, et al. (2007). Impact of antioxidative therapy on the activity of salivary glutathione-dependent enzymes in patients with fluorosis. Clin. Lab. Diag., 22: 35-37. [270] Zhang et al. (2007), Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons Toxicol. 2007; 236:208-216. [271] Mittal et al. (2007), Vitamin E supplementation protects oxidative stress during arsenic and fluoride antagonism in male mice. Drug Chem Toxicol. 2007;30(3):263-81. [272] Shanthakumari, D et al. (2007) Effect of fluoride intoxication on the levels of intestinal antioxidants studied in rats, Methods Find Exp Clin Pharmacol 2007, 29(2): 93 [273] Izquierdo et al (2008), Decreased in vitro fertility in male rats exposed to fluorideinduced oxidative stress damage and mitochondrial transmembrane potential loss. Toxicology and Applied Pharmacology. 2008;230(3):352357. [274] Garcia et al (2009), Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress. Toxicology. 2009;263(2-3):7583 [275] Ailani V, et al. (2009), Oxidative stress in cases of chronic fluoride intoxication Indian J Clin Biochem. 2009 October; 24(4): 426429. [276] Bharti and Srivastava (2009), Fluoride-induced oxidative stress in rat's brain and its amelioration by buffalo (Bubalus bubalis) pineal proteins and melatonin.Biol Trace Elem Res. 2009 Aug;130(2):131-40. [277] Dlugosz et al. (2009), Oestradiol Protects Against the Harmful Effects of Fluoride More by Increasing Thiol Group Levels than Scavenging Hydroxyl Radicals, Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 2009 105, 366373 [278] Gutowska et al (2010), Fluoride as a pro-inflammatory factor and inhibitor of ATP bioavailability in differentiated human THP1 monocytic cells. Toxicol Lett. 2010 Jul 1;196(2):74-9. [279] Hassan and Aziz (2010), Evaluation of free radical-scavenging and anti-oxidant properties of black berry against fluoride toxicity in rats Food Chem Toxicol. 2010 AugSep;48(8-9) [280] Morales-Gonzlez JA et al (2010), Effect of Sodium Fluoride Ingestion on Malondialdehyde Concentration and the Activity of Antioxidant Enzymes in Rat Erythrocytes, Int J Mol Sci. 2010 Jun 11;11(6):2443-52. [281] Varol E, et al. (2011). Evaluation of total oxidative status and total antioxidant capacity in patients with endemic fluorosis. Toxicology & Industrial Health Dec. 8 [282] Amaravadi NV, Vasant RA. (2011), Amelioration of fluoride induced oxidative stress by Mangifera indica L. fruit. Spatula DD. 2011; 1(4): 181-188. [283] Rao et al (2011) Morphometry of buccal mucosal cells in fluorosis A new paradigm, Hum Exp Toxicol November 2011 vol. 30 no. 11 1761-1768 [284] Bandyopadhyay et al. (2012), Effect of Fluoride Toxicity on Some Clinical, Biochemical and Physiological Aspects of Albino Rats Int. J. Res. Chem. Environ. Vol. 2 Issue 1 January 2012 (160-165) [285] Shuhua et al. (2012), A role of fluoride on free radical generation and oxidative stress in BV-2 microGlia cells. Mediators of Inflammation. 2012;2012:8 pages.102954 [286] Katararaki and Rao (2012), Fluoride and oxidative stress in postmenopausal women IOSR Journal of Pharmacy ISSN: 2250-3013, Volume 2 Issue 5, Sep-Oct. 2012, PP.57-59 [287] Agalakova N, and Gusev G., (2012), Molecular Mechanisms of Cytotoxicity and Apoptosis Induced by Inorganic Fluoride, ISRN Cell Biology Volume 2012, Article ID 403835, 16 pages [289] Xu et al (2013)., Relationship between intracellular Ca and ROS during fluorideinduced injury in SH-SY5Y cells, Environ Toxicol. 2013 Jun;28(6):307-12. doi: 10.1002/tox.20721. 56 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [290] Yan et al. (2013)., JNK and NADPH Oxidase Involved in Fluoride-Induced Oxidative Stress in BV-2 Microglia Cells, Mediators Inflamm. 2013; 2013: 895975. [291] Yamaguti et al.( 2013)., Effects of Single Exposure of Sodium Fluoride on Lipid Peroxidation and Antioxidant Enzymes in Salivary Glands of Rats, Oxid Med Cell Longev. 2013; 2013: 674593. [292] Miltonpraubu and Thangapandiyan (2013)., Protective Effect of Epigallocatechin Gallate on Fluoride-Induced Oxidative Stress Related Haematotoxicity in Rats. Journal of Pharmacology and Toxicological Studies, Volume 1 | Issue 2 | October-December, 2013 [293] Varol et el. (2013) Evaluation of total oxidative status and total antioxidant capacity in patients with endemic fluorosis, Toxicol Ind Health March 2013 vol. 29 no. 2 175-18 [294] Yammaguti et al. (2013) Effects of Single Exposure of Sodium Fluoride on Lipid Peroxidation and Antioxidant Enzymes in Salivary Glands of Rats, Oxid Med Cell Longev. 2013; 2013: 674593. [295] Saralakumari D, Rao RP., Red cell membranes alterlations in human chronic fluoride toxicity. Biochem Int 23: 639-648, 1991 [296] Jeji.J, Sharma R, Jolly SS, Pamnani S: Implication of glutathione in endemic fluorosis. Fluoride 18 117-119,1985 [297] Li J, Cao S: Recent studies on endemic fluorosis in China. Fluoride 27: 125-128, 1994 [298] Sushella A.K, Bhatnagar M., Reversal of Fluoride induced cell injury through elimination of fluoride and consumption of diet rich in essential nutrients and antioxidants Molecular and Cellular Biochemistry 234/235:335-340, 2001 [299] Stern A, Red Cell Oxidative Damage in Oxidative Stress. Academic Press, London, 1985, pp 331-350 [300] Shivarajashankara YM, et al. (2001), Oxidative stress in children with skeletal fluorosis. Fluoride 34:103-07. [301] Cao SR, Cao IX, Li JX., Developments in the prevention and treatment of fluorosis caused by coal burning in China(1986-1993).Proceedings of the XXth conference of ISFR, Beijing, China ,September, 1994, P145 [302] Wang ZC, Fu D, Wang YP, Guan DH, Lix D, Van JL, Wu Y.,Effect of free radicals on the development of fluorosis and the protective effects by SOD and vit E. Proceedings of the XXth conference of ISFR, Beijing, China, September, 1994, p145 [303] McCully K. S., Chemical Pathology of Homocysteine. IV. Excitotoxicity, Oxidative Stress, Endothelial Dysfunction, and Inflammation, Ann Clin Lab Sci Summer 2009 vol. 39 no. 3 219-232 [304] Sbarra AJ, Karnovsky ML. The biochemical basis of phagocytosis. I. Metabolic changes during the ingestion of particles by polymorphonuclear leukocytes. J Biol Chem 1959;234:13551362. [305] Gabler WL, Leong PA. Fluoride inhibition of polymorphonuclear leukocytes. J Dent Res 1979;58:19331939. [306] Gabler WL, Creamer HR, Bullock WW. Role of extracellular calcium in neutrophil responsiveness to chemotactic tripeptides. Inflammation 1986;10:281292. [307] Curnutte JR, Babior BM, Karnovsky ML. Fluoride-mediated activation of the respiratory burst in human neutrophils. A reversible process. J Clin Invest 1979;63: 637647. [308] Sushella A.K, Bhatnagar M., Reversal of Fluoride induced cell injury through elimination of fluoride and consumption of diet rich in essential nutrients and antioxidants Molecular and Cellular Biochemistry 234/235:335-340, 2001 [309] Oxygen/Nitrogen Radicals Cell injury and Disease. Edited by Val Vallyathan, 2002 Kluwer Academic Publishers [310] Dreher D, Junod AF. Role of oxygen free radicals in cancer development. Eur J Cancer. 1996 Jan;32A(1):30-8. [311] Verschoor M,L., Verschoor C.P. Singh G., Ets-1 global gene expression profile reveals associations with metabolism and oxidative stress in ovarian and breast cancers, Cancer & Metabolism 2013, 1:17
57 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [312] Xu Z, Xu B, Xia T, He W, Gao P, Guo L, Wang Z, Niu Q, Wang A. Relationship between intracellular Ca and ROS during fluoride-induced injury in SH-SY5Y cells. Environ Toxicol. 2013 Jun;28(6):307-12. doi: 10.1002/tox.20721. Epub 2011 Jul 22. [313] L. Li, The biochemistry and physiology of metallic fluoride: action, mechanism, and implications, Critical Reviews in Oral Biology and Medicine, vol. 14, no. 2, pp. 100114, 2003. [314] Murthy KS, Makhlouf GM. Fluoride activates G protein-dependent and -independent pathways in dispersed intestinal smooth muscle cells. Biochem Biophys Res Commun. 1994 Aug 15;202(3):1681-7. [315] Melien O.Heterotrimeric G proteins and disease. Methods Mol Biol. 2007;361:119-44. [316] Spiegel, A. M., A. Shenker, and L.S. Weinstein. 1992. Receprot-effector coupling by Gproteins: implications for normal and abnormal signal transduction. Endocr. Rev. 13:536565 [317] Insel, P.A., and S.I. Wasserman, 1990. Asthma: adisorder of adrenergic receprots. FASEB (Fed. Am. Soc. Exp. Biol) J. 4:2732-2736 [318] Reihsaus, E.M. Innis, N. MacIntyre, and S.B. Liggett. 1993. Mutations in the gene encoding for the ,adrenergic receptor in normal and asthmatic subjects. Am J. Respir. Cell. Mol. Biol. 8:334-339 [319] Spiegel A M, Weinstein L S, and A Shenker. Abnormalities in G protein-coupled signal transduction pathways in human disease. J Clin Invest. 1993 September; 92(3): 1119 1125. doi: 10.1172/JCI116680 [320] Thompson M.D., Percy M. E., Burnham M. W., David E. Cole C. G Protein-Coupled Receptors Disrupted in Human Genetic Disease, 2008, Methods in Molecular Biology, Volume: 448: 109-137. [321] Zvi Farfel,Henry R. Bourne, and Taroh Iiri. The Expanding Spectrum of G Protein Diseases, N Engl J Med 1999; 340:1012-1020 [322] "Physiology or Medicine 1994 - Press Release". Nobelprize.org. Nobel Media AB 2013. Web. 7 Jan 2014. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/1994/press.html> [323] Evora P. R.B., Nobre F, The Role of G-Proteins in the Pathophysiology of the Cardiovascular Diseases, Arq Bras Cardiol volume 72, (n 2), 1999 [324] Lyons, J., C.C. Landis, G.Harsh, L. Vallar. K. Grunewald. H. Feichtinger, Q.-Y. Dub, O.H. Clark, E Kawasaki, H.R. Bourne, et al. 1990. Two G proteins oncogenes in human endocrine tumors. Science (Wash. D.C). 249; 655-659 [325] Young, D., G. Waitches, C. Birchmeier, O, Fasano, and M. Wigler. 1986. Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domain. Cell. 45:711-719 [326] Kensler T. W., and Trush M. A., Role of Oxygen Radicals in Tumor Promotion, Environmental Mutagenesis 6593-616 (1984) [327] Copeland E.S., Free Radicals in Carcinogenesis, Cancer Research 46, 5451, October 1986 [328] Sainz RM, Mayo JC, Tan DX, Len J, Manchester L, Reiter RJ. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate. 2005 Apr 1;63(1):29-43. [329] Lissoni P, Barni S, Meregalli S, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer.1995 Apr;71(4):854-6. [330] Cos S, Gonzalez A, Martinez-Campa C, et al. Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev. 2006;30(2):11828. [331] Sanchez-Barcelo EJ, Cos S, Mediavilla D, et al. Melatonin-estrogen interactions in breast cancer. J Pineal Res. 2005 May;38(4):217-22. [332] Suzen S. Recent developments of melatonin related antioxidant compounds. Comb Chem High Throughput Screen. 2006 Jul;9(6):409-19. 58 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [333] Schernhammer E, Chen H, Ritz B. Circulating melatonin levels: possible link between Parkinson's disease and cancer risk? Cancer Causes Control. 2006 May;17(4):577-82. [334] Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004 Feb;43(2):192-7. [335] Srinivasan V, Pandi-Perumal S, Cardinali D, Poeggeler B, Hardeland R. Melatonin in Alzheimer's disease and other neurodegenerative disorders. Behav Brain Funct. 2006;2(1):15. [336] Konturek SJ, Konturek PC, Brzozowski T, Bubenik GA. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol. 2007 Dec;58 Suppl 6:23-52. [337] Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci. 2002 Oct;47(10):2336-48. [338] Hardeland Rdiger, Melatonin in Aging and Disease Multiple Consequences of Reduced Secretion, Options and Limits of Treatment, Aging Dis. 2012 April; 3(2): 194 225.Published online 2011 February 10. [339] Ferlay et al. Estimates of the cancer incidence and mortality in Europe in 2006, Annals of Oncology 18: 581-592,2007 [340] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010 Dec 15;127(12):2893-917. doi: 10.1002/ijc.25516. [341] Turner CH, Garetto LP, Dunipace AJ, Zhang W, Wilson ME, Grynpas MD, Chachra D, McClintock R, Peacock M, Stookey GK. Fluoride treatment increased serum IGF-1, bone turnover, and bone mass, but not bone strength, in rabbits. Calcif Tissue Int. 1997 Jul;61(1):77-83. [342] Lau, W.K.H., Farley, J.R., Freeman, T.K., and Baylink, D.J. (1989). A proposed mechanism of the mitogenic action of fluoride on bone cells: Inhibition of the activity oif osteoblastic acid phosphatase. Metabolism 38, 858-863 [343] Lau KH, Goodwin C, Arias M, Mohan S, Baylink DJ. Bone cell mitogenic action of fluoroaluminate and aluminum fluoride but not that of sodium fluoride involves upregulation of the insulin-like growth factor system. Bone. 2002 May;30(5):705-11. [344] Ammann P, Rizzoli R, Caverzasio J, Bonjour JP. Fluoride potentiates the osteogenic effects of IGF-I in aged ovariectomized rats. Bone. 1998 Jan;22(1):39-43. [345] Roddam, A.W., Allen, N.E., Appleby, P., Key, T.J., Ferrucci, L., Carter, H.B., Metter, E.J., Chen, C., Weiss, N.S., Fitzpatrick, A. et al. (2008) Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. Ann. Intern. Med., 149, 461471, W483468. [346] Smith Armstrong and Singer 1950 Proc. Soc. Exp. Biol. (N.Y) 102, 170. [347] Pirkko-Liisa Mkinen, Biochemical Studies on a Novel Vanadate- MolybdateSensitive Acid Phosphatase from Human Epidermis, Journal of Investigative Dermatology (1985) 85, 118124; doi:10.1111/1523-1747.ep12276514 [348] Kirschenbaum A, Liu XH, Yao S, Leiter A, Levine AC. Prostatic acid phosphatase is expressed in human prostate cancer bone metastases and promotes osteoblast differentiation. Ann N Y Acad Sci. 2011 Nov;1237:64-70. [349] Taira A, Merrick G, Wallner K, Dattoli M. Reviving the acid phosphatase test for prostate cancer.Oncology (Williston Park). 2007 Jul;21(8):1003-10. [350] Ishibe M, Rosier RN, Puzas JE. Human prostatic acid phosphatase directly stimulates collagen synthesis and alkaline phosphatase content of isolated bone cells. J Clin Endocrinol Metab. 1991 Oct;73(4):785-92. [351] Henneberry MO, Engel G, Grayhack JT. Acid phosphatase. Urol Clin North Am. 1979 Oct;6(3):629-41. [352] Coombes RC, Greenberg PC, Hillyard C, et al: Plasma- immunoreactive calcitonin in Patients with non-thyroid tumors. Lancet 1:1080-1083,1974 [353] Milhaud C, Calmette C, Taboulet J, et al: Hypersecretion of calcitonin in neoplastic conditions. Lancet 1:462, 1974
59 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [354] Tashjian,A.H.,Jr.,Howland,B.G.,Melvin,K.E.W.,and Hill,C.S.,Jr.(1970).Immuno assay of human calcitonin.Clinical measurement, relation to serum calcium and studies on patients with medullary carcinoma. New Engl. J. Med., 283, 890-895 [355] Pflger K H, Gropp C, Havemann K, Ectopically produced calcitonin in human hemoblastoses. Klin Wochenschr. 1982 Jul 1;60(13):667-72. [356] Sakura H, Fujii T, Okamoto K. A study of human calcitonin in an ovarian carcinoid and ovarian cancers. Exp Clin Endocrinol. 1991 Mar;97(1):91-6. [357] Tatsunosuke Ichimura ,Satoshi Kondo, Shunichi Okushiba,Toshiaki Morikawa, Hiroyuki Katoh, A Calcitonin and vasoactive intestinal peptide-producing pancreatic endocrine tumor associated with the WDHA syndrome, nternational Journal of Gastrointestinal Cancer June 2003, Volume 33, Issue 2-3, pp 99-102 [358] James Paul O'Neill, Anaplastic thyroid cancer Irish epidemiology and novel chemotherapeutic strategies, Royal College of Surgeons in Ireland.2009[359] Women and Cancer in Ireland, 1994-2001 National Cancer Registry, Womans Health council. [360] Cancer in Ireland 2011: Annual report of the National Cancer Registry [361] Estimated age standardised incidence rates for invasive female breast cancer: 2008. European Cancer Observatory (ECO). Available online at: http://eu- cancer.iarc.fr/cancer-13breast.html,en . Accessed 17 th May 2012 [362] European Age-Standardised rates calculated by the Cancer Research UK Statistical Information Team, 2011, using data from GLOBOCAN 2008 v1.2, IARC, version 1.2 [363] Source: Lymphona Forum of Ireland, Guidelines on Diagnosis and Treatment of Malignant Lymphomas [364] Cancer in Ireland 1994-2004: A comprehensive report, Chapter 24: Leukaemia (C91C95) NICR/NCRI. [365] National Cancer Registry/Northern Ireland Cancer Registry All-Ireland Cancer Atlas 1995-2007.Cork/Belfast, 2011. [366] European Medicines Agency: Web: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/07/WC500130 122.pdf [367] Featherstone JD. Dental caries: a dynamic disease process. Aust Dent J. 2008 Sep;53(3):286-91. doi: 10.1111/j.1834-7819.2008.00064.x. [368] Balakrishnan M, Simmonds RS, Tagg JR.Dental caries is a preventable infectious disease. Aust Dent J. 2000 Dec;45(4):235-45. [369] Caufield PW, Griffen AL. Dental caries. An infectious and transmissible disease. Pediatr Clin North Am. 2000 Oct;47(5):1001-19, v. [370] World Health Organisation, European Region, HFA Satabase, January 2013. [371] Bilici M, Efe H, Koroglu MA, Uydu HA, Bekaroglu M, Deger O. Antioxidative enzyme activities and lipid peroxidation in major depression: Alterations by antidepressant treatments. J Affect Disord. 2001;64:4351 [372] Yao JK, Reddy RD, Kammen DP. Oxidative damage and schizophrenia: an overview of the evidence and its therapeutic implications. CNS Drugs. 2001;15:287310. [373] Bouayed J, Rammal H, and Soulimani R.,Oxidative stress and anxiety, Relationship and cellular pathways. Oxid Med Cell Longev. 2009 Apr-Jun; 2(2): 6367. PMCID: PMC2763246 [374] Boskovic M., Vovk T., Plesnicar K.B., Grabnar I, Oxidative Stress in Schizophrenia, Curr Neuropharmacol. 2011 June; 9(2): 301312. [375] Ling Yan, Shengnan Liu, Chen Wang, Fei Wang, Yingli Song, Nan Yan, Shuhua Xi, Ziyou Liu, and Guifan Sun, JNK and NADPH Oxidase Involved in Fluoride-Induced Oxidative Stress in BV-2 Microglia Cells, Mediators Inflamm. 2013; 2013: 895975. [376] Friedman E, Wang HY. Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects. J Neurochem. 1996 Sep;67(3):114552. [377] V. K. Bharti and R. S. Srivastava, Fluoride-induced oxidative stress in rat's brain and its amelioration by buffalo (Bubalus bubalis) pineal proteins and melatonin, Biological Trace Element Research, vol. 130, no. 2, pp. 131140, 2009. 60 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [378] Xi Shuhua, Liu Ziyou, Yan Ling, Wang Fei, and Guifan Sun, A Role of Fluoride on Free Radical Generation and Oxidative Stress in BV-2 Microglia Cells.Mediators of Inflammation, Volume 2012 (2012), Article ID 102954, [379] Refsnes, M., Lag, M., Skuland, T., Thrane, E. V., Samuelsen, J. T., and Schwarze, P. E. (1999b). Mechanisms of fluoride-induced apoptosis in human lung epithelial cells (A549 cells). Toxicol. Lett. 109(Suppl. 1), 74. [380] Clinical Handbook of Schizophrenia, Edited by kim T Muerer and Dilip V. Jeste, 2008 [381] Ba Y, Zhang H, Wang G, Wen S, Yang Y, Zhu J, Ren L, Yang R, Zhu C, Li H, Cheng X, Cui L. Association of dental fluorosis with polymorphisms of estrogen receptor gene in Chinese children. Biol Trace Elem Res. 2011 Oct;143(1):87-96. doi: 10.1007/s12011-0108848-1. Epub 2010 Sep 18. [382] Yamaguti et al.( 2013) Oxid Med Cell Longev. 2013; 2013: 674593. [383] Bayani Uttara, Ajay V. Singh, Paolo Zamboni, and R.T Mahajan, Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options, Curr Neuropharmacol. 2009 March; 7(1): 6574.doi: 10.2174/157015909787602823 PMCID: PMC2724665 [384] Yun-Zhong F, Sheng Y, Guoyao Wu. Free radicals, antioxidants, and nutrition. Nutrition. 2002;18:872879. [385] Freidovich I. Fundamental aspects of reactive oxygen species, or whats the matter with oxygen? N.Y. Acad. Sci. 1999;893:13. [386] Cabot M.R., The incidence and prevalence of schizophrenia in the Republic of Ireland, Soc Psychiatry Psychiatr Epidemiol (1990) 25:210-215 [387] Depressive disorders in Europe: prevalence figures from the ODIN study, The British Journal of Psychiatry (2001) 179: 308-316 [388] Neurological care in Ireland, Medical Independent, March 2010 [389] Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593602 [390] ESEMed/MHEDEA 2000 investigators, author. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiat Scand. 2004;109:2127 [391] Lpine JP. The epidemiology of anxiety disorders: prevalence and societal costs. J Clin Psychiatry. 2002;63:48 [392] Bleich, S, Carl, M, Bayerlein, K, Reulbach, U, Biermann, T, Hillemacher, T, Bonsch, D, Kornhuber, J (2005) Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS).. Alcohol Clin Exp Res 29: pp. 334-336 [393] Bjelland, I, Tell, GS, Vollset, SE, Refsum, H, Ueland, PM (2003) Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study.. Arch Gen Psychiatry 60: pp. 618-626 [394] Bottiglieri, T, Laundy, M, Crellin, R, Toone, BK, Carney, MW, Reynolds, EH (2000) Homocysteine, folate, methylation, and monoamine metabolism in depression.. J Neurol Neurosurg Psychiatry 69: pp. 228-232 [395] Frieling, H, Rmer, K, Rschke, B, Bnsch, D, Wilhelm, J, Fiszer, R, de Zwaan, M, Jacoby, GE, Kornhuber, J, Bleich, S (2005) Homocysteine plasma levels are elevated in females with anorexia nervosa.. J Neural Transm 112: pp. 979-985 [396] Bosco P, Gueant-Rodriguez RM, Anello G, Barone C, Namour F, Caraci F, et al. Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Am J Med Genet A. 2003 Sep 1;121A(3):219-24. [397] Panagiotakos DB, Pitsavos C, Chrysohoou C, Tsetsekou E, Papageorgiou C, Christodoulou G, Stefanadis C. Increased plasma homocysteine concentrations in healthy people with hostile behavior: the ATTICA study. Med Sci Monit. 2004 Aug;10(8):CR457-62. Epub 2004 Jul 23. 61 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [398] Kuhn W, Roebroek R, Blom H, et al. Elevated plasma levels of homocysteine in Parkinsons disease. Eur Neurol. 1998;40:225-227. [399] Muller T, Werne B, Fowler B, Kuhn W. Nigral endothelial dysfunction, homocysteine, and Parkinsons disease. Lancet. 1999;354:126-127. [400] Schwarz S, Zhou G-Z. N-methyl-D-aspartate receptors and CNS symptoms of homocystinuria. Lancet. 1991;337:1226-1227. [401] Wierzbicki AS. Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res. 2007 Jun;4(2):143-50. [402] Malinow, M. Ren, Plasma Homocyst(e)ine and Arterial Occlusive Diseases: A minireview. Clin.Chem. 1995;40:173-176. [403] Ueland PM. Homocysteine species as components of plasma redox thiol status. Clin.Chem. 1995;41:340-342. [404] Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. The Lancet 1995;346:1395-98. [405] Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem. 1990;1:228-237. [506] The Handbook of Environmental Chemistry, Ed Alasdair H. Neilson: ISBN 0-38709688-4 Springer-Verlag Berlin Heidelberg New York, 1994 [407] Muzard M, Vandenplas C, Guillerm D, Guillerm G.The mechanism of inactivation of S-adenosylhomocysteine hydrolase by fluorinated analogs of 5'-methylthioadenosine. J Enzyme Inhib. 1998 Sep;13(6):443-56. [408] Siming Liu , Chong-sheng Yuan , and Ronald T. Borchardt Aristeromycin-5carboxaldehyde: A Potent Inhibitor of S-Adenosyl- l-homocysteine Hydrolase, J. Med. Chem., 1996, 39 (12), pp 23472353 DOI: 10.1021/jm950916u [409] Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Annu Rev Med. 2009;60:39-54. doi: 10.1146/annurev.med.60.041807.123308. [410] R C Austin, S R Lentz and G H Werstuck, Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease, Cell Death and Differentiation (2004) 11, S56S64. doi:10.1038/sj.cdd.4401451 [411] R C Austin, S R Lentz and G H Werstuck, Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease, Cell Death and Differentiation (2004) 11, S56S64. doi:10.1038/sj.cdd.4401451 [412] Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease, JAMA 1995;274:13:1049-1057. [413] Malaguarnera M, et al.Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med. 2004;42(9):1032-5. [414] O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L, Dewey RB Jr, Bottiglieri T, DiazArrastia R. Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations. Arch Neurol. 2004 Jun;61(6):865-8. [415] Sachdev PS, et al. Homocysteine as a risk factor for cognitive impairment in stroke patients. Dement Geriatr Cogn Disord. 2003;15(3):155-62. [416] Miller JW. Homocysteine and Alzheimer's disease. Nutr Rev. 1999 Apr;57(4):126-9. [417] Guttormsen AB, Svarstad E, Ueland PM, Refsum H. Elimination of homocysteine from plasma in subjects with end-stage renal failure. Irish J Med Sci 1995;164 (Suppl. 15):8.11. [418] Bostom AG, Lathrop L. Hyperhomocysteinemia in end-stage renal disease (ESDR): Prevalence,etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int 1997;52:10-20. [419] Gowiska B, Urban M, Peczyska J, Florys B, Szydowska E. Elevated concentrations of homocysteine in children and adolescents with arterial hypertension accompanying Type 1 diabetes. Med Sci Monit. 2001 Nov-Dec;7(6):1242-9. [420] Ruiz et al., Homocysteine levels in children and adolescents are associated with the methylenetetrahydrofolate reductase 677C>T genotype, but not with physical activity, fitness or fatness: The European Youth Heart Study, British Journal of Nutrition(2007),97 , 255262 62 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [421] Refsum H, Wesenberg F., and Ueland P. M., Plasma Homocysteine in Children with Acute Lymphoblastic Leukemia: Changes during a Chemotherapeutic Regimen Including Methotrexate, Cancer Research, 51, 828-835, February 1, 1991 [422] Kishi et al. Homocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia, Journal of Clinical Oncology, Vol 21, No 16 (August 15), 2003: pp 3084-3091 [423] Pasca SP, Nemes B, Vlase L, Gagyi CE, Dronca E, Miu AC and Dronca M (2006) High levels of homocysteine and low serumpara-oxonase 1 arylesterase activity in children with autism. Life Science 78 : 22442248. [424] Joanna Kauna-Czapliska, Monika Michalska and Jacek Rynkowsk, Homocysteine level in urine of autistic and healthy children Acta ABP, Biochimica Polonica, Vol. 58, No 1/2011 3134 [425] Etsuo Niki, Do free radicals play causal role in atherosclerosis? Low density lipoprotein oxidation and vitamin E revisited J Clin Biochem Nutr. 2011 January; 48(1): 37. Published online 2010 December 28. doi: 10.3164/jcbn.11-007FR PMCID: PMC3022060 [426] Helfand, M. 2004. Screening for subclinical thyroid dysfunction in nonpregnant adults: A summary of the evidence for the U.S. Preventive Services Task Force. Ann. Intern. Med. 140(2):128-141. [427] Weetman, A.P. 1997. Hypothyroidism: Screening and subclinical disease. Br. Med. J. 314(7088): 1175-1178. [428] Ercan Varet al, Biological Trace Element Research, Violume 133, Number 2/February, 2010 [429] Ercan Varol et al, Science of the Total Environment, Volume 408, Issue 11, 1 May 2010 Pages 2295-2298 [430] Song et al, Observations on fluoorotic aorta sclerosis by two doimensional echo cardiography Endemic diseases Bulliten 5, 1990, (1) 91-93 [431] Liang et al., Investigation and analysis of cardiovascular disease in endemic and nonendemic fluorosis areas, He Bei Province Journal of Endemiology 12, (1984) 44. [432] Turla, M, B. Gnegy,. Margaret, E,. Epps, S,. Shlafer, M. Loss of calmodulin activity in cardiac sarcoplasmic reticulum after ischemia. Biochemical and Biophysical Research Communications Volume 130, Issue 2, 31 July 1985, Pages 617620 [433] Pogwizd SM, Bers DM. Na/Ca exchange in heart failure: contractile dysfunction and arrhythmogenesis. Ann N Y Acad Sci. 2002 Nov;976:454-65. [434] Varol E, Akcay S, Ersoy IH, Ozaydin M, Koroglu BK, Varol S (2010a) Aortic elasticity is impaired in patients with endemic fluorosis. Biol Trace Elem Res 133(2):121127 [435] Varol E, Akcay S, Ersoy IH, Koroglu BK, Varol S (2010b) Impact of chronic fluorosis on left ventricular diastolic and global functions. Sci Total Environ 408(11):22952298 [436] Varol E Varol S., Effect of fluoride toxicity on cardiovascular systems: role of oxidative stress, Arch Toxicol (2012) 86:1627 [437] Yuxin Li et al. Association of vascular fluoride uptake with vascular calcification and coronary artery disease, Nuclear Medicine Communications 2012, 33:1420. [438] Takamori,T.et al, Electrocardiographical Studies of the inhabitants in High Fluorine Districts, Tokushima J of Exp. Med. 3:50, (1956) [439] Iwasi, Tadashi, Studies on the Glycogen and Phosphorylase Variations in Myocardium, Skeletal Muscle and Liver in Experimental Fluorosis, Shikoku Actu Medica 12:616, (1956) [440] Ma Y, Niu R, Sun Z, Wang J, Luo G, Zhang J, Wang J (2012) Inflammatory responses induced by fluoride and arsenic at toxic concentration in rabbit aorta. Arch Toxicol [441] Klaus Ley and Yuqing Huo, VCAM-1 is critical in atherosclerosis, J Clin Invest. 2001 May 15; 107(10): 12091210. [442] Harrington J.R. The role of MCP-1 in Atherosclerosis. Stems cells Fundamentals of Cancer medicine, Stem Cells 2000; 18:65-66 [443] Apostolakis S, Interleukin 8 and cardiovascular disease, Cardiovascular Research (2009) 84, 353360 [444] Jan H. Von der Thsen, et al, Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential, Pharmacol Rev March 1, 2003 55:133-166; published online March 1, 2003, doi:10.1124/pr.55.1.5 63 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [445] Schieffer B,.et al. Impact of interleukin-6 on plaque development and morphology in experimental atherosclerosis.Circulation. 2004 Nov 30;110(22):3493-500. [446] Dong, M.Z et al. Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice, American Heart Association, 2000; 101: 2290-2295. [447] Molenaar J.M. et al. P-selectin as a candidate target in atherosclerosis, Biochemical Pharmacology Volume 66, Issue 5, 1 September 2003, Pages 859866 [448] Burger PC, Platelet P-selectin facilitates atherosclerotic lesion development, Blood 2003 Apr 1;101(7):2661-6. Epub 2002 Dec [449] Kots Aya, Gumanova NG, Akhmedzhanov NM, et al - The GTP-binding regulatory proteins, Gs and Gi, are altered in erythrocyte membranes of patients with ischemic heart disease resulting from coronary atherosclerosis. Arterioscler Thromb 1993; 13: 1244-51 [450] World Heart Federation. Cardiovascular Risk Factors [451] Leblanc R., Feindel W., Yamamoto L. Y. Milton J.G. et al. 1984. The Effects of Calcium Antagonism On The Epicerebral Circulation In Early Vasospasm. Stroke Vol 15, No6, 1984 [452] Arning, C., Schrattenholzer, A.,Lachenmayer L. Cervical Carotid Artery Vasospasms Causing Cerebral Ischemia, Detection by Immediate Vascular Ultrasonographic Investigation, Stroke. 1998; 29: 1063-1066 [453] The Lancet, Jan. 28, 1961, p. 197, Tokushima J. Exper., Med. 3-50-53, 1956 [454] Wang et al, Toxicity From Water Containing Arsenic and Fluoride in Xinjiang Fluoride Vol. 30 No. 2 81-84 1997 [455] NHS Centre for Reviews and Dissemination, A systematic review of water fluoridation, The University of York, Report 18, Sept 2000 [456] O'Mullane DM, Harding M, Whleton HP, Cronin MS, Warren JJ. Dental Fluorosis in Primary Teeth of 5-year-olds in Ireland. Paper presentation at American Association for Dental Research conference, San Antonio, USA in March 2003. [457] Browne D, Whelton H, O Mullane D, Oral Health Services Research Centre, University Dental School, Cork. Fluoride metabolism and fluorosis, Journal of Dentistry, Volume 33 Issue 3, March 2005, Pages 177-186 [458] Verkerk, Robert H.J. The paradox of overlapping micronutrient risks and benefits obligates risk/benefit analysis, Journal of Toxicology, Feb 2010. [459] Risk Factors for Heart Disease, Cardiac Rehabilitation Unit, Wexford General Hospital. May 2006 [460] WHO HFA Database 2007 [461] Geological Survey of Finland, Special Paper 27, 85-96-1999 [462] Calcium and Magnesium in Drinking-Water Public Health Significance, World Health Organization, 2009 [463] Crawford M.D. GARDNER. M.J. Morris J .N. Cardio Vascular Disease and the mineral content OF drinking Water. British Medical Bulletin, VOL 27 No 1. Pp 21-24 [464] Bernardi, D., Dini, F.L., Azzarelli, A., Giaconi, A., Volterrani, C. and Lunardi, M. (1995) Sudden cardiac death rate in an area characterized by high incidence of coronary artery disease and low hardness of drinking water. Angiology 46, 145-149. [465] Lahermo P, Backman B (2000) The occurrence and geochemistry of fluorides with special reference to natural waters in Finland. Geological Survey of Finland. Report of Investigation 149. 40p. [466] Lahermo P, Ilmasti M, Juntunen r & Taka M (1990) The geochemical atlas of Finland, Part 1. The hydrogeochemical mapping of Finnish groundwater. Espoo, Geological Survey of Finland. [467] Libby P. Inflammation and disease. Nutr Rev 2007;65(12 Pt 2):S140-6. [468] Egger G. In Search of a Germ Theory Equivalent for Chronic Disease. Prev Chronic Dis 2012;9:110301. DOI: http://dx.doi.org/10.5888/pcd9.110301External Web Site Icon. [469] Neel BA, Sargis RM. The paradox of progress: environmental disruption of metabolism and the diabetes epidemic. Diabetes 2011;60(7):1838-48. [470] Dieppe P., Chronic Musculoskeletal Pain, BMJ 2013;346:f3146 [471] WHO Department of Health and Measurement information 2008. 64 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [472] Groth, E (1973).The Issues of Science and Public Policy. Air pollution Control in the San Francisco Bay Area, and Fluoridation of community water schemes. PH.D Dissertation. Department of Biological Sciences, Stranford University, May 1973. [473] Teotia SPS, ET al. (1976) Symposium on the Non-Skeletal Phase of Chronic Fluorosis: The Joints. Fluoride. 9(1) 19-24. [474]Cook. HA. 1971. Fluoride Studies in a Patient with Arthritis. The Lancet 1. 817 [475] Pak CY. (1989). Fluoride and osteoporosis. Proceedings of the Society for Experimental Biology and Medicine 191: 278-86. [476] Boivin G, et al. (1989). Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients. Bone 10:89-99. [477]Montakarn Namkaew,Phongtape Wiwatanadate, Association of fluoride in water for consumption and chronic pain of body parts in residents of San Kamphaeng district, Chiang Mai, Thailand, Tropical Medicine & International Health, Volume 17, Issue 9, pages 1171 1176, September 2012 [478]Waldbott GL (1998) The preskeletal phase of chronic fluoride intoxication. Fluoride 31, 1320. [479] Wang Y, Yin Y, Gilula LA & Wilson AJ (1993) Endemic fluorosis of the skeleton: radiographic features in 127 patients. American Journal of Roentgenology 162, 9399. [480] Susheela AK, Bhatnagar M. 2002. Reversal of fluoride induced cell injury through elimination of fluoride and consumption of diet rich in essential nutrients and antioxidants. Mol Cell Biochem 234/235:335-340. [481] The Irish Longitudinal Study on Ageing (TILDA) 2010 [482] InSites Consulting Pain Proposal Patient Survey. August September 2010 (Conducted in 2,019 people with chronic pain across 15 European counties. Funded by Pfizer Ltd). [483] Arthritis Ireland. http://www.arthritisireland.ie/go/about_arthritis/arthritis_facts [484] Montgomery SM, Morris DL, Pounder RE, Wakefield AJ. Asian ethnic origin and the risk of inflammatory bowel disease. Eur J Gastroenterol Hepatol 1999; 11:543-546. [485] Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J Gastroenterol 2006;12(38):610208. [486] Sawczenko A, Sandhu BK, Logan RF, et al. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet. 2001;357:10934. [487] Cosgrove M, Al-Atia RF, Jenkins HR. The epidemiology of paediatric inflammatory bowel disease. Arch Dis Child. 1996;74:4601. [488] Heyman MB, Kirschner BS, Gold BD, et al. Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr. 2005;146:35 40. [489] Shivananda S; Lennard-Jones JE; Logan RF; Fear N; Price A; Carpenter L; Van Blankenstein M; and the EC-IBD Study Group.(1996) Incidence of Inflammatory bowel disease across Europe: is there a difference [490] Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter I et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996; 39:690-697. [491] W. G. Humphreys, J. S. Brown, and T. G. Parks, Crohn's disease in Northern Ireland--a retrospective study of 440 cases. Ulster Med J. 1990 April; 59(1): 3035 [492] Loftus EVJr, Silverstein MD, Sandborn WJ, et al. Crohns desease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence and survival. Gastroenterology 1998; 114:1161-1168. [493] Eason RJ, Lee SP, Tasman-Jones C. Inflammatory bowel disease in Auckland, New Zealand. Aust N Z J Med. 1982 Apr;12(2):12531. [494] Richard B Gearry, Andrew S Day, Inflammatory bowel disease in New Zealand childrena growing problem, Journal of the New Zealand Medical Association, 03-October2008, Vol 121 No 1283 65 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [495] Yap J, Wesley A, et al. Paediatric inflammatory bowel disease in New Zealand Journal of the New Zealand Medical Association, 03-October-2008, Vol 121 No 1283 [496] Hope B, Shahdadpuri R, Dunne C, Broderick AM, Grant T, Hamzawi M, O'Driscoll K, Quinn S, Hussey S, Bourke B (2012) 'Rapid rise in incidence of Irish paediatric inflammatory bowel disease'. Archives of Disease in Childhood, [497] Farrell D, Inflammatory bowel disease: a beast of burden, School of Nursing andf Midwifery, University College Cork. Web: http://publish.ucc.ie/boolean/2011/00/Farrell/13/en [498] Schlup M, Maclaurin BP, Barbezat GO, de Lambert BM. Crohn's disease: a ten year retrospective review at Dunedin hospitals. N Z Med J. 1986 Mar 12;99(797):1414. [499] Wigley RD, Maclaurin BP. A study of ulcerative colitis in New Zealand, showing a low incidence in Maoris. Br Med J. 1962 Jul 28;5299:22831. [500] Eason RJ, Lee SP, Tasman-Jones C. Inflammatory bowel disease in Auckland, New Zealand. Aust N Z J Med. 1982 Apr;12(2):12531. [501] Gearry RB, Richardson A, Frampton CM, et al. High incidence of Crohn's disease in Canterbury, New Zealand: results of an epidemiologic study. Inflamm Bowel Dis. 2006 Oct;12(10):93643. [502] http://www.medicalobserver.com.au/news/australian-crohns-disease-rates-revealed [503] Economou M, Pappas G., New Global Map of Crohns Disease: Genetic, Environmental, and Socioeconomic Correlations, Inflamm Bowel Dis 2007;00:000 000 [504] ubuku, Effects of systemic fluoride intake on rat gastric mucosa, Pediatric Dental Clinic Uludag University, Faculty of Medicine Gorukle Campus 16059 Bursa-Turkey, Ege Tp Dergisi 44 (2) : 81 - 85 , 2005 [505] Easmann RP, Pashley DH, Birdsong NL, McKinney RV, Whitford GM. Recovery of rat gastric mucosa following single fluoride dosing. J Oral Pathol 1985; 14: 779-792. [506] Pashley DH, Allison NB, Easmann RP, McKinney RV, Horner JA, Whitford GM. The effects of fluoride on the gastric mucosa of the rat. J Oral Pathol 1984; 13: 535-545 [507] Easmann RP, Steiflik DE, Pashley DH, McKinney R V, Whitford GM. Surface changes in rat gastric mucosa induced by sodium fluoride: a scanning electron microscopic study. J Oral Pathol 1984; 13: 255-264. [508] Spak CJ, Sjstedts G, Eleborg L, et al. Studies of human gastric mucosa after application of 0,42 % fluoride gel. J Dent Res 1990; 69: 426-429. [509] Spak CJ, Sjstedts G, Eleborg L, et al. Tissue response of gastric mucosa after ingestion of fluori de. Br Med J 1989; 298: 1686-1687. [510] Whitford GM, Pashley DH, Garman RH. Effects of fluoride on structure and function of canine gastric mucosa. Digestive Diseases and Sciences 1997; 42: 2146-2155 [511] LeCompte EJ, Whitford GM. (1982). Pharmacokinetics of fluoride from APF gel and fluoride tablets in children. J Dent Res. 61(3):469-72. [512] Whitford GM, et al. (1987). Topical fluorides: effects on physiologic and biochemical processes. J Dent Res. 66(5):1072-8. [513] Lecompte EJ. (1987). Clinical application of topical fluoride productsrisks, benefits, and recommendations. J Dent Res. 66(5):1066-71. [514] Johnston DW. (1994). Current status of professionally applied topical fluorides. Community Dent Oral Epidemiol. 22(3):159-63. [515] Susheela AK, et al. (1992). Fluoride ingestion and its correlation with gastrointestinal discomfort. Fluoride 25: 5-22. - See more at: http://www.thenhfireland.com/?page_id=69#sthash.3m4lUBSD.dpuf [516] Waldbott, G.L. 1956. Incipient chronic fluoride intoxication from drinking water. II. Distinction between allergic reactions and drug intolerance. Int. Arch. Allergy Appl. Immunol. 9(5):241-249. [517] Petraborg, H.T. 1977. Hydrofluorosis in the fluoridated Milwaukee area. Fluoride 10(4): 165-168. 66 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [518] Grimbergen, G.W. 1974. A double blind test for determination of intolerance to fluoridated water. Preliminary report. Fluoride 7(3):146-152. [519] Feltman, R., and G. Kosel. 1961. Prenatal and postnatal ingestion of fluorides Fourteen years of investigation. Final report. J. Dent. Med. 16(Oct.):190-198. [520] Scariati PD et al. A longitudinal analysis of infant morbidity and the extent of breastfeeding in the United States." Pediatrics 1997 Jun;99(6):E5 [521] Roholm K. Fluorine Intoxication: A Clinical-Hygienic Study. HK Lewis, London I937 p l38 [522] Harold G.C. (1945) Safety Eng. 90,78-81 [523] Bona Tome, J.M. (1949) Folia Med, (Naples) 32, 289. [524] Schwartz, L. (1942) Ind. Med. 11, 467. [525] Feltman (1956) Dental Dig. 62, 353-357. [526] Kaplan L. (1952), j. Am. Med. Assoc. 151, 1188-1190 [527] Klauder, J.V., Shelanski, L., and Gabriel, K. (1955), A.M.A. Arch. Ind . Health 12, 412-419 [528] Waldbott, G.L. (1955a) Australian J. Dentristry 59, 13-20 [529] Waldbott, G.L. (1955b) Folia Clin. Intern, 5, 144 [530] Waldbott, G.L. (1955c) Intern. Arch. Allergy Appl. Immunol, 7, 70-74 [531] Waldbott, G.L. (1956a) Acta Med. Scand. 156, 157-168. [532] Waldbott, G.L. (1956b) Intern. Arch. Allergy Appl. Immunol. 9, 241-249. [533] Demole , V. and Held, A.J. (1953), Schweiz. Med, Wochschr. 83, 362-364 [534] Waldbott George L, MD, The Preskeletal Phase of Chronic Fluoride Intoxication 1998, Fluoride, 31:1, 13-20 [535] Effects of fluorides in Acne Vulgaris. Stanford Med. Bull., 9:243-253-47, 1951 [536] Waldbott, G.L. and Cecilioni, V.A. (1969) Neighbourhood Fluorosis, Clinical Toxicology 2, 387-396 [537] Colombini, M.,Mauir,C., Olivo R., and Vivoli, G.: Observations on Fluorine Pollution Due to Emissions from an Aluminium Plant in Trentino. Fluoride, 2:20-48, 1969. [538] Giovanazzi, A., Tomasi, A., Nardelli,G. and DAndrea, F. (1980) Proceedings of the first National Congress of Environmental Aspects in the Aluminium Industry, Venice, pp.8998. [539] Waldbott, G.L.: Allergic Reactions to Fluoride. J.Asthma Res., 2:51-64,1964 [540] Saunder , M.A., Jr.: Fluoride Toothpaste: A cause of achne-like Eruptions. Arch. Dermatol., 111:793,1975. [541] Melette, J.R., Aeling, J.L., Nuss, D.D.:Fluoride Toothpaste- A cause of Perioral Dermatitis. Arch. Dermatol., 112: 730-731, 1976 [542] Modly CE, Burnett JW. Dermatologic manifestations of fluoride exposure. Cutis 1987; 40: 89-90. [543] Williams H et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol. 1999 Jan;103(1 Pt 1):125-38. [544] Lamberg et al. Symptoms experienced during periods of actual and supposed water fluoridation, Community Den Oral Epidemiol 1997: 25: 291-5 [545] Bowcock A., Cookson W., The genetics of psoriasis, psoriatic arthritis and atopic dermatitis, Hum. Mol. Genet. (2004) 13 (suppl 1): R43-R55. [546]http://www.ucd.ie/medicine/ourresearch/researchcentres/ucdcharlesinstituteofdermatolo gy/skindiseasesinireland/ [547]http://www.ucd.ie/medicine/ourresearch/researchcentres/ucdcharlesinstituteofdermatolo gy/skindiseasesinireland/ [548] Emerson RM et al. Severity distribution of atopic dermatitis in the community and its relationship to secondary referral.Br J Dermatol 1998; 139: 73-6.
67 | P a g e
The Contribution of Artificial Fluoridation to the Burden of Chronic Disease. Waugh D. 2014 [549] Williams H et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol. 1999 Jan;103(1 Pt 1):125-38. [550] Harrop et al. Eczema, Atopy and allergen exposure in adults: a population-based study, Clinical and Experimental Allergy, 37, 52653 [551] Hanifin JM, Reed ML; Eczema Prevalence and Impact Working Group. A populationbased survey of eczema prevalence in the United States. Dermatitis. 2007 Jun;18(2):82-91. [552] 2012 Annual Report: National Network for the Treatment of Childhood Eczema, Paediatric Society of New Zealand. Web: http://www.paediatrics.org.nz/index.asp?pageID=2145899148 [533] Michael S Gold and Andrew S Kemp, Atopic disease in childhood, Med J Aust 2005; 182 (6): 298-304. [554] Robertson CF, Roberts MF, Kappers JH (2004) Asthma prevalence in Melbourne schoolchildren: have we reached the peak? Med J Aust 180: 273276. doi: 10.1002/bimj.19700120316 [555] Grize L, Gassner M, Wuthrich B, Bringolf-Isler B, Takken-Sahli K, et al. (2006) Trends in prevalence of asthma, allergic rhinitis and atopic dermatitis in 57-year old Swiss children from 1992 to 2001. Allergy 61: 556562. doi: 10.1111/j.1398-9995.2006.01030. [556] Marthaler TM. Overview of salt fluoridation in Switzerland since 1955, a short history. Schweiz Monatsschr Zahnmed. 2005;115(8):651-5. [557] B Snchez-Lerma,FJ Morales-Chirivella,I Peuelas,C Blanco Guerra,F Mesa Lugo, Aguinaga-Ontoso,F Guilln-Grima, High Prevalence of Asthma and Allergic Diseases in Children Aged 6 and 7 Years From the Canary Islands: The International Study of Asthma and Allergies in Childhood, J Investig Allergol Clin Immunol 2009; Vol. 19(5): 383-390 [558] Hardisson, A., Rodriguez, M.I., Burgos, A., Flores, L.D., Gutierrez, R. and Varela, H. 2001 Fluoride levels in publically supplied and bottled drinking waters in the island of Tenerife,Spain. Bulletin of Environmental Contamination and Toxicology,67(2), 163170 [559] Sunil Dogra, Savita Yadav, Indian Journal of Dermatology, Venereology, and Leprology, Vol. 76, No. 6, November-December, 2010, pp. 595-601 [560] Gottlieb, A.B. and Krueger, J.G. (1990) HLA region genes and immune activation in the pathogenesis of psoriasis. Arch. Dermatol., [561] Bowcock A., Cookson W., The genetics of psoriasis, psoriatic arthritis and atopic dermatitis, Hum. Mol. Genet. (2004) 13 (suppl 1): R43-R55. [562] Raychaudhuri SP, Farber EM. The prevalence of psoriasis in the world. JEADV 2001; 15: 16-7. [563] Christophers E. Psoriasis epidemiology and clinical spectrum. Clin Exp Dermatol 2001; 26: 314-20. [564] M.A. Cimmino , Epidemiology of Psoriasis and Psoriatic Arthritis [565] Psoriasis in Ireland, Powell F, Younf m., Barnes J. Irish Journal of Medical Science December 1982, Volume 151, Issue 1, pp 109-113 [566] Tobin, A M., Higgins, E M., Norris, S.,Kirby, B Prevalence of psoriasis in patients with alcoholic liver disease. Clin Exp Dermatol. 2009 Aug;34(6):698-701. Epub 2009 Apr 27. [567] Warnakulasuriya S, Harris C, Gelbier S, Keating J, Peters T. 2002. Fluoride content of alcoholic beverages. Clin Chim Acta 320:14. [568] Drzdz M, Kucharz E, Grucka-Mamczar E. Effect of sodium fluoride on collagen content in skin and lungs of growing rats. Acta Biol Med Ger. 1980;39(2-3):287-93. [569] Linehan, C., Kett M., Brady G., Kelleher C.,The prevalence of Epilepsy in Ireland, Brainwave The Irish Epilepsy Association,May 2009. [570] Variability in adult epilepsy prevalence in the United Kingdom, 2011 [571] Forsgren L, Beghi E, Oun A, Sillanp M. The epidemiology of epilepsy in Europe - a systematic review. Eur J Neurol. 2005 Apr;12(4):245-53. [572] Epilepsy foundation http://www.epilepsyfoundation.org/aboutepilepsy/whatisepilepsy/statistics.cfm
68 | P a g e

חוות דעת ייצוגית Declan Waugh

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

חוות דעת ייצוגית Declan Waugh

Uploaded by

Copyright:

Available Formats

14th January 2014 This information is submitted on behalf of the people of Israel to Tel Aviv District Court upon

The Contribution of Artificial Fluoridation to the Burden of Chronic Disease

2. Fluoride and Infant Exposure

3. Fluoride Exposure of Adults

4. Fluoride, Endocrine Disorders, Health effects and Pathophysiological Mechanism

5. Fluoride, Impaired Glucose Tolerance, Diabetes and Obesity.

6. Fluoride Inhibition of Enolase, Health effects and Pathophysiological Mechanisms

7. Fluoride inhibition of Lactate, Health effects and Pathophysiological Mechanisms

8. Fluoride, Folate, Health effects and Pathophysiological Mechanisms

9. Fluoride inhibition of Lipase, Health effects and Pathophysiological Mechanisms

10.Fluoride inhibits Calcium Homeostasis

11.Fluoride inhibits Magnesium Homeostasis

12.Fluoride inhibition of Manganese metallenzyme arginase

14.Fluoride, Increased production of Free radicals, Oxidative stress and Cancer

Figure 1. Comparison of Cancer incidence for RoI and European Region

16. Fluoride, Inhibition of Homocysteine, Health effects and Pathophysiological Mechanisms

17. Fluoride, Free Radicals and Vascular Disease.

18. Fluoride, Inflammation and Disease

19. Fluoride and Epilepsy

You might also like