In humans, the major manifestations of chronic ingestion of excessive fluoride are osteosclerosis and mottled enamel. Mottling is one of the first visible signs of excess fluoride intake during childhood. Continuous use of water containing ~1 ppm of fluoride may result in very mild mottling in 10% of children; at 4-6 ppm the incidence approaches 100%, with a marked increase in severity. Osteosclerosis is characterized by increased bone density secondary both to elevated osteoblastic activity and to the replacement of hydroxyapatite by the denser fluorapatite. Ref: Friedman P.A. (2011). Chapter 44. Agents Affecting Mineral Ion Homeostasis and Bone Turnover. In L.L. Brunton, B.A. Chabner, B.C. Knollmann (Eds), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e.