Fluoride toxicity

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Fluoride poisoning
Classification and external resources
ICD-10 T59.5
DiseasesDB 29228
eMedicine emerg/181
MeSH D005458

In high concentrations, soluble fluoride salts are toxic and skin or eye contact with high concentrations of many 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) 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 greatest examples of fluoride poisoning arise from fluoride-rich ground water.[5]

Causes[edit]

Regulatory background[edit]

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 are possible at fluoride levels far above this recommended dosage. The U.S. 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. see:http://www.reuters.com/article/2011/01/08/us-usa-fluoride-idUSTRE7064CM20110108

Acute toxicity[edit]

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.[7]

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]

Historically, most cases of acute fluoride toxicity have followed accidental ingestion of sodium fluoride based insecticides or rodenticides.[8] Currently, in advanced countries, most cases of fluoride exposure are due to the ingestion of dental fluoride products.[9] Although exposure to these products does not often cause toxicity, in one study 30% of children exposed to fluoride dental products developed mild symptoms.[9] Other sources include glass-etching or chrome-cleaning agents like ammonium bifluoride or hydrofluoric acid,[10][11] 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]

Organofluorine compounds[edit]

Organofluorine compounds only rarely release F under biological conditions and thus are rarely sources of fluoride poisoning. In order for fluoride poisoning to occur, a compound must release fluoride (F) ions. Whereas most organofluorine compounds may not release F because of the strength of the carbon–fluorine bond and its tendency to strengthen as more fluorine atoms are added to a carbon, some compounds do, such as methoxyflurane. The fluorine atom is pervasive in drugs, e.g. Prozac, and many other substances such as freon, Teflon, and blood serum (PFOS, PFOA, and PFNA).

Fluoride in toothpaste[edit]

Children may experience gastrointestinal distress upon ingesting sufficient 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.[12]

Effects[edit]

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

Brain[edit]

A meta analysis conducted on epidemiological studies conducted in China concluded that exposure to "high" levels of fluoride (variously defined) in childhood was associated with a reduction in IQ of about 7 points.[13][14] The authors of the meta analysis noted 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] 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.[16]

Bones[edit]

Whilst fluoridated water is associated with decreased levels of fractures in a population, [17] 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 1-4mg/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]".[18]: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.[19]

Kidney[edit]

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.[20][21][22]

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.[18]:281 Those with impaired kidney function are more susceptible to adverse effects.[18]: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,[23] which is likely when the dose of methoxyflurane exceeds 2.5 MAC hours.[24][25] (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[edit]

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–∞). Here, "aesthetic concern" is a term used in a standardized scale based on what adolescents would find unacceptable, as measured by a 1996 study of British 14-year-olds.[17][dead link]

Thyroid[edit]

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][26] 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.[18]:263 Its mechanisms and effects on the endocrine system remain unclear.[18]:266

Mechanism[edit]

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.[27] 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".[18]:219 This topic has been identified previously as cause for concern.[26] The NRC noted that rats administered fluoride had twice as much aluminum in their brains.[18]: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,[28] and a 2002 study found that fluoride increased the urinary excretion of aluminum.[29]

History[edit]

Danish researcher Kaj Roholm published Fluorine Intoxication in 1937, which was praised in a 1938 review by dental researcher H. Trendley Dean as "probably the outstanding contribution to the literature of fluorine".[30] Since that time, the fluoridation of public water has been widely implemented and has been hailed as one of the top medical achievements of the 20th Century.[31] The effects of fluoride-rich ground water became recognized in the 1990s.[5]

References[edit]

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  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 c 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. ^ 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. Lay summary: NHMRC, 2007.
  8. ^ Nochimson G. (2008). Toxicity, Fluoride. eMedicine. Retrieved 2008-12-28.
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ "Developmental fluoride neurotoxicity: a systematic review and meta-analysis.". Environ Health Perspect. USA: National Center for Biotechnology Information. 
  14. ^ "Neurobehavioural effects of developmental toxicity". The Lancet Neurology, Volume 13, Issue 3, Pages 330 - 338, March 2014. USA: Elsevier Ltd. 
  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. ^ 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. 
  17. ^ a b McDonagh MS, Whiting PF, Wilson PM et al. (2000). "Systematic review of water fluoridation" (PDF). BMJ 321 (7265): 855–9. doi:10.1136/bmj.321.7265.855. PMC 27492. PMID 11021861.  The full report is at: McDonagh MS, Whiting PF, Bradley M et al. (2000). A systematic review of water fluoridation (PDF). CRD Report 18. NHS Centre for Reviews and Dissemination. 
  18. ^ 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. Lay summaryNRC (September 24, 2008). . See also CDC's statement on this report.
  19. ^ 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. 
  20. ^ Cousins MJ, Skowronski G, Plummer JL. Anaesthesia and the kidney. Anaesth Intensive Care. 1983 Nov;11(4):292-320.
  21. ^ Baden JM, Rice SA, Mazze RI. Deuterated methoxyflurane anesthesia and renal function in Fischer 344 rats. Anesthesiology. 1982 Mar;56(3):203-6.
  22. ^ Mazze RI. Methoxyflurane nephropathy. Environ Health Perspect. 1976 Jun;15:111-9.
  23. ^ Cousins MJ, Greenstein LR, Hitt BA, Mazze RI. Metabolism and renal effect of enflurane in men. Anesthesiology 1976; 44:44-53.
  24. ^ 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.
  25. ^ 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/
  26. ^ a b Strunecká A, Strunecký O, Patocka J (2002). "Fluoride plus aluminum: useful tools in laboratory investigations, but messengers of false information". Physiol Res 51 (6): 557–64. PMID 12511178. 
  27. ^ 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. 
  28. ^ 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.
  29. ^ 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.  Free full-text.
  30. ^ Dean T.H. (1938). Fluorine Intoxication. Am J Public Health Nations Health 28: 1008–1009. Free full text.
  31. ^ Division of Oral Health, National Center for Chronic Disease Prevention and Health Promotion, CDC. Achievements in public health, 1900–1999: Fluoridation of drinking water to prevent dental caries. MMWR Morb Mortal Wkly Rep. 1999;48(41):933–40. Contains H. Trendley Dean, D.D.S. Reprinted in: JAMA. 2000;283(10):1283–6. doi:10.1001/jama.283.10.1283. PMID 10714718.