1. 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

2. 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

3. 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

4. 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.

5. 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

6. American Association of Poison Control Centers Toxic Exposure Surveillance System Annual Report : F Toothpaste AgeOutcome Treated in Health Care Facility 19NoneMinorMod Major Death 200122,79020,730 8601,1633915,0141,328 3840 200224,08721,965 9541,1294114,8521,218 4011 200324,81222,5961,0641,1124055,4131,33714410 200424,18021,8901,0261,2134405,1871,272 4200 200522,53120,2481,0731,1644144,6601,160 4100 Year No. of Exposures

7. 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 LD 100 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

8. Details of three deaths associated with the use of F-containing dental products 27 mo. 3 yr Age Body Wt (kg) Dose (mg F/kg) CommentReference 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 3 rd and 97 th 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.

9. 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)

10. 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 10 6 g of water Water density = 1 g/ml Therefore, water with 1 ppm F = 1 g of F - per 10 6 ml of water = 1 g of F - per 10 3 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 ppm 0.1 % = 1,000 ppm 0.05 % = 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

11. How much is too much? Adapt from: Monograph Concentration of Product Rinse* NaF0.050.023 230215 ml Toothpaste NaF0.220.1100050 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 Normal size of product 18 oz (530 ml) bottle 8 oz (~200 g) tube 100 tablets container MFP1.140.15150033 g 1 g ¼ tube 1/6 tube ⅓ bottle = 50 mg F x 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%

12. 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

13. 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 gel2.721.2312,300 Salt Fluoride % %ppm Amount containing PTD for 10 kg child (1-2 year old) Typical amount used 4 ml5 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!!!

14. 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

15. 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% CaCl 2 or calcium gluconate, milk

16. Can ingestion of fluoridated water cause acute toxicity? PTD (Probably Toxic Dose) = 5 mg/kg Optimal fluoridation 1 ppm = 1 mg/L 50 10 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

18. Chronic Fluoride Toxicity Long term ingestion of low level of fluoride (in water) Allergic reaction, cancer, birth defects, genetic disorders, etc Claim:

19. 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

20. ‘…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

21. Dosage of Fluoride Ingestion and Effects Acute 5 mg/kg Probable Toxic (PTD) 10-20 years 0.15-0.33 mg/kg/day Skeletal Fluorosis Until age 6 > 0.10 mg/kg/day Dental Fluorosis - 0.05-0.07 mg/kg/day Optimal DurationDosageEffect 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.

23. 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. 2 nd 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.

24. 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!