I nremat ional CI inic al Ps1-choplrurmacolo 91'( I 994), 9, 79 - 82
of fluoride:
a review
Psychopharmacology
B. Spittle
Department of PsychologicalMedicine, Universityof Otago Medical School, PO Box 913,
Dunedin, New Zealand
Although the blood-brain barrier is relatively impermeable to ffuoride, it doesnot posean absolute barrier and fluoride has the
ability to enter the brain. The literature was examined to assessthe quality of the evidencefor cerebral impairment occurring
due to exposure to fluoride from therapeutic or environmental sources. Several surve!'s of persons chronically exposedto
industrial fluoride pollution reported s.r-mptomsrelated to impaired central nervous systemfunctioning with impaired cognition and memory. Examination of individual casereports showed the evidencefor aetiologicalrelationships betweenslmptoms
and fluoride exposure to be of variable quality. The evidencewas seenas being suggestiveof a relationship rather than being
definitive. The difficulties with concentration and memory described in relation to exposure to fluoride did not occur in iso.lation but $ere accompanied by other symptoms of which general malaise and fatigue were central. Possible mechanisms
whereby fluoride could affect brain function include influencing calcium currents, altering enzyme configuration b1'forming
strong hydrogen bonds with amide groups, inhibiting cortical adenylyl cvclase activity and increasing phosphoinositide
hydrolysis.
Keywords: Case reports - Chronic toxicity - Cognition - Cognitive impairment - Concentration - Fluoride - Nlemory Psychopharmacology
INTRODUCTION
agent.fluorAlthoughnot usedasa ps1'chopharmacologic
ide from therapeuticor environmentalsourcesis able to
enterthe brain and thus hasthe potentialto affect cerebral
brain function.Yu-huan and Si-shung(1988) notedthat
fluoridemetabolismin the centralnervoussystemhad not
beenthoroughly and systematicallystudied.They postulated however that fluorine might damage the nervous
systemdirectly. This followed seeingpatientswith high
body fluoridelevelswitll nervoussystemsymptomswhich
improvedafterthey wereremovedfrom the higherlevel of
fluorideexposurewith a consequentdecreasein body fluoride levels.As a recentreviewofchronic fluorinepoisoning in humans(Anand and Roberts.1990)did not consider
the psychopharmacology.a further examination of this
areaappearedto be appropriate.
ABSORPTION
ANDENTRYOF FLUORIDE
INTO
T H EB R A I N
S-hitford ( 1990)reportedthat in the absenceof high concentrationsofdivalent and trivalentcations,about 807oof
ingestedfluoride was absorbedfrom the gastrointestinal
tract. Absorption from the stomachwas enhancedby a
low'erpH suggestinghydrofluoricacid (HF) ratherthan
ionic fluoride was the perrneatingmoiety. Fluoride is
not bound b1' plasma proteins and it is consideredthat
interstitial ffuid and plasma fluoride concentrationsare
e 199.{Raoid Communicationsof Oxtbrd Ltd
virtuallyidentical.In studiesofthe soft tissuedistribution
of fluoride.plasmafluoridelevelsareusedastheref'erence
extracellular concentrations. Plasma fluonde levels
increase in proportion to the chronic level of fluoride
intakeratherthanbeing homeostaticallycontrolledaswas
once believed.Plasmalevels can be used as an index of
previousexposureto the ion. HF ratherthan ionic fluoride
is consideredto be in diffusion equilibrium acrosscell
Yu-huanand Si-shung(1988) found that in
membranes.
normal individuals fluoride was in dynamic equilibrium
betweenthe blood and cerebrospinalfluid (CSF) rvith the
CSF fluoride being similar to or slightly lower thanthat in
blood. Whitford et al. (1979\ found a low brain tissueto
plasma fluoride ratio of 0.08 I h after the intravenous
injection of fluoride in ratsand consideredthat. at leastin
the short term, the blood-brain barrier was relatively
impermeableto fluoride.Geeraertset al. (1986) similarly
found a relativeimpermeabilityof the rat blood-brainbarrier to fluoride. but noted that the barrier was unable to
excludethe fluoride ion tiom enteringnerve tissue.They
found that the maximum concentrationwas reached2 h
after oral ingestion.Atier 3 h the brain tissue to plasma
ratios had a rangeof 0.05-0.07.In humansa mean brain
ffuoridelevelof 1.8ppm lrange0.2-6.1)hasbeentbundin
personsexposedto air pollution by fluoride,with the mean
for thosenot so exposedbeing 1.5 (0.4-3.6)(Ctll et al.,
I965).
InternationalClinical Psvchopharmacology.Vol 9. 199-l
79
ACUTETOXICITY
"probablytoxic dose",i.e. the minimum dose that
The
deathand
couldcausetoxic signsandsymptomsincluding
and
intervention
therapeutic
that shouldtrigger immediate
fluoride
tWhitford'
for
hospitalization,is about 5 mg/kg
1990). The affinity of fluoride for calcium may lead to
hypocalcaemiamanifestedby tetany.seizures'depression
oi1h. ..nt.ul nervous system and impairment of blood
coagulation(Baltazar.1980).Othercationssuchas zinc'
manganeseand magnesiummay be renderedunavailable
resultingin the inhibirionof enzl'mesystemsdependent
on thesetracemetals.Interferenceby fluoride in the potassiumfluxesbetweenredblood cellsand serummay lead
to hyperkalaemiaand a lethal ventriculararrhvthmia'
TOXICITY
cHRONIC
central nervoussystemdysfunction may also come trom
the studyof individuais.The evidenceis strongerw henan
associationis found between the presenceof s1'mptoms
and exposureto fluorideadministeredin a double-blind
m a n n e rW
. a l c l b o t(t1 9 5 5 ,1 9 5 6 .1 9 6 2 , 1 9 1 91' 9 8 0 '1 9 8 3 ) '
Waldbottand Lee (1978)and Waldbottet al' ( 1978)have
describedI I caseswhere psychiatricsymptomssuchas
lethargy, memory impairment and difficulties rvith concentrationand thinking cameon afterexposureto fluoride'
This usually occurredwith fluoridateddrinkin-swater but
in threecasesinvolved industrialexposure'The temporal
relationshipof the symptomsto fluoridewas supportedby
testdouble-blindtestingin two individuals,sin-sle-blind
in
three
levels
fluoride
environmental
high
ing in four, and
cases.Trvo of thesepersonsalsohadhigh individualfluoride levels.Similarly Petraborg( 1974)describeda 36-yearold man who becameunwell shortlyafter his watersupply
was fluoridated.His symptomssettledwith usingnon-fluoridatedwater and returnedwith using fluoridatedwater'
No challengetestswere given. The l2 casesreportedby
Waldbott, Waldbott and Lee' Waldbott et al' andPetraborg are summarizedin Table I'
Skeletal and dental fluorosis are establishedmanifestationsof chronicfluoridetoxicity (Singhet al..1963)but
a syndromeof cerebralimpairmentdue to fluoridehasnot
beenestablishedto the stageof warrantingrecognitionin
standardtextson organicpsychiatry(e.g.Lishman' 1987)'
Roholm (1937), in a study of 68 cryolite workers 847oof
DISCUSSION
whom had skeletalfluorosis,found that 22% had symp'
The difficulties with concentrationand memorydescribed
tomsclassifiedas beingof a nervouscharacter'involvins
in relationto exposureto fluoridedid not occurin isolation
indisposition.headacheand gidditiredness.sleepiness.
but were accompaniedby other symptoms of which
n e s s .G e a l l a n d B e i l i n ( 1 9 6 4 ) d e s c r i b e do p t i c n e u r i t i \
generalmalaiseandfatiguewerecentral.Others1'mptoms
developingin associationwith the therapeuticuse of
included those involving joints. the -uastrointestinal
sodium fluoride.Grimbergen(197'l) found by doublethe urinary tract. peripheralnervesand muscles'
blind testingthat someindividualsdevelopedmigraine- system,
The relatively small number of reportsof casesand the
with a
anddepression
visualdisturbances
like headaches,
varying degreesof scientificrigour presentin demonstratdaily intake of 1mg fiuoride.Czerwinskiand Lankosz
ing a reiationshipbetweenexposureto fluoride and cer(197'7)studied60 aluminium smelterworkers' 977o of
ebral impairmentsupportthe view that thereis suggestive
whom had skeletalfluorosis,and found 23Vcro havepsyratherthandefinitiveevidencethatchronic toxicitv affectchiatric disturbanceswith depression,mental sluggishing cerebralfunctioning can follow exposureto fluoride'
nessand memory disturbances.Waldbott (1979) studied
A numberof possiblemechanismsexist wherebyfluor23 personsresiding within 3 miles of an enamelfactory
ide could affectcerebralfunction' In view ofthe trequency
which emitted excessiveamountsof airborne hydrogen
of the symptomof amnesiait is of interestthatintracellular
fluoride. Environmentaicontaminationwith fluoride was
fluoridehasbeenfound to alter the time courseof calcium
confirmedby finding excessiveler els in vegetationand a
curents from hippocampalneuronesin guinea-pigs(Kay
domestic animal. A chronologicalrelationshipwas preHoweveralthoughChanet a/. ( 1983)found'
sent bettveenthe onsetof illness and the commencement et at.,1986).
of 30 elementsstudied,that fluorine showedthe highest
of the pollution.Thoseresidingfunher away tiom the facregionaldifferencesin the brain in rats,the highestlevels
tory were less affected and had lower urinarv fluoride
ratherthanthe
tatiguewas the outstand- occurredin the midbrain,ponsandmedulla
progressive
levels.Generalized
(198
the amidethat
l)
noted
al.
et
Emsley
hippocampus.
uith a distinctdeclinein
ing featureand was associated
hydrostrongest
was
second
the
bond
hydrogen
fluoride
mentalacuity.increasedtbrgetfulness.inabilitl' to coordithe
tluoride
that
certain
it
seemed
that
and
known
natethoughtsancla reducedabilitl' to write' Neurological gen bond
for the N-H bond in
to competesuccesstuily
symptomswere describedin 2l casesinvolling paraes- ion was able
proteins.
This u'asseenas
in
as
occur
such
amiclesystems
t h e s i a s( 1 5 t ,c e p h a l g i at l 4 ) . v e n i g o( 7 ) , i m p a i r e dv i s i o n
disruptkey
ion
could
fluoride
the
how
of
an explanation
(6) and scotomata(7).
found
olet
Eduards
systems.
\198-l)
sitesin biological
Evidenceto suppon an aetiolosicalrelationshipbein
perturbations
induced
significant
indicating that fluoridebinding
tween exposureto fluoride and s-"-mpton.rs
80
. Vol 9 ' 199'l
Intemllional Clinical PslchoplrottnxcologY
PSYCHOPHARMACOLOGY OF FLUORIDE
TABLEl. CaserePorts
References
Patient
and age
F source
Clinicalfeatures
Evidence
Waldbott(1955,1980)
waldbott et al. (1978)
MrsMJ,
35 years
Water
Weakness,drowsiness,
impairedconcentrallon,
impairedmemory
Temporalassociation,
testing
single-blind
Waldbott(1956)
Waldbottet al. (1978)
MrsHM,
49 years
Water
Weakness,
impairedthinking
Temporalassociation
Waldbott(1956)
MrsCAT,
53 years
Water
Weakness,
impairedconcentration,
impairedmemory
Temporalassociation
Waldbott(1962,1980)
MTsWEA,
62 years
water,toothpaste,
trifluoperazine
Lethargy,
cerebrallassitude
Temporalassocialion,
testing,
single-blind
double-blindtesting
Waldbott(1962)
MrsES,
57 years
Water
Lethargy,
impairedmemory
Temporalassociation,
raisedurine F,
single-blindtesting
Waldbott(1962)
Mr FLP,
61 years
Water
Lethargy,
impairedconcentralion,
impairedmemory
Temporalassociation,
testing
single-blind
Petraborg(1974)
Mr FT,
36 years
Water
Lethargy,tension,
depression
Temporalassocialion
Waldbottet al. (1978)
Waldbott(1980)
MissCD,
13years
Water
Reducedmentalalertness
Temporalassociation,
double-blindtesting
Waldbottet al. (19781
MrsMMc.
54 years
Air.
Al smelter
Weakness,
mentalconfusion,
impairedmemory
Temporalassociation,
raisedenvironmentalF
Waldbottet al. (19781
MissCC,
24yearc
Water
Lethargy,
impairedconcentratlon,
impairedmemory
Temporalassoctatton
Waldbottand Lee (1978)
Waldbott(1983)
MTKAM.
57 years
Air,
unit
oil alkylation
Weakness,
decreasedintellectual
power,
impairedspellingand
writing
Temporalassociation,
raisedbone F,
raisedenvironmentalF
Waldbott(1983)
MrWJ,
50 years
Air,
waterplant
Lethargy,
decreasedmentalaculty,
impairedconcentratlon,
impairedmemory
Temporalassociation,
raisedenvironmentalF
the enzyme structure of cytochrome c peroxidase.An
active-sitearginine residue was consideredto move in
order to optimize hydrogen-bondedinteractionsrvith the
fluorine atom thus altering the shapeof the active site
and the enzvme's activitr'. In revieu'ing the subcellular
effects of fluoride, Elsair and Khelfat (1988) noted that
effects could occur on protein synthesis.the membrane
sodiumpump. glycolysis.Krebs c1'cleand ox)'genconsumption.Jope(1988)found that sodiumfluoridestimuin rat cortical
lated the hydrolysisof phosphoinositides
slices. It was consideredthat this occuned throu-shthe
formationof aluminium fluoridewhich activateda G protein which servedas a transducerbet*een receptorsand
phospholipaseC. PhospholipaseC' in turn, cataly'sedthe
hydrolysis of phosphoinositidesto produce two second
messengers,inositol triphosphate and diacf i,elycerol.
Aluminium fluoride may also inhibit cortical adenylyl
cyclaseactivity resultin-sin lower cyclic AMP levelssimilar to thosefound in Alzheimer's disease(Cowburn er c/.,
t992).
CONCLUSION
There would appear to be some evidence that chronic
exposure to fluoride may be associatedwith cerebral
impairment affecting particularly concentration and
' Vol 9 ' 199'l
IntemationalClinical Psychopharmacology
8l
B. SPITTLE
memory in some individuals. These symptoms are reminiscent of those seen in the chronic fatigue syndrome. At
present the evidence is suggestive rather than definitive. A
number of possible mechanisms exist whereby such
effects could be mediated. This relationship between fluoride and psychiatric symptomatology warrants further
investigation.
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Cowburn RF, O'Neill C, Ravid R. Winblad B and Fowler CJ
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GW ( 1974)A double-btind
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(Received 3 October 1993; accepted 15 October 1993)