As described above, fluoride is likely to cause
decreased melatonin production and to have
other effects on normal pineal function,
which in turn could contribute to a variety of effects in
humans. Actual effects in any individual depend
on age, sex, and probably other factors,
although at present the mechanisms 
are not fully understood.

PINEAL GLAND

The pineal gland is a small organ (150 mg in humans)
located near the center of the brain. 

       One of the major components of the mammalian circadian system, it lies in the upper margins of the thalamus in the dorsal aspects of the third ventricle and has both physical and
neuronal connections with the brain.

Although the pineal gland lies outside the blood-brain barrier, it has access to the cerebrospinal fluid. The pineal gland’s major neuronal connections with the brain are the sympathetic nerve fibers coming from the superior cervical ganglion; the activity of these sympathetic nerves controls synthesis and release of the pineal hormone melatonin (Cone et al. 2002).¹¹ Other substances (primarily peptides) are also secreted from the pineal gland and have been reported to have various physiological effects, including antigonadotropic, metabolic, and antitumor activity (Anisimov 2003).

Most melatonin production occurs during darkness (Reiter 1998; Salti et al. 2000; Cone et al. 2002; Murcia García et al. 2002). Peak serum concentrations of melatonin occur during childhood in humans, with decreasing concentrations during adolescence before stabilization at the low concentration characteristic of adults (García-Patterson et al. 1996; Murcia García et al. 2002); further decreases in melatonin occur at menopause in women and at a corresponding age in men (Reiter 1998).

Melatonin affects target tissues, such as the hypophyseal pars tuberalis, that have a high density of melatonin receptors. The primary effect seems to be temporally specific activation of cAMP-sensitive gene expression in the pars tuberalis by the sensitization of adenylyl cyclase, thus synchronizing the suprachiasmatic nucleus of the hypothalamus and clock-controlled genes in peripheral tissue (Stehle et al. 2003). In humans, changes in melatonin are associated with the status of the reproductive system—onset of puberty, stage of puberty, menstrual cyclicity, menopause (Reiter 1998; Salti et al. 2000)—but the functional relationships are not fully understood. The elevated melatonin concentrations characteristic of prepubertal age suggest an inhibitory effect on pubertal development (Aleandri et al. 1997; Salti et al. 2000); sexual maturation begins when serum melatonin starts to decrease (Aleandri et al. 1997; Reiter 1998). Melatonin also seems to be involved with anxiety reactions; for example, the beneficial effects of fluoxetine (Prozac) in mice during an anxiety test are not found if the pineal gland has been removed (Uz et al. 2004).

Melatonin and pineal peptides have been associated with a number of other physiological effects, including regulation of circadian rhythms and

 Melatonin is also found in cells lining the gut from stomach to colon. Its functions are mainly protective, including free radical scavenging.  Some of melatonin’s actions are receptive-mediated an involve the central and peripheral sympathetic nervous systems (Reiter et al. 2003a).

Suggested Citation: “8 Effects on the Endocrine System.” National Research Council. 2006. Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. Washington, DC: The National Academies Press. doi: 10.17226/11571.

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sleep (Arendt 2003; Cajochen et al. 2003); regulation of reproductive physiology in seasonal breeders (Aleandri et al. 1997; Reiter 1998; Stehle et al. 2003); effects on calcium and phosphorus metabolism, parathyroid activity, bone growth, and development of postmenopausal osteoporosis (Chen et al. 1990, 1991; Sandyk et al. 1992; Shoumura et al. 1992; el-Hajj Fuleihan et al. 1997; Roth et al. 1999; Cardinali et al. 2003; Goodman 2003); oncostatic or anticarcinogenic effects (Cohen et al. 1978; García-Patterson et al. 1996; Panzer 1997; Anisimov 2003); antioxidant actions (Srinivasan 2002; Reiter et al. 2003b); and effects on the central nervous system, psychiatric disease, and sudden infant death syndrome (García-Patterson et al. 1996; Reiter 1998; Delagrange et al. 2003). Panzer (1997) suggested that the simultaneous decrease in melatonin concentrations and the exponential increase in bone growth during puberty could be a factor in the typical age distribution of osteosarcoma.

Pineal Gland Calcification

The pineal gland is a calcifying tissue; in humans, calcified concretions can be found at any age, although the likelihood increases with age (Vígh et al. 1998; Akano and Bickler 2003) and may be associated with menopause (Sandyk et al. 1992). The occurrence of pineal calcifications varies among different populations and nations (Vígh et al. 1998), possibly in association with the degree of industrialization (Akano and Bickler 2003), rates of breast cancer (Cohen et al. 1978), and high circannual light intensity near the equator (Vígh et al. 1998). Osteoporosis might be associated with fewer concretions (Vígh et al. 1998).

Melatonin secretion is well correlated with the amount of uncalcified pineal tissue (Kunz et al. 1999) but not with the size of pineal calcification (Vígh et al. 1998; Kunz et al. 1999). An increase in calcification of the pineal gland in humans probably represents a decrease in the number of functioning pinealocytes and a corresponding decrease in the individual’s ability to produce melatonin (Kunz et al. 1999). The degree of calcification, relative to the size of an individual’s pineal gland, has been suggested as a marker of the individual’s decreased capability to produce melatonin (Kunz et al. 1999).

As with other calcifying tissues, the pineal gland can accumulate fluoride (Luke 1997, 2001). Fluoride has been shown to be present in the pineal glands of older people (14-875 mg of fluoride per kg of gland in persons aged 72-100 years), with the fluoride concentrations being positively related to the calcium concentrations in the pineal gland, but not to the bone fluoride, suggesting that pineal fluoride is not necessarily a function of cumulative fluoride exposure of the individual (Luke 1997, 2001). Fluoride has not been measured in the pineal glands of children or young adults, nor

Suggested Citation: “8 Effects on the Endocrine System.” National Research Council. 2006. Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. Washington, DC: The National Academies Press. doi: 10.17226/11571.

has there been any investigation of the relationship between pineal fluoride concentrations and either recent or cumulative fluoride intakes.

In Vitro Studies

Few studies have examined the effects of fluoride on pineal function. NaF (2.5-20 mM, or fluoride at 47.5-380 mg/L) produces markedly increased adenylyl cyclase activity (up to four times control activity) of rat pineal homogenates in vitro (Weiss 1969a,b), as it does in other tissues (Weiss 1969a); ATPase activity in the homogenates was inhibited by up to 50% (Weiss 1969a). Potassium fluoride (7-10 mM, or fluoride at 133-190 mg/L) has been used experimentally to increase adenylyl cyclase activity in rat pineal glands in vitro (Zatz 1977, 1979).

Animal Studies

Details of the effect of fluoride on pineal function are presented in Appendix E, Table E-15. Luke (1997) examined melatonin production as a function of age and time of day in Mongolian gerbils (Meriones unguiculatus). On an absolute basis, melatonin production by the low-fluoride group was constant at ages 7-28 weeks, with no difference between males and females. Relative to body weight, melatonin output declined progressively with age until adulthood (by 11.5 weeks in females and 16 weeks in males). In contrast, prepubescent gerbils fed the high-fluoride diet had significantly lower pineal melatonin production than prepubescent gerbils fed the low-fluoride diet. Relative to body weight, the normal higher rate of melatonin production in sexually immature gerbils did not occur.

Sexual maturation in females occurred earlier in the high-fluoride animals (Luke 1997); males had increases in melatonin production relative to body weight between 11.5 and 16 weeks (when a decrease normally would occur), and testicular weight at 16 weeks (but not at 9 or 28 weeks) was significantly lower in high-fluoride than in low-fluoride animals. The circadian rhythm of melatonin production was altered in the high-fluoride animals at 11.5 weeks but not at 16 weeks. In high-fluoride females at 11.5 weeks, the nocturnal peak (relative to body weight) occurred earlier than in the low-fluoride animals; also, the peak value was lower (but not significantly lower) in the high-fluoride animals. In males, a substantial reduction (P < 0.00001) in the nocturnal peak (relative to body weight) was observed in the high-fluoride animals.

Suggested Citation: “8 Effects on the Endocrine System.” National Research Council. 2006. Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. Washington, DC: The National Academies Press. doi: 10.17226/11571.

Human Studies

Although no studies are available that specifically address the effect of fluoride exposure on pineal function or melatonin production in humans, two studies have examined the age of onset of menstruation (age of menarche) in girls in fluoridated areas (Schlesinger et al. 1956; Farkas et al. 1983; for details, see Appendix E, Table E-15);¹² the earlier study was discussed by Luke (1997) as part of the basis for her research. No comparable information on sexual maturation in boys is available.

In girls examined approximately 10 years after the onset of fluoridation (1.2 mg/L, in 1945) in Newburgh, New York, the average age¹³ at menarche was 12 years, versus 12 years 5 months among girls in unfluoridated Kingston (Schlesinger et al. 1956).¹⁴ The authors stated that this difference was not statistically significant. Note that those girls who reached menarche during the time period of the study had not been exposed to fluoride over their entire lives, and some had been exposed perhaps for only a few years before menarche (they would have been 8-9 years old at the time fluoridation was started). Those girls in Newburgh who had been exposed to fluoridated water since birth (or before birth) had not yet reached menarche by the time of the study.

A later study in Hungary (Farkas et al. 1983) reported no difference in the menarcheal age of girls in a town with “optimal” fluoride concentration (1.09 mg/L in Kunszentmárton, median menarcheal age 12.779 years) and a similar control town (0.17 mg/L in Kiskunmajsa; median menarcheal

12	Both Schlesinger et al. (1956) and Farkas et al. (1983) referred to tables of the distribution of ages at the time of first menstruation, but, in fact, both studies provided only frequencies by age (presumably at the time of study, in either 1-year or 0.5-year increments) of girls having achieved menarche by the stated age. Farkas et al. (1983) specifically indicated use of the probit method for ascertainment of the median age at menarche; the data provided by Schlesinger et al. (1956) appear to correspond to that method, but they do not specifically mention it. The probit (or status quo) method appears to be routinely used to estimate the median (or other percentiles of) age at menarche, sometimes in conjunction with an estimated mean age at menarche based on recall data (e.g., Wu et al. 2002; Anderson et al. 2003; Chumlea et al. 2003; Padez and Rocha 2003). According to Grumbach and Styne (2002), “The method of ascertainment of the age of menarche is of importance. Contemporaneous recordings are performed with the probit method of asking, ‘yes’ or ‘no,’ are you menstruating? These may be incorrect because of social pressures of the culture and socioeconomic group considered. Recalled ages of menarche are used in other studies and considered to be accurate within 1 year (in 90% of cases) during the teenage years and in older women, too.”
13	Probably the median age, although the text simply says “average.” Similar studies appear to use the term “average age at menarche” to refer to the “estimated median age at menarche” (Anderson et al. 2003).
14	For comparison purposes, estimates of mean or median age at menarche for the white population in the United States include 12.80 years for 1963-1970 (Anderson et al. 2003) and 12.55-12.7 years for 1988-1994 (Wu et al. 2002; Anderson et al. 2003; Chumlea et al. 2003).

Suggested Citation: “8 Effects on the Endocrine System.” National Research Council. 2006. Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. Washington, DC: The National Academies Press. doi: 10.17226/11571.

age 12.79 years). This study shows postmenarcheal girls present at younger ages in the higher fluoride town than in the low-fluoride town, although the reported median ages were the same (Farkas et al. 1983).

Discussion (Pineal Function)

Whether fluoride exposure causes decreased nocturnal melatonin production or altered circadian rhythm of melatonin production in humans has not been investigated. As described above, fluoride is likely to cause decreased melatonin production and to have other effects on normal pineal function, which in turn could contribute to a variety of effects in humans. Actual effects in any individual depend on age, sex, and probably other factors, although at present the mechanisms are not fully understood.

ASSESSMENT OF GROUNDWATER QUALITY WITH
SPECIAL REFERENCE TO FLUORIDE AND ITS IMPACT ON
IQ OF SCHOOLCHILDREN IN SIX VILLAGES OF THE MUNDRA REGION,
KACHCHH, GUJARAT, INDIA