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Fluoride and Pineal Gland

DOI:10.3390/app10082885
Authors:
Dariusz Chlubek
Dariusz Chlubek
Maciej Sikora at Hospital of the Ministry of Interior in Kielce, Poland
Maciej Sikora
  • Hospital of the Ministry of Interior in Kielce, Poland
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Abstract

The pineal gland is an endocrine gland whose main function is the biosynthesis and secretion of melatonin, a hormone responsible for regulating circadian rhythms, e.g., the sleep/wake cycle. Due to its exceptionally high vascularization and its location outside the blood–brain barrier, the pineal gland may accumulate significant amounts of calcium and fluoride, making it the most fluoride-saturated organ of the human body. Both the calcification and accumulation of fluoride may result in melatonin deficiency.
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applied
sciences
Review
Fluoride and Pineal Gland
Dariusz Chlubek 1, * and Maciej Sikora 1,2
1Department of Biochemistry and Medical Chemistry, Pomeranian Medical University,
Powsta´nców Wlkp. 72, 70-111 Szczecin, Poland; sikora-maciej@wp.pl
2Department of Maxillofacial Surgery, Hospital of the Ministry of Interior, Wojska Polskiego 51,
25-375 Kielce, Poland
*Correspondence: dchlubek@pum.edu.pl
Received: 28 March 2020; Accepted: 20 April 2020; Published: 22 April 2020


Abstract:
The pineal gland is an endocrine gland whose main function is the biosynthesis and secretion
of melatonin, a hormone responsible for regulating circadian rhythms, e.g.,
the sleep/wake cycle
.
Due to its exceptionally high vascularization and its location outside the blood–brain barrier,
the pineal
gland may accumulate significant amounts of calcium and fluoride, making it the most
fluoride-saturated organ of the human body. Both the calcification and accumulation of fluoride may
result in melatonin deficiency.
Keywords: fluoride; pineal gland; calcification of soft tissues; melatonin
1. Introduction
The effect of fluoride on the human body is characterized by a very narrow margin of safety,
which means
that even relatively low concentrations may cause various adverse or even toxic
effects
[1–5]
. The risk naturally increases with the intensity and duration of the exposure,
with long-term
exposure resulting in chronic poisoning [
6
,
7
]. One of the defense mechanisms protecting the body
against the effects of fluoride toxicity seems to be its deposition in calcified tissues [
2
]. The most
important role is played by hard tissues; bones; and teeth [
2
,
8
–
10
], in which fluoride accumulates in
the form of fluorohydroxylapatite and fluoroapatite, replacing hydroxyl ions in the hydroxylapatite
structure [
11
,
12
]. These processes may occur at any point in life, starting as early as in the prenatal
period [
13
–
15
], and their effects are observed even in the skeletons and dentition of archaeological
excavations from the times when exposure to fluorine compounds was incomparably lower to
modern times [
16
–
18
]. Significantly, the deposition of fluoride in hard tissues may have its own
adverse effects. The symptoms of excessive fluoride accumulation in bones and teeth are known and
well documented, classified as skeletal fluorosis and dental fluorosis, respectively [
19
–
24
]. In addition
to deposition in hard tissues, fluoride may also be found in calcification areas in soft tissues such as
the aorta [
25
–
29
], coronary arteries [
30
,
31
], placenta [
32
–
41
], tendons [
42
–
44
], or cartilage [
42
,
45
,
46
].
In these cases
, however, this accumulation may not be classified as a defense mechanism triggered
by an excessive exposure to fluoride. Unlike in hard tissues, calcium accumulation in soft tissues
is never a physiological phenomenon and almost always leads to some undesirable effects, e.g.,
complications in
pregnancy [
47
,
48
]. This indicates that the saturation of soft tissues with fluoride is a
natural consequence of their calcification. On the other hand, fluoride itself may stimulate the formation
of calcification foci in the soft tissues [
27
,
49
], which suggests that fluoride accumulation is the primary
phenomenon in calcification. Yet, regardless of the exact mechanisms, concentration of fluoride in the
bloodstream, and thus the risk of adverse effects in the body, is reduced as fluoride accumulates in the
soft tissues. Obviously, the exceptions to this are the fluoride-accumulating
soft tissues
; for example,
extensive deposits
of calcium fluoride in the placenta may impair blood flow through this organ and
thus impair fetal nutrition [32,33,50,51].
Appl. Sci. 2020,10, 2885; doi:10.3390/app10082885 www.mdpi.com/journal/applsci
Appl. Sci. 2020,10, 2885 2 of 10
One of the most interesting soft tissues able to accumulate fluoride is the pineal gland [
1
,
52
–
55
].
However, while knowledge of the calcification of this organ dates back to the 17th century [
56
],
the first
reports on its accumulation of fluoride appeared only in the mid-1990s [54].
2. Pineal Gland—Anatomy and Physiology
In humans, the pineal gland is a neuroendocrine gland weighing about 150 mg [
57
]. The organ,
part of the epithalamus, is located between the colliculi superiores of the lamina tecti, at the back of the
posterior wall of the third brain ventricle [
58
] (Figure 1). The pineal gland is characterized by a very
rich network of blood vessels, which ensures blood flow of 4 mL/min/g, second only to the blood
supply to the kidneys [
58
–
60
]. Another unique anatomical feature of the gland is its location outside
the blood–brain barrier [
58
,
59
]. Therefore, unlike most other brain structures, the pineal gland has
open access to blood and all of its components. Extremely rich vascularization and no significant
restrictions in transport from the bloodstream make it possible for the pineal gland to accumulate
significant amounts of various substances, mainly, calcium [
58
,
61
–
66
]; microelements such as cobalt,
zinc, and selenium [67]; and fluoride [52–54].
Appl. Sci. 2020, 10, x FOR PEER REVIEW 2 of 10
calcium fluoride in the placenta may impair blood flow through this organ and thus impair fetal
nutrition [32,33,50,51].
One of the most interesting soft tissues able to accumulate fluoride is the pineal gland
[1,52–55]. However, while knowledge of the calcification of this organ dates back to the 17th
century [56], the first reports on its accumulation of fluoride appeared only in the mid-1990s [54].
2. Pineal gland—anatomy and physiology
In humans, the pineal gland is a neuroendocrine gland weighing about 150 mg [57]. The organ,
part of the epithalamus, is located between the colliculi superiores of the lamina tecti, at the back of
the posterior wall of the third brain ventricle [58] (Figure 1). The pineal gland is characterized by a
very rich network of blood vessels, which ensures blood flow of 4 mL/min/g, second only to the
blood supply to the kidneys [58–60]. Another unique anatomical feature of the gland is its location
outside the blood–brain barrier [58,59]. Therefore, unlike most other brain structures, the pineal
gland has open access to blood and all of its components. Extremely rich vascularization and no
significant restrictions in transport from the bloodstream make it possible for the pineal gland to
accumulate significant amounts of various substances, mainly, calcium [58,61–66]; microelements
such as cobalt, zinc, and selenium [67]; and fluoride [52–54].
Figure 1. T1-weighted midline sagittal magnetic resonance imaging (MRI) with an arrow pointing to
a normal pineal gland (case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 10767).
The basic function of the pineal gland is the production and secretion of melatonin [58,64], a
hormone found in all vertebrates [60], including humans, which regulates circadian rhythms such
as the sleep–wake cycle [64] (Figure 2). It is also a strong antioxidant [68–70] and an
anti-inflammatory agent [71,72]. Although melatonin can be synthesized in almost all organs and
tissues, including skin [73], intestines [74], bone marrow [75], testicles [76], ovaries [77], or the
placenta [78], the proper biological response is regulated by the pineal hormone [64].
Figure 2. Chemical structure of melatonin.
Biosynthesis of melatonin (Figure 3) occurs in pinealocytes, which constitute about 95% of the
pineal gland’s volume [79]. The remaining part of the organ consists of astrocytes, microglia,
Figure 1.
T1-weighted midline sagittal magnetic resonance imaging (MRI) with an arrow pointing to a
normal pineal gland (case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 10767).
The basic function of the pineal gland is the production and secretion of melatonin [
58
,
64
],
a hormone
found in all vertebrates [
60
], including humans, which regulates circadian rhythms such as
the sleep–wake cycle [
64
] (Figure 2). It is also a strong antioxidant [
68
–
70
] and an anti-inflammatory
agent [
71
,
72
]. Although melatonin can be synthesized in almost all organs and tissues, including
skin [
73
], intestines [
74
], bone marrow [
75
], testicles [
76
], ovaries [
77
], or the placenta [
78
], the proper
biological response is regulated by the pineal hormone [64].
Appl. Sci. 2020, 10, x FOR PEER REVIEW 2 of 10
calcium fluoride in the placenta may impair blood flow through this organ and thus impair fetal
nutrition [32,33,50,51].
One of the most interesting soft tissues able to accumulate fluoride is the pineal gland
[1,52–55]. However, while knowledge of the calcification of this organ dates back to the 17th
century [56], the first reports on its accumulation of fluoride appeared only in the mid-1990s [54].
2. Pineal gland—anatomy and physiology
In humans, the pineal gland is a neuroendocrine gland weighing about 150 mg [57]. The organ,
part of the epithalamus, is located between the colliculi superiores of the lamina tecti, at the back of
the posterior wall of the third brain ventricle [58] (Figure 1). The pineal gland is characterized by a
very rich network of blood vessels, which ensures blood flow of 4 mL/min/g, second only to the
blood supply to the kidneys [58–60]. Another unique anatomical feature of the gland is its location
outside the blood–brain barrier [58,59]. Therefore, unlike most other brain structures, the pineal
gland has open access to blood and all of its components. Extremely rich vascularization and no
significant restrictions in transport from the bloodstream make it possible for the pineal gland to
accumulate significant amounts of various substances, mainly, calcium [58,61–66]; microelements
such as cobalt, zinc, and selenium [67]; and fluoride [52–54].
Figure 1. T1-weighted midline sagittal magnetic resonance imaging (MRI) with an arrow pointing to
a normal pineal gland (case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 10767).
The basic function of the pineal gland is the production and secretion of melatonin [58,64], a
hormone found in all vertebrates [60], including humans, which regulates circadian rhythms such
as the sleep–wake cycle [64] (Figure 2). It is also a strong antioxidant [68–70] and an
anti-inflammatory agent [71,72]. Although melatonin can be synthesized in almost all organs and
tissues, including skin [73], intestines [74], bone marrow [75], testicles [76], ovaries [77], or the
placenta [78], the proper biological response is regulated by the pineal hormone [64].
Figure 2. Chemical structure of melatonin.
Biosynthesis of melatonin (Figure 3) occurs in pinealocytes, which constitute about 95% of the
pineal gland’s volume [79]. The remaining part of the organ consists of astrocytes, microglia,
Figure 2. Chemical structure of melatonin.
Biosynthesis of melatonin (Figure 3) occurs in pinealocytes, which constitute about 95%
of the pineal gland’s volume [
79
]. The remaining part of the organ consists of astrocytes,
microglia,
vascular endothelial cells
, and nerve fibers [
79
,
80
]. The precursor of melatonin is
Appl. Sci. 2020,10, 2885 3 of 10
tryptophan [
58
],
and most
of the hormone is produced during sleep [
81
]. Its plasma concentration
reaches its maximum between 2 and 3 o’clock in the morning (80–150 pg/mL) [
82
].
The mechanism
conditioning this effect is initiated by reducing the activity of the suprachiasmatic nuclei,
which occurs
at night
. The effect is the activation of postganglionic sympathetic fibers and the release
of norepinephrine
from their nerve endings. This neurotransmitter stimulates
β
-adrenergic receptors, inducing activation
of the adenylate cyclase-cyclic adenosine monophosphate (AMP) system.
As a result of
the increased
cyclic adenosine monophosphate (cAMP) concentration in pinealocyte cytosol, the activity of serotonin
N-acetyltransferase increases, which leads to the stimulation of melatonin synthesis [83,84].
Appl. Sci. 2020, 10, x FOR PEER REVIEW 3 of 10
vascular endothelial cells, and nerve fibers [79,80]. The precursor of melatonin is tryptophan [58],
and most of the hormone is produced during sleep [81]. Its plasma concentration reaches its
maximum between 2 and 3 o’clock in the morning (80–150 pg/mL) [82]. The mechanism
conditioning this effect is initiated by reducing the activity of the suprachiasmatic nuclei, which
occurs at night. The effect is the activation of postganglionic sympathetic fibers and the release of
norepinephrine from their nerve endings. This neurotransmitter stimulates β-adrenergic receptors,
inducing activation of the adenylate cyclase-cyclic adenosine monophosphate (AMP) system. As a
result of the increased cyclic adenosine monophosphate (cAMP) concentration in pinealocyte
cytosol, the activity of serotonin N-acetyltransferase increases, which leads to the stimulation of
melatonin synthesis [83,84].
Figure 3. Biosynthesis of melatonin.
3. Calcium accumulation in the pineal gland
Calcium accumulates in the pineal gland in the apatite structure, similar to that found in bones
and teeth [63,85,86], and as calcium carbonate (calcite) [87]. The process is initiated in childhood
[88], and even in newborns [89,90], so some scientists see it as a physiological phenomenon [64]. It
is, however, difficult to agree with such a conviction in the face of ample evidence showing the
relationship between pineal calcification and various pathological states. This includes mental
illnesses and disorders [91–93], neurodegenerative disorders [94,95], primary brain tumors [96],
ischemic stroke [97], migraine [98], and sleep disorders [99]. The accumulation of calcium in the
pineal gland is also related to aging processes [100] (Figure 4).
Figure 4. Computer tomography (CT) scan through the brain with calcification of the pineal gland
(case courtesy of Radswiki, Radiopaedia.org, rID: 11770).
Figure 3. Biosynthesis of melatonin.
3. Calcium Accumulation in the Pineal Gland
Calcium accumulates in the pineal gland in the apatite structure, similar to that found in bones
and teeth [
63
,
85
,
86
], and as calcium carbonate (calcite) [
87
]. The process is initiated in childhood [
88
],
and even
in newborns [
89
,
90
], so some scientists see it as a physiological phenomenon [
64
].
It is
,
however, difficult to agree with such a conviction in the face of ample evidence showing the relationship
between pineal calcification and various pathological states. This includes mental illnesses and
disorders [
91
–
93
], neurodegenerative disorders [
94
,
95
], primary brain tumors [
96
], ischemic stroke [
97
],
migraine [
98
], and sleep disorders [
99
]. The accumulation of calcium in the pineal gland is also related
to aging processes [100] (Figure 4).
Appl. Sci. 2020, 10, x FOR PEER REVIEW 3 of 10
vascular endothelial cells, and nerve fibers [79,80]. The precursor of melatonin is tryptophan [58],
and most of the hormone is produced during sleep [81]. Its plasma concentration reaches its
maximum between 2 and 3 o’clock in the morning (80–150 pg/mL) [82]. The mechanism
conditioning this effect is initiated by reducing the activity of the suprachiasmatic nuclei, which
occurs at night. The effect is the activation of postganglionic sympathetic fibers and the release of
norepinephrine from their nerve endings. This neurotransmitter stimulates β-adrenergic receptors,
inducing activation of the adenylate cyclase-cyclic adenosine monophosphate (AMP) system. As a
result of the increased cyclic adenosine monophosphate (cAMP) concentration in pinealocyte
cytosol, the activity of serotonin N-acetyltransferase increases, which leads to the stimulation of
melatonin synthesis [83,84].
Figure 3. Biosynthesis of melatonin.
3. Calcium accumulation in the pineal gland
Calcium accumulates in the pineal gland in the apatite structure, similar to that found in bones
and teeth [63,85,86], and as calcium carbonate (calcite) [87]. The process is initiated in childhood
[88], and even in newborns [89,90], so some scientists see it as a physiological phenomenon [64]. It
is, however, difficult to agree with such a conviction in the face of ample evidence showing the
relationship between pineal calcification and various pathological states. This includes mental
illnesses and disorders [91–93], neurodegenerative disorders [94,95], primary brain tumors [96],
ischemic stroke [97], migraine [98], and sleep disorders [99]. The accumulation of calcium in the
pineal gland is also related to aging processes [100] (Figure 4).
Figure 4. Computer tomography (CT) scan through the brain with calcification of the pineal gland
(case courtesy of Radswiki, Radiopaedia.org, rID: 11770).
Figure 4.
Computer tomography (CT) scan through the brain with calcification of the pineal gland
(case courtesy of Radswiki, Radiopaedia.org, rID: 11770).
In the study in adolescents and adults, Kunz et al. [
61
] demonstrated an inverse correlation between
the degree of pinealocyte calcification and pinealocyte count. Although there was no significant
Appl. Sci. 2020,10, 2885 4 of 10
correlation between gland calcification and plasma melatonin concentration, it was noted that the
reduction in pinealocyte count caused by calcification was accompanied by a reduction in melatonin
synthesis. Hence, the conclusion that pineal gland calcification has an indirect effect on the production
and secretion of this hormone. These observations were confirmed by Liebrich et al. [
101
], who,
using magnetic
resonance imaging, showed a positive correlation between the size of the uncalcified
part of the pineal gland and the concentration of melatonin in saliva.
According to some authors, the concentration of melatonin in the cerebrospinal fluid plays a
decisive role in the regulation of circadian rhythms, while plasma hormone concentrations are of little
importance in exerting biological effects in this respect [102,103]. As pineal calcification results in the
reduction of melatonin concentration in the cerebrospinal fluid, its relation to diseases of the central
nervous system becomes understandable. The pathomechanism of this relationship is to reduce the
antioxidant effects of melatonin, which favors neuronal damage by reactive oxygen species (ROS) and,
thus, to accelerate the development of neurodegenerative changes [
64
,
70
]. For example, it has been
found that the concentration of melatonin in the cerebrospinal fluid in Alzheimer’s disease is only 20%
of that recorded in healthy individuals [104].
4. Fluoride Accumulation in the Pineal Gland and Its Consequences
Both calcified and calcium-free areas of the pineal gland undergo mineralization and accumulate,
among other things, magnesium, iron, manganese, zinc, strontium, orcopper [
105
]. However,
it was
not
until the 1990s that it was discovered that the foci of calcification within the gland may be accompanied
by extremely high concentrations of fluoride for soft tissue [
54
]. In 2001, Luke [
52
] first published the
results of fluoride concentration measurements in pineal glands taken from
human corpses
.
The mean
concentration was 297 mg F/kg of wet weight (ww), but the range of recorded values was very wide
(14 mg/kg–875 mg/kg ww). It is not difficult to notice that they are similar or even higher than those
observed in bones and teeth and many times exceed the concentrations observed in other soft tissues
(e.g., in muscles, they are about 1 mg F/kg ww). After converting these values into dry weight (dw),
we obtain
concentrations of 1485 +1285 mg F/kg dw. Although these data come from older individuals
(studies were conducted on a group of deceased people aged 70 to 100 years), this does not disprove
the idea that the pineal gland may be considered the most fluoride-saturated organ of the human body.
It has been observed that the fluoride content in pineal gland apatite is higher than in any other natural
apatite and may even reach 21000 mg/kg [52,53].
The results of Luke’s research also revealed a strong positive correlation between calcium and
fluoride concentrations (r =0.73, p<0.02) [
52
]. Ten or so years later this observation was confirmed,
albeit not for the full range of fluoride concentrations. Tharnpanich et al. [
53
] demonstrated that
a statistically significant correlation occurs only when the fluoride concentration exceeds 50 mg/kg
of fresh gland tissue. They recorded the values of these concentrations, which ranged anywhere
from
0 mg F/kg ww
to 831 mg F/kg ww (mean 75.5 +228 mg F/kg ww). This suggests that the
accumulation of fluoride in the pineal gland is rather a secondary phenomenon to the primary
calcification of this organ and at some point the relation between them reaches the status of a very
strong positive correlation (r =0.915, p<0.001). It is also worth noting that pineal glands in the study
by Tharnpanich et al. [
53
] were collected from deceased persons aged 33 to 91 years (mean 67 years),
who had inhabited an area with low fluoride contamination, which is a strong argument for the idea
that a smaller or larger accumulation of fluoride in the gland occurs even when the organism is not
exposed to particularly large amounts of fluorine compounds in the environment.
Regardless of how accumulation of fluoride in the pineal gland takes place, whether this is primary
or secondary to calcification, the most important issue is the effects of this phenomenon. It is obvious
that they will primarily concern the physiological function of the gland.
Assuming the preferential accumulation of fluoride in the pineal gland and the related possible
risk of toxic effects, Malin et al. [
11
] have recently published a study on the processes of sleep regulation
among older adults in the United States. They tried to answer the question of whether chronic exposure
Appl. Sci. 2020,10, 2885 5 of 10
to low doses of fluoride has an effect on sleep patterns and daytime sleepiness in the studied population.
The study investigated adolescents aged 16–19 years (mean =17 years), who had declared that they
had no sleeping disorders, who were exposed to low doses of fluoride (mean concentration in drinking
water =0.39 mg/L), and who had low concentrations of fluoride in plasma (mean =0.35
µ
mol/L).
Higher water fluoride levels were connected with higher odds of participants reporting snorting,
gasping, or apnea, while sleeping at night. Additionally, adolescents who lived in areas with higher
fluoride levels in tap water experienced more frequent daytime sleepiness. The authors [
11
] were of the
opinion that fluoride exposure may contribute to increased pineal gland calcification and subsequent
decreases in nighttime melatonin production that contribute to sleep disturbances.
For obvious reasons, there are very few reports on the accumulation of fluoride in the pineal gland
and its effect on the functionality of the organ in humans. Therefore, it is worth noting the studies
carried out in both experimental and free-living animals.
In the pineal glands taken from the common merganser (Mergus merganser), Kalisi´nska et al. [
1
]
recorded very high fluoride contents (mean >1000 mg/kg dw), which even exceed the concentrations
observed in the bones of these birds. Such a high concentration of fluoride in the gland is explained
by the incompleteness of the blood–brain barrier in birds, which facilitates the penetration of various
substances into the central nervous system.
Mrvelj and Womble [
79
] conducted a study to determine the effect of fluoride removal from the
diet of aged rats (over 26 months of age) on the pineal cell structure and to compare the results with
rats receiving fluoride with food (control). It was observed that in animals deprived of fluoride for
8 weeks, the number of pinealocytes was higher than in control animals, which suggests a harmful
effect of fluoride contained in the diet on pineal morphology and thus on the production and secretion
of melatonin.
In turn, studies conducted by Bharti and Srivastava [
106
,
107
] in rats showed the beneficial
effect of melatonin and pineal proteins on fluoride-induced oxidative stress, which is one of the
best known effects of fluoride on the body [
108
,
109
]. The animals were exposed to different
doses of fluoride and melatonin and proteins obtained from buffalo pineal (Bubalus bubalis).
The severity
of oxidative stress was measured by the degree of activity of antioxidative enzymes:
superoxide dismutase (SOD)
,
catalase (CAT)
, glutathione peroxidase (GPx), glutathione reductase
(GR), as well as the concentration of reduced glutathione (GSH) and malondialdehyde (MDA) in the
brains of the animals [
6
].
The antioxidant
system parameters were markedly improved by the intake
of melatonin and
pineal proteins
; in the latter case, the beneficial effect was even stronger. The action
consisted of increased activity of antioxidant enzymes, increased GSH concentration, and decreased
MDA concentration
. All these parameters were adversely affected in the group of animals receiving
fluoride only (decreased activity of enzymes and GSH concentration and increased MDA concentration,
which is a marker of increased oxidative stress), painting a very disturbing picture of the effects of
fluoride accumulation in the pineal gland. Since it is known that fluoride reduces the production and
secretion of melatonin [
79
], a substance which reduces the oxidative stress induced by them [
107
],
the accumulation
of fluoride in the pineal gland may be a significant factor in enhancing the effects of
reactive oxygen species, with all potential adverse consequences.
Finally, it is worth mentioning that the concentrations of fluoride in the pineal gland at the
magnitude of several dozen or even several hundred mg/kg ww, revealed in the studies by Luke [
52
]
and Tharnpanich et al. [
53
], may show inhibitory activity on melatonin synthesis pathway enzymes.
Fluoride having this effect has been known for a long time in relation to many enzymes [
108
,
110
].
Thus, it cannot be excluded that the restriction of melatonin synthesis associated with pinealocyte
calcification may be caused not only by a decrease in the number of active pinealocytes but also by the
direct influence of fluoride accumulated in the gland on enzymatic activity. This issue undoubtedly
needs to be clarified in the future.
Author Contributions:
Both authors contributed equally in this article. All authors have read and agreed to the
published version of the manuscript.
Appl. Sci. 2020,10, 2885 6 of 10
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
... Its tissue is subject to mineralization, with calcification producing concretions up to several millimeters in diameter [10]. This calcification consists of hydroxyapatite, similar to that of bones or teeth [11][12][13]. It has been found to accumulate high levels of fluoride [10] even from low fluoride consumption due to fluoride's high affinity for hydroxyapatite [12]. ...
... It has been found to accumulate high levels of fluoride [10] even from low fluoride consumption due to fluoride's high affinity for hydroxyapatite [12]. This vulnerability could increase the risk of pineal gland fluoride toxicity [13,14]. In older individuals, fluoride measurements in the pineal gland have been shown to be roughly equivalent to those in teeth [10]. ...
... Fluoride accumulates in the pineal gland to a similar degree as in teeth [10] and the pineal gland in older individuals contains more fluoride than any other soft tissue [49]. This accumulation is likely due to fluoride's high affinity for hydroxyapatite [12], as pineal fluoride concentration is directly correlated with pineal calcium concentration [10,49], as well as the fact that it sits outside of the blood brain barrier, has a substantial blood supply [13], and may be 'sampling' the blood in circulation [49]. One study found that the association between pineal fluoride and calcium was very strong (r 2 = 0.92) only for pineal glands with high levels of fluoride, which implies that high pineal fluoride is associated with increased calcification [12,13]. ...
View
... Its tissue is subject to mineralization, with calcification producing concretions up to several millimeters in diameter [10]. This calcification consists of hydroxyapatite, similar to that of bones or teeth [11][12][13]. It has been found to accumulate high levels of fluoride [10] even from low fluoride consumption due to fluoride's high affinity for hydroxyapatite [12]. ...
... It has been found to accumulate high levels of fluoride [10] even from low fluoride consumption due to fluoride's high affinity for hydroxyapatite [12]. This vulnerability could increase the risk of pineal gland fluoride toxicity [13,14]. In older individuals, fluoride measurements in the pineal gland have been shown to be roughly equivalent to those in teeth [10]. ...
... Fluoride accumulates in the pineal gland to a similar degree as in teeth [10] and the pineal gland in older individuals contains more fluoride than any other soft tissue [49]. This accumulation is likely due to fluoride's high affinity for hydroxyapatite [12], as pineal fluoride concentration is directly correlated with pineal calcium concentration [10,49], as well as the fact that it sits outside of the blood brain barrier, has a substantial blood supply [13], and may be 'sampling' the blood in circulation [49]. One study found that the association between pineal fluoride and calcium was very strong (r 2 = 0.92) only for pineal glands with high levels of fluoride, which implies that high pineal fluoride is associated with increased calcification [12,13]. ...
Fluoride exposure and duration and quality of sleep in a Canadian population-based sample
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Background Fluoride from dietary and environmental sources may concentrate in calcium-containing regions of the body such as the pineal gland. The pineal gland synthesizes melatonin, a hormone that regulates the sleep-wake cycle. We examined associations between fluoride exposure and sleep outcomes among older adolescents and adults in Canada. Methods We used population-based data from Cycle 3 (2012–2013) of the Canadian Health Measures Survey. Participants were aged 16 to 79 years and 32% lived in communities supplied with fluoridated municipal water. Urinary fluoride concentrations were measured in spot samples and adjusted for specific gravity (UFSG; n = 1303) and water fluoride concentrations were measured in tap water samples among those who reported drinking tap water (n = 1016). We used multinomial and ordered logistic regression analyses (using both unweighted and survey-weighted data) to examine associations of fluoride exposure with self-reported sleep outcomes, including sleep duration, frequency of sleep problems, and daytime sleepiness. Covariates included age, sex, ethnicity, body mass index, chronic health conditions, and household income. Results Median (IQR) UFSG concentration was 0.67 (0.63) mg/L. Median (IQR) water fluoride concentration was 0.58 (0.27) mg/L among participants living in communities supplied with fluoridated municipal water and 0.01 (0.06) mg/L among those living in non-fluoridated communities. A 0.5 mg/L higher water fluoride level was associated with 34% higher relative risk of reporting sleeping less than the recommended duration for age [unweighted: RRR = 1.34, 95% CI: 1.03, 1.73; p = .026]; the relative risk was higher, though less precise, using survey-weighted data [RRR = 1.96, 95% CI: 0.99, 3.87; p = .05]. UFSG was not significantly associated with sleep duration. Water fluoride and UFSG concentration were not significantly associated with frequency of sleep problems or daytime sleepiness. Conclusions Fluoride exposure may contribute to sleeping less than the recommended duration among older adolescents and adults in Canada.
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... Among the several chemical contaminants, excess concentration of nitrate, arsenic, and fluoride (F − ) ions are found to show harmful health effects to living organisms. Public health concerns are centered towards the presence of excess F − in drinking water (for >1.5 mg F − /L) and have shown several adverse health effects to human beings that sought considerable attention from the research community (Ayoob and Gupta, 2006;Grandjean, 2019;Agalakova and Nadei, 2020;Chlubek and Sikora, 2020;Johnston and Strobel, 2020;Kumar et al., 2020;Mondal and Chattopadhyay, 2020;Onipe et al., 2020;Skórka-Majewicz et al., 2020;Wimalawansa, 2020;Vandana et al., 2021;Li et al., 2021). A group of diseases termed as 'fluorosis' is a common sight for those who regularly consume drinking water with excess fluoride. ...
... It has been established that it reduces the intelligent quotient (IQ) and growth hormone production of school-aged children. In fact, several studies have been conducted to assess the seriousness of F − exposure and resulting brain functions in children (Grandjean, 2019;Agalakova and Nadei, 2020;Chlubek and Sikora, 2020;Johnston and Strobel, 2020;Skórka-Majewicz et al., 2020;Mondal and Chattopadhyay, 2020;Onipe et al., 2020). A few studies showed that high F − intake might decrease testosterone production and follicle-stimulating hormones (Susheela and Jethanandani, 1996;Ortiz-Pérez et al., 2003;Skórka-Majewicz et al., 2020). ...
Fluoride Sources, Toxicity and Fluorosis Management Techniques - A Brief Review
Article
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  • Jul 2021
Fluoride contamination in drinking water is a global issue. Frequent over-exposure to fluoride causes several health problems such as fluorosis, neurological, thyroid, osteoporosis, etc. The guideline values prescribed by the WHO and other nationals for fluoride in drinking water are reasonable but mostly relevant to fluorosis. However, these guideline values cannot be satisfied in some regions due to economic and financial shortcomings. Several fluorosis management techniques were suggested to address excess fluoride in drinking water, but each has specific drawbacks. Defluoridation techniques like the Nalgonda technique, reverse osmosis (RO), and adsorption using activated alumina have found to be promising to reduce fluoride concentration within the prescribed limits, and RO water is most widely used for drinking in fluorosis affected regions. However, these techniques are still associated with certain drawbacks, and prior research on this theme has focused on one dimension of removing excess fluoride from water. Hence, it is essential to understand the basic problems associated with fluoride contamination, such as sources of fluoride exposure, adverse health effects and defluoridation techniques feasibility. Furthermore, perception of the effect of co-existing ions with fluoride in drinking water is crucial in deciding fluoride toxicity level and developing efficient strategies for fluorosis mitigation.
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... However, other organs may also be the target group of this anion. For example, the accumulation of fluoride in soft tissues such as the thyroid and pineal glands can disrupt their functions [14,15]. About one-third of the world's population has chosen groundwater for various uses and many countries around the world are affected by fluoride-induced water pollution [16]. ...
Comparing groundwater fluoride level with WHO guidelines and classifying at-risk age groups; based on health risk assessment
Article
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  • Dec 2020
The main route of fluoride uptake is drinking water. Fluoride absorption in the acceptable range (0.5–1.5 mg L⁻¹) is suitable for the body, but its too much consumption can have irreversible health effects. To compare fluoride concentration with the WHO guidelines, 112 water samples were taken from groundwater aquifers in 22 villages of Garmsar County, the central part of Iran, during 2018 to 2019. Fluoride concentration was measured by the SPANDS method and its non-carcinogenic impacts were calculated using EDI and HQ. The statistical population was divided into four categories of infant, children, teenagers, and adults. Linear regression and Spearman rank correlation coefficient tests were used to investigate the relationships between the well’s depth and fluoride concentration in the water samples. The annual mean concentrations of fluoride in 2018 and 2019 were 0.75 and 0.64 mg L⁻¹and, the fluoride mean concentration in the samples classifying the cold and hot seasons of the studied years was 0.709 and 0.689 mg L⁻¹, respectively. The amount of fluoride in 27% of the samples in both years was less than the acceptable minimum (0.5 mg L⁻¹). Also, 11% of the samples in 2018 (6 samples) had fluoride levels higher than 1.5 mg L⁻¹. The HQ showed that the children were vulnerable; teenagers and adults were in the next ranks, respectively. Statistical tests showed a reverse and significant correlation (R² = – 0.02, β < 0.0001) between well depth and fluoride content. The border between the usefulness/harmfulness of fluoride is very narrow and requires extensive studies.
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... Regardless of mechanism of the effect of fluoride on melatonin, whether this is primary via melatonin receptors or secondary through pineal calcification, its intervention could have the wide spectrum of pathological effects [119]. Additional prospective human studies are needed to explore the impact of fluoride on melatonin for healthy physical and mental development and aging [131,132]. ...
Mechanisms of Fluoride Toxicity: From Enzymes to Underlying Integrative Networks
Article
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  • Oct 2020
Fluoride has been employed in laboratory investigations since the early 20th century. These studies opened the understanding of fluoride interventions to fundamental biological processes. Millions of people living in endemic fluorosis areas suffer from various pathological disturbances. The practice of community water fluoridation used prophylactically against dental caries increased concern of adverse fluoride effects. We assessed the publications on fluoride toxicity until June 2020. We present evidence that fluoride is an enzymatic poison, inducing oxidative stress, hormonal disruptions, and neurotoxicity. Fluoride in synergy with aluminum acts as a false signal in G protein cascades of hormonal and neuronal regulations in much lower concentrations than fluoride acting alone. Our review shows the impact of fluoride on human health. We suggest focusing the research on fluoride toxicity to the underlying integrative networks. Ignorance of the pluripotent toxic effects of fluoride might contribute to unexpected epidemics in the future.
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Fluoride exposure causes behavioral, molecular and physiological changes in adult zebrafish (Danio rerio) and their offspring
Article
Fluoride exposure through drinking water, foods, cosmetics, and drugs causes genotoxic effects, oxidative damage, and impaired cognitive abilities. In our study, the effects of fluoride on anxiety caused by the circadian clock and circadian clock changes in a zebrafish model were investigated at the molecular level on parents and the next generations. For this purpose, adult zebrafish were exposed to 1.5 ppm, 5 ppm, and 100 ppm fluoride for 6 weeks. At the end of exposure, anxiety-like behaviors and sleep/wake behaviors of the parent fish were evaluated with the circadian rhythm test and the novel tank test. In addition, antioxidant enzyme activities and melatonin levels in brain tissues were measured. In addition, morphological, physiological, molecular and behavioral analyzes of offspring taken from zebrafish exposed to fluoride were performed. In addition, histopathological analyzes were made in the brain tissues of both adult zebrafish and offspring, and the damage caused by fluoride was determined. The levels of BMAL1, CLOCK, PER2, GNAT2, BDNF and CRH proteins were measured by immunohistochemical analysis and significant changes in their levels were determined in the F- treated groups. The data obtained as a result of behavioral and molecular analyzes showed that parental fluoride exposure disrupts the circadian rhythm, causes anxiety-like behaviors, and decreases the levels of brain antioxidant enzymes and melatonin in parents. In addition, delay in hatching, increase in death and body malformations, and decrease in blood flow velocity, and locomotor activity was observed in parallel with dose increase in offspring. On the other hand, an increase in offspring apoptosis rate, ROS level, and lipid accumulation was detected. As a result, negative effects of fluoride exposure on both parents and next generations have been identified.
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Morphine-element interactions - The influence of selected chemical elements on neural pathways associated with addiction
Article
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Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical dopaminergic pathways play an important role in modulation of cognitive processes and decision making and, therefore, changes in dopamine metabolism are considered the central basis for the development of dependence. Disturbances caused by excesses or deficiency of certain elements have a significant impact on the functioning of the central nervous system (CNS) both in physiological conditions and in pathology and can affect the cerebral reward system and therefore, may modulate processes associated with the development of addiction. In this paper we review the mechanisms of interactions between morphine and zinc, manganese, chromium, cadmium, lead, fluoride, their impact on neural pathways associated with addiction, and on antinociception and morphine tolerance and dependence.
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Fluoride exposure and sleep patterns among older adolescents in the United States: A cross-sectional study of NHANES 2015-2016
Article
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Background: Fluoride from environmental sources accumulates preferentially in the pineal gland which produces melatonin, the hormone that regulates the sleep-wake cycle. However, the effects of fluoride on sleep regulation remain unknown. This population-based study examined whether chronic low-level fluoride exposure is associated with sleep patterns and daytime sleepiness among older adolescents in the United States (US). Method: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (2015-2016). We analyzed data from adolescents who had plasma fluoride (n = 473) and water fluoride (n = 419) measures and were not prescribed medication for sleep disorders. Relationships between fluoride exposure and self-reported sleep patterns or daytime sleepiness were examined using survey-weighted linear, binomial logistic or multinomial logistic regression after covariate adjustment. A Holm-Bonferroni correction accounted for multiple comparisons. Results: The average age of adolescents was 17 years (range = 16-19). Median (IQR) water and plasma fluoride concentrations were 0.27 (0.52) mg/L and 0.29 (0.19) μmol/L respectively. An IQR increase in water fluoride was associated with 1.97 times higher odds of reporting symptoms suggestive of sleep apnea (95% CI: 1.27, 3.05; p = 0.02), a 24 min later bedtime (B = 0.40, 95% CI: 0.10, 0.70; p = 0.05), a 26 min later morning wake time (B = 0.43, 95% CI: 0.13, 0.73; p = 0.04), and among males, a 38% reduction in the odds of reporting snoring (95% CI: 0.45, 0.87, p = 0.03). Conclusions: Fluoride exposure may contribute to changes in sleep cycle regulation and sleep behaviors among older adolescents in the US. Additional prospective studies are warranted to examine the effects of fluoride on sleep patterns and determine critical windows of vulnerability for potential effects.
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Revisiting the pineal gland: a review of calcification, masses, precocious puberty, and melatonin functions
Article
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  • Nov 2019
The pineal gland, an endocrine organ of the posterior cranial fossa famously involved in sleep and wakefulness, has continually been a topic of scientific advancement and curiosity. We review present an up-to-date review including the anatomy, embryology, and physiology of the pineal gland and its ability to secrete hormones including melatonin, pathophysiology of pineal gland tumors, cysts, and calcifications, their clinical presentation including their association with parkinsonism and precocious puberty, and various treatment approaches. It is imperative that clinicians and diagnosticians are able to distinguish manifestations of an overlooked gland.
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Fluoride-Free Diet Stimulates Pineal Growth in Aged Male Rats
Article
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The pineal gland is a naturally calcifying endocrine organ which secretes the sleep-promoting hormone melatonin. Age-related changes of the pineal have been observed, including decreased pinealocyte numbers, increased calcification, and a reduction in melatonin production. Since fluoride is attracted to calcium within the pineal gland, this study sought to examine the effects of a fluoride-free diet on the morphology of the pineal gland of aged male rats (26 months old). All animals had previously been raised on standard fluoridated food and drinking water. These control animals were compared to other animals that were placed on a fluoride-free diet (“fluoride flush”) for 4 or 8 weeks. At 4 weeks, pineal glands from fluoride-free animals showed a 96% increase in supporting cell numbers and at 8 weeks a 73% increase in the number of pinealocytes compared to control animals. In contrast, the number of pinealocytes and supporting cells in animals given an initial 4-week fluoride flush followed by a return to fluoridated drinking water (1.2 ppm NaF) for 4 weeks were not different from control animals. Our findings therefore demonstrate that a fluoride-free diet encouraged pinealocyte proliferation and pineal gland growth in aged animals and fluoride treatment inhibited gland growth. These findings suggest that dietary fluoride may be detrimental to the pineal gland.
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A comparative study of dental fluorosis and non-skeletal manifestations of fluorosis in areas with different water fluoride concentrations in rural Kolar
Article
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Background Fluorosis is an endemic disease which results due to excess exposure to high fluoride from different sources. The climatic factors and dependency on ground water add to the risk of fluorosis in Kolar. In addition to it, the epidemiological studies conducted on fluorosis in Kolar are very few. Aims (1) To estimate age-specific prevalence of dental fluorosis in the study population. (2) To determine the proportion of study subjects with non-skeletal manifestations of fluorosis (3) To assess and compare the influence of various socio-epidemiological factors in the occurrence of dental fluorosis among the study population in areas with high and normal fluoride. Methodology A cross-sectional study was conducted among the residents of three randomly selected villages, Thimmasandra and Batwarahalli (high fluoride) and Maddinayakanahalli (normal fluoride) belonging to Bangarpet taluk, Kolar for 1 year. Dental fluorosis was assessed by the Dean's grading. Non-skeletal manifestations were elicited based on clinical features. Fluoride levels of drinking water sources were estimated by ion-electrode method. The Chi-square and Fisher's exact tests were used to see the difference in proportions and a P value of <0.05 was considered for statistical significance. Results The prevalence of dental and non-skeletal fluorosis in the study groups with high and normal fluoride groups were 13.17%, 5.5%, 3.84%, 1.9%, respectively. The prevalence of dental fluorosis was significantly higher among the children and adolescents compared to adults (P < 0.05). Conclusion Dental fluorosis is a public health problem mainly affecting children and adolescents in Bangarpet.
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Skeletal fluorosis in Vavuniya District: an observational study
Article
Full-text available
  • Sep 2018
Background: The WHO recommended safe upper limit for fluoride in drinking water is 1.5 mg/l. Groundwater sources in many parts of Sri Lanka often exceed this limit. The high fluoride content of groundwater and high environmental temperatures in Vavuniya District predispose to pre-skeletal fluorosis and skeletal fluorosis in adults. Objectives: To identify residents of Vavuniya District with clinical features of pre-skeletal and skeletal fluorosis; to describe their clinical, biochemical and radiographic features; to determine the fluoride content of blood and urine in individuals with established diagnoses, and of their drinking water. Methods: In 98 volunteers we detected 60 with clinical features of pre-skeletal and skeletal fluorosis. Clinical examination, biochemical and radiographic investigations were performed. Forty four with confounding factors were excluded. The balance 16 had radiographic investigation for fluoride bone disease, and assessment of clinical features for pre-skeletal fluorosis. The radiographic criteria of skeletal fluorosis were trabecular haziness, osteosclerosis, osteophytes, cortical thickening and ligamentous or muscle attachment ossification. All 16 had “spot” samples of 15 ml of venous blood taken for biochemical tests and fluoride estimation; and 30 ml of urine, and water from 16 dug wells for fluoride. Results: The 16 selected (11 males) had BMI between 20.6 and 31.9 kg/m2, and were between 22 and 84 years (x̅ = 59.9 + 20.4). They used water from domestic dug wells for drinking. All had adequate renal function. All serum and urine samples had raised fluoride levels way above the reference ranges for serum (0.02 – 0.18 mg/l) and urine (0.6 – 2.0 mg/l). The 16 water samples showed a mean fluoride content of 2.90 +0.93 mg/l. Interpretation: In a cohort of 60 individuals in Vavuniya with symptoms suggestive of skeletal fluoride toxicity, 6 had skeletal fluorosis, 10 had pre-skeletal fluorosis, and groundwater sources had fluoride levels much higher than WHO recommended upper limit for drinking water. Residents in Vavuniya are predisposed to pre-skeletal and skeletal fluorosis. All 16 had been misdiagnosed as various types of arthritis.
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Fluoride concentration in synovial fluid, bone marrow, and cartilage in patients with osteoarthritis
Article
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The aim of this study was to compare the concentrations of fluoride (F) in cartilage, bone marrow, and synovial fluid taken from patients with osteoarthritis (OA). We also determined the correlation between OA risk factors, including age, sex, obesity, and hypertension, and F concentrations in the studied materials. The cartilage (n=27), bone marrow (n=29), and synovial fluid (n=22) were obtained from 29 patients (21 women and 8 men) with OA during knee replacement surgery. The median concentrations of F observed in studied materials could be arranged in the following descending order: cartilage > bone marrow > synovial fluid. The examination did not show a correlation between OA risk factors and F concentrations in the analyzed materials. Based on literature data and on the results of this study, we noticed that the level of F in the bone marrow and synovial fluid in patients with OA did not exceed 1.5 mg/L and 0.5 mg/L, respectively. The present study reports the first documentation of F concentrations in the synovial fluid and bone marrow of patients with OA.
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Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland
Article
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The pineal gland is a unique organ that synthesizes melatonin as the signaling molecule of natural photoperiodic environment and as a potent neuronal protective antioxidant. An intact and functional pineal gland is necessary for preserving optimal human health. Unfortunately, this gland has the highest calcification rate among all organs and tissues of the human body. Pineal calcification jeopardizes melatonin’s synthetic capacity and is associated with a variety of neuronal diseases. In the current review, we summarized the potential mechanisms of how this process may occur under pathological conditions or during aging. We hypothesized that pineal calcification is an active process and resembles in some respects of bone formation. The mesenchymal stem cells and melatonin participate in this process. Finally, we suggest that preservation of pineal health can be achieved by retarding its premature calcification or even rejuvenating the calcified gland.
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Skeletal fluorosis: don’t miss the diagnosis!
Article
  • Sep 2019
Skeletal fluorosis is a rare toxic osteopathy characterized by massive bone fixation of fluoride. The disease occurs as an endemic problem in some parts of the world and is the result of prolonged ingestion or rarely by inhalation of high amounts of fluoride. Radiographic presentation is mainly characterized by bone changes with osteocondensation and later ossification of many ligaments and interosseous membranes. Skeletal fluorosis is not clinically obvious and can be confused with other rheumatologic disorders. Its severity lies in the development of skeletal deformities and neurological complications. Management of fluorosis generally focuses on symptom treatment.
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Curse of Fluorosis
Article
  • Jan 2018
Fluoride was identified to have caries preventive properties and was widely used for fluoridation of water since 1940, especially in developed countries. After this there was sudden increase in the use of fluorides in food items and in oral medicinal products like toothpastes and mouth washes. Inadvertent use of above has lead to increase in fluorosis as a public health problem. In many places high fluorides are naturally present in earth crust leading to high water fluoride content increasing the risk of fluorosis. Maintaining a fine balance of fluorides in the body is mandatory for exploiting its advantages. World Health Organization (WHO) has fixed permissible limit of fluorides in water to 1.5 mg/L as a preventive step to contain fluorosis. Fluorosis has three clinical components: Dental, Skeletal and Non-Skeletal Fluorosis. It occurs with increasing level of fluorides in the body. Acute toxicity due to fluorides is also known and occurs as a result of sudden exposure to high levels of fluorides, usually by ingestion. Once fluorosis occurs it is irreversible without any cure. Only symptomatic and supportive management is possible. Hence prevention is the mainstay of management. Prevention is by using alternative sources of water or its de-fluoridation. National Program for Prevention and Control of Fluorosis (NPPCF) was launched in 2008–9 to identify areas with high fluoride content of water, manage the water bodies, screen schools and community for fluorosis and comprehensive management of cases. Improving quality of drinking water as per standards and improving nutritional status of children are also important components of prevention of fluorosis.
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