DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY

9 April 2008
Outline
Historical perspective of fluoride toxicity and
current incidences
Toxic doses of fluoride from dental products

Guideline/recommendation for safe use

Symptoms of fluoride toxicity

Principle of emergency treatment

Chronic fluoride toxicity

Objectives:
Acute and chronic fluoride toxicity
Appropriate use of fluoride products
Optimal and toxic level of fluoride intake

Fluoride Toxicity As a dental practitioner, we should be aware fluoride is a

Excessive ingestion / short time: hazardous substance. We have to make sure that fluoride
Acute toxic effects
is used to enhance health with minimal adverse effects.
Gastric disturbance
Nausea, vomiting Ingestion of fluoride over a short time span can have
Death
acute toxic effects, ranging from gastric disturbance,
Excessive ingestion / long period during tooth
development:
nausea, vomiting, or even death. Excessive ingestion of
Dental fluorosis fluoride over a long period during tooth development can
The effect of long term fluoride exposure on
bone is still controversial
cause dental fluorosis. The effect of long term fluoride
exposure on bone is still controversial.

Historical perspective of fluoride toxicity Historical perspective of fluoride toxicity

Fluoride was used as a pesticide Fluoride was used as a pesticide, such as powder to kill
Mistaken for powder milk, salt, baking soda, flour
1933-1955: 607 fatal cases in the US. cockroaches. Unfortunate events were when fluoride was
Pittsburgh 1940: mistaken for powder milk, salt, or baking soda. From
Salvation Army service center
Mistaken NaF for flour in pancake 1933-1955, 607 fatal cases of fluoride toxicity were
40 poisoning cases & 12 deaths
reported in the US. In 1940, NaF was added to pancakes
Oregon 1943:
State hospital at a Salvation Army center in Pittsburgh. 40 persons were
Mistaken roach powder for powder milk
10 gallons of scrambled eggs + 17 lbs NaF affected, and 12 died. In 1943, a hospital in Oregon put
263 poisoning cases & 47 deaths
Lidbeck WL et al., JAMA1943;121:826-827.
17 pound of NaF in 10 gallons of mixture for scrambled
eggs. There were 263 poisoning cases with 47 deaths.

Current incidences of F toxicity The current incidence of fluoride toxicity with fatal
US poison control centers outcomes is much lower. Todays fluoride compounds
>20,000 reports/year of over-ingestion of fluoride are rarely used in pesticides. Still, more than 20,000
Sources of fluoride
Vitamins, dietary supplements, dental products (fluoridated
reports were filed each year to US poison control centers
toothpastes or mouthwashes) concerning the possible overingestion of fluoride.
~ 90% are young children
Sources of fluoride are vitamins, dietary supplements, and
~5% had minor symptom

~2% were treated in healthcare facility dental products. Nearly 90% are young children, and a
a few cases with life-threatening symptoms and DEATH lot of those cases involved fluoridated toothpastes or
mouthwashes.

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Current data shows that from those reports, a few percents were treated in medical facility, and about 5%
had minor symptoms. There were more than a few cases that were life-threatening and even death.
Probably a lot of reports were parents who read the back of toothpaste tubes, which have information for
consumers to report any incidence. The topic of fluoride toxicity is of concern to parents for the safety of
their children. There are several ongoing discussions on the internet. As a healthcare provider, you have
to be aware of fluoride toxicity and be able to give an informed advice.

Toxic Exposure Surveillance System Annual Report : F Toothpaste

American Association of Poison Control Centers

Age Treated Outcome

No. of in Health
Year Care
Exposures
<6 6-19 >19 Facility None Minor Mod Major Death

2001 22,790 20,730 860 1,163 391 5,014 1,328 38 4 0

2002 24,087 21,965 954 1,129 411 4,852 1,218 40 1 1
2003 24,812 22,596 1,064 1,112 405 5,413 1,337 144 1 0
2004 24,180 21,890 1,026 1,213 440 5,187 1,272 42 0 0
2005 22,531 20,248 1,073 1,164 414 4,660 1,160 41 0 0
2006 22,168 19,522 903 972 313 4,189 1,038 45 0 0

How much is too much?

Details of three deaths associated with the use of F-containing dental products
Fatal dose or Minimum lethal dose is not established for fluoride
Several variables affect the outcome Body Wt Dose
Age Comment Reference
(kg) (mg F/kg)
Exact doses were not precisely documented

27 mo. Not 3.1 4.5* Ingested ca. 100 F Dukes

Hodges and Smith (1965): Certainly Lethal Dose (CLD) tablets (0.5 mg); death
reported (1980)
occurred 5 days later.
Equivalent to LD100
Ingested dose that would be lethal to everyone if not 3 yr 12.5 16 Ingested ca. 200 F Eichler et
treated promptly tablets; vomited; death al. (1982)
occurred 7 hours later.
Based on case reports
3 yr Not 24 - 35* Swallowed stannous Church
reported fluoride rinse solution;
CLD = 5-10 g of NaF for adult 70 kg bodyweight (1976)
vomited; death
= 32-64 mg F/kg occurred 3 hours later.

* Calculated by use of the 3rd and 97th percentile values for three-year-old US boys
Note: NaF has 45% fluoride by weight

Whitford GM. J Dent Res 1990;69(Spec Iss):539-549.

Toxic doses of fluoride from dental products

How much is too much? The fatal dose or minimum fatal dose is not established for fluoride because there
are several variables that can affect the outcome, and the exact doses involving fluoride poisoning in
humans are not precisely documented.
By reviewing case reports, Hodges and Smith concluded that a Certainly Lethal Dose is 5-10 g of NaF
for adults with 70 kg bodyweight, equal to 70-140 mg NaF/kg or 32-64 mg F/kg. (Note that NaF has
~45% F by weight)
Certainly Lethal Dose is LD100, which is defined as a dose that everyone who ingests that much fluoride
will die if not treated promptly.

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Three cases of fluoride-associated deaths of children were reported around 1980. The lethal doses ranged
from less than 5 mg F/kg to approximately 30 mg F/kg. The durations of the toxic episodes were inversely
related to the quantities of fluoride ingested. Clearly, there was insufficient time of effective therapeutic
intervention in the two cases where more than 15 mg F/kg were ingested. These cases bring forward the
more useful from clinical perspective: a Probably Toxic Dose (PTD).

How much is too much? PTD is the threshold dose that should trigger immediate
Probably Toxic Dose (PTD): emergency treatment (including hospitalization), even if
Threshold dose that could cause toxic signs and symptoms,
including death
it is only suspected that the PTD dose has been
Trigger immediate emergency treatment ingested. PTD is 5 F/kg.
More useful clinically
PTD for 1-2 year old child, ~ 10 kg (22 lb) is 50 mg F.
Not include chronic effect like fluorosis
PTD for 5-6 year old child, ~ 20 kg (44 lb) is 100 mg F.
***PTD = 5 mg F/kg***
PTD for adult, ~ 60 kg (130 lb) is 300 mg F (0.3 g).
PTD for 1-2 year old child, ~ 10 kg (22 lb) = 50 mg F
PTD for 5-6 year old child, ~ 20 kg (44 lb) = 100 mg F
Note that PTD has nothing to do with dose that can
PTD for adult, ~ 60 kg (130 lb) = 300 mg F (0.3 g) cause chronic effect like fluorosis, which is a much
lower dose but requires long term exposure.

Some calculations of fluoride concentration Some calculations of fluoride concentration:

The most popular unit: ppm = part per million (wt/wt ; vol/vol) The most popular unit for fluoride is ppm. ppm
Water with 1 ppm F = 1 g of F- per 106 g of water Water density = 1 g/ml means part per million (either weight by weight
Therefore, water with 1 ppm F = 1 g of F- per 106 ml of water
= 1 g of F- per 103 litre of water
or volume by volume). For example, water with
= 1 mg of F- per 1 litre of water 1 ppm F means 1 g of F ions per 106 g of water.
Therefore, water with 1 ppm F = 1 mg/L
Water density is 1 g/ml. Therefore, water with 1
At higher concentration, usually use % 1 % = 10,000 ppm
(F-containing products) 0.1 % = 1,000 ppm ppm F equals to 1 g of F ions per 106 ml of
0.05 % = 500 ppm
water, which is equivalent to 1 g of F ions per
Note that the concentrations can be either F-salt or F ions
The most common F-salt is NaF, which has 45 % F ions 1000 litre of water, or 1 mg F per litre.
(Na = 23; F = 19 ; MW NaF = 42 ; %F = 45 %)
e.g. A mouthrinse with 0.05 % NaF = 500 ppm NaF ~ 230 ppm F
At higher F concentration like dental products,
% is the easier unit to use. 1% is 10,000 ppm;
0.1 % is 1,000 ppm, and 0.05 % is 500 ppm.
Note that the concentrations can be either F-salt or F ions. The most common F-salt is NaF, which has 45
% F ions (atomic weight Na = 23; F = 19; molecular weight of NaF = 42; therefore % F = 45 % by
weight). For example, a mouthrinse contains 0.05 % NaF is equivalent to 500 ppm NaF, or approximately
230 ppm F ions.
One day you may get a phone call from your patient, panicking that their child ate something that should
not be eaten. Can you tell them if its serious? The Probably Toxic Dose (PTD) for a 10 kg child, usually
1-2 years old, is 50 mg F. A child has to swallow 50 g (2 oz) of toothpastes (or tube) with 1000 ppmF,
or 215 ml of 0.05 % F-mouthrinse (1/3 bottle), or 50 tablets of 1 mg F-supplement to reach PTD. Some
toothpastes are extra-strength and contain 1500 ppmF. Therefore the PTD for these high F toothpastes is
only 33 mg (or 1/6 tube) for a 10-kg child. Some prescription mouthrinses contain 0.2 or 0.4% F, 4 times
higher than over-the-counter products. Note also that there are 3 doses of F-supplement, 0.25, 0.5, and 1
mg tablets, depending on the age of the child.

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 How much is too much? A normal dose of these products does
x 2 for 20-kg child (5-6 years old) = 50 mg F
not pose serious toxicity. For example,
Concentration of Amount Typical Normal
Product containing PTD amount size of toothpaste is usually applied in 1 g,
Salt Fluoride
for 10-kg child used product
% % ppm (1-2 year old) mouthrinse 10 ml, and 1 a day for the
Rinse* bottle tablet.
NaF 0.05 0.023 230 215 ml 10 ml 18 oz (530 ml)
* Prescription mouthrinses: 0.2 or 0.4% bottle For an older child with higher weight,
Toothpaste tube
NaF 0.22 0.1 1000 50 g (~2 oz) 1g 8 oz (~200 g) for example, a 5-6 years old child with
tube
MFP 1.14 0.15 1500 33 g 1/6 tube 1g 20 kg weight, just multiply the PTD by
F supplement* 100 tablets a factor of 2.
1 mg F - - - 50 tablets 1/day
container
* 0.25, 0.5, 1 mg tablets depend on age

Adapt from: Monograph

2 out of 3 deaths of children caused by fluoride in

2 out of 3 deaths of children caused by fluoride in dental products dental preparations were from the ingestion of
were from the ingestion of fluoride tablets.
ADA recommends no more than 120 mg fluoride dispensed at once
fluoride tablets. ADA recommends no more than
Recommendations for parents:
120 mg fluoride be dispensed at one time.
Child-proof containers Recommendations for parents: F mouthrinses and
Keep products out of reach of young children
Supervise children when brushing / rinsing
tablets should be in child-proof containers. Parents
Do not swallow toothpaste / mouthrinse should keep these products out of reach of young
children and supervise their children when brushing
PTD Acute toxicity
or rinsing not to swallow the products.
Amount of fluoride ingested less than PTD
Note that these numbers are PTD that can cause
Chronic effect (fluorosis)
acute toxicity. Ingestion of fluoride in the lower
amount still can cause chronic effect, like fluorosis.

Possible acute toxicity in dental clinic: APF gel One exception to the amount of a normal use F
1.23% fluoride in phosphoric acid product that can trigger acute toxicity is the topical
Upper and lower trays of 1.2-6 g/tray
Acidic condition (pH 3.5) enhances absorption
APF gel applied in dental practice. APF gel has
Because of acidity, a small volume can adversely affect the gastric 1.23% fluoride in phosphoric acid, and is usually
mucosa and lead to nausea or vomiting in some cases
applied in upper and lower trays of 1.2-6 g/tray.
Concentration of Amount
containing PTD
Typical PTD for 1.23% APF gel in 10-kg child is 4 ml. So
Product Salt Fluoride amount
for 10 kg child
% % ppm (1-2 year old)
used the amount used is twice the PTD level, serious
APF gel 2.72 1.23 12,300 4 ml 5 ml toxicity can occur if a child swallows only half of
Example: 5 g/tray x 2 trays = 10 g = 0.123 g F = 123 mg F
the applied gel. For example: 5 g/tray x 2 trays =
> Double
PTD for 1-2 year old child, ~ 10 kg (22 lb) = 50 mg F
PTD!!! 10 g = 0.123 g F = 123 mg F. PTD for 1-2 year old
child, ~ 10 kg (22 lb) = 50 mg F.
Thats more than double PTD!!! In addition, acidic condition enhances the absorption process. Because of
the acidity, in some cases even a small volume of APF gel can adversely affect the gastric mucosa and lead
to nausea or vomiting.

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 Symptoms of fluoride toxicity Symptoms of fluoride toxicity
Symptoms develop very fast, a few minutes after ingestion
Symptoms of fluoride toxicity develop fast, a few
Low Dosage High Dosage
= low dosage symptom PLUS minutes after ingestion. At relatively low dosage as
Nausea Convulsion
Hypocalcemia
&
in case of APF gel, patient can experience nausea,
Vomiting Spasm of the extremities
Abdominal pain Hyperkalemia Generalized weakness vomiting, and abdominal pain. There may also be
Diarrhea Blood pressure drop
Hypersalivation Cardiac arrhythmias
some non-specific symptoms like hypersalivation,
Tears Respiratory acidosis tears, discharge from nose and mouth, diarrhea, and
Discharge from nose and mouth Extreme disorientation
Headache Coma headache. Acute toxicity from high dosage of
Death
May occur within
fluoride has these symptoms plus convulsion, spasm
the first few hours of the extremities, and generalized weakness, which
are signs of low plasma calcium (hypocalcemia) and
rising potassium level (hyperkalemia).
Blood pressure often falls to a dangerous zone and cardiac arrhythmias may develop. A respiratory
acidosis develops as the respiratory center is depressed. Extreme disorientation or coma usually precedes
death, which may occur within the first few hours. Prognosis is good if surviving the first 1-2 days.
Treatment of Fluoride Toxicity Principle of emergency treatment
Need immediate treatment
Reduce absorption
The immediate treatment of fluoride toxicity is to
Induce vomiting immediately (providing no risk of aspiration) reduce the amount of fluoride available for absorption
Reduce bioavailability : 1% CaCl2 or calcium gluconate, milk
at the gastrointestinal tract. Vomiting should be
Transfer to hospital (as soon as possible)
Additional washing of stomach with lime water induced immediately providing no risk of aspiration,
IV fluid replacement
+ calcium gluconate : blood calcium level
such as, patient has no gag reflex or unconsciousness.
+ sodium bicarbonate : urine flow rate & urinary pH Then follow by oral administration of 1% calcium
Other monitoring and supportive therapies
chloride or calcium gluconate to reduce
Generally, if death has not occurred in 1-2 days the prognosis is good.
Exception: 2 year-old boy died 5 days after ingesting 100 tablets 0.5 mg F bioavailability. If not available, give as much milk as
can be ingested.

The hospital emergency department should be informed and the patient should be transferred to the
hospital as soon as possible. The emergency team may insert endotracheal tube if the patient is
unconscious and do additional washing of stomach with lime water. IV fluid replacement should include
calcium gluconate to maintain blood calcium levels and sodium bicarbonate to maintain urine flow rate
and elevate urinary pH. Other monitoring and supportive therapies are given by the medical team until the
vital signs and serum chemistry are within normal ranges. Generally, if death has not occurred during the
first one or two days the prognosis is good. Although there is a case that a 2 years old boy died five days
after ingesting 100 tablets of 0.5 mg fluoride supplements.
Can ingestion of fluoridated water cause acute toxicity? At the optimal level of 1 ppm, a 10 kg child has to
drink 50 L of water to reach the PTD. However, there are incidents of acute toxicity from accidental over-
fluoridation of school or community water supplies. Most of the incidents had relatively minor symptoms.
The most serious incident was in Alaska in 1992, when the fluoride level in the water supply was 150 ppm.
Almost 300 people experienced nausea, vomiting, abdominal pain, and diarrhea. There was one death in
that accident.

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 Can ingestion of fluoridated water cause acute toxicity?

PTD (Probably Toxic Dose) = 5 mg/kg

Optimal fluoridation 1 ppm = 1 mg/L

10 kg child has to drink 50 L of water with 1 ppm to reach PTD

Acute toxicity from water fluoridation

Accidental over-fluoridation of school or community water supplies
Most were relatively minor

Alaska, 1992
150 ppm F in water supply
Almost 300 people had nausea, vomiting, abdominal pain, diarrhea
One death

Chronic Fluoride Toxicity Chronic fluoride toxicity

Claim:
Long term ingestion of low level of fluoride (in water)
Allergic reaction, cancer, birth defects, genetic disorders, etc
There are several antifluoride groups, an example is this
website. Most of them are against water fluoridation.
Since water fluoridation was introduced some 60 years
ago, there were numerous claims of harm from long
term ingestion of low level of fluoride in water. The
claims include allergic reaction, cancer, birth defects,
genetic disorders, for instance.
Is it true? No, not those claims. But overingestion of
fluoride can cause chronic fluoride toxicity.

Critical reviews on the risk of chronic fluoride exposure

Critical reviews on risk of chronic fluoride exposure
USPHS ad Hoc Committee on Fluoride, 1991 associated with fluoride concentration in drinking water
Long term ingestion of low levels of fluoride up to about 5 ppm state that:
(e.g., 5 ppm in water for years)

1. No detectable risks of cancer in humans

1. No detectable risks that cancer in humans is
2. No indication that organ systems are affected associated with the consumption of optimally
3. No association with birth defects, including Downs syndrome fluoridated water.
4. Skeletal fluorosis: relatively high F intake > 10 years

5. Osteoporosis & bone fracture: Benefit or Harmful or None ?

2. No indication that organ systems are affected by
6. Dental fluorosis increase: Cosmetic or Toxic ? chronic, low level fluoride exposure.
3. Fluoride exposure is not associated with birth
defects, including Downs syndrome.
4. Crippling skeletal fluorosis (the severe form of skeletal fluorosis) is not a problem in the US. Skeletal
fluorosis happens after a prolonged relatively high F intake for more than 10 years.
5. The beneficial or harmful effect of fluoride on osteoporosis & bone fracture is inconclusive.
6. The prevalence of dental fluorosis is higher than in 1940s. There is disagreement whether this is a
cosmetic problem or toxic effect.
The possible chronic effect of fluoride is dental fluorosis, and in rare cases, skeletal fluorosis.
The association between bone cancer in humans with the consumption of optimally fluoridated water is
debatable at the moment because of this Harvard bone cancer study published last year.

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 Harvard bone cancer study Bassin et al reported an association between fluoride
an association between fluoride in drinking water during childhood
in drinking water during childhood and the incidence
and the incidence of osteosarcoma...among males diagnosed less of osteosarcoma among males diagnosed less than
than 20 years old, but no consistent association among females.
Bassin EB, et al. Cancer Causes Control 2006;17:421-428
20 years old, but no consistent association was found
among females. Right after the publication, the
Positive association between fluoride and osteosarcoma in the first
set of cases (1989-1992) reported by Bassin et al. Principal Investigator of that study (who, somehow,
The second set of cases (1993-2000) collected from the same
hospitals and similar methods of fluoride exposure does not is not the author in the paper) sent a letter to the
replicate the association found in the first set.
editor that the different findings are being prepared
Fluoride level within the bone proximal to the lesion is not
associated with the excess risk of osteosarcoma. for publication. They also found a positive
Douglass CW, Joshipura K, Caution needed in fluoride and
osteosarcoma study. Cancer Causes Control 2006;17:481-482 association between fluoride and osteosarcoma in
the first set of cases (1989-1992) reported by Bassin.

But the second set of cases (1993-2000) collected from the same hospitals and similar methods of fluoride
exposure does not replicate the association found in the first set. They also analyzed fluoride content in the
bone and found no association between fluoride level within the bone proximal to the lesion and the excess
risk of osteosarcoma.

Dosage of Fluoride Ingestion and Effects This table combines dosage of fluoride ingestion for
Effect Dosage Duration optimal effect, and those that can do harm either in a
Optimal 0.05-
0.05-0.07 mg/kg/day -
chronic manner or acute toxicity. What we have to
Dental Fluorosis > 0.10 mg/kg/day Until age 6

Skeletal Fluorosis 0.15-

0.15-0.33 mg/kg/day 10-
10-20 years
be careful about is dental fluorosis, because the
Probable Toxic (PTD) 5 mg/kg Acute threshold is only slightly higher than the optimal
2 years old child (10 kg) + optimal water fluoridation (0.7-1.2 ppm)
level, and it happens in children under 6 years old.
Skeletal fluorosis can occur when one ingests more
Dietary fluoride intake ~ 0.5 mg (0.05 mg/kg/day).
than double the optimal fluoride level for longer than
ADA & American Academy of Pediatrics recommendation:
No fluoride supplement for children under 6 years old raised in
10 years.
water fluoridation community.

It has been calculated that the daily dietary fluoride intake of young children (about 2 years old, 10 kg)
living in areas with water fluoridation in the range of 0.7 to 1.0 ppm, is approximately 0.5 mg (0.05
mg/kg/day). This is quite close to the threshold for fluorosis. Therefore, ADA and American Academy of
Pediatrics recommend the children under 6 years old raised in water fluoridation communities (0.7 1.2
ppm) should receive no fluoride supplements.

There are also websites that support water

fluoridation. One of them, is from a group of
dentists. The best one is probably the ADA website.

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 Recommended references

1. Ekstrand J, Fejerskov O, Silverstone LM (Eds). Fluoride in Dentistry.

Copenhagen: Munksgaard 1988. Chapters 3 & 7.
2. Whitford GM. The Metabolism and Toxicity of Fluoride. 2nd ed.
Monographs in Oral Science Vol 16. Chapters VII & VIII.
3. Warren JJ, Levy SM. Systemic Fluoride. Sources, amounts, and effects
of ingestion. Dent Clin N Am 1999;43:695-711.
4. Bowen WH. Fluorosis. Is it really a problem? J Am Dent Assoc
2002;133: 1405-1407.

Harvard bone cancer study

Bassin EB, Wypij D, Davis RB, Mittleman MA. Age-specific fluoride exposure
in drinking water and osteosarcoma (United States). Cancer Causes Control
2006;17:421-428.
Douglass CW, Joshipura K, Caution needed in fluoride and osteosarcoma
study. Cancer Causes Control 2006;17:481-482.

Your patient calls: her 2 years old son drank F-mouthrinse.

1. How much? A bottle is 18 oz (530 ml), she thinks he drank of it ~ 14 oz ~ 400 ml

2. What is the concentration? It should be in the ingredient: 0.05% NaF

3. Calculate the concentration of fluoride (e.g., in ppm): (Its easier to do in steps)

1 % = 10,000 ppm ; 0.1 % = 1000 ppm ; 0.05 ppm = 500 ppm as NaF
NaF has ~ 45 % F ; therefore the concentration of F is ~ 230 ppm F

4. Then calculate the amount of fluoride

We know that 1 ppm = 1 mg/L, therefore 230 ppm = 230 mg F/L
The boy drank 400 ml, therefore he got (230 x 0.4) = 92 mg of fluoride

5. What is the boys weight? His mother says about 24 lb ~ 11 kg

Calculate PTD for the boy = 5 mg/kg x 11 kg = 55 mg

Therefore, the amount of mouthrinse he drank is almost double PTD!

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JDB. J Dent Res 83(Spec Iss C):C39-C42, 2004.
http://www.biomed.lib.umn.edu/ => E-journals => Journal of Dental Research
The concept of caries balance: prevention & control of dental caries process by reducing the pathological
factors or enhancing the protective factors.