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===Brain===
===Brain===
A meta analysis conducted on 27 epidemiological studies (most from China), concluded that exposure to "high levels" of fluoride in childhood was associated with a reduction in IQ. The authors note that this research is not applicable to the safety of artificial [[water fluoridation]] because the adverse effects on IQ was found with fluoride levels that were much higher than typically found in artificially fluoridated water.<ref>{{cite news|last=Lefler|first=Dion|title=Harvard scientists: Data on fluoride, IQ not applicable in U.S.|url=http://www.kansas.com/2012/09/11/2485561/harvard-scientists-data-on-fluoride.html|accessdate=5 March 2014|newspaper=The Wichita Eagle|date=11 September 2012}}</ref> However, they conclude that more research is required to assess the adverse effects on children’s neurodevelopment.<ref name=neuro>{{cite journal|title=Developmental fluoride neurotoxicity: a systematic review and meta-analysis.|location=USA|publisher=National Center for Biotechnology Information|authors=Anna L. Choi, Guifan Sun, Ying Zhang, and Philippe Grandjean|year=2012|pmc=3491930|pmid=22820538|doi=10.1289/ehp.1104912|volume=120|issue=10|journal=Environ. Health Perspect.|pages=1362–8}}</ref><ref>{{cite web|url=http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(13)70278-3/fulltext|title=Neurobehavioural effects of developmental toxicity|work=The Lancet Neurology, Volume 13, Issue 3, Pages 330 - 338, March 2014|location=USA|publisher=Elsevier Ltd}}</ref> The meta analysis has been criticized for failing to account for confounding factors. For example, in some of the studies fluoride exposure came from the burning of high fluoride content coal, and used a control group from an area in which wood was used as fuel.<ref>{{cite journal |author=Sabour S, Ghorbani Z |title=Developmental fluoride neurotoxicity: clinical importance versus statistical significance |journal=Environ. Health Perspect. |volume=121 |issue=3 |pages=A70 |date=March 2013 |pmid=23455234 |pmc=3621182 |doi=10.1289/ehp.1206192 |url=}}</ref> A more recent study followed individuals over 38 years to see if fluoride exposure affected IQ and they concluded there was no link between fluoride exposure and IQ, or fluoride as a neurotoxin.<ref>{{cite journal|last1=Broadbent|first1=Jonathan M.|last2=Thomson|first2=W. Murray|last3=Ramrakha|first3=Sandhya|last4=Moffitt|first4=Terrie E.|last5=Zeng|first5=Jiaxu|last6=Foster Page|first6=Lyndie A.|last7=Poulton|first7=Richie|title=Community Water Fluoridation and Intelligence: Prospective Study in New Zealand|journal=American Journal of Public Health|date=15 May 2014|pages=e1–e5|doi=10.2105/AJPH.2013.301857|url=http://ajph.aphapublications.org/doi/abs/10.2105/AJPH.2013.301857|accessdate=4 July 2014}}</ref>
A meta analysis conducted on 27 epidemiological studies (most from China), concluded that exposure to "high levels" of fluoride in childhood was associated with a reduction in IQ. The authors note that this research is not applicable to the safety of artificial [[water fluoridation]] because the adverse effects on IQ was found with fluoride levels that were much higher than typically found in artificially fluoridated water.<ref>{{cite news|last=Lefler|first=Dion|title=Harvard scientists: Data on fluoride, IQ not applicable in U.S.|url=http://www.kansas.com/2012/09/11/2485561/harvard-scientists-data-on-fluoride.html|accessdate=5 March 2014|newspaper=The Wichita Eagle|date=11 September 2012}}</ref> However, they conclude that more research is required to assess the adverse effects on children’s neurodevelopment.<ref name=neuro>{{cite journal|title=Developmental fluoride neurotoxicity: a systematic review and meta-analysis.|location=USA|publisher=National Center for Biotechnology Information|authors=Anna L. Choi, Guifan Sun, Ying Zhang, and Philippe Grandjean|year=2012|pmc=3491930|pmid=22820538|doi=10.1289/ehp.1104912|volume=120|issue=10|journal=Environ. Health Perspect.|pages=1362–8}}</ref><ref>{{cite web|url=http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(13)70278-3/fulltext|title=Neurobehavioural effects of developmental toxicity|work=The Lancet Neurology, Volume 13, Issue 3, Pages 330 - 338, March 2014|location=USA|publisher=Elsevier Ltd}}</ref> The meta analysis has been criticized for failing to account for confounding factors. For example, in some of the studies fluoride exposure came from the burning of high fluoride content coal, and used a control group from an area in which wood was used as fuel.<ref>{{cite journal |author=Sabour S, Ghorbani Z |title=Developmental fluoride neurotoxicity: clinical importance versus statistical significance |journal=Environ. Health Perspect. |volume=121 |issue=3 |pages=A70 |date=March 2013 |pmid=23455234 |pmc=3621182 |doi=10.1289/ehp.1206192 |url=}}</ref> A more recent study followed individuals over 38 years to see if fluoride exposure affected IQ and they concluded there was no link between fluoride exposure and IQ, or fluoride as a neurotoxin.<ref>{{cite journal|last1=Broadbent|first1=Jonathan M.|last2=Thomson|first2=W. Murray|last3=Ramrakha|first3=Sandhya|last4=Moffitt|first4=Terrie E.|last5=Zeng|first5=Jiaxu|last6=Foster Page|first6=Lyndie A.|last7=Poulton|first7=Richie|title=Community Water Fluoridation and Intelligence: Prospective Study in New Zealand|journal=American Journal of Public Health|date=15 May 2014|pages=e1–e5|doi=10.2105/AJPH.2013.301857|url=http://ajph.aphapublications.org/doi/abs/10.2105/AJPH.2013.301857|accessdate=4 July 2014}}</ref>
Studies in rats has shown that fluoride through drinking water triggers damage to soft tissues such as the brain.<ref>{{cite journal|last1=Mullenix|first1=PJ|last2=Denbesten|first2=PK|last3=Schunior|first3=A|last4=Kernan|first4=WJ|title=Neurotoxicity of sodium fluoride in rats.|journal=Neurotoxicology and teratology|date=1994|volume=17|issue=2|pages=169-77|pmid=7760776}}</ref>
Studies in rats has shown that fluoride through drinking water triggers damage to soft tissues such as the brain.<ref>{{cite journal|last1=Mullenix|first1=PJ|last2=Denbesten|first2=PK|last3=Schunior|first3=A|last4=Kernan|first4=WJ|title=Neurotoxicity of sodium fluoride in rats.|journal=Neurotoxicology and teratology|date=1994|volume=17|issue=2|pages=169-77|pmid=7760776}}</ref>{{MEDRS}}


===Bones===
===Bones===

Revision as of 00:09, 29 March 2015

Fluoride toxicity
SpecialtyEmergency medicine Edit this on Wikidata

Although safe and even healthy at low concentrations, sustained consumption of large amounts of soluble fluoride salts is dangerous. Referring to a common salt of fluoride, sodium fluoride (NaF), the lethal dose for most adult humans is estimated at 5 to 10 g (which is equivalent to 32 to 64 mg/kg elemental fluoride/kg body weight).[1][2][3] Ingestion of fluoride can produce gastrointestinal discomfort at doses at least 15 to 20 times lower (0.2–0.3 mg/kg or 100 to 150 mg for a 50 kg person) than lethal doses.[4] Although helpful for dental health in low dosage, chronic exposure to fluoride in large amounts interferes with bone formation. In this way, the most widespread examples of fluoride poisoning arise from consumption of ground water that is abnormally fluoride-rich.[5]

For optimal dental health, the World Health Organization recommends a level of fluoride from 0.5 to 1.0 mg/L (milligrams per litre), depending on climate.[6] Adverse effects become possible at fluoride levels far above this recommended dosage. The United States Health and Human Services Department recommends 0.7 milligrams of fluoride per liter of water – the lower limit of the current recommended range of 0.7 to 1.2 milligrams.[7]

Chronic toxicity

World map with several land areas highlighted, especially in China, India, east Africa, southwest U.S., and Argentina.
Geographical areas associated with groundwater having over 1.5 mg/L of naturally occurring fluoride, which is above recommended levels.[8]

In India an estimated 60 million people have been poisoned by well water contaminated by excessive fluoride, which is dissolved from the granite rocks. The effects are particularly evident in the bone deformations of children. Similar or larger problems are anticipated in other countries including China, Uzbekistan, and Ethiopia.[5]

Acute toxicity

Historically, most cases of acute fluoride toxicity have followed accidental ingestion of sodium fluoride based insecticides or rodenticides.[9] Currently, in advanced countries, most cases of fluoride exposure are due to the ingestion of dental fluoride products.[10] Although exposure to these products does not often cause toxicity, in one study 30% of children exposed to fluoride dental products developed mild symptoms.[10] Other sources include glass-etching or chrome-cleaning agents like ammonium bifluoride or hydrofluoric acid,[11][12] industrial exposure to fluxes used to promote the flow of a molten metal on a solid surface, volcanic ejecta (for example, in cattle grazing after an 1845–1846 eruption of Hekla and the 1783–1784 flood basalt eruption of Laki), and metal cleaners. Malfunction of water fluoridation equipment has happened several times, including a notable incident in Alaska.[4]

Occurrence of fluoride in everyday life

Organofluorine compounds

Twenty percent of modern pharmaceuticals contain fluorine.[13] These organofluorine compounds are not sources of fluoride poisoning. The carbon–fluorine bond is too strong to release fluoride.

Fluoride in toothpaste

Children may experience gastrointestinal distress upon ingesting excessive amounts of flavored toothpaste. Between 1990 and 1994, over 628 people, mostly children, were treated after ingesting too much fluoride-containing toothpaste. "While the outcomes were generally not serious," gastrointestinal symptoms appear to be the most common problem reported.[14]

Effects

Excess fluoride consumption has been studied as a factor in the following:

Brain

A meta analysis conducted on 27 epidemiological studies (most from China), concluded that exposure to "high levels" of fluoride in childhood was associated with a reduction in IQ. The authors note that this research is not applicable to the safety of artificial water fluoridation because the adverse effects on IQ was found with fluoride levels that were much higher than typically found in artificially fluoridated water.[15] However, they conclude that more research is required to assess the adverse effects on children’s neurodevelopment.[16][17] The meta analysis has been criticized for failing to account for confounding factors. For example, in some of the studies fluoride exposure came from the burning of high fluoride content coal, and used a control group from an area in which wood was used as fuel.[18] A more recent study followed individuals over 38 years to see if fluoride exposure affected IQ and they concluded there was no link between fluoride exposure and IQ, or fluoride as a neurotoxin.[19] Studies in rats has shown that fluoride through drinking water triggers damage to soft tissues such as the brain.[20][unreliable medical source?]

Bones

Whilst fluoridated water is associated with decreased levels of fractures in a population,[21] toxic levels of fluoride have been associated with a weakening of bones and an increase in hip and wrist fractures. The U.S. National Research Council concludes that fractures with fluoride levels 1–4 mg/L, suggesting a dose-response relationship, but states that there is "suggestive but inadequate for drawing firm conclusions about the risk or safety of exposures at [2 mg/L]".[22]: 170 

Consumption of fluoride at levels beyond those used in fluoridated water for a long period of time causes skeletal fluorosis. In some areas, particularly the Asian subcontinent, skeletal fluorosis is endemic. It is known to cause irritable-bowel symptoms and joint pain. Early stages are not clinically obvious, and may be misdiagnosed as (seronegative) rheumatoid arthritis or ankylosing spondylitis.[23]

Kidney

Fluoride induced nephrotoxicity is kidney injury due to toxic levels of serum fluoride, commonly due to release of fluoride from fluorine-containing drugs, such as methoxyflurane.[24][25][26]

Within the recommended dose, no effects are expected, but chronic ingestion in excess of 12 mg/day are expected to cause adverse effects, and an intake that high is possible when fluoride levels are around 4 mg/L.[22]: 281  Those with impaired kidney function are more susceptible to adverse effects.[22]: 292 

The kidney injury is characterised by failure to concentrate urine, leading to polyuria, and subsequent dehydration with hypernatremia and hyperosmolarity. Inorganic fluoride inhibits adenylate cyclase activity required for antidiuretic hormone effect on the distal convoluted tubule of the kidney. Fluoride also stimulates intrarenal vasodilation, leading to increased medullary blood flow, which interferes with the counter current mechanism in the kidney required for concentration of urine.

Fluoride induced nephrotoxicity is dose dependent, typically requiring serum fluoride levels exceeding 50 micromoles per liter (about 1 ppm) to cause clinically significant renal dysfunction,[27] which is likely when the dose of methoxyflurane exceeds 2.5 MAC hours.[28][29] (Note: "MAC hour" is the multiple of the minimum alveolar concentration (MAC) of the anesthetic used times the number of hours the drug is administered, a measure of the dosage of inhaled anesthetics.)

Elimination of fluoride depends on glomerular filtration rate. Thus, patients with renal insufficiency will maintain serum fluoride for longer period of time, leading to increased risk of fluoride induced nephrotoxicity.

Teeth

The only generally accepted adverse effect of fluoride at levels used for water fluoridation is dental fluorosis, which can alter the appearance of children's teeth during tooth development; this is mostly mild and usually only an aesthetic concern. Compared to unfluoridated water, fluoridation to 1 mg/L is estimated to cause fluorosis in one of every 6 people (range 4–21), and to cause fluorosis of aesthetic concern in one of every 22 people (range 13.6–∞).[21]

Thyroid

Fluoride's suppressive effect on the thyroid is more severe when iodine is deficient, and fluoride is associated with lower levels of iodine.[clarification needed][30] Thyroid effects in humans were associated with fluoride levels 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.[22]: 263  Its mechanisms and effects on the endocrine system remain unclear.[22]: 266 

Effects on aquatic organisms

Fluoride accumulates in the bone tissues of fish and in the exoskeleton of aquatic invertebrates. The mechanism of fluoride toxicity in aquatic organisms is believed to involve the action of fluoride ions as enzymatic poisons. In soft waters with low ionic content, invertebrates and fishes may suffer adverse effects from fluoride concentration as low as 0.5 mg/L. Negative affects are less in hard waters and seawaters, as the bioavailability of fluoride ions is reduced with increasing water hardness[31] Seawater contains fluoride at a concentration of 1.3 mg/L.[32]

Mechanism

Like most soluble materials, fluoride compounds are readily absorbed by the stomach and intestines, and excreted through the urine. Urine tests have been used to ascertain rates of excretion in order to set upper limits in exposure to fluoride compounds and associated detrimental health effects.[33] Ingested fluoride initially acts locally on the intestinal mucosa, where it forms hydrofluoric acid in the stomach.

The NRC report stated that "many of the untoward effects of fluoride are due to the formation of AlFx [aluminum fluoride] complexes".[22]: 219  This topic has been identified previously as cause for concern.[30] The NRC noted that rats administered fluoride had twice as much aluminum in their brains.[22]: 212  When water (1 ppm fluoride) is boiled in aluminum cookware more aluminum is leached and more aluminum fluoride complexes are formed. However, an epidemiological study found that a high-fluoride area had one-fifth the Alzheimer's that a low-fluoride area had,[34] and a 2002 study found that fluoride increased the urinary excretion of aluminum.[35]

References

  1. ^ Gosselin, RE; Smith RP; Hodge HC (1984). Clinical toxicology of commercial products. Baltimore (MD): Williams & Wilkins. pp. III-185–93. ISBN 0-683-03632-7.
  2. ^ Baselt, RC (2008). Disposition of toxic drugs and chemicals in man. Foster City (CA): Biomedical Publications. pp. 636–40. ISBN 978-0-9626523-7-0.
  3. ^ IPCS (2002). Environmental health criteria 227 (Fluoride). Geneva: International Programme on Chemical Safety, World Health Organization. p. 100. ISBN 92-4-157227-2.
  4. ^ a b Bradford D. Gessner; Michael Beller; John P. Middaugh; Gary M. Whitford (13 January 1994). "Acute fluoride poisoning from a public water system". New England Journal of Medicine. 330 (2): 95–99. doi:10.1056/NEJM199401133300203. PMID 8259189.
  5. ^ a b Pearce, Fred (2006). When the Rivers Run Dry: Journeys Into the Heart of the World's Water Crisis. Toronto: Key Porter. ISBN 978-1-55263-741-8.
  6. ^ WHO Expert Committee on Oral Health Status and Fluoride Use. Fluorides and oral health [PDF]. 1994.
  7. ^ http://www.reuters.com/article/2011/01/08/us-usa-fluoride-idUSTRE7064CM20110108
  8. ^ National Health and Medical Research Council (Australia). A systematic review of the efficacy and safety of fluoridation [PDF]. 2007 [Retrieved 2009-10-13]. ISBN 1-86496-415-4. Summary: Yeung CA. A systematic review of the efficacy and safety of fluoridation. Evid Based Dent. 2008;9(2):39–43. doi:10.1038/sj.ebd.6400578. PMID 18584000.
  9. ^ Nochimson G. (2008). Toxicity, Fluoride. eMedicine. Retrieved 2008-12-28.
  10. ^ a b Augenstein WL, Spoerke DG, Kulig KW; et al. (November 1991). "Fluoride ingestion in children: a review of 87 cases". Pediatrics. 88 (5): 907–12. PMID 1945630. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  11. ^ Wu ML, Deng JF, Fan JS (November 2010). "Survival after hypocalcemia, hypomagnesemia, hypokalemia and cardiac arrest following mild hydrofluoric acid burn". Clinical Toxicology (Philadelphia, Pa.). 48 (9): 953–5. doi:10.3109/15563650.2010.533676. PMID 21171855.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Klasaer AE, Scalzo AJ, Blume C, Johnson P, Thompson MW (December 1996). "Marked hypocalcemia and ventricular fibrillation in two pediatric patients exposed to a fluoride-containing wheel cleaner". Annals of Emergency Medicine. 28 (6): 713–8. doi:10.1016/S0196-0644(96)70097-5. PMID 8953969.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Emsley 2011, p. 178.
  14. ^ Jay D. Shulman; Linda M. Wells (1997). "Acute Fluoride Toxicity from Ingesting Home-use Dental Products in Children, Birth to 6 Years of Age". Journal of Public Health Dentistry. 57 (3): 150–158. doi:10.1111/j.1752-7325.1997.tb02966.x. PMID 9383753.
  15. ^ Lefler, Dion (11 September 2012). "Harvard scientists: Data on fluoride, IQ not applicable in U.S." The Wichita Eagle. Retrieved 5 March 2014.
  16. ^ "Developmental fluoride neurotoxicity: a systematic review and meta-analysis". Environ. Health Perspect. 120 (10). USA: National Center for Biotechnology Information: 1362–8. 2012. doi:10.1289/ehp.1104912. PMC 3491930. PMID 22820538. {{cite journal}}: Unknown parameter |authors= ignored (help)
  17. ^ "Neurobehavioural effects of developmental toxicity". The Lancet Neurology, Volume 13, Issue 3, Pages 330 - 338, March 2014. USA: Elsevier Ltd.
  18. ^ Sabour S, Ghorbani Z (March 2013). "Developmental fluoride neurotoxicity: clinical importance versus statistical significance". Environ. Health Perspect. 121 (3): A70. doi:10.1289/ehp.1206192. PMC 3621182. PMID 23455234.
  19. ^ Broadbent, Jonathan M.; Thomson, W. Murray; Ramrakha, Sandhya; Moffitt, Terrie E.; Zeng, Jiaxu; Foster Page, Lyndie A.; Poulton, Richie (15 May 2014). "Community Water Fluoridation and Intelligence: Prospective Study in New Zealand". American Journal of Public Health: e1–e5. doi:10.2105/AJPH.2013.301857. Retrieved 4 July 2014.
  20. ^ Mullenix, PJ; Denbesten, PK; Schunior, A; Kernan, WJ (1994). "Neurotoxicity of sodium fluoride in rats". Neurotoxicology and teratology. 17 (2): 169–77. PMID 7760776.
  21. ^ a b McDonagh, Marian S.; Whiting, Penny F; Wilson, Paul M.; et al. (7 October 2000). "Systematic review of water fluoridation". BMJ. 321 (7265): 855–859. doi:10.1136/bmj.321.7265.855. PMC 27492. PMID 11021861.
  22. ^ a b c d e f g National Research Council (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. Washington, DC: National Academies Press. ISBN 0-309-10128-X. {{cite book}}: Unknown parameter |laydate= ignored (help); Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help). See also CDC's statement on this report.
  23. ^ Gupta R, Kumar AN, Bandhu S, Gupta S (2007). "Skeletal fluorosis mimicking seronegative arthritis". Scand. J. Rheumatol. 36 (2): 154–5. doi:10.1080/03009740600759845. PMID 17476625.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Cousins MJ, Skowronski G, Plummer JL. Anaesthesia and the kidney. Anaesth Intensive Care. 1983 Nov;11(4):292-320.
  25. ^ Baden JM, Rice SA, Mazze RI. Deuterated methoxyflurane anesthesia and renal function in Fischer 344 rats. Anesthesiology. 1982 Mar;56(3):203-6.
  26. ^ Mazze RI. Methoxyflurane nephropathy. Environ Health Perspect. 1976 Jun;15:111-9.
  27. ^ Cousins MJ, Greenstein LR, Hitt BA, Mazze RI. Metabolism and renal effect of enflurane in men. Anesthesiology 1976; 44:44-53.
  28. ^ VanDyke R. Biotransformation of volatile anesthetics with special emphasis on the role of metabolism in the toxicity of anesthetics. Can Anaesth Soc J 1973;20:21-33.
  29. ^ White AE, Stevens WC, Eger EI II, Mazze RI, Hitt BA. Enflurane and methoxyflurane metabolism at anesthetic and subanesthetic concentrations. Anesth Analg 1979;58:221-4/
  30. ^ a b Strunecká A, Strunecký O, Patocka J (2002). "Fluoride plus aluminum: useful tools in laboratory investigations, but messengers of false information" (PDF). Physiol Res. 51 (6): 557–64. PMID 12511178.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ Camargo, Julio A. (January 2003). "Fluoride toxicity to aquatic organisms: a review". Chemosphere. 50 (3): 251–264. doi:10.1016/S0045-6535(02)00498-8.
  32. ^ Joseph A. Cotruvo. "Desalination Guidelines Development for Drinking Water: Background" (PDF). Retrieved January 26, 2015.
  33. ^ Baez, Ramon J.; Baez, Martha X.; Marthaler, Thomas M. (2000). "Urinary fluoride excretion by children 4–6 years old in a south Texas community". Revista Panamericana de Salud Pública/Pan American Journal of Public Health. 7 (4): 242–248. doi:10.1590/s1020-49892000000400005.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  34. ^ Li L (2003). "The biochemistry and physiology of metallic fluoride: action, mechanism, and implications". Crit. Rev. Oral Biol. Med. 14 (2): 100–14. doi:10.1177/154411130301400204. PMID 12764073. Free full-text.
  35. ^ Chiba J, Kusumoto M, Shirai S, Ikawa K, Sakamoto S (March 2002). "The influence of fluoride ingestion on urinary aluminum excretion in humans". Tohoku J. Exp. Med. 196 (3): 139–49. doi:10.1620/tjem.196.139. PMID 12002270.{{cite journal}}: CS1 maint: multiple names: authors list (link) Free full-text.
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