1. NAME

1.1 Substance

Iodine (USAN) (Fleeger, 1994)

1.2 Group

Antiseptics and disinfectants (D08)/Iodine product/ (D08G) (ATC classification index, [WHO] 1992]

1.3 Synonyms

Eranol, Iodin (French), Iodine Colloidal, Iodine Crystals, Iodine Sublimed, Iodine-127, Iodio (Italian), Jod (German, Polish), Jood (Dutch), Iode, Iodum, Jodum, Yodo.

(Reynolds, 1993)

1.4 Identification numbers

1.4.1 CAS number

7553-56-2

1.4.2 Other numbers

RTECS

NN 1575000

1.5 Brand names, Trade names

Betadine (Datlabs, Zimbabwe); Ethiodol (Savage, USA); Guttajod (Blucher, Schering, Germany), Iodex (Smith Kline & French, Australia, Switzerland etc) Fodex (Menley & James, UK); Sclerodine (Ondee, Canada); Telepaque (Rhone Poulenc, France); Urografin, Gastrofin (Rhone Poulenc, U.K.) (To be completed by each Centre using local data)

1.6 Manufacturers, Importers

DATLABS, Zimbabwe (To be completed by each Centre using local data)

1.7 Presentation, Formulation

Iodine is available in solid form, in solution, and in tinctures, e.g. Povidone iodine antiseptic solution, surgical scrub 7.5%, povidone iodine 200 mg pessaries, povidone antiseptic ointment 100 mg/g. Tincture of iodine, USP, contains 2% cent iodine and 2.4% sodium iodide diluted in 50% ethanol.

Aqueous solutions of iodine are Strong Iodine Solution USP (compound iodine solution, Lugol's solution) containing 5% iodine and 10% potassium iodide, and Iodine Topical Solution (USP) containing 2% iodine and 2.4% potassium iodide. Aqueous Iodine Solution BP contains the same amount of free and combined iodine per ml (130 mg/mL) as does the USP Strong Iodine Solution. (Reynolds, 1993) Potassium iodide aqueous cough expectorant. Povidone-iodide (Betadine) is an organically bound iodide compound containing 1% iodine in a water soluble base. Other organically bound iodide compounds are undecoylium chloride, diiodo hydroxyquin, tetraglycine hydroperiodide (60% iodine). These organic iodide compounds release iodine slowly and have a toxicity of one fifth of their iodine content (Haddad & Winchester, 1983). Povidone iodine antiseptic solution and surgical scrub are in 5 litre containers, pessaries, ointment (see 1.7).

2. SUMMARY

2.1 Main risks and target organs

Concentrated iodine is corrosive. Main risks in acute exposure to high iodine concentrations are largely due to the highly corrosive effect of iodine on the entire gastrointestinal tract and resultant shock. If rupture occurs mediastinitis or peritonitis develop. Target organs are mucous membranes of pharynx, larynx and oesophagus for the concentrated iodine, and thyroid for the diluted form as a systemic effect. Iodine is not a frequent cause of toxicity in the amounts available in the household. 2.2 Summary of clinical effects

Ingestion of iodine may cause corrosive effects such as oedema of the glottis, with asphyxia, aspiration pneumonia, pulmonary oedema and shock, as well as vomiting and bloody diarrhoea. The CNS , cardiovascular and renal toxicity following acute iodine ingestion appear to be due to the corrosive gastroenteritis and resultant shock. Vomiting, hypotension and circulatory collapse may be noted following severe intoxication. Eye Eye exposure may result in severe ocular burns. Cardiovascular Tachycardia, hypotension and circulatory collapse may be due to the ingestion of concentrated corrosive iodine solutions. Respiratory Inhalation of iodine vapour may result in severe pulmonary irritation leading to pulmonary oedema. Oedema of the glottis and pulmonary oedema have also resulted from oral ingestion.

Neurological Headache, dizziness, delirium and stupor may be noted following severe intoxication. Gastrointestinal A severe corrosive oesophagitis and gastroenteritis characterised by vomiting, abdominal pain and diarrhoea may be noted following ingestion. The vomitus is blue if starch is present in the stomach. A metallic taste may be noted. Dermatological Dermal application of strong iodine solutions may result in burns. Chronic ingestion may result in iodism characterised from acne form skin lesions and other skin eruptions. Cutaneous absorption may be significant and result in systemic symptoms and death. Endocrine Hypothyroidism, as well as hyperthyroidism, has been reported. Immunological Hypersensitivity reactions including angioedema and/ or serum sickness-like reactions may be noted. 2.3 Diagnosis

Clinical diagnosis is difficult, but iodine ingestion should be considered in cases of corrosive injuries to the pharynx and oesophagus. Iodine may or may not be seen in measurable levels in biological fluids.

2.4 First aid measures and management principles

Inhalation Exposure In case of inhalation move victim to fresh air. If victim is not breathing, give artificial respiration, if breathing is difficult give oxygen. Dermal Exposure In case of contact with iodine, immediately flush skin or eyes with copious amounts of water for at least 15 minutes. Remove and discard contaminated clothing and shoes. Keep victim quiet and maintain normal body temperature. Effects may be delayed so keep victim under observation. Oral Exposure In case of ingestion of concentrated iodine, do NOT induce

vomiting or gastric lavage. Call a physician or transport victim to a medical facility. Sodium thiosulphate, 100 mL orally of a 1% solution, has been recommended as an antidote because it immediately reduces iodine to iodide. However iodine is mostly already inactivated by combination with gastrointestinal contents. See Section 10 for management principles of iodine.

3. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of the substance

Iodine is found in igneous rocks 3x10-5 % by wt. and in sea- water 5x10-8 % by wt. Extracted from Chilian nitrate-bearing earth (caliche) and from seaweed. (Windholz , 1983).

3.2 Chemical structure

Structural Formula I-I Molecular formula I2 Molecular weight 253.81 Chemical name Iodine

3.3 Physical properties

3.3.1 Properties of the substance

3.3.1.1 Colour

Blue greyish-black with a metallic crystalline sheen

3.3.1.2 State/Form Solid brittle plates or small crystals

3.3.1.3 Description Characteristic acrid odour. Iodine volatilises slowly at room temperature. Boiling point 185.24 °C Melting point 113.60 °C Solubility is 1 in 3500 of water, 1 in 8 of alcohol, 1 in 6 of carbon tetrachloride, 1 in

30 of chloroform, 1 in 5 of ether, 1 in 125 of glycerol. Very readily soluble in strong aqueous solutions of iodides. A solution in alcohol, ether, or aqueous solutions of iodides is reddish-brown. In chloroform, carbon tetrachloride, or carbon disulphide it is violet-coloured. (Reynolds, 1989) pH No data available, but see 3.4.5.

3.3.2 Properties of the locally available formulation(s)

To be completed by each Centre using local data 3.4 Other characteristics

3.4.1 Shelf-life of the substance

The shelf-life of iodine solutions vary with the concentration. The stability of alcoholic solutions of iodine increases as the iodide/free iodine ratio increases and for a given concentration, with increased strength of alcohol (Reynolds, 1989).

3.4.2 Shelf-life of the locally available formulation(s)

To be completed by each Centre using local data

3.4.3 Storage conditions

Iodine topical solution should be stored in light- resistant containers at a temperature not exceeding 35 °C and iodine tincture should be stored in air-tight containers.

3.4.4 Bioavailability

To be completed by each Centre using local data

3.4.5 Specific properties and composition

Degradation of iodine is associated with a fall in pH which might come down to pH = 2, (Reynolds, 1989).

4. USES

4.1 Indications

4.1.1 Indications

In many countries culinary salt is iodized to prevent the development of goitre. In the pre-operative treatment of thyrotoxicosis to produce a thyroid gland of firm texture suitable for operation, it avoids the increased vascularity and friability of the gland with increased risk of haemorrhage. In the immediate treatment of thyrotoxic crisis.

Its powerful bactericidal action is used for disinfecting unbroken skin before operation. Iodine may also be employed as a weak solution for the first- aid treatment of small wounds and abrasions, but it is rapidly inactivated by combining with tissue substances, and so delays healing. It has been applied topically in the treatment of herpes simplex (Reynolds, 1989). Iodine has been used in the treatment of dendritic keratitis (Grant, 1974). Iodine has been used in the purification of drinking water in case of emergencies (Osol, 1980). Strong iodine solution: (Lugol's solution, aqueous solution of iodine, solution Iodi aquosa; compound

iodine solution) contains in each 100 ml, 4.5 to 5.5 g of iodine, and 9.5 to 10.5 g of potassium iodide. This solution is used in the treatment of many conditions in which the action of iodine ion is desired such as thyrotoxicosis, keratoscleritis, keratitis associated with excessive keratin. Iodine-containing solutions are used as contrast media in radio-diagnosis. Potassium iodide has been used as a mucolytic agent. Radioisotopes: radioactive iodine finds its widest use in the treatment of hyperthyroidism and in the diagnosis of disorders of thyroid function. The greatest use has been made of sodium iodide I131. Sodium iodide I123 is available for scanning purposes (Gilman et al., 1990).

4.1.2 Description

Not relevant

4.2 Therapeutic dosage

4.2.1 Adults

Skin disinfectant 10 to 25 mg/g often in combination with potassium or sodium iodide. Oral Lugol's solution Therapeutic dose range is 50 to 150 mg/day but up to 500 mg of iodine per day is often used, (Haynes, 1990). For the pre-operative treatment of thyrotoxicosis iodine may be given in the form of Aqueous Iodine Oral Solution BP or Strong Iodine Solution USP (both of

which contain iodine 130 mg/mL) at a dose of 0.1 to 0.3 mL three times a day for up to 10 days (Reynolds, 1993). Cough mixture Potassium iodide aqueous expectorant is given at a dose of 300 mg every 6 hours. (Haynes, 1990) Purification of drinking water In case of emergencies, 5 to 10 drops of tincture to a quart of water is both amoebicidal and bactericidal (Osol, 1980). Radioisotope dosages The effective dose in the treatment of hyperthyroidism by I131 differs for individual patients. The optimal dose of I 131 expressed in terms of microcuries taken up per gram of thyroid tissue, varies in different laboratories from 80 to 150 microCi. The usual total dose is 4 to 10 microCi (Haynes, 1990). Lower dosage I 131 therapy (80 microCi/g thyroid) has been advocated to reduce the incidence of subsequent hypothyroidism (Cevallos et al., 1974).

4.2.2 Children

No relevant data available.

4.3 Contraindications

Iodine preparations should not be taken regularly during pregnancy and lactation. Because iodine may cause burns on occluded skin, an iodine- treated wound should be covered with a light bandage. As iodine and iodides can affect the thyroid gland, the administration of such preparations may interfere with tests of thyroid functions (Reynolds 1989; McEvoy, 1990). Potassium iodide should not be used in adolescent patients because of its potential to induce acne and its effects on the thyroid gland (Bouillon ,1988). Iodine or iodides should not be administered to patients with a history of hypersensitivity to such compounds.

5. ROUTES OF ENTRY

5.1 Oral

Toxic effects in humans can occur via accidental or suicidal poisonings, (Gosselin et al., 1984). Toxic effects of iodine compounds resulting from ingestion of seaweed, mucolytic expectorants or X-ray contrast are reported. 5.2 Inhalation

With industrial exposure to vapour of iodine, it will be absorbed from the lungs and converted in the body to iodide.

5.3 Dermal

Topical iodine (especially with multiple applications) can be absorbed, causing toxic effects.

5.4 Eye

Eye drops can cause systemic toxic effects.

5.5 Parenteral

Contrast media.

5.6 Other

No data available.

6. KINETICS

6.1 Absorption by route of exposure

Oral Iodine appears to be inactivated by combination with gastrointestinal contents. Absorption is poor due to rapid conversion of iodine to iodide. (Reynolds, 1989; Gilman et al., 1990). Inhalation Iodine is absorbed from the lungs, converted to iodide in the body, (ILO 1971). Pulmonary absorption of vapour may result in systemic poisoning (Gosselin et al., 1984). Dermal Only very small quantities of iodine are absorbed through an intact skin, (Reynolds, 1989). Iodine can be absorbed by wounds and abrasions. Enhanced absorption occurs through denuded skin, decubitus ulcers, mucosal surfaces with high absorptive capacity (vagina), or large areas of intact skin, (Dela Cruz et al., 1987; Vorherr et al., 1989; Prager & Gardner 1979; Cosman et al., 1988). Eye Iodine can be absorbed when applied on the eye, (Geisthoevel, 1984). Parenteral No data available.

6.2 Distribution by route of exposure

Oral When taken by mouth iodine is rapidly converted to iodide and is stored in the thyroid as thyroglobulin, (Reynolds, 1989).

Iodine reaches the blood stream mainly in form of iodide, and it is incorporated into the thyroglobulin form in the thyroid gland, (Jones, 1977). Inhalation Iodine is readily distributed into the lungs. Dermal Distribution is poor due to low absorption through intact skin. Enhanced distribution occurs through denuded skin.

6.3 Biological half-life, by route of exposure

No data available. 6.4 Metabolism

Iodine is an easily oxidisable substance. Food that is present in the digestive tract, will oxidize iodine to iodide which is not corrosive to the gastrointestinal tract, (Reynolds, 1989; Gosselin et al., 1984).

6.5 Elimination, by route of exposure

Iodine is excreted mainly in the urine, (ILO 1971) and in smaller quantities in saliva, milk, sweat, bile and other secretions, (Clayton & Clayton, 1981-1982). Renal iodine clearance is related to glomerular filtration rate. Normal renal excretion is 12000 µg/day (Hunt et al. ,1980). 7. PHARMACOLOGY AND TOXICOLOGY

7.1 Mode of action

7.1.1 Toxicodynamics

Local Iodine precipitates proteins. The affected cells may be killed. The effect is similar to that of a corrosive acid. Systemic Acute inhibition of the synthesis of iodotyrosine and iodothyronine (Wolff & Chaikoff, 1984).

7.1.2 Pharmacodynamics Topical Iodine has bactericidal activity, e.g. a 1% tincture will kill 90% of bacteria in 90 seconds, a 5% tincture in 60 seconds and a 7% tincture in 15 seconds (Gershenfeld, 1968). Oral The primary function of iodine is to control the rate

of cellular oxidation through its presence in the biosynthesis of iodated thyroid hormone. 7.2 Toxicity

7.2.1 Human Data

7.2.1.1 Adults

The fatal dose is usually approximately 2 or 3 g (Reynolds, 1989).

7.2.1.2 Children

No data available.

7.2.2 Relevant animal data

No data available.

7.2.3 Relevant in vitro data

No data available.

7.3 Carcinogenicity

There is no evidence as to whether iodine is carcinogenic or not. However, connections have been established with deliberate or inadvertent intake of radioactive elements or their compounds that concentrate in certain organs or tissues. Thus intake of labelled iodine and derivatives concentrating in the thyroid gland, have been known to give rise to cancer in that organ (Harbison, 1980; Dukes, 1988).

7.4 Teratogenicity

Iodides diffuse across the placenta. Infant and neonatal death from respiratory distress secondary to goitre has been reported in mothers taking iodides(Parmalee et al., 1940; Galima et al., 1962). Chronic topical maternal use of povidone-iodine during pregnancy has been associated with clinical and biochemical hypothyroidism in the infant (Danziger et al., 1987). Exposure to I 131 can damage or ablute the developing thyroid of the human foetus. Hypothyroidism, either congenital or of late onset, has been reported in at least 5 children whose mothers were exposed to I 131 during pregnancy (Shepard, 1980) 7.5 Mutagenicity

No data available.

7.6 Interactions

No data available.

7.7 Main adverse effects

Endocrine system effects

Iodine and iodides produce goitre, hypothyroidism as well as hyperthyroidism. These effects have also been reported in infants born to mothers who had taken iodides during pregnancy (Reynolds, 1989). Side effects of iodine given for radioprotection In iodine-induced goitre and iodine-induced hypothyroidism, special risk groups are foetus and neonates. Iodine-induced hyperthyroidism special risk group are people living in iodine deficient areas and people with a history of hyperthyroidism, (Bouillon, 1988). Extrathyroidal side effects are gastrointestinal complaints (nausea, pain), taste abnormalities, cutaneous and mucous membrane such as irritation, rash, oedema (including face and glottis), allergic-like reactions such as fever, eosinophilia, serum- sickness-like symptoms, vasculitis. Special risk groups are patients with hypocomplementic vasculitis, (Bouillon, 1988). Allergic effects Whether iodine is administered topically or systematically, iodine and iodides can give rise to allergic reactions: urticaria, angioedema, cutaneous haemorrhage or purpuras, fever, arthralgia, lymphadenopathy and eosinophile, acne-form or severe eruptions. Iodism effects A mild toxic syndrome called iodism results from repeated administration of small amount of iodine. Iodism is characterised by hyper-salivation, coryza, sneezing, conjunctivitis, headache, laryngitis, bronchitis, stomatitis, parotitis, enlargement of the submaxillary glands, skin rashes and gastric upsets, (Reynolds, 1989, Gosselin et al, 1984). In rare cases jaundice, bleeding from mucous membranes and bronchospasm may occur. Inflammatory states may be aggravated by these adverse reactions, (Bouillon, 1988). Gastrointestinal effects Acute effects due to ingestion of iodine are mainly due to its corrosive effects or action which arises at least in part

from oxidizing potential of this element on the gastrointestinal tract. Symptoms include a metallic taste, vomiting, abdominal pain, and diarrhoea. Oesophageal stricture may occur if the patient survives the acute stage, (Reynolds, 1989; Gosselin et al., 1984). Cardiovascular and respiratory effects Death may occur due to circulatory failure, oedema of the glottis resulting in asphyxia, aspiration pneumonia, or pulmonary oedema, (Reynolds, 1989, Sittig 1981). Kidney effect Anuria may occur 1 to 3 days after exposure, (Reynolds, 1989). 8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

8.1 Sample

8.1.1 Collection

8.1.2 Storage

8.1.3 Transport

8.2 Toxicological analytical methods

- Both amperometric titration and leucocrystal violet (LCV) colorimetric methods give acceptable results when used to measure free iodine in drinking water, (National Research Council 1980). - With the aim of indicating environmental pollution effects on humans, none destructive activation analysis was applied to 382 normal Japanese hair samples, (Ohmori et al, 1981).

8.2.1 Tests for active ingredient

8.2.2 Tests for biological sample

8.3 Other laboratory analyses

8.3.1 Biochemical investigations

Blood Elevated serum transaminases and bilirubin concentrations are reported (Lavelle et al., 1975; Peitch & Meakins, 1976). Serum creatinine levels up to 3.5 mg/dL have been reported by Dela Cruz et al., (1987). Elevated TSH concentrations and low T4

concentrations has been demonstrated in neonates with topical povidone-iodine (Cosman et al., 1988). Urine No data available. Other No data available. 8.3.2 Arterial blood gas analyses

Severe metabolic acidosis is reported in topically- treated burn patients (Peitsch & Meakins, 1976).

8.3.3 Haematological or haemostasiological investigations

No data available.

8.3.4 Other relevant biomedical analyses

8.4 Interpretation

8.5 References (in section 13) 9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

Ingestion of iodine may cause corrosive effects such as oedema of the glottis, with asphyxia, aspiration pneumonia, pulmonary oedema and shock, vomiting and bloody diarrhoea. The CNS, cardiovascular and renal toxicity following acute iodine ingestion appear to be due to the corrosive gastroenteritis and resultant shock. Vomiting, hypotension and circulatory collapse may be noted following severe intoxication.

9.1.2 Inhalation

Inhalation of iodine vapour is very irritating to mucous membranes. Headache, dizziness, delirium, collapse and stupor, death due to circulatory collapse, asphyxia from oedema of glottis, aspiration pneumonia or pulmonary oedema has been reported. Occasionally haemorrhagic nephritis may occur within 1 to 3 days, oesophageal and pyloric stenosis have been reported, (Gosselin et al., 1984). 9.1.3 Skin exposure

Skin contact with iodine may give rise to hypersensitivity reaction, fever and skin eruption. Death following skin contact covering one third of body surface is reported to have occurred, (Gosselin et al., 1984).

9.1.4 Eye contact

Iodine vapour causes irritation and lachrymation in human eyes, (Grant, 1974).

9.1.5 Parenteral exposure

Injection of iodine compounds may cause sudden fatal collapse (anaphylaxis) as a result of hypersensitivity. Symptoms are dyspnea, cyanosis, fall of blood pressure, unconsciousness and convulsions, (Dreisbach & Robertson, 1987).

9.1.6 Other

No data available.

9.2 Chronic poisoning

9.2.1 Ingestion

Repeated administration of small amounts of iodine may result in a mild toxic syndrome called "iodism". It is characterised by hyper-salivation, coryza, sneezing, conjunctivitis, stomatitis, parotitis, enlargement of

the submaxillary glands, and skin rashes (Barker & Wood, 1940; Ehrich & Seifter, 1949). Hypotension, tachycardia, cyanosis and signs of shock are frequent symptoms of iodine ingestion. (Gosselin et al., 1984). Iodated glycerol used as a mucolytic expectorant in the treatment of respiratory disorders inhibited the biosynthesis of thyroid hormone and induced hypothyroidism (Drinka & Nolten, 1988; Gommolin, 1987). Amiodarone, an iodine rich drug widely used in the treatment of tachyarrhythmias, represents one of the most common sources of iodine-induced thyrotoxicosis (Martino et al., 1987; Regouby et al., 1985). Tablets of seaweed, sold over the counter, is one of the less common sources of iodine-induced hyperthyroidism (Shilo & Hirsch, 1990).

9.2.2 Inhalation

No data available.

9.2.3 Skin exposure

Intact skin Irritant contact dermatitis caused by povidone-iodine has been reported, (Okano, 1989). Liberal application of the tincture or povidone-iodine to the skin resulted in significant plasma and urine iodine levels and may cause systemic iodine toxicity (Luckhardt et al., 1920; Smerdely et al., 1989; Pyati et al., 1977; Chabrolle & Rossier, 1978; Coakley et al., 1989; L'Allemand et al., 1987; Dantzigen et al., 1987; Schoenberger & Grim, 1982). Injured skin Continuous postoperative wound irrigation with povidone-iodine resulted in death of a patient. Toxic manifestations of systemic iodine absorption appeared to cause the death, (D'Auria et al., 1990; Glick et al., 1985). Application of povidone-iodine on skin burns may cause systemic iodine toxicity (Lavelle et al., 1975; Peitsch & Meakins, 1976).

9.2.4 Eye contact

Iodine-containing eye drops caused hyperthyroidism (Geisthoevel, 1984). 9.2.5 Parenteral exposure

Iodine-containing contrast media may cause hyperthyroidism; the most frequent thyroid disorders, usually of a temporary nature, occur after choledochal contrast media (Steidle, 1989). In premature infants

they cause hypothyroidism (L'Allemand et al., 1987).

9.2.6 Other

No data available.

9.3 Course, prognosis, cause of death

If the patient survives 48 hours after the ingestion of iodine, recovery is likely, although stricture of the oesophagus or pyloric sphincter may be a complication, (Dreisbach & Robertson 1987). It is probable that the pathological changes recorded in fatal cases of iodine poisoning and attributed to the systemic effects of iodine

are largely the result of shock due to massive loss of fluid from the gastrointestinal tract and tissue hypoxia (Gilman et al.,1990).

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

Cardiovascular effects are not due directly to iodine or iodide. Hypotension, tachycardia circulatory collapse may occur secondary to corrosive gastroenteritis due to ingestion of highly concentrated iodine solutions. In acute iodine inhalation, hypotension and tachycardia have been reported, (Gosselin et al., 1984).

9.4.2 Respiratory

Inhalation of fumes leads to irritation of mucous membranes of the respiratory tract, which may result in asphyxia. Oedema of the glottis from ingestion was reported in early literature as a frequently mentioned cause of death, (Finkelstein & Jacobi, 1937). Pulmonary oedema and tachypnoea have been reported following ingestion of an unspecified large quantity of Lugol's solution, (Dyck et al., 1979).

9.4.3 Neurological

9.4.3.1 Central nervous system (CNS)

Headache, dizziness and delirium have been reported in severe intoxications. Altered sensorium (agitation, confusion, hallucinations) have occurred in association with elevated serum iodine concentrations, (Alvarez, 1979; Gosselin et al., 1984). Continued administration of iodine may lead to mental depression, nervousness and insomnia (Reynolds, 1989).

9.4.3.2 Peripheral nervous system

No data available.

9.4.3.3 Autonomic nervous system

No data available.

9.4.3.4 Skeletal and smooth muscle

No data available.

9.4.4 Gastrointestinal

Excessive ingestion of iodine solutions can lead to gastrointestinal irritation, vomiting and ulceration at various levels of the upper gastrointestinal tract. Late oesophageal and pyloric stenosis have been reported, (Gosselin et al., 1984). If the stomach contains starch the emesis is coloured blue.

9.4.5 Hepatic

Elevated serum transaminases and bilirubin concentrations have been reported occasionally in patients with elevated serum iodine concentrations, (Lavelle et al., 1975; Peitsch & Meakins, 1976).

9.4.6 Urinary

9.4.6.1 Renal

Poisoning is manifested by serum creatine and levels up to 3.5 mg/dL (309 mmol/L) has been reported, (Dela Cruz et al., 1987). The renal lesions, which sometimes resemble acute tubularnecrosis, may be exacerbated by haemolytic anaemia, (Gosselin et al., 1984). Nephrotoxicity by iodine contrast media is reported by Cacoub et al., (1987).

9.4.6.2 Others

No data available.

9.4.7 Endocrine and reproductive systems

Transient hypothyroidism characterised by elevated urinary iodide concentrations, elevated serum iodine concentrations, elevated TSH concentrations, and low T4 concentrations have been demonstrated in povidone- iodine exposed mothers and their infants (L'Allemand et al., 1987). Iodine induced thyrotoxicosis is a condition that may develop in older patients with long-standing iodine deficiencies who receive high doses of iodine (Kobberling et al., 1985; Fradkin, 1983; Klein & Levey, 1983). Iodine containing drugs caused thyrotoxic crisis (Mackenroth, 1990).

Excessive iodine intake can cause thyroid autoimmunity in endemic goitre, (Boyages et al., 1989). Organically bound iodine in the form of iodinated glycerol used as a mucolytic expectorant can inhibit the biosynthesis of thyroid hormone and induce hypothyroidism, (Drinka & Nolten, 1988). Hypothyroidism has also been described in neonates treated with topical povidone-iodine (Cosman et al., 1988). Topical iodine containing antiseptics may induce hypothyroidism in very-low-birthweight infants, (Smerdely et al., 1989). Multiple applications of povidone iodine in pregnancy, and lactation caused transient congenital hypothyroidism in a 6 week old girl, (Danziger et al., 1987). Iodine in contrast agents and skin disinfectants is the major cause for hypothyroidism in premature infants during intensive care, (L'Allemand et al., 1987). Iodated glycerol, an organic form of iodine, prescribed as a mucolytic-expectorant induced a mild hypothyroidism in a patient with a previous history of severe potassium iodide-induced hypothyroidism. Amiodarone, an iodine-rich drug widely used in the treatment of tachyarrhythmias, represents one of the most common sources of iodine-induced thyrotoxicosis. It developed not only in patients with underlying thyroid disorders, but also in subjects with apparently normal thyroid gland. Thyrotoxicosis occurred either during treatment with or at various intervals after withdrawal of amiodarone. Classical symptoms were often lacking, the main clinical feature being a worsening of cardiac disorders, (Martino et al., 1987). Tablets of seaweed, sold over the counter, is a real source of iodine. A 72-year-old female developed hyperthyroidism while ingesting these tablets. After stopping, the symptoms of hypothyroidism disappeared, (Shilo & Hirsch, 1990). Continuous povidone-iodine irrigation caused iodine toxicity with symptoms of metabolic acidosis, changes in mental status and the patient died (Glick et al., 1985). Administration of iodine containing eye-drops used as a cataract treatment caused hyperthyroidism (Geisthoevel, 1984).

9.4.8 Dermatological

A case of fatal dermatitis following the use of a 2.5% solution of resublimated iodine in pure industrial alcohol before a surgical operation has been reported. The reaction was thought to be due to idiosyncrasy to iodine. Skin disinfection with iodine has caused goitre and hypothyroidism in 5 of 30 newborns under intensive care (Bouillon, 1988).

Prolonged exposure to tincture of iodine can induce superficial necrosis. At least one death has been reported consequent to extensive skin involvement. Solutions of iodine applied to the skin should not be covered with occlusive dressings. Topical application of povidone-iodine on burn patients may lead to increased iodine/iodide absorption (Lavelle et al., 1975) and the development of a metabolic acidosis, renal failure and an altered mental status although a cause and effect relationship has not been definitely established. The older literature reports systemic symptoms which occurred immediately to 24 hours later, rarely following cutaneous application of one-half to one normal strength iodine tincture. Symptoms included fever, diarrhoea, pain, headache and delirium. Skin eruptions included urticaria to erythema to exfoliative dermatitis. Mortality was 47% in those 15 cases reported (Seymour, 1937). Repeated applications of iodophors may cause contact dermatitis. Allergic reactions occur 12 to 20 hours after application (Harvey, 1985; Kudo et al., 1988).

9.4.9 Eye, ear, nose, throat: local effects

Exposure to iodine vapour may cause burning in the eyes, blepharitis, and severe ocular burns (Finkelstein & Jacobi, 1937). Iodine vapour may cause rhinitis. Stomatitis and pharyngitis may result from exposure to iodine vapour or solutions and mucous membranes are coloured brown. (Finkelstein & Jacobi, 1937).

9.4.10 Haematological

Neutropenia has been reported in association with elevated serum iodine concentrations, (Alvarez, 1979). Thrombotic thrombocytopenic purpura has been observed after repeated administration of small amounts of iodine, (Ehrich & Seifter, 1949) Haemolysis has also been reported (Dyck et al., 1979).

9.4.11 Immunological

Reactions to iodine may occur acutely or after chronic use and may be characterised by coryza, headache, salivary gland pain, conjunctivitis, fever or skin reactions (urticaria, acneform, eruptions, erythema, bullous, ioderma). Oral and intravenous iodine containing radio-contrast media (e.g Telopaque (R); I125, I131) may cause iodine hypersensitivity reaction as well as anaphylactic type reactions, (Crocker & Vadam, 1963).

9.4.12 Metabolic

9.4.12.1 Acid-base disturbances

Metabolic acidosis may be associated with iodine toxicity. There is an increased anion gap due to elevated serum lactate levels (47 micromol/L) (Dyck et al., 1979; Dela Cruz et al., 1987)

9.4.12.2 Fluid and electrolyte disturbances

Elevated serum sodium (hypernatraemia) (156 mEq/L) has been reported (Dela Cruz et al., 1987). Hyperchloremia (127 mEq/L) has also been reported but probably represents a spurious elevation due to interference in the assay by iodine (Dela Cruz et al., 1987). Elevations in calculated osmolarity (340 in Osm/L) have also been reported (Dela Cruz et al., 1987).

9.4.12.3 Others

No data available.

9.4.13 Allergic reactions

Intolerance to iodised X-ray contrast media may cause reactions consisting of fever, chills, malaise, nausea and vomiting, skin rash, diarrhoea and even hypotension. These may be classified as idiosyncratic. In patients with a history of idiosyncratic reaction premedication with corticoids and histamines is

indicated or non-ionic contrast reagents should be used,(Soyer & Levesque, 1990). After interleukin-2 administration an increased incidence of hypersensitivity to iodine was observed, (Zukiwski et al., 1990). Hypersensitivity reactions were reported in 14 cases, secondary to the application of iodine-alcohol solutions to the skin. Symptoms reported were fever and generalised skin eruption of varying types. Despite the wide use of tincture of iodine the incidence of systemic reactions is low (Seymour, 1937).

9.4.14 Other clinical effects

No data available.

9.4.15 Special risks

Pregnancy Maternal ingestion of iodine containing substances during pregnancy can cause (transient) primary hypothyroidism in the newborn, (Coakley et al., 1989).

Exposure to iodine and radioactive iodine in pregnancy may lead to permanent hypothyroidism or goitre in the newborn. Such goitres may become very large and even create problems during delivery or mechanical compression during early postnatal life (Bouillon, 1988). Breast feeding Similar warnings to those given for pregnancy against the use of iodine or iodine-containing drugs applies during lactation since iodine is actively secreted in milk, (Bouillon, 1988). 9.5 Other

No data available.

9.6 Summary

Not relevant

10. MANAGEMENT

10.1 General principles

Do not induce vomiting nor do gastric lavage. Treatment is symptomatic. In symptomatic patients, early endoscopy is indicated in order to provide an early evaluation of the corrosive lesions in the oesophagus and the stomach.

10.2 Relevant laboratory analyses

10.2.1 Sample collection

Blood and urine samples should be collected.

10.2.2 Biomedical analysis

The urine may reveal albumin, casts, red blood cells, and leucocytes. Evidence of haemolysis may be found. Metabolic acidosis (lactic acidemia) has been reported.

10.2.3 Toxicological analysis

Plasma iodine levels are not clinically useful but may aid in diagnosis. Analysis of iodine in blood and urine may be done by colorimetry or gas chromatography.

10.2.4 Other investigations

10.3 Life supportive procedures and symptomatic/specific

treatment

Support cardiovascular and respiratory functions. Oxygen with assisted ventilation may be needed. Observe for gastrointestinal lesions, particularly rupture of the oesophagus or stomach which may result in mediastinitis or peritonitis, respectively. Be prepared to treat an anaphylactic type reaction. Monitor fluid and electrolyte carefully. 10.4 Decontamination

Oral exposure Do not induce vomiting nor do gastric lavage.

10.5 Elimination

Dialysis is reported to be effective in an early phase, (Peitsch & Meakins, 1976). Saline diuresis is useful if renal function is adequate, (Dreisbach & Robertson, 1987).

10.6 Antidote treatment 10.6.1 Adults

No antidote available.

10.6.2 Children

No antidote available.

10.7 Management discussion

Not relevant.

11. ILLUSTRATIVE CASES

11.1 Case reports from literature

Case 1 Continuous irrigation with povidone-iodine in a 34-month- old patient with mediastinitis was associated with iodine toxicity, resulting in fatalities, (Glick et al., 1985). It is suggested that povidone-iodine continuous irrigation of the mediastinum be a contraindication. Case 2 A 63-year-old woman with a suppurative mediastinitis, treated with continuous Polyvinyl-pyrrolidone-iodine (PI) irrigation developed an acute oliguric renal failure due to systemic toxicity of PI. The withdrawal of PI was followed by a complete improvement of renal function, (Campistol et al., 1988).

Case 3 Two patients with leg ulcers got worse after the application of a compound mixture of sugar and povidone iodine (sugar/PI compound). Patch-tests showed positive reactions to 10% povidone-iodine in water and 5% potassium iodide in water with no response to sugar. They were also tested with sugar/PI compound containing 3% povidone iodine, resulting in another positive reaction. They improved after the application of sugar/PI compound was discontinued, (Kudo et al., 1988). Case 4 A 34-year-old male with burns covering 80% BSA and a 22- year-old female with a 45% BSA burn, showed hyperthyroidism induced by topical treatment with 1% povidone-iodine. After

topical treatment with povidone-iodine was discontinued circulating thyroid hormones returned to normal values within weeks (Rath and Meissl,1988). Case 5 Fifteen episodes of infection due to Pseudomonas aeruginosa, including peritonitis and other site infections, occurred in nine patients receiving continuous ambulatory peritoneal dialysis over a 27 month period. Occurrence of P. aeruginosa infection was significantly associated with use of povidone-iodine solution to cleanse the catheter site. Local irritation and alteration in skin flora caused by antiseptic solution or low-level contamination of povidone-iodine solution are potential mechanisms of infection (Goetz and Muder, 1989) Case 6 Vaginal douching with polyvinyl pyrrolidone iodine (PVP-I) during pregnancy resulted in maternal iodine overload and increased the iodine content of amniotic fluid. The possible effect of this therapy was evaluated on the thyroid of the fetus by investigating 62 women with a mean duration of amenorrhoea of 20 weeks who solicited controlled abortion. Nineteen of them douched daily with PVP-I for 2 consecutive days before abortion (treated group). The other 43 women were not treated (control group). In both groups the iodine content was determined in the foetal thyroid and in amniotic fluid and maternal urine at the time of abortion. In addition, in the treated group the concentrations of iodine were also determined in amniotic fluid and urine before therapy and in urine after 4 days of therapy. There were no differences in the concentrations of iodine in urine and amniotic fluid in the control group and in the treated group before therapy. Iodine content increased more rapidly in the treated group (from 1 to 7.7 micrograms) than in the control group (from 1 to 2.5 micrograms) P less than 0.05 (Mahillon et al., 1989). Case 7 Approximately 570,000 newborns were tested for congenital

hypothyroidism between May 1977 and December 1986. One hundred and sixty cases of primary hypothyroidism, were later found to be transient. 14 out of the transient cases were due to excessive intake of iodine. In two, this was due to maternal ingestion of iodide during pregnancy and in 12 the babies received large amounts of topical iodine antiseptic. Two cases were caused by maternal anti-thyroid antibodies and in eight instances the cause was unknown. The large number of cases due to topical application of iodine antiseptic emphasizes the need for caution when using this substance in neonates (Coakely et al., 1989).

11.2 Internally extracted data on cases

No data available.

11.3 Internal cases

To be completed by the Centre using local data

12. ADDITIONAL INFORMATION

12.1 Availability of antidotes

No data available.

12.2 Specific preventive measures

Do not use iodine as an antiseptic in neonates.

12.3 Other