Fluoride, usually in the millimolar range, has a number of effects on immune cells, including polymorphonuclear leukocytes, lymphocytes, and neutrophils. Fluoride interferes with adherence to substrate in vitro. The variety of biochemical effects on immune cells in culture are described in Table 9-4. Fluoride also augments the inflammatory response to irritants. Several mechanisms have been proposed, and the main route is thought to be by means of activation of the G-protein complex. It appears that aluminum combines with fluoride to form aluminum fluoride, a potent activator of G protein. In a study by O’Shea et al. (1987), for example, AlF₄ had a greater influence on lymphocyte lipid metabolism than did fluoride in the absence of aluminum. On the other hand, Goldman et al. (1995) showed that the aluminofluoride effect of activating various enzymes in macrophages is independent of the G-protein complex.

There is no question that fluoride can affect the cells involved in providing immune responses. The question is what proportion, if any, of the population consuming drinking water containing fluoride at 4.0 mg/L on a regular basis will have their immune systems compromised? Not a single epidemiologic study has investigated whether fluoride in the drinking water at 4 mg/L is associated with changes in immune function. Nor has any study examined whether a person with an immunodeficiency disease can tolerate fluoride ingestion from drinking water. Because most of the studies conducted to date have been carried out in vitro and with high fluoride concentrations, Challacombe (1996) did not believe they warranted attention. However, as mentioned previously in this chapter, bone concentrates fluoride and the blood-borne progenitors could be exposed to exceptionally high fluoride concentrations. Thus, more research needs to be carried out before one can state that drinking water containing fluoride at 4 mg/L has no effect on the immune system.

The committee did not find any human studies on drinking water containing fluoride at 4 mg/L where GI, renal, hepatic, or immune effects were carefully documented. Most reports of GI effects involve exposures to high concentrations of fluoride from accidental overfeeds of fluoride into water supplies or from therapeutic uses. There are a few case reports of GI upset in subjects exposed to drinking water fluoridated at 1 mg/L. Those effects were observed in only a small number of cases, which suggest hypersensitivity. However, the available data are not robust enough to determine whether that is the case.

Studies of the effects of fluoride on the kidney, liver, and immune system indicate that exposure to concentrations much higher than 4 mg/L can affect renal tissues and function and cause hepatic and immunologic alterations