DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY

14 April 2008

Outline
Delivery means of fluoride as caries preventive agents
Effectiveness of fluoride
CPP-ACP
Consideration for clinical use
Risk factors for fluorosis
Sample questions

Objectives:
Rationale for clinical use of fluoride and calcium phosphate
Risk factors for development of dental fluorosis

Delivery Means of Fluoride

Fluoride has to be delivered to the environment

surrounding the tooth to inhibit or reverse caries
development. The major caries preventive effect
of fluoride is post-eruptive. Two main routes of F
administration are systemic fluoridation and
topical application. Systemic fluoride has both
pre- and post-eruptive effect, topical application is
post-eruptive. Systemic fluoride also has topical
effect because the ingested fluoride elevates
fluoride content of saliva.

Systemic fluoride (pre & post-eruptive)

Water fluoridation

community approach

Salt, milk, sugar fluoridation

Individual-based

Fluoride supplements

Topical fluoride (post-eruptive)

Professional (Operator-applied) fluoride products
Over-the-counter fluoride products

Individual-based

Fluoride-containing restorative materials

Note: Fluoride works best to prevent/control smooth surface
caries, but not as effective on occlusal caries.

Water, salt, milk, sugar fluoridation and fluoride supplements are in the systemic category. Topical
fluoride application includes professionally-applied fluoride in various forms and over-the-counter
products. Fluoride containing restorative materials can be classified as topical form of fluoride as well.
Some of these fluoride preparations are community approach, some are individual base, and some has to
be delivered by dental personals. They are different in the effectiveness and cost-benefit ratio.
Note: Fluoride works best to prevent/control smooth surface caries, but not as effective on occlusal caries.
Effectiveness of fluoride products

Effectiveness of Fluoride
Water fluoridation
High caries prevalence : 40-60 %
Low caries prevalence & use of other F-products: ~ 20%
Ripa LW. J Dent Res 1990;69(Spec Iss):786-796.

Fluoridated toothpastes
Prevented Fraction 24 % regardless of fluoridated drinking water.
Cochrane Database of Systematic Reviews 2003

Fluoride mouthrinses (> 6 years old)

Supervised weekly rinse: 0.2% NaF (920 ppm F)
Over-the-counter daily rinse: 0.05% NaF (230 ppm F)
Preventive Fraction: 29% in permanent teeth with no additional
fluoride exposure and for a caries-preventive effect on root caries.
Twetman S et al. Acta Odontol Scand 2004;62:223-30.

Water fluoridation: When caries

prevalence is high, water fluoridation
reduces 40-60% of caries. In population
with low caries prevalence and receive
other forms of F-products, especially Ftoothpaste, the effectiveness of water
fluoridation decreases to ~ 20%.
Fluoridated toothpaste is the most
important means for the topical application
of fluoride. Brushing with F-toothpaste
significantly reduce caries incidence.

Clinical studies showed caries preventive effect of F-toothpaste to be about 24 % regardless of whether
their drinking water is fluoridated. In addition, the cariostatic effect in life-long use in population may
be much greater due to the cumulative effect.
Fluoride mouthrinse is another form of topical F application that can be prescribed or bought over-thecounter. Fluoride compounds used are NaF, SnF2, amine fluoride. Because of the risk of fluoride
ingestion, fluoride rinses are not recommended to children under the age of 6 years. High concentration
rinses, e.g., 0.2% NaF (920ppm F), are used in supervised, school-based weekly rinsing programs or
prescribed for those with high caries risk. Over-the-counter fluoride rinses are for daily basis, such as
0.05% NaF (230 ppm F) in ACT. The efficacy is highly influenced by caries risk, dental awareness, and
access to dental care. Systematic review of F-mouthrinses revealed limited evidence for the cariespreventive effect (PF 29%) of daily or weekly sodium fluoride rinses compared with placebo in permanent
teeth of schoolchildren and adolescents with no additional fluoride exposure and for a caries-preventive
effect on root caries in older adults.
Effectiveness of Fluoride
Fluoride gels
2425 ppm F (SnF2), 1.23% APF
Prevented Fraction 28 %, independent of F toothpaste or F water

Fluoride varnishes
Highest F concentration (5%) among F-containing product
Prevented Fraction 30-46 %, independent of F toothpaste or water
Cochrane Database of Systematic Reviews 2003

F-containing restorative materials

Glass ionomer cements provide protection against recurrent
caries in high risk patients (e.g., xerostomia) who did not
routinely used topical fluoride (less compliance).
McComb D et al. Oper Dent 2002;27:430-437.
Haveman CW et al. J Am Dent Assoc 2003;134:177-184.

Fluoride gel: There is clear evidence of a

caries inhibiting effect of fluoride gel. A
systematic review involved 7,747 children
received fluoride gels ranged from 2425 ppm
F (SnF2) to 1.23% APF gel estimated the
prevented fraction to be 28%, independent of
F toothpaste or fluoridated water.
2 trials reported on adverse events.
Fluoride varnishes increase fluoride
retention on the tooth surface. Duraphat
varnish has the highest F concentration of all
products (5%).

However, the amount of F ingested from F varnish is not high due to the small amount applied. Metaanalysis study indicated caries reductions of 30-46% independent of F-toothpaste or fluoridated water.
F-containing restorative materials. Fluoride can be released from restorative materials as part of the
setting reaction or it may be added to the formulation with the specific intention of fluoride release. Glass
ionomer cements may be the only reliable product in terms of fluoride release and substantial clinical
effect. Why do we need F-containing restorative materials? Because secondary caries is the main reason
for restoration failure. The anticariogenic effect of glass ionomers is remarkably crucial in high-risk cases
such as in xerostomic patients who did not routinely use topical fluoride (less compliance).
Milk protein derivative CPP-ACP
Anticariogenic properties of milk and dairy products are known. Studies by the University of Melbourne
in Australia showed that a particular part of the casein protein in milk, the casein phosphopeptides (CPP),
was responsible for the anticariogenic properties. Casein phosphopeptides can stabilize amorphous
calcium phosphate (ACP) in a solution. CPP binds well to dental plaque. By doing so, calcium and
phosphate ions are localized in dental plaque at higher concentration, thus inhibit demineralization and
promote remineralization.
2

A sugar-free chewing gum with CPP-ACP significantly increased enamel remineralization compared to
control. Tradename of CPP-ACP is Recaldent. Manufacturers have incorporated Recaldent in various
products, range from consumer products like chewing gum, to a dentist-prescribed Ca/P topical cream, MI
paste. The MI paste is recommended to use in patients with erosion, active caries, or xerostomia.
Milk Protein Derivative CPPCPP-ACP

CPPCPP-ACP enhances remineralization process

Casein protein contributes to anticariogenic properties of milk

Sugar-free gum + CPP-ACP

100%

enamel remin vs control

Casein phosphopeptides (CPP) derived from casein protein

Reynolds EC et al.
J Clin Dent 1999;10:86-8.

stabilize amorphous calcium phosphate (ACP) in solution

CPP binds well to dental plaque

CPP-ACP
Tradename:

CPP localizes calcium and phosphate ions

Recaldent

Inhibit demin and promote remin

Reynolds EC. J Spec Care Dent 1998;18:8-16.

Consideration for clinical use of fluoride

Consideration for Clinical Use of Fluoride
What factors
to consider?

Which
method?

Cost-Benefit
ratio

caries risk, product efficacy, patient compliance, cost-effectiveness

ratio, background F exposure, access to dental care, safety issues
Frequent exposure to low level F is more effective
Patients compliance may be more effective than the product per se
Example
F toothpaste + good dental care
Low caries prevalence
Water fluoridation + F toothpaste
Is professional fluoride application necessary?

Caries incidence in low caries group = 0.25 DMFS / year

Fluoride gel (2X year) reduced caries 22 %
How much?
Safety issues

Chronic toxicity or long-term effect

Save 0.055
DMFS per year

Dental fluorosis

Which method is the most suitable for

clinical use of fluoride? and how much is
needed? Factors to be considered are:
caries risk, product efficacy, patient
compliance, cost-effective ratio,
background F exposure, access to dental
care, and safety issue.
Which delivery method? In general,
frequently exposure to low level of fluoride
is more effective than those that are
infrequently used. Patients compliance to
the proper use may be more effective than
the product per se.

Cost-benefit ratio should be considered. This is related to caries risk. In many European countries
without water fluoridation, children maintain their low caries prevalence just by using fluoride toothpaste.
Therefore in the area with water fluoridation plus children use fluoride toothpaste, additional fluoride
supplement is not recommended.
For example, a recent reviews show that twice a year application of fluoride gel reduced caries 22 %. In
low caries population, a mean caries incidence can be 0.25 DMFS per year. This means that 22%
reduction save 0.055 DMFS per year, therefore the cost-benefit ratio is unfavorable in this group.
Fluoride safety: The amount of fluoride exposed and the related safety is one of the most important
issues. Acute toxicity should not happen in normal practice. Chronic toxicity or long-term effect in terms
of dental fluorosis is more likely to occur, especially by multiple F exposure.

Percentage of fluorosis cases attributable to specific fluoride sources

Optimally fluoridated community
F supplement:
During year 1-2

13 %

Nonfluoridated population
F supplement: (pre-1994)
Year 1
Year 2-8

Tooth brushing:

29 %
65 %

Tooth brushing:

> pea-sized &

> once per day

46 %

Began during Y 1 & 2

> once per day

34 %

> pea-sized &

once per day

22 %

Began during Y 1 & 2

once per day

8%

pea-sized &
> once per day

2%

Began after Y 2
> once per day

6%

Used > pea-sized

45 %

Formula (powder
concentrate)

9%

Formula feeding

Pendrys DG. JADA 2000;131:746-755.

Attributable risk for dental fluorosis

This study determined the attributable
risk for mild to moderate enamel
fluorosis in two groups of children 1014 years old. 429 grew up in
nonfluoridated community, 234 grew
up in optimally F community.
Attributable risk is the proportion of
cases of mild to moderate enamel
fluorosis associated with exposure to
specific fluoride sources. Note that the
numbers do not add up to 100%
because the child can have more than
one way of F exposure.

In the optimally fluoridated community, the highest attributable risk is using more than pea-size amount of
toothpaste in young children. If the pea-size amount of toothpaste was used, the attributable risk is small
even the child brushed more than once per day. Also noted that formula reconstituted with fluoridated
water contributed to 9 % of the attributable risk.
In the non-fluoridated community, the highest attributable risk is fluoride supplement. But that was before
the recommendation was changed to the current one. The next highest attributable risk is using more than
pea-size amount of toothpaste in young children, and the frequency of brushing in toddler.
Risk factors for dental fluorosis

Risk Factors for Dental Fluorosis

Tooth brushing behavior with F toothpaste
32% of children under age 2 brushed with F toothpaste
91% among 4-year-olds brushed with F toothpaste
Preschoolers swallowed 55-79% (max 90 %) of toothpaste
34% of fluorosis in non-fluoridated areas:
children < 2 years old brushed > 1 per day
45% from > pea-sized amount of F toothpaste
68% of fluorosis cases in areas with optimal
water fluoridation: > pea-sized amount of F toothpaste

Odds ratio for fluorosis with the use of F-toothpaste = 1.6-1.8

Tooth brushing behavior with fluoride

toothpaste: US national data showed that
32% of children under age 2 brushed with F
toothpaste, the figure increased to 91%
among 4-year-olds. Parents have to
supervise when they brush because children
tend to swallow a lot of toothpaste.
Preschoolers frequently swallowed 55-79%
of the toothpaste, and as high as 90% was
found.

A study found that about 34% of fluorosis cases in non-fluoridated area were associated with children
younger than 2 years old using F toothpaste. And 68% of the fluorosis cases in areas with optimally water
fluoridation were from children younger than 1 year old ingested F toothpaste. Odds ratio for risk of
developing fluorosis with the use of F-toothpaste is 1.6-1.8.

Toothpastes with flavor for children also tend to be

swallowed more. Special toothpastes for young
Special toothpaste with
500 ppm F for young children
children with lower F concentration, 500 ppm F in
Children < 6 years old, unless fully developed
comparison to 1000 ppm F in regular toothpastes are
swallowing reflex:
Pea-size amount of F toothpaste
available. A small pea-sized amount of toothpaste is
Toddler:
recommended for children younger than 6 years old,
No F toothpaste until 2 years of age
unless fully developed swallowing reflex. ADA
ADA, Nov 2006
recommends not using fluoride toothpaste in toddlers
(under 24 months of age). There is a warning label for
use in children the back of toothpaste tube.
Toothpaste manufacturers do not recommend fluoride toothpaste for children under 6 years old unless
suggested by a dentist or a physician!
Toothpastes with flavor for children
Is that a good idea???

Risk Factors for Dental Fluorosis

Risk factor - Fluoride supplements:

Fluoride supplements

The inappropriate use of fluoride supplements is

one of the significant causes of fluorosis.
Fluoride supplements in the form of tablets or
vitamins are prescribed for use in children by
dentists and physicians. Before prescribe
fluoride supplements, dentists and physicians
have to test the childs water supplies for
fluoride content. And be aware that there are
several other sources of fluoride than drinking
water from the tap, like juice or bottle water.

Inappropriate use causes fluorosis

Prescribed by dentists/physicians
Not in areas with water fluoridation
Test F in the water supplies.
Other sources of fluoride: juice or bottled water
Animal studies: threshold plasma F level for dental fluorosis
One spike of 0.2 ppm/day for 1 week

dental fluorosis

One or two spikes of 0.1 ppm/day for 1 week

no dental fluorosis

If a child (5 kg,10 lb, ? < 1 year old) is given 0.5 mg F = 0.1 mg/kg
Ingesting 0.1 mg/kg can raise plasma F level to exceed 0.2 ppm

Animal studies showed a threshold plasma F level for dental fluorosis. One spike of 0.2 ppm/day for 1
week can cause dental fluorosis. One or two spikes of 0.1 ppm/day for 1 week is fine. If a child (5
kg,10 lb) is given 0.5 mg F, equivalent to 0.1 mg/kg, plasma F can exceed 0.2 ppm, a threshold level that
can cause dental fluorosis.
Recommended Dietary Fluoride Supplement Schedule
Fluoride concentration in community drinking water

Age

< 0.3 ppm

0.3-0.6 ppm

> 0.6 ppm

None

None

None

6 months 3 years

0.25 mg/day

None

None

3 6 years

0.50 mg/day

0.25 mg/day

None

6 12 years

1.0 mg/day

0.50 mg/day

None

0 6 months

To optimize benefits: maximize topical exposure (ie., chew or suck F tablets).

Guideline on Fluoride Therapy; Revised 2007, The American Academy of Pediatric Dentistry

Percentage of fluorosis cases attributable to specific fluoride sources

Optimally fluoridated community
F supplement:
During year 1-2

13 %

Nonfluoridated population
F supplement: (pre-1994)
Year 1
Year 2-8

29 %
65 %

This table is the latest recommended fluoride

supplement schedule. Currently it is
recommended that F supplement should never
been used in areas with water fluoridation.
The previous schedule had higher dose of
fluoride. One reason for the change came
from this study, in which significant
percentages of fluorosis cases were attributed
to fluoride supplement. The recommendation
may change again in the future, depending on
the evidence. To optimize benefit for fluoride
supplement, it should be slowly dissolved in
the mouth to maximize topical exposure.

How much fluoride is in my water?

http//apps.nccd.cdc/gov/MWF

My Waters Fluoride
National Center for
Chronic Disease
Prevention and Health
Promotion, CDC

The amount of fluoride a child receives on a daily basis has to be known before prescription of fluoride
supplement. How much fluoride is in my water? The information of community water fluoridation level
in the US can be found at http//apps.nccd.cdc/gov/MWF/Index.asp, a website of the National Center for
Chronic Disease Prevention and Health Promotion, Center for Disease Control and Prevention. (My
Waters Fluoride, Oral Health Resources). Example of Minneapolis as of April 13, 2008.
Where to send water to test fluoride content?
Fluoride Testing Service
School of Dentistry, University of Minnesota
Order water kit box from: Doug Magne 612-624-9123
Dr. Robert Ophaug 612-625-5198

Where to send water to test fluoride content? Order

the kits from Doug Magne 612-624-9123. It is done
here - Fluoride Testing Service, School of Dentistry,
UMN. MN Department of Health no longer has the
fluoride test service. There are some private
companies that do the testing (about double the fee
charged by the Dental School). Inside there is a form
to fill and a plastic test tube for the water to be tested.
Send a check (20 $ per sample), and the results will be
sent back to both the dentist and patient.
If a child has multiple sources of drinking water,
the amount of fluoride received has to be
calculated accordingly. For example, a 5-year old
boy drinks about 50-50 % water at home and
school. Home water has 0.25 ppm F, school water
is 1 ppm F. Calculate the Effective F
concentration from fractional fluoride
concentration of each water source. Home water
= 0.25 x 0.5 = 0.125 ppm F. School water = 1.0 x
0.5 = 0.5 ppm F. Therefore, the Effective F
concentration that the boy receives per day is 0.5
+ 0.125 = 0.625 ppm F.

Multiple sources of drinking water

Example 5 year old child
Home water is 0.25 ppm F
School water is 1 ppm F
Ingest 50 % from each source
0.25 ppm x 0.5 = 0.125 ppm F
1 ppm x 0.5 = 0.5 ppm F
Effective concentration = 0.625 ppm F
Therefore, if you base the recommendation according to home water
fluoride level, the child will get 0.5 mg F supplement.
However, according to the effective concentration, the child does not
need any F supplement.

According to the supplementation schedule for the effective F concentration, the child does not need any F
supplement. However, if you base the recommendation according to home water fluoride level alone, the
child will get 0.5 mg F supplement, which will be too much and increase risk of dental fluorosis.

Risk Factors for Dental Fluorosis

USDA National Fluoride Database of Selected Beverages and Foods

http://www.nal.usda.gov/fnic/foodcomp/Data/Fluoride/fluoride.pdf

Fluoridated water
Drinking optimally F water by itself is not a risk factor
Most bottled waters < 0.3 ppmF
Home filtration (distillation/reverse osmosis) removes > 90% F

Aquafina

0.05 ppm

Crystal

0.24 ppm

Dannon

0.11 ppm

Dannon Fluoride To Go

0.78 ppm

Dasani

0.07 ppm

Perrier

0.31 ppm

Carbon/charcoal filters do not remove F

FDAs health claim notification (Oct 2006)
Fluoridated water may reduce the risk
of dental cavities.

Juices: 0.02 2.8 ppmF; 42% > 0.6 ppmF (halo)

Soft drinks: 0.02 1.28 ppmF ; 77% > 0.6 ppmF (halo)

FDA does not allow claims for bottled water

products specifically marketed for use by infants

Risk factor - Fluoride in water: Drinking optimally F water by itself is not a risk factor for dental
fluorosis. A person lives in a community without water fluoridation can get fluoride in drinking water
from other sources such as child care or school. There is also a halo effect from water fluoridation
somewhere else. Now we also drink a lot of bottle waters, most of them contain less than 0.3 ppm, but
10% contain close to 0.7 ppmF. Home filtration systems (distillation and reverse osmosis) remove 90 %
or more F from water, but the carbon/charcoal systems do not. Juices had upto 2.8 ppm F, 42% had more
than 0.6 ppm. Fluoride level in soft drinks ranged from 0.02 to 1.28 ppmF depend on the plant they were
made. Overall, 77% of soft drinks had more than 0.6 ppmF.
There is a concern that caries increase with the increase consumption of bottled water. These are some
data of fluoride content in bottled water from an USDA website. A distillation or reverse osmosis
removed fluoride from water, so most of the bottled water does not have optimal level of fluoride. Some
bottled water has added fluoride, for example, Dannon F to go.
U.S. Food and Drug Administration's health claim notification October 14 , 2006 allowing bottlers to
claim that fluoridated water may reduce the risk of dental cavities or tooth decay. This one, which have
the picture of baby in the label has worried me, although it probably the best option in community without
fluoridated water. It is good for children and adults, but we should be aware that FDA does not allow
bottlers to make the claim for products specifically marketed for use by infants.
Risk factor - Infant formula reconstituted
with fluoridated water:

Risk Factors for Dental Fluorosis

Infant formula reconstituted with fluoridated water

Powder concentrates infant formula plus

fluoridated water can have 1 ppm, and liquid
concentrates infant formula plus fluoridated
water can have 0.5 ppm. This is a significant
source of fluoride, especially when more than 1
L is ingested. (5 kg infant will pass the
threshold of dental fluorosis which is 0.1
mg/kg/day). Infant formula reconstituted with
fluoridated water is responsible for 9% of
dental fluorosis in fluoridated community.

Significant source of F (1 ppm for powder concentrates,

0.5 ppm for liquid concentrates), especially when > 1 L is
ingested.
Responsible for 9% of dental fluorosis
Breast milk and cow milk: very low in fluoride (0.01-0.04 ppm)
1979: US manufacturers voluntarily reduced fluoride content
of infant formual to 0.15-0.30 ppm

Note: Infant chicken product can have 8 ppm F; 20 times higher than infant fruit

Breast milk and cow milk are very low in fluoride (0.01-0.04 ppm). Infant formula used to have high
fluoride content. In the 80s US manufacturers voluntarily reduced F in infant formula to 0.15 to 0.3 ppm.
In November 2006, ADA has issued an Interim
Guidance on Fluoride Intake for Infants and Young
Children, stated that for infants who get most of
their nutrition from formula during the first 12
months, ready-to-feed formula is preferred to help
ensure that infants do not exceed the optimal
amount of fluoride intake. If liquid concentrate or
powdered infant formula is the primary source of
nutrition, it can be mixed with water that is fluoride
free or contains low levels of fluoride to reduce the
risk of fluorosis.

ADAs Interim Guidance on Fluoride Intake for Infants and

Young Children
http://www.ada.org/prof/resources/positions/statements/fluoride_infants.asp
November 2006

For infants (birth to 12 months): Liquid concentrate or

powdered infant formula should be mixed with water
that is fluoride free or contains low levels of fluoride.
Bottled water labels: purified, demineralized, deionized,
distilled or reverse osmosis filtered water

Examples of water that has low level of fluoride

are those labeled purified, demineralized,
deionized, distilled or reverse osmosis filtered
water.

Recommended references
1. Brambilla E. Fluoride - Is it capable of fighting old and new dental
diseases? Caries Res 2001;35(suppl 1):6-9.
2. Ripa LW. An evaluation of the use of professional (operator-applied)
topical fluoride. J Dent Res 1990;69(Spec Iss):786-796.
3. Zimmer S. Caries-preventive effects of fluoride products when used in
conjunction with fluoride dentifrice. Caries Res 2001;35(suppl 1):18-21.

Note: Infant chicken product can have as high as

8 ppm F due to the deboning process which add
fluoride from chicken bone into the product.

4. Warren JJ, Levy SM. Systemic Fluoride. Sources, amounts, and effects
of ingestion. Dent Clin N Am 1999;43:695-711.
5. Bowen WH. Fluorosis. Is it really a problem? J Am Dent Assoc
2002;133: 1405-1407.
6. Pendrys DG. Risk of enamel fluorosis in nonfluoridated and optimally
fluoridated populations: considerations for the dental professional. JADA
2000;131:746-755.

A patient calls: her 3 years old son ate F-toothpaste.

1. How much? Each tube is 8 oz (200 g), she thinks he ate 1/4 tube ~ 2 oz ~ 60 g
2. What is the concentration? It should be in the ingredient: 0.24% NaF
3. For solid, it is easier to calculate the amount of fluoride because you dont have
to change unit from volume (oz or ml) to mg.
0.24 % NaF = 0.24 g of NaF per 100 g of toothpaste
= ~ 0.11 g of F per 100 g of toothpaste
= 110 mg of F per 100 g of toothpaste
The boy ate 60 g, therefore he got (0.6 x 110) = 66 mg of fluoride
4. What is the boys weight? His mother says about 32 lb ~ 14 kg
Calculate PTD for the boy = 5 mg/kg x 14 kg = 70 mg
The amount of toothpaste he ate is a bit less than PTD
Even if its only suspicious, thats enough to trigger emergency treatment
Note: if you remember the Table from last lecture, PTD of a 10 kg child for 1000
ppm toothpaste is tube.