adverse effects. 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, which is likely when the dose of methoxyflurane exceeds 2.5 MAC hours. (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–∞). Thyroid Fluoride's suppressive effect on the thyroid is more severe when iodine is deficient, and fluoride is associated with lower levels of iodine. 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. Its mechanisms and effects on the endocrine system remain unclear. 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. 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