• Acute and chronic fluoride toxicity

• Appropriate use of fluoride products

• Optimal and toxic level of fluoride intake

Objectives:

DENT 5302 TOPICS IN DENTAL BIOCHEMISTRY

11 April 2007

Outline

Historical perspective of fluoride toxicity and current incidences

Toxic doses of fluoride from dental products

Symptoms of fluoride toxicity

Guideline/recommendation for safe use

Principle of emergency treatment

Chronic fluoride toxicity

Fluoride Toxicity

Excessive ingestion / short time:

Acute toxic effects

Excessive ingestion / long period during tooth

development:

The effect of long term fluoride exposure on bone is still controversial

Gastric disturbance

Nausea, vomiting

Death

Dental fluorosis

Historical perspective of fluoride toxicity

Fluoride was used as a pesticide

Mistaken for powder milk, salt, baking soda, flour

1933-1955: 607 fatal cases in the US.

Oregon 1943:

State hospital

Mistaken roach powder for powder milk

10 gallons of scrambled eggs + 17 lbs NaF

263 poisoning cases & 47 deaths

Pittsburgh 1940:

Salvation Army service center

Mistaken NaF for flour in pancake

40 poisoning cases & 12 deaths

Lidbeck WL et al., JAMA1943;121:826-827.

Current incidences of F toxicity

US poison control centers

>20,000 reports/year of over-ingestion of fluoride

Sources of fluoride

Vitamins, dietary supplements, dental products (fluoridated

toothpastes or mouthwashes)

~ 90% are young children

~5% had minor symptom

~2% were treated in healthcare facility

a few cases with life-threatening symptoms and DEATH

American Association of Poison Control Centers

Toxic Exposure Surveillance System Annual Report : F Toothpaste

Age OutcomeTreated in Health

Care Facility<6 6-19 >19 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

YearNo. of

Exposures

How much is too much?

‘Fatal dose’ or ‘Minimum lethal dose’ is not established for fluoride

Several variables affect the outcome

Exact doses were not precisely documented

Hodges and Smith (1965): ‘Certainly Lethal Dose’ (CLD)

Equivalent to LD100

Ingested dose that would be lethal to everyone if not

treated promptly

Based on case reports

Note: NaF has 45% fluoride by weight

CLD = 5-10 g of NaF for adult 70 kg bodyweight

= 32-64 mg F/kg

Details of three deaths associated with the use of F-containing dental products

27 mo.

3 yr

3 yr

AgeBody Wt

(kg)Dose

(mg F/kg) Comment Reference

Not

reported

12.5

Not reported

3.1 – 4.5*

16

24 - 35*

Ingested ca. 100 F tablets (0.5 mg); death occurred 5 days later.

Ingested ca. 200 F tablets; vomited; death occurred 7 hours later.

Swallowed stannous fluoride rinse solution; vomited; death occurred 3 hours later.

* Calculated by use of the 3rd and 97th percentile values for three-year-old US boys

Dukes

(1980)

Eichler et

al. (1982)

Church

(1976)

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

How much is too much?

Threshold dose that could cause toxic signs and symptoms,

including death

Trigger immediate emergency treatment

More useful clinically

Not include chronic effect like fluorosis

‘Probably Toxic Dose’ (PTD):

***PTD = 5 mg F/kg***

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

PTD for adult, ~ 60 kg (130 lb) = 3000 mg F (3 g)

Some calculations of fluoride concentration

The most popular unit: ppm = part per million (wt/wt ; vol/vol)

Water with 1 ppm F = 1 g of F- per 106 g of water Water density = 1 g/ml

Therefore, water with 1 ppm F = 1 g of F- per 106 ml of water

= 1 g of F- per 103 litre of water

= 1 mg of F- per 1 litre of water

Therefore, water with 1 ppm F = 1 mg/L

At higher concentration, usually use %(F-containing products)

1 % = 10,000 ppm0.1 % = 1,000 ppm0.05 % = 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

(Na = 23; F = 19 ; MW NaF = 42 ; %F = 45 %)

e.g. A mouthrinse with 0.05 % NaF = 500 ppm NaF ~ 230 ppm F

How much is too much?

Adapt from: Monograph

Concentration ofProduct

Rinse*NaF 0.05 0.023 230 215 ml

ToothpasteNaF 0.22 0.1 1000 50 g (~2 oz)

F supplement*1 mg F - - - 50 tablets

Salt Fluoride

% % ppm

Amount containing PTD for 10-kg child (1-2 year old)

Typical amount

used

10 ml

1 g

1/day

Normalsize of product

18 oz (530 ml)bottle

8 oz (~200 g)tube

100 tabletscontainer

MFP 1.14 0.15 1500 33 g 1 g

¼ tube

1/6 tube

⅓ bottle

= 50 mg Fx 2 for 20-kg child (5-6 years old)

* 0.25, 0.5, 1 mg tablets depend on age

* Prescription mouthrinses: 0.2 or 0.4%

Amount of fluoride ingested less than PTD

Chronic effect (fluorosis)

PTD Acute toxicity

Recommendations for parents:

Child-proof containers

Keep products out of reach of young children

Supervise children when brushing / rinsing

Do not swallow toothpaste / mouthrinse

2 out of 3 deaths of children caused by fluoride in dental products

were from the ingestion of fluoride tablets.

ADA recommends no more than 120 mg fluoride dispensed at once

1.23% fluoride in phosphoric acid

Upper and lower trays of 1.2-6 g/tray

Possible acute toxicity in dental clinic: APF gel

Acidic condition (pH 3.5) enhances absorption

Because of acidity, a small volume can adversely affect the gastric mucosa and lead to nausea or vomiting in some cases

Concentration of

Product

APF gel 2.72 1.23 12,300

Salt Fluoride

% % ppm

Amount

containing PTD

for 10 kg child

(1-2 year old)

Typical

amount

used

4 ml 5 ml

Example: 5 g/tray x 2 trays = 10 g = 0.123 g F = 123 mg F

PTD for 1-2 year old child, ~ 10 kg (22 lb) = 50 mg F

> Double PTD!!!

Convulsion

Spasm of the extremities

Generalized weakness

Blood pressure drop

Cardiac arrhythmias

Respiratory acidosis

Extreme disorientation

Coma

Death

Symptoms of fluoride toxicity

Low Dosage

Nausea

Vomiting

Abdominal pain

Diarrhea

Hypersalivation

Tears

Discharge from nose and mouth

Headache

High Dosage

Symptoms develop very fast, a few minutes after ingestion

= low dosage symptom PLUS

Hypocalcemia &

Hyperkalemia

May occur within the first few hours

Reduce absorption

Treatment of Fluoride Toxicity

Need immediate treatment

Additional washing of stomach with lime water

IV fluid replacement

+ calcium gluconate : blood calcium level

+ sodium bicarbonate : urine flow rate & urinary pH

Other monitoring and supportive therapies

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

Transfer to hospital (as soon as possible)

Induce vomiting immediately (providing no risk of aspiration)

Reduce bioavailability : 1% CaCl2 or calcium gluconate, milk

Can ingestion of fluoridated water cause acute toxicity?

PTD (Probably Toxic Dose) = 5 mg/kg

Optimal fluoridation 1 ppm = 1 mg/L

5010 kg child has to drink 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

Long term ingestion of low level of fluoride (in water)

Allergic reaction, cancer, birth defects, genetic disorders, etc

Claim:

Long term ingestion of low levels of fluoride

(e.g., 5 ppm in water for years)

1. No detectable risks of cancer in humans

2. No indication that organ systems are affected

3. No association with birth defects, including Down’s syndrome

4. Skeletal fluorosis: relatively high F intake > 10 years

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

6. Dental fluorosis increase: Cosmetic or Toxic ?

USPHS ad Hoc Committee on Fluoride, 1991

Critical reviews on risk of chronic fluoride exposure

‘…an association between fluoride in drinking water during childhood

and the incidence of osteosarcoma...among males diagnosed less

than 20 years old, but no consistent association among females.’

Bassin EB, et al. Cancer Causes Control 2006;17:421-428

Harvard bone cancer study

Positive association between fluoride and osteosarcoma in the first set of cases (1989-1992) reported by Bassin et al.

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.

Fluoride level within the bone proximal to the lesion is not associated with the excess risk of osteosarcoma.

Douglass CW, Joshipura K, Caution needed in fluoride and osteosarcoma study. Cancer Causes Control 2006;17:481-482

Dosage of Fluoride Ingestion and EffectsDosage of Fluoride Ingestion and Effects

AcuteAcute5 mg/kg5 mg/kgProbable Toxic (PTD)Probable Toxic (PTD)

10-20 years10-20 years0.15-0.33 mg/kg/day0.15-0.33 mg/kg/daySkeletal FluorosisSkeletal Fluorosis

Until age 6Until age 6> 0.10 mg/kg/day> 0.10 mg/kg/dayDental FluorosisDental Fluorosis

--0.05-0.07 mg/kg/day0.05-0.07 mg/kg/dayOptimalOptimal

DurationDurationDosageDosageEffectEffect

2 years old child (10 kg) + optimal water fluoridation (0.7-1.2 ppm)

Dietary fluoride intake ~ 0.5 mg (0.05 mg/kg/day).

ADA & American Academy of Pediatrics recommendation:

No fluoride supplement for children under 6 years old raised in

water fluoridation community.

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 ¾ 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): (It’s 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 boy’s 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!