Medicine:Fluoride toxicity

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Short description: Condition in which there are elevated levels of the fluoride ion in the body
Fluoride toxicity
Other namesFluoride poisoning
SpecialtyEmergency medicine, toxicology

Fluoride toxicity is a condition in which there are elevated levels of the fluoride ion in the body. Although fluoride is safe for dental health 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 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 10 to 15 mg for a 50 kg person) than lethal doses.[4] Although it is helpful topically for dental health in low dosage, chronic ingestion of 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]

Recommended levels

For optimal dental health, the World Health Organization recommends a level of fluoride from 0.5 to 1.0 mg/L (milligrams per liter), depending on climate.[6] Fluorosis becomes possible above this recommended dosage. As of 2015, the United States Health and Human Services Department recommends a maximum of 0.7 milligrams of fluoride per liter of water – updating and replacing the previous recommended range of 0.7 to 1.2 milligrams issued in 1962. The new recommended level is intended to reduce the occurrence of dental fluorosis while maintaining water fluoridation.[7]

Toxicity

Chronic

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 deformities of children. Similar or larger problems are anticipated in other countries including China, Uzbekistan, and Ethiopia.[5]

Acute

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] 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

Organofluorine compounds

Twenty percent of modern pharmaceuticals contain fluorine.[13] These organofluorine compounds are not sources of fluoride poisoning, as the carbon–fluorine bond is too strong to release fluoride.[14]

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.[15] However given the low concentration of fluoride present in dental products, this is potentially due to consumption of other major components.

Fluoride in drinking water

Around one-third of the world's population drinks water from groundwater resources. Of this, about 10 percent, approximately 300 million people, obtains water from groundwater resources that are heavily contaminated with arsenic or fluoride.[16] These trace elements derive mainly from leaching of minerals.[17] Maps are available for locations of potential problematic wells via the Groundwater Assessment Platform (GAP).[18]

Effects

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

Brain

Some research has suggested that high levels of fluoride exposure may adversely affect neurodevelopment in children, but the evidence is of insufficient quality to allow any firm conclusions to be drawn.[19]

Bones

Main page: Medicine:Skeletal fluorosis

Whilst fluoridated water is associated with decreased levels of fractures in a population,[20] 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]".[21]: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.[22]

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.[23][24][25]

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.[21]:281 Those with impaired kidney function are more susceptible to adverse effects.[21]: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,[26] which is likely when the dose of methoxyflurane exceeds 2.5 MAC hours.[27][28] (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 chronic kidney disease 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–∞).[20]

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][29] 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.[21]:263 Its mechanisms and effects on the endocrine system remain unclear.[21]:266

Testing on mice shows that the medication gamma-Aminobutyric acid (GABA) can be used to treat fluoride toxicity of the thyroid and return normal function.[30]

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 develop adverse effects from fluoride concentration as low as 0.5 mg/L. Negative effects 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.

References

  1. ↑ Gosselin, RE; Smith RP; Hodge HC (1984). Clinical toxicology of commercial products. Baltimore (MD): Williams & Wilkins. pp. III–185–93. ISBN 978-0-683-03632-9. 
  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. pp. 100. ISBN 978-92-4-157227-9. 
  4. ↑ 4.0 4.1 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. ↑ 5.0 5.1 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 (1994). Fluorides and oral health. Geneva: World Health Organization. ISBN 92-4-120846-5. http://whqlibdoc.who.int/trs/WHO_TRS_846.pdf. Retrieved 2013-09-01. 
  7. ↑ "Archive-It – News Releases". https://www.hhs.gov/about/news/2015/04/27/hhs-issues-final-recommendation-for-community-water-fluoridation.html. 
  8. ↑ National Health and Medical Research Council (Australia) (2007). A systematic review of the efficacy and safety of fluoridation. ISBN 978-1-86496-415-8. http://nhmrc.gov.au/_files_nhmrc/file/publications/synopses/Eh41_Flouridation_PART_A.pdf. Retrieved 2009-10-13.  Summary: Yeung CA (2008). "A systematic review of the efficacy and safety of fluoridation". Evid-Based Dent 9 (2): 39–43. doi:10.1038/sj.ebd.6400578. PMID 18584000. 
  9. ↑ Nochimson G. (2008). Toxicity, Fluoride . eMedicine. Retrieved 2008-12-28.
  10. ↑ "Fluoride ingestion in children: a review of 87 cases". Pediatrics 88 (5): 907–12. November 1991. doi:10.1542/peds.88.5.907. PMID 1945630. http://pediatrics.aappublications.org/cgi/content/abstract/88/5/907. Retrieved 2009-04-17. 
  11. ↑ "Survival after hypocalcemia, hypomagnesemia, hypokalemia and cardiac arrest following mild hydrofluoric acid burn". Clinical Toxicology 48 (9): 953–5. November 2010. doi:10.3109/15563650.2010.533676. PMID 21171855. 
  12. ↑ "Marked hypocalcemia and ventricular fibrillation in two pediatric patients exposed to a fluoride-containing wheel cleaner". Annals of Emergency Medicine 28 (6): 713–8. December 1996. doi:10.1016/S0196-0644(96)70097-5. PMID 8953969. 
  13. ↑ Nature's Building Blocks: An A-Z Guide to the Elements. Oxford University Press. 2011. p. 178. ISBN 978-0-19-960563-7. 
  14. ↑ O'Hagan, David (March 2008). "Understanding organofluorine chemistry. An introduction to the C–F bond". Chemical Society Reviews 37 (2): 308–319. doi:10.1039/b711844a. PMID 18197347. https://pubs.rsc.org/en/content/articlelanding/2008/cs/b711844a. Retrieved 21 March 2021. 
  15. ↑ 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. 
  16. ↑ Eawag (2015). Geogenic Contamination Handbook – Addressing Arsenic and Fluoride in Drinking Water . C. A. Johnson, A. Bretzler (eds.), Swiss Federal Institute of Aquatic Science and Technology (Eawag), Duebendorf, Switzerland.
  17. ↑ Rodríguez-Lado L, Sun G, Berg M, Zhang Q, Xue H, Zheng Q, Johnson CA (2013). "Groundwater arsenic contamination throughout China". Science 341 (6148): 866–868. doi:10.1126/science.1237484. PMID 23970694. Bibcode: 2013Sci...341..866R. https://www.dora.lib4ri.ch/eawag/islandora/object/eawag%3A7346. Retrieved 2020-09-13. 
  18. ↑ Groundwater Assessment Platform (GAP) .
  19. ↑ "Developmental fluoride neurotoxicity: a systematic review and meta-analysis". Environ. Health Perspect. 120 (10): 1362–8. 2012. doi:10.1289/ehp.1104912. PMID 22820538. 
  20. ↑ 20.0 20.1 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. PMID 11021861. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 National Research Council (2006). Fluoride in Drinking Water: A Scientific Review of EPA's Standards. Washington, DC: National Academies Press. doi:10.17226/11571. ISBN 978-0-309-10128-8. http://books.nap.edu/catalog.php?record_id=11571#toc. Retrieved March 27, 2009. . See also CDC's statement on this report .
  22. ↑ "Skeletal fluorosis mimicking seronegative arthritis". Scand. J. Rheumatol. 36 (2): 154–5. 2007. doi:10.1080/03009740600759845. PMID 17476625. 
  23. ↑ "Anaesthesia and the kidney". Anaesth Intensive Care 11 (4): 292–320. November 1983. doi:10.1177/0310057X8301100402. PMID 6359948. 
  24. ↑ "Deuterated methoxyflurane anesthesia and renal function in Fischer 344 rats". Anesthesiology 56 (3): 203–206. March 1982. doi:10.1097/00000542-198203000-00009. PMID 7059030. 
  25. ↑ "Methoxyflurane nephropathy". Environ Health Perspect 15: 111–119. June 1976. doi:10.1289/ehp.7615111. PMID 1001288. 
  26. ↑ "Metabolism and renal effect of enflurane in man". Anesthesiology 44 (1): 44–53. 1976. doi:10.1097/00000542-197601000-00009. PMID 1244774. 
  27. ↑ "Biotransformation of volatile anesthetics with special emphasis on the role of metabolism in the toxicity of anesthetics". Can Anaesth Soc J 20 (1): 21–33. 1973. doi:10.1007/BF03025562. PMID 4571972. 
  28. ↑ "Enflurane and methoxyflurane metabolism at anesthetic and at subanesthetic concentrations". Anesth Analg 58 (3): 221–224. 1979. doi:10.1213/00000539-197905000-00011. PMID 572159. 
  29. ↑ "Fluoride plus aluminum: useful tools in laboratory investigations, but messengers of false information". Physiol Res 51 (6): 557–64. 2002. PMID 12511178. http://www.biomed.cas.cz/physiolres/pdf/51/51_557.pdf. Retrieved 2008-12-31. 
  30. ↑ "γ-Aminobutyric acid ameliorates fluoride-induced hypothyroidism in male Kunming mice". Life Sci. 146: 1–7. February 1, 2016. doi:10.1016/j.lfs.2015.12.041. PMID 26724496. 
  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. PMID 12656244. Bibcode: 2003Chmsp..50..251C. 
  32. ↑ Joseph A. Cotruvo. "Desalination Guidelines Development for Drinking Water: Background". https://www.who.int/water_sanitation_health/dwq/nutrientschap2.pdf. 
  33. ↑ Baez, 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 7 (4): 242–248. doi:10.1590/s1020-49892000000400005. PMID 10846927. 

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