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DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY

2 April 2008

Outline
Overview of fluoride
Fluoride, dental caries, and fluorosis: Historical perspective
How does fluoride work? (anticaries mechanisms)
Effect of fluoride on plaque bacteria
Structurally-bound fluoride

Objectives:

Fluoride in saliva and dental plaque

Role of fluoride in dental caries


Role of fluoride in the prevalence of dental fluorosis
The effect of fluoride on plaque bacteria

Overview about fluoride


Fluoride
Fluoride: ionic form of fluorine
Fluorine:
Halogen group
The most electronegative element
13th most abundant in the crust of the earth
Found in virtually all inanimate and living things
F- + H+

HF

Hydrofluoric acid (pKa ~ 3.4)

Fluoride:
Potent inhibitor of many enzymes
Elimination by kidneys
Avid calcified tissue seeker
Inhibit and even reverse the formation of dental caries

Fluoride is the ionic form of an element fluorine, a


halogen and the most electronegative. Fluorine is
the 13th most abundant element in the crust of the
earth, and has been found in virtually all inanimate
and living things.
Fluoride can reversibly combine with hydrogen ions
to form hydrogen fluoride or hydrofluoric acid.
Much of the physiological behavior of fluoride can
be explained in terms of the diffusibility of HF,
which dominates when pH is lower than pKa (3.4).

Fluoride is a potent inhibitor of many enzymes, for example, in the glycolytic pathway.
The elimination of fluoride from the body by the kidneys is many times greater than that of other
halogens. Fluoride is an avid calcified tissue seeker and its ability to inhibit and reverse the formation of
dental caries is unique.

F: The cornerstone of modern preventive dentistry


Remarkable decline in dental caries
Systemic and topical fluoride
Water fluoridation
Top 10 public health achievements of
the 20th century

(CDC)

Fluoride is a hazardous substance


when large doses are taken acutely
when lower doses are taken chronically
Dental fluorosis
Reversible gastric disturbances
Skeletal fluorosis
Death

Fluoride is highly regarded as the cornerstone of


modern preventive dentistry. The remarkable
decline in dental caries is largely attributed to the
proper use of ingested and topical form of fluoride.
Various fluoride compounds are added to products
such as dentrifrices, mouthrinses, topical gels.
The Centers for Disease Control and Prevention
have named water fluoridation as one of the 10
most important public health achievements of the
20th century.

We should be aware that fluoride is a hazardous substance when large doses are taken acutely or when
lower doses are taken chronically. The effects range from dental fluorosis, reversible gastric
disturbances, to skeletal fluorosis and death.
1

Fluoride, Dental Caries, and Fluorosis


Mottled enamel
Endemic in several regions of the southwestern USA
Colorado Springs
McKay FS. The relation of mottled enamel to caries.
J Am Dent Assoc 15:1429-1437, 1928.

these mottled enamel casesare singularly


free from caries.

Mottled enamel = Dental fluorosis


F

? substance in drinking water ?

Regular consumption of drinking water with fluoride


Reduction of dental caries

Historical perspective of fluoride and fluorosis


Our knowledge of the dental effects of fluoride
began in the early 1900s with the search for the
etiological factor of mottled enamel, a condition
which was endemic in several regions of the
southwestern USA. Dr. McKay, a dentist in
Colorado Springs observed his patients and
reported these mottled enamel casesare
singularly free from caries. He postulated that a
substance in drinking water was responsible for
both the brown stain and low rate of dental caries.

The substance was later identified as fluoride, which occurred naturally in water supplies. And the
mottled enamel is now known as dental fluorosis. Regular consumption of drinking water with fluoride
was associated with reduction of dental caries.

Dean et al: various levels of fluoride in most water supplies

Later work, primarily by Dean et al., found


various levels of fluoride in most water supplies,
and water fluoride level of near 1 ppm produced
that best balance of caries prevention and low
prevalence of dental fluorosis.

Water fluoride level ~ 1 ppm

Dental fluorosis or mottled enamel is a


hypomineralization of enamel that results from
excessive fluoride exposure, usually from
ingestion, during tooth development. The
appearance of fluorosis varies from barely
detectable white flecks (common) to severe
brown staining with pitting (rare). Mild fluorosis
is a minor cosmetic defect, severe fluorosis can
increase caries risk because of pitting and loss of
the outer enamel.

Caries prevention
Low prevalence of dental fluorosis

Dean HT et al., Domestic water and dental caries: V. Additional studies of the relation of fluoride domestic
waters to dental caries experience in 4425 white children, aged 12-14 years, of 13 cities in 4 states.
Public Health Rep 57:1155-1179, 1942.

Dental Fluorosis
Hypomineralization of enamel from excessive fluoride ingestion
during tooth development

Mild fluorosis (common)


Minor cosmetic defect

Overintake of fluoride from birth to 6 years old


causes dental fluorosis. The prevalence on
primary teeth is less than permanent teeth
because most of them develop prenatally. The
level of fluoride intake between 15-30 months is
the most critical for the development of fluorosis
of maxillary central incisors, the most
esthetically important teeth.

Severe fluorosis (rare)


Increased caries risk:
Pitting & Loss outer enamel

Overintake of fluoride from 0-6 year old


Generally less in primary teeth (develop prenatally)
Most critical between 15-30 months of age: maxillary central incisors

Why are we concerned about dental fluorosis?


The prevalence of fluorosis has increased
Optimal water F level (~ 1 ppm)
20 % prevalence of very mild or mild fluorosis
Dentistry: Mild fluorosis is an acceptable tradeoff for
caries prevention
Esthetic: mild cosmetic defect ?
No fluorosis: 27 % dissatisfied with their tooth color
Mild fluorosis: 50% dissatisfied

Why are we concerned about dental fluorosis?


Because the prevalence of fluorosis is increasing.
The optimal level of 1 ppmF in water is
accompanied by very mild or mild fluorosis with
about 20% prevalence. Dental profession believe
that mild fluorosis is an acceptable tradeoff for
caries prevention. However, when esthetics is
becoming more important, this mild cosmetic
defect is gaining interest.
27% of people without fluorosis were dissatisfied
with their tooth color. 50% with mild fluorosis
were dissatisfied with the color of their teeth.
Water fluoridation: The addition of fluoride to the
water supply started in 1945 in Grand Rapids,
Michigan. By 1948, children from Grand Rapids
had 60% less DMFT than those from Muskegon, the
control city.

Water Fluoridation
1945
Grand Rapids
Michigan

1948: Grand Rapids had 60% less DMFT than Muskegon control city
Optimal level: 0.7 - 1.2 ppm F
Colder climates

drink less water

need higher fluoride level

EPA (Environmental Protection Agency)


Max. Contaminant Level (Primary Drinking Water Standards) = 4 ppm F
Naturally existed F in some municipal water & wells : 4-8 ppm F or higher

Water sources with adjusted fluoride concentrations


have fluoride levels between 0.7 and 1.2 ppm
depending on the area temperature. Water systems
in cold climate needs to have higher fluoride level,
because people presumably consume less water.

EPA (Environmental Protection Agency) Maximum Contaminant Level under the Primary Drinking
Water Standards for fluoride is 4 ppm. Some municipal water sources with naturally occurring fluoride
may have up to 4 ppm F, some private wells may have up to 8 ppm F or higher.

USA: 67% (170 millions) on public water


system receive fluoridated water
Centers for Disease Control and Prevention, 2002

The most cost-effective community-based approach for caries prevention


Direct annual cost of fluoridation: $ 0.68-3.0 per person per year
$1 invested in water fluoridation saves > $38 in treatment costs

Halo effect
Persons not residing in fluoridated communities
Foods and beverages produced with fluoridated
water

Data from the CDC in 2002 reported that about 67%


of the US population on public water system (170
million) receives fluoridated tap water. Water
fluoridation is the most cost-effective communitybased approach to dental caries prevention in the
US. Data from 2005 showed that direct annual cost
of fluoridation ranges from $ 0.68-3 per person per
year. In most communities, $1 invested in water
fluoridation saves $38 or more in treatment costs.

The availability of fluoridated water has produced a halo effect, whereby persons not residing in
fluoridated communities receive some of the benefits of fluoridation from consuming products
manufactured with fluoridated water.
3

Discussion: (group of 6-8)

How does fluoride work?

1. The optimal level of fluoride in water as determined by this graph is 1 ppm.


What are the rationales?

Historical perspective

2. Why in Minnesota the level of added fluoride in water varies from 0.7 to
1.2 ppm?

Cariostatic effect of fluoride


Systemic incorporation into enamel during development
More perfect enamel crystals (Fluorapatite)
Less acid soluble
The more fluoride incorporated, the better cariostatic effect

Shark enamel (100% fluorapatite) can develop caries lesion!


gaard B et al. Scand J Dent Res 96:209, 1988.
Microradiographic study of demineralization of shark enamel in a human caries model.

How does fluoride work?


It was believed that the cariostatic effect of fluoride was due to its systemic incorporation into enamel
during development, resulted in more perfect enamel crystals that were less acid soluble. The higher
concentration of fluoride incorporated, the better the cariostatic effect.
Is that true? Shark enamel which consists of 100% fluoroapatite can develop caries lesion.
Current philosophy
The caries-reducing effect of fluoride is primarily achieved by its presence during
active caries development at the plaque/enamel interface where it directly alters
the dynamics of mineral dissolution and reprecipitation, and to some extent, affect
plaque bacteria.

Anticaries Mechanism of Fluoride


Change tooth morphology
Controversial and not universally accepted
Effect on plaque bacteria
Debatable: need much higher concentration of fluoride to be effective
Inhibit demineralization and enhance remineralization process

Goal: Try to maximize benefit with minimal adverse effects

MORE IS NOT NECESSARILY BETTER!

Current philosophy: The caries-reducing effect of


fluoride is primarily achieved by its presence during
active caries development at the plaque/enamel
interface where it directly alters the dynamics of
mineral dissolution and reprecipitation, and to some
extent, affects plaque bacteria.
Anticaries mechanisms of fluoride: change tooth
morphology, effect on plaque bacteria, and inhibit
demineralization and enhance remineralization.

The effect of fluoride on tooth morphology is controversial and not universally accepted. The effect on
plaque bacteria is debatable. The concentration of fluoride needed for antimicrobial effects is much
higher than the concentration needed to affect the demineralization and remineralization process.
Why do we need to know what the mechanisms are? Because we should maximize the benefit of
fluoride and minimize the adverse effects. Like most things in life, more is not necessarily better.
Effect of fluoride on plaque bacteria

Effect of fluoride on plaque bacteria

As early as 1940, it was shown that fluoride


inhibited carbohydrate metabolism in pure culture
of streptococci and lactobacilli. Since then, there
are many publications about the effects of fluoride
on oral bacteria and dental plaque ecology. Most
of these effects imply a reduced risk of caries.

1940: Fluoride inhibited carbohydrate metabolism in pure cultures of


streptococci and lactobacilli.
Bibby BG, van Kesteren M. The effect of fluoride on mouth bacterial.
J Dent Res 1940:19;391-402.

Fluoride affects oral bacteria and dental plaque ecology


IMPLY a reduced risk of caries

The major effects of fluoride on dental plaque are:

Effect on dental plaque bacteria

1. Inhibit bacterial absorption

F inhibits bacterial adsorption


In vitro: 9500 ppm F in solution inhibit bacterial adsorption to hydroxyapatite

2. Reduce proportion of cariogenic bacteria in


dental plaque

Clinical: rinses & toothpaste with Sn or amine F reduce plaque deposit

F reduces proportion of cariogenic bacteria in dental plaque


Chemostat: 19 ppm F prevent MS from growing to a larger proportion

3. Decrease acid production of dental plaque

Clinical: only high concentration of fluoride works!


No difference in subjects from area upto 21 ppm F in water

The first step in plaque formation is the adsorption


of salivary glycoprotein and bacteria to the tooth
surface. In vitro experiment showed that 9500
ppm F in solution is needed to inhibit the
adsorption of bacteria.

Reduced MS in plaque after daily use of APF gel (12,300 ppm F)

F decreases acid production


Fluoridated water or daily rinse with 0.2% (~900 ppm) NaF solution
Reduce 0.1 - 0.2 unit in pH drop after a sucrose challenge
No effect after 0.05 % (~200 ppm) rinse

In humans, reduction in plaque deposit was found after the use of mouthrinses and toothpaste with
stannous or amine fluoride. But it is questionable if the effect came from the antimicrobial action of the
cations (stannous or amine) or fluoride.
After adherence, competition between bacteria will determine the final composition of dental plaque. In
a chemostat experiment, where several bacteria grow together, 19 ppmF could prevent mutans
streptococci from growing to a larger proportion. It seems like fluoride has selective effect on
cariogenic bacteria. However, in vivo this effect could only be seen with high concentration of fluoride.
Proportion of MS in occlusal plaque was reduced after daily application of APF gel (12,300 ppm). In
rats, reduced number of MS was found when the drinking water had 250 ppmF, while no difference in
plaque flora was found in subjects living in area upto 21 ppmF in drinking water.
Fluoride reduces the acid production by plaque in vivo. A reduction of 0.1 - 0.2 unit in pH drop after a
sucrose challenge was found in plaque from individuals drinking fluoridated water or rinsing daily with
0.2% (~900 ppm) NaF solution. No effect was found after a 0.05 % (~200 ppm) rinse.
Antimicrobial effect of fluoride

Antimicrobial effect of F

To have the antimicrobial effect, first fluoride has


to enter the cell. When external pH is lower than
pKa (3.4), HF is dominated. Fluoride enters the
cell as HF, not F-, thus it can accumulate in the
cell against the concentration gradient. Because
cells normally maintain internal pH near neutral
(pH across the cell membrane), HF dissociates
into H+ and F-. This lowers the intracellular
concentration of HF, and results in a continued
diffusion of HF into the cell, which again
dissociates.

HF forms when external pH is lower than pKa (3.4)


H+

F-

HF

Fluoride enters cell as HF (not F-)

HF

H+ + FAccumulation of fluoride

Accumulation of H+

Cytoplasmic acidification

2
Bound to enzymes
- Enolase
- Proton-extruding ATPase

This leads to the accumulation of H+ (cytoplasmic acidification) and the accumulation of fluoride in the
cell. Fluorides bind to enzymes enolase and proton-extruding ATPase and inhibit the carbohydrate
metabolism of bacteria.
5

In spite of the evidence for inhibitory


effects of fluoride on plaque metabolism, it
is not clear to what extent these effects
contribute to caries prevention, or how
much fluoride is needed. Fluoride
concentration needed for antimicrobial
effects is much higher than the
concentration that patients exposed on a
regular basis and surpasses the
concentration needed to reduce the
solubility of apatite.

Fluoride has inhibitory effects on plaque metabolism


To what extent do these effects contribute to caries prevention?

How much fluoride is needed for antimicrobial effect?


In vitro: 9500 ppm F in solution inhibit bacterial adsorption to hydroxyapatite
Reduced MS in plaque after daily use of APF gel (12,300 ppm F)
Fluoridated water or daily rinse with 0.2% (~900 ppm) NaF solution
reduced 0.1 - 0.2 unit in pH drop after a sucrose challenge
No effect in pH drop after 0.05 % (~200 ppm) NaF rinse
No reduction of MS in plaque in subjects from area upto 21 ppm F
in drinking water

How much fluoride is needed to reduce enamel solubility?


ppm F to reduce solubility << ppm F for antimicrobial effect

At pH 4-5
Fluoride in solution
reduces the amount of
enamel dissolved
Effective at a few ppm F

As shown in this graph, the presence of


fluoride in solution reduces the amount of
enamel dissolved at all pH values. Even
low concentrations of fluoride, at a few ppm
range, are effective. This brings us to the
most important cariostatic mechanism of
fluoride: effect on the demineralization and
remineralization process. (next lecture)

The most important cariostatic mechanism of F: De- and Remineralization

Fluoride in HAP crystal:


StructurallyStructurally-bound F
F- substitute OHDecrease
crystal
dimension
(F- is smaller)

Strong attraction
with calcium
(F: the most
electronegative)

F
OH
Ca

Hydroxyapatite lattice structure

F- fill vacancy
H-bond with O

Stabilize the lattice structure


Improve the crystallinity
Lower dissolution rate

H-bond

Fluorhydroxyapatite Fluoridated hydroxyapatite


Fluoroapatite-like material

Fluoride in HAP crystals: Structurally-bound fluoride


To understand the effect of fluoride on de- and remineralization, we have to know how fluoride affects
the crystal structure of hydroxyapatite. During mineralization or remineralization, fluoride ions can
substitute hydroxyl ions. The atomic size of fluoride ions is smaller, which results in a decrease in
dimension in the crystal. In addition, F is the most electronegative of the elements, which results in a
strong attraction with calcium. This stabilizes the lattice structure.
Fluoride also improves the crystallinity of enamel apatite by filling in the vacancies in the crystal
structure. Fluoride forms a strong hydrogen bond with the oxygen atom in the hydroxyl group. With
improved crystallinity and more crystal stability, partially fluoridated hydroxyapatite is less soluble than
the pure HAP.
Fluoride incorporated into the crystal lattice of HAP is structurally-bound fluoride. They are called with
different names: fluorhydroxyapatite or fluoridated hydroxyapatite or fluorapatite-like material.
Discussion: (group of 6-8)

How much fluoride is in dental plaque?


I believe that the main anticaries effect of fluoride is by
changing the equilibrium towards remineralization,
not antimicrobial effect.

Range from 5-50 ppm wet weight


1% is available as fluoride ion
15-75% is ionizable
Some firmly-bound fluoride (bacterial uptake?)

Why?

Plaque matrix concentrate fluoride from saliva:


+ve charges in matrix & on bacterial surface attract Ca2+
Ca2+ bind fluoride.

Fluoride in saliva and dental plaque


Total fluoride in dental plaque ranges from 5-50 ppm wet weight. Of this, 1% is available as fluoride
ions, 15-75% is ionizable, and the rest is firmly-bound, possibly uptake by bacteria. The plaque matrix
may concentrate fluoride from saliva. Negative charges on the bacterial surface and matrix attract
calcium ions which can bind fluoride.
Plaque fluid F and Saliva F after 1-min rinse with
NaF ( 900 ppm) or MFP ( 1000 ppm)

F decreases exponentially
Elevated for ~ 3 hours
(baseline ~ 0.04 ppm)
Plaque fluid F

Clinical study:
F level in saliva and
plaque remained for 18 h

Saliva F

F reservoir
Calcium fluoride
Oral mucosa?

Ekstrand J. Enhancing effects of fluoride. Cariology for the nineties, 409-420.

Fluoride concentration in plaque fluid after a


1-min rinse with NaF (0.2%) or MFP
(toothpaste slurry; 1000 ppm) rinse was
elevated from the baseline value of 0.4 ppm
for almost 3 hours. Fluoride level in saliva
and plaque decreases exponentially with time
after a topical application. According to this,
the effect of F should not last longer than an
hour after brushing. However, a clinical study
showed that F level in saliva and plaque
remained increased 18 h afterwards.

This also supports the concept that there is reservoir for F somewhere. One of that is CaF2-like material,
and probably the oral mucosa is also a reservoir for F.
What characters affect caries development?
Characteristics
DMFT
Decay surface

Low
Caries-Active

High
Caries-Active

4.8 + 5 *

18.9 + 7.3

0*

3.8 + 3.1

Age

26 + 8

24 + 8

Male / female

9 / 14

13 / 11

Salivary flow (ml/min)

1.5 + 0.3

1.5 + 0.5

MS (log CFU/ml saliva)

4.2 + 1

5.3 + 1

Lactobacilli (log CFU/ml saliva)

3.8 + 0.8

4.5 + 1.2

Brushing time (min)

2.8 + 1.6

2.6 + 2

Amount of toothpaste (g)

1.1 + 0.5

1.2 + 0.6

Rinse frequency

1.5 + 0.7 *

3.6 + 1.9

Amount of water to rinse (ml)

70 + 60 *

190 + 10

F in saliva (immediate) (mM)


F in saliva (accumulate) (mMmin)

0.6 + 0.4 *
6.9 + 3.9 *

0.3 + 0.3
3.9 + 2.9

ten Cate JM, van Loveren C. Fluroide Mechanisms. Dent Clin N Am 1999;43:713-742.
Adapted from Sjgren T, Birkhed D. Caries Res 1993;27:474.

Interesting study:
Rinsing pattern and retention of fluoride affected caries development. Caries risk factors were compared
between low and high caries activity groups. There were no differences in salivary flow rate, MS and
lactobacilli counts, brushing time and the amount of toothpaste used. But there were significant
differences in how many times they rinsed, the amount of water used, the immediate and accumulated
amount of F in saliva after brushing.
Can behavior modification affect caries activity?

Recommended references
1. Ten Cate JM, van Loveren C. Fluoride Mechanisms. Dent Clin North Am
1999;43(4):713-742.
2. Featherstone JD. The science and practice of caries prevention. J Am Dent
Assoc 2000;131:887-899.
3. Gordon Nikiforuk. Understanding Dental Caries 1. Etiology and
Mechanisms, Basic and Clinical Aspects. Basel; New York: Karger 1985.
Chapters 4.
4. Gordon Nikiforuk. Understanding Dental Caries 2. Prevention, Basic and
Clinical Aspects. Basel; New York: Karger 1985. Chapters 3.
5. van Loveren C. Antimicrobial activity of fluoride and its in vivo importance:
Identification of research questions. Caries Res 2001;35(suppl 1):65-70.
6. Fejerskov O. Changing paradigms in concepts on dental caries:
Consequences for oral health care. Caries Res 2004;38:182-191.
7. Ten Cate JM. Review on fluoride, with special emphasis on calcium fluoride
mechanisms in caries prevention. Eur J oral Sci 1997;105:461-465.
8. Fagin D. Second thoughts about fluoride. Scientific American Jan 2008.

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