Fluoride Toxicity

Lecture outline Introduction Fluoride metabolism Acute Toxicity Chronic toxicity

Introduction

Introduction Fluoride can be a potent toxin. NaF was used in pesticides (white powder). Easily mistaken for powder milk, salt, or baking soda. Resulted in reported fatalities in the past.

Introduction Pittsburgh, 1940: Salvation Army Center. Mistaken NaF for flour in pancakes. 40 poisoned,12 died. Oregon, 1943: State hospital. Mistaken NaF for powdered milk in scrambled eggs. 263 poisoned, 47 died.

Introduction Currently: Almost 20,000 reports of possible over-ingestion each year in the US. Sources are vitamins, dietary supplements, and dental products. Majority reported no or minor symptoms. A few had major symptoms or even lead to death. 2 out of 3 deaths of children caused by fluoride in dental preparations were from the ingestion of fluoride tablets.

Introduction Nearly 90% are young children (6 or younger). A lot of those cases involved toothpastes or mouthwashes.

Fluoride metabolism

Fluoride absorption Absorption is by ‘Passive Diffusion’. 80-90% of ingested F typically absorbed in GI tract. F absorption is pH dependent Impacted by the acidity of adjacent body fluid compartments Most absorption occurs in the stomach, in the form of HF

Fluoride absorption Absorption half-time is 30 minutes. The presence of cations such as Ca and Al forms insoluble compounds with F Reduced absorption Fluoride not absorbed (10-20%) excreted with feces.

Fluoride Metabolism Peak plasma F concentration reached within 20-60 minutes of ingestion. F in plasma is not bound by proteins. Diffusion from plasma to other tissues and body fluids is dependent on the pH gradient across the membrane crossed.

Fluoride Metabolism Examples: Soft tissues: Intracellular F concentrations are 10-50% lower than in plasma. CSF: 50% or less than in plasma. Milk: 50% or less than in plasma. Gingival cervicular fluid: 10% higher than in plasma. Ductal saliva: slightly higher than plasma.

Whitford (1992)

Fluoride Metabolism Plasma levels usually go back to pre-ingestion levels in 3-6 hours. Clearance from plasma: About 50% retained in calcified tissue. About 50% excreted in urine within 24 hours. Minor amount excreted in sweat and feces. 50:50 distribution shifts in favour of retention in calcified tissue in young children. E.g: 87% of F ingested was retained by infants in a study.

Acute toxicity

Acute toxicity Dependent on the dose ingested. Develop a few minutes following ingestion. F generally impacts metabolism by: Interfering with the activity of proteolytic and glycolytic enzymes. Inducing efflux of potassium from RBCs Inducing hyperkalaemia and hypocalcaemia.

Signs and symptoms Low dose (as low as 2 - 3 mg F/kg): Production of HF acid in the stomach (highly corrosive) GI irritation: Nausea and vomiting. Diarrhea. abdominal pain. Headache. Hypersalivation and tears. Discharge from nose and mouth MFP might be less of an irritant than NaF (due to lower free F- availability in stomach.

Signs and symptoms High dose: Same symptoms of lower dose + symptoms of hypocalcemia and hyperkalemia: Hypocalcemia: Parasthesia. Paresis. muscle fibrillation. Convulsions. Tetany. decreased myocardial contractility. Hyperkalemia: Ventricular arrythmias. Cardiac arrest.

Signs and symptoms Drop in blood pressure. Cardiac arrhythmias. Respiratory acidosis develops as the respiratory center is depressed. Extreme disorientation or coma. Death. Prognosis is good if surviving the first 1-2 days.

Death was reported following ingestion of 16 mg F/kg Acute toxicity Minor: up to 5mg/kg. Moderate: 5 – 15 mg/kg. Severe: above 15 mg/kg. Death was reported following ingestion of 16 mg F/kg

Probable Toxic Dose (PTD) “The minimum dose that could cause toxic signs and symptoms, including death, and that should trigger immediate therapeutic intervention and hospitalization” F = 5mg/kg. Doesn’t represent minimum dose for chronic toxicity (such as fluorosis)

Certain Lethal Dose (LD100) The dose at which everyone who ingests that much fluoride will die if not treated promptly 32 - 64 mg F/kg Cardiac or respiratory failure

Calculation of fluoride ingested If given in ppm: 1 ppm F = 1 mg F/L = 0.001 mg F/ml If given in concentration (%): Convert to mg/ml by X10 (e.g. 2% = 20 mg/ml) Find F content by multiplying by compound molecular weight onversion ratio: NaF = 1/2, SnF = 1/4, NaMFP = 1/8 Note: APF concentration listed is actual concentration of F.

Example A 10kg child swallowed 10ml of an 8% SnF topical treatment Calculate the total amount of fluoride ingested. Calculate the dose ingested per kg. Answer: Total amount= 8 (%) x10 (to convert to mg/ml) x 0.25 (to adjust for SnF ratio) x 10 (amount of solution) = 200 mg F Dose per kg= 200/10 (weight)= 20 mg/kg

Management The aims are to: Reduce the amount of F available for absorption in the GI tract. Admit to hospital to remove F from body fluids and support vital signs.

Reduce the amount of F available in the GI tract. Induce vomiting (Ipecac syrup), providing no risk of aspiration. Reduce bioavailability of F (1% calcium chloride or calcium gluconate). If not available, give as much milk as can be ingested.

Admission to hospital Emergency teams might wash the stomach with lime water. IV fluid replacement: Calcium gluconate to maintain blood calcium levels. Sodium bicarbonate to maintain urine flow rate and elevate urinary pH. monitoring and supportive therapies until the vital signs and serum chemistry are within normal ranges.

Precautions at home F mouthrinses and tablets should be in child-proof containers. Parents should keep these products out of reach of young children Parents should supervise their children when brushing or rinsing. Pea-sized or smear-sized amounts of toothpaste need to be used in young children.

Precautions in clinic Use the recommended dose and procedure for every topical product (gel, foam, varnish). Avoid gel in young children or those who are at risk to swallow (favour varnish). Don’t combine methods of application at once. Keep containers of topical F out of the reach of patients. Never leave the patient unattended during F application.

Chronic fluoride toxicity

Chronic fluoride toxicity Induced by a low dose of F for a long time (can be much lower that PTD). Most fluoride absorbed into hard tissues, leading to: Dental fluorosis Skeletal fluorosis

Dental Fluorosis Occurs as a result of excess F ingestion during tooth formation. Impacted by the amount and duration of F ingestion. Enamel might have white opaque appearance due to hypomineralized subsurface. Pitting and loss of enamel surface might occur, leading to secondary staining.

Impacts on enamel matrix mineralization Interacts with nucleating sites in the enamel matrix disrupting crystal growth in all stages of enamel formation. Fluoroapatite binds more tightly to enamel proteins, leading to decreased matrix proteinase activity and increased retention of amelogenin proteins in maturation stage.

Impact on ameloblast function Enamel development can be divided into 4 major stages: Pre-secretory. Secretory. Transitional. Maturation stages.

Mechanism of dental fluorosis Pre-secretory. Chronic exposure to F: Does not affect tooth morphogenesis. The size and form of the teeth is not changed. Secretory. Chronic exposure to F: Disrupts the vesicular transport in ameloblasts. Increases intracellular degradation of protein matrix. Might lead to reduced thickness of enamel

Mechanism of dental fluorosis Transitional stage. Chronic exposure to F: Induces ameloblasts to detach occasionally from the surface and form subameloblastic cysts. Gives rise to shallower occlusal pits. Leads to formation of accentuated perikymata (grooves).

Mechanism of dental fluorosis Maturation stage. Chronic exposure to F: Causes abnormal modulation cycles and reduces their number in a dose-dependent manner. Delays final mineralization of the enamel matrix, contributing to subsurface hypomineralization.

Factors influencing fluorosis Amount and duration of F ingestion. Timing of fluoride exposure in relation to tooth development. Metabolic factors: Rate of skeletal growth. Periods of bone remodelling. Nutrition.

Amount and duration of F ingestion Risk increases with fluoride dose (ingestions of fluoride from multiples sources, including F supplements). Longer duration of exposure before maturation stage increases severity of fluorosis.

Timing of exposure Exposure during maturation is most important factor. Lower risk with F exposure only during the secretory stage (< 15 months of age). Highest risk occurs with exposure during both secretion and maturation stages.

Timing of exposure (Ishi and Suckling, 1986): Highest risk of fluorosis is when child is ≤ 3 years old. (Ishi and Suckling, 1986): Children who had high F water (7.8 mg/L) and then changed to low F water (0.2 mg/L). Change at around 35 – 42 months (tooth in maturation stage): had severe fluorosis of upper central incisor. Change at 11 to 33 months (secretory stage): had very mild or no fluorosis.

Metabolic factors Rate of skeletal growth: Large surface area and rich blood supply means that F is rapidly absorbed from the plasma by the bones. Removal of F from plasma initially reduces the amount of F available to the developing enamel. However, F accumulated in bones forms a large reservoir of F to be released locally to the toothgerms.

Metabolic factors Renal activity: Renal insufficiency can result in F retention and result in fluorosis. Nutrition: Ca inhibits F absorption

Histological appearance Enamel subsurface porosity. Hyper and hypomineralized bands within enamel. Increased severity porosity extends to EDJ and enamel surface can break – pitting and secondary discolouration. Severity of fluorosis is directly related to amount of F in enamel and subsurface porosity.

Clinical appearance Bilateral opaque white areas in the enamel

Clinical appearance With increasing levels of fluoride – enamel becomes striated, mottled and/or pitted. Severe cases – opaque areas become stained yellow to dark brown.

Dean’s fluorosis index Name and code Criteria Normal (0) The enamel has normal structure. The surface is smooth, glossy and usually of pale creamy white colour. Questionable (1) The enamel has a few white flecks to occasional white spots. Very mild (2) Small, opaque, paper white areas scattered irregularly over the tooth but not involving as much as approximately 25% surface. Teeth showing no more than about 1 – 2mm of white opacity at the tip of the cusps. Mild (3) White opaque areas involve as much as 50% the tooth. Moderate (4) All enamel surfaces are affected. Surfaces subject to attrition show wear. Brown stain is frequent. Severe (5) All enamel surfaces are affected and hypoplasia is so marked. Discrete or confluent pitting and brown stains are widespread. Teeth often present a corroded-like appearance.

Skeletal Fluorosis Skeletal fluorosis is an excessive accumulation of fluoride in bone associated with increased bone density and outgrowths (exostoses). Associated with high fluoride intake (8-10 ppm or more in the drinking water) for approximately 10 years or more.

Skeletal Fluorosis Endemic problem India, Pakistan, China (High F in water and hot climates). The total quantity of F ingested is the single most important factor. The severity of symptoms correlates directly with the level and duration of F exposure.

Skeletal Fluorosis F stimulates osteoblasts (abnormal). F increases the stability of the crystal lattice in bone, but makes bone more brittle. Bone changes include osteosclerosis, osteomalacia, osteoporosis and exostosis formation. Secondary hyperparathyroidism in a proportion of patients.

Signs and Symptoms Joint pain and stiffness (arthritis-like) Osteosclerosis. Calcification of ligaments. Crippling deformities (spine and major joints) Muscle wasting. Neurological defects/compression of spinal cord. Clinical symptoms mimic arthritis, could be easily misdiagnosed.

Prevention of skeletal fluorosis Education of population Provide safe drinking water

Other suspected effects of F No detectable risks of cancer associated with the consumption of optimally F water. No indication that organ systems are affected by chronic, low level fluoride exposure. Fluoride exposure is not associated with birth defects, including Down’s syndrome. The beneficial or harmful effect of fluoride on osteoporosis & bone fracture is inconclusive.

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